SECTION 1

Introduction
 1
Birth and Youth of Prenatal and
Perinatal Obstetrics

E Saling

INTRODUCTION 1960s. This, therefore, can be considered the beginning

of prenatal medicine and the related clinical
Singular observations of the infant in the prenatal
subspecialty ‘prenatal and perinatal obstetrics’.
period, as well as the first elementary attempts at
According to Dobbs and Gairdner four innovative
diagnostics and therapy, stretch back over
techniques brought about the real breakthrough. They
generations, centuries and up to thousands of years.
stated:
However, until the beginning of the 1960s, the only
possible method of clinical ‘assessment’ of the ‘With the advent of the techniques of amnioscopy
intrauterine patient, apart from the fetal movements and foetal blood sampling and of amniocentesis
observed by the mother herself, was auscultation of and foetal transfusion, we witness the end of the
the fetal heart beats with a simple stethoscope. The long period of foetal inaccessibility, and we
following statement made in 1966 by two English hopefully believe the start of the science of foetal
pediatricians Dobbs and Gairdner in an editorial in medicine.’1
Archives of Disease in Childhood 1 aptly sums up the
situation:
AMNIOCENTESIS AND FETAL TRANSFUSION
‘Up to now the formidable inaccessibility of the
As far as we have been able to ascertain, the first
human foetus has meant that foetal medicine (apart
report about amniocentesis appeared in 1881 by
perhaps from foetal electrocardiography [author’s
Lambl, as a means of decompressing a hydramnion.2
note: Which was in a basic experimental state and
In 1930, Meness and colleagues performed the first
should not be mistaken for cardiotocography.]) has
amniography.3 Not until 70 years after Lambl’s first
virtually not existed. In an age when man has been
amniocentesis was this technique used by Bevis in
able to measure most things from an atom to a
1952 for diagnosing Rh erythroblastosis.4 This was an
galaxy, it is thus paradoxical that to measure his
important prerequisite for both spectrophotometric
own size during the most critical and precarious
analysis of amniotic fluid5 and the first trials involving
period of his life, he still has to depend upon the
the treatment of the preterm fetus with severe Rh
extreme fallibility of the palpating hand.’
disease6 developed by Liley in Australia. Liley is
Thus, today we can draw the following conclusion: especially renowned for the development of his ‘Liley
systematic exploration of the intrauterine space Scheme’ which has been used as a nomogram for
during pregnancy and labor did not start until the bilirubin limits. Using this method, clinicians were
4 Textbook of Perinatal Medicine

provided with information enabling them to decide insufflation and various other methods were still
whether the fetus should be treated by intra- being used.9 We came to the conclusion that most of
abdominal blood transfusion, or if the pregnancy these methods were not effective enough. 10 This
should be terminated when the fetus was sufficiently motivated us to develop equipment for endotracheal
mature, in order to perform an exchange transfusion O2 respiration and we began to prove its efficiency.
immediately postpartum. Today, amniocentesis is one One component of the equipment was a laryngoscope
of the standard techniques used in various fields of for newborns which, according to a recent
prenatal obstetrics. recommendation in a text book of anesthesi-ology11,
Intrauterine transfusion developed by Liley in 19636 is particularly suitable for the intubation of very small
was used in cases of severe Rh erythroblastosis. This premature newborns.
measure is one of the very first milestones of prenatal An important development was that for the very
obstetrics in as far as it was the first real breakthrough first time we had been successful in catheterizing the
in intra-uterine, i.e. fetal, therapy. The effectiveness aorta of the newborn immediately after delivery via
of intra-uterine transfusion can be explained by the the easily accessible umbilical arteries.12 We used this
fact that the fetus resorbs through its peritoneum the method for a new two-catheter technique (Fig. 1.1) of
compatible donor blood that is injected into the exchange transfusion in erythroblastotic newborns13
peritoneal cavity. Gradually the donor erythrocytes and, in addition, we withdrew samples for blood
reach the fetal blood circulation via the ductus analysis from the central circulation of the
thoracicus. asphyxiated newborn to prove the efficiency of the
In the meantime intrauterine intraumbilical different techniques of resuscitation.10 For these
transfusions have been performed since 1986 mainly examinations, in cooperation with K. Damaschke, we
with the help of ultrasound7 and even intracardial developed a fast micro-method in order to determine
transfusions have been described.8 the oxygen saturation in very small blood samples.14
A decisive step forward came with the idea of
Fetal Blood Sampling withdrawing fetal blood samples from the presenting part
Of broader clinical importance, fetal blood sampling of the fetus in cases of Rh erythroblastosis, thus
during labor – as a method of daily routine in the labor enabling us to perform, before delivery, the most
room – was the main step initiating the start of a important serologic and hematologic examinations,
completely new medicine, which up to that point was such as the Coombs test, hemoglobin concentration,
non-existent. hematocrit and the blood group. This brought
Before the introduction of fetal blood analysis, we important progress in some cases of severe Rh
were using other techniques, which, subsequently, erythroblastosis as it enabled us to begin exchange
brought us nearer this special new field. Several of transfusions shortly – in six cases, 5–10 min – after
the described progressive steps have been achieved delivery.15
by us as clinically engaged obstetricians. Today these The fast O2 micro analysis, which had recently
activities seem rather curious in so far as such efforts been developed, and the knowledge that blood
have belonged to the domain of neonatologists for samples could be taken so easily from the skin of the
some decades. presenting part of the fetus provided us with the
At the end of the 1950s we started examinations additional idea of performing fetal blood gas analyses.
to determine the most effective method for This was the birth of fetal blood analysis (FBA).
resuscitation of an asphyxiated newborn immediately Almost at the same time, equipment for measuring
after delivery. At that time, the thorax compression pH in micro blood samples was developed and we
methods, mouth-to-mouth respiration, intragastric O 2 were able also to examine fetal acid–base balance.
 Birth and Youth of Prenatal and Perinatal Obstetrics 5

Fig. 1.1: Two options using the two-catheter technique for exchange transfusion in a newborn. Left: infusion and
simultaneous exfusion to and from aorta. Right: infusion into venous system and simultaneous exfusion from aorta

The first FBA during labor with pH and O2 saturation delivery is achieved by the Apgar score for the basic
measurement and pCO2 calculation was performed on clinical status combined with our acidity values
June 21st, 1960. This was the first documented direct giving information about the biochemical status of the
approach to the human fetus before birth. newly born baby. Historically, these two above
Information on FBA was first published in the form mentioned days were of special importance in the
of a report of a lecture presented at an official meeting field of combined examination of the acid–base balance in
of the Berlin Society of Obstetrics and Gynecology in the fetus and neonate immediately after delivery. The way
1961.16 The first original article appeared in a journal which we practiced the method can be seen in (Fig.
in 1962.17 In 1984, this latter publication became a so- 1.2) in which the rubber stamp used in the labor room
called ‘citation classic’ of Current Contents after it had is described. The first publications describing the
been identified by the Institute for Scientific combined diagnosis of the newborns’ condition, using
Information in Philadelphia as one of the most cited the modified Apgar score as the clinical (physical) part
items in its field. and our acidity score as the biochemical part with the
Only one day later, on June 22nd 1960, a blood recommendation for routine clinical use appeared in
sample for FBA was taken from the buttock of a fetus. 196518 and 196619 in German as well as 196820 and
In addition to the fetal blood analysis during labor 197421 in English.
for the first time, for clinical purposes we performed FBA received international attention through the
an acidity measurement in the umbilical artery and activities of the Montevideo group. Joseph Bieniarz,
umbilical vein blood of this infant. Thus, the a co-worker of Roberto Caldeyro-Barcia for many
complementary assessment of the newborn by also years, with knowledge of the German language,
measuring the pH in umbilical vessels, employed by undertook the task of reviewing German scientific
many obstetricians today, was also created. The best literature. In this way, our first publication on FBA in
routine assessment of the newborn immediately after 1962 17 and our studies published later in 196322
6 Textbook of Perinatal Medicine

Fig. 1.2: Rubber stamp for summary of all results obtained

concerning fetal and neonatal assessment19,20. In the first
column the time in hours (hr) and minutes (min), actual pH and
pH qu 40 (pH after equilibration of a blood sample with 40 mm
Hg pCO2. This pH expresses the metabolic acidity and can
directly be compared with actual pH values) of the lowest fetal
blood pH measured during labor is recorded and in the second
column (UA) the umbilical arterial actual pH and pH qu 40
immediately after delivery. The points achieved in our main score
(MSc), a modified Apgar score, and in a subsidiary scoring
system (SSc), are recorded in the left and right hand boxes,
respectively. The subsidiary score contains the timed first
breath, the first cry, the regular respiration and pink flash after
delivery and is more objective and more reliable than Apgar Fig. 1.3: Actual pH values of fetal scalp blood samples and of
score blood from umbilical vessels during different stages of normal
labor(x ± 2 s). Cx, cervix dilatation (cm); II, second stage; Pf,
presenting part on pelvic floor; Po, on pelvic outlet18–20

concerning normal fetal blood gas and acid–base

values during labor of which actual pH values (Fig. meconium actually occurs which can then be detected
1.3) were the most important, aroused particular amnioscopically (see below). A further advantage of
interest in Montevideo. In 1964, Roberto Caldeyro- amnioscopy is that amniotic fluid stays green for
Barcia, who unfortunately passed away on 2nd several days, and therefore, it can safely be diagnosed
November 1996, organized an historic meeting. The by amnioscopic checks at intervals of 48 h.
invited guests were Stanley James, Edward Hon, Fred Amnioscopy continues to enjoy widespread
Kubli and myself. A photograph of the main popularity particularly in countries with limited
participants and a short report on this international financial resources, because it is simple to use and
symposium can be found in the Editor’s Preface in does not require a great deal of equipment and takes
the first issue of the Journal of Perinatal Medicine.23 After only a short time. Furthermore amnioscopy, as already
this meeting, FBA also attracted attention in North mentioned, is very reliable in its early selection of
America and was introduced step by step in many fetuses at chronically advanced hypoxic risk. The
places, its importance becoming accepted clinically method has failed if a fetus with amnioscopically clear
and for research purposes. amniotic fluid, i.e. no passage of meconium, should
die. This happened only eight times in more than
AMNIOSCOPY
12 000 supervised high-risk pregnancies, i.e. only 0.6
Another procedure that was also developed at the per thousand.25
beginning of the 1960s and which immediately Some pathophysiological backgrounds which gave
became widespread, is amnioscopy, a report of which amnioscopy such a high diagnostic reliability are
was first published by us in 1962.24 This procedure is based on common circulatory reactions special to the
based on the fact that hypoxic risks to the fetus in late fetus and can be explained by the concept we
pregnancy progress very slowly in most cases and that developed in 1966, namely, the O2 conserving adaptation
in more than 99% of these fetuses, passage of of the fetal circulation.26,27
 Birth and Youth of Prenatal and Perinatal Obstetrics 7
This concept, now more than 30 years old, confirmations have been published in the same
represents the basic principle for the Doppler direction.
diagnostics used today (Fig. 1.4). Our explanation in Many years after our publications the new term
the 1960s was that the borderline oxygenated fetus ‘brain sparing effect’ appeared in the Anglo-American
reduces its O2 consumption by restricted circulation literature. This was certainly regrettable as the
of those organs that are not of vital importance and colleagues who created this new term and
increases, relatively, the circulation in the vital organs ‘rediscovered’ the known principle overlooked two
such as brain and heart. Reduction of different areas decisive facts:
of circulation has been found by Dawes in many 1. There was already a more appropriate term
animal experimental studies.28,29 According to our which had been in existence for many years
concept, the intestinal organs are also affected, where without the necessity of formulating a new one;
the intestine reacts with hyperperistalsis. As a result 2. The new term, as far as it went, was incorrect
of this there will be a passage of meconium with high since the pathophysiological situation concerned
certainty during the last 4–6 weeks before the date of does not only contain a ‘brain sparing’ but also
birth which can be easily detected via amnioscopy. a ‘heart sparing’ effect and possibly also sparing
Results of Doppler ultrasound investigations effects on other organs, for instance, the adrenals.
initially achieved by Arabin and co-workers in our Some of the following comments about ‘birth and
Institute as early as 198730 provided an interesting youth of pre- and perinatal obstetrics’ are mainly
new confirmation of our O2 conserving adaptation based on our previous report about ‘historic
concept, at this time already 20 years old. In severely landmarks of perinatal medicine in obstetrics’.31
growth-retarded fetuses even when a loss of end
diastolic blood flow velocities had already occurred CARDIOTOCOGRAPHY
in the umbilical artery and in the fetal aorta, there In 1968, eight years after FBA was introduced,
was an increase in the end diastolic flow in the cardiotocography also became available for clinical use.
common carotid artery. Since then many further Cardiotocography is one of the important landmarks

Fig. 1.4: Our first concept of the ‘oxygen-conserving-adaptation of the fetal circulation26,27 . Left: normal arterial supply, with full
oxygenation, to heart, brain and all other parts. Right: reduction of oxygen supply leading to vasoconstriction in extremities,
abdominal viscera and lungs. Local hypoxemia leads to anaerobic glycolysis
8 Textbook of Perinatal Medicine

in prenatal obstetrics. Historic steps lead back to ultrasound-cardiotocography found widespread

Pestalozzi, who in 1891 recorded the heart beats of a popularity in the 1970s due to the simplicity of
twin in breech presentation with a sphygmograph32 applying the wide-angled transducer operating on the
and also Hofbauer and Weiss who recorded the first abdominal wall of the mother. However, due to the
phonocardiogram in the year 1908.33 Cremer was considerable deviations from the real beat-to-beat
successful in designing the first electrocardiogram in variability that sometimes occurred, it was heavily
1906. 34 The first continuous cardiotachogram, criticized. It was not until the beginning of the 1980s
conducted from an anencephalic fetus, was described that ultrasound cardiotocography was accepted by
by Caldeyro-Barcia and co-workers in 1958. 35 The expert circles; this happened after the industry –
electrode was inserted into the rump of the fetus namely the Toitu company in Japan – employed the
through the abdominal wall of the mother using the so-called ‘auto-correlation principle’ in 1977 which
harpoon principle. The same principle was success- made a recording available that was much more in
fully used by Rech in 1931 in animal experiments.36 accordance with the beat-to-beat variability.
In 1966, with his ‘one-poled’ silver–silver chloride From the very beginning we warned against using
electrode (CLIP-electrode), that could be inserted cardiotocography as a single method and we
vaginally, Hon introduced direct fetal electrocardio- introduced the combined fetal monitoring during
tocography during labor.37 An electrode is fixed on labor for the first time by recommending the use of
the fetal head; a second counterelectrode lies in the both methods – cardiotocograph routinely and if
vagina where it is in contact with the mother. The indicated [abnormal cardiotocograph (CTG)],
spiral electrodes most widely used were developed additionally FBA. This was, already in 1968, the start
by Junge in 1967.38 All these recordings of the fetal of combined electronic and biochemical monitoring of the
heart rate, combined with the recording of the fetus.40 This kind of monitoring remains the safest and
intrauterine contractions, pioneered by the above most efficient way of supervision of the fetus during
mentioned Caldeyro-Barcia and Hon, required the labor, provided it is used clinically according to our
usage of very complicated equipment and could, experience and to the recommended strategy. In the
therefore, only serve experimental and scientific meantime a great number of papers have been
considerations. The real breakthrough leading to published in which fetal blood analysis formed either
practical clinical usage came in the mid 1960s when solely or partly the subject matter. We also contributed
Hammacher, in cooperation with Hewlett and and tried to explain further basic aspects, additional
Packard was successful in developing the clinical findings and recommen-dations as well as
cardiotocograph which is still known by the same criticisms about misuse of modern fetal monitoring
name today. The equipment was based on the phono- during labor. 41-46
cardiographic principle and enabled the elimination In connection with such a critical statement we
of all disturbing noises by electronically controlled once gave a humorous, less scientific but impressive
comparisons of the time interval between two and illustrative description of the advantages and
successive first heart beats and two successive second disadvantages of cardiotocography in simple terms.44
heart beats.39 In this way it was possible to achieve For this purpose we took an example from nature:
reliable, specific registrations of the fetal heart rate.
The first prototype of the equipment for routine use ‘The cardiotocogram situation can be compared
was tested by Hammacher in Düsseldorf in 1966. with the screaming of monkeys in the jungle: when
Widespread clinical usage started in 1968. The first danger is imminent they always scream. When
systematic comparisons between pathological there is a threat of hypoxia, the CTG is almost
cardiotocograms and the acid–base balance of the always suspicious or pathological. But monkeys
fetus were published by us in 1968. 40 Doppler- have the typical attribute of screaming much too
 Birth and Youth of Prenatal and Perinatal Obstetrics 9
often; especially when there is no danger at all. The ULTRASOUND SCANNING
CTG often does this too, in the figurative sense. It Without doubt one of the most important landmarks
is suspicious or pathological, but there are no real of prenatal obstetrics is ultrasonic diagnostics. It not
reasons to suspect dangerous fetal hypoxia – as only serves to supplement the typical attribute of the
measurements of the acid–base balance can clearly obstetrician’s acknowledged palpatory skill, but in
prove. This is unfortunately the reverse side of many respects competes with it as an instrument of
cardiotocography which many obstetricians either equal or superior capability.
fail to recognize or push aside with naive credulity. The ‘father’ of obstetrical and gynecological ultra-
If the newborn are vigorous after operative delivery sonic diagnostics is Ian Donald. He and his co-
– as regards their acidity and clinical state – then workers in 1958 published the first scans of fetuses
many colleagues excuse their management by aged 14 gestational weeks. 47 Donald and Brown
saying that a hypoxia had just been avoided by published pictures of a hydatid mole, a hydro-
well-timed intervention. Anyone who performs
cephalus and the first prenatal measurements of the
fetal blood analysis, can give enough examples how
biparietal diameter with the help of the A-mode
often such excuses are self deception or a
procedure in 1961.48 This was the beginning of fetal
misguidance to the patient’.
biometry and of the diagnosis of gestational age later
improved by measuring the crown–rump length.
Unfortunately too many clinicians and
Sonographic placental diagnostics began when
investigators did not follow the recommendations we
Gottesfeld demonstrated cross-section pictures of the
had expressed from the very beginning, namely not
placenta.49,50 Important steps forward were made in
to use cardiotocography as a single method to
supervise the fetus but to combine it with FBA when the diagnosing of malformations through the progress
an abnormal heart rate pattern appears. The adverse achieved in ultrasonic techniques and by the detailed
effects of the last 30 years are well known. They reach presentation of fetal organs, particularly with the
from the polemic public discussions about fetal gray-scale technique developed by Kossoff and co-
monitoring to recent debate about the rare workers.51
intrapartum origin of cerebral palsy. We think most Sonographic vitality diagnostics started with the
of such negative consequences could have been first registration of fetal movements in the 7th week
avoided with the use of combined electronic– of gestation by Ian Donald,52 and also with the first
biochemical supervision. So for instance, the registration of fetal heart movements with the help
argument that false estimation of ‘modern of the Doppler procedure performed by Callaghan
monitoring’ was the main reason for the wrong and co-workers in 1964.53 In 1967, Kratochwil and
conclusion, that cerebral palsy was so often caused Eisenhut reported on evidence of fetal heart actions
by malpractice of obstetricians in the labor ward, is in the 6th week of gestation with the help of the A-
not correct from our point of view. This misleading mode procedure. 54 In 1973, Reinold reported on
assumption would never have happened if combined qualitatively different movement patterns of the fetus
supervision of the fetus during labor (CTG plus FBA) and their prognostic value.55 In 1971, before real-time
– which has now been available for almost three ultrasound had been developed, Boddy and Robinson
decades – had always been correctly used everywhere gave proof of fetal thorax movements with the help
as standard method in routine practice; for the of an A-scan.56
pathogenetic contradiction (cerebral palsy without Stimulated by studies resulting from animal
proven hypoxia) would then have been obviously experiments by Dawes, 29 numerous systematic
recognized at the very beginning and not now after investi-gations of fetal breathing movements, among
almost 30 years. others by Gennser, 57 were undertaken with the help
10 Textbook of Perinatal Medicine

of real-time procedure. Studies on the complex value in cases with hypertonic or hyperactive uterine
behavioral pattern of the fetus in early pregnancy dysfunction. Tocolysis has also led to considerable
were published by De Vries and co-workers58 and on improvements in the external version of the fetus from
behavioral states in the advanced pregnancy by breech to vertex presentation. Unnecessary Cesarean
Nijhuis and colleagues.59 sections can be avoided using this method and a
Blood flow measurements using the ultrasound number of infants are spared the risk of vaginal breech
Doppler technique are a new landmark in prenatal delivery. We performed an external version near term
supervision. With the help of this technique it was under tocolysis for the first time in 1974, published
possible to make non-invasive measurements of the in 1975.68 The method, when properly applied, does
uterine and fetal blood flow, which allow conclusions not provide any serious risk to the fetus. Up to now,
to be drawn concerning the placental hemodynamics. no infant has died as a result of use of this method in
The first report on the use of the Doppler technique over 2000 versions performed in our department.
for examining fetal blood flow in the umbilical artery
was published in 1977 by Fitzgerald and Drumm.60 CERVICAL RIPENING
Studies followed on the first measurements in the
Further progress in modern obstetrics was achieved
umbilical vein, by Gill61, and on measurements of
by the introduction of cervical ripening by
blood flow in the fetal aorta, by Eik-Nes and co-
prostaglandin application into routine practice by
workers62. Campbell and colleagues presented a new
Calder in 1975,69 after Lippert had developed the
important contribution in 1983 enabling us to measure
prostaglandin gel principle in 1973 in this country for
the uteroplacental flow.63
use in artificial abortion.70 By means of general local
TOCOLYSIS administration (extra-amnially, intracervically,
intravaginally), of prostaglandin E 2, numerous
Another step forward created during the ‘youth-era’ operative deliveries can be avoided in cases with
was the application of betamimetics to inhibit unripe cervix.
contractions. The now classical term ‘tocolysis’ was
introduced by Mosler in 1964.64 The use of tocolytics LUNG MATURATION DIAGNOSTICS
for prevention of prematurity is now obsolete as the
origin of prematurity is caused mostly by ascending The clinical picture of ‘respiratory distress syndrome’
infection. At the present time, the real task of tocolytic was first described by Hochheim in 1903.71 In 1947,
substances applied antepartum is to postpone Gruenwald suggested there was linkage with the
premature labor for a short period of a few days to surface tension in the lungs.72 Clements called the
perform lung maturity treatment of the highly postulated components reducing the surface tension
endangered premature fetuses. ‘pulmonary surfactant’ and discussed its central
There is no controversy as to the advantage of importance as an antiatelectasis factor in 1956.73 In
using betamimetics during labor for intrauterine 1959, for the first time, Avery and Mead suggested a
resuscitation. The first clinical applications were relation between low surface activity and the
undertaken in 1969 by the Caldeyro-Barcia group65 occurrence of respiratory distress syndrome.74 Graven
and shortly afterwards by Gamissans and co- reported in 1968 on the determination of
workers66 and by Esteban-Altirriba and associates.67 phospholipids in human and monkey amniotic fluid
It has been confirmed that acute hypoxic and assumed an association between a low
complications in the fetus can be relieved by the concentration of phospholipids and the probability
administration of a relatively high dose of bolus of respiratory distress syndrome developing.75 Gluck
injection or an infusion to the mother. The use of and co-workers were able to prove a close relation
tocolysis during labor has also proved to be of clinical between the phospholipid content of the amniotic
 Birth and Youth of Prenatal and Perinatal Obstetrics 11
fluid and fetal lung maturity. They started their work structural consequences. Basically, some points should
in 1968 and, in 1971, published the most often cited be taken into consideration when describing the
study on this particular subject.76 history of this new ‘prenatal medicine’ or ‘prenatal
obstetrics’ as a whole. We believe that such a
LUNG MATURATION THERAPY recapitulation is of importance as our mainly foreign
Neonatal morbidity and mortality have been decreas- colleagues, particularly the younger ones, no longer
seem to be aware how, where and when this new
ing during the past decades. The reasons for this are:
medicine started.
1. The improvement in neonatal intensive care,
The foundation of scientific associations concerned
particularly in artificial respiration techniques
with this speciality developed accordingly. In 1967,
and application of surfactants;
the first national society, the ‘German Society of
2. The widespread use of tocolytic substances has
Perinatal Medicine’ was founded. One year later
enabled us to delay premature delivery until lung
(1968), in Berlin, we started the first international
maturation can be improved with the aid of
society, the ‘European Association of Perinatal
various drugs. The glucocorticoids hold the
Medicine’.
leading position in this group.
The term ‘perinatal’ instead of ‘prenatal’ in the
In 1968, Buckingham and co-workers developed
German and European Societies has been chosen
the hypothesis that glucocorticoids promote fetal lung
because, from the very beginning, we wanted to
maturation–on account of the stimulation of the
achieve close cooperation with neonatologists. In fact,
alkaline phosphatase proved in experiments on
it mainly concerned and represented the medical
animals.77 Liggins supported this hypothesis in 1969
progress which prevailed in the prenatal part and was,
with his observations during artificial induction of
for instance, reflected in 80–90% of topics of prenatal
labor; the lungs of prematurely induced lambs that
medicine at nearly all German congresses in this field,
had been given glucocorticoids were clearly more
each of which attracted more than 2000 participants.
mature than the lungs of lambs of the same gestational
The Society of Perinatal Obstetricians in America
age that had not been treated in this way. He
was founded in 1977 and represents one of the most
postulated, after this chance observation, that dynamic national societies in the world at the present
glucocorticoids bring about an acceleration in the time.
formation of surface-active substances in the lung via During our life-time not only has outer space been
enzyme induction.78 opened up in such a spectacular fashion, but also on
In 1972 Liggins and Howie, in their epochal a biological level an equally important development
prospective study, were able to transfer the experience has started rolling and has still by no means come to
achieved in animal experiments to human beings.79 a halt; I mean the medical exploration of our own
The occurrence of respiratory distress syndrome after ‘intrauterine space’, our ‘prenatal cradle’. Very few
antepartum administration of betamethasone to the people are aware of this fact.
mother could be reduced from 24 to 4.3% compared A disastrous conclusion drawn by many influential
to the control group who received no therapy. colleagues in our country and also in many other
According to Liggins and Howie, the preventive effect places was to think from the beginning that we were
of betamethasone is all the more efficient, the lower dealing with a special narrow and limited field – a
the gestational age (26–32 weeks). field of medicine of particular interest to only a few
colleagues and practiced mainly by the younger ones
GENERAL DISCUSSION AND CONCLUSIONS from time to time. And so it was thought, based on
The last part of this contribution is directed to further the conventional all-round structure of obstetrics and
historical facts, to some general views and to gynecology as a whole and according to the status quo
12 Textbook of Perinatal Medicine

ante, that all these revolutionary events could be taken Birth and youth of prenatal obstetrics and perinatal
into consideration and the rotation principle could medicine was to a large extent a product of European
still be maintained. The consequences of this grave clinicians and scientists, although many impulses in
error of judgement continue, even today, to give cause numerous fields of medicine since the Second World
for concern to a wide extent in some parts of Europe. War have come from abroad, particularly from North
Realization of structural consequences began at an America. It is therefore particularly commendable that
appropriately early stage in the United States. The the European Association of Perinatal Medicine again
setting up of ‘Units of Maternal–Fetal Medicine’ took up the initiative and, under the leadership of
begun in 1972, made successful the consequent use such a powerful and outstanding colleague as Asim
of the prenatal part of perinatal medicine within the Kurjak together with the participation of so many
framework of the complete field of obstetrics and renowned experts, is publishing an extensive current
gynecology. review about our great field of perinatal medicine.
The term ‘fetal medicine’ which is still used today These great steps forward have by no means come
in the form of ‘maternal–fetal medicine’ had probably to a halt, as many opposed to this direction of
not been considered enough when it was introduced development have been artlessly suggesting for years.
at the very beginning for clinical purposes. It would be most improbable if a practically newly
Unfortunately, it does not include the embryonic opened extensive area – as represented by the
period which also belongs to our clinical competence. intrauterine space up to the beginning of the 1960s –
The consequence is that other subspecialties have should be fully explored medically within only 38
been more aware of this and are using this term for years. It will certainly go on and perhaps when the
example, in the name of their society, namely next generation period is over, several of the modern
‘European Society of Human Reproduction and achievements, of which we are so proud today, may
Embryology’. We, therefore, prefer the general term be regarded as obsolete. New pioneers will take over
‘prenatal medicine’, which some colleagues use our role then, and the next generation will again
erroneously for only a special subordinated field, continue this course of medical science and course of
mainly for diagnostics of anomalies and some special life.
therapeutic procedures in early pregnancy. As an
alternative, the term ‘pre- and perinatal obstetrics’ REFERENCES
would be appropriate, if preferred. 1. Dobbs RH, Gairdner D. Foetal medicine: Who is to
On the basis of the enormous progress already practice it? Arch Dis Child 1966;41:453.
achieved in 1967, we recommended a structural 2. Lambl D. Ein seltener Fall von Hydramnion. Zentralbl
Gynäkol 1881;14:14
reform of the discipline in our country and the setting 3. Meness TO, Miller JE, Holly LE. Amniography. Am J
up of units of modern obstetrics and prenatal Roentgenol 1930;2:363.
medicine.80 However, up to now many European 4. Bevis DCA. Antenatal prediction of haemolytic disease
of the newborn. Lancet 1952;I:395.
university departments particularly in our country do
5. Liley AW. Liquor amnii analysis in the management of
not have such units. The consequences are depressing the pregnancy complicated by rhesus sensitization. Am
as regards highly qualified research activities and our J Obstet Gynecol 1961;82:1359.
international image. Due to the lack of the necessary 6. Liley AW. Intrauterine transfusion of fetus in haemolytic
disease. Br Med J 1963;ii:1107.
requirements, not enough interested colleagues could 7. Berkowitz RL, Chitkara U, Goldberg JD, et al.
remain working in this field for a longer period to Intravascular transfusion in utero: The percutaneous
become adequately specialized and to obtain approach. Am J Obstet Gynecol 1986;154:622.
appropriate career chances. Consequently, some 8. Hansmann M, Bald R, Gembruch U. Ultraschall-
kontrollierte intrauterine Transfusion – intravasal-
European countries concerned have only a few intrakardial, mit Austausch? Ultraschall in Klinik und
internationally reputed ‘perinatal obstetricians’. Praxis 1986;(Supp 1):68.
 Birth and Youth of Prenatal and Perinatal Obstetrics 13
9. Saling E. Zur Frage der optimalen Behandlung des 30. Arabin B, Bergmann PL, Saling E. Simultaneous
scheintoten Neugeborenen. Geburtshilfe Frauenheilkd assessment of blood flow velocity waveforms in
1958;18:128. uteroplacental vessels, the umbilical artery, the fetal aorta
10. Saling E. Über die Wirksamkeit von älteren und neuen and the fetal common carotid atery. Fetal Ther 1987;2:17.
Asphyxiebehandlungsmethoden. Geburtshilfe 31. Saling E, Arabin B. Historic landmarks of perinatal
Frauenheilkd 1960;20:325. medicine in obstetrics. J Perinat Med 1988;16:5.
11. Strauss H. Technische Hilfsmittel zur Intubation. In Biro 32. Pestalozzi E. Graphische Darstellung des fötalen
P, Pasch Th, eds. Die schwierige Intubation. Göttingen, Herzimpulses. Arch Gynäkol 1891;39:137.
Toronto, Seattle: Hans Huber Bern, 1995:52. 33. Hofbauer J, Weiss O. Photografische Registrierung der
12. Saling E. Austauschtransfusion beim Neugeborenen über fötalen Herztöne. Zentralbl Gynäkol 1908;32:429.
die Aorta abdominalis. Geburtshilfe Frauenheilkd 34. Cremer M. Über die direkte Ableitung der Aktionsströme
1959;19:230.
des menschlichen Herzens vom Ösophagus und über das
13. Saling E. Die Zwei-Katheterverfahren für den
Elektrokardiogramm des Fötus. Münch Med Wochenschr
Blutaustausch beim Neugeborenen. Dtsch Med
1906;53:811.
Wochenschr 1961;86:294.
35. Caldeyro-Barcia R. Estudio de la anoxial fetal
14. Saling E, Damaschke K. Neue Mikro-Schnell-Methode
intrauterina mediante el ECG fetal y el registro continuo
zur Messung des Blutsauerstoffs auf elektrochemischem
Wege. Klin Wochenschr 1961;39:305. de la frecuencia cardiaca fetal. In Proceedings of III Congr
15. Saling E. The antenatal detection of haemolytic disease Latinoamer Obstet Ginec Vol 2. Mexico 1958:383.
of the newborn. Germ Med Mth 1961;6:326. 36. Rech W. Untersuchungen über die Herztätigkeit des
16. Saling E. Neue Untersuchungsmöglichkeiten des Kindes Fetus. I. Teil. Arch Gynäkol 1931;145:714.
unter der Geburt. Zentralbl Gynäkol 1961;83:1906. 37. Hon EH. A foetal electrographic electrode. Yale J Biol Med
17. Saling E. Neues Vorgehen zur Untersuchung des Kindes 1966;39:54.
unter der Geburt (Einführung, Technik, Grundlagen). 38. Junge H. Über die kontinuierliche Kontrolle der fetalen
Arch Gynäkol 1962;197:108. Herztätigkeit durch Aufzeichnung des fetalen
18. Saling E. Zustandsdiagnose beim Neugeborenen Herzfrequenzdiagramms. Z Geburtshilfe Gynäkol
unmittelbar nach der Geburt. Gynaecologia 1965;160:133. 1967;166:159.
19. Saling E. Das Kind im Bereich der Geburtshilfe. Stuttgart: 39. Hammacher K. Neue Methoden zur selektiven
Thieme, 1966. Registrierung der fetalen Herzschlagfrequenz.
20. Saling E. Foetal and Neonatal Hypoxia in Relation to Geburtshilfe Frauenheilkd 1962;22:1512.
Obstetric Practice. London: Arnoldt (Publication), 1968. 40. Saling E. Elektronische und biochemische Überwachung
21. Boenisch H, Saling E. A combined clinical–biochemical des Feten unter der Geburt. Bull Soc Roy Belge Gynéc
scoring of the newborn. Results of the past four years. J Obstet 1968;38:289.
Perinat Med 1974;2:122. 41. Brandt-Niebelschütz S, Saling E. Indications for operative
22. Saling E. Die Blutgasverhältnisse und der Säure-Basen- termination of labor on cardiotocography and fetal blood
Haushalt des Feten bei ungestörtem Geburtsverlauf. Z analysis: the reliability of these methods. J Perinat Med
Geburtsh Gynäkol 1963;161:262. 1994;22:19.
23. Caldeyro-Barcia R. Editorial. J Perinat Med 1973;1:5. 42. Saling E, Dudenhausen JW. The present situation of
24. Saling E. Die Amnioskopie, ein neues Verfahren zum clinical monitoring of the fetus during labor. J Perinat
Erkennen von Gefahrenzuständen des Feten bei noch
Med 1973;1:75.
stehender Fruchtblase. Geburtshilfe Frauenheilkd
43. Saling E. Fetal scalp blood analysis. J Perinat Med
1962;22:830.
1981;9:165.
25. Dudenhausen JW, Saling E. Die Amnioskopie zur
44. Saling E. Introduction and clinical aspects of biochemical
Überwachung des Föten bei EPH-Gestose der Mutter. In
monitoring of the fetus. J Perinat Med 1988;16(suppl
Rippmann ET, Rippert C, eds. EPH-Gestose. Berlin: de
Guyter, 1972:101–6. 1):23.
26. Saling E. Die O2-Sparschaltung des fetalen Kreislaufes. 45. Saling E, Langner K. Fetal acid–base measurements in
Geburtshilfe Frauenheilkd 1966;26:413. labor. In Spencer JAD, ed. Fetal Monitoring. Tunbridge
27. Saling E. Oxygen-conserving adaptation of the foetal Wells: Castle House Publications, 1989.
circulation. Mod Trends Paediatr 1970;3:51. 46. Saling E, Bartnicki J. Clinical importance of biochemical
28. Dawes GS, Mott JC. Changes in O 2 distribution and monitoring of the fetus during labor with demonstration
consumption in foetal lambs with variations in umbilical of typical cases. In Chatterjee MS, ed. Biochemical
blood flow. J Physiol 1964;170:524. Monitoring of the Fetus. New York: Springer, 1993:1–12.
29. Dawes GS. Revolutions and clinical rhythm in prenatal 47. Donald I, MacVicar J, Brown TG. Investigation of
life. Fetal respiratory movements rediscovered. Pediatrics abdominal mass by pulsed ultrasound. Lancet
1973;51:965. 1958;I:1188.
14 Textbook of Perinatal Medicine

48. Donald I, Brown TG. Demonstration of tissue interfaces distress. In Perinatal Factors Affecting Human
within the body by ultrasonic echo sounding. Br J Radiol Development. Sci Publ No 185. Washington: Pan
1961;34:539. American Health Organization, 1969:248.
49. Gottesfeld KR. The practical application of ultrasound 66. Gamissans O, Esteban-Altirriba J, Gomez S, et al. Estudio
in obstetrics and gynecology. In Diagostic Ultrasound. de la accion utero-inhibidora de un nuevo beta-
New York: Plenum Press, 1966. adrenergico (derivado de la orciprenalina) en clinica
50. Gottesfeld KR, Thompson HE, Holmes JH, Taylor ES. obstetrica. Acta Ginecol (Madrid) 1968;19:445.
Ultrasonic placentography – A new method for placental 67. Esteban-Altirriba J, Gamissans O, Duran P, et al.
localization. Am J Obstet Gynecol 1966;96:538. Administration of beta-mimetic agents to the mother as
51. Kossoff G, Garrett WJ, Radovanovich G. Grey scale a conservative therapy in cases of intrapartum fetal
echography in obstetrics and gynecology. Aust Radiol acidosis. In Saling E, Dudenhausen JW, eds. Perinatale
1974;18:62. Medizin Band III. Stuttgart: Thieme, 1972:198–208.
52. Donald I. Clinical application of ultrasonic techniques
68. Saling E, Müller-Holve W. External cephalic version
in obstetrical and gynaecological diagnosis. Br J Obstet
under tocolysis. J Perinat Med 1975;3:115.
Gynaecol 1962;69:1036.
69. Calder AA, Embrey MP, Tait T. Ripening of the cervix
53. Callaghan D, Rowland TC, Goldman DE. Ultrasonic
with extraamniotic prostaglandin E in viscous gel before
observation of the fetal heart. Obstet Gynecol
induction of labour. Br J Obstet Gynaecol 1975;84:264.
1964;23:637.
54. Kratochwil A, Eisenhut L. Der früheste Nachweis der 70. Lippert Th, Moldy T. Induction of abortion by extra-
fetalen Herzaktion durch Ultraschall. Geburtshilfe amniotic administration of prostaglandin gel. J Obstet
Frauenheilkd 1967;27:176. Gynaecol Br Commonw 1973;80:1025.
55. Reinold E. Clinical value of fetal spontaneous 71. Hochheim K. Über einige Befunde in den Lungen von
movements in early pregnancy. J Perinat Med 1973;1:65. Neugeborenen und die Beziehung derselben zur
56. Boddy K, Robinson JS. External method for detection of Aspiration von Fruchtwasser. Zentralbl Pathol
fetal breathing in utero. Lancet 1971;II:1231. 1903;14:537.
57. Gennser G. The dynamics of fetal respiratory movements 72. Gruenwald P. Surface tension as a factor in the resistance
in man. In Bennet MJ, Campbell S, eds, Realtime of neonatal lungs to aeration. Am J Obstet Gynecol
Ultrasound in Obstetrics. Oxford: S. Blackwells, 1980. 1947;53:966.
58. De Vries JIP, Visser GHA, Prechtl HFR. The emergence 73. Clements JA. Surface tension of lung extracts. Am J
of fetal behaviour. I Quantitative aspects. Early Hum Dev Physiol 1956;187:592.
1982;7:301. 74. Avery ME, Mead J. Surface properties in relation to
59. Nijhuis JG, Prechtl HFR, Martin CB Jr, Bots RSGM. Are atelectasis and hyaline membrane disease. Am J Dis
there behavioural states in the human fetus? Early Child 1959;97:517.
Human Dev 1982;6:177. 75. Graven SN. Phospholipids in human and monkey
60. Fitzgerald DE, Drumm JE. Non-invasive measurement amniotic fluid. Pediatr Res 1968;2:318.
of human fetal circulation using ultrasound. Br Med J 76. Gluck L, Kulovich MV, Borer RC, et al. Diagnosis of
1977;2:1450. respiratory distress syndrome by amniocentesis. Am J
61. Gill RW. Quantitative blood flow measurement in deep- Obstet Gynecol 1971;109:440.
lying vessel using pulsed Doppler with the Octoson. In 77. Buckingham S, McNary FF, Sommers SC, Rothschild J.
White DN, Lyons EA. Ultrasound in Medicine. New
Is lung an analogue of Moog’s developing intestine? I.
York: Plenum Press 1978;4:341.
Phosphatases and pulmonary alveolar differentiation in
62. Eik-Nes SH, Brubakk A, Ulstein M. Measurement of
fetal rabbits. Fed Proc 1968;27:328.
human fetal blood flow. Br Med J 1980;1:283.
78. Liggins GC. Premature delivery of foetal lambs infused
63. Campbell S, Diaz-Recasens J, Griffin DR. New Doppler
with glucocorticoids. J Endocrinol 1969;45:515.
technique for assessing uteroplacental blood flow. Lancet
1983;I:675. 79. Liggins GC, Howie RN. A controlled trial of antepartum
64. Mosler K-H. Bericht über das 3. Symposion über glucocorticoid treatment for prevention of the respiratory
Physiologie und Pathologie der Wehentätigkeit. distress syndrome in premature infants. Pediatrics
Würzburg 1964 . Zentralbl Gynäkol 1965;87:197. 1972;50:515.
65. Caldeyro-Barcia R, Magana JM, Castillo JB, et al. A new 80. Saling E. Vorschläge zur Neuordnung der Geburtshilfe.
approach to the treatment of acute intrapartum fetal Geburtshilfe Frauenheilkd 1967;27:572.
 2
Memories of WAPM

Shouichi Sakamoto

INTRODUCTION international congress of perinatology which was

unfortunately discontinued and secondly Prof. E.
WAPM is the abbreviation of World Association of
Cosmi proposed the foundation of international level
Perinatal Medicine.
federation on the occasion of European congress of
The first international Congress of Perinatal
perinatology, Rome, in 1987 and preparatory work
Medicine 1991 was the first global meeting of
scientists, clinicians, midwives and persons who are just started. In 1989, on the occasion of FIGO congress,
concerned with perinatal medicine. Although Rio de Janeiro, Prof. R. Caldeyro-Barcia who was a
academic exchange in this field had been active on famous perinatologist in Uruguay and former FIGO
the regional level, this congress was the first president had meeting with the invited participants
worldwide meeting of its kind following agreement from about 40 countries, total around 70 doctors, for
at the Rio de Janeiro FIGO meeting in 1989. discussion how to set up International body. The
objectives were unanimously approved, but
HOW WAS THE WAPM BORN? IT’S HISTORY substantial method of setting up the proposed
On the occasion of the new publication of federation was hard to make decision. Then I
perinatology, we had better to look back the history proposed “Let’s have one international congress
of the international congress of perinatal medicine to under a suitable person in suitable place, and at the
know how the WAPM started its activity. end of the congress, Mr. Chairman, you should have
Since 1960’s, in perinatology, scientific general assembly and ask the delegates again for
breakthrough started by the remarkable development voting whether the foundation of international body
of medical science. is necessary or not ?”. Prof. Caldeyroi Bareia and parti-
According to such the development, many cipants all agreed with this idea and finally nominated
federations of perinatology were born. European me as the congress president, requesting the congress
congress of perinatology started firstly by (1968). High autumn 1991 in Tokyo. Preparation for the congress
level scientific exchange system in USA, Asia Oceania was thought to be finished within full 2 years.
Federation of perinatology (1979) and Latin – Then the congress was held under the name of the
American Federation (1980’s) were born. First International Congress of Perinatal medicine,
The idea to have international level body for from 5-8 November 1991, Tokyo Keio Plaza hotel
perinatal medicine came to the brain of pioneers. In attended by 1580 participants from 45 countries, and
Europe Prof. E. Saling had the initiative to set up the total 516 invited and oral and poster papers were
16 Textbook of Perinatal Medicine

presented. It ended with great success. Prof. R. cares, which address the safety and happiness of
Caldeyro Barcia chaired the general assembly mother and child, have always been pursued in
immediately after the congress was over and about earnest by both obstetricians and pediatricians. At
60 delegates from 45 countries joined. They evaluated last, in 1968, the academic outline of perinatal
the first congress very much and foundation of medicine, called Perinatology was established in
International body named WAPM, “World Europe. Hence, Perinatal medicine has become new
Association of Perinatal Medicine”, was unanimously and important area in academic fields. During the
accepted. following two decades, with remarkable
Here, the WAPM was born safely and happily. All advancements in science, important discoveries
members signed to be founder. Annual fee etc were were made, in succession, about the fetus, which
carefully discussed, but as it took time, chairman previously had been kept in a black box. It is truly
proposed the election of officers only and entrust them noteworthy that neonatology also has become a
to promote every preparatory work. brilliant specialty, and academic findings are now
I was then nominated as the first president of vigorously exchange in feedback between
WAPM by the election. Other officers were also researchers. As a biologist, I fully understand that
elected by the same method. perinatology in a broad sense consists of maternal
I thought the Second congress should by held in medicine, fetal medicine and neonatology.
Europe and I proposed Prof-Cosmi as congress I am deeply impressed that scholars from many
president, and Rome as congress site. As Cosmi and specialties reached beyond their own territories
I worked for FIGO as the member of executive Broad, and exchange expertise to establish a new academic
I knew he had strong will to be the congress president. branch, the core of which is new life. I am
Then chairman closed this session, with convinced that deep reverence of life as well as love
congratulation remarks. of mankind has made it possible. I would like to
I believe that WAPM is really Prof. Robert praise the pioneers and their followers who gather
Caldeyro Bareia’s Legacy, likely FIGO, IFFS and here today.
IAMANEH are called as the Hubert de Watteville’s
When we reflect on the situation of mother and
Legacy. And this 1st international Congress was
child at a global level, we realize that the
nominated naturally as the 1st congress of WAPM
achievements from advanced studies benefit only
afterwords.
people in advanced nations. I am pained to think
HIS IMPERIAL MAJESTY AKIHITO’S that young mothers, newborn babies and infants
OPENING ADDRESS in many developing countries where people face
problems associated with population explosion do
He kindly attended the opening ceremony of the 1st not benefit from the fruits of advanced studies. All
International Congress of perinatal medicine and lives, great or small, have an equal right to enjoy
welcome party with her Majesty Michiko. happiness and maintain dignity. I pray that you
The success of this congress, I believe, was due to take that initiative to extend helpful hands to these
his speech which was full of deep thoughts and less fortunate people.
stimulating messages. In this International Congress, not only
By the request of the 6th President WAPM, Prof. advancements from studies but also other efforts
Kurjak, I describe here our emperor’s Address. are joined to spread reality-based information. In
It is my heart-felt pleasure to convene the First that regard, the Congress will make great
International Congress of Perinatal Medicine in achievements. It is my sincere hope that the
Tokyo, where the East meets the West. Perinatal Congress will create a milestone?
 Memories of WAPM 17
The above is the speech given by His Majesty the The following decade, 1975-1985, was a period of
Emperor at the opening ceremony of the First long term management of abnormal fetuses during
International Congress of Perinatal Medicine. The pregnancy. An introduction of ultrasonographic
Emperor and Empress are extremely concerned with observation brought us new diagnostic techniques in
Perinatal Medicine. His Majesty spoke with infinite fetal inspection.
care to make sure no word is left unheard. Everyone This decade, including 1985 to 1990, is an era of a
at the opening ceremony could not help but be new frontier in fetal therapy in which we can apply
captivated by his Majesty’s warm personality. It was individualized diagnostic measures and therapeutic
the moment where people who have taken separate devices to different type of fetal disorders.
ways to reach the peak of Perinatal Medicine came
together to achieve the ideas of the future. Establishment of Fetal Emergency Care
Fetal emergency care was established by the progress
PROGRESS AND DEVELOPMENT OF FETAL in fetal monitoring. Cardiotocography and chemical
MEDICINE AT THE 1ST CONGRESS 1991 diagnosis of fetal blood gave a very accurate diagnosis
Fetal care was initially developed to prevent fetal of fetal distress. Biochemical analysis of maternal
disorders by improving obstetrical care related to hormone secretion and blood enzymatic distribution
labor and delivery. It became clear that neonatal care, also provided criteria for placental dysfunction. These
in collaboration with obstetrics and pediatrics, was led to diagnosis chronically affected fetuses.
essential in obtaining better prognosis in newborn Therapeutic effects, caused by oxygen inhalation and
infants which led to the establishment of Perinatal maternal infusion therapy, could be satisfactorily
Medicine. evaluated and gave a more accurate timing of
Since 1960’s, 20 years has passed. Perinatal emergency care for the fetus. However, caution
Medicine has achieved tremendous progress in safety against unnecessary management due to over-
care for mother and child. Furthermore, as neonatal diagnosis was claimed elsewhere.
care developed to neonatology, fetal therapy is now In this period, diagnostic criteria for fetal distress
becoming a new scientific field as fetal medicine. But by different methods were proposed by distinguished
when looking back the scientific level at around 1980’ researchers. Pathophysiological diagnosis for
was like this encephalopathy of fetus and neonate, and fetal
endocrinology have become wide research targets.
Development of Perinatology
Long-term Management of Fetus in Utero
Experiments in perinatal medicine, such as patho-
The second decade of progress in perinatology was
physiology of the fetus and neonatal hypoxia and
defined between 1975-1985. Progress in ultrasonic
metabolic analysis of thermogenesis of neonates were
diagnosis of the fetus brought the second advanced
potentially carried out during the sixties.
stage in fetal care. Abnormalities in fetal growth could
be accurately diagnosed by fetometry. In addition,
Progress in Fetal Medicine
cross sectional view of the fetus gave us new
Progress in fetal therapy, can be divided into three indication for therapeutic measures, such as fetal
phases according to therapeutic objectives. The first surgery, fetal biopsy, reproductive physiology etc.
decade, 1960-1975, is defined as a period of fetal Blood flow determination by Doppler ultrasound
emergency care. Many trials were concentrated on enabled us to monitor circulatory conditions in fetus.
diagnosis of fetal distress (this word has been changed These contributed to long-term management of the
nowadays) and resuscitation of newborn infants. fetus in utero.
18 Textbook of Perinatal Medicine

Congenital hydrocephalus develops rapidly growth factors and endothelial functions of chorionic
around the 28th week of gestation. villi gave basic consideration of pathogenesis of
Close observation of cerebral thickness gives the IUGR.
exact timing of induction of labor. Radical neuro- Feto-maternal interaction was clearly
surgery to construct permanent drainage followed by demonstrated by IGF-1 regulation in relation to fetal
delivery saves the baby from mental disorders. growth. This is an example of research work picked
Accurate diagnosis of placenta previa and precise up from many works.
determination of fetal growth could be easily obtained Production of IGF-1 is switched over from the
by ultrasonography. maternal liver to the placenta. Activity of IGF-1 in the
Intrauterine blood transfusion or even an exchange placental environment is regulated by the autocrine
transfusion through the umbilical vein when blood function of the villi and paracrine function of villi and
incompatibility occurs, could be carried out by guided decidua. The hPL and placental GH stimulate IGF-1
catheterization under ultrasonography. and its binding protein production in the maternal
liver. Binding protein is also regulated by protease
Genetic diagnosis done by amniocentesis,
from deciduas. These facts suggest that duplicate
chorionic villi sampling (CVS) and neonatal blood-
cycle for IGF-1 regulation functions during pregnancy.
sampling, developed during this period, was also one
Fetal growth factors are independent of the maternal
of the remarkable progresses in fetal medicine. Some
side; however, they show their activity substrate
of the inborn errors of metabolism which affect the
dependency by maternal transport of nutrients. IGFs
mental development of the newborn, such as methyl
mainly have three types of structure, IGF-1,2,3 and
maronic acidemia or galactosemia, can be treated by
they have different functions, respectively. Other
maternal administration of cyanocobalamin or a low
growth factors concerning the fetal growth should be
galactose diet for the mother. Follic Acid therapy has studied carefully.
been recommended to prevent the fetal spina bifida.
Typical medical intervention in handicapped fetus Coagulation and Fibrinolysis System-
of hydrocephalus is described as an example. Thrombomoduline
Enlargement of BPD was clearly shown ultrasono-
This system is another example of the new approach
graphically. Progress of ventricular dilatation and
to analyze placental circulation in PIH. It became clear
thinning of cerebral cortex by CT were carefully
that trophoblast has an endothelial function
monitored along with fetal growth and maturation.
maintaining smooth blood circulation in the
Our case was born at 36 weeks of gestation by
intervillous space, where most slow and complicated
cesarean section followed by neurosurgery of
blood streams exist and easily forms infarction during
continuous drainage. Both the fetus’ maturation
abnormal conditions, in the case such as PIH. Our data
tolerate to surgical stress and the prognostic limitation clearly indicated decreased trophoblastic thrombo-
of the ventricular enlargement were carefully taken modulin activity in PIH, which referred to endothelial
into consideration in determining the time of delivery. function. This is one of the explanations for the fact
By CT scanning, performed one week after that remarkable IUGR takes place in severe PIH.
surgery, remarkable reduction in ventricular size was Endothelial function in pregnancy is also an important
noted. The baby recovered smoothly and obtained field to study.
normal mental development at the age of one.
Fetal Surgery
Individualization in Fetal Therapy
Direct therapeutic approach to the fetus, such as
Advances in bioengineering and molecular biology catheter replacement and experimental trial of gene
in recent years contribute greatly to the scientific bases manipulation, may lead to radical treatment in utero.
of perinatal medicine. Feto-maternal interaction of Open fetal surgery may lead to complete correction
 Memories of WAPM 19
of fetal anomalies. Direct catheter replacement to half physics, the 21st century is the era of chemistry and
delivered fetuses with urethral obstruction at the genome, and can be called the period to respect life
thirtieth week through incised uterine window was and establish human dignity. People who are sick or
first performed in 1990. The window was closed and suffer from extreme poverty long for the
the amnion was supplied through a catheter. The baby normalization of the QOL and the life worth living. It
was successfully managed for an considerable period is our duty to deal with such evidence and respond
in utero after surgery. Radical urethral reconstruction to the wish of those countless people. Naturally, these
was performed in the neonatal period. This evidences
actions require highly advanced science and
show that fetal medicine is obtaining general
appropriate as well as reasonable means of healing.
consensus for clinical use.
Medicine must not only be highly advanced but also
Several years ago, the International Symposium
bring peace to lonely souls. Life-long education also
“The fetus as a Patient” was held with anticipation
is our own choice and duty, imposing on our
and hope of all perinatologists. Fetal medicine, started
from emergency care of fetal distress 25 years ago, is experience. Physicians must be always disciplined to
now able to apply total medical-care to the fetus. Our be humble. Medical care should not be ruled by
hope symbolized in ‘The fetus as a Patient’ is now temporally good intention or judgment, but should
being realized. aim at the future of humankind, especially of mother
Finally, I would like to conclude by saying… and child.
Whenever, wherever, we have our hopes and dreams, For the young generation:
they will certainly be realized and bring a brighter
• What we should do, are taught by the mind and
future in perinatal medicine.
body of patients.
These were samples of perinatal research and
treatment performed around 1980’s. More developed • What we should not do, we learn from the history
research work had been performed by the pioneer but of evidence, and valuable experience.
member of which were quite limited. Lastly, I would like to close my remarks with my
In this book most developed datas are to be own view for medicine which was firstly proposed
described. You may find dramatic development of in 1991 congress.
perinatal medicine in the period from 1991 until 2005.
“May our international festival of academia be a
CLOSING REMARKS forum and an opportunity to turn human dreams to
While the 20th century was the era of advance in hopes, and hopes to reality, thus bringing to all
science and technology, placing the emphasis on humanity true peace and happiness. (1991)”.
20 Textbook of Perinatal Medicine

3
Perinatal Medicine in the
United States

Edward J Quilligan

AN OVERVIEW A more specific date can be set for the beginning of

the subspecialty of Maternal Fetal Medicine in the
It is always difficult to set a date as to when Perinatal
United States. The American Board of Obstetrics and
medicine began in the United States. During the
Gynecology, under the leadership of Gordon W.
1940’s, 1950’s and 1960’s there seemed to be a
Douglas M.D., organized a meeting in 1969 to
significant increase in research, both basic and clinical,
determine the feasibility of subspecialty certification
regarding the pregnant mother and her fetus. This was
or boards in Obstetrics and Gynecology. 3 I was
fueled by the increase in federal grant funds, the
fortunate to chair the discussion on Maternal Fetal
increased numbers of full-time faculty in Obstetrics
Medicine. It was the consensus of our committee and
and Gynecology and the developing technology ultimately the Board that there were adequate
which would allow measurement of hitherto numbers of obstetricians and gynecologists who were
inaccessible fetal and maternal parameters. For primarily interested in maternal fetal medicine from
example the intrauterine catheter allowed the a clinical and research standpoint to justify a
development of new understandings of the work subspecialty board or certification. A similar
required by the uterus during labor and how conclusion was reached in regards to oncology and
abnormalities of the contraction pattern may lead to reproductive endocrinology. The next two years were
abnormal labor. 1 The development of more spent developing the subspecialty divisions and
sophisticated electronics allowed the recording of the getting the necessary approval from the American
fetal heart rate through out labor. 2 Board of Medical Specialties. It was decided that
Another factor important in the development of rather than being subspecialty boards, the parent
Perinatal medicine was the growing awareness that board would offer certificates of special competence
a pregnant patient with medical complications, such in the areas of maternal-fetal medicine, oncology and
as diabetes needed completely different care than a reproductive endocrinology. This was primarily due
non-pregnant diabetic. In the past it was usually the to the fact that the American Board of Medical
case that the obstetrician managed the pregnancy and Specialities had recently granted several subspecialty
an internist managed the diabetes. The occasionally boards and had a temporary moratorium on new
lead to difficulties as the two physicians were not ones. We felt it was of no particular advantage to be
working in concert. It was found that the well a subspecialty board.
prepared obstetrician could manage both with better The American Board of Obstetrics and Gynecology
outcomes for mother and fetus. did establish divisions of Maternal Fetal Medicine,
 Perinatal Medicine in the United States 21
Oncology and Reproductive Endocrinology in 1969. or training which had not been board approved; the
I was appointed the first head of the division of grandfathers. Three choices were available:
Maternal Fetal Medicine. There was one 1. Have no grandfathers, make all candidates have
representative of the parent board in our division, Dr. board approved training,
Harry Prystowsky. There were four additional 2. Permit anyone who thinks they are qualified take
members of the original division, Donald L. the examinations. This would be for a specified
Hutchinson M.D., Edgar L. Makowski M.D., Joseph period of time.
Seitchik M.D. and Fredrick P. Zuspan M.D. 3. Allow all grandfathers to receive a certification.
The purposes of our division were as follows: There was a lively discussion of this question with
1. To improve the health care of mother and fetus many feeling there should be no grandfathers. The
suffering from diseases peculiar to or related to threat of a protracted suit in one of the other divisions
gestation, by elevating the standard of education lead us all to accept number two; permit those who
and training related to abnormal obstetrics: by thought themselves qualified to take the examination.
enhancing the recruitment of qualified physicians This option would only be open for a period of three
it this field: by improving the organization and years after the initial examination. The candidates
distribution of patient care: and by increasing choosing this option were required to submit an
knowledge, thereby improving the treatment of application which described their residence training
women with pregnancy disorders. and any fellowship training they taken. In addition
2. To evaluate the qualifications of educational we required a case list of all complicated pregnancies
programs offering training in maternal and fetal they had managed during the previous two year as
medicine for the purpose of providing improved well as the total number of normal pregnancies they
patient care and adequate preparation and had managed during the same time period. A
experience of the physician intending to become bibliography of all articles, book chapters and
a specialist in this field. abstracts, including reprints of original articles was a
3. To define periodically and to publish from time requirement. The type of application gave the
to time the detail of formal training which the Division material needed to make a judgment as
division considers essential to attain eligibility for whether an individual qualified as a grandfather.
examination. The number and type of examinations was rather
4. To establish procedures whereby the knowledge easily determined. The parent board had both and
and skills of a candidate for advanced written and oral examination. All sub specialty
certification may be evaluated, and examinations divisions decided to follow that example. The scope
designed to determine the individuals of the written examination included:
competence as a specialist in maternal and fetal 1. Genetics, biochemistry of genes and
medicine. chromosomes, gene transformation in man,
5. To recommend to the Board for advanced cytogenetics and karyotyping, population
certification physicians who have demonstrated genetics and genetic counseling.
to the satisfaction of the Division their possession 2. Teratology, knowledge of embryology, drugs
of special knowledge and a high degree of which affect the fetus, viral effects on the fetus,
professional competence in the management of bacterial effects on the fetus and radiation effects
disorders of mothers and fetus.4 on the fetus.
One of the first major decisions which had to be 3. Maternal physiology.
made was one that affected all the divisions, namely 4. Fetal physiology.
how to treat those individuals who considered 5. Effects of maternal disease on the fetus.
themselves sub specialists but had no formal trainings 6. Effects of pregnancy on maternal disease.
22 Textbook of Perinatal Medicine

7. Immunology. c. A newborn care unit with a noenatologist

8. Evaluation of fetal welfare during pregnancy and director and adequate numbers of newborns
labor. requiring intensive care.
9. Newborn adjustments and adaptations to health d. A pathology service with a qualified fetal and
and disease. newborn pathologist.
10. Infection in mother and fetus, diagnosis and 4. A program director certified as a Diplomate of
therapy. the American Board of Obstetrics and
11. Immunologic disorders. Gynecology who is judged to be qualified to
12. Intrapartum disorders. direct such a program. This last requirement was
13. General knowledge of investigative concepts and soon changed to a person certified as a sub
techniques and knowledge necessary to critically specialist in maternal fetal medicine. Each new
evaluate studies in maternal and fetal medicine. training program was inspected by one or more
An individual passing the written examination division members.
was eligible to take the oral examination after two A significant number of changes have occurred
years of practice. The two years of practice was waved since the initial since the initial candidates were
for grandfathers. Requirements for the oral examined in 1973. After the second oral examination
examinations included a case list for the two years of the neonatologists were not used since this area was
practice and a thesis of original clinical or basic felt to be primarily in the realm of a new sub specialty.
research. The oral examination was two examiners within pediatrics, neonatology. 1975 the case list for
and a neonatologist questioning the candidate for thee oral examination was reduced to 18 months before
hours on the thesis, case list, knowledge of maternal the application was submitted. 5 1977 obstetric
fetal medicine including investigative concepts.4 anesthesia was added the scope of the oral
The division developed the required training examinations and an obstetric anesthesiologist was a
program which was two years in duration with the required part of the training program. 6 The 1978
following requirements: bulletin did specify that” The program must include
1. Training could be obtained in one or more two university-level courses, one in qualitative
institutions. techniques which should include biostatistics and
2. At all times there must be evidence of a patient other areas such as epidemiology and research design
population adequate to assure the candidate of and implementation. The second course must be
a satisfactory experience. relevant to the specific subspecialty. Both courses must
3. Comprehensive care of maternal and fetal be approved by the division. All courses must have
disorders requires, an examination which the candidate must pass.” Also
a. A high risk pregnancy unit with adequate in 1978 the thesis requirement was changed to a paper
numbers of pregnant patients presenting in press or published within the past three years in a
special problems defined as high risk, peer review journal.7 1979 ultrasound unit is required
adequate supervision by individuals in the training program and ultrasound became a part
competent in the care of high risk pregnant of the written and oral examinations.8 In 1986 a Guide
patients and adequate laboratory and of Learning was published by the Board which gave
monitoring equipment . a much more complete outline of the scope of
b. A genetics unit with a qualified geneticist and knowledge required by a subspecialist. 9 Perhaps the
laboratory to perform genetic analysis most significant change occurred in 1998 when the
including karyotyping and biochemical division decided to lengthen the training to three
studies. years.10 The Division, from its inception, felt that
 Perinatal Medicine in the United States 23
research was a very important part of the training perinatal mortality and stillbirth rate. The integration
program. The was evident in the first Bulletin which of care in a single individual who in focused on the
stated“ The candidate must possess (a) an under- pregnant patient with a complication such as diabetes
standing and general knowledge of investigative or hypertension, in my opinion, must result in
concepts and techniques as they relate to maternal improved care.
health and fetal development and (b) the knowledge
necessary to evaluate studies relative to maternal and REFERENCES
fetal medicine”. It was expected, though not
1. Caldeyro-Barcia R, Pose S V, Alverez H Uterine
specifically stated, that one of the three years be spent contractility in polyhydramnios and the effects of
in research. withdrawal of the excess of amniotic fluid. Am J Obstet
The type of practice for a maternal and fetal Gynecol 1957;73(6):1238-54.
2. Hon EH and Hess OW The clinical value of fetal
medicine subspecialtist has changed significantly electrocardiography. Am J Obstet Gynecol 1960;79:1012-
during the 30 years since the inception of the division. 38.
Initially the subspecialtist was primarily a consultant 3. The American board of Obstetrics and Gynecology: A
for pregnancy with complications. With development personalized history 1980-2000 Albert B. Gerbie
Published by the American Board of Obstetrics and
of sophisticated ultrasound and increasing Gynecology.
understanding of genetic abnormalities, a significant 4. Bulletin of the Division of Maternal-Fetal Medicine 1973
portion of the supspecialtist’s time is spent doing Published by the American board of Obstetrics and
Gynecology.
ultrasound.
5. Bulletin of the Division of Maternal-Fetal Medicine 1975
A reasonable question might be what is the result Published by the American Board of Obstetrics and
of the development of the subspecialty of maternal Gynecology.
and fetal medicine? The can be answered both 6. Bulletin of the Division of Maternal-Fetal Medicine 1977
Published by the American board of Obstetrics and
numerically and philosophically. Numerically there Gynecology.
are currently 62 approved programs in maternal and 7. Bulletin of the Division of Maternal-Fetal Medicine 1978
fetal medicine. There has been 1542 candidate Published by the American board of Obstetrics and
certified. Philosophically I believe it has resulted in Gynecology.
8. Bulletin of the Division of Maternal-Fetal Medicine 1979
significantly better care for the pregnant patient with Published by the American board of Obstetrics and
complications. This is difficult to prove because there Gynecology.
have been so many changes in practice during the 9. Bulletin of the Division of Maternal-Fetal Medicine 1986
Published by the American board of Obstetrics and
same time period such as development of neonatal
Gynecology.
intensive care units, antepartum fetal monitoring and 10. Bulletin of the Division of Maternal-Fetal Medicine 1998
the development of ultrasound. All of these and more Published by the American board of Obstetrics and
may have resulted in the significant decreases in Gynecology.
24 Textbook of Perinatal Medicine

4
A Prospective on
Perinatal Medicine

Ermelando V Cosmi

Introduction and because the uterus of the ewe does not at once
The process of fetal growth and development of the contracts has been used for various studies, including
human fetus at birth has always attracted the attention fetal breathing movements (FBMs) and lung maturity.
of scientists. Hippocrates, 460-370 b.c., suggested that The fetal Rhesus monkey has been studied mainly
when the onset of labor is near “the fetus becomes because its brain is more closely related to that of the
agitated and breaks the membranes”. Leonardo da human fetus and of the newborn at birth; furthermore,
Vinci said that “the child grows daily more within since the lamb’s brain is only 1.3% of body weight at
the body of its mother that when it is outside of the birth, whereas that of the fetal Rhesus monkey is 12%,
body, and this teaches us….”. In the seventeenth the latter is a better model for studying the
century Sir William Harvey suggested a direct role of distribution of cardiac output (C.O.).
the fetus in the initiation of parturition, a concept that Finally, the hemochorial placenta of the Rhesus
was endorsed by Van Deventer in the same century monkey and also of the pig is more suitable for the
and by Spielberg in 1882. study of placental transfer of gases, of others supplies
Subsequently many animal experimentations and and of drugs than the cotyledonary placenta of the
human observations have attempted to discover the ewe.
many mysteries of fetal and neonatal growth and The beginning of fetal physiology is rooted in the
development, the features of the cardiovascular and measurements of placental and fetal growth and in
respiratory systems, some relevant aspects of energy comparative studies of placental histology that were
metabolism, temperature control and their integration made long before physiologic data could be collected
by hormonal and nervous mechanisms, the role of the and properly understood. The pioneers to this
placenta, the initiation of labor, the transition from approach are many; they include: Sir Joseph Barcroft
intrauterine to the extrauterine life of the fetus, etc. (1946) and around 1960s, D. H. Barron, H. Prystowski,
Considering comparative physiology it has been C.A. Villee, P. Grunewald, R. Margaria (Turin, Italy),
recognised that general principles should hold in R.E. Cooke, E. Ramsey, I. Leitsch, F.C. Hytten, E.G.
every species with peculiar adaptation to particular Makowski, F.C. Battaglia, G. Meschia, and others.
needs. Because perinatal biology encompasses marked
Some species lend themselves well to a particular differences among mammals in placentation, fetal and
type of study, e.g. the fetal lamb, because it is relatively neonatal development, and in the adaptation made
large and comparable by weight to the human fetus by the mother during pregnancy and lactation, the
 A Prospective on Perinatal Medicine 25
young of different species are often said to be at Considerable efforts have been made to elucidate
different maturity at birth. Nevertheless, most the morphology and the physiology of the placenta
mammals and the human infants have one thing in because the homeostasis of the mammalian fetus
common, i.e., they all must have developed, by the depends almost entirely on its function and on
time they are born, the circulation and the lungs, maternal homeostasis. Chorioallantoic placentas
which will permit of maintaining an independent differ remarkably in shape and structure from one
existence outside the uterus. Initially, following acute mammal to another and their classification on the
experiments in animals, Barcroft believed that the basis of shape, morphometry, morphology, function,
fetus was living in utero under conditions of and presence or absence of a maternal (decidual)
anaerobiosis or semianaerobiosis thereby introducing component has resulted in considerable controversy.
the concept of “the Everest in utero”, i.e. the fetus In humans the implantation and subsequent
living under low oxygen tension. This concept was development of the placenta depend on certain
further supported by the low Po2, pH and high Pco2 changes in the endometrium that culminate in the
found at birth in umbilical arteries and vein of the formation of the decidua. Basically, the human
human fetus. Chronic experiments performed in placenta has a chorioallantoic structure in which the
several pregnant animals and their fetuses have precocious differentiated mesoderm of the allantois
denied this misconception and have shown instead forms the umbilical cord.
that the oxygen supply and consumption, and the acid Prof. P.M. Motta from the University “La
Sapienza” of Rome has contributed significantly with
– base status of the fetus are similar to that of the
electron microscopy to clarify the process of
mother. These results have been substantiated in the
implantation of the fertilised human ovum.
human fetus by James et al, Caldeyro - Barcia and
In humans shortly after fertilisation the ovum is
Saling. They have found that during labor and
implanted and the trophoblast erodes the endometrial
delivery fetal Po2 and pH decrease whereas Pco2 and
capillaries. At the end of the second week the
buffer base increase.
endometrial veins have been eroded and
The introduction of the micro - method of P. Astrup
communicate with lacunar spaces. At about the
of blood sampling and acid – base status analysis has
fifteenth day, endometrial spiral arterioles are eroded
permitted the confirmation of these studies in animals
and maternal inflow to the intervillous space is
and subsequent studies in the human fetus and
established. By the sixteenth day the entire surface of
neonate. Normally, although the Pao2 of the fetus is
the ovum is covered with branching villi containing
around 30 Torr., hemoglobin – O2 saturation is around vascular primordia. Between days 20 and 21 after the
90% also because of the double (maternal and fetal) beginning of nidation the chorionic villi show a well
Bohr effect on the O2 transfer across the placenta. defined ultrastructure with a relatively undifferen-
Another concept that was put forward was that, tiated Langhans’ layer and highly differentiated
although the fetus has a relatively high tolerance to syncytiotrophoblast layer, located peripherally. By
noxious agents, many noxious factors can effect its days 22 and 23 the embryonic vessels have formed
normal intrauterine development, physiologic an anastomotic network of channels within the villi.
performance, and subsequent adaptation to the By 12 weeks, other villi are found which fill the
extrauterine life. These factors may originate in the intervillous space. Each primary villus with his
mother, the placenta, or in the fetus itself. Other branching and rebranching villi constitutes a fetal
sources of trouble include environmental, nutritional, cotyledon, which is the functional unit of the placenta.
pharmacologic and toxicologic factors; hematologic, The villous core contains fetal capillaries, fibroblasts,
hormonal, metabolic, immunologic, genetic disorders, the Hofbauer cells (which are morphologically similar
and infections diseases (for a review see 12). to macrophages, originate from the mesemchyma,
26 Textbook of Perinatal Medicine

and possess pinocytotic and histiocytic activity), and Different types of fetal nucleated cells have been
other mesenchimal elements. found in maternal blood by Adinolfi and our group
One of the major advances in perinatal genetic providing the possibility for non invasive prenatal
diagnosis has been the introduction by Bruno diagnosis of genetic abnormalities; however, the
Brambati (Milan, Italy) of chorionic villi sampling results of these and further studies have been
which can be performed at 9-10 weeks’ gestation inconclusive. The same holds for the study of fetal
thereby offering earlier diagnosis than amniocentesis nucleated cells obtained by washing of the cervical
and the analysis of the amniotic fluid which is fornix.
performed between 14 and 18 weeks’ gestation, or Lo et al, Farina and Rizzo et al have studied the
cordocentesis which is performed around 20 weeks’ DNA of fetal cells in maternal circulation for
gestation for hematologic, infections, metabolic and nonmonogenic diseases such as abortion, pre-
enzymatic diseases. However, chorionic villi and eclampsia, IUGR. Although promising this approach
cordocentesis are coupled with significant higher needs further studies.
complications than amniocentesis. The basement The placenta, like the fetus and the mother,
membrane contains immunoglobins IgG and IgA, produces certain enzymes and hormones which
which probably represent maternal blocking influence not only its function but those of the other
antibodies to a trophoblastic antigens, thereby two compartments – e.g., composition of the nutrients
preventing the rejection of the placenta. Various supply from the maternal circulation to the fetus,
proteins are produced by the placenta in increasing maternal and fetal metabolism, and eventually fetal
amounts during gestation. Some, such as pregnancy growth. Conversely, placental function is influenced
– specific β1 – glycoprotein (SP1, PSβ1G), pregnancy by fetal and maternal enzymes and hormones. The
associated plasma protein – C (PAPP-C) and α 2 placenta possesses enzymes, which are absent in the
glycoprotein (PAPP α2G), are probably trophoblast – fetus, and enzymes lacking in the placenta are present
specific antigens described by Bohn. These are mainly in the fetus. The integrated placental and fetal
released into the maternal circulation, where they can functions act as a unit, and the feto - placental unit is
be measured and used as an index of placental indispensable for the production of most steroids
function whereas other proteins have enzymatic or hormones as suggested by E. Diczfalusy (see below).
hormonal activity. Recently, for prenatal genetic Several enzymes have been isolated and their
diagnosis the following tests have been introduced activity varies during gestation, i.e., lysosomal
using maternal blood: hydrolase activity reflects the need for specialised
1. double test - determination of PAPP – A and hCG functions (e.g., lysosomal hyaluronidase, which
– β (free) performed between 9 and 13 weeks’ probably plays an important role in the regulation of
gestation vis à vis fetal nuchal translucency; placental permeability, increases with gestation).
2. triple test - determination of hCG – β or hCG – β The human placenta synthesises and stores
(free), α – fetoprotein and free estriol between 14 carboydrates, lipids, proteins, nucleotides and nucleic
and 19 weeks; acids, possesses mixed function oxidation systems
3. quadruple test – as above plus determination of and aryl hydrocarbon hydrolase (AHH) involved in
PS – β at the same gestational age; pentatest – as the transportation of xenobiotics and epoxides. It is
above plus inhibin. rich in 11β – ol – dehydrogenase which converts active
The reliability of these tests is much less than that steroids into inactive 11 – ketosteroids. Therefore, the
of amniocentesis and fetal cell culture. However, they question has been posed as to whether certain
may be indicative of certain fetal chromosomal corticosteroids, e.g., betamethasone, administered to
abnormalities. the mother reach the fetus in sufficient quantities to
 A Prospective on Perinatal Medicine 27
elicit their biological effect – i.e., acceleration of fetal corroborated for the human in studies of the human
lung maturity. The placenta also contains monoamine- fetus itself.
oxidase and catechol–O–methyltransferase which A variable portion of the blood returning from the
significantly effect the transfer of the catecholamines. fetal placenta via the umbilical vein is distributed to
Renin is also produced by the placenta. This enzyme both right and left lobes of the liver and reaches the
is released into the amniotic fluid. The placenta is interior vena cava via the hepatic veins. The
unique in its capacity to form proteins and steroid remainder of the blood returning from the placenta
hormones, i.e., hCG, hPL, hPRL, hCT (human is shunted directly to the inferior vena cava via the
chorionic thyrotropin) somatomedins C and A and ductus venosus in amounts varying between 20 and
ACTH – related peptides, i.e., hCG, α- melanocyte – 90 per cent of umbilical–portal blood flow. In the left
stimulating hormone (MSH), TSH and LH-releasing atrium, blood from the inferior vena cava mixes with
factors, β - lipotropin, and β- endorphin, as blood coming from the pulmonary veins in a ratio of
demonstrated by A. R. Genazzani et al. about 4.5:1. Thus the abdominal organs, the lower
The placenta produces large amounts of body, and the placenta are supplied with blood of a
progestogens and estrogens in increasing lower Po2 than the coronary circulation, heart, neck,
concentrations during pregnancy. These hormones and brain.
have important effects, such as the regulation of fetal The right and the left ventricles work in parallel
growth, development, and sexual differentiation; by virtue of the presence of the foramen ovale and
uterine growth and contractility; the onset of labor; the ductus arteriosus. Approximately 40 per cent of
and uteroplacental blood flow. Estrogen production the combined cardiac output (C.O.) returns to the
is not due solely to the placenta but to the interaction placenta, while only 7 per cent flows through the
between mother placenta and fetus, which act as a unit. lungs; the remainder perfuses body tissues. To define
The production of E 3 involves the formation of fetal C.O., Assali et al. introduced the term “effective
precursors by fetal and maternal adrenals; 16α – C.O.”-i.e., the total volume of the blood that is
hydroxylation of DHAS and E 1 or E1 sulphate by the distributed to the body and the placenta. This
fetal and the maternal livers; and aromatisation by represents the sum of the left ventricular output and
the placenta. The concentration of E3 in body fluids the ductus arteriosus blood flow, and does not include
increases steadily throughout a normal pregnancy. coronary blood flow and the flow to the lungs.
Concerning the fetal circulation in the mature Rudolph had introduced the term “combined
placenta, it is worth mentioning that in the definitive ventricular output” which represents the total volume
(tertiary) villi, arterioles and veins are given off from of blood ejected by both ventricles and includes
axially oriented trunks to supply and drain an pulmonary and coronary flows.
extensive anastomosing capillary network which lies It has been suggested that changes in differential
superficially beneath the surface syncytium. Fetal C.O. that may occur in the fetus as a result of changes
blood is in close contact with maternal blood being in the venous return or outflow impedance are
separated by thin syncytiocapillary membrane. adjusted homeometrically by the Frank-Starling
Information on the fetal circulation has been derived relationship. Rudolph (from the Cardio– Vascular
principally from animal experiments, using a variety Institute of San Francisco, directed by Julius Comroe),
of methods, i.e., cineangiocardiography, blood gas has criticised this theory and indicated that the Frank-
analyses, blood flow measurements by electro- Starling mechanism is essentially inoperative in the
magnetic flow meters, distribution of radioisotope- fetal myocardium because of the large shunts between
labelled microspheres, dye dilution, radioisotopes the left and the right sides of the heart, and because
methods, and Doppler ultrasound. Some of the of the fact that the two ventricles work in parallel.
findings from these experiments have been Thus, in contrast to the adult, the fetus has only a
28 Textbook of Perinatal Medicine

limited ability to increase C.O. by increasing stroke defense mechanism is similar to that of diving
volume. The increase in C.O. is accomplished mammals – e.g., the ability of the fetus of the seal and
primarily by increasing the heart rate (HR). of other mammals to survive its’ mother prolonged
The cardiovascular system of the fetus is under dives also called, less precisely, brain sparing effect.
the direct control of the autonomic nervous system However, it is limited, for although C.O. remains
through peripheral chemoreceptors and baro- virtually constant, the blood redistributed to vital
receptors. In the human fetus the clearest evidence organs may be diverted away from the placenta,
for autonomic activity is the transient bradycardia thereby further reducing the oxygen supply to the
associated with uterine contraction and abolished by fetus. A fall in C.O. will cause a marked reduction in
administration of atropine to the mother as shown by umbilical blood flow. The survival time of the
Caldeyro Barcia at al. The fetal cardiovascular system asphyxiated fetus depends on the concentration of
is capable of responding to various humoral and glycogen in the myocardium before the asphyxial
pharmacological agents. episodes.
Moderate fetal hypoxemia and/or hypercapnia
cause a rise in arterial pressure, vasoconstriction in Fetal Heart Rate and ECG
the lungs, and little change in umbilical vascular FHR and ECG monitoring are the oldest and most
resistance. At the same time, umbilical, coronary, frequently used methods of fetal surveillance. The
carotid, and superior sagittal sinus blood flows ultrasound technique, based on Doppler principle,* is
increase, ensuring a better oxygen uptake and supply the method most widely used for recording FHR.
to vital organs. FHR increases initially in response to Concern still exists as to its relative value, accuracy
hypoxemia, but if hypoxemia persists and/or of interpretation, and prognostic significance.
becomes more pronounced, bradycardia develops. Caldeyro – Barcia et al combined the recording of
Fetal hypoxemia of a marked degree and/or uterine contractility with FHR monitoring.
acidemia also induces an increase in blood flow to Subsequently, Hon applied a similar method and
vital organs (i.e., heart, brain, and adrenal glands), obtained analogous results.
but causes a decrease in blood flow to non-vital organs Direct fetal ECG was obtained by placing a bipolar
(i.e., lungs, gut, spleen, kidneys and the carcass). The electrode directly on the fetus either transcervically
selective vasoconstriction in the latter organs is or by maternal transabdominal puncture. With this
accompanied by hypertension and bradycardia and method one detects changes in ECG pattern and FHR
later, if it persists, by anaerobic glycolysis and that may coincide with early alterations in fetal
metabolic acidemia. Although hypertension tends to homeostasis and neonatal morbidity. The technique
increase perfusion pressure and umbilical blood flow, has been refined by the use of special nonpolarisable
with marked hypoxia and bradycardia umbilical clips, suction, hooks or other types of transcervical
blood flow will fall. electrodes, monitoring devices and group averaging
The cardiovascular response of the fetus to of a series of consecutive ECG complexes. In Italy fetal
hypoxia and acidosis with redistribution of the ECG has been studied extensively by Pardi et al.
systemic circulation is a defense mechanism for Opinions pertaining to alterations in fetal ECG and
conserving the oxygen supply to vital organs and for their reliability and accuracy in predicting fetal
adjusting to the effects of accumulated metabolites, distress vary considerably. Prolongation of the P-R
such as carbon dioxide and hydrogen ions. This and Q-T intervals, widening of the QRS complex, and

∗This principle was theorised in 1794 by the Italian biologist Lazzaro Spallanzani, i.e., the bat’s ability to “see”. The bat gets
bearing by sound rather than light.
 A Prospective on Perinatal Medicine 29
isoelectric or inverted T waves have been observed and Reiffersheid, and in animals from 1781 until 1941.
in conjunction with fetal hypoxia and acidosis. These reports have been almost universally ignored
Shortening of the Q-T and P-R intervals with peaked, or discounted as artefacts, and subsequent studies
biphasic, and inverted P-waves; and inversion of the have in general denied that FBMs are normally
T-wave have been also recorded in the presence of present in utero, provided the fetus is not disturbed
severe fetal asphyxia. Forms of “arrhythmias” have by physical stimuli or asphyxia. They have been
been observed – i.e., nodal extrasystoles, atrial flutter, rediscovered around 1970 in the fetal lamb by Dawes
atrial and ventricular premature beats in the form of et al, Condorelli, Cosmi and Scarpelli. Studies in
persistent bigeminy, paroxysmal atrial tachycardia, human fetuses have demonstrated the FBMs are
and heart block. However, in both the human and the normal phenomena of intrauterine development.
animal fetuses, no definite relationship was found Observation of both animal and human fetuses have
between ECG abnormalities and the acid-base status indicated that FBMs might provide an index of fetal
of the fetus. Although ECG abnormalities could well – being. In the human fetus, FBMs have been
represent a possible early sign of fetal distress, their studied by injecting isotopes into amniotic fluid, by
significance in relation to fetal homeostasis and means of force transducers placed on the maternal
neonatal outcome has not been settled. abdomen, and, more precisely, by ultrasound. Various
Doppler ultrasound has been recently introduced systems have been used to quantify ultrasonic signals
in the study of fetal circulation and several vessels of FBMs, including A – mode, continuous Doppler
including umbilical artery (UA), descending aorta systems, T – mode, time – distance recording systems
(DA), internal carotid artery (ICA), middle cerebral and real – time B – scan.
artery (MCA) and renal artery (RA) have been Recently we have measured nasal flow velocity
investigated. Preliminary statistical correlations waveforms (NFVW) with continuous or power
between perinatal complications and abnormalities Doppler, vis à vis the thoracic and abdominal
in indices of flow resistance have been reported, movements in more than 1800 human fetuses and
suggesting a potential role for Doppler ultrasound in have observed that during gestation the fetal
the management of high-risk pregnancies. Several respiratory patterns are similar to those we had
indices have been introduced to analyse flow velocity observed in preterm and term newborns, i.e., they
waveform including Pulsability Index (PI) and start at around 20 weeks’ gestation as abdominal
Resistance Index (RI) by several groups including movements followed by thoracic movements and
Arduini and Rizzo, Campbell, Kurjak et al, and NFVW as gestational age advances. We have
Chervenak. It has been found that absent or reversed correlated FBMs during gestation with fetal lung
diastolic blood flow of umbilical artery and low PI in maturity (FLM) and have found that the full
MCA are often associated with alteration of FHR. development of FBMs indicates FLM.
However, no reference values on large population
Amniotic fluid indices: Amniocentesis and the analysis
studies are available for flow velocity waveforms.
of amniotic fluid (AF) have been introduced
Transcutaneous Po 2 and pulse oximetry and
successfully by Bevis, Liley and Freda for the
computerised FHR have also been introduced to
spectrophotometric analysis of AF at wavelength
improve the accuracy of the latter with variable
between 300 and 700 nm in case of Rh–
results.
alloimmunisation and erythroblastosis fetalis. When
Fetal breathing activity in utero has been a matter of AF contains bile pigments which absorb
controversy for a long time. Rhythmic, periodic FBMs monochromatic light at the wavelength between 525
were observed and/or recorded in humans between and 375 nm there is an elevation above the expected
1888 and 1911, by Ahlfeld, Weber, Ferroni of Florence slope of the curve, with a peak around 400 nm. The
30 Textbook of Perinatal Medicine

magnitude of this departure from the expected curve been introduced including lamellar bodies count and
(between 525 and 375 nm) is proportional to the Doppler ultrasound. These tests have good predictive
concentration of bilirubin and related pigments, while values, high specificity and sensitivity.
its width is constant and reflects the condition of the We have demonstrated that fetal urine contributes
fetus Liley’s method offers a more precise to AF PLs, although in much less concentrations than
quantification of AF bilirubin concentration, but the fetal pulmonary PLs.
upper limits of normality are too low, leading to an The pulmonary surfactants play a critical role in
overestimation of the degree of fetal compromise. the survival of the fetus in the extrauterine life,
Freda’s method takes into consideration the trend especially in case of premature delivery and other
rather than the absolute concentration of bilirubin and forms of high-risk pregnancy because a prompt and
related pigments. During the same year Freda effective ventilation is required at birth. In turn, this
introduced Rh gammaglobulins for the prevention of depends on the alveolar stability (alveolar resistance
Rh alloimmunisation since then the disease has to collapse) and thus on lung maturity. When fetal
practically disappeared. lung maturity is not fully reached, delivery almost
Amniocentesis has been widely used for culturing invariably results in NRDS. This disease is responsible
and karyotyping of AF cells by C. Valenti, Steele and for a major portion of perinatal mortality and
Breg. Recently diagnosis of many genetic diseases has morbidity (including neurologic and intellectual
been performed particularly after the completion of defects).
the study of genome mapping and the introduction In recent years our understanding of perinatal
of FISH (fluorescence in situ hybridisation) and PCR lung development and of the pathophysiology of
(polymerase chain reaction) techniques. It is possible neonatal lung adaptation has increased considerably
to diagnose fetal sex and a variety of genetic disorders as result of intensive studies by various investigators.
including Down’s syndrome, Duchenne/Beker Much experimental work has focused on the
muscular dystrophy, deafness, cystic fibrosis, fragile functional significance of the surfactant system of the
X-syndrome, hemoglobinopathies e.g., hemophilia, lung during transition from fetal to neonatal life, on
inborn errors of metabolism. Amniocentesis is its role in the pathogenesis of NRDS, and on various
performed between 14 and 18 weeks’ gestation. methods that can facilitate the adaptation of the
premature infant to extrauterine life.
Fetal lung maturity: In recent years various laboratory In 1903 Hochheim first described the formation of
tests for AF constituents to predict FLM have been hyaline membrane in the lungs of two infants dying
developed. They can be divided into biochemical from respiratory insufficiency in the neonatal period.
(determination of surfactant phospholipids) and Because of this finding, the term generally used to
biophysical methods (e.g., surface tension, describe this disorder until 1959 was “hyaline
microviscosity). Gluck et al were the first to membrane disease” (HMD). Subsequently, it was
demonstrate that the lecithin – sphiengomyelin ratio realised that early pathologic hallmarks of HMD are
(L/S) of AF provides an index of FLM. This ratio can atelectasis and intra-alveolar edema (in part perhaps
be used to predict whether or not neonatal respiratory representing unresorbed fetal pulmonary fluid (FPF)),
distress syndrome (NRDS) will develop in the infant whereas hyaline membranes, which develop at a later
if born within 24 to 48 hours of amniocentesis. The stage of the disease, may be absent in infants dying
same group measured other AF phospholipids (PLs) within a few hours of birth. The membranes are made
i.e., phosphatidylinositol (PI), and phosphatidyl- up of degenerated epithelial cells, blood cells, fibrin,
glycerol (PG) and introduced the lung profile. and components of the alveolar lining layer.
Clements et al. in 1972 introduced a simple and rapid NRDS begins shortly after birth. The classical
screening method: the shake test. Various tests have picture of tachypnea, expiratory grunting, sternal and
 A Prospective on Perinatal Medicine 31
intercostals inspiratory reactions, inability to maintain surface tension, antiedema” theory to Pattle. The
adequate oxygenation in room air, cyanosis, the implication of this is that surface tension is of primary
diffuse hypolucency, and the air bronchogram at chest importance in maintaining alveolar stability in the
X-ray all indicate alveolar instability, i.e., decreased newborn infant as compared to older individuals,
functional residual capacity (FRC). Expiratory since the former have less rigid chest walls, and
grunting represents an attempt by the newborn infant therefore the opposing force to alveolar collapse is
to overcome alveolar collapse. In fact, by prolonging low. Many diverse theories have been proposed to
the expiration and increasing the pressure within the define the ethiology and pathogenesis of NRDS, most
alveoli, the neonate obtains a better diffusion of of which emphasize the prominent role of surfactant
oxygen across the air-blood barrier. It is noteworthy deficiency, secondary to prematurity. Liggins showed
that the method of therapy with mechanical in the 1960s that ablation of the anterior pituitary
ventilation of the lung under positive end-expiratory gland of the lamb fetus resulted in prolongation of
pressure (PEEP) is based on this premise. In fact, pregnancy, whereas subsequent administration of
Gregory noted that when cyanotic babies cried they adrenocorticotropic hormone or corticosteroids
turned pink as a result of Valsalva’s manoeuvre (66). initiated labor. In the latter case, the preterm newborn
The clinical picture of NRDS may be mimicked by seldom had serious lung problems such as RDS. This
“transient tachypnea”, or the so called NRDS type II, indicates both to Liggins and to M. E. Avery that
due to slow resorption of FPF. However, this latter administration of glucocorticoids to the mother might
symptomatology usually disappears in less than 24 accelerate fetal lung maturity. Liggins also
hours, whereas that of NRDS lasts at least 24 hours. demonstrated a primary role for progesterone in the
The pathophysiology of NRDS was poorly maintenance of pregnancy in the sheep model, an
understood until the discovery of pulmonary observation that led to the estrogen/progesterone
surfactants. In 1959 Avery and Mead were the first to ratio hypothesis developed by Csapo. Controlled
demonstrate the deficiency of surfactants in saline clinical trials have been performed with IM injection
extracts of lungs from infants who had died of NRDS. of 1, 2, 3 doses of betamethasone (12 mg each, 24 hours
Several subsequent reports have confirmed that lungs apart), dexamethasone (12 mg a day) or
of newborn infants with NRDS have a high surface hydrocortisone (a single dose of 100 mg) to the mother.
tension and therefore tend to collapse. This finding is The results have been in general promising with few
in agreement with the abnormal characteristics side effects. To avoid these it has been suggested by
observed in pressure-volume curves from lungs of NIH consensus conferences and the European Study
infants with NRDS: high opening pressure required Against Immature Lung (EURAIL) that one course
to inflate the alveoli, more important poor ability to of betamethasone should be used avoiding a second
maintain a residual volume of air once all distending course of one week apart. Other drugs have been used
pressure is removed, and small hysteresis between both in animals and humans to accelerate FLM with
inflation and deflation curves. less promising results than glucocorticoids. Cosmi et
Under normal conditions, the surface tension on al. have injected supplementary surfactant (SS)
expiration is extremely low because surfactants are obtained from pig lungs into the amniotic liquid close
present in the alveolar air – liquid interface. King and to the nostrils of the human fetus after the
Clements have suggested that the alveolar stability administration of aminophylline to the mother to
is determined by low surface compressibility. induce FBMs, thereby favouring the entrance of SS
Colacicco and Scarpelli, in their in vitro studies on into the fetal trachea and upper airways, in cases of
surface properties of pulmonary dipalmitoyl lecithin severe fetal distress and/or preterm labor, and have
(DPL), have indicated that surface tension is virtually obtained good results. These findings have been
zero and have thus substantiated the original “zero confirmed in human by a Chinese group and in
32 Textbook of Perinatal Medicine

animal experiments. It should be noted that after the with cocaine and other drugs, smoking and alcohol
pioneering study of Fujiwara in 1980 has been used being particularly offensive.
successfully for the treatment of rescue babies, i.e., Stress generically and related biologically active
with NRDS and recently for early (prophilactic) substances such as oxytocin, antidiuretic hormone,
treatment of NRDS (for review see 80). catecholamines, and certain placental hormones also
Other important discoveries have been made in involved in the perception of pain, have been
perinatal medicine i.e., that prostaglandins have a recognised as labor-inducers. Indeed, humans and
definite role in parturition followed the observations animals under stressful conditions tend to initiate
that there is a surge of certain prostaglandins in labor. The best example is given by the siege of
maternal plasma and urine during parturition, that Leningrad during World War 2, when half of the
the administration of drugs such as aspirin and pregnant women either aborted or delivered preterm
indomethacin suppresses uterine activity, and that overnight.
administration of prostaglandin precursors (either Notable advances are being made by researchers
exogenous, e.g., arachidonic acid, or endogenus, e.g., and public health officials to ameliorate the socials
PLs from fetal urine into the amniotic fluid ) is capable economic challenges and to find new therapeutic
of inducing labor. It is now universally recognised that approaches, e.g., in the areas of pain relief, inhibition
certain prostaglandins are clinically effective for of preterm labor and fetal therapy, including surgical
induction of labor. approaches. The pioneering transabdominal
A link between infection and preterm delivery was
intrauterine recording method induced five decades
proposed by Romero et al. in 1988. the paradigm of
ago by Alvarez and Caldeyro-Barcia has led to useful
infection-driven preterm labor has led to a better
observations on the pharmacology of the human
understanding of the cytokines produced by the
uterus and on the effects of uterine contractions upon
placenta and the fetal membranes and by deciduas.
the fetus. Many utero-inhibitory drugs have been
It triggered the discovery of new uterotonins such as
introduced and tested with different results. A major
interleukin (IL)-1β, IL6, tumors necrosis factor,
advance of pain relief during labor and delivery has
endothelin-1 and transforming growth factor β-1, and
been the introduction of regional (epidural and spinal)
of certain uterine relaxants, such as relaxin,
blocks with the i.v. prophylactic hydradation of the
prostaglandin, thromboxane and, more recently, nitric
mother combined with 1,000 NS or 500 dextrane
oxide (NO). Cytokines and eicosanoids appear to
solution 1 hour before the block to avoid hypotension
interact on each other’s production in a cascade.
At this point the complexities of the labor-delivery from sympathetic blockade.
issue are abundantly clear as fetal-placental-maternal Many formidable challenges remain. For example,
parameters search for a unifying mantle (placental the mode of delivery, vaginal vs. Caesarean section,
insufficiency, fetal distress and endorphins?) or new is a matter of continuous debate; the biophysical
biologically active substances (peptides such as approach to fetal monitoring during labor is moving
corticotrophin-releasing hormone, placental activin into the era of computers and maybe of
and oxytocin?). nanotechnology; the invasive technique of fetal scalp
The unique stresses, both positive and negative, blood sampling and acid-base status determination
that Homo Sapiens brings to the “evolutionary” picture have been replaced by pulse oximetry and other
are also quite considerable. For example, preterm techniques. Ultrasound and Doppler technology,
labor is now linked to social, economic and including three-dimensional imaging, have entered
environmental factors, including low economical the labor world. New methods of pain relief are
status, poor working conditions, environmental sought and used with increased frequency. New
pollution, maternal malnutrition and substance abuse technologies are being introduced at such a pace that
 A Prospective on Perinatal Medicine 33
soon they will be extended to the home environment, It seems that we are now in a period of
where the use of telemedicine can be applied, not only development of that art which may be characterised
for monitoring uterine activity, blood pressure and as the period of assimilation into academic medicine
maternal glycemia, but also the neonatal and medical practice. To one degree or another each
cardiorespiratory system for the diagnosis and one of us has known the aura of anxiety in which
treatment of apnea of prematurity and S.I.D.S. Perinatal Medicine is cast. To whom it belongs?
Assisted reproduction techniques also pose a Obviously, it belongs to the perinatologist. But then,
particularly intriguing challenge to the perinatology who is the perinatologist? Of course he is each one of
team, i.e., the obstetrician, biologist, neonatologist, us. He is the obstetrician, the fetologist, the
anesthesiologist, midwife and nurse, because of the neonatologist, the pediatrician, the anesthesiologist,
increased incidence of complications during the basic scientist… he is in fact the amalgamation of
pregnancy, labor and delivery. Amongst the chances all and in this amalgamation he looses the primordial
brought by the new technologies that address the fetus title as he practices and becomes the perinatologist.
and its mother directly, are the questions of propriety At some centres he is so-designated, and his discipline
and ethics, which are among those covered in many – Perinatal Medicine – is so-recognised. But at too
Symposia, Workshops, Congresses and Books of many other centres he continues to strive to dispel
Perinatal Medicine. the anxiety and to complete the assimilation. There is
It is noteworthy that in 1984 I have founded in no question that the fall of departmental barriers will
Erice (Sicily, Italy) a permanent School of Perinatal result in even greater achievements in this new era of
Medicine, which is very active. Furthermore, around perinatal care. Eleanor Roosevelt once said that we
the same year, I founded the Italian Society of are indeed one world and should strive to live our
Perinatal Medicine which is composed of the above lives that way. Similarly, Perinatal Medicine is a
specialists. unified body of knowledge, a science in its own right.
 SECTION 2
Neonatology
M Levene, MRG Carrapato
 5
Transition at Birth

Ola Didrik Saugstad

INTRODUCTION transport functions of different organs mature in late

fetal and early neonatal life.
The transition from fetal to postnatal life is
After birth the newly born infant is responsible
characterised by a number of dramatic changes in
for its own oxygenation and ventilation. The partially
physiological, biochemical, immunological, and
inhibited status of the fetus is immediately reversed
hormonal functions. The fetus is fully dependent on
at birth. It is awake, aroused, breathing and crying.
the maternal supply not only of oxygen and nutrients
Metabolism increases with a subsequent increased
but also of a number of hormones and other
oxygen demand, and the newborn can initiate
important substances. The thermal control of the fetus
lipolysis and mobilize glucose. The higher oxygen
is also taken care of by the mother. Intestinal and
consumption of the brain is one reason the newborn
breathing movements as well as non-shivering
brain is more vulnerable to hypoxia than in fetal life.
thermo genesis are partially inhibited. Large organs
The sharp increase in oxygen exposure makes it
as the lungs and liver are not very active. The fetus
necessary for the newborn infant to protect itself
is also asleep most of the time. These are some
from oxygen toxicity.Transition to birth is therefore
important reasons the oxygen requirements and
not only a matter of redistribution of the circulation,
metabolism are low in fetal life. Cardiac output is
maturation of the lungs and the surfactant system
low with a low systemic blood pressure. A relatively with alveolar gas exchange, it is much more complex
low blood glucose level and oxygen supply is and probably only a small part of this is understood.
therefore sufficient to ensure substrate for energy In the following some of these aspects will be
metabolism at this stage. discussed.
During the last trimester the fetus prepares itself
to meet the extra uterine milieu; energy stores are GROWTH
established, minerals and trace elements are
General Principles
deposited, both white and brown fat accumulate, the
lungs mature both structurally and biochemically. The greatest growth rate in human life occurs in the
The latter means that the surfactant system matures fetal period. The increase from a fertilized egg to a
and the antioxidative defence develops in order for term newborn infant is in weight 6 × 1012, in length
the fetus to breathe and to be able to withstand the 5000 fold, and in surface area 61 × 106. After birth
sudden increased oxidative stress induced by the high growth slows down still the greatest postnatal
oxygen concentration in ambient air. Many epithelial growth rate occurs immediately after birth.
38 Textbook of Perinatal Medicine

Prenatal growth is dependent on maternal, found in the umbilical cord with a gradual decrease
placental and fetal factors. In the first trimester over the next 3 months. Androgens decrease leptin
growth occurs by increase in cell number, in the values so that girls have higher concentrations than
second trimester there is an increase both in number boys from birth, the significance of this seem not to
and in cellular size. In the third trimester growth is be understood.
mainly by cellular growth since the rate of mitosis The changes in body composition the fetus
slows down. During the first two trimesters the fetus undergo with the advancement of gestation is a
has reached approximately 1/3 of its term weight. progressive decrease in total water, extra-cellular
In this period only 50 grams fat are accumulated by water, sodium and chloride and an increase in intra-
contrast to approximately 500 grams deposited the cellular water, potassium, calcium and magnesium.
last trimester. Of the approximately 95 kcal/kg/day The post-natal body composition changes are
needed by the fetus 40 kcal are spent for growth. characterised by increase in adipose tissue with a
Prenatal growth is dependent on autocrine and peak around 4-6 months, a progressive decrease in
paracrine growth factors as insulin like factors 1 and body water with a relative increase of intra-cellular
2; however insulin as well plays a major role in water. 1-6
prenatal growth. Macrosomia is a well known effect
of fetal hyper insulinism and these children have Fluid Shift
increased body fat at one year of age. Abnormal In early fetal life approximately 95% of the fetus is
patterns in insulin like growth factor 2 gene water which gradually decreases throughout
expression may lead to the Bechwith Wiedemann gestation being 80% at 8 months and 75% at term.
syndrome. These infants are large with elevated Mode of delivery does not seem to influence this.
insulin levels. Simultaneously with this decline in body water there
Postnatal growth is mainly regulated through is a drastic decrease in extra-cellular and a gradual
pituitary growth hormones, thyroid hormone and increase in intra-cellular water. This tendency
other hormones. In fetal life growth hormone (GH) continues until 9 months of age when body water
is high in the fetus; however the number of GH constitutes 62%. However, the total body water
receptors is low. That GH plays some role in fetal related to surface area does not change very much
growth is reflected in poor growth of children with in this period. Maximal intra-cellular water of 43%
GH deficiency or GH receptor deficiency (Laron of body weight is reached at 2 months of age at the
syndrome) and its action is mediated by insulin like same time extra-cellular water is 30%. The term
growth factors. During the first weeks of extra- newborn loses 5-10% of its body weight and the
uterine life GH falls and already the first day of life preterm more. This is mainly due to loss of water;
a pulsatile release of GH has been detected with a however, it is not clear whether this loss is
pulse periodicity of 73 minutes, with higher peaks predominantly from the extra or intra-cellular space
and more frequent pulses found in SGA than in AGA or perhaps both.
infants. This pulsatility is controlled by the stimu- In the newborn the first days of life the blood
latory GH-releasing hormone and the inhibitory volume is to a large extent dependent on placental
somatostatin both of these produced in the transfusion at time of delivery which can be up to 25
hypothalamus. Thyroid hormone is a major factor in to 50 mL/kg within 3 minutes. Whether or not this
postnatal growth and an acute elevation with a peak increase in blood volume of 50% is harmful is not
in TSH is found immediately after birth with a decline clear. A delayed cord clamping may lead to a gradual
the first 5-6 days after birth. Leptin is produced in increase in hematocrit within a couple of hours. This
adipose tissue and also regulates growth. Its role in is caused by plasma loss of 30mL/kg the following
fetal life is unknown, but high concentrations are 4 hours due to a shift of fluid from the plasma into
 Transition at Birth 39
the interstitial space in addition to an increased labour and delivery seems to blunt this decrease.
urinary output.7,8 With the initiation of feeding it increases and after
Recently it has become clear that specific water 24 hours is between 45 and 90 mg/dL.
channels Aquaporines play an important role in water Glucose can be metabolised to either lactate which
transport and water balance. Aquaporine 1 and 4 occurs in anaerobic conditions or acetyl-CoA (Ac-
has been found in the brain, 9 in the skin, 2 in the CoA) under aerobic conditions. Pyruvate can be
kidney etc. The newborn kidneys reduced ability to metabolised to either lactate or Ac-CoA, this is partly
concentrate the urine is probably due to lack of regulated by the relative amounts of the isoenzymes
aquaporines. Aquaporines are active also in the of lactate dehydrogenase (LDH). In adult brain the
perinatal period and probably are important for LDH isoenzyme composition favours aerobic
removing fluid from the lung and in so-called oxidation of glucose but in the fetal and newborn
transitoric tachypne of the newborn. brain the LDH composition allows anaerobic
glycolysis. The placenta is impermeable to both
Carbohydrates insulin and glucagon which are produced by the fetus
Glucose is the major source of energy in fetal life at least from the 10th week of gestation. Glucose
and the fetus is entirely dependent on glucose stimulates insulin in the third trimester only.
delivery from the mother. It seems that the human In late gestation approximately 50% of the glucose
fetus does not produce glucose until the end of the is converted to glycogen in the liver and muscle, and
gestation, and the brain requires a continuous glucose to fat in the liver and adipose tissue. Glucose storage
supply that is received from the mother - at term at is regulated primarily by insulin but also by
a rate of 4-7 mg/kg/min. This equals 6-10 g glucose/ glucocorticoids. Glycogen is low until approximately
kg/day and represents approximately 60% of the 36 weeks of gestation, however triples in the liver
calories needed by the fetus. Glucose is transported until term when it reaches a maximum both in the
by facilitated carrier-mediated placental diffusion. liver and skeletal muscles. In other organs as
Several facilitated glucose transporters have been myocardium and lungs the peak is reached somewhat
identified and recently cloned. They comprise a earlier declining toward term. Glycogen is the initial
family of structurally related families and are substrate for glucose but only for a few hours. Within
designated GLUT. The primary function of these is 24 hours after birth the glycogen stores are more or
to mediate the exchange of glucose between blood less exhausted. Gluconeogenesis from fat and protein
and the cytoplasm of the cell. Several of these GLUT is therefore necessary to meet the metabolic
are present in early fetal life. demands and this is in principle a post-natal event.
Blood glucose is lower in the fetus compared with Fat is therefore an important substrate for glucose
the mother but there is a significant correlation production in the early newborn period. Although
between maternal and fetal levels at least if the key enzymes for gluconeogenesis are present in the
maternal levels are not too low (< 4.4 mmol/L) under liver from early fetal life gluconeogenetic activity is
which fetal concentrations are independent of not expressed in utero at least not until near term.
maternal levels. At birth, the transplacental supply In late gestation fetal gluconeogenesis therefore
of nutrients is abruptly interrupted. The newborn occurs and may contribute to fetal glucose levels
infant therefore has to produce glucose from its own especially if the glucose supply from the mother is
endogenous stores until feeding is started. At birth reduced for instance during maternal fasting or by
blood glucose is 60-75% of maternal levels and then intrauterine growth retardation. Initiation of lipolysis
falls over the next 1-2 hours stabilising at 2.5-3.3 and gluconeogenesis is promoted by hormonal and
mmol/L (45-60 mg/dL) in healthy term infants within enzymatic changes occurring the first day of life. The
24 hours. Maternal glucose supplementation during insulin/glucagon ratio is rapidly decreasing after
40 Textbook of Perinatal Medicine

birth and the high postnatal concentrations of which are non-essential in postnatal life are essential
catecholamines, cortisone, and TSH contribute to this. in fetal life due to inadequate maturation of enzyme
In the newborn infant glycerol can be converted to systems. One example of this is the absence of
glucose contributing up to 20% of the hepatic glucose cysthionase making the fetus completely dependent
production. It has been shown that preterm infants on the mothers cystine supply. During the first hours
less than 28 weeks gestation have the capability of postnatally there is a rapid fall in plasma amino acid
gluconeogenesis from glycerol.9-13 levels.14,15

Proteins Lipids
In the second and third trimester protein synthesis The fetus requires both essential and non-essential
is especially high, however with a reduced rate fatty acids from the mother and fat represents 1/6
towards term. The term newborn infant has about of body weight at term.
0.5 kg of protein after a many-fold linear increase in Free fatty acid supply to the fetus may occur
the last half of the gestation. Protein synthesis slows through a process of facilitated membrane
down toward term but is still high, approximately 5 translocation involving a plasma membrane protein,
fold higher compared with adult levels. In fact, not placental synthesis and release into the umbilical
only synthesis is high in fetal life, but breakdown of circulation, or lipolysis of triglycerides, lipoproteins
proteins is also increased giving a high protein or phospholipids from either the maternal or fetal
turnover in the fetus. There is a substantial organ side. The free fatty acid concentration and
difference with the highest rate of protein synthesis composition in the fetus reflect maternal values. It is
in the placenta, heart and liver (half life 1 day) well known that maternal manipulation with diet
compared with half life of one week in muscle. A may change the growth and development of the
number of growth factors may be responsible for fetus. For instance, mothers fed a diet high in
this as the Insulin-like growth factor (IGF-1). For this Docosahexaenoic acid (DHA) deliver babies with
reason the amino acid concentration in fetal plasma higher birth weight. These children seem to mature
is higher than later in life and the fetal/maternal earlier and have a higher IQ at the age of 4.
amino acid ratio in plasma is high with a peak in the Triglycerides are hydrolysed to fatty acids by
second trimester when it is approximately 3:1 falling lipoprotein lipases which are secreted by capillary
to 1.5:1 towards term. Intrauterine growth endothelium. Lipoprotein lipase is stimulated by
retardation is characterised by a falling fetal/maternal insulin and is present in fetal life with low activities
plasma amino acid ratio mainly due to an augmen- in muscle and heart but higher in the lungs. This may
tation in the maternal levels. be of importance for surfactant synthesis and
Amino acids are transported across the placenta maturation. After birth the activity of this enzyme
both by a direct active transfer of essential amino increases both in preterm and term infants. However,
acids and placental cytosolic synthesis of non- in preterm infants the clearance of circulating
essential amino acids. A number of amino acid triglycerides is reduced due to a lower enzyme
transporters – at least 12- have recently been activity than in the term infants and this activity
identified. The rate of amino acid utilisation is about seems to be directly related to the degree of
4 g/kg/day similar to the estimated intake of very prematurity. In the human fetus, the enzymes for
premature infants. A protein intake in the postnatal cholesterol and liopoprotein metabolism develop
period of 2.8 g/kg/day is close to the minimal intake early in gestation. As LDL receptor expression also
needed to ensure weight gain and nitrogen retention increases in gestation serum cholesterol and LDL
equal to intrauterine rates and a protein intake of decrease to levels lower than observed in early
3-4.3 g/kg/day is recommended. Some amino acids postnatal life. In breast fed infants these metabolites
 Transition at Birth 41
increase rapidly and are doubled from day 1 to day there is a subsequent gradual increase reaching serum
7 of life but still only half of adult levels. calcium of about 2.5 mmol/L at one week of age. In
In the last 8 weeks of gestation subcutaneous fat one study serum ionized calcium concentrations
increases rapidly from approximately 20 to 350 decreased from in mean 1.45 mmol/L at birth to 1.33
grams, and deep body fat from 10 to 80 grams. The mmol/L at 2 hours and 1.23 mmol/L at 24 hours of
total fat content increases from 6 gram at 22 weeks age.
to 500 g at term. At birth parathyroid hormone is low increasing
Fatty acid catabolism is an important energy 2-4 fold during the first 2 days of life giving an
source in postnatal life. High concentrations of free efficient response after 3-4 days. By contrast,
fatty acids and glycerol soon after birth indicate the calcitonin levels are high in the newborn thereby
onset of lipolysis and lipid oxidation. Free fatty acids inhibiting calcium mobilization from bone.
and glycerol increase sharply and peak around 120 Magnesium, zink, and phosphorous are also
minutes after birth. Beta-oxidation of fatty acids transported actively across the placenta from the
occurs in the mitochondria. Ac-CoA is transesterified mother to the fetus. During the first week of life
to carnitine by carnitine acyltransferase located on magnesium levels show small variations, correlating
the inner mitochondrial membrane. Fatty acid directly with serum calcium and inversely with
oxidation is limited in the fetal myocardium because phosphorous. Adequate Zink levels are needed for
of a low concentration of carnitine and a limited normal fetal growth and postnatally the requirements
number of mitochondria. Liver, brain, placenta and are approximately 2mg/day. Zink deficiency in
lung also have limited capacity to oxidize fatty acids. infancy may lead to failure to thrive, and reduced
After birth, however, fatty acid oxidation increases immunological function. Globally zink deficiency
substantially and remains high until the time of represents a major health problem in infancy.20-23
weaning.
Lipogenesis is found in fetal tissue from 12 weeks HORMONES
gestation and is stimulated by insulin and inhibited The endocrine system is involved in growth,
by glucagon or cAMP. Fatty acid synthesis declines reproduction, cellular nutrition, as well as energy,
after birth when the diet is milk which is rich in fat. thermal, cardiovascular and fluid homeostasis. Many
Placental transfer of ketone body by contrast to hormones do not cross the placenta but are found in
glycerol has been described. The fetus uses the fetus around 10-12 weeks of gestation. This is
ketone bodies as substrates for oxidation and lipo- true for growth hormone, insulin, prolactin, and
genesis.10,16-19 thyroxin.
Prolactin may play an important role in regulating
MINERAL METABOLISM
fluid balance in fetal life. At term its levels are 20
The placenta actively transports calcium to the fetus fold higher than adult levels and decline rapidly in
to allow rapid fetal skeletal mineralization. From 20- the first weeks after birth. This reduction may be
26 weeks of gestation fetal levels are maintained linked to the decline in total body water after birth.
about 0.25 mmol/L (1mg/dL) above the maternal Prolactin may also have a maturational effect on the
level. The last trimester calcium stores quadruples. pulmonary surfactant system in combination with
In humans 2/3 of the mean 30 g calcium in healthy glucocorticoids and thyroidea hormones. Thyro-
term fetus is transported the last trimester. At birth tropin releasing factor regulates TSH and prolactin
the constant calcium supply is interrupted and there secretion. As early as 12 weeks of gestation it is clear
is a normal fall in serum calcium in the first hours that the fetus produces thyroxin and around 13 weeks
after birth reaching a stable level after 24-48 hours of gestation TSH producing cells have been
of age of about 2-2.25 mmol/L. During the next days identified. TSH both stimulates growth as well as
42 Textbook of Perinatal Medicine

contributes to differentiation of the thyroid gland. around birth mature the surfactant system by
TSH does not cross the placenta and T3 and T4 do inducing its synthesis, as well as antioxyenzymes in
not cross in sufficient quantity for the fetus. The fetus the lung and further play a role in the labour process.
is therefore dependent on its own pituitary and Corticosteroids also induce the expression of
thyroid hormones in addition to supply from the phenylethanolamine-N-methyl-transferase which
mother. By contrast, thyrotropin releasing factor converts norepinephrine to epinephrine. The
crosses the placenta and stimulates fetal TSH. Fetal transition at birth is characterised by high levels of
total and free T4 as well as thyroxin binding globulin catecholamines, angiotensin and vasopressin. The
values increase during the gestation and reach the catecholamine levels are higher than in any other
level of the mean adult values around 36 weeks. In period of life under physiological circumstances.
umbilical cord blood TSH is low and increases rapidly Norepinephrine constitutes approximately 85% of
within the first 10-15 minutes after birth, and T4 total catecholamines and in plasma is normally
reaches a peak after 48 hours as a response to the increased 20 fold or more during the first stage of
high TSH concentration. TSH remains high the first labor. Also in the newborn infant the catecholamine
days of life before it reaches its low normal adult levels are very high continuing to rise immediately
levels. The half time of T4 is much shorter in the after birth then decreasing to the prelabour levels
neonatal period compared with adult life making the during the first 24 hours or so. This is vital for the
thyroxin requirements many times higher than in the successful postnatal adaptation.
adult period.
The newly born infant is normally awake and alert.
From the 8th week of gestation the fetal adrenal
In these few hours, before it falls asleep, it is
converts prenenolone to dehydroepiandrosterone
supersensitive to sensory stimulation. This arousal
sulfate which in the fetal liver and other tissues is
might be caused by the catecholamine surge at birth.
hydroxylated to 16-hydroxy-dehydroepiandro-
An activation of catecholamines in the brain especially
sterone which passes to the placenta and forms
in the locus ceruleus in the brainstem finds place,
estriol. Since estrogen is important in maintaining
pregnancy the fetus therefore contributes to this and the turnover of norepinephrine increases several
itself. fold before birth. The high concentration of
The fetal adrenal cortex promotes fetal organ catecholamines also increases myocardial con-
enzyme maturation and in the last part of the tractility, increases peripheral vascular resistance,
gestation ACTH and cortisol levels increase in the promotes surfactant secretion, reduces production
fetus influencing maturation of enzyme systems in and increases absorption of lung water, mobilises
the lung, gastrointestinal tract and possibly other glucose and free fatty acids as energy substrates, and
organs. After birth cortisol levels decrease reaching initiates non-shivering thermogenesis. The increase
adult levels by the age of 2-3 months.2,22,24-27 in circulating catecholamines at birth therefore
probably is vital for cardiovascular adaptation at
STRESS AT BIRTH birth. Rhythmic lung inflation also increases plasma
There is a dramatic activation of the adrenal, the catecholamine levels as does cooling and umbilical
sympathetic, and the parasympathetic systems cord clamping.
towards term. The sympathoadrenal system Sympathetic nervous activity especially of the
develops in fetal life and the newborn infant has large baroreceptors and chemo receptors increases during
adrenals and extrachromaffin tissue in the gestation and the influence of the parasympathetic
paraganglia. The adrenal cortex matures towards system on the resting heart rate increases with
term and releases substantial amounts of epinephrine maturation. In fetal life sympathetic tone is high and
and norepinephrine near term. Corticosteroids is important in maintaining fetal arterial blood
 Transition at Birth 43
pressure. The basal sympathetic tone fluctuates in itself seems to stimulate respiration and may
the normal state and this is more important in fetal contribute to this establishment.
than in newborn life to generate blood pressure It is clear that respiratory control in the postnatal
variability and is related to change in behavioural period is multi-factorial. Important are airway
state of the fetus. At birth the activity increases mechanoreflexes, thermoregulation, chemoreflexes
further for instance in renal sympathetic nerves 3-4 and behavioral states. The influence of the behavioral
fold, this is however observed only in full term and states on newborn breathing patterns is important
not preterm animals. This effect is also blunted by especially since the newborn spends so much time
antenatal dexamethasone.28,29 asleep. During wakefulness and REM sleep breathing
is irregular, in quiet sleep breathing is slower and
DEVELOPMENT OF BREATHING more regular.
Immediately after birth thermal inputs play a
In the fetus spontaneous and rhythmic activity of
major role in regulating the respiration. A cool
the diaphragm and respiratory muscles occur already
environment stimulates breathing and it has been
from weeks 10-11 of gestation. The fetal breathing
suggested that the increased metabolic drive this
is, by contrast to postnatal breathing, not continuous
initiates in order to keep the infant in the thermo-
and with advancing gestational age fetal breathing
neutral zone stimulates breathing. After a few weeks
movements become more sporadic and occur only
the thermo-neutral zone widens and this mechanism
during electrophysiological activity comparable to
seems to be less influential. Instead vagal stimuli
rapid eye movement (REM) states. From about 30 become more important and stretch receptors in the
weeks of gestation the breathing seems to be more airways and lung parenchyma and chest wall
strongly influenced by the behavioral state and a determine both breathing depth and frequency. Lung
powerful central inhibitory mechanism is functioning inflation inhibits respiration, this phenomenon is
during non-REM activity. Near term the human fetus known as the Hering - Breuer reflex and is more
performs breathing movements approximately 25- active in the newborn than in the adult and more
30% of the time. By contrast to the adult in whom active in the term than in the preterm infant. Further,
hypoxemia stimulates breathing, in the fetus it causes it is more active during quiet sleep than in active
a rapid depression independently of the physiological sleep (REM sleep). The importance of mechano-
state this is also regulated centrally possibly via some sensory receptors in the airways in regulating the
metabolites such as adenosine. respiration plays only a minor role immediately after
The first breath occurs normally at 10-30 seconds birth and increases in the first weeks after birth.
of life but is delayed in birth asphyxia and also in The chemo receptors in the carotid body respond
those given pure oxygen compared with room air. both to pCO 2 and pO2. In fetal life the set point for
Immediately after birth breathing is irregular and pO2 is much lower than in postnatal life which means
deep but within minutes a regular breathing rhythm they are silenced immediately after birth. The
is established, and such a continuous breathing sensitivity of the chemo receptors both in the carotid
rhythm is activated by a number of stimulants. body and in the aorta then slowly shifts toward adult
Separation of the placenta in itself stimulates levels during the next few days. In fetal life the
respiration perhaps by decrease of inhibitory chemo receptors are increasing their activity when
substances such as adenosine and PGE2 which are paO2 decreases below 2.7-3.3 kPa (20-25 mmHg).
produced there. Since the concentration of for After birth resetting of the chemo receptors increases
instance PGI2 decreases relatively slowly after birth their activity if paO2 decreases below 12-13.3 kPa (90-
other factors must be responsible for the rapid 100 mmHg). The mechanism for this resetting is not
initiation of respiration. Oxygenation of the lungs fully understood and it has been suggested that the
44 Textbook of Perinatal Medicine

level of catecholamines such as dopamine in the Inflation

carotid body may play a role. Four to seven weeks
In fetal life the lungs are fluid filled and a normal
postnatally chemo regulation is established as the
fluid volume is a major determinant of normal lung
most important regulator of the respiration.
growth. Lung liquid is actively secreted by epithelial
Hypercapnia affects the fetal breathing
cells but the formation and volume decrease towards
movements in REM-like sleep only, however, much
term. At birth an abrupt stop is needed. It seems
more weakly than after birth when resistance to
that labour itself more than mechanical squeezing of
hypercapnic respiratory stimulation disappears
lung fluid clears the lung of its liquid. The secretary
during quiet sleep state. Sensitivity to CO2 increases
process in fetal life is abruptly switched to allow
with increasing gestational age and is therefore less
absorption from the lung lumen into the fetal
developed in the preterm than in the term infant.
circulation. Two hours after birth the lung liquid
Hypoxia in the term newborn infant results in
normally is cleared. Epinephrine but not
hyperventilation for some minutes followed by
norepinephrine, seems to be important to induce Na+
normalisation or reduced ventilation due to a fall in
transport out of the lumen. Epithelial sodium
respiratory frequency. This second phase of
(Natrium) channels (ENaC) are important regulators
ventilatory depression is more marked in the
of lung liquid clearance and parallels the rise of
preterm infant who often will not go through the
cortisol in late gestation of guinea pigs. Recently the
initial hyperventilation when exposed to hypoxia and
role of water channels, so-called Aquaporines, for
thus has a response to hypoxia similar to the
clearing lung water after birth has been focused (see
fetus.30-33
section 2.2). Transitory tachypnea of the newborn is
by many considered as a condition in which an
PERINATAL TRANSITION OF THE LUNGS
inadequate lung liquid clearance is found due to a
The lung development goes through several stages: low stress at birth (exemplified by C-section). At birth
the embryonic (3-7 weeks post conception), the infant must inflate its lungs to provide a large
Pseudoglandular (5-17 weeks), Canalicular (16-26 enough area for gas exchange in the course of a few
weeks), saccular (24-38 weeks), alveolar (36 weeks minutes. The first respiratory effort must be large
to 2 years postnatally). A detailed description of enough to overcome the great resistance caused by
these is found in several text books. Suffice here to the surface tension of the lung liquid. Pulmonary
mention that in the canalicular stage the appearance surfactant lowers the surface tension and therefore
of vascular canals multiply to form the alveolar- facilitates the expansion of the lung. In the absence
capillary respiratory membrane which is the air-blood of surfactant a positive end expiratory pressure of
barrier and the future gas exchange surface. The about 28 cm H2O to avoid lung collapse and maintain
epithelium is thinner and gas exchange may find place an adequate functional residual capacity is necessary.
at the end of this stage. The saccular stage is Inflation of the lung of a normal infant at birth is
characterised by dilatation of terminal respiratory probably nearly accomplished with the first cry if it
units into alveolar saccules and ducts with a reduction is vigorous. Karlberg and co-workers recorded the
in the interstitial tissue. The alveolar stage is first breath in a series of 11 normal term infants to
characterised by formation of secondary alveolar occur at the age of 6 to 93 seconds. Opening of alveoli
septa that partition the terminal ducts and saccules occurs serially, each unit going to full inflation before
into mature alveoli. The alveolar septa are becoming the next one opens. Lung inflation is extremely rapid
thinner during this stage which also increases the and after only one third of a second the lungs look
surface area of the lungs significantly. Most alveoli, inflated as assessed by chest X-ray. Pleural pressures
80%, are formed after birth.31,34 vary from 10-70 cmH2O sub atmospheric during the
 Transition at Birth 45
first breath. Others have registered opening pressures kPa (28 mm Hg) and quickly rises to 6.7-8 kPa (50-
around 30 Cm H2O. This large pressure is applied 60 mm Hg) within the first 20-60 minutes after birth
for only 0.5-1 second and during the first expiration and then gradually increases toward adult levels over
there is a high positive pleural pressure of 20-30 Cm the next days, depending on how quickly the foramen
H2O. The pressure difference from inspiration to ovale and the ductus arteriosus close.39
breathing. The tidal volumes of the first breaths in
term infants were found by Karlberg and co-workers Surfactant
to vary between 12-67 mL. Pulmonary surfactant is synthesised, stored, secreted,
Functional residual capacity increases quickly from and cleared in the type II cells in the alveoli. There
about 17 mL/kg at 10 minutes of age to 25-35 mL/ are almost twice as many type II cells than the flat
kg at 30 minutes, the same as 4 days of age. Lung type I cells but they cover only 5-10 % of the alveolar
compliance increases gradually during the first week surface. In addition to surfactant, they synthesise and
of life and by one to two days of life the compliance secrete many other bioactive components such as
is 4-5 fold greater than it was during the first few coagulation factors, cytokines, growth factors, and
breaths. Simultaneously resistance to airflow is lysozyme and lysosomal enzymes. Active synthesis
decreased by one half to one fourth of the first of surfactant begins in the second trimester and
registered values. around 35-36 weeks adult pool size is obtained. At
Following the initial inflation of the lung, the intra term only a fraction of normal amount of surfactant
alveolar lung fluid moves into the interstitium and is present in the alveoli. With lung inflation at birth
is partially absorbed by the capillaries. Cold, light, a dramatic secretion of surfactant occurs and a normal
noise, increased force of gravity and falling pO2 and pool of surfactant is established in the alveoli after
pH all contribute to the initial gasping and a few hours.
subsequent breathing. The intra- thoracic pressure Maturation of surfactant is delayed by 1-2 weeks
an infant can generate is also dependent on the in males compared with females and is not only
dependent on the amount of surfactant produced but
stability of the chest wall and the strength of the
also on the surfactant composition. It has been shown
respiratory muscles. Following aeration of the lungs
in several mammalian species that considerable
the pulmonary vascular resistance decreases and
changes take place in the composition of surfactant
pulmonary blood flow increases, left atrial pressure
as maturation of the fetus occurs. One of these is the
increases and the foramen ovale closes (see section
increase of phosphatidyl choline and dipalmitoyl
9).35-38
phosphatidyl choline with a concomitant decrease in
phosphatidyl ethanolamine. This is reflected by an
Gas Exchange
increasing lecithin/sphingomyelin ratio in amniotic
pH in the umbilical vein blood is in mean 7.33 in fluid during the maturation process. The percentage
normal term infants and in arterial umbilical blood of disaturated lecithin increases and reaches about
reaches a minimum of about 7.20-7.25 a few minutes 50% around 34 weeks of gestation. The acidic
after birth and then is normally between 7.33 and phospholipids of surfactant follow a different pattern.
7.36 at 20 minutes of age. In some investigations pH At around 34-35 weeks phosphatidyl glycerol
already at one hour reaches 7.40-7.42. PCO 2 in becomes present and increases, simultaneously
umbilical vein cord blood has a mean of 5.7 kPa (43 phosphatidyl inositol peaks before it decreases
mm Hg) and paCO2 peaks around 8-9.3 kPa (60-70 towards term.40
mm Hg) immediately after birth and then quickly
normalises to around 5.3 kPa (40 mm Hg) or even a Surfactant Proteins
little lower than this by 20-60 minutes after birth. Experiments with several animal species have shown
PaO2 in umbilical vein cord blood has a mean of 3.7 that the production of surfactant proteins in the fetal
46 Textbook of Perinatal Medicine

lung increases toward term. In humans mRNA for pulmonary vasculature. The fetal circulation is
surfactant proteins A, B and C were detected as early characterised by a low systemic and a high pulmonary
as 13 weeks of gestation and by 24 weeks their levels vascular resistance, the opposite situation of postnatal
were 50% and 15% of adult levels of mRNA for life. The fetal circulation is designed to provide a
surfactant protein B and C respectively. In contrast, large blood flow to the placenta and supply less to
mRNA for Surfactant protein A is very low before the lungs since the fetal lung has no gas exchange
24 weeks of gestation. In rat lung Surfactant protein until birth. Due to the large surface of the placenta
A increases substantially during the last 3-4 days of the fetal circulation has a low resistance, and the
gestation, reaching a peak at the first day of life. In blood pressure therefore needs not to be high. The
adult lungs its level doubles compared with the fetal circulation is further characterised by the
neonatal level. In humans Surfactant protein A presence of three shunts which facilitate venous
normally appears in amniotic fluid around 30-32 return from the placenta. These are the ductus
weeks of gestation and increases with surfactant venosus and the two right to left shunts reducing
lipids towards term. Surfactant protein B increases blood flow through the lungs (foramen ovale and
more gradually during gestation and continues to ductus arteriosus). Through the foramen ovale (the
do so the first days after birth with a slight decrease opening between the right and left atrium), and the
in the adult Glucocorticoids seem to increase the ductus arteriosus (the connection between the
production of surfactant proteins A, B, C, and D. pulmonary trunk and the aorta), blood is bypassed
The hydrophilic surfactant proteins A and D are away from lung tissue into the systemic circulation.
important for host defence and the hydrophobic The three shunts mentioned above therefore
proteins B and C for stabilization and rapid contribute to a separation between blood rich in
adsorption and spreading of the surfactant film. oxygen and nutrients supplied from the placenta via
Surfactant protein B deficiency is a rare autosomal the umbilical vein; this blood supplies the brain and
recessive disorder leading to lethal respiratory myocardium.
distress even in term infants. Recently mutations in During fetal life, blood is oxygenated in the
the transport of Surfactant protein B from the placenta and returns to the fetal body via the
lamellar bodies in type 2 cells to the surface have umbilical vein, which joins the portal vein in the
been detected giving a similar clinical picture as
hepatic sinus. About 40% of the combined ventricular
Surfactant protein B deficiency. Surfactant protein C
output goes through the placenta. This volume of
deficiency is an autosomal recessive disease and
blood, approximately 200 mL/kg fetal weight per
clinically not as dramatic as Surfactant protein B
minute, can be distributed through the ductus
deficiency but may lead to interstitial inflammation
venosus directly into the inferior cava vein bypassing
and pulmonary fibrosis.41-43
the hepatic micro- circulation, or it can pass via the
portal veins through the hepatic circulation and then
TRANSITION OF THE CIRCULATION
enter the inferior caval vein through the hepatic veins.
Vascular Changes In the fetal sheep about 70% of the venous return is
In fetal life the pulmonary and systemic vascular derived from the lower portion of the body, and
systems are coupled in parallel by contrast to the 20% from the superior vena cava. Of the remaining
postnatal period when the blood circulation is 10% approximately 7% comes from the pulmonary
coupled in series through the right side of the heart circulation - a fraction increasing toward term - and
to the lungs and then through the left side of the 3% from the myocardium. About 55% of the umbilical
heart to the systemic circulation to return to the right venous return passes through the ductus venosus and
side of the heart through the systemic and the the rest mainly through to the right lobe of the liver.
 Transition at Birth 47
The fetal liver is a highly compliant organ able to vein stream passing through the tricuspid valve
regulate the distribution of umbilical blood flow giving a pO2 in the right ventricle of 2.4 -2.5 kPa (18-
during fetal stress. Umbilical blood flow does not 19 mm Hg). The pO2 of the blood entering the left
change significantly from normal values when fetal ventricle and the ascending aorta is about 3.1 -3.3
hypoxemia is induced by maternal hypoxia, however, kPa (23-25 mm Hg), slightly less than in the proximal
the intra-hepatic circulation is redistributed so that part of inferior caval vein due to mixing with blood
flow through the ductus venosus is increased. This from the pulmonary veins in the left atrium. The
increased flow is distributed to favor the brain, descending aortic blood which is a mixture of blood
myocardium and placenta in order to secure more passing through the ductus arteriosus and the aortic
oxygenated blood to these vital organs during isthmus has a pO2 of 2.7-2.9 kPa (20-22 mm Hg).
hypoxemia. After traversal through the ductus Postnatally there is essentially no mixing of blood
venosus and entry into the inferior caval vein oxygenated in the lungs and systemic venous blood.
oxygenated blood from the placenta does not mix Fetal pulmonary vascular resistance falls with
with deoxygenated blood from the lower body. This advancing gestational age primarily due to the great
blood when entering the inferior caval vein streams increase in the number of pulmonary vessels,
in parallel with blood from the lower body. When expanding the total cross sectional area of the vascular
entering the right atrium the blood from placenta bed. Pulmonary blood flow and pulmonary artery
and the blood from the lower body are split by Crista pressure increase substantially in the fetal sheep from
Dividens and blood originating from the ductus mid-gestation towards term.44-49
venosus preferentially crosses the foramen ovale into
the left side of the heart and therefore the Establishment of the Post Natal Lung
myocardium and the head are supplied with oxygen The most dramatic changes in the circulation occur
enriched blood. Blood from the lower body and right at birth when gas exchange through the lungs is
liver lobe preferentially passes through the tricuspid established. Immediately after birth the umbilical
valve into the right ventricle together with blood placental blood flow is stopped and the pulmonary
from the superior vena cava. Thus blood with lower circulation is established adequately. Neither in the
oxygen content is pumped out of the right ventricle placenta nor the umbilical cord vessels adrenergic
and reaches the lower parts of the body. or cholinergic nerve fibers is detected. So the
Doppler studies in humans have demonstrated regulation of cord flow is probably mainly due to
that the ductus venosus is a narrow vessel projecting vasoactive factors. Within a minute after birth
a high- velocity jet posteriorly to reach the foramen umbilical blood flow is less than 1/5 of the fetal level.
ovale. The high peak velocity in the ductus venosus Simultaneously a significant decrease in umbilical
may give the blood sufficient momentum to reach artery and vein diameters are observed within
the foramen ovale without extensive mixing with another minute. The mechanisms behind this are not
deoxygenated and nutrient poor blood. Blood fully understood but both cooling, increased oxygen
streaming therefore not only occurs in parallel, but tension and stretching of the cord may play a role.
also side by side at different velocities when entering Locally produced mediators such as serotonin are
the right atrium. powerful constrictors of umbilical vessels. The
Umbilical venous blood has a pO2 of 4-4.7 kPa umbilical vessels also constrict by mechanical
(30-35 mm Hg). After mixing with portal venous and stimulation, particularly stretching, and the
inferior caval blood the pO2 is about 3.5 -3.7 kPa (26- constriction is upheld by the immediate increase in
28 mm Hg). Venous blood returning from the systemic oxygen tension. Simultaneously, venous
superior cava vein has a pO2 of 1.6 -1.9 kPa (12-14 return through the inferior cava vein is reduced by
mm Hg) and this combines with the inferior caval removal of the placental circulation. Cessation of
48 Textbook of Perinatal Medicine

venous return reduces flow through the ductus found in neonatal hypertrophic pyloric stenosis.
venosus and this vessel therefore closes passively Arachidonic acid metabolites are involved in the
within 3-7 days after birth. physiological regulation of the perinatal circulation.
After birth ventilation of the lungs with air results PGI2 is a strong pulmonary vasodilatator. Mechanical
in a four to ten fold increase in pulmonary blood stimulation of the lungs leads to PGI2 production and
flow which is associated with a relatively rapid fall ventilation of the fetal lung itself increases concen-
in pulmonary vascular resistance. These effects are tration of PGI2 in pulmonary venous blood. The
mediated both by mechanical lung changes, lowering release of this metabolite is also stimulated by
of pCO2 and increase in pO2, each factor accounting histamine, bradykinin, reactive oxygen species, and
for the pulmonary vasodilator effects seen after birth. adenosine triphosphate (ATP), as well as angiotensin
In addition to the structural adaptation of the II which is high immediately after birth.
pulmonary circulation after birth there are a number Bradykinin is a potent vasoconstrictor in the
of vasoactive substances participating in the umbilicoplacental circulation but otherwise is usually
regulation of the pulmonary vascular tone in the a vasodilatator. Bradykinin is released in fetal lungs
perinatal period. The pulmonary vascular endo- during ventilation with air or during hyperbaric
thelium is central in the regulation of vascular tone. oxygenation. It is therefore possible that bradykinin
By stimulation the endothelial cells may release could play a role in postnatal pulmonary circulatory
vasoactive substances into the circulation, or release changes. Endothelium dependent vasoconstriction
lung tissue enzymes involved in the activation or can also be stimulated by substances and factors such
inactivation of vasoactive mediators. as acetylcholine, thrombin, serotonin, physical forces,
In recent years endothelium derived relaxing and hypoxia. There are also endothelium derived
factors such as nitric oxide (NO) have been identified vascular constricting factors such as metabolites of
and together with PGI2 may be responsible for the
arachidonic acid (Thromboxane A2 and PGH2) as well
rapid decrease in pulmonary vascular resistance that
as endothelin and free radicals. In animal studies it
occurs at the onset of normal ventilation after birth.
has been shown that reactive oxygen species (ROS)
In fetal circulation there is an increased production
are able to potently constrict the pulmonary
of nitric oxide compared with adult levels is found.
vasculature and to dilate the ductus arteriosus. It
This nitric oxide contributes to the low vascular
has been shown both in the lungs and in the isolated
resistance and increased flow for instance in the
ductus arteriosus that ROS stimulate the production
gastrointestinal tract. Increased fetal oxygen tension
of prostaglandins. In the lungs there seems to be a
increases release of NO. The increase in pulmonary
balance between dilating and constricting
blood flow in response to the high oxygen
prostaglandins. The constrictor Tromboxane A 2
concentration at birth as well as distention of the
(TXA2 ) is elevated first followed by the dilator PGI2
lung seems to be mediated , at least partly by NO.
when the pulmonary circulation is exposed to free
This system seems to be especially potent near term,
the reaction of the preterm is diminished. oxygen radical generating systems. These substances
Endogenous NO production, is augmented due to therefore can have both constrictory and dilatory
induction of especially endothelial nitric oxide effects on the pulmonary circulation dependent on
synthase(e NOS). In the baboon both inducible and the balance between TXA 2 and PGI2. Superoxide
endothelial NOS activities increase during gestation radicals for instance can act by inactivating NO and
falling towards term. However the total NOS activity also by activation of endothelial cyclooxygenase
seems to be preserved. Both hypoxemia and products. In addition, endothelin and angiotensin II
diaphragmatic hernia decrease NOS expression. A have a prolonged effect on tone and structure of
lack of neuronal nitric oxide synthetase has been blood vessels.
 Transition at Birth 49
Remodelling of the pulmonary vasculature occurs the ductal wall. The functional closure of the ductus
immediately after birth contributing to the decrease therefore is promoted by increase in oxygen tension
in pulmonary vascular resistance. In the precapillary and a p450 hemoprotein located in the smooth muscle
arteries the endothelial cells shortly after birth plasma membrane is a receptor of the oxygen induced
become slimmer, the surface/volume ratio increases events. Further, a decrease in blood pressure within
so the vessel wall becomes thinner, and the lumen the ductus itself, a decrease in circulating PGE2 (due
diameter increases. Further, small unopened muscular to loss of placental Prostaglandin synthesis and
arteries are recruited to the pulmonary circulation increase in prostaglandin removal by the lungs), and
during the first days after birth. Thus a structural finally a decrease in PGE2 receptors in the ductus
adaptation to extra uterine life consists of changes in wall also contribute to constriction of the ductus. In
cell shape and position. The structural remodelling full-term infants closure of the ductus arteriosus
during the first two weeks of life in the pig lungs occurs in two phases with a functional closure within
contributes to the reduction in mean pulmonary the first hours after birth due to smooth muscle
artery pressure from 55 to14 mm Hg. constriction, and the anatomic closure due to closure
The baroreflex setting of heart rate mediated by of the lumen due to thickening of the intima and loss
baroreceptor fibers in the carotic body and aortic of smooth muscle cells. This is caused by progressive
arch is active in both fetal and newborn life however thickening of the intima so it eventually occludes the
with different sensitivity and shifts towards higher constricted lumen. Smooth muscles migrate from
pressures during development.46,50,51 media into the intima layer. Vascular endothelial
growth factor (VEGF) plays an important role in this
Ductus Arteriosus
intimal “cushion”.52-54
The open ductus arteriosus in fetal life diverts blood
away from the lungs towards the descending aorta. Myocardium
The patent ductus is regulated both by dilating and At the end of gestation right and left ventricular
contracting factors. Prostaglandins play an important systolic pressures are equal, 65-70 mm Hg. The
role in maintaining the patency and the ductus is
cardiac output of the right ventricle is, however, in
especially sensitive to the dilating action of PGE2.
fetal life 50% higher than the left ventricle mainly
Oxygen is a potent constrictor of the ductus and
due to the fact that the left ventricle has a high
becomes more effective the more mature the fetus
afterload caused by the high vascular resistance of
is. This is due to the fact that in early fetal life the
the head, neck, and forelimbs, while the right
ductus has decreased muscular development causing
ventricles afterload is lower because of the low
less contractile ability. In fetal lambs the ductus
umbilical-placental resistance. The removal of the low
arteriosus is also more sensitive to the dilating effect
resistance placental circulation results in an increase
of PGE2 in the preterm than near term. This is due
to a developmental alteration in sensitivity of the in systemic vascular resistance. The combined
vessels to prostaglandins. It is circulating PGE2, ventricular output in the fetal lamb is about 500 mL/
probably produced in the placenta, which probably kg/min, however, after birth there is an increase in
controls the ductus arteriosus in utero. After birth total cardiac output and during the first days each
when the oxygen tension increases the ductal wall is ventricle ejects approximately 350 mL/kg/min.
itself capable to produce PGE 2. Reactive oxygen During the next weeks in the newborn lamb there is
metabolites (ROS) may stimulate PGE2 synthesis in a rapid decrease in cardiac output to a level of about
the isolated ductal wall from fetal lambs. In the 150 mL/kg/min and then it falls slowly to the adult
ductus arteriosus ROS can therefore contribute to level of 70-80 mL/kg/min. Cardiac output changes
dilatation by turning on prostaglandin synthesis in parallels changes in oxygen consumption.
50 Textbook of Perinatal Medicine

O2 consumption is almost identical in the adult increase in heart rate gives a fall in end diastolic
and fetal hearts, however, the fuel used by them are volume and stroke volume unless ventricular diastolic
different since the adult heart uses fatty acids and filling is maintained. The rearrangement of the
the fetal heart is an obligatory user of carbohydrates circulation after birth leads to an increased end
as substrate for oxidative phosphorylation. In the diastolic left ventricular volume which leads to an
fetal lamb 60% of these carbohydrates are lactate, 35 increased stroke volume. The days after birth a
% glucose and 5% pyruvate. This can explain why a gradual decrease in cardiac output/kg is observed
fall in circulating glucose concentrations result in returning to the fetal levels.
myocardial depression in fetal and neonatal life but Fetuses at mid gestation have individualized heart
not later in life. In fact, it has been shown that fatty rates that are stable. The control of heart rate
acids are detrimental to fetal cardiac function. In variability seems to develop later and fetal heart rate
order to use fatty acids as fuel they must be variability is predictive of neonatal heart rate
transformed to Ac-CoA which is transesterified with variability not until 30 weeks. With increasing
carnitine and in this form transported across the gestation there is a reduced fetal heart rate variability
mitochondrial membrane by the transport enzyme and this demonstrates development of the autonomic
carnitine- palmitoyl transferase (CPT). CPT is nerve system during the gestation. Heart rate at birth
inhibited by malonyl-CoA which is high in fetal life. is around 160-180 beats per min and decreases to
Malonyl- CoA is regulated by glucagon and during 120 beats per min in sleeping newborn infants and
the delivery glucagon concentration increases sharply to 140-160 beats per min in awake newborn infants.
thereby reducing the concentration of malonyl-CoA The postnatal situation compared with the fetal is
and releasing CPT inhibition allowing fatty acid characterised by decrease in heart rate, post-
oxidation to proceed. extrasystolic potentiation increases, and inotropic
The contractile properties of the myocyte also responses to catecholamine elevation suggesting that
differ in fetal and adult life. Only about 30% of fetal the post natal heart has a greater potential reserves
cardiac muscle consists of contractile elements than in fetal life.45,46,49
compared with approximately 60% in the adult. The
velocity of shortening of the myocyte is also lower SHIFT IN OXYGEN TRANSPORT
in fetal life. Especially preterm infants and to some The newborn infant has a higher oxygen demand
degree also the term infants have therefore a much than the fetus and the oxygen consumption typically
reduced ability to tolerate an increase in afterload. is increased between 2 and 3 fold the first days of
The change from fetal to adult performance seems, life. O2 consumption per kg body weight is higher in
however, to occur quickly after birth. the newborn than in the adult and the fetus. In adult
At birth, cardiac output increases considerably life it is about half that in the immediate newborn
and left ventricular level is doubled compared with period, however, when compared with body surface
fetal levels. This higher left ventricular inotropy and area this age difference seems to disappear. The
performance is due to sympathethico-adrenal delivery of oxygen to the tissues depends on 1) the
stimulation after birth and triiodothyronine seems oxygen content of the blood, 2) the cardiac output,
to be important in maturation of the fetal myocardial 3) the distribution of the circulation and, 4) the
response. After birth myocardial contractility is affinity of oxygen to hemoglobin. In fetal blood there
greatly increased but because of the high demands is a high affinity to oxygen. The postnatal decrease
on the circulation to provide the increased oxygen in hemoglobin O2 affinity is caused by an increase in
requirements for metabolism, there is also little adult hemoglobin at the expense of fetal hemoglobin,
reserve available, and thus volume loading results and an increase from birth in the concentration of
in only a small rise in cardiac output. In a fetus an 2,3-diphosphoglycerate (DPG). During gestation
 Transition at Birth 51
until 34 weeks, fetal hemoglobin comprises about 90% schematically be divided into three parts. In step 1
of the total hemoglobin falling to 80% at term and glucose, amino acids and fatty acids are broken down
from birth to 8 months of age there is a gradual to acetyl coenzyme A (Ac-CoA). In the second step
decline in fetal hemoglobin to less than 2%. Fetal Ac-CoA enters the tricarboxylic acid (Krebs) cycle,
red cells have a higher oxygen affinity than adult a final common pathway of all fuel substrates in
ones which is achieved by a reduced interaction aerobic cells. Here acetyl groups are metabolized to
between fetal hemoglobin with 2,3-DPG than in adult form carbon dioxide and hydrogen ions. In step 3,
hemoglobin. The concentration of 2, 3-DPG in fetal the hydrogen ions enter the respiratory chain of the
and adult cells is almost the same. 2, 3- DPG present cell, a series of electron carriers linked to oxidative
in the erythrocytes decreases the affinity to O 2 phosphorylation, with ATP formed in a stepwise
through an allosteric action with the hemoglobin manner. Oxygen is the final electron acceptor and is
molecule. DPG does not bind as strongly to fetal necessary for a continuous oxidation of reduced
hemoglobin as the adult hemoglobin, in addition it coenzymes in the respiratory chain. Oxygen therefore
is low immediately after birth making a high O 2 can be considered as the “garbage cleaner” of energy
affinity immediately after birth with a p50 of metabolism taking care of its waste products, the
approximately 2.7 kPa (20 mm Hg) versus 4 kPa (30 electrons after having traversed through the
mm Hg) at 8 months of age. Therefore, in the respiratory chain.
newborn period and early infancy when the fetal The energy metabolism tends to keep the energy
hemoglobin concentration is high, intraerythrocyte charge, EC (EC = 0.5 ([ATP] +[ADP]/[ATP] + [ADP]
change in 2,3-DPG has little effect on p50, however, + [AMP] of the cell at an optimal level which is around
later in life the modulating effect of 2,3 -DPG on 0.85. This can be achieved in two ways; either by
oxygen affinity plays a more important role. In the increasing the ATP concentration or to increase the
fetal period the high oxygen carrying capacity and catabolism of AMP. In hypoxia with lack of energy
greater oxygen affinity of fetal blood in fact the cell might be forced to choose the latter
compensate for the 1/5th to 1/4th oxygen tension of alternative. An accelerated breakdown of adenosine
adult blood ending up with a rather similar oxygen monophosphate (AMP) occurs. This is a hazardous
saturation at term and in adult life. Fetal blood also compensation since the cells might loose its purine
is slightly hypercarbic and acidotic whereas the pool irreversibly. One of the intermediate break-
maternal blood is hypocarbic and alkalotic. The Bohr down products is, however, adenosine. This
effect, that is the shift in the oxygen equilibrium curve metabolite has important control feed back functions
to the right by increased pCO 2 or decreased pH, in brain hypoxia, partly because it is an active
giving a higher oxygen tension, is more pronounced vasodilatator and thus contributes to a higher oxygen
with a lower pH and more efficient in the fetus. In supply to hypoxic tissues and partly because
addition, a higher temperature of the fetus adenosine in itself cuts down brain metabolism.
contributes to a shift in the fetal dissociation curve When adenosine accumulates because of energy
to the right.55-57 deficiency, this metabolite fights back by contributing
to an increased oxygen supply and a decreased
TISSUE INJURY energy need. This is important also because a
Energy Metabolism breakdown product from adenosine is hypoxanthine.
This metabolite accumulates in tissues and body
Most of the oxygen taken into the body is used in fluids during hypoxia and its extracellular concen-
cell energy metabolism. The metabolic process is a tration reflects the intracellular energy charge.
redox process where energy is released in a stepwise However, hypoxanthine is also a potential oxygen
fashion and stored as ATP. Energy metabolism can radical generator during reoxygenation and it is
52 Textbook of Perinatal Medicine

therefore probably advantageous for the organism than 25 times longer and one day old rats about 10
to try to keep the hypoxanthine concentration as low times longer than adult rats. One part of the
as possible. explanation for this seems to be that newborn animals
Before the cell’s energy charge falls markedly, can preserve cerebral circulation and thus ensure
several biochemical compensatory mechanisms are supply of substrates for energy metabolism better
activated. First, glycolysis is accelerated many fold. than in the adult. Further, it is known that oxygen
Pyruvate is reduced to lactate, while nicotinamide demand of the brain is lower in fetal life and inceases
adenine nucleotide (NADH) is oxidised to NAD+ . with gestation. The immature brain has smaller
This is the basis for the use of lactate as a clinical neurons which are less branched with fewer
marker of hypoxia. Lactate augmentation merely synapses. The energy requirement is therefore lower
reflects the compensation mechanism. Although and the cerebral metabolic rate of oxygen is lower
hypoxanthine and lactate parallels each other in many in the immature brain compared with the adult. The
clinical settings, hypoxanthine nevertheless more fetal brain is also able to use alternative sources such
correctly reflects the intracellular energy status of as ketone bodies as fuel for energy metabolism.
the cells. Further, the glycolytic capacity allows the immature
As soon as oxygen delivery to the cells decline brain to regenerate ATP at a higher rate than in the
the mitochondria also change their metabolism to adult brain.
utilise available oxygen more efficiently. The The perinatal period is also accompanied by
compensation takes place 30-60 minutes after a dramatic neurochemical changes. The concentration
reduction in oxygen supply. In the fetus or in the of excitatory aminoacids such as glutamate peaks
immediate newborn period mitochondrial adaptation around term and may contribute to a higher
already is maximal. A fetus has a respiratory capacity sensitivity to hypoxia in the term compared with the
of about 300% of the adult, but by 10-14 days after preterm infant.58,59
birth the newborn and adult levels equate in this
respect. What does this mean for the fetus and Apoptosis and Necrosis
newborn? First, they are able to utilize the limited Apoptosis is an important part of development and
oxygen supply very efficiently. On the other hand, homeostasis. For instance in the developing brain
the fetus is unable to make cellular respiratory perhaps up to half of the cells undergo apoptosis, in
adaptations if hypoxia occurs. From this point of spite of the fact that the distinction between apoptotic
view, the fetus and newborn are more vulnerable to and necrotic death is considered less clear than
hypoxia than older patients. previously. These two modes of cell death are by
many considered as a continuum running from
Hypoxic Injury to the Perinatal Brain
apoptosis to necrosis more than two different
It has been known since Boyle’s classical experiment entities. Infants who have undergone secondary
in 1670 that newborn animals can resist hypoxia energy failure after for instance birth asphyxia have
longer than adult ones. In the 1960’s and 70’s it was a tendency to loose their neurons by necrosis, while
shown that the preterm monkey can withstand those dying in utero have experienced more
hypoxia longer than the term one. In fact, in the fetal apoptotic death. The same injury may induce
monkey there was an exponential relation between apoptosis in the fetus or newborn and necrosis in
duration of hypoxia and gestational age when the the adult organism. To make it more complex the
outcome measure was neurologic brain injury same cell may undergo apoptosis if the injury is mild
(cerebral palsy). The younger the animal the longer and necrosis if it is severe. Oxidative stress plays an
it could resist hypoxia before brain injury occured. important role for initiating apoptosis for instance
Thus mature fetal rats survive in pure nitrogen more through opening up the mitochondrial permeability
 Transition at Birth 53
transition pore. This reduces the mitochondrial THERMAL REGULATION
membrane potential and release of substances that
In fetal life the body temperature is efficiently
are involved in apoptosis for instance cytochrome C
regulated to be 0.5oC higher than the maternal. The
and Apaf-1, both of these activate caspase-3 that is
tight linkage between fetal and maternal body
specifically involved in the apoptotic execution. As
temperature is called a “heat clamp” that prevents
mentioned already the fetus is more susceptible to
the fetus from independent regulation of its
oxidative stress than the term newborn and therefore temperature. At birth a dramatic change in the
also perhaps more susceptible to this mechanism.60 thermal environment occurs. During the first hours
of life core body temperature can fall to less than 36
Development of Antioxidants 0
C if the newborn is not taken care of optimally. After
In fetal life paO2 is around 3.3 kPa (25 mm Hg) and 8 hours body temperature has usually returned to
after birth rises quickly to 8 kPa (60 mm Hg ) over the normal adult range. Since the newborn infant
the next 30 minutes. In order to survive in an oxygen has a relatively large body surface area and limited
rich atmosphere antioxidant systems must be well thermal insulation it is necessary to wrap the
developed at birth. A number of defense systems newborn infant adequately. The newborn infant in
have been described. In the lung and kidney a fact has the capability to regulate the temperature
maturation of anti-oxyenzymes as superoxide by sweating and can also respond to a cool
dismutases, glutathione peroxidase and catalase seem environment by increasing metabolic rate. This takes
to occur near term in animal fetuses. In fact the place without shivering, is activated by catechola-
maturation of these systems occurs in parallel with mines, and the heat is generated mainly from brown
the maturation of the surfactant system. fat which is present in large amounts in the full term
Furthermore, preterm infants with gestational age infant. Although the fetus may mobilise brown fat
of 24-29 weeks have only 50% activity of Cu/Zn the thermogenic responses still are very low. These
superoxide dismutase in cord erythrocytes compared require increased oxygen and substrate consumption.
with term infants. Glutathione is a major intracellular The combination of hypoxia and hypothermia
antioxidant and is found in high concentrations therefore is dangerous.25,65
(millimolar) in eukaryotic cells. Glutathione is the
substrate for glutathione peroxidase which catalyses SKIN
oxidation of reduced to oxidised glutathione at the The transition from intra- to extra-uterine life is
expense of hydrogen peroxide. The rate of dramatic for the skin, perhaps the largest organ of
glutathione synthesis from methionine is strongly the body. It immediately must be a barrier to water
reduced in preterm infants compared with term ones. loss, it takes part in thermoregulation, is protecting
These data therefore suggest that at least the against infections, has an antioxidant function, and
intracellular defence against free radicals is low in protects against UV light. The skin is a barrier to
many organs in fetal life and probably also in the chemicals and is needed for tactile discrimination as
human fetus. A preterm infant is therefore more well as being an important emotional and
vulnerable to increased oxidative stress and attacks psychological link between the child and its
of free radicals than a term one. By contrast to the caregivers. The skin of the term by contrast to the
intracellular defense, extracellular antioxidants seem preterm infant also has a highly developed
to be adequately developed at term, and the immunological system. In utero the skin is in a sterile
concentration of several extracellular antioxidants as environment but already in the birth canal it is
ascorbate is very high in umbilical cord. (see chapter colonized and specific cells in the epidermal layer
6).61-64 take part in host defense.
54 Textbook of Perinatal Medicine

Prenatally, lipid synthesis is necessary for This 12 hour rhythm disappears immediately after
production of vernix caseosa forming a barrier which birth and around 2-4 weeks the 24 hour rhythm is
is needed for a successful adaptation to postnatal established. It takes 8-12 weeks before postnatal
life. The vernix also may function as an endogenous circadian rhythms in sleep and wakefulness as well
skin cleanser removing for instance carbon particles. as plasma cortisol and melatonin are established.25,67
Of interest is that both the stratum corneum of
epidermis and the brain contains very high GENE ACTIVATION AT BIRTH
concentrations of ceramides. The close embryological In the near future the transition at birth will be
relation between these two organs both derived described by shift in different gene activity and not
ectodermally makes this an interesting observation. only by physiological and biochemical changes.
At birth the epidermis is pH neutral but rapidly over Labour affects the mRNA encoding for a number of
the first postnatal weeks, develops an “acid mantle” enzymes such as tyrosine hydroxylase, dopamine-
which is characteristic of human skin. This acidic beta-hydroxylase. mRNA encoding for substance P
surface can be destroyed by using alkaline soaps for increases many folds in the nucleus tractus solitarius
infant bathing and is delayed in very low birth the first days of life. Substance P probably plays a
weight infants. The acid mantle is believed to be role for the central respiratory control by promoting
important in antimicrobial defense as well as keeping the hypoxic drive from peripheral chemo receptors.
the integrity of the epidermal barrier. Postnatally Depression of genes is also described at birth and in
transepidermal water loss that increases after birth some circumstances there is a shift from one isoform
is an important regulator of DNA and lipid synthesis to the other. One example is the expression of genes
in the epidermis.66 that encode the muscle–specific and non-muscle
specific isoforms of cytochrom oxidase subunit VIa
CIRCADIAN RHYTHMS during pre- and postnatal life of striated muscle in
The clock for the circadian rhythms is set by the the mouse. The non-muscle form is the predominant
suprachiasmatic nucleus. It is fascinating that the isoform in fetal life and is gradually at the end of
neurons in this area of the brain in vitro oscillate with gestation and early neonatal life replaced by the
a period close to 24 hours. This is regulated by light muscle-specific isoform both in cardiac and skeletal
which in a complex way affects gene expression of muscle.68
transcription factors. Efferent pathways from the
supra chiasmatic nerve control the pineal function, CONCLUSION
and regulate the rhythms of endocrine, cardio- In order to understand both normal development as
vascular, temperature and even behavioural circadian well as disease processes in the newborn infant it is
variations. necessary to have insight into the complex changes
From mid-gestation the suprachiasmatic nucleus which occur in relation to birth. Previously the
is present in the fetus and diurnal rhythms are found physiological processes have been emphasized giving
in the human fetus after 20 weeks. Whether or not us valuable knowledge in the perinatal transition of
they are intrinsically regulated or due to maternal the cardiovascular and pulmonary systems. Recently
control for instance via maternal melatonin rhythms biochemical changes in relation to birth have been
is unclear. However, in fetal life the maternal rhythms understood more in full as for instance the maturation
are mainly followed by the rhythm of the mother of the surfactant system and antioxidative systems.
exemplified by cortisol fluctuations. By contrast, fetal Presently more and more data will accumulate,
autonomic activity that controls the heart rate follows teaching us how the transition at birth is regulated
a 12 hour cycle and not the mother’s 24 hour rhythm. at the gene level. In this way it could hopefully be
 Transition at Birth 55
possible to modulate the disease processes in relation neonatal physiology 3rd edition, pp 487-493.
(Philadelphia: Saunders).
to the birth processes in a much more efficient and
13. Sunehag, A, Ewald, U. and Gustafsson, J (1996).
powerful way than we understand today. Extremely preterm infants (< 28 weeks) are capable of
gluconeogenesis from glycerol on their first day of life.
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3rd edition, pp 880-889. (Philadelphia: Saunders). glutathione metabolism in foetal and newborn rat liver.
57. Wood, W.G. (1982). Erythropoiesis and haemoglobin Biochem. J., 274, 891-893.
production during development. In Jones, C.T. (ed.) 65. Power GG, Blood AB, Hunter CJ. (2004). Perinatal
thermal physiology. In Polin R.A., Fox W.W. and
Biochemical development of the fetus and neonate. pp.
Abman S.H.(eds) Fetal and neonatal physiology 3rd
127-162.(Amsterdam: Elsevier Biomedical Press).
edition, pp 541-548. (Philadelphia: Saunders).
58. Myers, R.E.(1977). Experimental models of perinatal
66. Hoath SB. Physiologic development of the skin. (2004).
brain damage: relevance to human pathology. In Gluck,
In Polin R.A., Fox W.W. and Abman S.H.(eds) Fetal and
L. (ed.) Intrauterine asphyxia and the developing brain, neonatal physiology 3rd edition, pp 595-611.
pp 37-97 (Chicago:Year book publishers, Inc). (Philadelphia: Saunders).
59. Levene MI, Anthony MY (1993) Perinatal asphyxia and 67. McMillen, C. (1993). Biological rhythms. In Gluckman,
neonatal seizures. In Gluckman, P.D. and Heymann, P.D. and Heymann, M.A. (eds.) Perinatal and pediatric
M.A. (eds.) Perinatal and pediatric pathophysiology, pp. pathophysiology, pp. 254-256. (London: Edward
274-279 (London:Edward Arnold). Arnold).
60. Mehmet H, Bessley J, Edwards D. (2004). Apoptosis and 67. Parssons WJ, Williams RS, Shelton JM, Luo Y, Kessler
necrosis. In Polin R.A., Fox W.W. and Abman S.H.(eds) DJ, Richards JA. (1996). Developmental regulation of
Fetal and neonatal physiology 3rd edition, pp 72-79. cytochrome oxidase subunit VIa isoforms in cardiac and
(Philadelphia: Saunders). skeletal muscle. Am J Physiol 270:H 567-74.
58 Textbook of Perinatal Medicine

6
Neonatal Jaundice

Firmino Rubaltelli, Carlo Dani

INTRODUCTION serum bilirubin level at any point in time is dependent

upon the rate of bilirubin production minus the rate
Neonatal jaundice is one of the most common
of bilirubin excretion.
conditions of the newborn. Neonatologists are
The largest portion of bilirubin derives from heme
concerned about this problem, not only for the risk
breakdown of hemoglobin, myoglobin, mito-
of bilirubin encephalopathy in very-low-birthweight
chondrial and microsomal cytochromes, catalase, and
infants and in full-term infants with hemolysis due
peroxidase. Heme degradation probably occurs by
to different causes (rhesus and ABO hemolytic
disease, glucose-6-phosphate dehydrogenase auto-oxidation after reduction of ferric (Fe3+) heme
deficiency, etc.), but also because of the anxiety that to the ferrous state (Fe 2+) by the action of heme
jaundice in the full-term neonate gives to parents. oxygenase and NADPH cytochrome c (P450)
In neonates, jaundice becomes apparent at higher reductase.3,4 The methene bridge carbon of the heme
bilirubin serum concentrations in comparison to is eliminated as carbon monoxide. At the end of this
adults (5-7 mg/dl or 85-120 mmol/l in comparison process biliverdin is formed, and is subsequently
to 2-3 mg/ dl or 35-50 mmol/1). If we take into reduced to bilirubin through the activity of biliverdin
account clinically evident jaundice, we can say that reductase. For each molecule of bilirubin formed, a
almost 60-70% of term infants and almost all molecule of CO is produced, which constitutes the
prematures present with jaundice. But, if we consider basis for measuring bilirubin production by deter-
a cut-off of > 12.9 mg/dl (220 mmol/1), which in mination of the CO concentration in the expired air,
full-term infants is the most accepted limit to consider or the carboxyhemoglobin content of the blood.2
jaundice as deserving attention, only 5% or less Three isoforms of HO have been isolated,
present with a bilirubin serum concentration higher inducible heme oxygenase (HO-1), constitutive heme
than that. 1,2 oxygenase (HO-2), and the more recently discovered
Neonatal jaundice is principally the result of and less active heme oxygenase isoform (HO-3).5 HO-
transient deficiency of bilirubin conjugation, some 1 is a known stress response protein, whose
deficiency of hepatic uptake and intracellular transcription can be induced by a whole array of
transport, and an increased enterohepatic circulation stresses, including endotoxin, transition-metals,
of the pigment. It is notable that bilirubin production heme, hemoglobin and other heme proteins.6 Indeed,
in the newborn is two or more times greater than it has been suggested that HO-1 induction might
that in the adult per kilogram of body weight.2 The represent a generalized response to oxidative
 Neonatal Jaundice 59
stress5,7,8 and that it could confer cellular protection between direct-reacting (mostly the conjugated form)
against oxidant stress. However, recent studies and indirect-reacting (unconjugated) bilirubin.
suggest that HO-1 induction might not always be
beneficial and that the release of redox-active iron DISTRIBUTION OF BILIRUBIN IN THE BODY
from heme might induce an increase of oxidative The distribution of bilirubin in the body is essentially
stress.9,10 Moreover, in vitro studies11,12 suggested determined by its firm binding to albumin. However,
that the possible protective antioxidant action of HO- the presence of a visible jaundice seems due, at least
1 could occur within a narrow range, as occurs when in part, to the presence of bilirubin in the skin.
HO-1 is over-expressed and free iron release may Therefore, there is a dynamic competition between
obviate any cytoprotective effect against oxidative tissue binding sites and albumin binding sites. In fact,
stress.13 albumin binds bilirubin according to the law of mass
action:
BILIRUBIN SOLUBILITY
Bilirubin + albumin H albumin-bilirubin
Bilirubin is derived from heme by separation from Two classes of binding sites have been observed:
an amethyne bridge. The configuration on the C-5 a primary binding site with an extremely high affinity
and C-14 bridges is very important, and bilirubin for bilirubin (KA1 = 7 x 1071/mol at 37°C), and one
preferentially takes the Z form. Moreover, (Z,Z)- or two other binding sites with a lesser affinity (KA2
bilirubin IXa has a configuration that makes the = 5 x 1051/mol). The concentration of free bilirubin
formation of intramolecular hydrogen bridge is mostly determined by the molar relationship
linkages possible. For this reason it is almost between bilirubin and albumin. However, bilirubin
insoluble in aqueous media (1-10 nmol/l at pH 7.4), can be displaced from its binding site by certain drugs,
but dissolves readily in a number of non-polar such as sulfisoxazole, benzoate, salicylate, etc.
solvents. The degree to which bilirubin (B) ionizes Nowadays, every drug intended for use in newborns
with the propionic acid residue depends on the pH, must be accompanied by evidence that it has no effect
and this is decisive both for the distribution of the on bilirubin-albumin binding.15
molecule and for its toxicity: At the hepatic level, bilirubin is taken up at the
B2- + H+ H BH-; BH - + H+ -+ BH2 sinusoidal membrane level, but about 40% is then
The dissociation constants cannot be determined regurgitated into the plasma again. The albumin-
with absolute precision owing to the problem of bilirubin complex seems to bind to specific receptors
solubility, but they are found to be approximately pl
located on the basolateral surface of the sinusoidal
l = 4.4 and plasmatic membrane of the hepatocyte much better
pK2 = 6.5.14
than bilirubin alone.16 In the hepatocyte, bilirubin
All modifications of the molecule which prevent
reacts with binding proteins, the most important
the formation of hydrogen bridges cause an increase
being glutathioneS-transferase, thus preventing its
in water solubility. In the human, this takes the form
regurgitation into the plasma. Bilirubin has a low
of an esterification of the residue of propionic acid
solubility in water due to the fact that its hydrophilic
with glucuronic acid, which makes excretion in the
bile possible. Obviously, monoconjugated bilirubin groups are masked by hydrogen bonds; however, it
is less soluble than diconjugated bilirubin, and can is made hydrosoluble by esterification in the
thus precipitate in the biliary tract forming stones. endoplasmic reticulum, with one or both propionic
Alkalinization (salt formation) or the addition of non- acid side-chains reacting with a sugar residue to form
polar solvents, such as chloroform, methanol, ethanol, mono- or diesters; in this way the formation of
etc., also result in better solubility, and this is the hydrogen bonds is prevented. 17
key mechanism used in the laboratory to differentiate (albumin-bilirubin) = KA albumin x bilirubin.
60 Textbook of Perinatal Medicine

The formation of bilirubin glycosides is catalyzed hydrogen superoxide during the degradation of
by uridine diphosphate (UDP) glycosyltransferase, heme, the induction of ferritin synthesis, which
an enzyme system that utilizes bilirubin as an acceptor sequesters redox-active iron, and the regulation of
substrate, and UDP sugars (especially glucuronic acid) superoxide anion production. Other possible
that act as donor substrates. Transfer from binding mechanisms could involve the multiple ways by
proteins to the enzyme system does not necessarily which carbon monoxide (CO) modulates inflam-
require a higher affinity for the enzyme binding site, matory processes, such as the reduction of neutrophil
because bilirubin is far more soluble in membranes adhesion and extravasation 30, the reduction of
than in the aqueous cytoplasm, and the reaction could histamine release from mast cells and human
therefore take place simply by means of a favorable basophils 31,32, inhibition of the expression of pro-
partitioning. Furthermore, the bilirubin monoglucu- inflammatory cytokines such as TNFα and IL-1β and
ronide could be converted into diglucuronide by the an increase of anti-inflammatory cytokine IL-10.33
same enzyme system, following a 180° rotation of These studies confirmed the findings of Yigit et
the monoglucuronide molecule, or it could even be al.34 who found no correlation between oxidative
excreted without modification in the bile. stress and total bilirubin in preterm infants with non-
hemolytic hyperbilirubinemia, and Gopinathan et
OXIDATIVE STRESS AND NEONATAL al.35 who observed no correlation between bilirubin
HYPERBILIRUBINEMIA plasma level and total plasma antioxidant capacity
Several reports emphasized the antioxidant role of in preterm infants. On the other hand, Belanger et
bilirubin, which in human neonatal plasma seems to al.36 found an association between reduction of the
have a greater antioxidant potency than urates, α- antioxidant capacity of plasma after exchange
tochoferol, or ascorbates. 18 In particular, unconju- transfusion, and the ensuing decrease of bili-
gated bilirubin is able to scavenge singlet oxygen rubinemia. This result, however, as indicated by the
with high efficiency, to react with superoxide anions authors, could be explained by factors other than
and peroxyl radicals, and to serve as reducing bilirubin decrease, such as oxidative stress induced
substrate for peroxidases in the presence of hydrogen by a large amount of transfused blood and the
peroxide or organic hydroperoxides. Nevertheless, consequent overload of iron through transfusion.
although the antioxidant effect of bilirubin as a Hammerman et al37 found a correlation between Btot
scavenger of reactive oxygen species (ROS) is well and plasmatic antioxidant capacity, but the
documented in vitro19-22 as well as in animal studies23, bilirubinemia of their patients was lower than that
its role in vivo has not been definitively cleared in reported in other studies. To explain these conflicting
preterm infants.22-27 results it may be considered that the correlation
Recently, two studies investigated the possible between bilirubin plasma level and the antioxidant
relationship between bilirubin plasma levels and capacity of plasma could change at low and high
oxidative stress in newborn infants28-29 excluding that values, and could be affected by phototherapy
bilirubin acts as antioxidant agent “in vivo”. It was through its lowering effect on bilirubin, which,
demonstrated that the decrease of bilirubin plasma moreover, could also explain the lack of correlation
level (probably induced by phototherapy) was between bilirubin and HO-activity.
associated with the concurrent increase of HO-1
activity in blood and the decrease of oxidative stress, CAUSES OF NEONATAL JAUNDICE
suggesting an antioxidant effect of HO-1 exerted ”in
Physiological Jaundice
vivo” by mechanisms other than bilirubin formation.
These protective mechanisms could involve the So-called physiological or developmental jaundice
removal of the pro-oxidant heme, the removal of (which could be especially harmful for the small pre
 Neonatal Jaundice 61
term infant) is due to an imbalance between increased concentrations of unconjugated and esterified
pigment load and reduced hepatic handling. The bilirubin, and the proportion of diesterified (as
latter seems mainly determined by the low activity percentage of esterified bilirubin) pigment, appeared
of bilirubin UDP glucuronosyltransferase, the hepatic not to be different between the two groups of infants,
microsomal enzyme which conjugates bilirubin with showing that bilirubin production and conjugation
one or two sugar moieties. It is now accepted that, were not different.43 In addition, a recent study
even in the absence of impaired biliary secretion, a comparing the incidence of neonatal jaundice in 605
fraction of the esterified bilirubins formed in the liver infants exclusively breast-fed on demand, in 623 who
normally refluxes from hepatocyte to plasma. received both breast- and formula-feeding, and in
Measuring the esterified bilirubins in the plasma of 226 exclusively formula-fed, demonstrates that the
newborn infants has made it possible to demonstrate incidence of neonatal hyperbilirubinemia (> 12.9 mg/
definitively that neonatal jaundice is mainly due to dl or 220 mmol/1) in full-term infants is both
an increased bilirubin production with subnormal insignificant (< 5%) and not correlated with demand
conjugation.38 On the other hand, infants with the breast-feeding. 1 These results were recently
lowest plasma concentration of total bilirubin confirmed in a population of 2174 infants with
exhibited the highest fraction of conjugates. The gestational age > 37 weeks where hyperbilirubinemia
percentage of diconjugates relative to total conjugates was not found to be correlated with breastfeeding,
is 15% on the first day of life. This value tends to but rather with an increased weight loss, dehydration,
increase slightly with age.38 In premature infants, and caloric deprivation which could enhance the
serum monoconjugates paralleled the course of total enterohepatic circulation of bilirubin.44
and unconjugated bilirubin, but the values were
significantly lower than those found in full-term Hemolytic Jaundice
infants.17,38 Fetomaternal blood group incompatibility,
From the practical point of view, we can rule out particularly ABO and rhesus hemolytic disease, are
the diagnosis of physiological jaundice if plasma or the most common causes of severe jaundice.
serum bilirubin concentration exceeds at any time Nowadays, rhesus hemolytic disease is infrequent
12.9 mg/dl (220 mmol/1) in full-term infants or 5-8 due to maternal prophylaxis with anti-rhesus
mg/dl (85-138 mmol/1) in preterm infants 39 , if immunoglobulins. However, ABO hemolytic disease
jaundice becomes evident in the first 24 h of life, if still remains an important cause of indirect
bilirubin concentration increases more than 5 mg/dl hyperbilirubinemia and anemia in full-term as well
(85 mmol/1) per day, and if direct reacting plasma as preterm neonates. Suspicion of ABO or rhesus
bilirubin exceeds 1.5-2 mg/dl (25-35 mmol/1) (it is hemolytic disease must be confirmed by a direct
important to determine conjugated bilirubin by a Coombs test carried out on the newborn blood.
chromatographic method.17,38
Glucose-6-phosphate Dehydrogenase
Jaundice in Breast-fed Neonates (G-6-PD) Deficiency
An increased incidence of early-onset jaundice has G-6-PD deficiency is frequently associated with
been reported in breast-fed infants, both full-term neonatal jaundice and sometimes kernicterus. The
and preterm. 40,41 However, an increased bilirubin pathogenesis of this jaundice remains in part unclear,
synthesis, demonstrated by an increased CO because increased erythrocyte breakdown is not
production, possibly secondary to caloric deprivation, always a major factor in its development.45 In some
has not been proven. 42 The process of bilirubin patients overt hemolysis, due to different substances,
conjugation, investigated in breast-fed and formula- is detected, and in others no signs of hemolysis are
fed infants by means of the determination of serum detectable (normal level of carboxyhemoglobin). In
62 Textbook of Perinatal Medicine

this group of patients it has been shown that a described the case of an infant who developed a
deficiency in bilirubin conjugation does exist.45 It is kernicterus at a total bilirubin concentration of 31.7
possible that G-6-PD is also involved in some steps mg/dL and unbound bilirubin concentration of 7.7
(possibly UDP glucuronic acid synthesis) of bilirubin µg/dL. 48 However, in preterm infants bilirubin-
conjugation. induced changes in auditory brainstem response can
begin at unbound bilirubin level of 0.5 µg/dL and
Congenital Non-obstructive, kernicterus becomes likely at 1-1.5 µg/dL.49
Non-hemolytic Jaundice
Crigler-Najjar disease is a rare disorder of bilirubin Effects of Bilirubin on Neurologic Functions
metabolism caused by a deficiency of hepatic UDP- It is well known that bilirubin acts to uncouple
glucuronyltransferase, and characterized by high oxidative phosphorylation and, consequently, inhibits
serum levels of unconjugated bilirubin that appear the respiratory chain by causing certain toxic effects.50
in the first days after birth and continue through However, a number of studies carried out on
life. Based on the responsiveness of the serum experimental animals show no difference in bilirubin
bilirubin concentration to phenobarbital, this disease
binding between different brain regions, nor in the
can be distinguished as either type 1, which does
rate of bilirubin disappearance from the cerebral
not respond to phenobarbital, or type 2, which
tissues. 51 Moreover, it is still unclear as to why
responds to barbiturates and other drugs that induce
bilirubin has a preferential localization at the level
enzyme synthesis. Type 2 is probably caused by a
of the basal ganglia. One proposed explanation relies
partial enzymatic deficiency. In type 1 and type 2
on the possibility that bilirubin may be metabolized
CriglerNajjar disease, it is possible to detect traces
of monoconjugated but not diconjugated bilirubin locally at different rates.51 In fact, the typical findings
both in serum and in bile.46 of kernicterus are a yellow staining of the
subthalamic, dentate and inferior olivary nuclei and
BILIRUBIN ENTRY INTO THE BRAIN the globus pallidus. Cellculture models suggest that
bilirubin initially interacts with cellular membranes,
Some clinical observations suggest that several
affects ion channels and neurotransmitters, and
mechanisms may be involved with the entry of
ultimately leads to deranged metabolism and cell
bilirubin pigment into the brain. In fact, bilirubin
death.52 The clinical picture of kernicterus is also fairly
seems to enter into the brain both as free bilirubin
uniform in these children, with convulsions and
acid and as bilirubinalbumin complex, by passage
opisthotonus followed by hypotonia, high-pitched
through a disrupted bloodbrain barrier that is often
caused by hyperosmolality and hypercarbia. It seems crying and fever. The sequelae in the survivors
that even during physiological jaundice there is a consist of neurogenic hearing disorders, choreo-
steady passage of unbound bilirubin across this athetosis with asymmetrical spasticity and paralysis
barrier. Furthermore, these low levels of bilirubin of upward gaze, together with other neurologic
do not seem to be harmful; in fact, it is also possible manifestations. Ambulation, despite severe athetosis,
that cerebral stores of bilirubin oxidase are able to is generally reached by the age of 5 years.53
metabolize bilirubin in loco. Obviously, the entry of Brain-stem auditory-evoked potentials are altered
bilirubin into the brain can be significantly increased by bilirubin in various ways.54,55 In some studies it
in the presence of high plasma bilirubin has been observed to change the conduction latencies,
concentrations, particularly if the albumin binding in others it lowered the conduction wave amplitude,
capacity is exceeded.47 Ahlfors et al. reported that in both of which fit with the follow-up observation of
term newborns unbound bilirubin levels between 0.9 deafness in kernicteric babies. Some studies note
and 2 µg/dL produce subtle and reversible changes reversibility of these altered potentials through
in auditory brainstem response latency, and lowering of high bilirubin levels.456,57
 Neonatal Jaundice 63
Bilirubin-induced membrane potential-lowering the tissues (brain) and the vascular space (‘free’
may impair nerve conduction along the auditory bilirubin theory). Thus, not only is the serum bilirubin
pathway, which may be reversible if each cell endures concentration important in judging whether an infant
only temporary malfunction or if a sufficient number is at risk of bilirubin toxicity, but the albumin
of neurons in the nerve survive the toxicity to concentration and the bilirubin/albumin ratio are also
maintain function. of critical importance. In fact, Ahlfors suggests that
It is commonly accepted that (1) bilirubin may be when the bilirubin/albumin ratio is < 8 mg/g (136
toxic for cells; (2) kernicterus can occur when mmol/g) and the neonate appears well, exchange
unconjugated bilirubin levels are high; and (3) the transfusion is probably not necessary.61
mechanism of bilirubin toxicity is mostly unknown. Exchange transfusion, first performed in 1925 by
Alfred Purvis Hart and then implemented by L.K.
MEASUREMENT OF BILIRUBINEMIA Diamond in 1947 using the umbilical vein to
The majority of published studies on bilirubin in withdraw and to perfuse blood, was the only
infants were made measuring its level on capillary treatment available until 1958 when Cremer and
blood with spectrophotometric methods. Some colleagues 62 showed that both sunlight and blue light
studies compared capillary and venous measurement were able to reduce jaundice in newborns. In fact,
of bilirubinemia, but their results were con- phototherapy is now the most widely used method
flicting.58,59 Therefore, to confirm a high value of worldwide for the treatment of jaundiced babies.
bilirubin plasma level in a venous sample is not The mechanisms by which light renders the
recommended. Recently, new devices have insoluble bilirubin molecule (bilirubin IX-alpha Z,Z),
permitted an easier and more reliable transcutaneous at physiologic pH, soluble and rapidly excretable in
measurement of bilirubin. The Chromatics Colormate the biliary tract are the transformation of the Z,Z
III™ (Chromatics Color Science International Inc., configuration at the C4-C5 and C15-C16 double bonds
New York, NY, USA) is still based on the colour of to the E configuration in one or both double bonds,
the skin, estimating serum bilirubin from skin- thus forming the configurational isomers E,Z or Z,E
reflectance (skin colour) whereas the BiliCheck™ or E,E.63-65 Of these isomers, the predominant one is
(Respironics, Murrysville, Pennsylvania, USA the Z,E form. However, the Z,E change is reversible,
measures transcutaneous bilirubin by utilizing the and after phototherapy it reconverts in the bile or in
entire spectrum of visible light (380 to 760 nm) the intestines to the Z,Z isomer. In addition,
reflected by the skin. Data obtained using Bili- intramolecular cyclization of bilirubin can occur as a
Check™ suggest that this device provides result of phototherapy, to form a structural isomer
measurements within 2-3 mg/dL (34-51 µmol/L) of called lumirubin, which cannot be reconverted to
the bilirubin serum concentration. 60 These devices native bilirubin. Moreover, lumirubin, which is
could be used as screening tools but, in some formed at a lower rate in comparison to the
circumstances, also as substitutes for serum bilirubin configurational isomers, seems to be excreted more
measurements, in particular when its value is lower rapidly in the bile than the other isomers.
than 15 mg/dL (257 µmol/L). There is a striking regional selectivity that causes
isomerization to take place at the double bond of
TREATMENT OF NEONATAL
the CH-bridges. Because of the specific preference
HYPERBILIRUBINEMIA
evidenced by one-half of the bilirubin molecule in
Bilirubin is bound to albumin in the blood, and when binding to human albumin, the E configuration in
its concentration exceeds the binding capacity of the position 15 is the main isomer formed. This selectivity
carrier, unbound or free bilirubin concentration is lacking to a large extent in a number of the animals
increases and results in its redistribution between used in experimental studies. Finally, the available
64 Textbook of Perinatal Medicine

data suggest that bilirubin is bound to albumin at discoloration was also present in the kidneys, liver,
the site of the light effect, namely in the skin. and peritoneum. Clark and associates67 and Rubaltelli
The extent to which isomerization, cyclization or and colleagues68, in particular, found anatomical signs
oxidation exert the therapeutic effect of light is of kernicterus in two newborns who died with this
determined mainly by the quantum yield of the syndrome. They considered this observation to be
photochemical reactions and the speed of the confirmation that the pigments responsible for BBS
transport processes up to the excretory phase. increase the risk of bilirubin neurotoxicity, as
The quantum yield of configurational isomeri- suggested by the reported decline in the albumin
zation is probably very high; isomers are formed very binding capacity.66,69
quickly, and they can be detected within a few In 1982 a notably higher concentration of
minutes after light treatment. On the other hand, porphyrins was found in the serum of patients with
photocyclization proceeds more slowly, and depends BBS.70 Two cases of this syndrome, with very high
on the wavelength employed. Moreover, the serum porphyrins, probably due to some degree of
quantum yield of bilirubin oxidation is very low, and cholestasis, were described.71,72 The porphyrins were
it is most probable that the excretion of catabolites identified as Cu2+ -uro, Cu2+ -copro-, and Cu”-proto-
formed in the process takes place rapidly. Since the porphyrin. In fact, the absorption spectrum of serum
excretion rate of lumirubin is very high, it is specimens from infants with BBS showed spectral
conceivable that, in phototherapy for neonatal features typical of bilirubin (peak absorption around
jaundice, bilirubin photocyclization is the most 460 nm), as well as an intense band with a peak at
effective mechanism of bilirubin photometabolism, about 400 nm and broad absorbance in the near-UV
followed by configurational isomerization and, and the 600-700 nm region. The latter two features
finally, photooxidation.
were not confirmed by the absorption spectra of
control sera. The sera of bronze babies also exhibited
THE BRONZE BABY SYNDROME
a wide range of fluorescence emission spectra, with
The bronze baby syndrome (BBS) is a rare peaks at 585, 619, and 670 nm. This finding indicates
pathological condition that appears during photo- that absorption in the 400 nm band does not reflect
therapy. The typical characteristic is a greyish-brown the presence of residual hemoglobin in the serum
discoloration of the skin, serum, and urine. This because hemoproteins are known to be devoid of
condition was first described by Kopelman and any appreciable fluorescence in the red region.
colleagues66, who observed the typical discoloration
Instead, the emission spectra observed are
in the skin of a newborn following phototherapy.
characteristic of porphyrin compounds.
They found that the onset of the syndrome was
Chromatographic separation led to the conclusion
linked to an increase in conjugated bilirubin, implying
that the main component is Cue+-proto-porphyrin
a cholestatic disorder; moreover, they also related it
IX, although small amounts of Cue+-copro-porphyrin
to hemolytic anemia. Since then, various authors have
II and Cue+-uroporphyrin III are also present. These
attempted to explain the biochemical mechanism
porphyrins do not seem to have an appreciable
responsible for the onset of this syndrome. 67,68 In
this connection, Kopelman and colleagues noted a photosensitizing effect. Furthermore, there was no
reduced bilirubin binding capacity in newborns evidence of significant alterations in the UV spectrum
suffering from BBS. They suspected that bilirubin of irradiated serum from infants with BBS or in cord
photoproducts might be responsible both for the blood serum with added synthetic Cue+-porphyrins.
bronze discoloration and for the change in binding This is due to the well-known shortening of the half-
capacity ascertained by the salicylate method”. life of excited porphyrin as a consequence of the
Autopsy evidence later showed that this peculiar binding of the Cue+ ion on the tetrapyrrolic ring.73
 Neonatal Jaundice 65
These investigations show that the greyish-brown It is recommended that phototherapy be started
skin color is a result of the photolability of the Cu2+- during the first 24 h of life if the serum bilirubin
porphyrins. Indeed, Cue+-porphyrins in the serum level exceeds 4-7 mg/dl (70-120 mmol/1), or during
of infants with BBS or in aqueous solutions are the second 24 h of life if it exceeds 11-15 mg/dl 190-
converted under irradiation with visible light into 260 mmol/1), and in all cases whenever it exceeds 15
brown photoproducts with a higher absorption in mg/dl (260 mmol/1). Phototherapy should be carried
near-UV and red spectral regions. Moreover, the out for at least 24 h, and should be interrupted when
presence of bilirubin increases the photodegradation
bilirubin serum concentration is decreased by >_ 2
rate of Cue+-porphyrins, suggesting that bilirubin acts
mg/dl (>_ 35 mmol/1).
as a photosensitizer in this process.
However, the American Academy of Pediatrics
GUIDELINES FOR THE TREATMENT OF has recently published guidelines for the
UNCONJUGATED HYPERBILIRUBINEMIA management of hyperbilirubinemia in the newborn
infant of 35 or more weeks gestation, which report
Full-term Newborn Infants
in depth on current recommendations for prevention,
Neonatal jaundice (total bilirubin serum con- diagnosis, and treatment of neonatal jaundice.75 The
centration > 12.9 mg/dl (220 mmol/1), occurs in approach to jaundice in preterm infants appears more
around 5% of normal neonates.1 In the majority of difficult because there are no specific evidence-based
cases it is a physiologic or developmental jaundice
1,74
guidelines for the use of phototherapy and exchange
, which does not need any treatment. However,
transfusion in these infants. Different authors have
it is important to exclude the presence of a rhesus or
reported a range of bilirubin plasma level for
ABO hemolytic disease, and the possibility that the
intervention in various circumstances, but none of
jaundice could be an early sign of an inborn error of
metabolism, or sepsis, etc. these indications has greater validity than another.39
It is suggested that a direct Coombs test plus However, considering that in preterm infants
blood group and rhesus determination should be kernicterus has almost disappeared probably due to
carried out on the cord blood of every neonate, and, aggressive phototherapy, it is probable that the
when jaundice is present, the neonatologist should current management of jaundice in these infants is
evaluate the appropriateness of a serum bilirubin correct.
determination in relation to the day of appearance Other possible therapeutic interventions are
and intensity of the jaundice, etc. A bilirubin serum immunoglobulin therapy in immune hemolytic
level of 20 mg/dl (340 mmol/1) in a normal full erm jaundice and administration of the heme oxygenase
newborn infant is no longer considered an indication inhibitor Sn-mesoporphyrin. Alcock et al., in a meta-
for exchange transfusion. 74 In the absence of a analytical study on term and preterm infants with
hemolytic disorder, and with a bilirubin level in the rhesus and ABO incompatibility, found that the rate
range 20-25 mg/dl (340-425 mmol/1) exchange of exchange transfusion decreased significantly in the
transfusion might be considered, but this decision immunoglobulin treated group. The mean number
must be based on a careful evaluation of the risk/
of exchange transfusions per infant was also
benefit ratio.
significantly lower in the immunoglobulin treated
Following Wennberg’s suggestions47, one should
group.76 As for Sn-mesoporphyrin, its use is very
take into consideration not only the serum bilirubin
level but also the albumin serum concentration: that promising both for the prevention and the treatment
is, by multiplying the albumin value in grams by of neonatal jaundice. However, this drug is as yet
seven, a value is obtained which corresponds to the under research and is not commercially available.77
level when an exchange transfusion is indicated. (Kappas)
66 Textbook of Perinatal Medicine

Premature Newborn Infants 4. Yoshinaga T, Sassa S, Kappas A. A comparative study

of heme degradation by NADPH-cytochrome-c
In the last few years, a number of studies have shown reductase alone and by the complete heme oxygenase
that currently neither kernicterus nor clinical signs system. J Biol Chem 1982;257:7794-802.
5. Keyse SM, Applegate LA, Tromvoukis Y, Tyrrell TM.
of bilirubin encephalopathy are found in premature Oxidant stress leads to transcriptional activation of the
babies (see the important review of Conolly and human heme oxygenase gene in cultured skin fibroblast.
Volpe78). These findings were reported despite the Mol Cell Biol 1990;10 :4967-9.
6. Lamb NJ, Quinlan GJ, Mumby S, Evans TW, Gutteridge
fact that higher bilirubin serum concentrations were JMC. Haem oxygenase shows pro-oxidant activity in
allowed compared with studies reported in the 1960s microsomal and cellular systems :implication for the
and 1970s, when kernicterus was not a rare release of low-molecolar-mass iron. J Biochem
1999;344 :153-8.
occurrence.79,80 It is possible that the improved quality 7. Vile GF, Basu-Modak S, Waltner C, Tyrrell RM. Heme
of health care has reduced the appearance of preterm Oxygenase 1 mediates an adaptive response to
kernicterus, the pathogenesis of which is still not oxydative stress in human skin fibroblasts. Proc Natl
Acad Sci USA 1994;91:2607-10.
completely understood.80-85
8. Lautier D, Luscher P. Tyrrell RM. Endogenous
The definition of prematurity (< 37 weeks of glutathione levels, modulate both constitutive and UVA
gestational age) includes neonates of very different radiation/hydrogen peroxide inducible expression of the
gestational ages. Moreover, a generous use of human heme oxygenase gene. Carcinogenesis
1992;13:227-32.
phototherapy has allowed a reduction of high 9. Gutteridge JMC. Fate of oxygen free radicals in
bilirubin serum concentrations, and as a result extracellular fluids. Biochem Soc Trans 1982;10 :72-73.
exchange transfusion ís no longer used very often. 10. Dennery PA, Spitz DR, Yang G, Tatarov A, Lee CS,
Shegog ML, Poss KD. Oxygen toxicity and iron
However, it seems rational to initiate light treatment accumulation in the lungs of mice lacking heme
independently of the age of the premature infant, oxygenase-2. J Clin Invest 1998;101:1001-11.
whenever the bilirubin serum concentration is >_ 8 11. Dennery Pa, Sridhar KJ, Lee CS, Wong HE, Shokoohi
V, Rodgers PA, Spitz DR. Heme oxygenase-mediated
mg/dl (135 mmol/1), provided that no hemolysis is resistance to oxygen toxicity in hamster fibroblasts. J
present. In fact, exchange transfusion must be Biol Chem 1997;272:14937-42.
considered when bilirubin reaches the level of 18 mg/ 12. Suttner DM, Sridhar K, Le CS, Tomura T. Hansen TN,
dl (305 mmol/1). Furthermore, for the premature Dennery PA. Protective effects of transient HO-1
overexpression on susceptibility to oxygen toxicity. Am
newborn one can use Wennberg’s formula47 to J Physiol 1999;276:L443-51.
identify infants needing exchange transfusion: 13. Dennery PA. Regulation and role of heme oxygenase
multiplying by six the value of serum albumin in oxidative injury. Curr Top Cell Regul 2000;36:181-99
14. Jãhrig K, Jãhrig D, Meisel P. Phototherapy. Treating
concentration (in grams) one obtains the threshold Neonatal Jaundice with Visible Light. München:
value for exchange transfusion. Quintessenz-Verlag s-GmbH, 1993.
15. Brodersen R. Binding of bilirubin to albumin. CRC Crit
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20. Hardy P, Peri KG, Lahaie I, Varma DR, Chemtob S. 34. Yigit S, Yurdakok M, Kilinc K, Oran O, Erdem G,
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27. Siimes MA, Addiego JE, Dallman PR. Ferritn in serum, infant as an index of bilirubin production. IV. Effects of
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M, Rizzuti G, Rubaltelli FF. Bilirubin plasma level and Unconjugated and conjugated bilirubin pigments during
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Ciofini S, Rossetti M, Gallori G, Ciuti R, Buonocore G, 44. Bertini G, Dani C, Tronchin M, Rubaltelli FF. Is
Paffetti P, Mannaioni PF, Rubaltelli FF. Pediatr Res, in breastfeeding really favoring early neonatal jaundice?
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30. Ndisang JF, Masini E, Mannaioni PF, Wang R. In : 45. Kaplan M, Rubaltelli FF, Hammerman C, Vilei MT,
Carbon monoxide and cardiovascular inflammation. R. Leiter C, Abramov A, Muraca M. Conjugated bilirubin
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31. Mirabella C Baronti R, Berni LA, Gai P, Ndisang JF, 46. Rubaltelli FF, Novello A, Zancan L, Vilei MT, Muraca
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32. Di Bello MG, Berni L, Gai P, Mirabella C, Ndisang JF, 48. Ahlfors CE. Unbound bilirubin in a term newborn with
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Wysk M, Davis RJ, Flavell RA, Choi AM. Carbon 70.
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51. Hansen WR. Bilirubin in the brain. Distribution and concentration of copper porphyrins. Acta Paediatr
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52. Ochoa EL, Wennberg RP, An Y, et al. Interaction of in neonates with deficiency of bilirubin excretion and
bilirubin with isolated presynaptic nerve terminals: bronze baby syndrome. Acta Paediatr Scand 1982;71:
functional effects on the uptake and release of 415-20.
neurotransmitters. Cell Mol Neurobiol 1993;13:69-86. 70. Jori G, Reddi E, Rubaltelli FF. Bronze baby syndrome:
53. Rubaltelli FF, Griffith PF. Management of neonatal evidence for an increased serum porphyrin concen-
hyperbilirubinemia and prevention of kernicterus. tration. Lancet 1982;1:1073.
Drugs 1992;43:864-72. 71. Jori G, Reddi E, Rubaltelli FF. Porphyrin metabolism in
54. Karplus N, Lee C, Cashore WJ, Oh W. The effect of brain the bronze baby syndrome. In Stern L, Bard H, Friis
bilirubin deposition on auditory brain stem evoked Hansen B, eds. Intensive Care in the Newborn. New
responses in rats. Early Hum Dev 1988;16:185-94. York: Masson Publ Co., 1993:41-5.
55. Vohr BR, Lester B, Rapisardi G, et al. Abnormal 72. Rubaltelli FF, Jori G, Reddi E. Bronze baby syndrome:
brainstem function correlates with acoustic cry features a new porphyrin-related disorder. Pediatr Res 1983;17:
in term infants with hyperbilirubinemia. J Pediatr 1989; 327-30.
115:303-8. 73. Cauzzo G, Gennari G, Jori G, Spikes JD. The effect of
56. Nakamura H, Takada S, Shimabaku R, et al. Auditory the chemical structure on the photosensitizing efficiency
nerve and brainstem responses in newborn infants with of porphyrins. Photochem Photobiol 1977;25:389-95.
hyperbilirubinemia. Pediatrics 1985;75:703-8. 74. Newman TB, Maisels MJ. Evaluation and treatment of
57. Wennberg RP, Ahlfors CE, Bickers R, et al. Abnormal jaundice in the term newborn: a kinder, gentler
auditory brainstem response in a newborn infant with approach. Pediatrics 1992;89:809-18.
hyperbilirubinemia: improvement with exchange 75. American Academy of Pediatrics. Management of
transfusion. J Pediatr 1982;100:624-6. hyperbilirubinemia in the newborn infant 35 or more
58. Leslie GI, Philips JB, Cassady G. Capillary and venous weeks of gestation. Pediatrics 2004;114:297-316.
bilirubin values : are they really different? Am J Dis 76. Alcock GS. Immunoglobulin infusion for isoimmune
Child 1987;141:1199-200. haemolytic jaundice in neonatesCochrane Database Syst
59. Eidelman AI, Schimmel MS, Algur N, Eylath U. Capillary Rev. 2002;(3):CD003313.
and venous bilirubin values : they are different-and 77. Kappas A. A method for interdicting the development
how! Am J Dis Child 1989;143:642. of severe jaundice in newborns by inhibiting the
60. Bertini G, Rubaltelli FF. Non-invasive bilirubinometry production of bilirubin, Pediatrics 2004;113:119-23.
in neonatal jaundice. Semin Neonatol 2002;7:129-33. 78. Connolly AM, Volpe JJ. Clinical features of bilirubin
61. Ahlfors CE. Criteria for exchange transfusion in encephalopathy. Clin Perinatol 1988;17:371-9.
jaundiced newborns. Pediatrics 1994;93:488-94. 79. Harris RC, Lucey JF, MacLean RJ. Kernicterus in
62. Cremer RJ, Perryman PW, Richards DH. Influence of premature infants associated with low concentration of
light on the hyperbilirubinemia of infants. Lancet 1958;1: bilirubin in the plasma. Pediatrics 1958;21:875-83.
1994-7. 80. Gartner LM, Snyder RN, Chabon RS. Kernicterus: high
63. Cohen A, Ostrow J. New concepts in phototherapy: incidence in premature infants with low serum bilirubin
photoisomerization of bilirubin IX-alpha and the concentrations. Pediatrics 1970;45:906-17.
potential toxic effect of light. Pediatrics 1980;65:740-50. 81. Jardine DS, Rogers K. Relationship of benzyl alcohol to
64. Lightner D, Wooldridge T, McDonagh A. Con- kernicterus, intraventricular hemorrhage, and mortality
figurational isomerization of bilirubin and the in preterm infants. Pediatrics 1989;83:153-60.
mechanisms of jaundice phototherapy. Biochim Biophys 82. Seidman DS, Paz I, Stevenson DK, et al. Neonatal
Res Comm 1979;86:235-43. hyperbilirubinemia and physical and cognitive
65. Lightner D, Woolridge T, McDonagh A. Photobilirubin: performance at 17 years of age. Pediatrics 1991;88:828-
an early bilirubin photoproduct detected by absorbance 33.
difference spectroscopy. Proc Natl Acad Sci 1979;76:29- 83. Van de Bor M, Ens-Dokkum, Schreuder AM, et al.
32. Hyperbilirubinemia in low-birthweight infants and
66. Kopelman AE, Brown RS, Odel GB. The bronze baby outcome at 5 years of age. Pediatrics 1992;89:359-64.
syndrome: a complication of phototherapy. J Pediatr 84. O’Shea TM, Dillard RG, Klinepeter KL, et al. Serum
1972;81:446-50. bilirubin levels, intracranial hemorrhage, and the risk
67. Clark CF, Torii S, Hamamoto Y, Kaito H. The ‘bronze of developmental problems in very-low-birthweight
baby’ syndrome: postmortem data. J Pediatr neonates. Pediatrics 1992;90:888-92.
1976;88:461-4. 85. Bergman I, Hirsch RP, Fria TJ, et al. Cause of hearing
68. Rubaltelli FF, Da Riol R, D’Amore ESG, Jori G. The loss in the high-risk premature infant. J Pediatr 1985;106:
bronze baby syndrome: evidence of increased tissue 95-101.
 Management of Hypotensionb in the Neonatal Period 69

7
Management of Hypotension
in the Neonatal Period

Sharon J English

INTRODUCTION resulted in two widely accepted definitions of

hypotension:
Hypotension is a commonly encountered problem
1. Mean arterial blood pressure less than the tenth
on the neonatal intensive care unit. It occurs in up to
centile for gestation/birth weight and postnatal
40% of very low birth weight (<1500g) infants, and
age.1
is almost universally seen in the extreme preterm
2. Mean arterial blood pressure less than gestational
baby, most commonly in the first 48 hours after birth.
age in weeks. This is derived from the first
Its importance lies in its possible causal link with
definition, following the observation that the 10th
brain injury in these infants.1-4
centile for mean blood pressure is roughly equal
There are numerous controversies surrounding
to the gestational age.5 It is worth remembering,
the management of hypotension in the preterm
however, that this is only valid in the first 48 hours
infant. As more extremely preterm babies are
of life, and that blood pressure rises steeply over
surviving, our accepted definitions of hypotension
the first five postnatal days.
are being challenged. The level of blood pressure
Most neonatal units use the gestational age as a
required to maintain tissue perfusion in these babies
guide when instituting treatment for hypotension.
is unknown, and the effects of standard therapy are
It is important, however, to assess other markers of
relatively under-researched. As a result, the level of
tissue perfusion, such as capillary refill time, the
hypotension at which treatment is instigated, and
presence of metabolic acidosis, and urine output when
the treatment chosen, largely remain subject to
deciding whether to treat.
personal preference.
PATHOGENESIS
DEFINITION
Hypovolaemia
Normal blood pressure has proven difficult to define
in preterm babies, partly because it varies with Hypovolaemia causes hypotension by decreasing the
gestational and postnatal age,5,6 but also because the preload, leading to reduced cardiac output. In
range of blood pressure, that will ensure adequate neonates hypovolaemia may result from acute
organ perfusion, is not known. There have been a haemorrhage (antenatal or postnatal), or from fluid
number of studies attempting to define the normal loss due to capillary leak, as seen in septicaemia or
range of blood pressure in the neonate. These have acute abdominal pathology. It is generally accepted
70 Textbook of Perinatal Medicine

that hypovolaemia is an uncommon primary cause CLINICAL RELEVANCE

of hypotension in the sick preterm infant.7 It may,
Tissue Perfusion
however, be implicated in a small number of babies,
and should always be considered. In neonatology blood pressure is regularly used as
a marker of systemic organ perfusion, and our efforts
Myocardial Dysfunction to maintain a normal blood pressure are based on
the belief that we are preserving tissue perfusion.
There is good evidence that myocardial dysfunction
Unfortunately, there are little data to support this.
plays an important role in the development of
In preterm infants there is only a weak correlation
hypotension in preterm infants in the first few hours
between blood pressure and cardiac output. 17
of life.8 There are several factors which contribute
Furthermore, since blood pressure is the function of
to myocardial dysfunction, the foremost of which is
blood flow and systemic vascular resistance, blood
immaturity of the myocardium. Hypoxic damage to
pressure may not reflect the blood flow in end
the heart muscle, acidosis, sepsis, and the presence
organs, as the vascular resistance will vary. Several
of a ductal shunt will all adversely affect myocardial
methods that may be useful for assessing systemic
function, leading to decreased cardiac output and
blood flow and tissue perfusion in neonates are being
hypotension. Congenital structural heart defects may
evaluated.
also present with hypotension secondary to reduced
Left ventricular output is often used in adults to
cardiac output.
assess systemic blood flow. Measurements of
Down-regulation of Adrenergic Receptors ventricular outputs in neonates may be confounded
by shunts through a patent ductus or foramen ovale.
There is growing evidence that a proportion of sick Systemic blood flow in the superior vena cava of
preterm infants have relative adrenal insufficiency, newborn infants has been successfully measured,
demonstrating a low cortisol response to human using Doppler echocardiography. Flow in the
corticotrophin releasing hormone. 9-12 Because superior vena cava is thought to reflect blood flow
glucocorticoids have a role in regulating the in the upper body, particularly the brain, and appears
expression of cardiovascular adrenergic receptors, to correlate well with left ventricular output in
these infants may be incapable of responding to babies with a closed duct.18
endogenous or exogenous sympathomimetic agents.13 Near infrared spectroscopy (NIRS) has been used
to measure haemoglobin flow and venous saturation
MEASUREMENT
in the forearm of hypotensive preterm babies. 19
Intra-arterial blood pressure monitoring through an Using this technique it is has been demonstrated that
umbilical or peripheral arterial catheter is widely peripheral oxygen delivery and consumption are
accepted as the gold standard. Studies comparing lower in hypotensive babies, but that oxygen
oscillometric with invasive measurement demons- extraction is similar to normotensive controls, with
trate that, providing cuff size is standardised, no rise in lactate concentration. This suggests that in
oscillometric measurement seems to be accurate hypotensive babies, peripheral oxygen delivery is still
within the normal range.14,15 However, concern has adequate for tissue demands, challenging the need
been expressed that at the lower levels it consistently to routinely correct hypotension. NIRS has also been
overestimates the blood pressure, providing false used to monitor cerebral circulation in sick premature
reassurance to the clinician. 16 In situations where infants. Unfortunately it has not clearly demonstrated
intra-arterial monitoring is not possible, it is whether there is a direct relationship between mean
important to also assess other markers of tissue arterial blood pressure and cerebral intravascular
perfusion. oxygenation.20,21
 Management of Hypotensionb in the Neonatal Period 71
As NIRS and cardiac output measurements are If one of the above causes is identified the primary
not continuous, their role in the decision to treat a treatment of the hypotension is to institute the specific
blood pressure level remains unclear. They do treatment for the underlying condition. In most
however question our present practice of using a instances, a cause for hypotension in the neonatal
single value below which treatment should be period will not be determined, although myocardial
started. Further research in this area is obviously dysfunction has been identified as a common factor,
needed before techniques such as this have direct and treatment will be initiated on the basis of unit
relevance to the management of hypotension. protocols. These normally follow a step-wise
approach beginning with volume support followed
Cerebral Injury by inotropes and in some the use of steroids.
Sick VLBW infants have reduced cerebral vascular
Volume Support
autoregulation compared with term infant, with the
postulated effect that significant hypotension may As previously discussed, hypovolaemia is an
lead to cerebral hypoperfusion. 22,23 Episodes of infrequent cause of hypotension in the sick preterm
systemic hypotension have been linked to cerebral infant.7 It is also difficult to diagnose in the immediate
haemorrhage, ischaemia, and to an increased risk of postnatal period, as indicators such as urine output
long term neurological sequelae.1,3,4 Hypotension is and capillary refill time are unreliable. However,
thought to lead to intraventricular haemorrhage by because it does occasionally occur, and it is relatively
causing ischaemic damage to the germinal matrix, easy to treat, most units adopt a policy of moderate
which bleeds on re-perfusion. It is unlikely that over- volume replacement prior to the institution of
enthusiastic correction of hypotension is involved, inotropes.
as episodes of hypertension are not associated with Fluids available for volume replacement may be
the occurrence of intraventricular haemorrhage. either crystalloid or colloid. The main difference
There is no clear evidence that systemic hypotension, between the two is the oncotic pressure effect,
in itself, leads to periventricular leukomalacia, 3 according to Starling’s law, and the theoretical
although it may be a factor in babies who are also difference in the length of time they remain in the
septic. Interestingly, there is little evidence to support intravascular space. However, the volume
the view that treating hypotension prevents any of administered appears to be more important than
these sequelae. protein content in producing a sustained increase in
blood pressure in preterm infants, 24 and isotonic
MANAGEMENT saline has been shown to be as effective as 5% albumin
The aim of treating hypotension is to preserve for treating hypotension in this population. 25
adequate organ perfusion and thus to prevent Crystalloids are also significantly cheaper than
complications such as cerebral injury. However, a colloids, and do not carry the same infection risk.
cause for hypotension should always be sought before As colloid and crystalloid are equally effective in
treatment is instituted. Important conditions to treating hypotension in the neonatal period, and
exclude include: considering the other advantages of using isotonic
• Blood loss saline, it would seem that the safest approach to
• Pneumothorax volume replacement would be to use 10-20ml/kg
• Sepsis 0.9% saline given over 30 minutes in the first instance.
• Patent ductus arteriosus 4.5% albumin should be reserved for babies who are
• High positive intrathoracic pressure (secondary likely to be hypovolaemic secondary to protein losing
to mechanical ventilation) conditions, such as babies who have undergone
• Heart failure gastrointestinal surgery.
72 Textbook of Perinatal Medicine

Dopamine and Dobutamine order to define a maximum dose for dopamine as

the use of high doses (> 25 ug/kg/min) has not been
Since myocardial dysfunction plays an important role
studied.
in the development of hypotension in preterm infants
Dobutamine is a relatively cardioselective
in the first few hours of life,8 it is clear that inotropic
sympathomimetic amine which exerts its positive
agents should be of some benefit in the management
inotropic action by direct stimulation of cardiac α-
of hypotension in these babies. The use of inotropes
and β-adrenoceptors. It has several theoretical
is, however, historically based rather than evidence
advantages over dopamine: (a) it has limited
based, and there are few data relating to associated
chronotropic effect (b) its use is not associated with
mortality and morbidity.
an increase in systemic vascular resistance27 (c) it does
Unsurprisingly, dopamine is more effective than
not rely on release of endogenous catecholamines
volume expansion in restoring normal blood pressure
for any part of its action.
in preterm infants.26 Dopamine is an exogenous
There is relatively little research into the use of
sympathomimetic amine which exerts its cardio-
dobutamine in preterm neonates, and it is generally
vascular effects by the dose dependent stimulation
used as a second line drug, in patients unresponsive
of dopaminergic and α- and β-adrenergic receptors.
to dopamine. It is infused at rates of 5-20µg/kg/
In the preterm population dopamine causes a dose
min, 27,32-35 and has been shown to increase left
dependent increase in mean arterial blood pressure
ventricular performance in these doses.36 The use of
in doses of 5-20µg/kg/min.27-29
high doses (> 25 ug/kg/min) has not been studied.
The main haemodynamic effects of dopamine are
Dobutamine can cause hypercontractile heart failure
to increase myocardial contractility and peripheral
in the presence of left ventricular hypertrophy,
vascular tone. The increase in myocardial contractility
resulting in paradoxical hypotension. 37 It should
is due both to a direct stimulation of α- and β-
therefore be used with caution in babies with existing
adrenoceptors, and indirectly through its action on
cardiac disease.
β 2-adrenoceptors, stimulating the release of
In the preterm infant dopamine is significantly
endogenous noradrenaline.30 In adults, the vasotonic
more effective than dobutamine in the treatment of
effects of dopamine are dose dependent. At doses
systemic hypotension, with no differences in short-
<5µg/kg/min dopamine stimulates peripheral
term complications such as intraventricular
dopaminergic receptors resulting in the selective
haemorrhage and necrotising enterocolitis.38 No data
dilatation of renal, mesenteric and coronary arteries.
are available on long term outcome for either drug.
At higher doses >10µg/kg/min it causes vaso-
constriction by stimulation of α-adrenergic
Other Agents
receptors. The dose dependent effects of dopamine
on vascular tone in the preterm neonate are less Most neonatal units advocate the use of adrenaline
clear,29,30 although there are emerging concerns that or noradrenaline in cases where dopamine and
it may have a potent vasoconstrictive effect on the dobutamine have failed to maintain ‘normal’ blood
pulmonary vasculature.31 pressure. However, very few studies have looked
Studies in adults suggest that, in sick hypotensive at the use of these agents in preterm infants, most of
patients, there is a down-regulation of adrenergic the data originating from animal studies. Both
receptors, requiring much higher doses of dopamine adrenaline and noradrenaline, when used in addition
to maintain blood pressure.13 However there have to dopamine, do restore normal blood pressure in
been no such studies in neonates. The fact that some sick, hypotensive neonates without causing
preterm infants may also have relative adrenal significant cerebral, myocardial or renal vaso-
insufficiency9 may explain the occurrence of pressor constriction.39,40 The use of these agents is however
resistance. Further research is clearly required in associated with a high mortality rate of over 50%.
 Management of Hypotensionb in the Neonatal Period 73
Dopexamine, a relatively new synthetic term risk of adverse neurological outcome, are well
catecholamine, with predominant â2-adrenergic and documented and probably prohibit prophylactic
dopaminergic activity, has been shown to be effective use. 48
in raising blood pressure, and improving arterial pH Based on the available evidence the use of
and urine output.41 In neonates who are hypotensive steroids in the treatment of severe, intractable
secondary to septic shock, methylene blue, an hypotension, resistant to inotropes, is probably
inhibitor of soluble guanylate cyclase, has been shown justified. This may be in the form of a single dose of
to be effective in increasing blood pressure.42 250µg/kg dexamethasone or a five day tapering
Further research is clearly needed in this area course of hydrocortisone starting at 2.5mg/kg qds.
before the routine use of any of these agents can be Obviously there is a balance of risks against benefits,
recommended. but the short term benefit of preventing death must
outweigh the long term risks, which are anyway
Steroids unproven. Further research is obviously needed to
Antenatal steroids are now commonly given to determine the optimum dose and course.
mothers in preterm labour. They have been shown
to have an independent effect (from the effect on CONCLUSION
respiratory distress syndrome) on reducing the The management of hypotension in preterm infants
incidence of hypotension in the preterm infant.43 remains a controversial area in current neonatal
In neonates with hypotension who are practice. Research in this area is relatively limited,
unresponsive to volume or pressor administration, which in part is probably due to the difficulty in
there is growing evidence that steroids may be of obtaining continuous measures of tissue perfusion.
some value. The theory is that infants with refractory There is no consensus on either the definition of
hypotension may have relative adrenal
hypotension or the level at which treatment should
insufficiency.9-12 The resulting low levels of circulating
be initiated. The effects of aggressive correction are
cortisol in these babies may be insufficient to
relatively under-researched, and there are few data
counteract any down-regulation of cardiovascular
on morbidity and mortality in relation to the use of
adrenergic receptors which occurs in critical illness,13
volume support and inotropes. The aim of
rendering them resistant to treatment with
management must be to attain adequate tissue
sympathomimetic agents.
perfusion and oxygenation, but there may be little
In infants with severe hypotension refractory to
or no relation between blood pressure and organ
both volume expansion and inotropes, treatment with
perfusion. Further research is required into methods
either single dose dexamethasone or a five-day
of assessing tissue perfusion, which can be used
course of hydrocortisone has been shown to be
alongside monitoring of blood pressure to guide the
successful, with discontinuation of inotropes within
54 hours. This effect is sustained for many days neonatologist in deciding when to intervene.
following the administration of steroids. 12,44-46 Continuous invasive arterial blood monitoring
Although the effect may not be evident for up to six remains the preferred method of recording blood
hours, in my experience it is usually seen within two pressure. Decisions to treat hypotension should be
hours of treatment. based on the general condition of the infant, not on
There are some groups who have advocated the the mean arterial blood pressure alone. On the basis
use of hydrocortisone in smaller doses as prophylaxis of the available evidence Fig. 7.1 outlines a suggested
against hypotension in at risk VLBW infants.47 Side guideline for the management of hypotension in the
effects from post-natal steroids, including the long neonatal period.
74 Textbook of Perinatal Medicine

Volume expansion 10-20ml/kg 0.9% saline 11. Heckmann M, Wudy SA, Haack D, Pohlandt F. Serum
cortisol concentrations in ill preterm infants less than
30 weeks gestational age. Acta Paediatr 2000;89(9);1098-
1103.
1st line inotrope Dopamine 5-20µg/kg/min 12. Ng PC, Lam CWK, Fok TF et al. Refractory hypotension
in preterm infants with adrenocortical insufficiency. Arch
Dis Child Fetal Neonatal Ed 2001;84:F122-F124
2nd line inotrope Dobutamine 5-20µg/kg/min 13. Hausdorff WP, Caron MG, Lefkowitz RJ. Turning off
life threatening the signal: desensitization of b-adrenergic receptors.
hypotension FASEB J 1990;4:33-40
14. Kimble Kj, Darnall RA, Yelderman MD. An automated
Noradrenaline technique for estimating mean arterial pressure in
0.2-1µg/kg/min critically ill newborns. Anesthesiology 1981;54:423-425
15. Dellagramaticas HD, Wilson AJ. Clinical evaluation of the
Dinamap non-invasive blood pressure monitor in pre-
term neonates. Clin Phys Physiol Meas 1981;2:271-276.
Rescue therapy Dexamethasone 250µg/kg single dose 16. Diprose GK, Evans DH, Archer LNJ, Levene MI.
Fig. 7.1: Flow chart for management of hypotension in neonates Dinamap fails to detect hypotension in very low
(reproduced with permission) 49 birthweight infants. Arch Dis Child 1986;61:771-773.
17. Kluckow M, Evans N. Relationship between blood
pressure and cardiac output in preterm infants requiring
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18. Kluckow M, Evans N. Superior vena cava flow in
1. Watkins AMC, West CR, Cooke RWI. Blood pressure
newborn infants: a novel marker of systemic blood
and cerebral haemorrhage and ischaemia in VLBW
flow. Arch Dis Child Fetal Neonatal Ed 2000;82:F182-
infants. Early Hum Dev 1989;19:103-110.
187.
2. Miall-Allen VM, De Vries LS, Whitelaw AGL. Mean
19. Wardle SP, Yoxall CW, Weindling AM. Peripheral
arterial BP and neonatal cerebral lesions. Arch Dis Child
oxygenation in hypotensive preterm babies. Pediatr Res
1987;62:1068-1069.
1999;45(3):343-349.
3. Dammann O, Allred EN, Kuban KC et al. Systemic
20. Tsuji M, Saul JP, du Plessis A et al. Cerebral intravascular
hypotension and white-matter damage in preterm
oxygenation correlates with mean arterial pressure in
infants. Dev Med Child Neurol 2002;44(2):82-90. critically ill premature infants. Pediatrics 2000;106(4):625-
4. Low JA, Froese AB, Galbraith RS et al. The association 632.
between newborn hypotension and hypoxemia and 21. Wardle SP, Yoxall CW, Weindling AM. Determinants of
outcome during the first year. Acta Paediatr 1993; cerebral fractional oxygen extraction using near infrared
82(5):433-437. spectroscopy in preterm neonates. J Cereb Blood Flow
5. Nuntnarumit P, Yang W, Bada-Ellzey HS. Blood pressure Metab 2000;20(2):272-279.
measurements in the newborn. Clin Perinatol 1999; 22. Panerai RB, Kelsall AWR, Rennie JM et al. Cerebral
26:981-996. autoregulation dynamics in premature newborns.
6. Lee J, Rajadurai VS, Tan KW. Blood pressure standards Stroke 1995;26:74-80
for very low birthweight infants during the first day of 23. Pryds O, Edwards AD. Cerebral blood flow in the
life. Arch Dis Child Fetal Neonatal Ed 1999;81:F168-170. newborn infant. Arch Dis Child Fetal Neonatal Ed
7. Dimitriou G, Greenough A, Mantagos J, Skinner S. 1996;74:F63-69.
Metabolic acidosis, core-peripheral temperature 24. Emery EF, Greenough A, Gamsu HR. Randomised
difference and blood pressure response to albumin controlled trial of colloid infusions in hypotensive
infusion in hypotensive, very premature infants. J preterm infants. Arch Dis Child 1992;67:1185-1188.
Perinat Med 2001;29(5):442-445. 25. King W So, Tai F Fok, Pak C Ng et al. Randomised
8. Gill AB, Weindling AM. Cardiac function in the shocked controlled trial of colloid or crystalloid in hypotensive
very low birthweight infant. Arch Dis Child 1993;6817- preterm infants. Arch Dis Child Fetal Neonatal Ed
6821. 1997;76:F43-46.
9. Scott SM; Watterberg KL. Effect of gestational age, 26. Gill AB, Weindling AM. Randomised controlled trial of
postnatal age, and illness on plasma cortisol concen- plasma protein fraction versus dopamine in hypotensive
trations in premature infants. Pediatr Res 1995;37(1):112- very low birth weight infants. Arch Dis Child 1993;
116. 69:284-287.
10. Tantivit P, Subramanian N, Garg M et al. Low serum 27. Roze JC, Tohier C, Maingueneau C et al. Response to
cortisol in term newborns with refractory hypotension. dobutamine and dopamine in the hypotensive very
J Perinatol 1999;19(5):352-357. preterm infant. Arch Dis Child 1993;69:59-63.
 Management of Hypotensionb in the Neonatal Period 75
28. Padbury JF, Agata Y, Baylen BG et al. Dopamine 39. Seri I, Evans J. Addition of epinephrine to dopamine
pharmacokinetics in critically ill newborn infants. J increases blood pressure and urine output in critically
Pediatr 1986;110:293-298. ill extremely low birthweight neonates with
29. Seri I, Abbasi S, Wood D, Gerdes JS. Regional uncompensated shock. Pediatr Res 1998; 43(4)suppl
hemodynamic effects of dopamine in the sick preterm 2:194.
neonate. J Pediatr 1998:133:728-734. 40. Derleth DP. Clinical experience with norepinephrine
30. Seri I. Cardiovascular, renal, and endocrine actions of infusions in critically ill newborns. Pediatr Res 1997;41(4)
dopamine in neonates and children. J Pediatr part 2:145.
1995;126:333-344. 41. Kawczynski P, Piotrowski A. Circulatory and diuretic
31. Liet J-M, Boscher C, Gras-Leguen C et al. Dopamine effects of dopexamine infusion in low-birth-weight
effects on pulmonary artery pressure in hypotensive infants with respiratory failure. Intensive Care Med
preterm infants with patent ductus arteriosus. J Pediatr 1996;22(1):65-70.
2002;140:373-375. 42. Driscoll W, Thurin S, Carrion V et al. Effect of methylene
32. Klarr JM, Faix RG, Pryce CJE, Bhatt-Mehta V. blue on refractory neonatal hypotension. J Pediatr
Randomized, blind trial of dopamine versus dobutamine 1996;129:904-908.
for treatment of hypotension in preterm infants with 43. Moise AA, Wearden ME, Kozinetz CA, Gest AL.
respiratory distress syndrome. J Pediatr 1994;125:117- Antenatal steroids are associated with less need for
122. blood pressure support in extremely preterm infants.
33. Greenough A, Emery EF. Randomized trial comparing Paediatrics 1995;95(6):845-850.
dopamine and dobutamine in preterm infants. Eur J 44. Bourchier D, Weston PJ. Randomised trial of dopamine
Pediatr 1993;152(2):164-165. compared with hydrocortisone for the treatment of
34. Hentschel R, Hensel D, Brune T et al. Impact on blood hypotensive very low birth weight infants. Arch Dis
pressure and intestinal perfusion of dobutamine or Child Fetal Neonatal Ed 1997;76:F174-F178.
dopamine in hypotensive preterm infants. Biol Neonate 45. Seri I, Tan R, Evans J. Cardiovascular effects of
1995;68(5):318-324. hydrocortisone in preterm infants with pressor-resistant
35. Miall-Allen VM, Whitelaw AGL. Response to dopamine hypotension. Pediatrics 2001;107(5):1070-1074.
and dobutamine in the preterm infant less than 30 46. Gaissmaier RE, Pohlandt F. Single-dose dexamethasone
weeks gestation. Crit Care Med 1989;17:1166-1169 treatment of hypotension in preterm infants. J Pediatr
36. Stopfkuchen H, Queisser-Luft A, Vogel K. Cardio- 1999;134:701-705.
vascular response to dobutamine determined by systolic 47. Rajah V. Treatment of hypotension in very low
time intervals in preterm infants. Crit Care Med birthweight infants (letter). Arch Dis Child Fetal
1990;18(7):722-724. Neonatal Ed 1998;78:F156.
37. Germanakis I, Bender C, Hentscel R et al. Hyper- 48. Sweet DG, Halliday HL. A risk-benefit assessment of
contractile heart failure caused by catecholamine therapy drugs used for neonatal chronic lung disease. Drug
in premature neonates. Acta Paediatr 2003;92:836-838. Safety 2000;22:389-404.
38. Subedhar NV, Shaw NJ. Dopamine versus dobutamine 49. Dasgupta SJ, Gill AB. Hypotension in the very low
for hypotensive preterm neonates. Cochrane Database birthweight infant: the old, the new, and the uncertain.
Systemat Rev 2000;2:CD001242. Arch Dis Child Fetal Neonatal Ed 2003;88:F450-F454.
76 Textbook of Perinatal Medicine

8
Cytokines and
Neonatal Disease

L Cornette, H. Logghe

ABSTRACT By definition, an inflammatory response is a

In this chapter, we summarise recent insights within protective response to an infection or an injury,
the context of fetal/neonatal cytokine production and mediated by pro-inflammatory cytokines, i.e. low
neonatal diseases. The currently available evidence molecular weight glycoproteins, predominantly
suggests a link between fetal/neonatal inflammatory produced by the monocyte-macrophage cell line at
responses and neonatal (neuro)morbidity. We will the inflammatory site. Pro-inflammatory cytokines
therefore be studying those factors affecting such (e.g. IL-1β, IL-18, IFN-γ, TNF-α) are primarily
relationship, i.e. (i) timing and (ii) nature of the responsible for initiating an effective defence (i.e.
infectious/inflammatory process, (iii) anti-insult acute phase response) against exogenous pathogens,
strategies, (iv) morbidity in organs other than the whereas anti-inflammatory cytokines (e.g. IL-4, IL-
brain, (v) genetic influences and (vi) environmental 10) are involved in the down-regulation of
factors. exacerbated inflammatory processes and maintenance
of homeostasis for proper functioning of the vital
FETAL AND NEONATAL organs. 1
INFLAMMATORY RESPONSES
This review is designed to guide the reader through Fetal Inflammatory Response Syndrome
the framework given in the accompanying figure, The majority of women delivering before 28 weeks,
summarising the concept of perinatal inflammation/ with or without preterm premature rupture of
infection and current factors that may influence the membranes (PrePROM), show evidence of intra-
overall outcome under study. Several diseases in the uterine infection. A mechanism postulated is
newborn, such as sepsis, chronic lung disease and microbial invasion of the uterine cavity resulting in
broncho-pulmonary dysplasia (CLD/BPD) and NEC a fetal systemic cytokine or inflammatory response
are characterized by the presence of inflammation. through aspiration, otitis, conjunctivitis or
Given the mounting evidence suggesting a continuum omphalitis.4 However, only a small proportion of
between ante- and postnatal inflammation, and
these women will have a positive amniotic fluid
adverse neonatal outcome,2,3 we will first study the
culture.5 Intra-amniotic inflammation would therefore
fetal inflammatory response, prior to expanding on
appear to be a better predictor for imminent preterm
inflammatory responses emerging in the neonatal
delivery rather than intraamniotic infection.6
period.
 Cytokines and Neonatal Disease 77

Fig. 8.1: The fetal/neonatal inflammatory response

Such active participation of the fetus in a systemic a FIRS, rather than the maternal infection, causes fetal
antenatal inflammatory response is therefore multi-organ injury.9
commonly studied using cordocentesis techniques.
Indeed, the fetal inflammatory response syndrome Fetal Brain/Fetal Neurotoxicity
(FIRS) was originally defined by relating increased The fetal brain has been extensively studied within
fetal cord plasma IL-6 to the onset of spontaneous the context of intra-uterine inflammation. 10,11
preterm labour (through increased fetal adrenal Funisitis, i.e. infection of the umbilical cord, and
cortisol production and subsequent prostaglandine chronic chorio-amnionitis have been associated with
release).7 More recent studies have revealed that the an increased risk for intraventricular haemorrhage
FIRS involves the synergistic action of different (IVH).12,13 Fetal vasculitis has been linked with an
cytokines and several complex host defence eleven-fold increased risk for development of
mechanisms. 8 In addition, through the study of periventricular echolucencies.14 Histopathological
differential placental versus fetal immune cytokine examination of infant brain specimens shows over-
responses within animal models, we now know that expression of TNF-a in the microglia cells of PVL
78 Textbook of Perinatal Medicine

lesions, with cytokine production being highest in administration of a low dose of bacterial endotoxin
infected infants.15 (LPS) dramatically sensitizes the immature brain to
However, a clear link between intrauterine injury and induces cerebral infarction in response to
infection/inflammation and neurologic outcome in short episodes of hypoxia-ischaemia that by
preterm babies is not confirmed in all studies, as themselves cause no or little injury. 18 Thirdly,
much of the confusion arises from different timings increased levels of IL-1 and TNF-α, and neutrophil
of blood sampling across different studies. Cytokine invasion into infarcted areas have been reported
levels in neonatal blood (day two or three) are likely following hypoxia-ischaemia in the absence of
to be influenced by respiratory or infectious infection.18-20 Fourthly, complex interaction effects
complications, as well as different levels of intensive between both inflammation and excitotoxicity exist,
care, and thus may be different from umbilical cord as for example IL-1β perpetuates excitotoxic brain
blood levels.16 In order to establish a causal link damage in vivo, whereas it ameliorates neuronal
between antenatal infection and neonatal brain death in vitro.20 Others have reported similar dual
disease in individual cases, one needs to provide neurotrophic and detrimental effects exerted by
evidence of placental infection, elevated cytokines following ischaemia.21 Finally, a complex
inflammatory mediators in both umbilical cord and interaction between hypoxia-ischaemia and
postnatal infant blood, presence of moderate to inflammation is also reflected in the neuropathology
severe encephalopathy and/or neuroradiological of WM abnormalities observed in infants born to
confirmation of brain injury. mothers with chorio-amnionitis.22 Careful review of
Proposed mechanisms for neurotoxicity associated animal work suggests that cytokines can be
with pro-inflammatory cytokines comprise (1) a neurotoxic through a process of “sensitising” the
direct cytolytic effect on neurones and oligo- immature brain, i.e. lowering the threshold at which
dendrocyte precursors (either through in situ a hypoxic-ischaemic insult triggers apoptosis.23
cytokine production, or through systemic cytokines Further clinical studies investigating the relationship
crossing the blood-brain-barrier), (2) induction of between fetal infection/inflammation, feto-placental
excitatory amino acid release, (3) increased caspase thrombosis and subsequent adverse neurological
activity resulting in amplified apoptosis, (4) outcome will therefore be challenging.24
abnormalities in the coagulation cascade or (5) fetal
hypotension.10,14,15,17 Further clarification of these Other Fetal Morbidity
and other mechanisms will increase the likelihood Fetal exposure to infection/inflammation, similar to
of successful therapeutic interventions. antenatal administration of glucocorticoids can, on
Many studies focus on the interaction between the one hand, result in maturation of the lungs.
cytokine and excitatory amino acid release (e.g. However, antenatal chorio-amnionitis can also prime
glutamate). It is now recognised that an antenatal the fetal lung to respond differently to postnatal
inflammation-related insult to the central nervous events, increasing the risk of CLD/BPD (see below).25
system comprises both infection (pro-inflammatory Histological chorio-amnionitis has been associated
cytokine release) and hypoxia-ischaemia (excessive with a noticeable reduction of volume and
excitatory neurotransmittor release). The interaction corticomedullary differentiation of the thymus, a
between both entities is, however, complex. Firstly, reduced number of thymocytes, and infiltration of
injury to the brain during antenatal infection may be macrophages into the parenchyma.26
secondary either to cytokinaemia, i.e. cytokines Finally, a FIRS can result in preterm delivery (and,
crossing the blood-brain-barrier, or to the hence, possible neonatal morbidity), as increased fetal
interruption of placental blood flow resulting in and not maternal serum IL-6 is one of several
asphyxia.17 Secondly, animal work indicates that cytokines that precedes imminent preterm delivery.8
 Cytokines and Neonatal Disease 79
Neonatal Inflammatory Responses Inflammatory mediators involved in NEC are
tissue and circulating pro-inflammatory cytokines
Sepsis
(IL-1, IL-6, IL-8, TNF-α), platelet-activating factor
The progression to septic shock in infants born to (PAF), leukotriene C4, iNOS, endothelin-1 (ET-1) and
mothers with acute chorio-amnionitis is rarely seen thromboxane. These mediators are believed to
in the immediate neonatal period. However, a stimulate signal transduction and gene transcription,
significant association between funisitis and leading to apoptosis or programmed cell death,
congenital sepsis, has been described.2 secondary inflammation, increased intestinal wall
Neonatal sepsis in the absence of chorio-amnionitis permeability and, ultimately, necrosis. Conversely,
is predominantly mediated by IL-1, IL-6 and IL-10, IL-11, IL-12, erythropoietin and epidermal
TNF-α. Sepsis-related mortality is well correlated growth factor (EGF) have been shown to play an
with multiple organ failure (MOF), caused by
important role in the prevention of intestinal injury.
uncontrolled inflammation, immunodeficiency
Using a neonatal rat model, the protective effect of
(prolonged neutropenia, lymphopenia, hypo-
maternal milk has been associated with increased ileal
gammaglo-bulinaemia) and endothelial injury with
production of anti-inflammatory IL-10.30 Also, enteric
thrombotic micro-angiopathy. Septic newborns have
organisms such as non-virulent Salmonella strains are
low vWF cleaving metalloprotease activity
capable of attenuating intestinal inflammatory
(ADAMTS13), resulting in high amounts of
responses.31
circulating ultra-large vWF multimers that lead to
microvascular platelet thrombosis and MOF.27
Chronic Lung Disease (CLD)/Bronchopulmonary
Little is known about the profile of pro- and anti-
Dysplasia (BPD)
inflammatory cytokines in septic preterm infants, in
whom the immune system may be considered as Many aspects of the inflammatory response in the
immature. An exaggerated pro-inflammatory context of CLD/BPD remain to be elucidated.
response together with an inadequate anti- On the one hand, artificially induced lung
inflammatory compensation may result in an adverse inflammation through intra-amniotic injection of pro-
clinical outcome, as a persistent high IL-6/IL-10 ratio inflammatory cytokines in rabbits results in increased
implies a poor prognosis in very low birth weight lung volumes, increased surfactant production and
patients.1 Alternatively, a persistently high IL-10 improved gas exchange.32 Likewise, fetal exposure
concentration can be an early indicator of a poor to chorio-amnionitis can lead to enhanced lung
prognosis in preterm neonates with sepsis.28 maturation, similar to the effect yielded by antenatal
glucocorticoids.25 This is in line with the findings from
Necrotizing Enterocolitis (NEC) the UK Epicure study, indicating that infants born
NEC is a devastating intestinal disease that primarily below 26 weeks gestation are more likely to die in
occurs in low birth weight premature infants. Its the absence of chorio-amnionitis and antenatal
aetiology is not well-known, and may consist of administration of glucocorticoids.33
intestinal immaturity, intestinal ischaemia, changes Alternatively, as previously mentioned, antenatal
in microbiological environment related to enteral inflammation can disrupt the process of
feeding practices, with an increased inflammatory alveolarization, resulting in alveolar simplification
response as the final common pathway. The evidence and priming of the fetal lung, rendering it vulnerable
suggesting a causal association between chorio- for further injury postnatally.25,34 Indeed, prolonged
amnionitis and subsequent NEC is very sparse, postnatal mechanical ventilation (>7 days) of lungs
although some retrospective case-control studies that are primed in this way, together with postnatal
suggest a significantly higher frequency of PrePROM infection (sepsis or pneumonia), may result in a
and chorio-amnionitis in infants with NEC.29 secondary inflammatory response and the
80 Textbook of Perinatal Medicine

development of CLD/BPD. 35,36 Support for this outcome either via infection/inflammation induced
hypothesis stems from the observation that white matter damage or via infection/inflammation
predominantly memory cells from the immune induced preterm birth.42,43 A recent meta-analysis (23
system, i.e. lymphocytes and monocytes, are studies) revealed a significant association between
observed in broncheo-alveolar lavage fluids obtained clinical chorio-amnionitis, cystic PVL (RR 3.0; 95%
from ventilated and antenatally inflamed animal CI, 2.2-4.0) and cerebral palsy (CP) (RR 1.9; 95% CI,
lungs.37 1.4-2.5), whereas histologic chorio-amnionitis was
Ongoing lung damage in the premature infant associated with cystic PVL (RR 1.6; 95% CI, 1.5-2.9)
may also be caused by failure to downregulate but less with CP (RR 1.6, 95% CI, 0.9-2.7).12 The same
inflammatory responses.38 Data suggest that preterm group recently described an increased risk for
newborns with lung inflammation may be unable to neurological sequelae in term infants with funisitis.44
activate the anti-inflammatory cytokine IL-10. It is also likely that postnatal infection/inflammation
Comparing preterm infants with term infants in contributes to a long-term adverse neuro-
respiratory failure, the ability of lung macrophages development, as a recent UK trial indicated a four
to produce TNF-a is nearly identical, whereas a trend times higher risk of CP amongst infants with neonatal
towards diminished levels of IL-10 expression exists sepsis compared to those without. 45 A significant
in the preterm group. 39 Such data suggest an association between increased levels of inflammatory
imbalance between pro- and anti-inflammatory cytokines in the newborn and the development of
responses, leading to CLD/BPD. spastic di-, quadri- and hemiplegia has been
The role of transforming growth factor-β (TGF- demonstrated, 24 with increased concentrations of
β), i.e. a cytokine participating in adult chronic cytokines (TNF-α, IL-1β, IL-6 and the anti-
inflammatory diseases, is still to be elucidated in inflammatory IL-10) correlating with cerebral lesions
neonatal inflammatory processes.40 detected by MRI.46
However, several variables account for the
Retinopathy of Prematurity (ROP) observation that not all studies suggest such
ROP is an ischemia-induced proliferative retinopathy, association between infection/inflammation and
affecting premature infants with low birth weight. adverse outcome in newborn infants (see Figure),
The process of retinal neovascularization in ROP is i.e. (1) timing issues, (2) nature of the infectious/
complex, involving several angiogenic factors, such inflammatory process, (3) established and new anti-
as vascular endothelial growth factor. Potential insult strategies, (4) morbidity in organs other than
medical therapies for ROP not only include the brain, (5) genetic influences and (6) environmental
modulators of such angiogenic factors but also factors.
endogenous inhibitors and anti-inflammatory drugs.
The latter drugs have shown to be efficacious against Timing Issues
neovascularization in several animal models of Clinical chorio-amnionitis is based on the acute
oxygen-induced retinopathy, and are currently presence of two or more of the following clinical signs:
already trialled for adult diabetic retinopathy and maternal temperature, maternal tachycardia, fetal
age-related macular degeneration.41 tachycardia, maternal leucocytosis, uterine
tenderness and foul smelling amniotic fluid.
PERINATAL INFLAMMATORY RESPONSES,
However, intra-uterine infection may also remain
NEONATAL DISEASE AND NEUROMORBIDITY
undetected for months as a chronic indolent
Both animal and clinical data suggest that intra-uterine inflammatory process. Also, bacterial vaginosis can
infection can be linked to adverse neurological result in intra-uterine colonization present at
 Cytokines and Neonatal Disease 81
conception; if the organisms are not cleared within unable to prospectively identify those infants at
four to eight weeks after the expanding membranes greatest risk for developing (neuro)morbidity; (2)
seal the endometrial cavity, the infection may result the presence of both beneficial and detrimental
in preterm delivery. Hence, in the absence of clear physiologic effects by cytokines complicates any
criteria to identify the severity and duration of in targeted intervention; (3) the origin of perinatally
utero infection, it is not surprising that the clinical acquired brain damage is currently thought to be
outcome is unpredictable, ranging from normal fetal multifactorial, possibly including hypoxia/perfusion
development with histologic chorio-amnionitis as an failure, thyroid hormone deficiency, genetic factors,
incidental finding, to severe chorio-amnionitis thrombotic processes, growth factor deficiency,
leading to in or ex utero death with long-term excess free reactive oxygen production, and antenatal
neurological sequelae.25 infection. 51

Type and Presence of Pathogen Antenatal Strategies

Not only timing but also the nature of the infection Steroids: Endogenous glucocorticoids, released by the
may determine the outcome. 43 For example, fetal adrenal cortex, down-regulate the expression
administration of a low dose of Escherichia Coli and action of cytokines both in the periphery and in
(O55:B5) endotoxin to rats, prior to short periods of the brain.52 Likewise, antenatal administration of
hypoxia-ischaemia, increases the overall brain exogenous steroids can result in a reduced FIRS.53
injury.18 However, the opposite effect is observed Antenatal steroids administered to women at risk
using a different bacterial toxin (lipoteichoic acid) in for preterm delivery decrease the risk of death,
a similar rat model.47 Amniotic fluid contaminated respiratory distress 54 and protect very-low-birth-
with Escherichia Coli but not Ureaplasma urealyticum weight infants against the risk of neuro-morbidity.55
and Mycoplasma increases the risk of CLD/BPD,48 However, antenatal steroids do not reduce the
although one could criticise that the latter two species incidence of CLD/BPD, as the drug induces alveolar
are more difficult to grow in vitro. simplification and hence primes the lungs for
Evidence suggests that preterm delivery and postnatal ventilation-mediated injury.25 In addition,
neonatal morbidity may be better predicted by the whereas betametasone yields an initial suppressive
degree and nature of the FIRS to infection (i.e. the effect on inflammation, it may ultimately result in
host response) than by the presence of (a combination “late inflammation”.56
of) pathogens (i.e. positive amniotic cultures).8,49 It It thus seems that the exposure to infection/
is within this context that functional polymorphisms inflammation together with antenatal administration
of the different cytokines may play a role as they of glucocorticoids can both “mature and injure” the
may determine each individual’s genetic susceptibility fetus. The “net effect” in terms of adverse neonatal
and response to infection (see below). outcome may depend on exposure to postnatal
noxious interventions such as ventilation, high
Anti-Insult Strategies concentration of oxygen, etc. These time-dependent
As perinatal infection/inflammation seems to be an interactions between steroids and inflammation
important risk factor for adverse neonatal outcome, warrant further investigation.
the development of appropriately designed (brain) Antibiotics: The administration of antibiotics following
protective strategies will, to a great extent, become PrePROM results in a significant reduction in chorio-
indispensable within neonatal care over the next amnionitis, a delay in delivery and reduced neonatal
decade. 50 However, the difficulties experienced morbidity (e.g. neonatal infection, use of surfactant,
hereto are at least threefold: (1) we are currently oxygen need, abnormal findings on cranial
82 Textbook of Perinatal Medicine

ultrasound).57 Due to an increased risk of NEC, co- indeed observed when treating monocytes with
amoxiclav should be avoided, whilst erythromycin dexamethasone in vitro.60 Although early post-natal
seems a better choice, possibly because of a smaller anti-inflammatory therapy could help in preventing
endotoxin release by damaged bacteria.58 The current CLD/BPD, prophylactic dexamethasone cannot be
treatment for clinical chorio-amnionitis is delivery recommended, as there are a number of potential
of the fetus and subsequent treatment with interactions between surfactant and cytokine effects
antibiotics. Maternal treatment in such cases is on the preterm lung which have not been fully
ineffective because the amniotic cavity is largely a evaluated.38 In addition, postnatal administration of
sequestered site, inaccessible to antibiotics. steroids has been associated with neurodevelop-
Mode of delivery: Normal labour is always associated mental impairment, warranting further randomised
with some form of hypoxic stress, which may be controlled evaluation of its risks versus benefits.61
detrimental if the fetal brain is more vulnerable to It is to be hoped that we will see multi-centre
hypoxia in the presence of antenatal infection/ clinical trials over the next decade, evaluating
inflammation. However, there is no clear evidence inflammatory protection and inflammatory response
that suggests an elective caesarean section is more modification in the newborn infant. Such requires
neuroprotective than normal labour in the case of further detailed animal work of immune modulatory
(chronic or acute) chorio-amnionitis. drugs and their kinetics within the newborn age
group. 62 Inflammatory protection can be achieved
Postnatal Strategies by exogenous administration of IL-10, although
complex differential effects between its central and
Non-specific therapy for severe sepsis comprises
peripheral effects need further exploration.63 The
antibiotics, aggressive fluid resuscitation, inotropes
exogenous administration of response modifiers/
and ventilatory support. More specific strategies are
receptor antagonists currently evaluated in animal
aimed at tapering of sepsis-related immunodeficiency
models (e.g. IL-1β receptor antagonist or soluble
syndromes by using recombinant growth factors,
TNF-receptor) may not be without risk, as many of
such as G-CSF, GM-CSF and interferon. Recombinant
the pro-inflammatory cytokines exhibit fragile
activated protein C is an anti-inflammatory, anti-
equilibria of biological activity.64 As an example, the
thrombotic and fibrinolytic agent that has been
presence of TNF-α can have beneficial effects,
successfully used in severe sepsis in adults.
whereas blocking TNF-α in adults with septic shock
However, its use is not approved in infants or
results in increased mortality. 65 Future strategies
children.59
therefore must aim to “redress the optimal cytokine
Treatment of NEC currently consists of antibiotics
balance” rather than “preventing the inflammatory
and haemodynamic stabilisation, with in some cases
response”.
the need to proceed to surgery. However, a better
understanding of the mechanisms underlying its Morbidity in Organs other than the Brain
pathogenesis is needed. For example, understanding
the protective effects of maternal milk could be Is there evidence that a neonatal inflammatory
beneficial either in the prevention of NEC or in the response (e.g. sepsis, NEC) involves an increased risk
development of future therapeutic strategies to cure for neuromorbidity ?
NEC.30
Postnatal steroids are commonly administered in Sepsis/NEC
severe CLD/BPD, as data suggest that preterm The role of pro-inflammatory cytokines during sepsis/
newborns with lung inflammation may be unable to NEC in the aetiology of CP remains controversial.
activate anti-inflammatory cytokine pathways. 39 However, preliminary reports suggest a significant
Dose-related inhibition of cytokine synthesis is association between TNF-α, IL-8, and an abnormal
 Cytokines and Neonatal Disease 83
cognitive and psychomotor outcome at the age of these cytokines in the fetal brain may be enough to
24-28 months.66 result in adverse neurological outcome.74
Such outcome related research is complicated by
Lung Inflammation the fact that (1) one needs to examine the frequencies
A complex interaction exists between lung and brain of several cytokine genotypes, (2) in infants as well
inflammatory processes. Lung disease has been as in mothers, (3) whilst taking into account
mimicked in transgenic mice that over-express demographics, newborn illness severity and several
human IL-1β in the respiratory epithelium. 67 The other risk factors. The ultimate goal is to use
expression of a number of genes participating in identified SNPs as a biologic guide to target new
inflammation was also increased in their brains, anti-inflammatory strategies towards the most
although no major histological differences were genetically vulnerable premature infants (i.e.
detected compared to control animals. Ventilation pharmaco-genomics).
of inflamed preterm lungs may also result in more
lung inflammation, creating an excess of cytokines Environment
in the systemic circulation, which in turn may Impaired neurodevelopment after a fetal/neonatal
promote the development of CLD/BPD, and, in inflammatory response most likely occurs via a
addition, may result in remote (brain) damage.37 complex interaction between genetic and
environmental processes, such as home environment,
Host–Genetics
maternal education, socio-economic and ethnic
Single-nucleotide polymorphisms (SNPs) consist of backgrounds.
single base substitutions in a DNA sequence. Almost
all genes contain SNPs, but only a minority of SNPs CONCLUSION
result in amino acid variation in protein products. In
We investigated the available evidence suggesting a
addition, many of the functional SNPs occur in the
link between inflammatory responses and adverse
promotor region rather than the gene itself and affect
neonatal outcome. Currently there is no silver bullet
protein levels through altered transcription.
to prevent an impaired neurodevelopmental outcome
Polymorphism-association studies compare the
in the event of a fetal and/or neonatal inflammatory
prevalence of a genetic marker in persons with a given
response. Future research needs to focus on (1) the
condition to the prevalence in controls. 68 Gene
relation between fetal, maternal and neonatal
polymorphisms that may influence perinatal outcome
inflammatory processes, i.e. CLD/BPD and NEC; (2)
through alteration of the response to infection, have
the interaction between inflammatory responses and
been reported for the IL-1 receptor antagonist,69 IL-
genetic or environmental factors; (3) the use of
6,70 Interferon-γ,71 and TNF-α.72 Likewise, cytokine
advanced techniques for laboratory research and
gene polymorphisms may modify the risk for brain
injury and hence act as an endogenous inflammatory neuro-imaging; (4) large and well-designed
response modification mechanism.22 As an example, observational studies that use well-defined outcome
the IL6-174(G|C) genotype has been associated with variables for transparent logistic regression analyses
impaired neurological outcome in preterm children.73 in large samples of patients, with sufficiently long
Cytokines are able to mediate intravascular cell periods of follow-up.64 Although such research will
adhesion, coagulation and/or thrombosis, and be complex, only then we may become successful in
vasoconstriction. In the presence of an existing the identification of pre- and postnatal risk profiles
thrombophilia or a cytokine polymorphism resulting that permit the introduction of new anti-
in increased susceptibility to infection, the actions of inflammatory interventions in the newborn.
84 Textbook of Perinatal Medicine

Figure 8.1 shows antenatal and postnatal 13. Hitti J, Krohn MA, Patton DL, et al. Amniotic fluid
tumor necrosis factor-alpha and the risk of respiratory
inflammatory responses and six factors that may
distress syndrome among preterm infants. AJOG 1997;
influence the overall outcome. 177: 50-56.
14. Leviton A, Paneth N, Reuss ML, et al. Maternal infection,
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increases intestinal IL-10 in a neonatal rat model. Ped important risk factor for cerebral palsy in very-low-
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31. Neish AS, Gewirtz AT, Zeng H, et al. Prokaryotic 364-367.
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interleukin-1 accelerates surfactant protein synthesis in 47. Palmer C, Roberts RL, Towfighi J, Housman C.
fetal rabbits and improves lung stability after premature Endotoxin pre-treatment protects neonatal rats from
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33. Costeloe K, Hennessy E, Gibson AT, Marlow N, 48. Mittendorf R, Covert R, Montag A et al. Association
Wilkinson AR. The EPICure study: outcomes to between fetal inflammatory response syndrome and
discharge from hospital for infants born at the threshold bronchopulmonary dysplasia. Ped Research 2003; 53:
of viability. Pediatrics 2000; 106: 659-671. 387A.
34. Willet KE, Kramer BW, Kallapur SG, et al. Intra-amniotic 49. Yoon BH, Romero R, Moon JB, et al. Clinical significance
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Neonate 2001; 79: 205-209. impact of neonatal intensive care practices on the
36. Van Marter LJ, Dammann O, Allred EN, Leviton A et developing brain. J Pediatr 2002; 140: 646-653.
al. Chorioamnionitis, mechanical ventilation, and 52. Goujon E, Parnet P, Aubert A, Goodall G, Dantzer R.
postnatal sepsis as modulators of chronic lung disease Corticosterone regulates behavioral effects of
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37. Kramer BW, Ikegami M, Jobe AH. Intratracheal Physiol 1995; 269: 154-159.
endotoxin causes systemic inflammation in ventilated 53. Crowley PA. Antenatal corticosteroid therapy: a meta-
preterm lambs. Am J Respir Crit Care Med 2002; 165: analysis of the randomized trials, 1972 to 1994. AJOG
463-469. 1995; 173: 322-335.
38. De Dooy JJ, Mahieu LM, Van Bever HP. The role of 54. Shimoya K, Taniguchi T, Matsuzaki N, et al. Chorio-
inflammation in the development of chronic lung amnionitis decreased incidence of respiratory distress
disease in neonates. Eur J Pediatr 2001;160:457-463. syndrome by elevating fetal interleukin-6 serum
39. Blahnik MJ, Ramanathan R, Riley CR, Minoo P. concentration. Hum Reprod 2000; 15: 2234-2240.
Lipopolysaccharide-induced tumor necrosis factor-alpha 55. Leviton A, Dammann O, Allred EN, et al. Antenatal
and IL-10 production by lung macrophages from corticosteroids and cranial ultrasonographic
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731. 56. Kallapur SG, Kramer BW, Moss TJ, et al. Maternal
40. Marek A, Brodzicki J, Liberek A, Korzon M. TGF-β glucocorticoids increase endotoxin-induced lung
(transforming growth factor-β) in chronic inflammatory inflammation in preterm lambs. Am J Physiol Lung Cell
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Sci Monit 2002; RA145-151. 57. Kenyon SL, Taylor DJ, Tarnow-Mordi W; ORACLE
41. Mechoulam H, Pierce EA. Retinopathy of prematurity: Collaborative Group. Broad-spectrum antibiotics for
molecular pathology and therapeutic strategies. Am J preterm, prelabour rupture of fetal membranes: the
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42. Dantzer R, Wollman EE, Vitkovic L, Yirmiya R. Group. Lancet 2001; 357: 979-988.
Cytokines, stress, and depression. Conclusions and 58. Kenyon SL, Taylor DJ, Tarnow-Mordi W; ORACLE
perspectives. Adv Exp Med Biol 1999; 461: 317-329. Collaborative Group. Broad-spectrum antibiotics for
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spontaneous preterm labour: the ORACLE II 67. Lappalainen U, Bry K. Lung disease in newborn mice
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2001; 357: 989-994. 53:461A.
59. Matthay MA. Severe Sepsis - A new treatment with 68. Peters RG, Boekholdt SM. Gene polymorphisms and the
both anticoagulant and anti-inflammatory properties. N risk of myocardial infarction - an emerging relation. N
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60. Schultz C, Rott C, Temming P, Schlenke P, Moller JC, 69. Witkin SS, Gerber S, Ledger WJ. Influence of interleukin-
Bucsky P. Enhanced interleukin-6 and interleukin-8 1 receptor antagonist gene polymorphism on disease.
synthesis in term and preterm infants. Pediatr Res 2002; Clin Infect Dis 2002; 34: 204-209.
51: 317-322. 70. Terry CF, Loukaci V, Green FR. Cooperative influence
61. Barrington KJ. The adverse neuro-developmental effects of genetic polymorphisms on interleukin 6
of postnatal steroids in the preterm infant: a systematic transcriptional regulation. J Biol Chem 2000; 275: 18138-
review of RCTs. BMC Pediatrics 2001; 1: 1. 18144.
62. Dembinski J, Behrendt D, Martini R, Heep A, Bartmann 71. Orsi N, Logghe H, Lynch K et al. Carriage of the high
P. Modulation of pro- and anti-inflammatory cytokine secreting interferon gamma polymorphism is associated
production in very preterm infants. Cytokine. 2003; with an increased risk of preterm delivery and
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63. Mesples B, Plaisant F, Gressens P. Effects of interleukin-
72. Hajeer AH, Hutchinson IV. Influence of TNF-α gene
10 on neonatal excitotoxic brain lesions in mice. Brain
polymorphisms on TNF-α production and disease. Hum
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64. Dammann O, Leviton A. Brain damage in preterm
73. Harding D, Dhamrait S, Humphries SE, Montgomery
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H, Whitelaw A, Marlow N. Is Interleukin-6 genotype
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protein. The Soluble TNF Receptor Sepsis Study Group. Antenatal Causes of Cerebral Palsy: Associations
N Engl J Med 1996; 334: 1697-1702. Between Inherited Thrombophilias, Viral and Bacterial
66. Lodha AK, Asztalos E, Moore AM. Elevated cytokines Infection, and Inherited Susceptibility to Infection.
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and NEC. Ped Research 2003; 53: 386A. 209-220.
 9
Advances in
Neonatal Ventilation

Steven M Donn, Sunil K Sinha

INTRODUCTION observe the potentially deleterious effects of

inappropriate airway flow, referred to as
Ever since Hippocrates first described the use of
‘rheotrauma’.1 The challenge is to identify the most
intubation and positive pressure ventilation to
appropriate device, technique and strategies
support respiration approximately 2400 years ago,
especially as philosophies of respiratory management
the goals of mechanical ventilation have remained
differ so widely amongst the individual clinicians
essentially unchanged. We continue to attempt to
and institutions.2
achieve and maintain adequate pulmonary gas
exchange, minimize the risk of lung injury, reduce
THE PAST
the patient work of breathing, and optimise patient
comfort. The introduction of surfactant replacement The last three decades brought tremendous advances
therapy, antenatal corticosteroid treatment, and the in the management of newborns with respiratory
deployment of state-of-the-art mechanical ventilators failure. The use of continuous distending pressure,
have all changed the demographics of the “old BPD” first introduced by Gregory et al,3 was a remarkable
and presented new challenges in neonatal intensive step in maintaining alveolar stability and improving
care. Although we have made a start, the evidence survival in premature infants with respiratory
as to how to best approach the problem is as yet distress syndrome (RDS). Mechanical ventilation of
insufficient upon which to draw specific therapeutic newborns resulted in the first report of a new
conclusions or make clinical recommendations. Until disorder, bronchopulmonary dysplasia (BPD, also
we have created a sufficient evidence base, it seems referred to as chronic lung disease, CLD), described
prudent, therefore, to rely on the basic tenet of by Northway et al in 1967, 4 in which infants
medicine, “Primum Non Nocere: First, Do No developed chronic parenchymal lung and airway
Harm.” Therapy, in this case mechanical respiratory injury characterized by inflammation and squamous
support, should be directed at avoiding the metaplasia of the respiratory epithelium.
potentially damaging effects of oxygen therapy, the The 1970s brought the widespread practice of
trauma from excessive pressure and/or volume; the mechanical ventilation to neonatal intensive care,
adverse consequences of atelectasis; and the role of utilizing primarily continuous flow, time-cycled,
inflammation and infection in the pulmonary injury pressure limited ventilators. It dramatically extended
sequence, which is now well established. In addition, the limits of viability, although the incidence of BPD
the new technology has given us the opportunity to continued to rise. In 1975 Philip attributed the
88 Textbook of Perinatal Medicine

pathogenesis of BPD to the combined effects of measure have failed to demonstrate a benefit in
exposure to oxygen and positive pressure ventilation lowering its incidence.
over time.5
The technological revolution accelerated in the Continuous Distending Pressure
1980s with the advent of high-frequency ventilation. Continuous positive airway pressure (CPAP) is a
This new form of mechanical ventilation utilized form of distending pressure applied to the airways
delivered gas volumes that were smaller than the of a spontaneously breathing infant. It works by
anatomical dead space at very high rates in an attempt abolishing the upper airway occlusion and
to lower airway pressure and achieve more uniform preventing atelectasis of the lungs, thus maintaining
gas distribution within the lung. Continuous non- adequate Functional Residual Capacity (FRC). CPAP
invasive monitoring was introduced, with as a primary strategy was popularized by the work
transcutaneous gas monitoring and pulse oximetry of Wung and colleagues beginning in the early
becoming readily available. Towards the end of the 1970s.8 This approach was based on a dependence
decade, surfactant replacement therapy became a on spontaneous breathing, the avoidance of sedative
reality, overcoming the biochemical effects of the and paralytic drugs, and acceptance of “abnormal”
premature lung. Yet, CLD persisted. blood gases. The approach did result in a dramatic
The 1990s were characterized by the continued reduction in CLD, but it was never subjected to a
proliferation of technology. Real-time breath-to- randomized clinical trial. Moreover, only pulmonary
breath pulmonary monitoring became feasible, and and not long-term neurodevelopmental outcomes
with it a host of new ventilator modes and modalities have been reported. In recent years, there has been
were introduced into clinical practice, such as a resurgence in the use of CPAP because it is a non-
synchronized intermittent mandatory ventilation, invasive technique and easy to apply. Several
assist-control (patient-triggered) ventilation, different devices and ways to administer CPAP are
pressure control ventilation, pressure support now available including the Infant Flow Driver® and
ventilation, and volume-targeted ventilation. This Bubble CPAP®.9,10
decade also saw a dramatic change in the The infant CPAP system™ (Electro Medical
demographics and the nature of CLD. Infants Equipment Ltd, Sussex, England) uses a dedicated
surviving RDS were even smaller and more flow driver and gas generator with fluid-flip, variable
premature. Chronic lung changes (the “new BPD”)6,7 flow, continuous positive airway pressure. The
were now characterized by a decrease in Bernoulli effect directs gas flow towards each nostril,
alveolarization of the lung, with less inflammation and the Coanda effect causes the inspiratory flow to
and scarring, but with diminished surface area and flip and leave the generator chamber via the
functional lung units. The incidence of CLD expiratory limb. This is supposed to assist
approached 30-40%, depending upon how one chose spontaneous breathing and reduce the work of
to define it. breathing by decreasing expiratory resistance and
maintaining stable airway pressure throughout the
THE PRESENT
respiratory cycle.
Management strategies in the new millennium In the Bubble CPAP system (Fisher and Paykel,
represent a broad spectrum with little consensus, Auckland, New Zealand), the blended gas is heated
ranging from “non-invasive” techniques to the highly and humidified and then delivered to the infant
invasive extracorporeal membrane oxygenation. through a secured nasal prong cannula. The distal
Almost all of the clinical trials conducted to date, end of the expiratory tubing is immersed underwater,
which have utilized CLD as the primary outcome and at 4 litres per minute of gas flow the CPAP
 Advances in Neonatal Ventilation 89
pressure generated is equal to the level of the CPAP in the best hysteresis and compliance axis, compared
probe. Varying the depth of the underwater to either ventilating at high FRC, the upper loop,
expiratory tube can vary the CPAP pressure. It has which leads to overexpansion and the risk of baro-
also been proposed that chest vibrations produced and volutrauma, or compared to ventilating at low
with bubble CPAP may contribute to gas exchange. FRC, the lower loop, which leads to atelectasis and
Bubble CPAP appears to be an effective and the risk of atelectotrauma. 11-14
inexpensive option for providing respiratory support The principles of mechanical ventilation are based
to premature infants. on pulmonary physiology. 15 Oxygenation is a
There are as yet no controlled trials to compare function of mean airway pressure. Mean airway
the efficacy or superiority of one system over pressure is usually adjusted by increasing the peak
another. Many questions are as yet unanswered. Is inspiratory pressure (PIP), the positive end-
there a “best” way to provide CPAP? Does primary expiratory pressure (PEEP), and/or the inspiratory
CPAP therapy delay or alter the benefit of surfactant time. Ventilation refers to carbon dioxide removal
replacement therapy in babies who ultimately require and is the product of tidal volume and frequency
it? Is caloric expenditure higher than with mechanical (rate). The tidal volume is proportional to the
ventilation? Does “bubble CPAP” confer any difference between the PIP and the PEEP, a value
physiologic advantages? referred to as the amplitude. It is crucial that clinicians
understand that there are significant differences
Conventional Mechanical Ventilation among the various neonatal respiratory disorders
Conventional mechanical ventilation (CMV) attempts and that differing pathophysiologic conditions call
to deliver physiologic tidal volumes to the patient for different strategies. For instance, a preterm baby
with the lung at or near functional residual capacity. with RDS (low lung volume, homogeneous disease)
In doing so, we are utilizing the steepest portion of is very different than a term baby with meconium
the pressure-volume relationship, where pulmonary aspiration syndrome (high lung volume, hetero-
compliance is the best and where the change in geneous disease).
delivered volume occurs at the lowest increment in Mechanical ventilation is as much an art as a
driving pressure. The concept is demonstrated nicely science. Great care must be taken to balance the life-
in Fig. 9.1, a schematic pressure-volume graph. saving benefit and the potentially injurious effects
Ventilation at normal FRC, the middle loop, results of positive pressure ventilation. Excessive inspiratory
pressure can be detected by real-time pulmonary
graphic monitoring.16 This is shown in Fig. 9.2. On
the left, the pressure-volume relationship
demonstrates hyperinflation, with exaggerated
hysteresis and an upper inflection point on the
inspiratory limb. A more normal pressure-volume
relationship is shown on the graph on the right.
Until recently, the effects of airway flow on
pulmonary mechanics have only been conceptual.
Airway flow, which is the time rate of volume
delivery, must be appropriately controlled.
Fig. 9.1: Static pressure-volume relationship. Optimal ventilation
occurs at normal FRC, where compliance is best and incremental
Rheotrauma refers to injury caused by inappropriate
volume changes occur at the least pressure change. Ventilating above flow. If flow is excessive, it may result in turbulence,
FRC results in overexpansion of the lung and increases the risks of gas trapping, and inadvertent PEEP, leading to
baro- and volutrauma; ventilating below FRC may result in atelectasis
and its attendant consequences. overdistension and the potential for thoracic airleaks.
90 Textbook of Perinatal Medicine

Fig. 9.2: Left: Real-time pressure volume loop demonstrating overinflation. Note the flattened portion at high pressure,
where no additional volume is recruited. Right: A normal pressure-volume loop, showing satisfactory hysteresis.

If flow is inadequate, it may create “air hunger” or to the zero flow baselines prior to the initiation of
“flow starvation” and increase the patient’s work of the next breath. This pattern calls for immediate
breathing. adjustments in ventilator parameters, such as a
Turbulence, or non-laminar flow, can be created reduction in flow, a decrease in the inspiratory time,
by excessive circuit flow. This can decrease the or a slowing of the ventilator rate if mandatory
efficiency of gas exchange. If inspiratory airway flow ventilation is being used.
exceeds expiratory airway flow, gas trapping and For more than 30 years, neonatal ventilation has
inadvertent PEEP may develop, increasing the risk been accomplished using time-cycled, pressure-
of airleaks and contributing to elevated pulmonary limited devices. This form of ventilation is easy to
vascular resistance. Paying close attention to use and leaves all parameters to the discretion of the
respiratory time constants, the product of resistance clinician. The baby may breathe spontaneously
and compliance, may help to avoid this. between the mechanical breaths from continuous
Gas trapping can also be detected by real-time flow in the ventilator circuit. These spontaneous
monitoring. Fig. 9.3 demonstrates an abnormality in breaths receive ventilatory support by Positive End
the expiratory flow waveform, which does not return Expiratory Pressure (PEEP) only. Recent
technological advances have introduced a variety of
newer modes of ventilation, which were not available
to neonatal populations before. They are also based
on sound physiological principles but often cause
confusion. It is important that clinicians make
themselves aware of the commonly used nomen-
clature. This can be best understood by using a
hierarchical organisation of ventilator modes:17
1. Parent mode – determined by the control variable.
This can be pressure, volume, or flow, and at any
one time the mechanical breath can be controlled
by only one of these.
Fig. 9.3: Real-time pressure (top) and flow (bottom) waveforms. The
2. The daughter mode – Determined by the breath
flow waveform demonstrates gas trapping. The expirator y portion type which has four phases (phase variables):
(below baseline) does not return to a zero flow state (baseline) before a. Initiation of inspiration (trigger).
the initiation of the subsequent breath, which prevents complete
emptying of the lung. b. Inspiration (limit).
 Advances in Neonatal Ventilation 91
c. The change from inspiration to expiration a fixed rate, selected by the clinician, with the patient
(cycle). able to breathe spontaneously between mechanical
d. Termination or Expiration (baseline variable). breaths. Synchronized intermittent mandatory
Pressure, volume, flow, and time are used as ventilation (SIMV) also involves a fixed mechanical
phase variables and determine the parameters of each rate, but the ventilator “looks” for spontaneous effort
ventilatory cycle. For example, in time-cycled, during a timing window in order to synchronize the
pressure-limited ventilation, the ventilator controls start of a mechanical breath with the start of a
the airway pressure and the inspiratory phase lasts spontaneous breath (see Triggered Ventilation,
according to the time set by the clinician. On the other below). Assist-control ventilation provides a
hand, in volume controlled ventilation, the ventilator mechanical breath each time the patient breathes
controls and measures the tidal volume generated spontaneously, provided the trigger threshold is met,
by the machine irrespective of lung compliance. A and also has a set control rate in case of patient apnea
ventilator is a flow controlled if the gas delivery is or inability to exceed the trigger threshold.
limited by flow. This type of ventilator also controls
the tidal volume even though it does not measure it Volume-targeted Ventilation
directly.
More recent technological advances have also
Pressure-targeted Ventilation enabled measurement of delivered tidal volumes and
made possible the reintroduction of volume-targeted
Modalities of ventilation that target pressure as the ventilation to newborn infants.18 This form of CMV
dependent or “limit” variable include time-cycled,
allows the clinician to select a specific tidal volume
pressure-limited ventilation (TCPLV); flow-cycled,
to be delivered to the patient. Pressure is permitted
pressure limited ventilation (FCPLV); pressure
to fluctuate, creating a “self-weaning” style of
control ventilation (PCV), and pressure support
ventilation. Volume cannot truly be used as a cycling
ventilation (PSV). What all of these have in common
mechanism in the newborn because of gas leaks
is a fixed pressure limit that the ventilator will not
around the uncuffed endotracheal tubes used in
exceed. Thus, delivery of tidal volume depends
clinical practice, so it is better to refer to this form
primarily on the patient’s lung mechanics, of which
of CMV as volume-targeted, volume-limited, or
compliance is the most contributory. TCPLV has a
volume-controlled ventilation. One of the advantages
fixed inspiratory time and flow rate, FCPLV has a
it offers over pressure-limited ventilation is that it
variable inspiratory time (set by the patient) and a
responds to changes in pulmonary compliance. If
fixed flow rate, and PCV has a fixed inspiratory time
and variable inspiratory flow rate, which is compliance improves (e.g., following the adminis-
proportional to patient effort. PSV is a spontaneous tration of surfactant), pressure is decreased.
mode, used to support spontaneous breathing, Conversely, if compliance decreases (e.g., with
generally during weaning. It can be used alone (if pulmonary edema), pressure is increased to provide
there is reliable respiratory drive) or in combination the desired tidal volume. Earlier technological
with SIMV. Pressure support breaths are flow-cycled, limitations of volume-targeted ventilation included
so there is variable inspiratory time, and offer high trigger sensitivity and asynchrony, slow
variable inspiratory flow proportional to patient response times (long trigger delays), highly compliant
effort. Pressure support breaths are pressure-limited circuits (leading to increased compressible volume
and may also be time-limited. loss), and the inability to both provide and measure
Pressure-targeted modalities may be used in the small tidal volumes required by premature
several modes. Intermittent mandatory ventilation infants. These have all been overcome (although not
(IMV) involves the delivery of mechanical breaths at all of the devices providing volume-targeted
92 Textbook of Perinatal Medicine

ventilation can accurately measure tidal volume at Mandatory minute ventilation is a modality, which
the proximal airway). combines SIMV and PSV. A desired minute
Few studies to date have examined the effects of ventilation (the product of tidal volume and
volume-targeted ventilation on neonatal outcomes. frequency per minute) is set by the clinician, and as
The investigation of Sinha et al(19) randomized larger long as the patient is able to meet this target
preterm infants to receive volume-targeted or spontaneously, all of the breaths are pressure-
pressure-target ventilation, with tidal volume supported. If the minute ventilation falls below the
delivery tightly controlled. Infants assigned to the desired level, the ventilator will provide additional
volume group had a shorter duration of ventilation, “catch-up” SIMV breaths, using a breath averaging
a strong trend to less CLD, and fewer severe technique. This form of ventilation is also being
neuroimaging abnormalities than the pressure group. actively investigated.
Since this study, advances in the technology have
enabled delivery of even smaller tidal volumes and Permissive Hypercapnia
extended the capability to provide volume-targeted A recent lung-protective strategy that has been
ventilation to the smallest premature infants. A large evaluated is permissive hypercapnia. This approach
clinical trial is presently underway. was based on an observation by Kraybill et al in
1989,25 in which infants displaying the highest carbon
Hybrid Forms of Ventilation
dioxide levels had the lowest incidence of BPD. The
Attempts have been made to combine the best features rationale behind permissive hypercapnia is that it
of both pressure-targeted and volume-targeted decreases volutrauma, reduces the duration of
ventilation, resulting in a number of hybrid ventilation, decreases the complications associated
modalities.18, 20-22 Volume-guarantee® and pressure- with hypocapnia, and increases oxygen unloading at
regulated volume control® ventilation utilize a the tissues by the Bohr effect. Two prospective
breath averaging technique to constantly adjust controlled trials26,27 did demonstrate a reduction in
delivered tidal volume in response to changing the duration of ventilation but failed to show a
patient lung mechanics. Volume-assured pressure decrease in the incidence of CLD. Although the
support (VAPS)® adjusts the delivery of gas during strategy is attractive, further work is necessary to
a single breath to provide a minimum tidal volume determine its place in the management of neonatal
by extending inspiratory time and slightly ramping respiratory failure.
inspiratory pressure until the desired volume has
been provided.23 All three of these modalities appear Triggered Ventilation
promising but are in need of further investigation. Although intermittent mandatory ventilation was the
Proportional Assist Ventilation (PAV) 24 is an major ventilatory mode utilized for newborns for
adaptive form of mechanical ventilation in which the more than 25 years (Fig. 9.4, left panel), it was not
inspiratory pressure is determined by the elastic and without hazard. One of its major drawbacks is the
resistive properties of the patient. In the only development of asynchrony, where the ventilator
published clinical trial, PAV was noted to be asso- cycles at a programmed rate and the patient breathes
ciated with lower mean airway and transpulmonary independently, sometimes with and sometimes
pressure at an equivalent fraction of inspired oxygen against the mechanical breath. Asynchrony has been
and similar carbon dioxide removal rate. Again, shown to have adverse physiological consequences.
preliminary results are encouraging and ongoing “Fighting the ventilator” may lead to inconsistent
evaluations may help to define the role of this tidal volume delivery, increased work of breathing
modality. (and the need for higher mechanical support),
 Advances in Neonatal Ventilation 93
before receiving mechanical support, thus increasing
the work of breathing and decreasing synchrony.29
Flow signals may also be used to terminate a
breath, thus fully synchronizing the baby and the
ventilator in both inspiration and expiration. This is
referred to as flow-cycling. Flow-cycling is
advantageous during assist-control ventilation as a
safeguard against gas trapping and inversion of the
inspiratory:expiratory ratio. If a baby becomes
tachypneic during time-cycled assist-control, the
fixed inspiratory time means that the expiratory time
Fig. 9.4: Graphic comparison of IMV (left) and flow synchronised
ventilation (FSV; assist-control) (right). Note the wide variability of will become shorter and shorter as the baby breathes
delivered tidal volumes in IMV, depending on whether the baby and faster and faster. With flow-cycling, the inspiratory
ventilator are in or out of phase. In FSV, every breath is the same,
since baby and ventilator are always 100% synchronous. time will become shorter, since the breath terminates
at a percentage of peak inspiratory flow rather than
inefficient gas exchange, and airleaks. Other organ at a fixed time. Flow-cycling is also incorporated in
systems may also be affected. Nearly 20 years ago, pressure support ventilation, where an inspiratory
Perlman and Volpe 28 demonstrated the adverse pressure “boost” is applied to spontaneous breaths
effects of asynchrony on cerebral blood flow velocity to help overcome the work of breathing imposed by
and its high association with intraventricular the narrow lumen endotracheal tube, ventilator
hemorrhage. circuit, and demand valve. Pressure support
Fig. 9.4 is a graphic comparison of intermittent ventilation is primarily a weaning mode, but is also
mandatory ventilation (left) and flow synchronized a form of synchronized ventilation. 30 (Fig. 9.5)
assist/control ventilation (right) and the difference Unfortunately, the evidence base for synchronized
is striking. In addition to the relatively feeble
spontaneous breaths, supported only be PEEP,
pressure-targeted IMV can result in widely variable
tidal volumes, depending upon whether the baby
and ventilator are in or out of phase with one another.
Synchronization results in a consistently reproducible
pattern of gas delivery with nearly identical
pulmonary mechanics with each breath.
Synchronized or patient-triggered ventilation
utilizes a patient-derived signal to initiate a
mechanical breath. The signal is a surrogate of
spontaneous breathing and may be a change in
airway flow or pressure, abdominal movement, or
thoracic impedance. One of the keys to successful
Fig. 9.5: Pressure (top) and flow (bottom) waveforms demonstrating
triggered ventilation is a short response time or
the differences between time-cycling and flow-cycling. In time-cycling,
trigger delay. This is the interval between reaching the inspiratory phase continues for a fixed period; expiration does not
the trigger threshold and the delivery of gas to the begin until the exhalation valve opens. This results in a plateau pressure.
In flow-cycling, inspiration ends as a percentage of peak inspiratory
proximal airway. Long trigger delays mean that the flow. Thus, inspiration cycles directly into expiration and results in a
baby may be considerably into the inspiratory cycle more spiked pressure waveform.
94 Textbook of Perinatal Medicine

ventilation is also variable, and its role in the a small reduction in the incidence of CLD, whereas
prevention of BPD still needs to be determined.31-33 the UKOS study of Johnson et al found no
reduction.39 The Courtney study utilized synchro-
High-frequency Ventilation nized intermittent mandatory ventilation with
High-frequency ventilation (HFV) is generally inspiratory times of 0.25-0.4 seconds in the
divided into two sub-categories. High-frequency jet comparison group; the Johnson study utilized
ventilation (HFJV) uses a jet injector and pulsed or intermittent mandatory ventilation with inspiratory
interrupted flow, usually in the range of 240-600 times set at 0.4 seconds. Perhaps the work of
breaths per minute. It involves passive exhalation breathing was higher in the former study and may
and is thus dependent on the elastic recoil of the explain some of the differences in the results.
lungs for emptying. It is used in tandem with a At present, the use of HFOV as a primary
conventional ventilator, which provides positive end- treatment strategy does not appear to be supported
expiratory pressure and conventional or sigh breaths. by the available evidence. The latest recommen-
High-frequency oscillatory ventilation (HFOV) is dation of the Cochrane Library40 is consistent with
different from HFJV and involves the use of this.
distending pressure to inflate the lung to a static
volume, and usually piston-driven displacement Extracorporeal Membrane Oxygenation (ECMO)
during inspiration and active exhalation. Typical rates ECMO is a form of extracorporeal life support in
for HFOV are 8-15 Hertz. The delivered gas volumes which the circulation is diverted from the body to
are even smaller than those during HFJV.
an artificial lung for gas exchange. ECMO was
Management is relatively straight forward, with
originally done through catheters placed in the right
oxygenation controlled by adjusting mean airway
common carotid artery and right internal jugular vein
(distending) pressure and ventilation controlled by
(veno-arterial), but this necessitated permanent
adjusting the amplitude of the oscillations.
ligation of these vessels. Veno-arterial ECMO has
HFJV was shown to be more effective than rapid
now been largely replaced by veno-venous ECMO,
rate CMV in the management of preterm infants with
using a double-lumen catheter in the right interval
pulmonary interstitial emphysema, but few studies
jugular vein. It has been shown to be efficacious in
have examined its effect on CLD as a primary
infants >34 weeks or >2000 g who have reversible
outcome measure. One study by Keszler et al34 did
respiratory failure, unresponsive to “conventional”
show a reduced incidence of CLD and a decreased
treatment, and with a >80% probability of death.
need for home oxygen, but the comparison group
Although ECMO is technically feasible in infants as
was ventilated with IMV and the results of this study
may not be applicable today. small as 800 g, it requires systemic anticoagulation,
HFOV has been more intensively studied but the and thus the risk of severe cerebral hemorrhage
investigations have yielded conflicting results. In precludes its use in smaller newborns.
1996, Gerstmann et al35 demonstrated increased Neonatal ECMO utilization for respiratory failure
survival without CLD, but Rettwitz-Volk et al 36-37 has declined substantially as newer treatments such
found no differences in a 1998 report. Thome et al as inhaled nitric oxide and HFV have evolved.
showed a shorter time to extubation in an earlier However, it remains as the penultimate rescue
trial, but a later study in 199938 found no differences technique in infants with suitable indications.41
in the incidence of death, CLD, or intraventricular
Inhaled Nitric Oxide Therapy
hemorrhage. The two most recent studies, both
published in 2002, also had discrepant results. The Nitric oxide in conjunction with appropriate
Neonatal Ventilation Study of Courtney et al37 found ventilatory support is currently indicated in the
 Advances in Neonatal Ventilation 95
management of newborns of term and near term In a recent controlled trial, Schreiber et al45 showed
gestation with hypoxemic respiratory failure a reduction in the combined outcome of survival
associated with evidence of pulmonary hypertension. without chronic lung disease in preterm infants given
Its use in the management of hypoxemic respiratory iNO early compared to those given placebo. The
failure in the preterm infant, however, has not yet effect was only seen in infants who had less severe
been established and any such use remains respiratory failure (OI<7) at entry and not in more
investigational. sick babies. Another study, the INNOVO trial from
The physiologic rationale for the clinical use of the UK failed to demonstrate any benefit,46 but it
iNO in hypoxemic respiratory failure is based on its recruited babies who had more severe respiratory
ability to achieve sustained and potent pulmonary failure. Additional trials are underway and until we
vasodilation without causing systemic hypotension. know more, the role of iNO in preterm infants
Persistent pulmonary hypertension of the newborn remains uncertain.
is a disorder associated with diverse underlying
pathologies which is characterised by high Monitoring
pulmonary vascular resistance causing extra- Continuous monitoring of the mechanically ventilated
pulmonary right-to-left shunting of blood across the newborn has also been a major technological advance.
patent ductus arteriosus, foramen ovale or both, In the earlier era of mechanical ventilation, moni-
leading to severe hypoxemia. iNO abolishes or toring was intermittent and inferential. Assessments
decreases this shunt by lowering the pulmonary were made on the basis of a daily chest radiograph
arterial pressure, often producing the immediate to crudely estimate lung volumes, and occasional
improvement in oxygenation seen in infants with blood gas measurements to evaluate gas exchange.
PPHN. Transcutaneous oxygen monitoring demonstrated
The Neonatal Inhaled Nitric Oxide Study Group the foibles of this approach. The development of pulse
(NINOS) 42 and the Clinical Inhaled Nitric Oxide oximetry and continuous invasive therapy has
Research Group (CINRGI) are the pivotal multicentre enabled tighter control of oxygenation and
randomised trials that have demonstrated that iNO ventilation, and the introduction of real-time
therapy improved oxygenation and reduced the need pulmonary graphic monitoring16 has finally given the
for ECMO treatment in term and near-term (=34 clinician breath-to-breath feedback about the
weeks gestation) infants with hypoxemic respiratory interaction of the ventilator and the patient. It allows
failure and persistent pulmonary hypertension by 15- for the customization or “fine tuning” of ventilation
24%. for the individual baby and the evaluation of
Finer recently reviewed the role of nitric oxide treatments which have a narrow therapeutic index.
for respiratory failure in infants born at or near Monitoring is not a substitute for close clinical
term.43 Twelve eligible randomised controlled trials observation, but it can serve to augment the bedside
were included in the analysis. iNO therapy was care of ventilated newborns.
shown to reduce the incidence of combined outcome
of death or need for ECMO. The reduction was Weaning from Mechanical Ventilation
purely in the need for ECMO; mortality was not Weaning refers to the process in which the work of
reduced. This finding is primarily results from the breathing is shifted from the mechanical ventilator
efficacy of rescue ECMO for these infants. to the patient. In order for the baby to be successfully
The role of iNO in preterm infants with hypoxemic weaned and extubated, there are a number of
respiratory failure is controversial. Unblinded physiologic essentials. The baby must have reliable
clinical studies and case reports have shown that iNO respiratory drive and be capable of sustaining
acutely improves oxygenation in preterm infants.44 alveolar ventilation once support is lessened, then
96 Textbook of Perinatal Medicine

removed. This requires neuromuscular competence. Controversies still abound regarding adjunctive
Adequate calories must be provided to fuel the work treatments during the weaning process. Although
of breathing (but too many non-nitrogen calories can studies do support the use of methylxanthines,
also increase carbon dioxide production). Factors concerns exist regarding long-term safety. Similarly,
known to impede the weaning process should be diuretics and bronchodilators have been used with
avoided or at least considered. They include varying success, but some measure of efficacy should
electrolyte imbalance and metabolic alkalosis, anemia, be assessed if treatment is to be continued. Corti-
infection, patent ductus arteriosus and/or congestive costeroids have received a great deal of attention,
heart failure, neurologic dysfunction, and the effects primarily related to their use in the prevention and
of pharmacologic agents, such as analgesics and treatment of BPD. Neurodevelopmental concerns
sedatives. appear justified,48,49 and the use of corticosteroids in
In general, the most harmful parameters should the weaning/extubation process should be limited
be decreased first. If the fraction of inspired oxygen to short-term treatment of infants who have failed
is high, it should be weaned to less than 0.4 as extubation because of upper airway edema.
oxygenation permits. If PIP or PEEP are high, they Prior prospective indices to determine readiness
should likewise be decreased. The advent of triggered for extubation have not been helpful. However, the
ventilation has altered weaning strategy, since ability to measure pulmonary mechanics, tidal
reduction in the ventilator rate during assist-control volume, and minute ventilation has been shown to
does little if the patient is breathing above the control have a high positive predictive value in determining
rate. Most studies to date have demonstrated that when to extubate a preterm infant recovering from
any form of triggered ventilation is superior to IMV RDS.50 Alternatively, in the larger infant, one might
in decreasing the time of ventilation.47 Care should consider extubation when the degree of support
be taken to avoid fatiguing the baby by decreasing appears to equal the imposed work of breathing. This
the ventilator rate during (S)IMV, since there is no is another area ripe for investigation.
support for spontaneous breathing other than PEEP.
Perhaps augmenting this with PSV will be the solution Optimising Mechanical Ventilation
(Fig. 9.6). How can we optimize conventional ventilation? First,
we need to ask good clinical questions. Second, we
need to design the right tools to answer them. Third,
we need to accurately and succinctly define our
terminology and our outcome measures. A
significant example of this is how we choose to define
“BPD.” There can be an enormous variation in the
incidence of BPD within the same population,
depending on how one chooses to define BPD. We
need to find a better way to do this, and the work
of Walsh and colleagues on determining a functional
or physiological definition of CLD is an encouraging
beginning.51
Fig. 9.5: Top: Larger breaths are mechanical SIMV breaths, smaller We clearly need to develop a better evidence base
breaths are spontaneous, supported only by PEEP. Bottom: Pressure with respect to the multiple ways we can now
support has been added to spontaneous breaths. These par tially
supported breaths are not quite as robust as the SIMV breaths (by
ventilate babies. From this, we should be able to ask
choice), but are far better than the unsupported spontaneous breaths even better questions. It is possible that we have
in the upper panel. relied too heavily on meta-analysis, and we need to
 Advances in Neonatal Ventilation 97
understand its limitations. Again, as an example, a clinician willing to investigate its optimal uses and
although the focus of most analyses has been on clinical applications.
ventilation practices, which very well may be the most Where do we go from here? The technology is
important variable affecting pulmonary outcomes, only going to become more complex, the choices more
are the cited studies adequately controlled for other numerous, and the decisions more perplexing. It will
clinical parameters which can and do impact the be imperative for us to harness the technology
pathogenesis of BPD, including nutritional practices; appropriately and, most importantly, safely.
management of blood pressure and fluids; the
approach to the PDA; the use of analgesics and ACKNOWLEDGEMENT
sedatives, and respiratory drugs; antibiotic practices; We acknowledge useful contribution from Dr Samir
ancillary care; and very importantly, the variability Gupta, Senior Clinical Fellow and Mrs Victoria Hall,
in the host response? PA, in preparing this manuscript.

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17. Carlo WA, Ambalavanan N, Chatburn RL. Classification Edition 2000;82(1):F5-F10.
of mechanical ventilation devices. In: Sinha SK, Donn 33. Donn SM, Greenough A, Sinha SK. Patient triggered
SM (eds). Manual of Neonatal Respiratory Care. ventilation. Arch Dis Child Fetal Neonatal Edition
Armonk, NY, Futura Publishing Co. Inc., 2000;122-127. 2000;83(3):F225-F226.
18. Sinha, S. and S. Donn, Volume- Controlled Ventilation: 34. Keszler, M., et al., Multicenter controlled clinical trial of
Variations on a theme. Clinics in Perinatology, 2001; high-frequency jet ventilation in preterm infants with
28(3):547-560. uncomplicated respiratory distress syndrome. Pediatrics,
19. Sinha, S.K., et al., Randomised trial of volume controlled
1997;100(4):593-9.
versus time cycled, pressure limited ventilation in
35. Gerstmann, D.R., et al., The Provo multicenter early
preterm infants with respiratory distress syndrome.
high-frequency oscillatory ventilation trial: improved
Archives of Disease in Childhood Fetal and Neonatal
pulmonary and clinical outcome in respiratory distress
Edition, 1997;77(3):F202-5.
syndrome. Pediatrics, 1996;98(6 Pt 1):1044-57.
20. Cheema, I.U. and J.S. Ahluwalia, Feasibility of tidal
36. Rettwitz-Volk, W., et al., A prospective, randomized,
volume-guided ventilation in newborn infants: a
multicenter trial of high-frequency oscillatory ventilation
randomized, crossover trial using the volume guarantee
compared with conventional ventilation in preterm
modality. Pediatrics, 2001;107(6):1323-8.
infants with respiratory distress syndrome receiving
21. Donn, S.M. and S.K. Sinha, Newer modes of mechanical
ventilation for the neonate. Current Opinion in surfactant. Journal of Pediatrics, 1998;132(2):249-54.
Pediatrics, 2001;13(2):99-103. 37. Courtney, S.E., et al., High-frequency oscillatory
22. Dekeon, M., Pressure Control Ventilation and Pressure- ventilation versus conventional mechanical ventilation
Regulated- Volume-Controlled Ventilation., in Manual for very-low-birth-weight infants. New England Journal
of neonatal respiratory care, S. Sinha and S. Donn, of Medicine, 2002;347(9):643-52.
Editors. 2000, Futura Publishing Company, Inc: 38. Thome, U., et al., Randomized comparison of high-
Armonk, NY.161-162. frequency ventilation with high-rate intermittent
23. Sinha SK, Donn SM. Volume Controlled Ventilation. In: positive pressure ventilation in preterm infants with
Assisted Ventilation of the Neonate, 4th Edition. respiratory failure. Journal of Pediatrics, 1999;135(1): 39-
Goldsmith JP, Karotkin EH. (Eds) Philadelphia, Elsevier, 46.
2003. 39. Johnson, A.H., et al., High-frequency oscillatory
24. Schulze, A. and E. Bancalari, Proportional assist ventilation for the prevention of chronic lung disease
ventilation in infants. Clinics in Perinatology., 2001; of prematurity. New England Journal of Medicine, 2002;
28(3):561-78. 347(9):633-42.
25. Kraybill EN, Runyan DK, Bose CL, Khan JH. Risk factors 40. Henderson-Smart, D.J., et al., Elective high frequency
for chronic lung disease in infants with birth weights of oscillatory ventilation versus conventional ventilation
750 to 1000 grams. J Pediatr 1989;115:115-120. for acute pulmonary dysfunction in preterm infants.
26. Amato, M.B., et al., Effect of a protective-ventilation Cochrane Database of Systematic Reviews (computer
strategy on mortality in the acute respiratory distress file), 2004;(2):CD000104.
 Advances in Neonatal Ventilation 99
41. Schumacher RE, Baumgart S. Extracorporeal Membrane 46. Field D. The Innovo Trial: Preliminary results for NO
Oxygenation 2001: The odyssey continues. Clin Perinatol use in preterm infants. Arch Dis Child 2003;88:A1.
2001;28(3):629-653. 47. Sinha SK, Donn SM. Weaning babies from mechanical
42. Anonymous, Inhaled nitric oxide in full-term and nearly ventilation. Seminars in Neonatology, 2002;7:421-428
full-term infants with hypoxic respiratory failure. The 48. Yeh, T., et al., Outcomes at school age after postnatal
Neonatal Inhaled Nitric Oxide Study Group.(erratum dexamethasone therapy for lung disease of prematurity.
appears in N Engl J Med 1997 Aug 7;337(6):434). New
N Engl J Med, 2004;350:1304-1313.
England Journal of Medicine., 1997;336(9):597-604.
49. Finer, N., et al., Postnatal steroids:short term gain, long
43. Finer, N.N. and K.J. Barrington, Nitric oxide for
respiratory failure in infants born at or near term. term pain? J Pediatr, 2000;137:9-13.
(update of Cochrane Database Syst Rev. 2000;(2): 50. Gillespie L, Whyte S, Sinha SK, Donn SM. Usefulness of
CD000399; PMID: 10796358). Cochrane Database of the Minute Ventilation Test in Predicting Successful
Systematic Reviews., 2001;(2):CD000399. Extubation in Newborn Infants: A Randomized
44. Kinsella, J.P., et al., Inhaled nitric oxide in premature Controlled Trial. Journal of Perinatology, 2003;23:205-
neonates with severe hypoxaemic respiratory failure: a 207.
randomised controlled trial.(comment). Lancet., 1999; 51. Walsh MC, Wilson-Costello D, Zadell A, Newman N,
354(9184):1061-5. Fanaroff A. Safety, reliability, and validity of a
45. Schreiber, M., et al., Inhaled nitric oxide in premature physiologic definition of bronchopulmonary dysplasia.
infants with the respiratory distress syndrome. J Perinatol 2003;23:451-456.
N.Engl.J.Med, 2003;349:2099-2107.
100 Textbook of Perinatal Medicine

10
Clinical Care of the very
Preterm Infant
L Hellström-Westas, LJ Björklund,
M Lindroth, S Polberger, V Fellman

REGIONALIZATION OF CARE choose may be taken on non-medical grounds, such

as convenient location.5 Deregionalization may also
The concept of regionalization of perinatal care was
be a result of too small tertiary neonatal units without
introduced in the late 1960s in Canada1, and during
possibility to admit all newborn patients requiring
the 1970s perinatal centers were established in
intensive care. As a result of the remarkable increase
developed countries. The goal was to identify the
high-risk pregnancies and to transfer mothers to in survival of the very preterm infants during the
tertiary hospitals, which were organized, staffed and last decades, the patient load in tertiary Neonatal
equipped for the multidisciplinary task of providing Intensive Care Units (NICUs) often exceeds their
optimal maternal and neonatal care. In Europe, the capacities. Thus, the criteria used for defining high-
regionalization of preterm infants in the late 1990s risk pregnancies tend to be stricter, i.e. only the most
was evaluated in a survey (EUROPET) showing that immature infants are transferred to level III units
there were great variations in the regionalization and less immature preterm infants with considerable
programs between different countries. 2,3 In some morbidity risks are increasingly treated in level II
countries, governmental policies exist; in others units. This development is unfortunate, since the way
national scientific societies issue guidelines, usually that perinatal care is organized may have a
stressing intrauterine transfers and delivery in level substantial impact on clinical outcomes, such as
III centers for very preterm infants. The size of the mortality and disability rates. Birth at a hospital with
delivery units varies considerably, the average a regional NICU is associated with a lower risk-
number of births per maternity unit being 500-3000. adjusted mortality than birth at a hospital with no
Large maternity units usually have adjacent level III NICU, intermediate NICU of any size, or small
neonatal intensive care units, although the community hospitals.6
organization of them varies.4 The size of the NICU has an impact on the
In USA, a trend towards deregionalization has outcome, as e.g. was reported in a Finnish national
occurred since the late 1980s, referring to a process study where the lowest mortality and disability rates
of moving away from transfers to referral centers were reported in the largest academic NICU.7 In a
providing the highest quality of care to promoting California study on preterm infants with a birth
competing hospitals with less expertise. The weight less than 2000 g, risk-adjusted neonatal
difference in functioning level is not clear to the mortality was significantly lower for births that
public, and thus decisions on which caring centers to occurred in hospitals with level III NICUs with an
 Clinical Care of the very Preterm Infant 101
average census of more than 15 patients per day. 8 The limited health resources can be efficiently
No evidence-based recommendations are available used with a well-organized tiered network with
on the optimal size of a NICU. However, a regionalization of highly specialized intensive care
reasonable sized NICU is mandatory for running a and several level II units for the intermediate care.11
neonatal service with all necessary functions: This organization model aims at a balance between
neonatologists available around the clock, efficiency and accessibility to services and requires
experienced staff, full range of medical intensive care transfer of the preterm infant after the intensive care
with cardiology and surgical services including period to the next level unit.
bedside operations, and capacities to expand the
TRANSPORT
facilities during high demand periods due to e.g.
preterm multiple births. Regional units should have Regionalization of perinatal care requires a well-
an academic function, providing high quality organized transfer service as well as presents an
specialist training and performing research on their opportunity to establish a safe and efficient transfer
preterm cohorts as well as repeated quality network. 12 The goal should be that all high-risk
assessments of treatment strategies. Further, tertiary pregnancies are identified antenatally and the
academic units should participate in national and transfer to the perinatal center with level III NICU
international networks, e.g. for collaborative use of should take place in utero. However, there will be a
quality improvement techniques, and translation of small group of preterm infants acutely delivered
research into practice, which may result in accelerated outside the tertiary perinatal center, as well as
and effective practice changes and implementation newborn infants with unexpected complications and
postnatal disorders, who need to be transferred
of evidence-based interventions. 9
postnatally to the regional center.
The rapid development of technology in newborn
Neonatal transport service requires an appropriate
medicine, e.g. ventilators and incubators for preterm
referral system, trained personnel and management
infants, leads to a continuous need for new
structures.13 Depending on the population base and
investments in intensive care equipments.
the geography different solutions can be applied. For
Centralization of neonatal care decreases the need
emergency postnatal transports of very preterm
for overlapping functions in level III and level II infants to the level III units, it is crucial that the
centers, especially investments in expensive transport team is trained in neonatal intensive care
technology. Regional resources for expensive front- of this patient group. Prior to the transfer the infant
line equipments should be allocated to the regional should be stabilized and the intensive care should
center, which should have responsibility for be continued and monitored during the transport.
evaluating them scientifically and keep them in According to the EUROPET survey in 1996 on large
continuous use thus providing a high-level of NICUs in Europe, the average national inborn rate
technical know-how in the staff. The performance of of preterm infants less than 30-32 weeks of gestation
intensive care could be facilitated by a computerized exceeded 75% in the majority of countries.14 Thus,
clinical information system, which ensures precision the need for postnatal transports of very preterm
in physician orders, improves medication manage- infants is fortunately an uncommon situation, which
ment, facilitates reporting, and provides detailed however, is a highly demanding task in order to avoid
documentation of care and continuous monitoring transport related complications.
of parameters from technical equipments. Imple-
menting of computerized physician order entry has THE NEONATAL INTENSIVE CARE UNIT
been shown to reduce medication turn-around times The goal should be to deliver all very preterm infants
and medication errors. 10 in a tertiary perinatal center with a neonatal unit well
102 Textbook of Perinatal Medicine

experienced in all aspects of intensive care. Active attempted. In vaginal deliveries, immediate postnatal
management has contributed to the improved stabilization of the very preterm infant can preferably
prognosis for very preterm infants during the last take place in the delivery room, close to the parents.
decade15,16 in addition to other factors, such as level The initial care of the very preterm infants should
of antenatal care and socioeconomic factors, and be very carefully planned.18 Evaporative heat loss
administration of antenatal steroids. Ideally, the during the first minutes of life can cause severe
NICU should be located close to the delivery unit cooling of these infants, and a low temperature on
and to the operating theatre, so that intrahospital admission to the NICU is an independent risk factor
transports can be avoided after delivery. It is of death.17 Radiant heater open beds designed for
necessary for neonatal units who treat very preterm resuscitation should be used. In addition, hypo-
infants to develop clinical routines for the care of thermia can be prevented by wrapping the wet body
these infants. Such routines should include guidelines of the infant in a plastic bag as soon as possible after
for minimal handling and strategies for keeping the birth.19,20 After rapid stabilization, the infant can be
number of invasive procedures to a minimum. The placed directly in a pre-heated incubator. This
noise level in the neonatal intensive care units is often transfer can be avoided by initial use of combination
high, and consequently measures should be taken to incubators with both radiant heater open bed and
reduce noise and light and include environmental double wall incubator alternatives. The incubator is
guidelines. then moved to the NICU and used for the continuing
care of the infant. In order to minimize the distur-
IMMEDIATE CARE AT BIRTH bance of the very preterm infant, all later procedures,
The initial clinical care of the very preterm infants e.g. insertion of umbilical lines, should be done
differs from the care of more mature infants in without moving the infant from the incubator.
several aspects. In this context we will emphasize It is of vital importance that adequate equipment
the initial care of extremely preterm infants born for resuscitation is available in the delivery room or
before 28 weeks gestation. The very preterm infants operating theatre. For this purpose, mobile
have higher mortality and are more likely to develop resuscitation beds are very useful. Modern pulse
intraventricular hemorrhages (IVH), symptomatic oximeters can give correct values for oxygen
persistent ductus arteriosus (PDA), sepsis, necrotizing saturation and heart rate within a few minutes after
enterocolitis (NEC) and bronchopulmonary dysplasia birth 21 , and it is no longer acceptable to rely on
(BPD) as compared to more mature infants.7,17 They intermittent heart rate auscultation and visual
are also at higher risk for developing cerebral palsy assessment of skin color. The pulse oximeter probe
and disturbances in attention and cognition. Close should preferably be placed on the right hand to
perinatal collaboration between obstetricians and assess preductal saturation.22 The more common
neonatologists is essential for healthy survival of placement on one foot may result in lower readings
these infants. early in life, with a risk for unnecessary oxygen
Prior to delivery, the parents should be informed treatment. Although current guidelines still
by the neonatal staff about expectations for survival recommend that 100% oxygen should be used for
and morbidity, based on recent statistics. The parents resuscitation 23 , there is increasing evidence
should always be allowed to express their own suggesting that lower oxygen exposure is beneficial
expectations, and if time allows also have the for newborn infants.24,25 Healthy, full term infants
possibility of a visit to the NICU before the delivery. are not expected to reach preductal oxygen saturation
This goal can sometimes be difficult to achieve, not above 90% until 10 minutes after birth25, and there
least with an expecting mother in active labor or with is no reason to strive for higher levels in premature
preeclampsia, nevertheless it should always be infants. The resuscitation bed must be equipped with
 Clinical Care of the very Preterm Infant 103
an inspired gas blender for precise oxygen and gas exchange will probably be very inefficient
administration.22 If oxygen saturation rises above unless the baby contributes by making gasps.36 Even
93%, oxygen supply should be rapidly reduced or so, the vast majority of small infants will respond to
discontinued.26 bag-and mask ventilation with a rapid increase in
The initial ventilatory management of the very heart rate. Once the baby starts breathing spon-
preterm infant is currently much debated. 27 In taneously, its efforts can be supported if adequate
general, previous studies recommended that equipment is available. Unfortunately, the commonly
premature infants should be intubated and given used self-inflating resuscitation bags have severe
prophylactic surfactant early after birth, but it has limitations. 37 The oxygen supply is difficult to
been questioned whether this is applicable to current regulate, and the bags have a poorly working
babies.28 These babies are often more immature, but pressure limitation. Consequently, high pressures (>
may paradoxically both have an accelerated lung 40 cm H2O) are easily generated, especially at high
maturation at birth and a highly vulnerable lung with ventilatory rates. Tidal volumes are unknown and
a disposition to develop BPD. 29 Animal studies can potentially become very large. Moreover, there
indicate that the immature lung may be particularly is usually no way of obtaining CPAP or positive end-
sensitive to ventilation-induced injury very early expiratory pressure (PEEP), and therefore no way
after birth30, and epidemiological studies imply that to effectively support the baby’s spontaneous
an aggressive initial respiratory management breathing.
including early intubation and surfactant may be The Neopuff ® Infant Resuscitator (Fisher and
associated with an increased risk for BPD.31 In many Paykel, Auckland, NZ) is a commonly used T-piece
centers, there is now a trend against routine delivery system with adjustable PEEP and peak pressure that
room intubation in favor of early application of can be attached to a facemask or an endotracheal
continuous positive airway pressure (CPAP). 32 A tube. It can easily be used to apply nasal or face mask
recent trial showed that delivery room intubation CPAP immediately after birth, see Fig. 10.1. It has
could be avoided in 53% of infants born at 24-25 been suggested that a relatively high distending
weeks’ gestation. 33 Another approach, aiming to pressure (up to 8 cm H 2O) should be used in this
avoid mechanical ventilation early in life, is to situation. 37 If the baby responds well, CPAP with
perform endotracheal intubation immediately after the same device can be continued during trans-
birth and give prophylactic surfactant, followed by portation to the NICU. In an experimental setting,
rapid extubation to nasal CPAP. However,
preliminary results from one study showed that, in
infants born at 27 to 29 weeks’ gestation, there was
no added benefit from prophylactic surfactant when
early CPAP was used.34 It is not known if the same
is true also for more immature infants. Ongoing
multicenter trials on delivery room management of
preterm infants may provide new evidence on
treatment strategies.27
Although the preterm infant may appear severely
depressed at birth, immediate intubation is usually
not indicated. Even if a prophylactic surfactant
strategy is chosen, there is no proven benefit from Fig. 10.1: Immediate care after deliver y. This vigorous and
spontaneously breathing infant is just about to be assisted with face
giving surfactant before the first breath.35 Bag-and- mask CPAP by the NeopuffÒ. An oxygen saturation probe is applied
mask ventilation of preterm infants may be difficult, to the right foot. Photograph courtesy of Mats Blennow.
104 Textbook of Perinatal Medicine

the Neopuff ® device produced reliable and of gaining venous access. Before use, the position
reproducible peak inspiratory pressures and should always be checked with x-ray and the catheter
PEEP.38,39 However, there are at present no published should always allow withdrawal of blood. An
clinical trials evaluating this method against other umbilical venous catheter, in correct position with
systems. the tip of the catheter in the inferior vena cava, is
At all very preterm deliveries, surfactant should suitable for supplementary parenteral nutrition
be immediately available. According to Scandinavian during the first days of life. Double lumen catheters
tradition, infants are not intubated for the sole are useful, since they allow a steady infusion in one
purpose of giving surfactant. However, if the very lumen while intermittent injections can be given in
preterm infant needs intubation for resuscitation, the other lumen without the need for additional
surfactant should be given as soon as the peripheral intravenous lines during the first days.
endotracheal tube is presumed to be in a correct After 3-4 days the umbilical venous catheter can be
position. Many infants respond rapidly and may soon replaced by a peripherally inserted central venous
be breathing room air on endotracheal tube-CPAP, catheter (PICC). When the tip of a PICC is optimally
in which case early extubation can be considered. located in the upper vena cava (as checked by x-ray)
Even if the infant is intubated and surfactant is it can often be used also for blood sampling.46
administered in the delivery room, there is usually Initially, an infusion of glucose is given, replaced
sufficient time to allow the parents to see their baby as soon as possible by a glucose-amino acid solution
before transportation to the NICU. The father can providing glucose at a rate of 4-6 mg/kg/min. 47
usually take part in this transport, and photographs Before the third day of life, there is usually no need
can be taken as a first memory. After arrival to the to add electrolytes except calcium. To reduce the risk
NICU and within the first hour of life, venous and of hyperchloremic metabolic acidosis, sodium acetate
arterial catheters are inserted for blood sampling, should be used instead of sodium chloride in the
infusion of glucose, and for arterial blood pressure intravenous solutions. Providing adequate nutrition
monitoring. and sufficient caloric intake is a problem during the
first week of life in very preterm infants.47 For this
NUTRITION reason, intravenous lipids should usually be started
The beneficial effects of early enteral feeding on the already in the second day of life, with close
development of the gut of the preterm infant are supervision of serum triglycerides. A multivitamin
well recognized.40,41 Recent data indicate improved preparation is included in the lipid solution to reduce
short-term and long-term outcome in preterm infants the risk of peroxidation. The initial daily dose of lipids
fed human milk as compared to formula-fed is usually 0.5 g/kg, which, if tolerated without
infants.42-44 Enteral feedings with small amounts of hyperlipidemia, is increased stepwise to 2 g/kg
human milk (1-2 ml every 3 h) can usually be started during the first week of life, only rarely increased to
within the first hours of life in very preterm infants.45 3 g/kg.48
The primary feed should be the infant’s own mother’s The enteral milk feedings are gradually increased
milk, but until it is available, heat-treated donor milk on a day-to-day basis. When the very preterm infant
is used. can tolerate 75-80% of the total volume intake by the
In order to reduce the number of invasive enteral route, i.e. 130-160 ml/kg of a total daily
procedures, indwelling central venous catheters volume intake of 170-200 ml/kg, the supplementary
(CVCs) for fluid and drug administration can be parenteral nutrition can be omitted. The infant’s own
used. Although the risks, e.g. thrombosis, with mother’s milk is the preferred source of the enteral
umbilical venous catheters are well known, this is nutrition. All mothers should be encouraged to
for the very preterm infants an easy and rapid way express their milk during the preterm period and to
 Clinical Care of the very Preterm Infant 105
breast-feed their infants after discharge from the require more during the first days of life. Serum
neonatal unit. If the mother cannot supply her infant levels of electrolytes (sodium, potassium and ionized
with milk, pasteurized banked donor milk is used, calcium) should be measured and monitored daily
or a preterm formula. Administered human milk can during the initial course. Hypocalcemia can usually
be analyzed for macronutrient content (protein, be corrected by i.v. administration of calcium, either
energy) 49,50 and thus the fortification can be as bolus or added to the intravenous infusion.
individually planned, aiming at a daily protein and Hypernatremia (serum sodium above 150 mmol/l)
energy intake of 3.5 (-4.0) g/kg and 120 kcal/kg, is usually caused by too low fluid intakes, or by too
respectively. Higher energy intakes are often large insensible water loss, or by adding sodium too
required in infants with BPD. Weekly biochemical early to intravenous infusions. Non-oliguric
monitoring of protein status should be performed in hyperkalemia sometimes occurs during the first days
the very preterm infants by e.g. measuring serum of life in the most immature infants and does not
levels of urea and transthyretin (prealbumin). 51 seem to be related to kidney function. 55 Kidney
Calcium and particularly phosphorus supple- function is difficult to evaluate in the very preterm
mentation is needed for adequate bone minera- infants during the first days of life. The serum
lization in human milk-fed infants.44 creatinine levels are often affected by the maternal
creatinine level, although very high serum creatinine
CLINICAL MONITORING and urea levels, and oliguria may be seen in infants
Respiratory and hemodynamic instability is common with poor kidney function. Urinary output mainly
in very preterm infants. Close surveillance is reflects the fluid balance and is also a sign that the
essential, both during the early acute phase, arterial blood pressure is sufficient. A diuresis of 1-
characterized by postnatal adaptation and respiratory 2 ml/kg/h after 24 h of age is usually adequate. Blood
distress, and at later stages when nosocomial transfusions are often needed in the initial care of
infections and recurrent apneas are common. Initial very preterm infants. In many hospitals, diuretics
clinical signs of infection may be subtle, but often are given as routine after blood transfusions. This
precede deterioration in vital parameters. The clinical strategy has no support by controlled studies, and
monitoring includes regular observations of vitality, a frequent use of diuretics may increase the risk for
color, heart rate, respiration, body temperature, nephrocalcinosis.56 Blood and urinary glucose levels
bowel movements and diuresis. should be checked regularly, particularly during the
Fluid and electrolyte balance are closely related first weeks of life, in order to avoid both
to evaporation and heat loss from the immature hypoglycemia and hyperglycemia. Almost all very
skin.52 The insensible water loss from the immature preterm infants need phototherapy for hyper-
skin is highest during the first two days of life, and bilirubinemia, and initially serum bilirubin should
then decreases during the first week.53 The skin of be checked daily. 57 In computerized clinical
the most immature infants often becomes dry and information systems, algorithms for insensible water
cracked during the first week of life. Various methods loss can be included providing continuous water
for preventing this, e.g. by applying prophylactic balance monitoring. Thus dehydration and hyper-
ointment have been evaluated, but shown that this natremia can be avoided. Continuous glucose
strategy may be associated with an increased risk infusion, without interruption, is important for stable
for nosocomial sepsis.54 Double-walled incubators blood glucose values. The most immature infants may
with a high humidity, starting at 80%, should be used need insulin infusion for adequate glucose intake.
in these infants to diminish the inevitable water Continuous monitoring of vital parameters is
losses. The daily fluid requirements average 85-100 necessary in the care of very preterm infants. These
ml/kg. However the most immature infants may infants often need monitoring of electrocardiogram
106 Textbook of Perinatal Medicine

or heart rate, respiration and oxygen saturation at INFECTIONS

least until they have reached 32-33 weeks gestation.
Perinatal infections (bacterial vaginosis, premature
In the initial phase, blood pressure is preferably
rupture of membranes (PROM), chorioamnionitis) are
monitored through an indwelling umbilical or
important causes of very preterm birth. In contrast,
peripheral artery catheter, since non-invasive blood
early-onset bacterial infections (positive culture
pressure monitoring is less reliable. Continuous
before 72 h age) in the offspring are uncommon, and
transcutaneous measurement of blood gases, i.e.
blood cultures drawn at the time of arterial line
partial pressures of oxygen and carbon dioxide, is
insertion are usually negative. An increasing use of
often very useful although the fragile skin during
antibiotics before and during labor has led to a
the first days of life sometimes limits the time when substantial decrease in early group B streptococcal
electrodes can be applied. Transcutaneous moni- infections, but simultaneously there has been an
toring of PCO2 levels can reduce the need for blood increase in prevalence of E. coli sepsis. 64 These
gas samples and give early indications of hypocarbia, infections may have a rapidly progressive course with
which indicates that ventilator settings should be severe hypoxic respiratory failure and early demise.
promptly reduced. Monitoring PCO2 is important Late-onset nosocomial bloodstream infections are
since low PaCO 2 values are associated with much more common, occurring in between 10% and
decreased cerebral blood flow and development of 30% of very low birth weight infants.65 They are
periventricular leucomalacia, and also with usually less severe than early infections, but are still
development of BPD.58 Continuous monitoring of associated with a significant morbidity. Coagulase-
oxygen saturation is a standard procedure in all negative staphylococci (CoNS) are by far the most
NICU’s, and most units have guidelines for oxygen common pathogens, being implicated in around 50%
saturation limits in very preterm infants, often with of cases.66 CoNS infections often occur at around 10
a wide range between 85 and 95%. However, more – 14 days of age. The source of bacteremia is usually
research is needed in order to obtain evidence on a CVC that has been colonized with CoNS, either by
whether the lower or higher values of this range skin contamination during insertion or through the
would be preferable.59 High, or unstable oxygen catheter hub during later manipulations.67 Symptoms
saturation is a risk factor for retinopathy of are unspecific and include apneas, increased oxygen
prematurity (ROP), and very preterm infants should requirement, respiratory insufficiency, and some-
be regularly examined by ophthalmologists from times also arterial hypotension. Serum level of C-
around 32 weeks gestation until full-term for early reactive protein is increased, but this may not be seen
detection and treatment of ROP. Continuous until after 12-24 hours. Treatment with vancomycin
monitoring of electrocortical activity with amplitude- is often started already when an infection is first
integrated EEG (aEEG), a simplified method utilizing suspected, leading to a substantial overuse of this
one or two channels of filtered and time-compressed drug. It is not known how long one can safely wait
EEG, is increasingly being used in neonatal units. before starting vancomycin treatment 67, but in
The method shows changes over time in cere- relatively stable infants it is usually possible to wait
broelectrical background activity and can be used until there is an increase in serum levels of C-reactive
also in preterm infants. Degree of electrocortical protein. If an adequate amount of blood (1 mL) is
background depression in aEEG activity shows good taken for culture, vancomycin can be discontinued
correlation with grade of IVH and outcome.60-62 The after 48 h if blood culture and ancillary tests are still
method also reveals subclinical seizure activity. negative.67 Antibiotic treatment of CoNS bacteremia
Normal data for very preterm infants have been is often started without removal of the CVC, but if
published recently.63 the baby has a delayed clinical response and if
 Clinical Care of the very Preterm Infant 107
bacteremia persists, the line must be withdrawn.68,69 factors are mechanical ventilation, CVC, and
CoNS bloodstream infections are not associated with treatment with broad-spectrum antibiotics,
an increased mortality70, but these infections often corticosteroids, or H2 blockers. Symptoms are often
herald the start of a period of clinical deterioration unspecific. Abdominal distension and discoloration,
with need for mechanical ventilation, opening of the and especially spontaneous intestinal perforation,
ductus arteriosus, development of BPD71,72, and an should raise suspicion of invasive candidiasis. 75
increased length-of-stay. There is also a concern that Though Candida is known to cause end-organ invasion
sepsis increases the likelihood of having an adverse (meningitis, renal candidiasis, endocarditis, endo-
neurodevelopmental outcome. phthalmitis), this is rarely evident at the time of first
Candida infections occur particularly in extremely symptoms. Serum level of C-reactive protein is
preterm infants. Colonization of mucoepithelial usually moderately elevated. Thrombocytopenia is
surfaces with Candida appears to be a prerequisite probably more pronounced in invasive candidiasis
for systemic infection73, and invasive disease usually than in other nosocomial infections.66 The diagnosis
results from a colonizing Candida strain, rather than of invasive candidiasis is difficult because blood
from some different isolate.74 Colonization is most cultures are often negative, but other diagnostic tests
often vertical from the mother at birth, usually with are currently under evaluation. Measurement of
Candida albicans, but horizontal colonization from care urinary D-arabinitol/L-arrabinitol ratio may be used
providers in the NICU also occurs, and is thought to in neonates.77,78
be the primary mode of transmission for Candida CVCs are extremely important in the pathogenesis
parapsilosis.74 Congenital cutaneous candidiasis is of neonatal candidiasis. These catheters are usually
relatively uncommon, presenting with diffuse skin not the primary port of entry, but once in the
rash, in some cases burn-like desquamations, and bloodstream, Candida organisms can adhere and even
sometimes pulmonary involvement in the first days penetrate into the catheter wall78, which becomes the
of life.69,75 There is usually no fungemia, but systemic source of end-organ damage, at the same time
treatment is definitely indicated in the very preterm making the organisms inaccessible to antimicrobial
infants. There is an association between the presence drugs. It has been stated that removal or replacement
of intrauterine contraceptive devices or cerclage of the CVC should be completed within 24 hours of
during pregnancy and congenital candidiasis. notification of a positive blood culture for Candida78
Some very immature infants (mean gestational age A recent review stated that if a Candida infection is
24 weeks) have invasive fungal dermatitis. Erosive suspected and the patient is clinically stable and has
skin lesions with crusting develop during the first not had previous antifungal therapy, fluconazole is
two weeks of life. Blood culture is often positive, suitable empiric therapy.79 Amphotericin B should
and the port of entry into the bloodstream is be considered in severe or life-threatening infections
probably through dermal vessels.75 One outbreak of pending results of cultures.
systemic candidiasis was associated with the use of Infections with Gram-negative bacteria are
a petrolatum ointment, emphasizing the risk that skin relatively uncommon, but often present with a more
care product may damage the delicate dermal barrier rapid clinical deterioration and may be associated
in immature infants. 76 However, the intestinal with shock, coagulation problems and increased
epithelium is considered the primary portal of entry mortality. 66,70 In many neonatal units, there has
for most systemic Candida infections.74 Such infections recently been a substantial increase in infection with
often occur in the second week or life or later, often Enterobacter, usually resistant to cephalosporins.80 An
in the aftermath of a CoNS infection treated with empiric antibiotic policy including ampicillin and
vancomycin, but sometimes as the first nosocomial cefotaxime was shown to be associated with an
infection in an extremely preterm infant. Other risk increased prevalence of resistant Gram-negative
108 Textbook of Perinatal Medicine

bacteria, especially Enterobacter, as compared with a DEVELOPMENTALLY SUPPORTIVE CARE

policy including penicillin and an aminoglycoside.81
Behavioral problems, including attention deficit and
Spread of Enterobacter between patients is well hyperactivity disorders, are common among
documented, and outbreaks have been contained by surviving children who were born very preterm.87,88
simple hygienic measures and restrictions in the use The reasons for this are not known, but it is believed
of cephalosporins.82,83 that environmental influence from the extrauterine
In view of the relative immune deficiency of environment negatively affects the development of
premature infants and the necessary invasive care the immature central nervous system.89,90
with multiple broken barriers, a high prevalence of One of the most important parts in the care of
nosocomial infections may seem inevitable. preterm infants is to promote emotional attachment
However, there is great variation among centers in between the infant and its parents. Family-focused
the incidence of such infections which is not explained neonatal care has been increasingly practiced during
by different case mix.65 It follows that these infec- the last two decades. Systematic strategies for this
tions should to a large extent be seen as preventable include free visiting hours and early involvement of
complications of treatment. A recent survey showed parents in care procedures, e.g. diaper changes and
that the staff of units with a particularly low rate of feeding, creation of good family memories with
nosocomial sepsis tended to see such infections as a hand- and footprints, photographs and diaries, etc.
breakdown in care that could have been prevented.65 Kangaroo care promotes attachment between the
Hand hygiene is of great importance in preventing infant and its parents, and development of preterm
the spread of bacteria and fungi between patients. infants.91,92 Kangaroo care can often start already
The availability of waterless alcohol hand rubs in during the first week of life, see Fig. 10.2.93
close proximity to the incubators makes compliance It was previously shown that reduced light, and
more likely. In adult wards, the education of patients day-and night light promoted sleep in preterm
about the importance of hand washing and asking infants, and this effect persisted several months after
that they remind their caregivers to wash has been discharge.94 Incubator covers are increasingly being
very successful84, and perhaps we should teach the
parents of preemies to do the same. Good nutrition
with an emphasis on enteral feeding with human milk
probably diminishes the risk of infection. Indwelling
venous catheters and intravenous lipids are important
risk factors for CoNS bloodstream infection.
Strategies for maximal barrier precautions and
aseptic techniques during catheter placement are
important, as well as strict guidelines for blood
sampling through catheters and for hub mani-
pulations. The use of “antibiotic locks” to prevent
catheter-related bloodstream infections seems to be
a promising technique, but it remains to be evaluated
in clinical trials.85 The use of fluconazole prophylaxis
to prevent neonatal candidiasis is probably safe and
Fig. 10.2: Double walled incubators are used for optimal thermal
can be considered in high-risk patients, but larger management of very preterm infants. When the infants are stable an
studies are needed.86 incubator cover can be used in order to reduce noise and light.
 Clinical Care of the very Preterm Infant 109
used in order to reduce light and noise. However, Thus individuals, as preterm infants, not capable of
as a single procedure in neonatal care their effect reporting pain would not experience such. However,
has only been investigated in a few studies. In a small based on empirical evidence it has been proposed
observational study there were only minor effects that physiological and behavioral responses are valid
on quiet sleep from the incubator covers in stable indicators of pain.100
preterm infants.95 Neonatal Individualized Develop- Whether the fetus feels pain, and if so, from which
mental Care and Assessment Program (NIDCAP) is gestational age has been a controversial issue. The
based on formal observations of the preterm infants thalamo-cortical fibers, which are considered crucial
during a care procedure. The observations are made for nociception, are present between the 20th and
by medical personnel, often neonatal nurses, who 34th week of gestation. The afferent fibers grow into
have received special training in this method. the cortical plate after the 26th week of gestation,
Individual recommendations for the nursing care are but already between 20 and 26 weeks synaptic circuits
made from the results of these observations, see Fig. occur between the subplate and the cortical plate
10.3. Treatment with NIDCAP is associated with indicating neuro-anatomical basis for the fetus to feel
shorter need for respiratory support and shorter pain. 101 Evoked potentials suggest that thalamic
duration of stay in the NICU.96,97 Recently, it was inputs reach the cortex at 29 weeks.102 Pain threshold
shown that NIDCAP is associated with structural is lower in preterm infants than in term infants and
changes of the brain, as shown by magnetic resonance later in life.103 Even in full term infants the threshold
imaging and diffusion tensor imaging techniques, and remains low after injury. 104 This suggests that the
with increased neurophysiological maturation, as exposure to multiple procedures in the neonatal
shown by EEG. 98 period increases pain awareness. Newborn infants
undergoing intensive care are subjected to repeated
PAIN AND TREATMENT OF PAIN daily procedures. Very preterm infants are likely to
Pain is defined by the International Association for experience a large number of invasive procedures
the Study of Pain as “an unpleasant sensory and during the neonatal care period. 105,106 The most
emotional experience associated with actual or immature infants may be exposed to several
potential tissue damage or described in terms of such hundreds of potentially painful procedures, including
damage”99 According to this definition, pain is always e.g. blood sampling and endotracheal intubation.105
a subjective phenomenon with subjective reporting. Neonatal pain experiences may alter later pain
responses in children. 89 The gentle care of very
preterm infants also includes some aspects of
standard care procedures, e.g. painful stimuli from
venous or arterial punctures for blood sampling.
Painful stimuli can cause fluctuation in arterial blood
pressure that may affect cerebral blood flow. This
could contribute to cerebral hemorrhages or
ischemia.107 However, it has also been shown that
blood sampling from umbilical artery catheters can
affect cerebral blood volume in preterm infants. This
can be avoided by very slow withdrawal of blood
from the catheter. 108 Other care procedures
Fig. 10.3: Kangaroo care of twins. The twin to the left is treated with
associated with changes in cerebral blood volume in
nasal CPAP and fed mother’s milk through a nasogastric tube. very preterm infants include endotracheal suctioning
Photograph courtesy of Ann-Cathrine Berg. and surfactant administration.109,110 Because on the
110 Textbook of Perinatal Medicine

many procedures and long-lasting mechanical whether to continue care or to withdraw ongoing
ventilation, routine opioid infusion or bolus injections intensive care. Such discussion may arise when the
were introduced during the early 1990s in many patient suffers from severe brain or pulmonary injury
NICUs as a pain relief during the first day(s) of life and the chance of survival is low and the possibility
to preterm infants undergoing assisted ventilation of healthy survival is extremely low.115 The first
and repeated procedures. Several behavioral pain principle of treatment is always to act in the best
scales have been developed for preterm infants, interest of the patient and the family according to
but are however, not widely used in clinical the Hippocratic rules, i.e. never to hurt or harm, if
routine.111-113 In order to administer optimal anal- possible to relieve, sometimes to cure, and always
gesia, repeated assessments using pain scales are to console.
recommended. When evaluating the question on withdrawal of
Controversies still exist regarding the severity of intensive care, the situation should be analyzed using
pain and need for pain relief for preterm infants the traditional ethical principles of 1) benefit, 2) harm,
undergoing intensive care. With the development of 3) autonomy, and 4) justice. This analysis should be
synchronized ventilation, preference of nasal CPAP, performed in a two dimensional model taking into
and indwelling lines to minimize procedures, the account the different interest groups, i.e. the infant,
liberal use of opioids has recently been questioned. parents, caretakers and even the society.116
In the NEOPAIN study113 infants were randomized For the evaluation, a summary of all medical facts
to receive either morphine or placebo infusion. The is needed, from which an estimated probable
results showed that opioid treated infants did not prognosis is derived. Sometimes the decision is not
have a more beneficial outcome than infants in the difficult or controversial, such as in babies with
placebo group and in some cases even worse Potter syndrome (absence of kidneys) or hydra-
outcome. Referring to this study, the goal would be nencephaly. However, when outcome is not
a priori to reduce the amount of distress and pain by inevitably fatal or the interest of the parents and the
the use of non-pharmacological means, including infants diverge, the decision-making needs a
individualized care. Only when obvious pain is thorough discussion. In these instances, non-medical
present, such as procedural or postoperative pain, a factors such as social or economical factors may
routine administration would be advisable. influence the decision. A decision to withdraw
Otherwise, the use of potentially hazardous analgesics treatment should always be taken by a senior
should only be given if a pain scale assessment or consultant, and usually by a team of them, after
behavioral observations indicate the presence of careful discussions with all involved staff. The
distress and pain despite non-pharmacological medical course and prognosis should be carefully and
intervention to minimize it. This approach would repeatedly explained to the parents, and their opinion
produce a more focused pain treatment, probably should be taken into consideration. If parents cannot
with fewer side effects. accept the recommendation to withdraw treatment,
the discussions should be repeated. A special
ETHICAL ASPECTS situation is prolonged delivery-room resuscitation
During the last 20 years there has been a growing of extremely premature infants at the limits of
concern about the ethical issues surrounding the most viability, where urgent decisions usually are needed
preterm infants who are at the limits of viability and in the interest of the infant. On such occasions,
intact survival. The majority of deaths, around 80%, thorough discussion with the parents before delivery
in very premature infants occur in the first three days is of greatest importance for the decision-making.117
of life in spite of full intensive care.114 Neonatologists There is usually time to arrange for death to be
caring for these infants need to address the question filled with dignity also for the most immature infants.
 Clinical Care of the very Preterm Infant 111
Good psychological care of the parents is essential
since they will continue to live with strong and sad
memories of this time. A professional, warm, and
empathic care by experienced staff will assist them
in this difficult situation. The parents´ wishes
regarding social or cultural ceremonies, e.g. baptism,
or for information to or presence of relatives or
friends should be fulfilled. Rituals connected to death
are important for coping with the loss and sorrow
after the death. The terminal care of the dying baby
should be carefully planned and performed,
including sufficient sedation and analgesia, in order Fig. 10.4: Giving support to an infant during care procedures is an
to omit further suffering. A dying infant should be important part of developmental care. This infant is supported by the
cared for in a single room together with the parents. hand of a parent during endotracheal suctioning. Photograph courtesy
of Ann-Cathrine Berg.
One or two experienced staff members should
participate and assist the parents in this situation. of infants with abnormalities.122,123 Severe handicap,
such as cerebral palsy, deafness, blindness, and
THE OUTCOME OF VERY PRETERM INFANTS mental retardation have in recent studies been
The outcome of very preterm infants has significantly reported to occur in 15 to 25%. 118,123 Even more
improved during the last two decades, and especially common are cognitive dysfunction and learning
of those with a gestational age below 28 weeks.118,119 disabilities. In a large VLBWI birth cohort study in
Most follow-up studies of preterm cohorts are the Netherlands, assessment at the age of 9 years
defined by birth weight, either including extremely showed that 56% of children in mainstream education
low birth weight infants (ELBWI, < 1000g) or very needed special assistance at school or were below
low birth weight infants (VLBWI, < 1500g). The the age-appropriate level.123 Similar results have been
mortality rate is correlated to immaturity, the more reported from other countries.124 Most of the learning
preterm the infant the higher the mortality.7 The limit difficulties seem to be related to low overall IQ. 88
of viability seems to be about 23 weeks of gestation, Several perinatal risk factors have been associated
since survival after 22 weeks of gestation is very rare, with poor school performance, such as low birth
but after 23 weeks about 10% according to weight, need for assisted ventilation, and IVH.125
regionalized long-term follow-up studies from the Intrauterine growth restriction in preterm infants is
post surfactant era, i.e. from the 1990s.120-122 In a associated with increased morbidity, and low
national cohort, the stillborn rate was 60% in infants postnatal growth resulting in smaller size at school
delivered after 22 gestational weeks, 35% after 23 age, and poorer school performance as compared to
weeks, and 25% after 24 weeks 7, suggesting that appropriately grown siblings.126 The high incidence
there may be a less active care during birth in the of sequele in very preterm infants warrants long-
very immature infants resulting in intrapartal death term follow-up of regional cohorts for quality control
or classification as dead if there is bradycardia at of the demanding perinatal care and long-lasting
birth. In this cohort, the long-term survival of live- neonatal intensive care.
born infants born after 24 weeks of gestation was
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Claure N, Bancalari E. Influence of infection on patent achievement. Acta Paediatr 1999;88:557-62.
ductus arteriosus and chronic lung disease in premature 88. Marlow N. Neurocognitive outcome after very preterm
infants weighing 1000 grams or less. J Pediatr birth. Arch Dis Child Fetal Neonatal Ed 2004;89:F224-
1996;128:470-8. F228.
72. Liljedahl M, Bodin L, Schollin J. Coagulase-negative 89. Anand KJ, Scalzo FM. Can adverse neonatal experiences
staphylococcal sepsis as a predictor of broncho- alter brain development and subsequent behavior? Biol
pulmonary dysplasia. Acta Paediatr 2004;93:211-5. Neonate 2000;77:69-82.
73. Chapman RL. Candida infections in the neonate. Curr 90. Nagy Z, Westerberg H, Skare S, et al. Preterm children
Opin Pediatr 2003;15:97-102. have disturbances of white matter at 11 years of age as
74. Bendel CM. Colonization and epithelial adhesion in the shown by diffusion tensor imaging. Pediatr Res
pathogenesis of neonatal candidiasis. Semin Perinatol 2003;54:672-9.
2003;27:357-64. 91. Charpak N, Ruiz-Pelaez JG, Figueroa de CZ, Charpak
75. Rowen JL. Mucocutaneous candidiasis. Semin Perinatol Y. A randomized, controlled trial of kangaroo mother
2003;27:406-13. care: results of follow-up at 1 year of corrected age.
76. Campbell JR, Zaccaria E, Baker CJ. Systemic candidiasis Pediatrics 2001;108:1072-9.
in extremely low birth weight infants receiving topical 92. Feldman R, Eidelman AI, Sirota L, Weller A. Compari-
petrolatum ointment for skin care: a case-control study. son of skin-to-skin (kangaroo) and traditional care:
Pediatrics 2000;105:1041-5. parenting outcomes and preterm infant development.
77. Sigmundsdóttir G, Christensson B, Björklund LJ, Pediatrics 2002;110:16-26.
Håkansson K, Pehrson C, Larsson L. Urine D- 93. Tornhage CJ, Stuge E, Lindberg T, Serenius F. First week
arabinitol/L-arabinitol ratio in the diagnosis of invasive kangaroo care in sick very preterm infants. Acta
candidiasis in newborn infants. J Clin Microbiol 2000; Paediatr 1999;88:1402-4.
38:3039-42. 94. Mann NP, Haddow R, Stokes L, Goodley S, Rutter N.
78. Benjamin Jr DK, Garges H, Steinbach WJ. Candida Effect of night and day on preterm infants in a newborn
nursery: randomised trial. BMJ 1986;293:1265-7.
bloodstream infection in neonates. Semin Perinatol
95. Hellström-Westas L, Inghammar M, Isaksson K, Rosén
2003;27:375-83.
I, Stjernqvist K. Short term effects of incubator covers
79. Bliss JM, Wellington M, Gigliotti F. Antifungal pharma-
on quiet sleep in stable preterm infants. Acta Paediatr
cotherapy for neonatal candidiasis. Semin Perinatol
2001;90:1004-8.
2003;27:365-74.
96. Als H, Lawhorn G, Duffy FH, McAnulty GB, Gibes-
80. Hervas JA, Ballesteros F, Alomar A, Gil J, Benedi VJ,
Grossman R, Blickman JG. Individualized developmental
Alberti S. Increase of Enterobacter in neonatal sepsis: a care for the very low birth-weight preterm infant. JAMA
twenty-two year study. Pediatr Infect Dis J 2001;20:134- 1994;272:853-8.
40. 97. Westrup B, Kleberg A, Stjernqvist K, Lagercrantz H. A
81. de Man P, Verhoeven BAN, Verbrugh HA, Vos MC, randomized controlled trial to evaluate the effects of
van den Anker JN. An antibiotic policy to prevent NIDCAP in a Swedish setting. Pediatrics 2000;105:66-72.
emergence of resistant bacilli. Lancet 2000;355:973-8. 98. Als H, Duffy FH, McAnulty GB, et al. Early experience
82. v Dijk Y, Bik EM, Hochstenbach-Vernooij S, et al. alters brain function and structure. Pediatrics
Management of an outbreak of Enterobacter cloacae in 2004;113:846-57.
 Clinical Care of the very Preterm Infant 115
99. Merskey H, Albe-Fessard DG, Bonica JJ, et al. Pain terms: ventilated preterm neonates: primary outcomes from
a list with definitions and notes on usage. Recommen- the NEOPAIN randomised trial. Lancet 2004;363:1673-
ded by the IASP Subcommittee on Taxonomy. Pain 82.
1997;6:249. 114. Meadow W, Reimshisel T, Lantos J. Birthweight-specific
100. Anand KJ, Craig KD. New perspectives on the mortality for extremely-low-birthweight infants
definition of pain. Pain 1996;67:209-11. vanishes by four days of life: Epidemiology and ethics
101. Mrzljak L, Uylings HB, Kostovic I, Van Eden CG. in the neonatal intensive care unit. Pediatrics 1996;97:636-
Prenatal development of neurons in the human 46.
prefrontal cortex: I A qualitative Golgi study. J Comp 115. Whitelaw A. Death as an option in neonatal intensive
Neurol 1988;271:355-86. care. Lancet 1986;2:328-31.
102. Klimach VJ, Cooke RWI. Maturation of the neonatal 116. Doyal L. The moral foundation of the clinical duties of
somatosensory evoked response in preterm infants. care: needs, duties and human rights. Bioethics
Dev Med Child Neurol 1988;30:208-14. 2001;15:520-35.
103. Fitzgerald M, Anand KJ. Developmental neuroanatomy 117. Goldschmidt JP, Ginsburg HG, McGettigan MC. Ethical
and neurophysiology of pain. In: Pain in infants, children decisions in the delivery room. Clin Perinatol
and adolescents. Schechter NL, Berde CB, Yaster M
1996;23:529-50.
(eds). Williams and Wilkins, Baltimore, 1993:11-31.
118. Tin W, Wariyar U, Hey E. Changing prognosis for
104. Andrews K, Fitzgerald M. Cutaneous flexion reflex in
babies of less than 28 weeks’ gestation in the north of
human neonates: a quantitative study of the threshold
England between 1983 and 1994. Northern Neonatal
and stimulus-response characteristics after single and
Network. BMJ 1997;314:107-11.
repeated stimuli. Dev Med Child Neurol 1999;41:696-703.
105. Barker DP, Rutter N. Exposure to invasive procedures 119. Darlow BA, Cust AE. Australian and New Zealand
in neonatal intensive care unit admissions. Arch Dis Neonatal Network Improved outcomes for very low
Child Fetal Neonatal Ed 1995;72: F47-F48. birth weight infants: evidence from New Zealand
106. Holsti L, Grunau RE, Oberlander TF, Whitfield MF. national population based data. Arch Dis Child Fetal
Specific Newborn Individualized Developmental Care Neonatal Ed 2003;88:F23-F28.
and Assessment Program movements are associated 120. Tommiska V, Heinonen K, Kero P, et al. A national 2
with acute pain in preterm infants in the neonatal year follow up study of extremely low birth weight
intensive care unit. Pediatrics 2004; 114: 65-72. infants born in 1996-1997. Arch Dis Child Fetal Neonatal
107. Wells JT, Ment LR. Prevention of intraventricular Ed 2003;88:F29-35.
hemorrhage in preterm infants. Early Hum Dev 121. Doyle LW, Victorian Infant Collaborative Study Group.
1995;42:209-33. Outcome at 5 years of age of children 23 to 27 weeks
108. Schulz G, Keller E, Haensse D, Arlettaz R, Bucher HU, gestation, refining the prognosis. Pediatrics 2001;108:134-
Fauchere JC. Slow blood sampling from an umbilical 41.
artery catheter prevents a decrease in cerebral 122. Yu VYH, Doyle LW. Regionalized long-term follow-up.
oxygenation in the preterm newborn. Pediatrics Semin Neonatol 2004;9:135-44.
2003;111:e73-6. 123. Hille ET, den Ouden AL, Bauer L, van den Oudenrijn C,
109. Skov L, Ryding J, Pryds O, Greisen G. Changes in Brand R, Verloove-Vanhorick SP. School performance
cerebral oxygenation and cerebral blood volume during at nine years of age in very premature and very low
endotracheal suctioning in ventilated neonates. Acta birth weight infants: perinatal risk factors and predictors
Paediatr 1992;81:389-93. at five years of age. Collaborative Project on Preterm
110. Skov L, Hellstrom-Westas L, Jacobsen T, Greisen G, and Small for Gestational Age (POPS) Infants in The
Svenningsen NW. Acute changes in cerebral oxy-
Netherlands. J Pediatr 1994;125:426-34.
genation and cerebral blood volume in preterm infants
124. Saigal S, Hoult LA, Streiner DL, Stoskopf BL,
during surfactant treatment. Neuropediatrics 1992;
Rosenbaum PL. School difficulties at adolescence in a
23:126-30.
regional cohort of children who were extremely low
111. Stevens B, Johnston C, Petryshen P, Taddio A.
birth weight. Pediatrics 2000;105:325-31.
Premature Infant Pain Profile: development and initial
validation. Clin J Pain 1996;12:13-22. 125. Bylund B, Cervin T, Finnstrom O, et al. Very low birth
112. Debillon T, Zupan V, Ravault N, Magny JF, Dehan M. weight children at 9 years: school performance and
Development and initial validation of the EDIN scale, a behavior in relation to risk factors. Perinat Neonat Med
new tool for assessing prolonged pain in preterm 2000;5:124-133.
infants. Arch Dis Child Fetal Neonatal Ed 2001;85:F36- 126. Monset-Couchard M, de Bethmann O, Relier J-P. Long
F41. term outcome of small versus appropriate size for
113. Anand KJ, Hall RW, Desai N, et al. NEOPAIN Trial gestational age co-twins/triplets Arch Dis Child Fetal
Investigators Group. Effects of morphine analgesia in Neonatal Ed 2004;89:F310-F314.
116 Textbook of Perinatal Medicine

11 Can We Establish A Universal

Lower Limit of Viability?
What are the Medical and Ethical Implications?

MRG Carrapato

INTRODUCTION LOWER LIMIT OF VIABILITY—FACT OR

NOT QUITE?
Over the last decades, perinatal mortality has been
greatly reduced and in most western countries now Biological survival will depend on not just the
stands in single figures, albeit with many presence of a given organ but on its functional
geographical assymetries. The overall good results maturation, a sequential evolution often referred to
achieved are primarily the consequence of National as the ‘developmental windows’. Alveolarisation,
Health Policies towards rationalisation of human and essential for survival, is a process that includes
financial resources with modern technology playing anatomical, physiological and biochemical
a subsidiary role for the high risk pregnancy and differentiation starting from about 24 weeks’
neonate. The development of neonatal intensive care gestation, progressing until term and continuing
has been shown to be effective in the survival of throughout the postnatal period and childhood.
preterm infants without a significant increase in later ‘Viability’, therefore, would be around 24 weeks. To
morbidity, at least for the larger, more mature lower this limit, strategies ranging from antenatal
neonates. steroids, postnatal surfactant and different
ventilatory modes have been attempted with some
The World Health Organisation places 22 weeks
success, but as an example, after 30 years of clinical
of gestational age or 500 grams birthweight as the
practice, antenatal steroids show quite disappointing
lower limit, at least for the purpose of perinatal
results at below 24 weeks gestation.2,3 and they might
statistics, and the International Classification of
also delay and alter postnatal alveolarisation.4-6
Diseases describes the perinatal period as starting at
Nevertheless, in recent years an increased survival
22 completed weeks. The European Association of
of very immature infants has been reported ranging
Perinatal Medicine (EAPM) defines the Perinatal
from 2-35% at 23 weeks and in some perinatal centres
Period: “... from 22 completed weeks (154 days)
in the USA these figures approach 50% amongst live-
gestation and ends 7 complete days after birth” 1
born infants, between 17-58% at 24 weeks and vary
which is to imply that the lower limit of viability
from 35-85% at 25 weeks.7-21
stands at 22 weeks of gestation. The question,
Survival and outcome data on extremely preterm
with all its medical, legal, social and financial
infants, between 22 and 26 weeks, has been widely
implications, is how close are we, as a whole, in this reported and reviewed. 7,10-12,15-18,22,23 Allen, in a
pursuit? retrospective study of infants born between 22 and
 Can We Establish A Universal Lower Limit of Viability? 117
25 weeks, showed that mortality at 6 months There can be several reasons and explanations.
corrected age was 75% for neonates born at less than First of all, many of the earlier studies referred to
24 weeks gestation, with no survivors at 22 weeks birthweight rather than to gestational age and
whilst at 25 completed weeks, survival was in the therefore included more mature babies who were
region of 80%.23 Hack and Kilpatrick showed similar growth retarded (although IUGR babies of the
survival rates of around 40 and 80% respectively for same gestational age usually have a poor prog-
24 and 26 weeks gestational age, especially after the nosis). 22,28-31 Then, again, with some of the earlier
introduction of steroids and surfactant. 12,15 Cooke reports referring to gestational age, how accurate
has reported an increasing survival rate of extremely was dating based on menstrual estimates in the
preterm infants from the early eighties to the absence of scanning in early pregnancy? Even in
nineties: in the early period, from 1982-85 there were recent data, gestational age is often inferred from
no survivors at 23 weeks gestational age whilst in the first day of the LMP with scanning only prevailing
the later part of the study, between 1990-93, 35% of if it differs more than two weeks from the menstrual
these infants survived to discharge. 7 Tin, in a dates.32-36 At this “threshold for viability”, a few days
prospective, population-based regional survey, also or a couple of hundred grams will make all the
showed that the survival of very immature infants difference when reporting survival rates. On the
has improved progressively since the early eighties, other hand, many studies are regional/population-
particularly after the introduction of surfactant in based 7,9,14,17,35,36 whilst others refer either to
clinical practice, although the impact of surfactant individual perinatal tertiary centres with very few
was only evident in those babies of 25 or more numbers as a whole, or to multicentre collaborative
gestational weeks.9 A national population-based studies13,15,23,33,34,37-41 with quite different outcomes.
study carried out in the UK and Ireland in the mid- Some studies refer to the outcome of pregnancy from
nineties, of all infants born between 22 and 25 weeks the beginning of labour, including still and live births,
gestation, revealed 2 survivors to discharge at 22 others include only live births, whilst others only
weeks, with increasing survival rates from 11% at 23 survival rates for infants admitted to the neonatal
weeks to 44% at 25 weeks.17 However, in the last intensive care units. This selection bias may
decade, survival among live births even at 22 weeks overestimate survival rates by as much as 100% at 23
has been reported as being from 14 to 19%.24-26 In a weeks and even up to 50% at 24 weeks.42 Also, in
survey of 21 European countries registered with the some perinatal centres, both obstetricians and
EAPM, representing a wide spectrum of different neonatologists may invest aggressively at these lower
regions from Scandanavia to southern, central and gestational ages whilst in others, no active
eastern European countries, the mortality rate for management will be contemplated because both the
infants weighing between 500–749 grams at birth, fetuses and babies are considered non-viable or
stands at 54.4% but showed very wide variations because of the very poor overall outcome in the event
within countries, approaching a 90% mortality rate of survival.43-48 Whether the mode of delivery at this
in the less-affluent countries as opposed to 26% in very low gestational age will make any appreciable
the more developed regions.27 It is quite obvious from difference for survival is very debatable and
the findings of this survey that obstetric and neonatal caesarean section has not been proved to be
practices, as well as available resources and facilities, better.24,27,49-53 Indeed, the increasing morbidity for
are playing a major role in the survival of these very the mother and the future consequences of a vertical
immature infants but, both human and financial incision at this stage of pregnancy should perhaps
resources apart, why should there be such a preclude a caesarean in favour of a vaginal delivery,
discrepancy for reported survival rates at the at least for fetal reasons. Further to all the
threshold of viability? aforementioned explanations for such discrepancies
118 Textbook of Perinatal Medicine

in survival reporting, other confounding data related impairment and chronic lung disease. At the time of
to pregnancy will also influence survival and, the survey in1998, almost everyone in Europe was
therefore the outcome, namely, IUGR, pre-eclampsia, using antenatal steroids, particularly between 26 and
PPRM/Oligohydramnios, antepartum haemorrhage, 32 weeks gestation, and postnatal surfactant, either
infection/chorioamnionitis, etc.15,24,49,54,55 Gender prophylactically or as a rescue. In those days there
and ethnicity, especially, meet with conflicting results was no criteria for the use of postnatal steroids. Seven
at these very low gestational ages.56-60 countries out of 21 would never use them whilst, of
the remaining 14, 6 would apply them early - mostly
WHAT IS THE OUTCOME FOR systemically, with the remainder only contemplating
THE SURVIVORS? their use late in the course of RDS, if ventilatory-
Survival is not (and should not be) the only goal in dependent. 27 (These figures might be somewhat
perinatal medicine when attempting to establish a distorted and not reflect usual medical practice in
‘lower limit of viability’. Outcome and quality of life Europe since some neonatal units were, at the time,
should, at the beginning of a new century, be a major enrolled in a controlled trial of postnatal steroid
priority. Although several follow-up studies on these studies - OSECT).
very immature babies have shown that increasing On this basis, it could be argued that as recently
survival has not been mirrored by an increase in as the last decade, these very immature infants were
cerebral palsy, the fact is that a proportionally higher receiving quite different treatment across the globe
number of infants are now survivors of very low - even from centre to centre within the same area.
gestational age and birthweight. Furthermore, the However, Vohr, reporting on the long-term outcome
major neuromotor, psychomotor, neurosensory and of a collaborative study of babies on the threshold
cognitive disfunctions are found especially in the of viability in the nineties in the USA, and Wood,
most immature infants, below 25 gestational from a population-based cohort in the UK and
weeks.10-14,17 Over a period of 12 years between 1983 Ireland, reporting on behalf of the EPICure study
and 1984 in the north of England, although the group, both showed that of the surviving children
survival rate at gestational age greater than 24 weeks with birthweights less than 750g or gestational ages
had improved (whilst at gestational age below 24 below 25 weeks, between 30-50% had moderate or
weeks the overall survivor rate remained unchanged severe neuromotor or neurosensorial disabilities and
at 4%) the proportion of survivors with severe very often had multiple handicaps.17,61 In a review
disability stayed unaltered at around 25%, with 10% of the world literature, Hack and Fanaroff estimated
being so profoundly disabled as to have to live a that of the survivors of 23 weeks gestation, over a
completely dependent life9 From the results of the third had a severe disability from cerebral palsy to
European survey, based either on regional or national blindness and/or deafness with sub-normal cognitive
data, it was also shown that chronic lung disease function. At 24 weeks gestation, the range of severe
ranged from 16.7%-60% at 36 weeks corrected age, disability was from 22-45% and at 25 weeks, from
ROP from 5.5%-40%, IVH Grade III from 15%-35%, 12-35% and, in general, these rates ovelaped those
NEC from 3%-23% and nosocomial infection from of children born before the nineties.62
23%-50%. All these complications were common to It is quite plausible that some of the adverse
all countries and were directly related to either the outcome in survivors at these low gestational ages
degree of prematurity or the survival rate, being may not be just the direct effect of prematurity and/
especially prevalent at 26 weeks gestation or less. or low birthweight per se but also the result of the
As expected, the picture was somewhat reversed, hostile intrauterine milieu leading to preterm
the countries with the better survival rates showing delivery from inflammatory mediators, to IUGR,
a higher incidence of sequelae, especially in visual hypoxic-ischaemic insults, metabolic imbalances, etc.
 Can We Establish A Universal Lower Limit of Viability? 119
These would perhaps explain the somewhat better, From animal data and observational human
and paradoxical, reported outcome of multiple studies, there is increasing concern that repeated
pregnancies at these very low gestational ages in courses of ANC may lead to immediate and long-
contrast to the general outcome of multiples at the term harmful effects upon growth, lung and brain
later stages of pregnancy, presumably because the development delay71-76 and at the present, only a
reasons for preterm delivery would rest with single course is advocated with subsequent courses
multiplicity alone, in the absence of the adverse reserved for randomised control trials.77 How much
factors for singletons’ preterm deliveries. 60 the widespread use of repeated courses of steroids
Postnatal events, from nosocomial infection to in the nineties may be playing a subsidiary role in
anaemia and haemodynamic instability, metabolic the adverse outcome of some of these tiny survivors,
derangements of hyper/hypoglycaemia and in addition to prematurity and low birthweight,
electrolytic disturbances, etc. may also play an remains an open question.
adjuvant role in the overall picture of survival with Postnatal steroids have been shown to promote
multiple handicaps. But one area in particular should early extubation in ventilatory-dependent ELBW
call for special caution: the possible role of infants but randomised control studies fail to
iacterogenically-induced disability. Many of these demonstrate any significant reduction in death rates
tiny babies are, from the very early start, often or in the development of chronic lung disease.78,79
subjected to a whole panoply of manoeuvres and Furthermore, in addition to the immediate effects of
medications known to alter haemodynamics, blood hyperglycaemia, hypertension, GIT bleeding and
flow and perfusion, from xantines to NSAI, namely perfuration, there is growing concern that they may
Indomethacin, diuretics, volume expanders, anti- also be responsible for adverse outcome on growth,
microbials with known toxic side-effects, paralysing cerebral palsy and neurosensory impairment.79-86 For
agents and sedatives, etc. etc. In recent years, two these reasons, at the present time, postnatal steroids
“old” tools in perinatal care have been submitted to should only be considered for the extubation of
re-evaluation and reappraisal, with growing concern ventilatory-dependent babies and only upon
as to their use and misuse. informed consent of the parents.
Antenatal corticosteroids (ANC) have been More than 60 years after the initial report of retinal
shown to be associated with a significant reduction blindness in preterm babies subjected to excess O2
of RDS, neonatal death and intra/periventricular supplementation, a high proportion of these tiny
haemorrhage 63-65 with a possible synergistic effect babies still survive these days with more or less
with post natal surfactant therapy.66 A single course severe ROP. The “optimal” level (and “correct”
of ANC results in benefits without significant monitoring) for O2 supplementation remains as yet
adverse effects with long-term follow-up studies up unknown. A few years ago an observational study
to adulthood showing no adverse neurological or of the case notes of surviving infants delivered before
cognitive outcome.67 Betamethasone has shown a 28 weeks’ gestation showed a significant decrease
reduced risk of cystic PVL and, therefore has become of ROP (6% v 27.2%) if they were maintained at SaO2
the recommended steroid for enhanced lung levels between 70–90%. Furthermore, it was also
maturation. 68 The available evidence of ANC in shown that there was much less time on ventilation,
multiple pregnancies is somewhat conflicting less oxygen dependency at 36 weeks corrected age,
regarding both use and outcome69, whilst the use of a better weight gain and, especially, no increase in
ANC in diabetic pregnancies is also controversial for mortality or CP.87 Not surprisingly, this publication
the reduction of RDS, as the adverse steroid-induced caused considerable polemic 88-93 and ongoing
hyperglycaemia on fetal lung maturation may offset debate.94-98 Understandably, SaO2 monitoring has
any beneficial effects.70 become common practice in most neonatal intensive
120 Textbook of Perinatal Medicine

care units with considerable benefit, i.e. comfort, country to country and sometimes between States
over repeated arterial punctures and complications within the same country.
from invasive procedures. However, there is very It would thus appear to be quite unrealistic to
little correlation between PaO2 levels and SaO2, both argue the attainability of a common denominator
below 84% and above 94% for SaO2 to keep an ideal derived from such widespread philosophical,
PaO2 between 50–70 mmHg.99 Also, SaO2 monitoring religious and moral views, to frame it within the
is dependent upon the methodology used100,101 and various legal requirements, to dictate the codes of
other variables will have to be considered, namely, rules and to expect it to be internationally accepted,
haemoglobin levels and associated medications that yet that is the essence of Ethics.
may interfere with cerebral and retinal blood flow In Perinatal Medicine, the overall ethical
principles of autonomy, beneficence and non-
and perfusion and not just SaO2/PaO2 levels.
maleficence are even more difficult to apply than in
Nevertheless, ROP is a significant handicap,
most branches of medicine due to the often
especially at the lower limit of viability, and caution
conflicting interests of the mother (and partner) and
should reappraise the “physiological” saturations
the fetus. The fetus, regardless of its semantic
inferred from the more mature infants and
definitions, its rights, its independent moral status
extrapolated to these extremely preterm babies,
and so forth112,113 is an entity representing human
especially in the first few days of life. life. The question is, of course, when does human
Over and above the immediate and short term life begin from the biological, moral, religious, legal
sequelae, how are these tiny survivors performing and social perspectives. Perhaps the concept of “a
at a later stage? The available long-term evidence - fetus as a patient, if not a person”, might be the
school age and above - generally shows that besides pragmatic answer, at least, for the immediate
neuromotor and neurosensorial impairments, a high implications of medical and ethical decisions.114,115
proportion of these children reveal significant For similar reasons we approach the subject of
learning difficulties and behavioural and educational neonatal ethics from a practising angle focusing on
problems, only adding further to the burden and medical management and decisions at the threshold
placing an enormous responsibility upon society as of viability. Far from guidelines, these thoughts,
a whole, particularly for the allocation of financial hopefully unbiased, express our concern, and
and human resources to provide the necessary independent views on the complexities of universal
collateral help.102-108 Furthermore, these children will medical ethics.
grow to adulthood into a competitive world of Reports in the last 10 years of survival at 22 weeks
“perfection”. How sensitive are we to handle their gestation24-26 and less than 400 grams birthweight116
multitude of needs and how prepared are we to have led to a change in legislation 117 and to a
integrate them into society with fairness and equity? redefinition of the “Perinatal Period” (1) and the aim
for the survival of the most immature of babies
WHAT ARE THE ETHICAL IMPLICATIONS? became only natural and pressing. Accepting the
(theoretical) concept of 22 weeks gestation as the
Ethics, the study of ideal conduct, classed as a branch lower limit of viability, what then is the evidence to
of Philosophy109, should be above cultural barriers, support this claim and what is the outcome? The
be universal and should centre upon respect for answer to the first question is the proverbial case
mankind: easily said, often not practised. Deonto- that confirms the exception and as for the quality of
logy, the science of duty, the branch of knowledge, survival, none of the reported survivors was free
which deals with moral obligations110, the science of from neurological sequelae.24-26,117-118
professional duties and etiquette111, is often referred And what about at 23 weeks (or 23 weeks and a
to as being synonomous with Ethics. Laws vary from couple of days)? From here on it is an open game
 Can We Establish A Universal Lower Limit of Viability? 121
and the stakes are high, with survival rates from 2- However, is it not also a sign of moral perfection
35% at 23 weeks to 35-85% at 25 weeks.7,10-14 It is when a society is prepared to accept the difference,
quite clear that there are enormous geographical showing compassion and solidarity with its less
asymmetries even within countries with similar fortunate members? On one issue at least, everyone
demographies and it is, thus, not surprising that some would agree, that whatever the dilemmas and
countries will place their lower limit of viability at however difficult, decisions must never be taken upon
24-25 weeks’ gestation. 27 account of sex, eugenics, religious or economic
The ethical questions to practising neonatologists prejudice, and never based on a doctor’s own cultural
are whether they should accept their own reality of or religious beliefs. 122-123
survival and try to improve on quality rather than Futile treatment is currently used in medicine to
quantity, or whether they should try to compete with mean that any treatment beyond a certain point
the more advanced countries and aim for the would be unjustifiable. Neonatologists, often young,
threshold of viability? Who should decide on that? are frequently faced in the middle of the night with
Should it be an individual (local) decision or a matter the crucial decision (based very often upon inaccurate
of national (regional) policy? What are the ethics and information on gestational age) of whether or not to
moral implications of these decisions? Could it initiate active, aggressive management of the
possibly be that in practice new technologies would extremely immature infant at the threshold of
change matters? What would be the financial viability.
resources needed, could they be afforded, and, again, In doubt, active resuscitative measures should be
what would be the ethical implications of started in the labour ward.124 The decision to further
discrimination on financial grounds? continue intensive care can always be reversed after
Of the general ethical principles of autonomy, revaluation and counselling to the parents but this
beneficence and non-maleficence, the first does not does not imply that decisions to continue or
apply to the neonate for obvious reasons. However, withdraw treatment should rest upon them. Decisions
as a person with independent moral status, the to withdraw or withhold treatment should always
newborn is entitled to the full demands and be the responsibility of the most senior physician,
obligations of beneficence and of primum non nocere. after discussion with all the staff, including the
In everyday practice the concept of “in the best nurses, and upon informing the parents. The
interest of the patient” has also gained access to “phantom of the law” is often used as an argument
neonatal medicine in order to surmount the subtleties for the continuation of futile intensive care. In fact,
of definition from “sustained life” to “quality of in most places what is unlawful is the preservation
life”.119-121 However, this begs the question, in the of life at all costs, against the dignity of the human
best interests of whom - the baby, the parents, or being. As for the ethics of treatment withdrawal,
society, and who should decide? Handicap is a notion once again, what is morally wrong is to prolong
often defined by healthy, normal people, which may useless and hopeless treatments, contradicting the
or may not be shared by the affected individuals Hippocratic rules of “not to harm, if possible to cure,
themselves. Perhaps it is a question of degree: what but always to relieve and console”. Yet, the same
is more acceptable, the survival of a severely European survey revealed that a considerable
physically handicapped but intellectually sound child number of countries had no policies or consensus
or, on the contrary, an individual who is completely for DNR/withdrawal of life support therapies (67%
mentally dependent but who has no physical and 48% respectively).27 Advancing technologies can
impairment? And who will be the judge? With the often cause procrastination over medical decisions
present low birth rate in most western societies, which, when based on a particularly sophisticated
“perfection” is understandably always the goal. tool, may be mistaken for good medical practice.
122 Textbook of Perinatal Medicine

Neuroimaging is often quoted in this context: but ACKNOWLEDGEMENTS

how reliable and infallible is neuroimaging for the
Grateful thanks are due to the collaborators from
prediction of function? It might assist but does not
the participating European countries for their
replace clinical judgement of when to withdraw or
invaluable assistance: Belgium van Reempts P: Croatia
withhold life-supporting therapies – that would be
Polak-Babic J: Cyprus Hadjidemetriou Czech Rep
quite unethical and unacceptable.
Zoban P: England Marlow N: Estonia Varrendi H:
Most importantly, once the medical decision has
Finland Jarvenpaa AL: Holland Fetter WE, Kollee L,:
been reached to withdraw advanced life-support
Hungary Temesvari P: Iceland Dagbjartsson A: Italy
treatment, the baby should be allowed to die in
Bevilacqua G: N Ireland Halliday H: Norway Meberg
privacy, with dignity, surrounded by the warmth,
A: Poland Gadzinowski J: Portugal Peixoto JC: Serbia
care and love of his parents with the full support of
Mulutina K: Slovenia Pajntar M: Spain Domenech E:
the medical and nursing staff. Fortunately, in most
Sweden Sedin G: Switzerland Moessinger A: Turkey Can
cases, parents accept medical judgements based on
G.
sound clinical evidence, knowledge and good faith
Also, to my departmental colleagues Catarina
and are almost always relieved that the decision has
Prior and Susana Tavares for their help with literature
been taken out of their hands. Occasionally, medical
searching.
decisions to withdraw or withhold treatment do not
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 The Offspring of Maternal Diabetes 127

12
The Offspring of Maternal Diabetes
Perinatal Events and Future Outcome

Carrapato MRG, Tavares S, Prior C, Calderia T

INTRODUCTION 24% of women with type 1 and 2 diabetes

respectively, even though women with type 1
The 1989 St Vincent’s Declaration stated, as a 5-year
diabetes were being followed at least biannually in
goal, “...that the outcome of the diabetic pregnancy
diabetic centres.15 Unplanned pregnancies, therefore,
should approach that of non-diabetic pregnancies”1
remained at similar levels to those observed in the
and indeed, over the last 25 years significant
1990‘s16 and close to the reported rates in a recent
reductions in spontaneous abortions, stillbirths,
congenital malformations and perinatal mortality survey in the USA.17 In a nationwide prospective
have been achieved at least in centres with a special study from the Netherlands between 1999-2000,
interest in diabetic pregnancy and in selected although planned pregnancies were observed in 84%
populations. 2-9 However, reports have shown that of women with type 1 diabetes and glycaemic control
even in western countries, spontaneous abortions was considered good (HbA1C< 7.0%), in about 75%
may be as high as 17%, the stillbirth rate to be 5- of subjects the outcome was considerably worse than
times greater, congenital malformations to range the general population with preeclampsia 12 times
from 4 to10 times the usual rate, perinatal mortality greater, cesarean sections 43%, perinatal mortality
to be 5-fold, neonatal mortality 15 times greater, and 2.8%, congenital malformations 8.8%, macrosomia
that infant mortality might be trebled as the result 45.1% with 27.4% of shoulder dystocia, and neonatal
of diabetic pregnancies. 10-13 Although population– hypoglycaemia in approximately two thirds of
based studies from Norway have reported neonates. 18 These poor results have also been
considerably better outcomes 14 , data from other reported for type 2 diabetics and range from
countries have continued to show bad results. In a congenital malformations 11 times greater, a 2-fold
cross-sectional study conducted in twelve perinatal risk of stillbirth, perinatal mortality 2.5 times higher,
centres in France between 2000–2001 involving 435 risk of neonatal deaths 3.5 times greater and a 6-
diabetic pregnancies, both type 1 and 2, perinatal fold risk of death in the first year of life.19,20
mortality was 6 times greater than the national rate, It would therefore appear that nearly 15 years on
severe congenital malformations were double and from the St. Vincent‘s Declaration the goal of a similar
preterm delivery 8 times the national level. Cesarean outcome for diabetic and non-diabetic pregnancies
rates at 59%, shoulder dystocia at 7.6% and has yet to be attained.
macrosomia at 17.3% added to the burden. When addressing diabetic embryofetopathy
Preconceptional care was provided in only 48.5% and several issues are necessarily raised: What are the
128 Textbook of Perinatal Medicine

problems? Why does it happen? What is the outcome? related to HbA1C levels, ranging from similar levels
Can it be avoided? to those of the general population, with “excellent
metabolic control” (HbA1C < 6.9%), to 5.1% (with
PERI(NEO)NATAL PROBLEMS OF THE INFANT “good metabolic control”, HbA1C 7.0% to 8.5%) to
OF THE DIABETIC MOTHER (IDM) 22.4% incidence with a greater than 8.6% HbA1C.27
Pregestational Diabetes Mellitus (preDM) Reid and Ylinen have also shown similar results and
correlation with HbA 1 C sugesting that a good
The potential complications affecting the conceptus metabolic control could greatly reduce the impact of
of the diabetic woman have been identified for congenital malformations in the outcome of diabetic
centuries21 and range from an increased incidence of pregnancies. 28,29 By enrolling diabetic women to
fetal demise to congenital malformations and a intensive metabolic control before conception,
multitude of immediate neonatal problems including: Furhmann showed that major congenital malfor-
macrosomia/IUGR, RDS, hypoglycaemia, polycy- mations could be reduced to 1.1%, rising to high
thaemia, hypocalcaemia, hyperbilirrubinaemia, heart uncorrected rates for those presenting later in
failure and cardiomyopathy, renal vein thrombosis pregnancy.30,31 Since then many other authors have
and small left colon. Although these clinical shown similar good results from preconceptional care
manifestations are seen especially in uncontrolled aimed at good metabolic glycaemic control.4-5,7-9,32-33
diabetic mothers, some of the morbidities, namely From the available evidence it would seem that tight
macrosomia, hypoglycaemia, jaundice and RDS, are metabolic control for at least 6–12 months prior to
still more common in the IDM despite good metabolic conception would greatly reduce the burden of
control and, in general, these neonates still require congenital malformations to almost normal rates.
a higher rate of neonatal intensive care unit admission Nevertheless, even in the best series, corrected rates
than the control population. for diabetes-related malformations are considerably
higher than those for the rest of the population,
Congenital Malformations
despite good metabolic control i.e. preconceptional
Although a whole range of congenital malformations care and HbA 1C levels. 4,5,7,18 This raises several
involving multiple organ systems, without specific points, from the evaluation of good metabolic control
syndromes, have been observed in preDM, both type and the best parameters, to the question of
1 and 2, some dysmorphies and malformations are compliance and whether hyperglycaemia is the only
more common, including the association of dysplastic teratogenic fuel per se or additional to other
external ears and oculo-auriculo-vertebral spectrum predisposing or adjuvant factors, as outlined in the
(OAVS).22 Caudal regression anomalies, in particular etiopathogeny of diabetic embryofethopathy.
saccral agenesis (with a 200-600 fold risk ratio),
neural tube and CNS defects (relative risk ranging Macrosomia
from 3 for anencephaly to a 40-400 fold risk for Ranging from 17-50% in the offspring of preDM15,
holoprosencephaly), cardiac malformations, from 18,34-36
macrosomia poses a major problem for both
ASD, VSD to TGV and truncus arteriosus (4-6 times Obstetricians and Neonatologists. In an attempt to
greater) to renal defects, from agenesis to ureter diagnose fetal macrosomia many different ultrasound
duplication with a risk ratio from 6 to 23 times parameters have been proposed with differing
respectively have all been repeatedly observed in results, from estimated fetal weight (EFW) to
diabetic pregnancies.18,23-26 Most of these congenital abdominal circumference, to the more sophisticated
malformations occur particularly in the offspring of evaluation of fetal subcutaneous fat tissue thickness
uncontrolled diabetic women with very poor, or no, (SCFTT) of various body segments (mid-arm and
preconceptional care. They appear to be directly mid-thigh fat and lean mass, abdominal and
 The Offspring of Maternal Diabetes 129
subscapular fat mass, cheek fat) to fetal fat layer, of hypoglycaemia. Moreover, what low blood sugar
intraventricular septal thickness, etc.37-39 How reliably level might be harmful? Will a (given) low blood sugar
can it be diagnosed by the practising obstetrician, in the absence of symptoms be less damaging than
outside major research institutes if, in effect, he is when coupled to clinical manifestations? And if, at
referring to a large-for-gestational-age (LGA) fetus the follow-up, these children are found to be
based on the estimated weight and abdominal performing below par, is it because of neonatal
circumference?40,41 This is an important question. hypoglycaemia or is it due to poor antenatal
Whilst both share common characteristics, the true metabolic control? Conversely, could it possibly be
macrosomic fetus will have other peculiarities due that in order to overcome hypoglycaemia, the
to its abnormal fat distribution, especially affecting neonate is able to utilize other substrates as an
the shoulder girdle, leading to dystocia and its alternative to glucose for brain metabolism? The
complications. Should, therefore, all (true) macro- answer is a partial ‘yes’ for lactate in the immediate
somic fetus be delivered by caesarean section? neonatal period but quite unlikely for other, more
Perhaps not, but in practice they are. As for the important fuels, namely ketone bodies, given the
paediatrician, the term macrosomia is also often used sustained hyperinsulinism-inhibiting lypolysis. For
to describe a large baby and, again, although sharing these reasons it would therefore be recommended
common problems of hypoglycaemia, polycythaemia, to keep blood levels in the range of >/= 2.6 mmol/
hypocalcaemia and hyperbilirrubinaemia, the true l regardless of gestational and postnatal age, by
macrosomic baby will also be a candidate for birth promoting early enteral feeds. If oral feeds are not
(intrapartum) asphyxia, brachial palsy and being tolerated or are contraindicated, i.v. glucose
cardiomyopathy. should be started at 5-6 mg/kg/min and may be
Moreover, rather than mentioning any given subsquently increased accordingly to the lack of
weight or babies weight/ gestational age, as is response to 8-10mg/kg/min.If the neonate has
traditionally done for macrosomia, it would be more symptomatic hypoglycaemia, especially related to
appropriate to refer to ponderal indices (PI = fetal neuroglycopaenia, a bolus i.v. glucose administration
weight in grams/fetal height in cm3 × 100) against of 0.25-0.05g/kg should be given followed by glucose
the estimated centile for gestational age.42-44 This infusion at the required rate to maintain normal
approach, besides differentiating the normal large glycaemia. As soon as possible, enteral feeds with
for gestational age (LGA) from the true macrosomic either breast milk or formula should be promoted
neonate, may also have other implications, and gradually increased to avoid reactive
particularly with regard to long term outcome. hypoglycaemia if glucose infusion is decreased too
rapidly. Glucagon administration of 200-300µg/kg
Hypoglycaemia may occasionally be required to enhance glucose
Another issue relates to neonatal hypoglycaemia and release from glycogen storages and to increase
its never-ending controversies. What in fact is hepatic acids oxidation.
neonatal hypoglycaemia and does it matter?
Respiratory Distress Syndrome
Methodological problems of glucose measurements
- capillary to venous blood, whole blood to plasma Premature delivery remains a hazard due to either
values, sample containers and transport, etc.- all maternal or fetal wellbeing, mostly in poorly-
account for the different definitions of hypo- controlled women or with associated pregnancy
glycaemia. Glucose concentration in whole blood is complications or due to underlying disorders
about 10-15% lower than in plasma and due to the secondary to diabetes itself. Hyaline membrane
usually high haematocrit of the IDM, plasma, rather disease (HMD) is more common in infants of diabetic
than whole blood, should be used for the definition mothers at any gestational age due to either
130 Textbook of Perinatal Medicine

inhibition or decreased surfactant synthesis, calcaemia, on the other hand, stimulates parathormon
consequence of fetal hyperinsulinism.45-50 In general, release. In pregnancy, calcium is actively transferred
both in vivo and in vitro, insulin opposes the across the placenta from maternal circulation under
glucocorticoid stimulating effect upon lung the influence of the parathyroid hormone-related
maturation51-53 by a complex cascade of impaired peptide (PTHrP) with maternal parathormon and
mecha-nisms, from blockade of fibroblasts – vitamin D having very little influence due to their
pneumocyte – factor (FBF) release and directly inability to cross the placenta. Fetal plasma calcium
inhibiting phospholipid synthesis by type 2 cells54 to is higher than maternal levels, especially with
reducing surface protein synthesis55 or both. advancing pregnancy (total and ionised calcium 10-
Antenatal corticosteroids have been shown to 11 mg/dl and 6 mg/dl respectively) and consequently
promote fetal lung maturation in normal pregnancies. the parathyroid glands show reduced activity.63-65
Their use in diabetic pregnancy remains controversial At birth, following the suppression of maternal-fetal
as the adverse steroid-induced hyperglycaemia on transferral of calcium, the plasma levels fall within
fetal lung maturation may offset any beneficial the first 24 hours of life, leading to parathormon
effects. 54 In addition, the acute rise of severe release and the normalisation of calcium levels by 2
hyperglycaemia in the mother needs to be taken into weeks of life.63,64 Total calcium concentrations in the
account and caution demands close monitoring neonate are dependent upon gestational age, albumin
during antenatal corticosteroid administration and levels and pH.
several schemes have been proposed for supple- Hypocalcaemia occurs in up to 50% of IDM, usually
mentary insulin to counteract the unbalanced on the first 3 days of age, often associated to
hyperglycaemic status.56-57 hyperphosphataemia and hypomagnesaemia63-65
Whether the routine assessment of fetal lung probably due to delayed parathyroid response and
maturation by lamella bodies counts, or lecithin/ correlated to the duration and severity of maternal
sphingomyelin ratios should be performed in reliably- diabetes although the mechanisms remain elusive63-
65
dated pregnancies, at term, is doubtful and lately is Pulmonary disease and/or asphyxia worsening the
becoming less advocated.58-62 hypocalcaemia.63,65
If HMD remains a common neonatal problem, In the absence of clinical manifestation, it is
RDS in the offspring of diabetic mothers is further debatable whether calcium determination should be
aggravated not only by the concommitant poly- performed routinely. On the contrary, with preterm
cythaemia and hyperviscocity, hypoxia and delivery, respiratory compromise, asphyxia, sepsis,
pulmonary hypertension, occasionally heart failure, etc. calcium levels should be performed and
but especially by the high rate of caesarean sections, corrected. Prolonged QTc (QT corrected for heart
often without previous labour. rate over 0.4 sec) on the ECG requires special attention
but with the possibility of heart block, refractory
Hypocalcaemia bradycardia and hypotension, calcium administration
Calcium homeostasis depends upon the equilibrium should be carefuly monitored.
between intestinal absorption and renal excretion Persistent hypocalcaemia may be the result of the
under hormonal regulation. Parathormon mobilises concommittant hypomagnesaemia and is unlikely to
calcium from bone, promotes its renal tubular be corrected if magnesium levels are not adjusted.
reabsorption and stimulates 1,25 hydroxy vitamin D With significant hyperphosphataemia (Ca2xPO4>80)
production. Vitamin D increases calcium and calcium administration may lead to calcification of
phosphate intestinal absorption and regulates bone the soft tissues if the high phosphate levels are not
metabolism mediated by parathormon. Hypo- lowered primarily.63-64,66
 The Offspring of Maternal Diabetes 131
Polycythaemia haemolysis, and macrosomia, with ponderal indices,
rather than weight/gestational age showing a better
The definition of polycythaemia may include infants
correlation with bilirrubin levels.69,73-75
with or without symptoms having haematocrits
greater then 65%. The reported incidence of
Gestational Diabetes Mellitus (GDM)
polycythaemia ranges from 0.4–12% in newborns, but
it affects up to 30% of infants of poorly controlled Gestational diabetes mellitus usually develops in the
diabetic mothers. second half of pregnancy. With advancing pregnancy
Fetal red cells have a larger mean cell volume and considerable demands are placed upon insulin to
are less deformable then more mature cells, leading meet increasing maternal metabolism. If the threshold
to increased viscosity. Low fetal oxygenation and is surpassed maternal hyperglycaemia may
tissue hypoxia increase erythropoietin levels supervene. Although some studies also point to a
stimulating erythropoiesis and leading to high fetal higher incidence of congenital malformations in
haemoglobin. Some authors speculate that fetal association with GDM, most cases are probably pre-
plasma erythropoietin concentration is significantly GDM diagnosed in pregnancy especially type 2, with
correlated to maternal high affinity HgA1C 67-69 pre-pregnancy BMI and advanced maternal age
whilst others suggest that the increased erythro- playing a very conspicuous role. 76-80 Congenital
poiesis in fetus of diabetic pregnancies may be malformations aside, the whole spectrum of
subsequent to fetal hypoxaemia, the result of peri(neo)natal problems overlap those of pre-GDM
hyperglycaemia, hyperinsulinaemia and hyper- and contribute to the high maternal-fetal and
ketonaemia, in line with Freinkel’s concept of neonatal morbidities.
“pregnancy as a tissue culture experience”.70-71 The The incidence of GDM varies from 3-5%
chronic hypoxaemic state in utero may thus explain depending upon whether screening is universal or
some cases of fetal death. In the neonate, symptomatic only for women at risk.
polycythaemia may present with RDS, congestive In our Institution over the two year period from
heart failure and, occasionally, pulmonary hyper- 1 January 2002 to 31 December 2003, from an
tension. Neurological signs include jitteriness, unselected population of 5930 women, after universal
irritability, seizures and apnoea. Potential sequelae 1 hour 50 grams glucose screening, followed by 3
of polycythaemia may be thrombosis, grangrene and hour 100 grams OGTT, 211 women were confirmed
stroke. The treatment of polycythaemia, especially as having GDM. Seven women, diagnosed in the first
if symptomatic, is the standard partial exchange weeks as having had possible preGDM detected only
transfusion. in pregnancy (mean BMI 32.5, mean age 32,4 years)
were eliminated from the study.
Jaundice Amongst the multigest and multipara, 7.2% had
Physiological jaundice is a common neonatal problem had previous GDM, with 24% miscarriage and 4.3%
due to transient glucoronyl-transferase deficiency, late fetal death.
immature hepatic intracellular uptake and transport, In the present pregnancy, the average gestational
increased enterohepatic circulation and occurring in age at the time of diagnosis was 27 weeks and the
60-70% of newborns. However, clinically significant mean HbA1C was 4,3 % (range 3,4% – 5,7%). Forty-
jaundice (total bilirrubin greater than 12.9 mg/dl at one women (20,4%) required insulin treatment to
term) affects only 5% of these babies. 72 maintain good metabolic control.
In the IDM the risk of clinically important jaundice Complications of pregnancy included pregnancy-
is up to 30% and is due to multifactorial causes from induced hypertension (8: 3,8%), preeclampsia (3,
prematurity, to polycythaemia and increased 1,4%), HELLP (3, 1,4%), placenta abruptio (3, 1,4%),
132 Textbook of Perinatal Medicine

thrombocytopenia (4: 1,9%), olygo/hydramnios (2: Table 12.1: Comparative neonatal morbidities of
0,9%), ACIU (2: 0,9%). There were no maternal or IDM and LGA
perinatal deaths. Morbidity IDM LGA X2
Delivery was by caesarean section in 43,9% and (n) (%) (n) (%) (p)
by instrument delivery in 8,8% whilst for a control Fractured
clavicles 4 2 9 5,4 0,79
group of macrosomic babies of non diabetic mothers
Brachial Plexus
these figures were 36,4% and 9,2% respectively. The Palsy 1 0,5 2 1,2 0,47
average birth weight at 38 weeks was 3121 grams Congenital
(SD 424 gr) and length 48,55 cm (SD 1,77cm). malformations 9* 4,3 9** 4,7 0,582
Prematurity 21 10,2 11 6,6 0,959
Neonatal morbidities expressed in Table 12.1, Hypoglycaemia 6 3,1 4 2,4 0,663
compared to large for gestational age (LGA) neonates RDS 8 4,1 4 2,4 0,342
of non-diabetic mothers, were considerably better Jaundice 63 32,6 28 16,8 <0,001
than in many series. Several points, though, need to Polycythemia 7 3,6 9 5,4 0,437
Hipocalcemia 9 4,7 2 1,2 0,054
be considered. The incidence of macrosomia (BW/
GA>90th centile) was identified in only 6 (2,9%) a *Hypospadias 2, Hydronephrosis 2, Hypoplasia of distal
phalanx 1, CHD 4 (3 VSD; 1 ASD)
figure that is just above that of our unselected **Epispadias 1, Hypospadias 1, Hydronephrosis 1, CHD 5 (2
population (2,8%). However, if ponderal indices (PI) VSD; 3 ASD); craniofacial dysmorphy 1
are applied instead of BW/GA, the incidence rises
to 31 (16,1%) of babies with PI >90th centile, especially accurate and true reflection of macrosomia than just
with advancing gestational age (22 and 25% at 39 birth weight/gestational age. Another area for
and 40 weeks respectively), suggesting a population concern is the high incidence of cesarean sections
of short obese babies within our population of which suggests labour induced failure, because even
gestational diabetes in contrast to LGA neonates of correcting for PI, only 16,1% were macrosomic
non-diabetic mothers which are large and long (Table newborns, questioning the current practice of elective
12.2). We would therefore consider PI to be a more induction at 38 weeks gestation. The proportion of

Table 12.2: Body proportions of IDM and LGA per gestational age
GA
(Weeks) IDM (207/5930) LGA (167/5930) Sig.
Weight Length PI Weight Length PI
(±SD) (±SD) (±SD) (±SD) (±SD) (±SD)
41 4650 54,8 3,3
(±167,19) (±1,85) (±0,35)
40 3389 49,0 2,9 4328 52,1 3,1 >0,005
(±231,90) (±1,79) (±0,39) (±211,08) (±1,27) (±0,22)
39 3332 49,1 2,8 4208 51,87 3,1 <0,005
(±341,51) (±1,73) (±0,29) (±263,40) (±1,63) (±0,22)
38 3121 48,5 2,7 3989 50,9 3,0 <0,005
(±424,14) (±1,77) (±0,26) (±137,89) (±1,57) (±0,31)
37 2900 47,8 2,6 3751 51,0 2,8 <0,005
(±337,07) (±1,80) (±0,21) (±204,07) (±1,24) (±0,21)
36 2645 46,5 2,6 3495 49,8 2,9 >0,005
(±220,76) (±1,62) (±0,22) (±111,13) (±2,68) (±0,47)
35 2343 44,0 2,8 3233 47,0 3,1 >0,005
(±82,14) (±2,74) (±0,45) (±101,16) (±2,60) (±0,49)
Total 3074,3 48,4 2,7 4133,6 51,55 3,0 <0,005
(±432,87) (±1,94) (±0,27) (±351,98) (±1,81) (±0,28)
 The Offspring of Maternal Diabetes 133
small for gestational age (SGA) within our diabetic diabetic embryofethopathy (Fig. 12.1). It is quite
population (10,3% versus 13,64 % in our general possible, however, that other metabolic fuels, either
population), suggests an adequate metabolic control. besides or in association with glucose, from lipids to
Although there were very few cases of RDS in amino acids, may also cross the placenta in a
our neonates, mostly due to the paucity of very small, concentration gradient inversely proportional to
extremely preterm infants, we observed that of those insulin availability, further contributing to the
with respiratory problems, more then half were abnormal fetal milieu. 70-71,87 Depending upon the
pulmonary adaptation syndromes in neonates timing of gestation, during critical developmental
delivered by caesarean section at 37 weeks gestation. stages, the same metabolic fuels would have different
In summary, even within perinatal centres, effects upon the fetus. Over the last 15 years there
although maternal and peri(neo)natal adverse results has been increasing evidence from animal and human
can be greatly improved, GDM remains a public studies to support the theory that in addition to
health problem of considerable proportions. sugars (glucose, galactose and mannose) other
metabolic fuels, from ketones to deranged lipid
WHY DOES IT HAPPEN? peroxidation, may be responsible for the patho-
In a theoretical model, according to Freinkel’s concept mechanisms of congenital malformations providing
of “pregnancy as a tissue culture experience”, the that they are present at certain (high) levels for a
whole pathogenesis and spectrum of fetal and reasonable amount of time and especially at crucial
neonatal mortality and morbidity could primarily be “developmental windows”. 88-91 Dietary supplemen-
attributed to the excessive transferral of glucose from tation of deficient substracts (arachidonic acid and
mother to fetus, inducing fetal hyperglycaemia, myo-inositol), free oxygen radical scavenging
leading to fetal pancreatic islet hypertrophy and bcell enzymes and anti-oxidants have been shown in vivo
hyperplasia with a consequent rise in insulin and in vitro to reduce the rate of malformation in
secretion81. Chronic fetal hyperinsulinism results in the offspring of diabetic animals.92-95 Whether such
raised metabolic rates and oxygen consumption strategies might be applicable to clinical practice
causing fetal hypoxaemia which, in turn, would be remain a promising but open question.
responsible for the increased rate of stillbirths and Similarly, the same general principles of
birth asphyxia as well as for the excessive erythro- multifactorial pathomechanisms have been postulated
poietin production and polycythaemia.68-70,82-83 In for macrosomia including and ranging from ketone
addition, fetal hyperinsulinism would be responsible bodies to free fatty acids, ‘selected’ amino acids and
for increased fetal substrate intake, leading to fat with a conspicuous role for IGF1 and IGF2 at local
synthesis, with the resulting adiposity, macrosomia level. Maternal insulin antibodies and insulin counter-
and visceromegaly. Furthermore, fetal hyperinsuli- regulatory hormones may, in addition, further
nism may also be responsible for the development contribute to the resulting macrosomia.96-101
of respiratory distress syndrome at birth by either Towards the end of the second trimester, at a
inhibiting or decreasing lung surfactant synthesis.45- time of increasing cerebral cortical differentiation
50 and maturation, it is quite conceivable that a
Neonatal hypoglycaemia may be a combination of
several factors including sustained hyperinsulinism metabolic insult may result in altered neurological
and lack of counter-regulatory hormonal responses or intellectual behaviour102-106 and, during the third
impairing hepatic glucose production, deficient lipo- trimester, proliferation of fetal adipocytes, muscle
lysis and increasing peripheral glucose uptake.84-86 It cells and pancreatic ßcells may then be responsible
would seem, therefore, that uncontrolled maternal for ‘programming’ the later development of several
hyperglycaemia could start the whole spectrum of adult disorders.107-111
134 Textbook of Perinatal Medicine

Fig. 12.1: Diabetic embryofethopathy

WHAT IS THE OUTCOME? The long-term outcome, on the other hand, poses
several questions. Some studies point to a higher
Neonatal complications of the IDM in spite of the
incidence of childhood obesity in the offspring of
high morbidities involved, are now quite well
these mothers whilst others fail to find such
managed with intensive neonatal care. It is
questionable whether these babies are more prone correlations. Conflicting results might be the result
to developing neurological, behavioural and learning of the different methodologies involved, including
disabilities and, if so, whether they are due to an different definitions and very often small numbers,
unfavourable intra-uterine metabolic environment or without adequate control populations.114-116
to other perinatal and early life events operating on Finally, a major issue is whether some adult
different fetal determinants. Most of the early diseases of metabolic and vascular disorders may
reports of severe brain damage are, reassuringly, have had a fetal origin- In recent years there has
now of historical interest.112,113 Nevertheless, well- been accumulating evidence, both from animal
documented evidence points to mild to moderate studies and epidemiological data, to suggest that fetal
psychomotor and psychosocial impairment in the bcell hyperplasia and hyperinsulinism may induce
offspring of these mothers. Whilst it is quite possible irreversible changes leading to obesity, glucose
that early neonatal events may play a role, available intolerance and even overt non insulin-dependent
data also places a suspicious emphasis on intra-uterine diabetes and, perhaps, a protective effect against type
life.102-105 1 diabetes later in life - a model very much in line
 The Offspring of Maternal Diabetes 135
with the ‘Barker Hypothesis’ of the fetal origins of treated unnecessarily. Argument, however, should
adult disease.107-111,117-118 What might be the relative concentrate not just on the immediate effects of GDM
weight of genetics versus intra-uterine events remains but on the long-term consequences for both the
to be confirmed (119,120) but it is quite interesting mother and her offspring.
that at least in experimental models the prevention
of hyperglycaemia in pregnancy significantly reduces ACKNOWLEDGEMENTS
the prevalence of diabetes in the next generations.111 The authors gratefully acknowledge the antenatal
data on Diabetic Mothers supplied by Dr Célia
WHAT CAN BE DONE?
Araújo.
Based on the assumption that poor maternal
homeostasis is at the core of the problem and that REFERENCES
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 The Offspring of Maternal Diabetes 137
41. Gilby JR, Williams MC, Spellacy WN. Fetal abdominal treatment for fetal lung maturation in diabetic
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Marko V, Zoran M, Marko M, Tomislav M. Gestational determination of fetal lung maturity: comparison to
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and perinatal outcome: who is growth retarded? Am J maturity in diabetes in pregnancy: a re-evaluation. J
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44. Dombrowski MB, Stanley MB, Johnson MP, Saleh AAS, 60. DeRoche ME, Ingardia CJ, Guerette PJ, Wu AH, LaSala
Sokol RJ. Birth weight – length ratios, ponderal indexes, CA, Mandavilli SR. The use of lamellar body counts to
placental weights, and birth weight – placenta ratios in predict fetal lung maturity in pregnancies complicated
a large population. Arch Pediatr Adolesc Med 1994; 148: by diabetes mellitus. Am J Obstet Gynecol 2002; 187: 908–
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45. Bourbon JR, Farrell PM. Fetal lung development in the 61. Piper JM. Lung maturation in diabetes in pregnancy: if
diabetic pregnancy. Pediatr Res 1985; 19: 253-67. and when to test. Semin Perinatol 2002; 26: 206–9.
46. Tyden O, Berne C, Eriksson U. Lung maturation in 62. Moore TR. A comparison of amniotic fluid fetal
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47. Warburton D. Chronic hyperglycaemia with secondary pregnancy. Am J Obstet Gynecol 2002; 186: 641–50.
hyperinsulinemia inhibits the maturational response of 63. Abrams SA. Neonatal hypocalcemia. In: UpToDate 2004.
fetal lamb lungs to cortisol. J Clin Invest 1983; 72: 433- Rose, BD (Ed), UpToDate, Wellesley, MA.
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cholinephosphate cytidyltransferase in fetal rat lung in Nicolaides KH. Fetal plasma erythropoietin in
organ culture. Lung 1980; 158: 151-5. pregnancies complicated by maternal diabetes mellitus.
51. Gross I, Smith GJ, Wilson CM, Maniscalco WN, Ingleson Am J Obstet Gynecol 1993; 168: 88-94.
LD, Brehier A, Rooney SA. The influence of hormones 68. Salvesen DR, Brudenell MJ, Nicolaides KH. Fetal
of the biochemical development in fetal rat lung in organ polycythemia and thrombocytopenia in pregnancies
culture. II. Insulin. Pediatr Res 1980; 14: 834 – 8. complicated by maternal diabetes mellitus. Am J Obstet
52. Smith BT, Girout CJ, Robert M, Avary ME. Insulin Gynecol 1992; 166: 1287-93.
antagonism of cortisol action on lechithin synthesis by 69. Mimouni F, Miodovnik M, Siddiqi TA, Butler JB,
cultured fetal lung cells. J Pediatr 1975; 87: 953-5. Holroyde J, Tsang RC. Neonatal polycythemia in infants
53. Pignol B, Bourbon J, Ktorza A, Marine L, Rieutort M, of insulin-dependent diabetic mothers. Obstet Gynaecol
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fetus. Pediatr Res 1987; 21: 436–41. 70. Freinkel N, Metzger BE. Pregnancy as a tissue culture
54. Carlson KS, Smith BT, Post M. Insulin acts on the experience: the critical implications of maternal
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55. Snyder JM, Kwun JE, O’Brien JA, Rosenfeld CR, Odom 71. Freinkel N, Metzger BE. Emerging challenges in
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following corticosteroid therapy in diabetic pregnancies. 72. Rubaltelli FF. Unconjugated and conjugated bilirubin
Diabet Med 2003; 20: 73–5. pigments during perinatal development. IV. The
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73. Peevy KJ, Landaw SA, Gross SJ. Hyperbilirrubinemia content of cultured rat conceptus: failure of aldose
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19. and dysmorphogenesis. Biochem Biophys Res Commun
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Hopp H. Neonatal Jaundice in Infants of Diabetic 90. Reece EA, Homko CJ, Wu YK. Multifactorial basis of
Mothers. Acta Paediatr Scand Suppl 1989; 360: 101-7. the syndrome of diabetic embryopathy. Teratology 1996;
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fetal macrosomia: significance of disproportionate 91. Eriksson UJ, Borg LA. Diabetes and embryonic
growth. J Pediatr 1993; 122: 115-9. malformations. Role of substrate-induced free-oxygen
76. Garcia – Patterson A, Erdozain L, Ginovart J, Adelantado radical production for dysmorphogenesis in cultured rat
JM, Cubero JM, Gallo G, de Leiva A, Corcoy R. In embryos. Diabetes 1993; 42:411-9.
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malformations are related to pre-pregnancy body mass EA, Eriksson UJ, Groner Y. Prevention of diabetes-
index and to severity of diabetes. Diabetologia 2004; 47: associated embryopathy by overexpression of the free
509–14. radical scavenger copper zinc superoxide dismutase in
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93. Goldman AS, Baker L, Piddington R, Marx B, Herold R,
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79. Sheffield JS, Butler-Koster EL, Casey BM, McIntire DD, 94. Khandelwal M, Wu YK, Borenstein M, Reece EA. Dietary
Leveno KJ. Maternal diabetes mellitus and infant phospholipid therapy, hyperglycaemia-induced
malformations. Obstet Gynecol 2002; 100: 925–30. membrane changes and associated diabetic embryo-
80. Mikhail LN, Walker CK, Mittendorf R. Association pathy. Am J Obstet Gynecol 1995; 172:265-71.
between maternal obesity and fetal cardiac malfor- 95. Khandelwal M, Reece EA, Wu YK, Borenstein M. Dietary
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81. Pedersen J. Hyperglycaemia-hyperinsulinism theory 96. Menon RK, Cohen RM, Sperling MA, Cutfield WS,
and birthweight. In “The pregnant diabetic and her Mimouni F, Khoury JC. Transplacental passage of insulin
newborn” 1977. Pedersen J (eds). Baltimore, Williams in pregnant women with insulin-dependent diabetes
and Wilkins. mellitus. Its role in fetal macrosomia. N Engl J Med 1990;
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Meschia G. Effects of a sustained insulin infusion upon 97. Reece EA, Homko C, Wiznitzer A. Metabolic changes
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83. Widness JA, Susa JB, Garcia JF et al. Increased erythro- 98. Rosenn BM, Miodovnik M, Khoury JC, Siddiqi TA.
poiesis and elevated erythropoeitin in infants born to Deficient counterregulation : a possible risk factor for
diabetic mothers and in hyperinsulinic rhesus fetuses. J excessive fetal growth in IDDM pregnancies. Diabetes
Clin Invest 1981; 67: 637–42. Care 1997; 20: 872–4.
84. Artal R, Platt LD, Kammula RK, Strassner HT, Gratacos 99. Schwartz R, Gruppuso PA, Petzold K, Brambilla D,
J, Golde SH. Sympathoadrenal activity in infants of Hiilesmaa V, Teramo KA. Hyperinsulinemia and
diabetic mothers. Am J Obstet Gynecol 1982; 142: 436–9. macrosomia in the fetus of the diabetic mother. Diabetes
85. Bloom SR, Johnston DI. Failure of glucagon release in Care 1994; 17: 640–8.
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T, Yanagisawa K, Omori Y. Insulin-like factors (IGFs)
86. Stern L, Ramos A, Leduc J. Urinary catecholamine
and IGF-binding proteins (IGFBP-1, -2, -3) in diabetic
excretion in infants of diabetic mothers. Pediatrics 1968;
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87. Milner RDG. Amino acids and beta cell growth in 101. Roth S, Abernathy MP, Lee WH, Pratt L, Denne S,
structure and function. In “The Diabetic Pregnancy: A Golichowski A, Pescovitz OH. Insulin-like growth factors
Perinatal Perspective” 1979. Merkatz IR, Adam PAJ I and II peptide and messenger RNA levels in
(eds). New York , Grune and Stratton. macrosomic infants of diabetic pregnancies. J Soc Gynecol
88. Reece EA, Homko C, Wiznitzer A. Metabolic changes Investig 1996; 3: 78–84.
in diabetic and nondiabetic subjects during pregnancy. 102. Ornay A, Ratzon N, Greenbaum G, Peretz E, Soriano
Obstet Gynecol Surv 1994; 49: 64-71. D, Dulitzky M. Neurobehaviour of school age children
89. Hod M, Star S, Passonneau JV, Unterman TG, Freinkel born to diabetic mothers. Arch Dis Child Fetal Neonatal
N. Effect of hyperglycemia on sorbitol and myo-inositol Ed 1998; 79(2): F94–9.
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103. Ornay A, Wolf A, Ratzon N, Greenbaum G, Dulitzky 113. Persson B, Gentz J. Follow-up of children of insulin-
M. Neurodevelopmental outcome at early school age dependent and gestational diabetic mothers:
of children born to mothers with gestational diabetes. Neuropsychological outcome. Acta Pediatr Scand 1984;
Arch Dis Child Fetal Neonatal Ed 1999; 81(1): F10–4. 73: 349–58.
104. Rizzo TA, Dooley SL, Metzger BE, Cho NH, Ogata ES, 114. Vohr BR, Lipsitt LP, Oh W. Somatic growth of children
Silverman BL. Prenatal and perinatal influences on long- of diabetic mothers with reference to birth size. J Pediatr
term psychomotor development in offspring of diabetic 1980; 97: 196–9.
mothers. Am J Obstet Gynecol 1995; 173: 1753–8. 115. Vohr BR, McGarvey ST, Tucker R. Effects of maternal
105. Rizzo TA, Metzger BE, Dooley SL, Cho NH. Early gestational diabetes on offspring obesity at 4–7 years
malnutrition and child neurobehavioural development: of age. Diabetes Care 1999; 22: 1284–91.
insight from the study of children of diabetic mothers. 116. Whitaker RC, Pepe MS, Seidel KD, Wright JA, Knopp
Child Dev 1997; 68: 26–38. RH. Gestational diabetes and the risk of offspring
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term effects of the intrauterine environment. The 117. Van Assche FA, Aerts L, Holemans K, Danneels L. Fetal
Northwestern University Diabetes in Pregnancy Centre. consequences of maternal diabetes. In “Immunobiology
Diabetes Care 1998; 21 (Suppl 2): B142–9. of normal and diabetic pregnancy” 1990. Andreani D,
107. Dorner G, Plagemann A, Reinagel H. Familial diabetes Bompiani G, Di Mario U, Faulk WP, Galluzo A. (eds).
aggregation in type I diabetics: gestational diabetes an New York John Wiley,.
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apparent risk factor for increased diabetes susceptibility
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children of diabetic mothers. In “Immunobiology of
108. Dorner G, Steindel E, Thoelke H, Schliack V. Evidence
normal and diabetic pregnancy” 1990. Andreani D,
for decreasing prevalence of diabetes mellitus in
Bompiani G, Di Mario U, Faulk WP, Galluzo A. (eds).
childhood apparently produced by prevention of
New York John Wiley.
hyperinsulinism in the foetus and newborn. Exp Clin
119. Hales CN, Barker DJ. Type 2 (non insulin-dependent)
Endocrinol 1984; 84: 134–42.
diabetes mellitus: the thrifty phenotype hypothesis.
109. Martin AO, Simpson JL, Ober C, Freinkel N. Frequency Diabetologia 1992; 35: 595-601.
of diabetes mellitus in mothers of probands with 120. Phillips DI, Barker DJ, Hales CN, Hirst S, Osmond C.
gestational diabetes: possible maternal influence on the Thinness at birth and insulin resistance in adult life.
predisposition to gestational diabetes. Am J Obstet Diabetologia 1994; 37: 150-4.
Gynecol 1985; 151: 471–5. 121. Johnston F. Outcome of pregnancy in diabetic women.
110. Pettitt DJ, Aleck KA, Baird HR, Carraher MJ, Bennett Authors did not define criterion for case selection
PH, Knowler WC. Congenital susceptibility to NIDDM. (author reply). BMJ 2001; 322: 614.
Role of intrauterine environments. Diabetes 1988; 37: 122. Golding J; ALSPAC (Avon Longitudinal Study of Parents
622–8. and Childen) Study Team. Outcome of pregnancy in
111. Van Assche FA, Holemans K, Aerts L. Fetal growth and diabetic women. More investigation is needed into
consequences for later life. J Perinat Med 1998; 26: 337– whether control of diabetes is really poorer in England
46. than Norway. BMJ 2001; 322(7286): 614–5.
112. Howarth JC, McRae KN, Dilling LA. Prognosis of infants 123. Hawthorne G, Irgens LM, Tie RT, Moe N, Jervell J.
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140 Textbook of Perinatal Medicine

13
Neonatal Seizures

Beke A, Papp Z

DEFINITION frequent among the major neurological disorders in

the neonatal period, their precise frequency is
Seizures have been defined as abnormal, paroxysmal,
unknown because many of the subtle manifestations
stereotypical clinical events that are initiated by the
of neonatal convulsions may escape recognition.
hypersynchronous activity of neurons in the brain.1
Conversely, jittery and tremulous movements,
They represent rapid alteration in the function of
common at this period, are often mistaken for
the nervous system by which the motor, behavioral
convulsive seizures, although their significance is
or autonomic functions (or all of these) are clinically
completely different. The true incidence of neonatal
affected. Seizures are far commoner in the first month
seizures varies in different series from 0,15 to
of life than at any other time. Neonatal seizures have
1,4%.5-10 Mark Scher and colleagues11 found that the
been described in both clinical and electrical terms.
incidence of seizures among all neonates admitted
Clinical seizures have been described as occurring in
to the intensive care unit was 2,3%, and the group
close association with electroencephalograph (EEG)
of preterm neonates of <30 weeks of gestational age
seizure activity (epileptic in origin), and without
had a seizure frequency of 3,9%, which was
accompanying EEG seizure activity (presumably
significantly higher than that of older preterm or full-
nonepileptic in origin). All the clinical seizures
term neonates. The very high incidence figure (up to
described indicate the presence of significant central
22.7%) reported in premature infants by Bergmann
nervous system dysfunction. In this regard, the
and colleagues6 are probably due to the frequency
findings of EEG monitoring studies do not change
of nonepileptic events in this group.1 Seay and Bray12
a fundamental concept concerning seizures of the
reported seizures in 20% of infants admitted to the
newborn: each newly diagnosed neonatal seizure
intensive care unit, weighing 2500 g or below. In
represents a neurological emergency.2
general, an incidence of neonatal seizures of between
4 and 6 per 1000 infants seems to be a realistic figure.
INCIDENCE
This figure is much higher among the most immature
Conventionally, the neonatal period is limited to the infants. Neonatal seizures appear to be associated
first 4 weeks of life. However, some authors3,4 define with major morbidities and surgical interventions in
neonatal seizures as those that occur up to 44 weeks very low birthweight infants. Continuous electro-
of postmenstrual age, to take into account premature encephalographic monitoring could be warranted in
birth. Although convulsive phenomena are the most infants following surgical treatment.114
 Neonatal Seizures 141
PATHOPHYSIOLOGY in the intensity of the stimulus at a single site
(temporal summation) or an increase in the number
The site of paroxysmal activity may arise from
of sites of stimulation (spatial summation). The
previously normal neurons. This fire due to a trigger
response may spread to muscle groups other than
and abnormal conduction occurs through neighboring
neurons. Alternatively the neuronal focus may be those originally stimulated (irradiation of the
inherently abnormal and fires repetitively. Seizures response). Both provoked and spontaneous tonic
in infants and children may due to either or both posturing and motor automatism may be suppressed
mechanism. 10 Seizures indicate the presence of a by restraint or repositioning of the body or affected
central nervous system dysfunction and may limbs. All of these features are typical of reflex
contribute to additional brain injury.13-15 behaviors24-26 and are not characteristic of epileptic
Brain maturation progresses rapidly during the seizures. On this basis, it has been proposed that
last weeks of gestation and in the postnatal period. tonic posturing and motor automatisms result from
Structural and functional development of the central depression of forebrain function and the consequent
nervous system is reflected in the rapidly changing disinhibition of the brain-stem centers that facilitate
bioelectrical activity and behavior of the brain. This primitive reflex behaviors.22-23 This hypothesis is
has been extensively documented during the past based not only on clinical observations but also on
decades in studies of various mammalian species16,17 the correlation of these findings with experimental
and human preterm and newborn infants.18-20 In the studies of reflex physiology in animals.23,27 Primitive
term newborn, the archicortex (i.e. diencephalon and reflex behaviors are normally mediated by spinal
brain-stem) is at a relatively more advanced stage of mechanisms and facilitated by centers within the
development than is the neocortex. A significant brain stem. These centers are tonically inhibited by
percentage of paroxysmal electrical discharges in the the forebrain and may be stimulated by pro-
newborn brain, which arise from subcortical grey prioceptive and entroceptive pathways activated by
matter, might not be identified by EEG scalp limb and truncal manipulation. When the forebrain
recordings. Two possible explanations exist for is depressed, brain-stem centers are disinhibited, and
clinical seizures without an electrographic signature.21 primitive reflexes may occur spontaneously or be
1. Tonic posturing and motor automatism are evoked by stimulation. It has been proposed that
epileptic but are generated in the brain stem, and these behaviors, as a group, be designated ‘brain-
the paroxysmal electrical epileptic activity is not stem release phenomena’ rather than epileptic
manifested at the scalp and not recorded by seizures.25,28 Although neurons are in place by the
surface EEG electrodes. time of birth, their axonal and dentritic ramifications
2. Tonic posturing and motor automatisms are and synaptic connections are still incompletely
generated and elaborated at a brain-stem level developed in the neonatal human brain29-30 , and
by a nonepileptic mechanism. myelination is limited to a few pathways not
It has been suggested that the latter explanation including the main hemispheric commissures.31 The
is more plausible.22,23 Although the lack of a close hyperexcitability of the immature cortex is explained
association to EEG seizure activity would only by the underdevelopment of the myelinisation and
suggest that tonic posturing and motor automatisms the characteristic phenomena32-34; the modification of
are not epileptic in origin, it is these clinical the shapes of spikes depends on the developmental
characteristics of the behaviors that provide the stage of dendrites; the propagation of discharges is
evidence for a nonepileptic mechanism. Tonic determined by the state of maturity of the cortical
posturing and motor automatism may be evoked by and subcortical and interhemispherial connections.35
tactile stimulation; a graded increase occurs in the Kolmodin and Meyerson36 found the age-related
magnitude of the response proportional to an increase variations of the potential stable and others observed
142 Textbook of Perinatal Medicine

the role of the enzymatic reactions.37-38 In addition, ment.117 Neonates have a low cerebral metabolic rate
synaptic connection and transport across synaptic and a fragmentary neuronal network, making them
membranes is much less efficient in the immature less vulnerable to neuronal damage and cell loss than
brain.39 Both inhibitory (γ-amino butyric acid (GABA) adults and more resistant to the toxic effects of
ergic) and excitatory receptors are present in the glutamate. However, seizures undoubtedly can
human newborn but are not fully developed or are inhibit brain growth, modify neuronal circuits and
not completely functional because of the incomplete increase neuronal excitability. Recurrent seizures
development of the appropriate circuitry.40-41 There during early development have been shown to result
is evidence that the inhibitory dopamine transmitters in impairment of visual-spatial learning and
have a predominant effect over excitatory trans- memory. 118-119 Status epilepticus and recurrent
mitters in the developing brain.42 The neonatal brain seizures have also been shown to predispose the brain
appears uniquely susceptible to seizure because to seizures in later life. 120 Magnetic resonance
neonatal [gamma]-amino butyric acid (GABA) spectroscopy studies shows areas of cerebral
receptors are excitatory, and are functionally more metabolic dysfunction in babies with seizures.121
active than N-methyl-D-aspartate receptors at this Status epilepticus can result in necrotic damage to
time of life.115 The absence of generalized tonic-clonic the thalamus in immature rats.122 The response of
seizures probably reflects both the lack of a sufficient the developing brain to epileptic seizures and to status
degree of cortical organization (which is necessary epilepticus is highly age-specific. Neonates with their
to propagate and sustain the electrical discharge) and low cerebral metabolic rate and fragmentary
the failure of interhemispheric transmission, resulting neuronal networks can tolerate relatively prolonged
from commissural immaturity. Experimental data seizures without suffering massive cell death, but
suggest that neonatal seizures may have a deleterious severe seizures in experimental animals inhibit brain
effect on the developing brain, depleting cerebral growth, modify neuronal circuits, and can lead to
glucose, which may interfere with DNA synthesis, behavioral deficits and to increases in neuronal
glial proliferation and differentitation, and myeli- excitability. Past infancy, the developing brain is
nisation.43-45 Younkin and associates46, using nuclear characterized by high metabolic rate, exuberant
resonance spectroscopy, showed a marked depletion neuronal and synaptic networks and overexpression
of brain phosphocreatine and adenosine triphosphate of receptors and enzymes involved in excitotoxic
during a subtle seizure, which was reversed following mechanisms. The outcome of seizures is highly model-
phenobarbital therapy and seizure cessation. Animal dependent. Status epilepticus may produce massive
studies have shown that seizures impair neurogenesis neuronal death, behavioral deficits, synaptic
and derange neuronal structure, function and reorganization or chronic epilepsy in some models,
connectivity (‘cells that fire together’). The hippo- little damage in others. We now have some models
campus has been well studied because it is which reliably lead to spontaneous seizures and
particularly susceptible to seizure-induced injury. chronic epilepsy in the vast majority of animals,
Seizures cause synaptic reorganization with aberrant demonstrating that seizure induced epileptogenesis
growth (sprouting) of the dentate granule cell axons can occur in the developing brain. The mode of cell
(i.e. the mossy fibers).116 There is also apoptosis in death from status epilepticus is largely (but not
the inner granule cell layer of the dentate hilus, and exclusively) necrotic in adult, while the incidence of
bilateral hippocampal sclerosis has been at autopsy apoptosis increases at younger ages. Seizure-induced
in human babies who suffered prolonged seizures. necrosis has many of the biochemical features of
Seizures lead to a mismatch between energy supply apoptosis, with early cytochrom release from
and demand, and although there is a rise in cerebral mitochondria and capsase activation. Wasterlain and
flow this may not be sufficient to meet require- colleagues speculate that this form of necrosis is
 Neonatal Seizures 143
associated with seizure-induced energy failure.123 pathophysiology, with the suggestion that some
Recent findings: neonatal seizures can permanently neonatal seizures are epileptic in origin and others
disrupt neuronal development, induce synaptic are not 47-48 (Table 13.1). 2 Seizure recognition,
reorganization, alter plasticity and “prime” the brain characterization and classification create the
to increased damage from seizure later in life. These foundation of care of the neonate who may be at
findings have led to a renewal of interest in the topic risk for central nervous system dysfunction. For
of neonatal seizures, particularly regarding classification of neonatal seizures and for make a
treatment.124 guide to clinical recognition a workshop was formed
Edwards and colleagues found that prenatal in USA [participants: Subcommission on Classi-
stress alters seizure threshold and the development fication and Terminology of Pediatric Epilepsy,
of kindled seizures infant and adult rats. Their Commission on Classification and Terminology,
findings indicate that stress, particularly during the International League Against Epilepsy (ILAE) and
latter half of pregnancy, may play an important role the Clinical Research Centers for Neonatal Seizures,
in increasing seizure vulnerability in the unborn
Table 13.1: Electroclinical classification of
offspring.125 The idea that stem cells may play role neonatal seizures*
in the pathophysiology or potential treatment of Clinical seizures with a consistent electrocortical signature
specific epilepsy syndromes is relatively new. 126 A. Focal clonic
Knowledge of the normal neurogenesis pathways in unifocal
multifocal
the mature brain has led to recent studies of alternating
neurogenesis in rodent models of acute seizures or migrating
epileptogenesis. Current evidence indicates that single hemiconvulsive
brief or prolonged seizures, as well as repeated axial
B. Myoclonic
kindled seizures, increase dentate granule cell (DGC) generalized
neurogenesis. Recent work also suggest that focal
pilocarpine induced status epilepticus increases rostral C. Focal tonic
forebrain subventricular zone (SVZ) neurogenesis asymmetric truncal
eye deviation
and caudal SVZ gliogenesis. These abnormalities Clinical seizures with no electrocortical signature
include aberrant mossy fiber reorganization, A. Motor automatisms
persistence of immature DCG structure (e.g. basal oral-buccal-lingual movements
ocular movements
dendrites), and the abnormal migration of newborn
progression movements
neurons, to ectopic sites in the dentate gyrus. Taken pedaling
together, these findings suggest a pro-epileptogenic stepping
role of seizure- or injury- induced neurogenesis in rotary arm movements
complex purposeless movements
the epileptic hippocampal formation. However, the B. Generalized tonic
induction of forebrain SVZ neurogenesis and extensor
directed migration to injury after seizures and other flexor
brain insults underscores the potential therapeutic mixed extensor/flexor
C. Myoclonic
use of neural stem cells as a source for neuronal generalized
replacement after injury. focal
Electrical seizures without clinical seizures
THE CLASSIFICATION OF *Infantile spasms and episodic apnea (associated with
NEONATAL SEIZURES electroencephalographic seizure activity) may also occur as
neonatal seizures, but they are rare and currently do not
Recently, neonatal seizures have been characterized warrant major classifications.
and classified according to their presumed From reference 2 with permission.
144 Textbook of Perinatal Medicine

National Institute of Neurological Disorders and Table 13.2: Classification of neonatal seizures*
Stroke, National Institute of Health (NIH), USA]. I. Clonic
The report of the newest classification was published A. unifocal : 1. limb 2. facial 3. hemiconvulsive
by Mizrahi this year.127 The classification system and B. multifocal: 1. alternating 2. bilateral, asynchronous
the infants presented in the workshop are based upon C. axial: 1. abdominal 2. diaphragm
II. Tonic
a prospective, clinical study of infants with seizures 1. focal: 1. ocular (sustained eye deviation) 2. limb
that have been documented by bedside, EEG-video posturing 3. asymmetric
monitoring. Each seizure was examined by all the 2. generalized: 1. symmetric-a. flexion b. extension c.
investigators together, characterized and then mixed flexion-extension. 2. asymmetric
III. Myoclonic
classified by consensus. 1. generalized
Approximately 65% of neonatal seizures are not 2. focal
clearly associated with apparent cortical electro- 3. multifocal (fragmentary)
graphic seizure activity on the basis of EEG IV. Spasm (generalized)
1. flexion
recordings from surface electrodes.23,49 Neonatal
2. extension
seizure types differ considerably from seizures 3. mixed extension flexion
observed commonly in older children, principally V. Motor automatisms
because the newborn infant is less able to sustain A. oral-buccal-lingual movements: 1. chewing 2. sucking
B. ocular signs: 1. random eye movements 2. blinking,
organized, generalized epileptiform discharges. The
rhythmic eye opening
most widely accepted and most often clinically C. limb (movements of progression): 1. pedaling 2.
applied classification scheme is that proposed and swimming
recently updated by Mizrahi and Kellaway (Table D. complex purposeless movements.
VI. Autonomic nervous system signs
13.2). Some clinical seizures are characterized by just
A. Respiratory: 1. tachypnea 2. respiratory pause
one type of movement. However other seizures are B. Cardiac.: 1. tachycardia 2. bradycardia
more complex. They may begin with one type of C. Cardiovascular: 1. hypertension 2. hypotension
movement that is then followed by others in a D. Vasomotor: 1. flushing 2. pallor
E. Pupillary dilatation
sequence typical for that specific seizure. The most
F. Salivation
effective application of this classification is to use it G. Other
as a basis to identify the individual components of VII. No clinical signs-electrical seizure only
a single seizure, rather to classify an entire complex VIII. Unclassified
event. ILAE-NIH Classification of Neonatal Seizures. Modified
Several seizures types are frequently occur from Reference 127.
together in the same infant; subtle seizures are
frequently associated with other types in severely ill associated with simultaneous epileptiform activity
neonate.5 In addition various seizure types may be on EEG.57 Two subtypes are recognized, focal clonic
generated by different mechanisms-either epileptic and multifocal.
or non-epileptic. The clinical characteristics of a Focal clonic seizures have limited, usually
specific seizure may designate its pathophysiology. unilateral, involvement of the face, limbs or axial
Thus, the classification of a seizure may suggest a muscles and are often not associated with alterations
specific mechanism of generation, leading eventually of the level of consciousness. In many instances, there
to considerations of therapy and long-term is an underlying focal lesion, e.g. focal cerebral
prognosis. infarction. However, it is important to realize that
metabolic derangements, e.g. hypoglycemia, may
Clonic Seizures present as focal seizures in the newborn.15 Cockburn
Clonic seizures consist of rhythmic muscle jerking et al. 58 reported clonic seizures with late
that can involve any part of the body and are often hypocalcaemia.
 Neonatal Seizures 145
Multifocal clonic seizures are observed more activity, the interictal EEG is usually severely
frequently in the term newborn, and are a relatively abnormal with marked voltage suppression.28
benign form. They involve non-synchronized clonic
movements of the extremities which differ from Myoclonic Seizures
multifocal clonic seizures in older infants in that Myoclonic seizures, which may be either focal,
abnormal movements in newborns usually migrate multifocal or generalized, are rare in the neonatal
in non-ordered, nonjacksonian fashion. For example, period. They may occur in infants of any gestational
clonic movements of one hand may be followed by age and are associated with time-synchronized EEG
the jerking of the opposite leg. 59 This particular discharges only in a minority of cases.23 They are
seizure type may be explained by the immature stage characterized by rapid, unilateral or bilateral, single
of development of the cerebral cortex of the term or multiple flexion jerks of the upper extremities, but
infant. Thus, although there is sufficient inter- to a lesser extent. Myoclonic seizures often signify
neuronal communication to permit sustained seizure severe structural or metabolic cerebral disturbance.
activity, the immaturity of synaptic development and They often persist into infancy as more or less atypical
axonal myelination may prevent the organized infantile spasms.60,63 A benign variety of neonatal
spread of electrical impulses. Because of this, genera- myoclonus has been described, which occurs
lized tonic-clonic seizures, which are symmetric characteristically only during sleep. Focal and
and synchronous, occur infrequently in the term multifocal myoclonic activity may be observed, which
newborn.29 is difficult to distinguish clinically from epileptic
seizures. However, the correlation with the sleep
Tonic Seizures state and the absence of associated EEG abnormalities
Tonic seizures are most often generalized, featuring may be helpful in this. It typically resolves spon-
tonic extension of all limbs (which resembles taneously before 6 months of age.64-66
‘decerebrate’ posturing), or, occasionally, flexion of
Spasms
the upper limb with the extension of the legs (which
resembles ‘decorticate’ posturing). Eye signs such as May be flexor, extensor, or mixed extensor and
opening or closing movements of eyelids, staring, flexor, may occur in clusters. Spasms cannot be
gaze deviation, or the occurrence of a few clonic jerks provoked by stimulation or suppressed by restraint.
may be a clue to their epileptic mechanism. Volpe29 Pathophysiology is epileptic.
found tonic seizures to be particularly common
among premature infants and they accounted for 70% Motor Aautomatisms (Subtle Seizures)
of fits seen in infants weighing 2500g or less. This Subtle seizures may be the most common type and
form of seizure occurs in infants with significant are present to some degree in most term newborns
cerebral injury (e.g. massive intraventricular with seizures. This category includes all paroxysmal
hemorrhage) and is associated with a bad prognosis. steps of behavior in newborns which may be
In approximately 85% of cases, the abnormal sustained, and which cannot be readily classified as
posturing is accompanied by electrical seizure activity myoclonic seizures. Subtle or minimal seizures are
or autonomic phenomena and the response to also termed “motor automatisms” by some investi-
anticonvulsant therapy is poor.12,29 This observation gators.50 The most common clinical manifestation is
raises the possibility that such posturing represents a variety of ocular movements, e.g. eye opening, tonic
abnormal brainstem release phenomena as opposed horizontal deviation of the eyes; orofacial move-
to true epileptic seizures. 22,29,62 In these instances, ments, as repetitive chewing, swallowing, drooling,
although there is no corresponding electrical seizure rotatory limb movements, or complex patterns as
146 Textbook of Perinatal Medicine

pedaling, boxing, swimming or stepping; and demonstrated that subtle clinical phenomena are
autonomic disturbances: hyperpnoea, vasomotor frequently accompanied by simultaneous electrical
abnormalities, salivation or modification of the heart discharges in premature infants.56 The EEG signs
rate. Abnormal eye movements, especially in the which are associated with subtle seizures occur
horizontal plane are of special diagnostic value.51,52 commonly in the temporal leads 57, which is not
Unlike sustained eye deviation is typical of focal tonic surprising as similar clinical features are frequently
seizure of epileptic origin; the ocular signs of motor observed in older children in complex partial seizures
automatisms are less well-defined. They include which originate in the temporal lobes. Alterations in
random eye movements, eye opening and blinking.127 the autonomic function as a seizure manifestation
Motor automatisms and generalized tonic posturing raise particular diagnostic problems. Thus, although
may co-exist, since their pathophysiologic mecha- apneic episodes in the premature infant may rarely
nisms are the same. be a manifestation of seizure activity56, they are much
more likely to be related to other mechanisms. In
Autonomic Nervous System Signs contrast, apnea in the term newborn appears to be
Autonomic nervous system signs are often combined associated with electrical seizure activity more
with motor automatisms Apneic seizures are commonly. Recently, the apneic episodes have been
common, sometimes in isolation53,54, but more often observed and differentiated in newborns and
in association with ocular or other autonomic signs. especially in prematures with a new polygraphic
Fenichel 55 found that apneic seizures were not computerized method (SLEEP Labor). We can also
accompanied by bradycardia, as opposed to the much determine the type of apnea exactly: central,
more frequent nonepileptic apneas of the premature obstructive or mixed. Figure 13.1. shows a poly-
infant, which last 20 sec or more. Other studies graphic investigation demonstrating a central apnea
involving simultaneous video/EEG investigations (cenA-) following the electrical activity change on

Fig. 13.1: Central apnea demonstrated by polygraph

 Neonatal Seizures 147
the FP1 channel. There is not significant change in metabolic disturbances (hypoglycemia, hypo-
ECG. (Examination of the author). Infantile spasms calcemia), intracranial infection, and cerebral cortical
and episodic apnea (associated with electro- dysgenesis. Table 13.3.
encephalographic seizure activity) may also occur as Hypoxic-ischemic encephalopathy (HIE) is the most
neonatal seizures, but they are rare and currently important cause of neonatal seizures in infants is in
do not warrant major classifications.3 all gestational ages.29 It has been estimated to account
for approximately two-thirds of all cases. Seizures
Isolated Seizures are a major manifestation of moderate or severe
Isolated seizures are relatively uncommon in the intrapartum hypoxic-ischemia encephalopathy in
neonatal period. The occurrence of at least a few approximately 50% of affected term newborns and
attacks in rule. However, neonatal seizures tend to are associated with long-term neurological sequel in
be self-limited and to last 24 to 96 hr 67-69, which at least 20-40% of cases.29,73 Many cases are probably
complicates the assessment of therapy further. of prenatal origin so a low weight for date and other
signs of dysmaturity are common findings. 59
Neonatal Status Epilepticus Postnatal respiratory insufficiency causes less than
Neonatal status epilepticus has been defined by 10% of cases of hypoxic encephalopathy.29 Ischemia
Dreyfus-Brisac and Monod70,71 as the repetition of is secondary to intrauterine asphyxia with cardiac
clinical and/or purely electrical seizures with the insufficiency. Seizures begin most frequently during
interictal persistence of an abnormal neurological the first day of life74-76, and 60% of the patients with
status. Cukier, et al69 redefined the term with greater this condition have already had fits by 12 h.29 The
precision as the occurrence of electrical seizure seizures are often isolated at the start. Seventy-five
discharges, each lasting at least 10 sec and repeated to 85% of the cases of “neonatal status epilepticus”
for several hours, in association with an abnormal have been attributed to hypoxic insult.29 Seizures may
neurological state and unconsciousness. Clinical Table 13.3: Correlation of time of onset of
seizures may or may not be present. The latter seizures and etiology
definition does not include repeated clinical seizures Most frequent time of onset Etiology of seizures
without ictal EEG concomitants such as those that <48 hours hypoxic-ischemic
may occur in neonates who have been convulsing encephalopathy
for many hours.72 The term serial seizures are perhaps intracranial hemorrhage
hypoglycemia
preferable to that of status epilepticus in the neonatal
sepsis-meningitis
period because it does not refer to an abnormal congenital viral infection
interictal neurological state, which may be impossible drug withdrawal
to assess reliably on account of the interference of local anesthetic intoxication
pyridoxine dependency
drug treatment. 3 With prolonged convulsive non-ketotic hyperglycinemia
episodes, there is a tendency for individual seizures urea cycle disorders
to change from well marked to poorly organized 48-72 hours Cerebral dysgenesis
attacks, clinically as well as electrically. cerebral infarction
ketotic hyperglycinemia
urea cycle disorders
ETIOLOGY >7 days cerebral dysgenesis
organic acidopathies
Although the etiology of neonatal seizures is amino acidopathies
extremely diverse, most can be attributed to hypoxic- urea cycle disorders
ischemic encephalopathy (about 65% of neonatal bacterial meningitis
seizures), intracranial hemorrhage (about 15%), Adapted from reference 50 with permission
148 Textbook of Perinatal Medicine

be of any type and are often prolonged and refractory radical generation that may lead to the oxidation of
to anticonvulsant therapy. Brown77 has pointed out brain cell membrane lipids, membrane enzymes,
that the seizures usually occur when infants show a receptor proteins, as well as the nuclear DNA
transition in muscle tone. The interictal EEG is of precipitating the hypoxic neuronal injury in the fetus
the “tracé paroxystique” or inactive tracing type in and newborn.
severe cases.78 The convulsions may be extremely
difficult to control by drugs. Levene and colleagues79 Intracranial Hemorrhage
have reported neonatal convulsions due to asphyxia This condition is often difficult to establish con-
to occur in 2 per 1000 full-term infants. Delivoria et clusively as a primary cause of seizure distinct from
al. studied the mechanism of cerebral hypoxia in the HIE or traumatic injury, because of the frequent
fetus and newborn that results in neonatal morbidity association of these conditions. There are three
and mortality as well a long-term sequel such as important types of hemorrhage according to
mental retardation, seizure disorders and cerebral localization:
palsy. Using electron spin resonance spectroscopy
Intraventricular hemorrhage is a very common lesion in
(ESR) they demonstrated that tissue hypoxia results
extremely premature infants, but germinal matrix/
in increased free radical generation in the cortex of
intraventricular hemorrhage is associated relatively
fetal guinea pigs and newborn piglets.128 Normally,
rarely with seizures. However, large intraventricular
more than 80% of the oxygen consumed by the cell
hemorrhages, especially if there is associated
is completely reduced by cytochrom oxidase to
intraparenchymal hemorrhagic infarction (which
reactions with the cytoplasm and mitochondria that
accounts for approximately 15% of all examples of
produce a superoxide anion radical. To protect cells
IVH) may occur together with generalized tonic
from the deleterious effects free radicals, a number
seizures, most often as part of a catastrophic
of enzymatic and nonenzymatic defenses such a
deterioration evolving to coma and respiratory
catalase, superoxide dismutase, glutathione peroxi-
arrest. This clinical setting and type of seizure signify
dase; ascorbic acid and vitamin E are present in cells.
an ominous prognosis.29
The hypoxia- induced increase in lipid peroxi-
dation products was showed also associated with a Subdural hemorrhage This variety of hemorrhage is
decrease in cell membrane Na+, K+-ATPase activity. most commonly associated with traumatic delivery
The direct demonstration of production of free or non-accidental shaking injury. The associated
radicals during hypoxia was documented by cerebral contusion frequently results in focal clonic
measuring the signal of spin adducts using ESR which and subtle seizures. Such seizures most commonly
allows direct identification and characterization of begin during the first 48 hours of life.80 Subdural
free radicals.129 The brain tissue hypoxia modified hemorrhage occurring as a result of tentorial tears is
the N-methyl-d-aspartate (NMDA) receptor ion- not necessarily fatal and may have a relatively good
channel recognition and modulation sites. A higher prognosis.
increase in NMDA receptor agonist-dependent Ca2+ Subarachnoid hemorrhage Primary subarachnoid
in synaptosomes was demonstrated. The increase in hemorrhage, especially of a minor degree, is a very
intracellular Ca2+ may activate several enzymatic common occurrence in newborns and is usually not
pathways such as phospholipase A and metabolism of major clinical significance. When seizures occur
of arachidonic acid by cyclooxygenase and lipoxy- secondary to the subarachnoid hemorrhage in the
genase, conversion of xanthine dehydrogenase to full-term infant, they occur most commonly on the
xanthine oxidase by proteases, and activation of nitric second day of life.81 During the interictal period,
oxide synthase. In summary, studies demonstrated affected infants often appear remarkably healthy,
that cerebral tissue hypoxia results in increased free leading to the descriptive term “well baby with
 Neonatal Seizures 149
seizures”. Spain authors publish neonatal convulsions Listeria monocytogenes and Escherichia coli are the
and subarachnoid hemorrhage after paroxetine most common. In addition to bacterial meningitis,
treatment in the third trimester of pregnancy. 130 meningo-encephalitis may occur due to herpes
simplex, Coxackie and toxoplasmosis. In the latter
Neonatal Stroke case, toxoplasmosis may be acquired in early
Billard et al82 reported eight infants presenting focal pregnancy and extensive brain damage may have
seizures between the age of 8 and 72 hours and all occurred by the time of delivery. Cytomegalovirus
had evidence of cerebral infarction on the CT scan. and rubella infections acquired in early pregnancy,
Only three of these infants showed evidences of may also present with neonatal fits, without any signs
subsequent handicap. Venkataraman and colleagues of other infections. Septicaemic infants, without
studied 11 full-term babies with neonatal stroke. meningitis, may also develop seizures. The cause of
Seizure was the most common presenting sign, with this can be the complication associated with infection
paucity of other focal neurological deficits.131 and hypoglycemia or hypotension. Diarrhea due to
The few days before and after birth are a time of infection may cause disturbances in the sodium
special risk for stroke in both mother and infant, balance which may also cause seizures. Herpes
probably related to activation of coagulation simplex virus type 1 (HSV-1) encephalitis is the most
mechanisms in this critical period. Arterial ischemic common cause of acquired epilepsy in human. Chen
stroke around the time of birth is recognized in about and colleagues studies in vitro HSV-1 infected
one in 4000 full-term infants, and may present with organotypic hippocampal slice culture to elucidate
neurological and systemic signs in the newborn.132 the underlying mechanisms of HSV-1-associated acute
Neonatal seizures are most commonly the clinical seizure activity. The results suggest that a direct
finding that triggers assessment. In other children, change in excitability of the hippocampal CA3
prenatal stroke is recognized only retrospectively, neuronal network and HSV-1-induced neuron loss
with emerging hemi paresis or seizure after the early resulting in subsequent mossy fiber reorganization
month of life. Risk factors for perinatal stroke include may play an important role in the generation of
hereditary or acquired thrombophilias and epileptiform activity.133
environmental factors. Perinatal stroke underlies an
important share of congenital hemiplegic cerebral Metabolic Disturbances
palsy, and probably some spastic quadriplegic Although a variety of metabolic derangement and
cerebrals palsy and seizure disorders. There is much certain intoxications are associated with convulsive
to be learned about the natural history of perinatal phenomena in newborn infants, abnormalities of
stroke, and there are as yet no evidence-based glucose and divalent cation homeostasis are the most
strategies for prevention or treatment. frequent.
Hypoglycemia is most common is in infants who
Intracranial Infection
are small for their gestational age (SGA) and in infants
Both the bacterial and non-bacterial types of of mothers with diabetes or gestational diabetes.83
intracranial infection are common causes of neonatal The brain can use few sources of energy, glucose
seizures. Seizures secondary to bacterial meningitis being the most important. Hypoglycemia may cause
are most likely to occur after the first week of life. devastating neurological damage when the brain’s
Like the common metabolic disturbances, they are energy reserves are exhausted. The most important
of particular concern because definitive therapy is of determinant of the occurrence of neurological signs
primary importance. Of the bacterial infections, in neonatal hypoglycemia appears to be the duration
meningitides secondary to group B streptococci, of this. Monod and associates84 observed that among
150 Textbook of Perinatal Medicine

the prematures, hypoglycemia may be very low, factors that appear to play a major role in the origin
without any seizures. Neurological symptoms consist of the convulsions. The definition of hypocalcaemia
most commonly of jitteriness, stupor, hypotonia and is taken to be serum calcium below 1.75 mmol/l (7
apnea, as well as seizures. The onset of the seizures mg/dl). The ionized calcium is a more important
is usually early, often on the second postnatal day. predictor; unfortunately this is a difficult
In many instances hypoglycemia occurs in the context measurement in the clinical practice. Ionized calcium
of HIE, IVH or infection. Secondary transient is responsible in part for axonal conduction as well
hypoglycemia may occur in association with as neuromuscular function. In addition, magnesium
meningitis or following exchange transfusion. is an important comineral for the function of the
Persistent hypoglycemia may be observed in certain neuromuscular junction.10 Functional hypocalcaemia
inborn errors of metabolism, e.g. galactosemia, can be diagnosed by assessing cardiac neuromuscular
fructosemia, leucin sensitivity, glucos-6-phosphatase conduction on the electrocardiograph. Early onset
deficiency, etc. Other rare disorders which must be hypocalcaemia is often observed in the context of
considered include the Beckwith-Wiedemann HIE, in newborns with low birthweight, in
syndrome, pancreatic islet cell tumors and anterior prematures with hyaline membrane disease, and in
pituitary hypoplasia. The importance of early infants of diabetic mothers. In rare cases, early severe
diagnosis and treatment of hypoglycemia has become hypocalcemia is due to parathyroid hypoplasia or
more critical. Recent data suggest that even moderate aplasia. The commonest condition associated with
hypoglycemia in premature newborn may be absent parathyroid is Di George syndrome. An
associated with poor outcome.85 infusion of intravenous calcium may be useful for
determining whether seizures are caused directly by
Electrolyte Disturbances the low calcium level. Late-onset hypocalcemia is
Divalent cations are regulators of the ion fluxes relatively uncommon and presents as an isolated
associated with membrane depolarization. Because condition without other associated or underlying
of this, abnormalities in their homeostasis are more diseases. Classically, such hypocalcemic infants are
likely to result in electrical seizures than in the large, term infants who have avidly consumed a milk
homeostasis in monovalent cations. However, both preparation with a suboptimal ratio of phosphorus
hyponatremia and hypernatremia have been to calcium and phosphorus to magnesium, e.g. cow’s
associated with seizures because of derangements milk. The neurological syndrome is consistent and
in cell volume. The most common cause for these distinctive, and it consists primarily of hyperactive
disturbances is inappropriate fluid therapy. In infants tendon reflexes. Hypocalcaemia fits are treated with
with serious neurological or pulmonary disease, the intravenous 10% calcium gluconate and the seizures
syndrome of inappropriate secretion of antidiuretic should stop soon after administration. Hypo-
hormone may result in severe hyponatremia and magnesaemia often coexists with hypocalcaemia and
seizures.29 convulsions are likely to occur at serum levels below
0, 3 mmol/l. Giving magnesium alone to hypo-
Hypocalcemia/hypomagnesaemia calcemic infants caused both serum magnesium, and
Infants with seizures due to hypocalcaemia are calcium to rise. 58 Manzar mentioned a case of a
usually alert between seizures and the seizures are newborn with late onset seizure with hypocalcemia,
often multifocal and migratory. Hypocalcaemia hyperphosphatemia and raised parathyroid
occurs at two peak times in the newborn period. Early hormone. The infant did not have any stigmata of
hypocalcaemia occurs in the first 2-3 days of life seems pseudohypoparathyreoidism. The hypocalcemia was
to be in association with other potential etiologic initially resistant to calcium therapy but responded
 Neonatal Seizures 151
to vitamin D analog therapy. Transient pseudo- migration are particularly likely to be associated with
hypoparathyroidism was entertained.134 abnormal neurological behavior and fits. Seizures in
these infants are usually very difficult to control.
Congenital Abnormalities Genetically determined disorders such as Sturge-
Tables 13.4 and 13.5 list inborn errors of metabolism Weber syndrome, tuberose sclerosis and inconti-
and neuronal storage diseases which may cause nentia pigmenti may also rarely cause neonatal
neonatal fits. 10 convulsion.10 Hennel found in his case with inconti-
nentia pigmenti evolution of acute micro-vascular
Pyridoxine dependency is a rare, autosomal recessive
hemorrhagic infarcts in the periventricular white
disorder of the pyridoxine metabolism. Pyridoxine
matter in the first week of life. The associated
is a co-factor necessary for the synthesis of the
magnetic resonance angiogram findings consisted of
inhibitory neurotransmitter gamma-aminobutyric
decreased branching and poor filling of intracerebral
acid (GABA), a deficiency which may presumably
vessels.136 Table 13.6 lists some congenital cerebral
produce severe neonatal seizures which are
abnormalities which may be associated with neonatal
recalcitrant to all treatment except the administration
convulsion.10 Wada and colleagues show a female
of large doses of pyridoxine. 86 Fewer, than 100
patient who has enlargement of lateral ventricles and
patients have been reported, and only four reports
atrophy of the brain associated with infantile spasms.
have included examples of brain imaging findings.
The ventriculomegaly was documented in utero at
Gospe and colleagues found in their patient
as early as 28th week of gestation with lactic acidosis
progressive MR changes–dilatation of ventricular
due to deficiency of the pyruvate dehydrogenase E1
system, cortical and white matter atrophy. The
(alpha) subunit, demonstrating that the changes
abnormalities may be due to chronic excitotoxicity
characteristic of this disease can occur antenatally.
caused by an imbalance of cerebral levels of GABA
The mechanism of infantile spasms in this disease
and glutamic acid.135
may be linked to mosaicism of the brain cells involving
Kernicterus the normal enzyme and the mutant enzyme.137

Bilirubin is a neurotoxic substance which may cause Intoxications

a clinical syndrome in severely jaundiced infants,
Local Anesthetics
referred to as kernicterus. The most severe form of
this condition includes opisthotonus, sunsetting and Seizure may occur when local anesthetics are
neonatal tonic seizures. administered to the mother for episiotomy, or for
Any abnormality in the cerebral development may other types of maternal analgesia. The major clinical
cause neonatal seizures but disorders of neuronal features of toxicity include very low Apgar score,

Table 13.5: Neuronal storage diseases which

Table 13.4: Inborn errors of metabolism which may cause neonatal fits
may cause neonatal seizures Adrenoleukodystrophy
Maple syrup urine disease Alexander,s disease
Urea cycle defects Alper’s disease
Tyrosinemia Gaucher’s disease
Non-ketotic hyperglycinemia Krabbe’s leukodystrophy
Proprionic acidemia Niemann Pick disease
Methyl malonic acidemia Tay Sachs disease
Other organic acidemias Zellweger’s syndrome
Adapted from reference 10 with permission Adapted from reference 10 with permission
152 Textbook of Perinatal Medicine

Table 13.6: Congenital cerebral abnormalities which may associated clinical manifestations on the one hand,
be associated with neonatal conculsions and etiology and prognosis on the other, it is difficult
Lissencephaly Neurofibromatosis to isolate well-defined “epileptic syndromes” during
Pachygyria Sturge-Weber syndrome the neonatal period. Most groupings are rather loose,
Micropolygyria Incontinentia pigmenti
Congenital porencephaly Tuberose sclerosis
and only familial seizures and a few rare syndromes
Hydrocephalus Hydranencephaly such as neonatal myoclonic encephalopathy88,89 stand
Holoprosencephaly out clearly.
Adapted from reference 10 with permission Neonatal myoclonic encephalopathy 29 is a syndrome
characterized clinically by the occurrence of erratic,
apnea or severe hypoventilation, severe bradycardia fragmentary myoclonus of early onset, usually in
and hypotonia and severe bradycardia. Seizures association with other types of seizures and, from
occur early and are commonly tonic in nature. These the EEG viewpoint, by a stable suppression-burst
features are also seen in HIE. There are two pattern persisting after 2 weeks of age.88,91,92 Seizures
distinguishing features which aid in its differentiation associated with the myoclonus include partial motor
from perinatal hypoxia: the absence of the pupillary seizures, massive myoclonias, and tonic spasms that
response to light and the absence of eye movement are not usually observed before 4 to 5 months of
with the oculocephalic (doll’s eye) maneuver. The age. The onset is in neonatal period and all affected
absence of these signs is unusual in hypoxic infants have severe neurological impairment, and half
encephalopathy during the first 12 h of life. of them die before the age of 6 months.91 Familial
Management depends on prompt recognition. The cases are frequent; a recessive inheritance is probable
half-life of the drug in the blood is approximately 8- in some of the cases. The syndrome may result from
10 h. undetermined metabolic defects or from brain
malformations. 93 The relationship of neonatal
Methylxanthine
myoclonic encephalopathy with early infantile
Both theophyllin and caffeine overdosage have epileptic encephalopathy (Ohtahara’s disease) is not
resulted in seizures in the neonatal period.8 entirely clear. The two conditions have several clinical
and EEG characteristics in common, including the
Drug Withdrawal occurrence of tonic spasms and of a suppression burst
Passive addiction of the newborn and drug pattern. Lombroso 94 accepts that early myoclonic
withdrawal may be related to maternal ingestion of encephalopathy is distinct from Ohtahara syndrome
cocaine, narcotic-analgesics and sedative hypnotics. but considers the latter only as a variant of infantile
Many findings demonstrate that exposure to alcohol spasms.
during brain development can permanently alter the
physiology of the hippocampal formation, thus Benign Familial Epilepsy
promoting epileptic activity, enhancing kindling, and An autosomal dominant syndrome of neonatal
facilitating spreading depression. seizures unrelated to recognized etiologies has been
described.95 The gene for this transient, primary
Epileptic Syndromes in the Neonatal Period epilepsy of infancy has been recently assigned to
Subgroups can be recognized among the neonatal chromosome 20q. 96 The onset of the seizures is
convulsions on the basis of the age at onset and/or usually on the second or third postnatal day, and in
characteristics of fits and associated neurological the interictal period the infants appear remarkably
manifestations. Although there is some relationship well. Seizures may occur with a frequency of 10-20
between the age at the onset of seizures and the per day or even more. The disorder is usually
 Neonatal Seizures 153
self-limiting. Neurological development is normal. generalized epilepsy with febrile seizure plus.
Because of the benign course yet striking clinical Similarly, the clinical spectrum associated with
presentation, the history of affected family members potassium channel, KQT-like mutations was
might easily be missed unless specifically sought.97 extended to include the channelopathy, myokymia
The “Fifth-day fits” syndrome is characterized by and neonatal epilepsy. Mutations in the non-ion
repeated seizures that occur between the third and channel genes, leucin-rich, glioma inactivated 1 gene
the seventh days of life in full term neonates without and Aristaless related homebox gene (causative gene
any abnormal gestational and obstetric antecedent in X-linked infantile spasms), have emerged as
and without any neurological abnormality during the important causes of their specific syndromes, with
first days of life. According to Dehan et al. 98, the mutations in the latter gene frequently underlying
attacks are of two main types; clonic focal or X-linked mental retardation with epilepsy.
multifocal convulsions and apneic spells. They last There are now nine ion channel sub-unit genes
on an average 20 hr. The interictal EEG shows implicated in ten syndromes of idiopathic epilepsy.
preserved rhythms and a normal organization of The boundaries between clinically defined
sleep. Bursts of alternating delta-rhythms or ‘théta ‘idiopathic’ and ‘cryptogenic’ epilepsies are being
pointu alternant’ are observed in three-quarters of blurred by the demonstration of sodium channel
the patients. Dehan et al and other authors have mutation in the infantile syndrome of severe
underlined the benignity of fifth-day fits when all myoclonic epilepsy in infancy (SMEI). Genetic
the criteria of the syndrome were present.98-100 heterogeneity has been so far proven for three of
Intrauterine seizures have been suspected in the syndromes: autosomal dominant frontal lobe
several reports. 101-102 Movements identified by epilepsy, benign familial neonatal seizure (BFNS) and
mothers as probably convulsive in nature occur generalized epilepsy with febrile seizure plus
mainly in the last days or weeks of gestation. (GEFS+). Considerable phenotypic heterogeneity
Pyridoxine dependency is a possible cause of occurs in association with mutations in four of the
intrauterine convulsions 101,103 , but other causes, genes described in GEFS + (sodium channel, (beta)1
especially brain dysplasia, can be suspected. subunit (SCN1B), (alpha)1 subunit (SCN1B),
Mulley and colleagues in their review describe (alpha)1subunit (SCN1A),(alpha)2 subunit (SCN2A)
the significant number of new gene associations with and GABAa receptor, (gamma)2 subunit (GABRG2).
epilepsy syndromes that have emerged during the Whether progress toward understanding the
past year, together with additional mutations and genetic basis for the rare epilepsies will relate to the
new electrophysiological data relating to previously development of therapies for the common epilepsies
known gene associations. Idiopathic epilepsies are remains to be established, but progress to date has
predominantly a family of channelopathies. The provided remarkable insights into the neurbiology
corresponding ion channel mutations show measur- of the pilepsies.138
able in-vitro abnormalities that are likely to affect
DIAGNOSIS
transmission between neurons. In the paper
autosomal dominant juvenile myoclonic epilepsy was First and second-line investigations in infants with
demonstrated to be a channelopathy associated with seizures are listed in Table 13.7.10
a GABAa receptor, (alpha) 1 subunit mutation. Diagnostic evaluation must begin with a careful
Benign familial neonatal infantile seizure were history and physical examination. From the maternal
delineated as another channelopathy of infancy, by history it is important to determine the possibility
molecular characterization of sodium channel, (apha)2 of drug abuse, intrauterine infection, and genetic or
subunit defects. A sodium channel, (alpha)2 subunit metabolic disorders. Laboratory investigations
defect was previously found to be associated with should focus initially on treatable causes, such as
154 Textbook of Perinatal Medicine

Table 13.7: First and second-line investigations Table 13.8: Clinical characteristics which distinguish
in infants with seizures jitteriness from seizures
In all infants immediately: Clinical features Jitteriness Seizures
clinical history
Stimulus-sensitive + –
blood sugar
movements
sodium
Movements cease + –
calcium
with restraint
magnesium
Associated abnormal – +
ultrasound brain scan
eye movements
lumbar puncture
Quality of movement Tremor Clonic jerking
blood culture
If the above are negative and the infant is still fitting: –, absent; +, present. Adapted from reference 50 with
prenatal viral screen permission
urine for amino acid chromatogram
urine for organic acid profile seizures may be difficult at times because both may
sugar chromatography for galactose
pyridoxine infusion
occur in a similar context, e.g. hypoxic-ischemic
computer tomography or magnetic resonance scan encephalopathy, hypoglycemia, hypocalcaemia. Drug
Adapted from reference 10 with permission withdrawal is another common cause of jitteriness.61

EEG in Diagnosis
metabolic disorders and infection. Lumbar puncture Despite advances in neuroimaging techniques over
or treatment with meningitic doses of antibiotics and the past decades that have helped identifying
acyclovir may be indicated. Rapid diagnosis of the structural lesions of the central nervous system, EEG
underlying etiology is of major importance to enable continues to provide valuable insight into brain
the institution of specific and definitive therapy as function by demonstrating focal or diffuse
well as for accurate prediction of the outcome. background abnormalities and epileptiform
However, in such instances the diagnosis of a specific abnormalities. It is extremely valuable test in patients
underlying disease may have important genetic suspected of epilepsy and in patients with altered
implications for the family. The time of the onset of mental status and coma. Patterns in the EEG make
seizures may assist in determining an underlying it possible to clarify the seizure type; it is
etiology. If the initial screening investigations fail to indispensable for the diagnosis of nonconvulsive
confirm the etiology, additional studies may be status epilepticus and for separating epileptic from
obtained, e.g. computed tomography (CT), cranial other paroxysmal (nonepileptic) episodes. There are
ultrasonography, magnetic resonance imaging, serum EEG patterns predictive of the cause of the
amino-acids, blood pyruvate and lactate, urine encephalopathy (i.e., triphasic waves in metabolic
amino-acids and organic acids, maternal and fetal encephalopathy) or the location of the lesion (i.e.,
titer of TORCH (Toxoplasma, Others, Rubella, focal polymorphic delta activity in lesions of the
Cytomegalovirus, Herpes (hepatitis)) group and subcortical white matter). An EEG is most helpful in
syphilis, and urinary drug screen.29,104 assessing normal or abnormal brain functioning in a
newborn because of the serious limitation in
Differential Diagnosis
performing an adequate neurological examination on
Jitteriness is a common movement disorder of the the neonate who is intubated or paralyzed for
newborn which may be misinterpreted as epileptic ventilatory control. Under such circumstances, the
seizures. The major features which distinguish EEG may be the only available tool to detect an
jitteriness from seizures are summarized in Table encephalopathic process or the occurrence of epileptic
13.8. 97 The distinction between jitteriness and seizures. 139 Neonatal EEG abnormalities may be
 Neonatal Seizures 155
transient and of benign significance, or may be and a decrease of discontinuity. A strong relationship
persistent and severe, indicating neurological was found between the post-menstrual age of the
morbidity. The clinical usefulness of the EEG is infants and EEG maturity, but there were exceptions
enhanced by recording as soon as possible after the to this rule. A longer duration of extra-uterine life
onset of symptoms of the suspected insult, although had a small accelerating influence on EEG maturation.
during the first day of life the stress of birth and the The relationship between EEG pattern types and
effect of anesthesia may complicate the interpretation behavioral states becomes more stable with
of the tracing. If an EEG appears abnormal, increasing age.106
recordings may be repeated in 48 to 72 h, and a Clinically significant and common EEG
weekly or biweekly interval until discharge or normal abnormalities noted in the neonatal period are the
patterns appear. Continuous EEG monitoring may next.107
be of value for the diagnosis of seizures in newborns Isoelectric pattern in the absence of hypothermia or
that are treated with muscular paralysis to improve acute systemic disorders indicates severe and diffuse
assisted ventilation. 105 cerebral dysfunction and is associated with a high
The major EEG correlates of neonatal seizures incidence of neurological sequel in survivors.
include focal or multifocal spikes or sharp waves and
The paroxysmal pattern, which is characterized by
focal monorhythmic discharges. Care must be taken
suppression-burst activity, must be distinguished
not to confuse epileptiform activity and normal sharp
from the discontinuous pattern of the normal
transients in recordings of premature newborns or
preterm, and consists of irregular bursts of abnormal
“tracé alternant” patterns of quiet sleep in term
activity on an isoelectric or markedly attenuated
newborns with seizures. Abnormal motor activity is
ground. The paroxysmal pattern usually associated
associated with EEG abnormalities on routine surface
with neurological sequel.
recordings in only approximately one-third of the
recordings. 104 Several modifications of electro- Excessively slow background pattern occur most
encephalographic techniques have been developed commonly in abnormal term newborns, lack the usual
recently to improve the quantification of the spectrum of beta, delta and transients, are poorly
frequency and the duration of the seizure activity. reactive, and are not associated with normal wake-
These include serial or continuous EEG recordings, sleep cycles; the incidence of neurological sequelae
and simultaneous video/EEG recordings. Cerebral is high.
function monitoring (CFM) is widely used to detect Persistent asymmetry of the background (reduced by
neonatal seizure but comparing with video recording, 50%) is sometimes associated with underlying
the observer usually detected generalized seizures structural lesions, including intracranial hemorrhage.
but approximately half of all focal neonatal seizures
Excessive interhemisheric asynchrony is commonly noted
may be missed using (CFM) only. The CFM may then
in association with other EEG abnormalities.
be useful for long term monitoring alone. The digital
EEG technology can improve the accuracy of EEG Positive rolandic sharp waves may occur in association
interpretation and lead to more accurate recognition with intraventricular hemorrhage in the newborn
of electroencephalographic features and thereby and the positive component is of high amplitude, may
improve the diagnostic utility of EEG. 140 Clinical be broad in configuration and may be followed by
interpretation of the EEG during this age-period is a lower amplitude negative wave, as well as with
difficult because of its rapidly changing morphology. other separate focal abnormalities. Positive rolandic
The main characteristics of EEG maturation in sharp waves have also been recorded in neonatal
preterm infants were a progressive spatio-temporal infants with nonhemorrhagic disorders and in
differentiation, with an increase of rhythmic activities apparently normal preterm infants.
156 Textbook of Perinatal Medicine

Electroencephalographic seizures in preterm and and to prevent recurrence of seizures. The choice of
term newborns are associated with a combined anticonvulsants in the treatment of neonatal seizures
mortality and neurological morbidity of should consider the unique characteristics of neonatal
approximately 30 percent; they appear as ictal, seizures and the efficacy, toxicity, and pharmacologic
repetitive focal or generalized spiking, rhythmic focal appropriateness of the drug. All aspects of toxicity
or generalized delta, and occasionally as rhythmic are to be considered, but two factors of immediate
alpha or theta-like activities. There are few specific concern in neonates are changes in heart rate and
pathologic EEG patterns associated with specific effects on brain growth.107 The generally used order
illnesses (neonatal herpes encephalitis, congenital of antiepileptic drugs and its doses are indicated in
malformations, or Aicardi’syndrome). the table 13.9.
Patrizi and colleagues observed the characteristics Phenobarbital continues to be the first-line drug
of EEG ictal activity in preterm and full term for the treatment of neonatal seizures. A loading dose
infants. 141 They investigated the trend for a closer of up to 40 mg/kg achieves therapeutic levels in the
relationship between behavioral changes during the serum within a short time. Therapeutic levels are 20-
electroencephalographic seizure when the back- 40 mg/l (80-160 mmol/l). Babies who are not
ground activity was normal or moderately abnormal artificially ventilated can be rendered apneic by a
than when background activity was severely single loading dose of 40 mg/kg, and it is usual to
abnormal. In both, preterm and full term infants, the give two separate doses of 20 mg/kg in this situation.
most common site of seizure origin was the temporal If clinical and EEG-revealed seizures persist despite
lobe. Full term infants commonly had sharp waves, phenobarbital concentration greater than 40 m/ml,
spikes, sharp and slow waves, and spike and slow phenytoin should be added; approximately one-third
waves at the onset of the ictus while rhythmic delta to a half of babies with seizure respond to
activity was most common in the preterm infants. phenobarbital about 90 percent respond to a
Preterm infants typically had a regional onset to the combination of phenobarbital and phenytoin. The
ictus whereas full term infants most frequently had dose of phenytoin is 15 mg/kg given as an
a focal onset. There was not a clear relationship intravenous “push” at a rate no greater tan 1 mg/kg
between onset, morphology, frequency or per min. phenytoin is probably the best choice as
propagation of the ictal discharge in both age groups. second-line treatment in babies who fail to respond
The results demonstrate that while the type of ictal to phenobarbital, but problems with hypotension
discharge is related to gestational age, there is a rich and arrhythmias have been reported when there is
variety in the onset, morphology and frequency of hidden myocardial damage accompanying hypoxic
the ictal discharges in both groups. Generally, ischemic encephalopathy.
neonatal ictal patterns lack a close correlation with Most of the benzodiazepines have been tried in
underlying pathology. newborn. The use of diazepam is controversial.
Diazepam has a very long half-life in babies, of
THERAPY approximately 30-75 h, and because of the respiratory
The newborn exhibiting seizure activity should be depressant effects that occur when level accumulate
treated on an urgent basis with adequate support this drug is not suitable for prolonged infusion.
ventilation and perfusion, correction of any under- Lorazepam and Clonazepam are also given, the latter
lying metabolic derangements and the use of is traditionally given intravenously or in infusion.
anticonvulsant medication. Hypersalivation and increased bronchial secretion
Treatment of neonatal seizures is directed toward are frequent side effects by that. Midazolam is a
minimizing physiological and metabolic derange- newer benzodiazepine that has proved effective in
ments which are associated with the epileptic process treating status epilepticus. Midazolam has been
 Neonatal Seizures 157
Table 13.9: Treatment of neonatal seizures

Initial therapy
1. Phenobarbital 20 mg/kg intravenously; if seizures continue, phenobarbital 10 mg/kg intravenously every 15-30 min to
a total of 40 mg/kg or to serum level 40 mg/ml
2. Phenytoin 20 mg/kg intravenously; if seizures continue, phenytoin 10 mg/kg intravenously to serum level 20 mg/ml .
If seizure contiune:

3. Diazepam Lorazepam Paraldehyde

0.1-0.3 mg/kg intravenously 0.05-0.10 mg/kg intravenously 200-400 mg/kg intravenously
repeated as necessary, or repeated as necessary over first hour; then 16 mg/kg/h
0.7-2.75 mg/h continuous intravenously; adjust infusion rate
intravenous infusion based on EEG response
Since clinical detection of seizures is frequently inaccurate, it is helpful to have continuos and video EEG monitoring
during the iniciation of therapy. The EEG is especially helpful in making decision regarding additional diazepam or
lorazepam, or in adjusting the rate of paraldehyde infusion
Maintenance therapy
1. Phenobarbital 3-4 mg/kg/day intravenously, intramuscularly or orally, starting 12 h after loading dose
2. Phenytoin 3-4 mg/kg/day intravenously starting after loading dose
3. Primidone 12-20 mg/kg/day
Adapted from reference 2 with permission. EEG: electroencephalograph

reported to cause myoclonic jerking and dystonic are secondary to an acute cerebral insult and thus
posturing in preterm babies when it was used to tend to resolve within 2 to 4 days. If there has been
achieve sedation. The neurodevelopment outcome status epilepticus or if seizures have not been
was better in a group of preterms sedated with controlled with phenobarbital alone, we continue
morphine, than it was when midazolam was used. anticonvulsants for at least 3 month.2
There is very little published experience with any
other antiepileptic drug in the newborn. Paraldehyde Specifics of the Pharmacology of
was popular during the 1970s and 1980s, but it is Antiepileptic Drugs in Neonates
now difficult to obtain. Sodium valproat has hepato- Binding Profile
toxicity. Vigabatrin is not available in an intravenous
form, and there is a risk of incurring visual field Painter and colleagues 108 found that there is
effects, which cannot be monitored precisely in significant correlation between phenobarbital and
babies. There is virtually no neonatal experience with phenytoin in vitro binding and the total protein and
lamotrigine or carbamazepine, nor with other, new albumin concentration. Phenobarbital is exclusively
antiepileptic drug, like oxcarbazepine, gabapentin, but weakly albumin bound. The finding, that in vivo
topiramate. In animal models the acute and chronic phenobarbital binding was not significantly
effects of hypoxia can be prevented by pretreatment correlated with total protein or albumin may
with topiramate. Topiramate were administered explained by the influence of other factors known to
before the hypoxic insult and prevented the affect albumin binding, such as Bilirubin
expression of the hypoxia-induced seizure. 142 concentration, pH changes, the elevations of free
Anticonvulsant therapy must be tailored to the fatty acid concentration and drugs administered by
individual needs of the child. Most neonatal seizures critically ill neonates.
158 Textbook of Perinatal Medicine

Half-life between favorable response to treatment and normal

neurological examination at hospital discharge and
Morselli109 studied the influence of age on the half-
at 1 year of age. It is necessary to confirm by means
life of diazepam. The metabolic pathway of
of EEG record the neonatal clinical convulsion before
Diazepam develops only some time after birth, so
and after having established the anticonvulsive
premature babies show a significantly longer half-
treatment, due to the control of electrical convulsion
life than full-term infants. Carbamazepine auto-
improves their neurological outcome.143
induces its own biotransformation, usually during
the first 4-6 weeks of treatment. Beginning at a Long-term Treatment
relatively low dose and progressively increasing the
dose can avoid the fall in drug concentration. There is little agreement on how long to continue
anticonvulsant therapy in the neonate. We agree with
Toxicity the opinion of Levene, who stops all drugs when the
infant had no seizure for seven days as long as they
Phenytoin toxicity is known to cause cardiac
show no neurological abnormality. 10 In those in
arrhythmias and exacerbate seizures. Elevated free whom seizures recur or who are neurologically
concentrations of phenobarbital are known to cause abnormal, medication is continued for three months,
hypotension and respiratory depression. Phenytoin when they are reviewed. Drugs are stopped if the
has less of a sedative effect than phenobarbital and infant appears to be neurologically normal.
clonazepam, thus allowing a more reliable clinical
assessment of improvement. 110 Interpatient PROGNOSIS
variability of the various antiepileptic drugs is
Several factors may influence the neurological
extensive in newborns, and intraindividual variation
outcome of neonates who have clinical seizures.
occurs in all premature and full term newborns
These include the nature and degree of underlying
during the neonatal period. The extensive variability
neuropathologic process, the possible adverse effects
means that the therapy should begin with a relatively
of epileptic activity on the developing brain, the
small dose, which is increased stepwise until either
secondary effects of the seizures (for example,
seizures are controlled or side effects occur.111
hypoventilation or hypoperfusion), and the potential
adverse effects of antiepileptic drugs. Several studies,
The Effect of Antiepileptic Drugs on the EEG
however, suggest that seizures associated with
Angela Bell and colleagues 112 show a marked certain etiologic factors have a worse prognosis than
depressant effect of phenobarbitone and diazepam others. (Table 13.10.) Normal outcomes occur with
on the EEG in newborn babies. The effect of sedation increasing frequency in each of the following:
on the maximum interburst interval was greater than hypoxic-ischemic encephalopathy, intracranial
expected, particularly when compared to reports on hemorrhage, hypoglycemia, unknown cause,
adults.113 The authors suppose that the drugs are hypocalcaemia.22 In monitored infants in whom
acting on subcortical generators, such as the thalamus outcome was assessed only at hospital discharge, the
and reticular formation, which play a major role in highest morbidity and mortality were associated
maintaining the background EEG in newborns. with seizures owing to hypoxic-ischemic encephalo-
Determination of effectiveness of therapy is important pathy and the lowest in infants with subarachnoid
in the management of neonatal seizures. With the hemorrhage, hypoglycemia and hypocalcaemia.23,27
antiepileptic treatment the clinical control of the The outcome of neonatal seizures is mainly
convulsions was obtained in more them 80% of the dependent on their cause. Newborns with seizure
cases, while control of the electrical convulsions was were three times more likely (16%) to develop
only in 62,5%. There was a high significant association cerebral palsy then were controls (6%). The adverse
 Neonatal Seizures 159
Table 13.10: Prognosis of neonatal seizures- useful indicators of the outcome. Thus, infants with
relation to neurological disease flaccid coma and seizures generally have an
Neurological disease Normal development (%) + unfavorable outcome, whereas infants with
Hypoxic-ischemic 50
consistently preserved consciousness, activity,
encephalopathy reflexes and tone have a more favorable outcome.81
Intraventricular 10 Infants, who had nonepileptic seizures consisting of
hemorrhage ^ tonic posturing and motor automatisms most often
Primer subarachnoid 90
hemorrhage had hypoxic-ischemic encephalopathy, interictal
Hypocalcemia lethargy or obtundation, the nature of the abnormal
Early onset 50** EEG, and the poor short-term outcome. In the infants
Late onset 100 who had epileptic seizures (focal- clonic or focal-
Hypoglycaemia 50
Bacterial meningitis 50 tonic), an association was noted with focal structural
Development defect 0 lesions, subarachnoid hemorrhage, and metabolic
*Prognosis is for those cases with the stated neurological
abnormalities; and with interictal alertness, normal
disease when seizures are a manifestation (thus, value background EEG activity, and a relatively good
usually will differ from overall prognosis for the disease) short-term outcome. These clinical and electrographic
;+values are rounded off to nearest 5%; ^usually severe features suggest a delimited process rather than
intraventricular hemorrhage associated with major
periventricular hemorrhagic infarcion; **represents primarly
diffuse injury, which is probably the important factor
the prognosis approches that later onset hypocalcaemia if in the relatively good short-term outcome of these
no or only minor neurological illness present. infants. Abnormal neurological examination on
Adapted from reference 29 with permission. discharge was a good predictor of an unfavorable
outcome and abnormal polysomnographic recording
outcomes observed after neonatal encephalopathy
a moderate predictor.144 Several investigators have
included both cerebral palsy and global develop-
demonstrated that the interictal EEG is a useful
mental delay without motor deficit. For years it has prognostic indicator in the term infants. In one large
been held that intellectual difficulties can only series, a normal interictal EEG was associated with
accompany motor problems in the post-asphyxia an 86% chance of normal development at the age of
syndrome, and are not seen in isolation, but this view 4 years.81 In contrast, infants with flat, periodic or
is now beginning to be challenged. Over the years multifocal EEGs had only an 8% probability of a
the reported outcome of neonatal encephalopathy normal outcome. The burst suppression pattern
with seizures has been remarkably consistent, with which is included in this group of EEGs with poor
about 25% adverse outcomes in babies with moderate a prognosis has a superficial resemblance to the tracé
encephalopathy and 66% adverse outcomes (33% alternant pattern seen in quiet sleep in the normal
dead, 33% disabled) in those with severe encepha- term newborn. Moreover, 25-35% of term newborns
lopathy, usually defined as coma. The background with seizures will have EEGs which are borderline,
electroencephalogram abnormality consistently or demonstrate less marked abnormalities which are
performs best as an outcome predictor; babies with associated with an uncertain prognosis. Bergman et
burst suppression or a markedly attenuated al6 demonstrated that the outcome of neonates who
background pattern that persists for longer than 12 had manifested seizures for more than 3 days was
h after birth have an adverse outcome.124 associated with moderate or severe neurological
injury. Babies with normal clinical examination,
The Role of EEG and the Clinical
cranial ultrasound, CT and EEG results at 7 to 14
Neurological Status
days usually have a good prognosis. Estimated of
The extreme ends of the spectrum of clinical the incidence of epilepsy in children with neonatal
neurological status during the newborn period are seizures vary from 15 to 20 percent.81
160 Textbook of Perinatal Medicine

MATERNAL EPILEPSY feeding should be allowed for the most anti-

convulsive drugs unless the infant becomes
Risk of Maternal Seizure
symptomatic.147
Pregnancy in women with epilepsy is accompanied
by increased maternal and fetal risk. During Fetal Anticonvulsant Syndrome
pregnancy, seizure can cause maternal and fetal
The cause of this is probably multifactorial, but recent
hypoxia and acidosis. The increase in seizure has been studies have indicated that antiepileptic drugs are a
reported to occur mostly during the first trimester30 major offending factor.14,19,20 If women with epilepsy
or evenly throughout pregnancy. 24-25 In animal are in need of antiepileptic drug for seizure control,
studies, estrogen is generally proconvulsant, then monotherapy at lowest effective dose should
progesterone, conversely, generally has an be employed. Offspring are the increased risk for
anticonvulsant effect. 44 Status epilepticus is an major congenital malformation: a rate of 4-7 % (2-3
uncommon complication of pregnancy, but when it % in normal population), including congenital heart
occurs it carries high maternal and fetal mortality disease, cleft lip/palate, neural tube defects and
rates (31 % and 48 %, respectively).25 The effects of urogenital defects. The risk for malformations
nonconvulsive seizures on the developing fetus are increases with the number of antiepileptic drugs to
not clear. which the fetus is exposed during pregnancy10,11 and
possibly with the daily amount or peak concentration
Antiepileptic Drug Pharmacokinetics During of individual drugs. Data for valproic acid are
Pregnancy and Lactation suggestive of a dose-response effect for the risk of
The ideal management of women with epilepsy neural tube defects. 9,12-14
during pregnancy and the postpartum period Results of studies investigating cognitive outcome
involves achieving an optimal balance between report an increased risk of mental deficiency in 1,4
minimizing fetal and neonatal exposure to the to 6 % of children of women with epilepsy (include
deleterious influences both of antiepileptic drugs and both seizures16 and in utero exposure to antiepileptic
of seizures.145 During the past decade, consensus drugs17, compared with 1 % of controls. Unlike major
malformations, antiepileptic drugs exposure during
guidelines have emphasized minimizing the
the last trimester may actually be the most detrimental
associated risk by optimalizing a woman’s anti-
for cognitive outcome.18
epileptic drug regimen and initiating supplemental
folic acid before conception, and high-dose folate REFERENCES
supplementation prior to conception and during
1. Mizrahi, E. M. Consensus and Controversy in the
organogenesis. However, there are no current Clinical Management of Neonatal Seizures. In Clinics in
guidelines regarding the best management once a Perinatology-Neonatal Neurology. Volpe JJ (ed.).
woman with epilepsy becomes pregnant. Because Philadelphia, London, Toronto, Montreal, Sydney,
Tokyo: W.B.Saunders Company 1989. Vol.16, No.2.
large intraindividual and interindividual variability, 2. Younkin, D. (1990). Neonatal seizures. In Nelson,
some authors recommend at least monthly moni- N.M.(ed.). Current Therapy in Neonatal-Perinatal
toring of antiepileptic drug concentration.146 During Medicine-2. (Toronto, Philadelphia: B.C.Decker Inc). 321-
327.
mothers taking the most of antiepileptic drugs
3. Aicardi, J. (1994). Epilepsy in Children 2nd edn. (New
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interpretation. J Clin Neurophysiol 1998;15(6):476-80. 147. Baumeister FAM. Epilepsy and pregnancy from the
141. Patrizi S, Holmes GL, Orzalesi M. Allemand F. Neonatal neuropaediatric perspective. Gynaekologische Praxis
seizures: Characteristics of EEG ictal activity in preterm 2003;27(3):425-31.
166 Textbook of Perinatal Medicine

14
Oxygen Toxicity

Rodolfo Bracci

INTRODUCTION radical molecules in free radical chain reactions,

which are stopped by antioxidant enzymes or protein
Although the toxic effects of oxygen have been
reactions. O2··- is the precursor of most ROS and a
known since the end of the 19th century1, the first
mediator in oxidative chain reactions. Dismutation
evidence of a relationship between oxygen toxicity
of O2·- by superoxide dismutase (SOD) produces
and neonatal diseases emerged in the early 1950s
H2O2 which in turn may be fully reduced to water
when retinopathy was observed in premature infants
by glutathione peroxidase (GSH-Px) and catalase
breathing high concentrations of oxygen.2 At about
(Cat) or partially reduced to OH·. The latter reaction
the same time, the red cells of newborns were
is called the Fenton-Haber Weiss reaction and is
demonstrated to have increased susceptibility to
catalysed by reduced transition metals.4-9
oxygen damage.3 This made it clear that oxygen
ROS are involved in the following reactions:
species were particularly toxic to neonatal red cells
which were damaged by exposure to H 2O2 and SOD
substances producing H2O2. O2·- ? H2O2
Great advances in our understanding of toxic
GSH-Px
effects of oxygen were made in the years that
H2O2 + GSH ? H2O + oxidized glutathione
followed, when oxygen toxicity was recognized to
be due to the development of reactive oxygen species Cat
(ROS). The main ROS are the superoxide anion H2O2 ? H2O + O2
(O 2–), hydrogen peroxide (H2O2), lipid peroxide
(LOOH), peroxyl radicals RO· 2 and the hydroxyl A deficiency of scavenging reduces the
radical (OH·). Other important radicals are the highly detoxification of H2O2 and O2·- and increases the
reactive electron delocalized phenoxyl radical formation of OH· by metal activation following the
(C6H5O·) and nitric oxide (NO ·).4-8 Fenton reaction:4-9
The term ROS includes free radicals, which are Fe2+ + H2O2 ? Fe3+ + OH· + OH-
atoms or molecules with one or more unpaired There is no specific scavenger for this radical: once
electrons. Free radicals may react with other radicals, released, OH reacts with lipoproteins, cell
the unpaired electrons forming a covalent bond. The membranes, lipids, proteins, DNA, amino acids and
resulting molecule may decompose other molecules other molecules. OH· is one of the strongest oxidants
into toxic products. Free radicals may react with non- in nature and may damage tissues.
 Oxygen Toxicity 167
Oxidative tissue damage may be mediated by important in the pathogenesis of fetal and neonatal
reactive nitroxide species.9-11 The reaction product diseases.
of NO· and O2··- is the unstable molecule peroxynitrite Intracellular and extracellular production of ROS
(ONOO-) which is regarded as highly reactive and is provided by activated phagocytes.24 ROS released
hence destructive, although it seems to be trapped inside phagocytes during infection and cytokine
by cellular antioxidants and other factors at low production can also alter the extracellular oxidative
concentration. 12-14 balance and harm tissues since the cells undergo an
It is important to remember that free radical efflux of O2·-.25 However, opsonization and activation
reactions are a normal occurrence in living organisms of phagocytes is also known to occur during the
and ROS are not necessarily toxic. Vascular tone hypoxanthine-xanthine oxidase reaction and,
appears to be modulated by the contrasting effects therefore during hypoxia-reoxygenation.26
of NO· and O2·-.15 Production of O2·- by phagocytes Mitochondria are the primary source of
is an important defense mechanism but extracellular superoxide and it has been demonstrated that
release of free radicals by activated phagocytes is mitochondrial dysfunction is responsible for
itself a mechanism of tissue damage during increased superoxide release. The mitochondrial
inflammation.5,16 Oxidative balance, therefore, is an electron transport chain contains redox centers which
intriguing question, and much recent research has may leak electrons to oxygen, constituting the
increased our knowledge of the relations between primary source of O2·- in most tissues.9 Research into
ROS and human diseases. myocardial physiology has demonstrated that under
normal conditions, mitochondrial electron transport
THE OXIDATIVE STRESS reduces 95% of oxygen to H 2O by tetravalent
An excess of ROS, as well as reactive nitrogen species reduction without any free radical intermediates and
(RNS), in relation to detoxification capacity is called the remaining 5% is reduced by the univalent
oxidative stress, a term used to describe imbalance pathway in which free radicals are produced.27,28
between oxidants and antioxidants that is a potential During acidosis and hypoxia ischemia, mito-
cause of damage. If oxidative stress is mild, cell chondrial dysfunction occurs and ROS production
defenses may increase by a complex mechanism increases while antioxidant defenses are depleted
which generally involves enhanced gene expression and metal ions may play a role in generating OH·.29
of ROS scavenging activities.6,17,18 Severe oxidative ROS production by mitochondria may increase during
stress is generally followed by cell injury which may hypoxia ischemia as a result of dramatic increases in
proceed to necrosis or apoptosis.4-6 The involvement cytosolic calcium concentrations. Since mitochondrial
of oxidative stress in the mechanism of apoptosis has enzymes, such as pyruvate dehydrogenase and á-
been extensively studied.19-22 oxyglutarate dehydrogenase, are normally regulated
The pathological conditions leading to oxidative by Ca cycling across the inner mitochondrial
stress are extremely complex. It is therefore necessary membrane, when intracellular Ca increases, cycling
to identify the biochemical basis of oxidative stress may become excessive and lead to increased ROS
in order to prevent or treat oxygen toxicity. 4-7,9,23 production, while structural alterations to the inner
mitochondrial membrane may be followed by
Ros Production mitochondrial respiratory chain disorganization with
Two main sites have been recognized as sources of further increases in ROS.30-33 During asphyxia, OH·
ROS: the extracellular compartment with phagocyte production also increases as a result of release of
activation and the endogenous source with iron from safe sites.27 Acidosis may therefore enhance
mitochondrial function. 13 Both these sites are OH·-mediated tissue injury.34
168 Textbook of Perinatal Medicine

When oxygen is restored to ischemic tissue, free lead to vasoconstriction 38 which also seems to be
radical reperfusion injury occurs by several enhanced by inhibition of PGI.43 Endothelial injury
mechanisms including the xanthine-xanthine oxidase due to oxidative stress has been demonstrated to
reaction.27,35 Reperfusion injury is considered a major play a key role in coagulation disorders by enhancing
source of oxidative stress and has been reported in procoagulant activity.44,45
heart, kidney, liver lung and intestine, particularly
in necrotizing enterocolitis (NEC).27,36 Antioxidants
Hyperoxia has been demonstrated to be The antioxidant system can be classified in two major
associated with increased mitochondrial production groups: enzyme activities and low molecular weight
of O2·-. 9 The rate of mitochondrial O 2·- production antioxidants.13 The enzyme group is represented in
increases linearly with increasing oxygen concen- the reactions mentioned above. Other important
tration.37 Under normobaric hyperoxic conditions, antioxidant enzymes are thioredoxin reductase and
the only organs affected by ROS formation are the glutathione transferase (GSH-T). It is important that
lungs since they are the only ones in direct contact O2·- dismutation be associated with balanced H2O2
with atmospheric oxygen. 9 However, under detoxification. It has been suggested that over-
hyperbaric conditions other tissues become exposed expression of SOD may lead to deleterious effects if
to a hyperoxic environment and increased ROS not balanced by GSH-Px. 46,47 This observation
formation has been found in other organs.9 Other underlines the key role of GSH in protecting against
sources of ROS include catecholamines, prostag- oxidative stress.48 The enzyme-based antioxidant
landins and xenobiotics previously reduced by system includes extracellular SOD, the only
certain enzymes.4-6 extracellular scavenger of O2·- which also plays a key
Endothelial dysfunction caused by oxidative stress role in scavenging O2·- produced in the extracellular
and leading to vascular disease has been extensively compartment by phagocytes, endothelium and other
investigated. 38-41 The endothelium is normally mechanisms.49
protected against ROS; however overproduction may The low molecular weight antioxidant group
occur via mitochondrial reactions, xanthine-xanthine contains a large number of compounds which are
oxidase reaction, vascular as well as phagocytic capable of preventing oxidative damage by direct or
NAD(P)H oxidases and toxin-induced reactions. indirect interactions with ROS. The effects of these
There is also growing body of evidence linking blood molecules are complex, since the same molecule may
cell and endothelial cell interactions in enhanced have pro-oxidant or antioxidant effects depending
production of ROS. 38-42 Oxidative stress to on bioavailability, metabolism and tissue properties
endothelium may be due to ROS or reactive NO as well as interactions between enzymic and non-
mediated peroxynitrite. 11 O 2·- therefore promotes enzymic antioxidants. Ascorbic acid may have pro-
tissue damage by reacting with NO, reducing NO oxidant and antioxidant properties.50 Coenzyme Q
bioavailability and producing toxic ONOO-.38-41 The is a source of O2·- when partially reduced and an
presence of non protein bound iron during acidosis, antioxidant when fully reduced.51 One of the most
hypoxia and infections causes OH· release and may studied antioxidants is á-tocopherol, but competition
exacerbate ROS mediated tissue injury.10,19,41,43 The between different forms and their uptake and the
resulting vascular endothelial dysfunction elicits a synergistic or inhibitory role of other compounds
number of maladaptive phenomena that impair are not yet understood. Furthermore, non-antioxi-
normal healthy blood vessels. The normal vascular dant effects of α-tocopherol have been demons-
environment is lost, exposing the lumen to the trated. 52 Iron binding proteins have major antioxi-
possibility of thrombosis, while the decrease in NO dant activity, protecting against metal induced OH·
production and enhanced endothelin 1 production production.53
 Oxygen Toxicity 169
REACTIVE OXYGEN SPECIES IN in adults have been observed.70,71 These differences
FETUS AND NEONATE can be ascribed to the study methods, the components
of antioxidant capacity tested and the timing of blood
Excessive oxidative stress and particularly OH· can
sampling. Infant condition also plays a role since
impair cell function and induce apoptosis in rapidly
asphyxia and acidosis may reduce certain
growing structures. An oxidised state can also be
components of antioxidant power. 72 Plasma
beneficial since ROS may activate transcription factors
antioxidant capacity is not correlated with any
and promote fetal development, but both of which
neonatal pathology. On the contrary, other markers
are sensitive to uncontrolled oxidative stress.54 The
suggest ROS toxicity in neonates.71,73-75 Irrespective
effects of ROS are secondary to its direct toxicity
of total antioxidant capacity, a deficiency in particular
and indirect effects, such as vasoconstriction in the
antioxidant factors, such as ceruloplasmin and
lung or systemic circulation.55,56 Another important
transferrin, may play an important role in neonatal
condition of oxidative stress produced by O2·- and
susceptibility to oxidative stress and particularly to
NO derived free radicals is impaired placental
metal-induced OH· production. 76,77 Low concen-
function, which may lead to fetal growth retar-
trations of transferrin have been found in neonates,
dation.57
especially premature ones, and high plasma levels of
Oxidative stress in the fetus and newborn may
ascorbic acid may create a condition of risk due to
result from decreased antioxidants, increased ROS
the pro-oxidant effect of iron. The finding of
or both. The fetus has a lower antioxidant capacity
increased bleomycin-detectable iron in premature and
than older babies and adults. Free radical scavenger
some full term infants is evidence of the real risk of
enzyme activities and many other components of the
increased prooxidant effects of iron in neonates.78
antioxidant system are low. Studies in various
High saturation of transferrin is therefore probably
animals have shown that the main ROS detoxifying
enzymes, GSH-Px, Cat and SOD, increase during a risk factor for oxidative stress. It is generally
intrauterine life.58,59 At least in the lungs and liver, accepted that non-transferrin bound iron (NTBI) is
detoxifying reactions ruled by SOD, GSH-Px, and a pathological manifestation and it is extremely rare
catalase are fully expressed only after birth. 58,59 in adults, in whom even the presence of non protein
Scavenger activities involving glutathione transferase bound iron (NPBI) in iron overload is uncommon.79
have been studied in the fetus and newborn and Levels of NPBI in plasma of newborns are correlated
seem to vary widely in different animal species.60 with other markers of oxidative stress and high
In the human newborn, the scavenger enzyme plasma NPBI has been found in hypoxic newborns
activities were first investigated in erythrocytes: Cat with poor outcome. 80 Compensatory protection
and GSH-Px were found deficient in most of infants, against oxidative stress in neonates is demonstrated
and SOD only in some.61,62,46 SOD activity is reported by high activity of glutathione reductase (GR) and
to increase in the lungs of the human fetus during high recycling of glutathione (GSH) in red cells.81
intrauterine life.64,65 Normal values of GSH-Px have However, several observations have shown that
been reported in leukocytes of full term newborns.66 preterm infants have lower and age-related plasma
Non-enzyme antioxidant factors are reported to concentrations of GSH and higher concentrations of
be lower in the fetus and newborn than in adults GSSG than adults.82 This is interesting since a low
and older babies67-69, partially because of deficient GSH/GSSG ratio is a reliable index of generalized
placental transfer of some antioxidants.54 However, oxidative stress. 83 Reliable markers such as F2-
antioxidant capacity of neonatal plasma is contro- isoprostanes, allantoin and the oxidized form of Co-
versial since peroxy-radical trapping capacity and enzyme Q provide further evidence of oxidative
chain-breaking antioxidants the same or higher than stress in neonates.72,84,85 Oxidative stress in neonates
170 Textbook of Perinatal Medicine

has also been demonstrated by higher values of ROS are involved in many diseases of newborns
CoQ120 in those born by vaginal delivery than by and adults such as necrotizing enterocolitis, renal
elective caesarean section.86 failure and septic shock. Neonatal conditions of
Oxidative stress is involved in tissue damage particular interest concern red cells, lung, retina and
induced by infection and sepsis. Although there is brain.
general agreement that neonatal phagocytes, and
especially those of premature infants have RED CELLS
abnormalities of various functions87, active neonatal Several observations in animal and human
secretion of proinflammatory cytokines suggests a erythrocytes have demonstrated that release of free
very complex situation in which oxidative stress radicals inside red cells may affect membrane
following infection may be more dangerous in structure during oxidation of hemoglobin. 98,99
newborns, especially if premature, than in adults.88 Membrane structure may also be damaged by ROS
The high levels of peroxides found in cord blood uptake from the extracellular medium where they
of fetuses with asphyxia are in line with the may arise from ischemia-reperfusion, phagocyte
hypothesis of high ROS production in the placenta activation, endothelial metabolism, hyperoxia,
and umbilical structures during hypoxia. 89-91 lipoprotein peroxidation and other sources.100-101
However, it should be remembered that the Uptake of free radicals by red cells can be regarded
oxidative balance of the fetus is not the same as that as a mechanism protecting the tissues from oxidative
of the neonate because of the peroxidase content of injury, since the high antioxidant enzyme activities
the placenta.92,93 of erythrocytes can scavenge extracellular ROS.
The first condition suspected to be responsible However, excessive oxidative stress leads to
for increased oxygen toxicity, namely hyperoxia, has hemolysis followed by free iron and free radical
recently been demonstrated to cause the oxidative release, and possible tissue damage.102 In newborns,
stress responsible for lung injury and possibly antioxidant activities are generally lower than in
generalized tissue damage. 94 The definition of adults, and seem to be even lower in premature
hyperoxia in newborns is closely related to oxygen infants.61-63,103,105 Activities such as GSH-Px increase
requirements during the first hours of life, when the rapidly in the first days, presumably as a result of
baby is suddenly exposed to higher oxygen tension increased exposure to ROS.106,107 Exposure of red cells
than in the uterus. The oxidative stress recorded in to ROS after birth is also demonstrated by a decrease
animal experiments with hyperoxia could occur in in GSH-T in the first days of life in response to ROS
neonates with oxygen tensions lower than previously production.108 Very active GSH recycling occurs in
considered.94 normal newborns but asphyxia and acidosis have
Endothelial injury by ROS following asphyxia or been reported to depress it, as well as ATP.81 GSH
infection may lead to vasoconstriction and recycling also seems deficient in infants with RDS
coagulation disorders which are particularly harmful and CLD. 109 Chemiluminescence assays have
to newborns, due to the procoagulative state of fetus demonstrated higher ROS production in newborns
and neonate.45 than adults.110 This observation is in line with the
Links between ROS and endothelial cell injury demonstration of high lipid peroxidation and
seem to play a role in the development of pre- decreased Co-enzyme Q 10. 111 The red cells of
eclampsia since increased oxidative stress has been newborns appear to be more susceptible to the toxic
demonstrated in preeclamptic woman.95,96 Although effects of oxidative stress than those of adults.112
the pathogenesis of preeclampisa is poorly Besides low scavenger enzyme activities, newborn
understood, it seems that oxidative stress plays an red cells have other characteristics, such as lipid
important role.97 content and composition, which predispose them to
 Oxygen Toxicity 171
oxidative stress.112 Vitamin E levels are not only much asphyxiated neonates. In conclusion, several reports
lower in the neonatal than the adult red cell, but suggest that acidosis and hypoxia may generate red
requirements of the vitamin are also higher, as shown cell damage via ROS.
by increased recycling.113 ROS are generated in red
cells not only under pathological but also under PULMONARY OXYGEN TOXICITY
normal conditions. 114,115 Animal studies have Oxygen toxicity is particularly harmful for the lungs.
demonstrated the key role of oxidative stress caused The mechanism of damage is complex. Lung injury
by intraerythrocyte iron release in a reactive form may be caused directly by ROS production in
and hydroxyl radical production in the development response to hyperoxia or indirectly by ROS due to
of membrane protein damage. 102 Oxidative cross- phagocyte activation and inflammation. The two
linking of membrane proteins can produce clustering mechanisms seem to be integrated.
of the major erythrocyte membrane spanning protein Chronic lung disease (CLD), a severe compli-
band 3.116,117 The clusters provide recognition sites cation of prematurity, was long thought to be due to
for antibodies against senescent cells and trigger their high concentrations of oxygen in inspired air and
removal from circulation. In the absence of efficient barotrauma. ROS are now generally accepted to be
protection by antioxidant factors, oxidative stress largely responsible for lung injury in preterm infants
therefore appears to be responsible for release of since several studies using different methods have
iron in a reactive form, predisposing red cells to demonstrated products of ROS reactions in
hemolysis through the formation of senescence premature infants with CDL.122-127 The particular
antigen.117 Paradoxically, recent observations show toxicity of ROS in the immature lung is due to the
that autoxidation of Hb may occur in vitro at low low antioxidant capacity of premature infants, which
oxygen tension. 118 does not increase rapidly as in the full-term lung, as
Studies in newborns have shown interesting well as to the possibly high toxicity of ROS in rapidly
analogies between experimental and clinical developing tissues.128 Increased production of ROS
observations. The free iron content of red cells of under certain conditions may also play a role. The
newborns is higher than that of adults and is main sources of ROS production in the immature lung
significantly correlated with pH and base deficit as are ischemia-reperfusion, phagocytosis and increased
well as with plasma lipid peroxide products, mitochondrial activity mainly due to hyperoxia.
expressed by malondialdehyde concentrations.119 Mitochondrial oxidative stress following hyperoxia
Incubation of newborn and adult red cells in vitro has been demonstrated by a decrease of
showed higher iron release in the former under intramitochondrial GSH/GSSG redox status.129 High
aerobic and anaerobic conditions. It is interesting that inspired oxygen fraction (FiO2) may be responsible
during anaerobic incubation, increased O 2·- for lung injury and high lipid peroxidation, as
production, free iron release and senescence antigen demonstrated by high F2-isoprostane levels in the
production showed the highest significant differences lungs of animals exposed to high oxygen concen-
between adults and neonates.110,120 In vitro studies trations.130 Effects of hyperoxia in the lung and a
show that incubated neonatal red cells release iron close relationship between oxidative stress and
in reactive form. This iron is recovered in the inflammation have been demonstrated. Magnetic
incubation medium at the end of incubation, resonance studies have confirmed the previously
apparently irrespective of hemolysis, demonstrating reported experimental data on the consequences of
that reactive iron may be released by stressed red hyperoxia in the lungs of premature newborn
cells and diffuse outside the cell. 121 This finding animals, namely edema, congestion, immune cell
suggests that oxidative stress in erythrocytes may infiltration and decreased number of alveoli per
be involved in the increase in NPBI in plasma of square meter. 131,132 Prolonged moderate hyperoxia
172 Textbook of Perinatal Medicine

induces airway hyperresponsiveness and histological infants with CLD and periventricular leukomalacia
changes similar to those of CLD.133 Increased type has been reported.78 Conditions of oxidative stress
IV collagenase in bronchoalveolar lavage suggests a possibly responsible for CLD and retinopathy have
role of this factor in lung damage and particularly in also been reported.143 These observations suggest a
disruption of the extracelluar matrix. It is interesting combined effect of oxidative stress in the pathogenesis
that injury produced by oxidative stress involves of CLD, brain damage and retinopathy.
matrix metalloproteinases (MMP) and tissue inhibitor
of matrix metalloproteinase (TIMP) which are also RETINOPATHY
involved in infections.134 Increased MMP-8 and MMP- Although the origins of retinopathy (ROP) are
9 associated with decreased TIMP have been multifactorial, (see chapter 12) the role of oxygen
reported in amniotic fluid during infection and toxicity, which was first detected half a century ago,
chorioamnionitis, a condition frequently associated has been confirmed by experimental and clinical
with development of CLD.88 These findings are in studies. ROS have been recognized to play an
line with reports of phagocyte activation and important role, particularly in the first stage of eye
increased cytokine production. The finding of a large injury when hyperoxia seems to affect the vascular
number of neutrophils and high concentrations of endothelium arresting normal blood vessel
interleukin-8 and leukotrienes in bronchopulmonary development.144 Hyperoxia also seems to inhibit
lavage of infants with severe CLD demonstrates the vascular endothelium growth factor and involvement
role of inflammatory reactions and ROS production of oxidative stress in vascular obliteration caused by
in the development of this disease.135,136 apoptotic vascular endothelial cells has also been
The toxic effects of ROS on the lungs appear to be suggested.144 The hypothesis of a complex mechanism
due to iron-mediated OH· release. 125 This radical of oxidative stress in the development of ROS is also
alters surfactant composition and causes decreased suggested by the observation of a role of iron
surfactant production by injuring type Il pneumo- intake145 , decreased GSH/GSSG ratio146, and NPBI147
cytes.125,137 Peroxynitrate formation from O 2·- and in patients with ROP. Morphological abnormalities
NO· can also cause lung injury.138 Reactive oxygen of ROP, such as “gap junctions”, are an expression of
species can modify production of vasoactive lipoperoxidation, which has been demonstrated in
substances by the endothelium, and this might be the retina as a result of free radical release.148
important in CLD since increased endothelin-1 has A relationship between free radical release,
been demonstrated to be associated with inflam- induced retinal injury and cyclo-oxygenase pathway
mation and lung disease.139 Oxidative stress has been activity has been reported. 149 Abnormalities of
studied in the lungs of premature rats and a complex retinal vasculature have demonstrated that reversal
orchestra of genes involved in inflammation, vasoconstriction by dilator prostaglandin during
coagulation, fibrinolysis, extracellular matrix oxidative stress in newborns may facilitate neovas-
turnover, cell cycle, signal transduction and alveolar cularization of the retina of premature animals.150
enlargement have been found to be affected by The role of peroxides in inducing abnormal retinal
oxidative stress. 140 The combined effect of oxygen vasculature has also been demonstrated by the
and inflammation on the origin of CLD also emerges marked vasoconstriction which these molecules
from studies of bronchopulmonary lavage and produce in the retinal vasculature of premature
tracheal aspirate in which increased levels of markers animals.151
of oxidative stress, such as protein carbonyls and
myeloperoxidase activity in neutrophils of premature BRAIN INJURY
infants who developed CLD, have been found.141,142 ROS may affect the brain by different interacting
Increased lipid peroxidation in plasma of premature systems involving membrane damage, astrocyte
 Oxygen Toxicity 173
dysfunction, abnormalities of n-methyl-D-aspartate, oxidative stress induced by OH· produced via the
receptors, and particularly increased intracellular Fenton reaction.164 The effects of ROS are also due
calcium and mitochondrial dysfunction.152,153 ROS to brain hypoxia-induced generation of NO free
may also cause indirect injury by inducing cerebro- radicals; peroxynitrite is formed when O 2·-
vascular spasms. 154 Iron-induced ‘OH production predominate over scavenger system and NO
may occur during brain injury because the low increases as an effects of increased NOS.153
transferrin content of cerebrospinal fluid (CSF) is However, during ischemia, a number of metabolic
saturated by iron released from cells with a high iron changes occur and prostaglandin metabolism and
content, and free and unbound iron becomes dopamine oxidation have been found to have a role
available for the Fenton reaction.152 in the release of ROS.165 The recent availability of
The brain is low in catalase and has moderate reliable markers of oxidative stress, such as
amounts of SOD and GSH-Px; its membrane lipids isoprostanes and particularly F2-isoprostane and 8-
are rich in polyunsaturated fatty acids which are isoprostane, has provided evidence of involvement
sensitive to oxidative stress. 152 In the fetus and of oxidative stress in the development of cerebral
newborn, protection against ROS seems to be even white matter injury, since these compounds were
poorer than in adults, especially in the glia, and detected in the CSF of premature infants with white
sensitivity to oxidative stress seems particularly high matter damage. 161 Further confirmation of this
in the first hours of life.152-157 The first mechanism of involvement was the finding of increased carbonyls,
brain damage due to ROS to be investigated was a marker of protein oxidation in CSF of these
neonates.161 It is interesting that none of the observed
that of ischemia-reperfusion and hypoxanthine-
infants had infections and their CSF, unlike in
xanthine oxidase reaction.158 The importance of this
meningitis, did not contain chlorotyrosine, a marker
mechanism emerged from the finding of high
of leukocyte oxidant activity.166 Indirect evidence of
concentrations of hypoxanthine in blood and CSF
the responsibility of ROS in brain damage of
during hypoxia, and from experimental data
asphyxiated infants comes from the observation of
demonstrating inhibition of ROS release by allo-
NPBI in CSF. 167 Increased NPBI resulting from
purinol, an inhibitor of xanthine oxidase.159 However,
asphyxia or hemorrhage has an important role in the
Delivoria et al.160 demonstrated that hypoxia results
development of brain injury, one reason being that
in brain cell membrane damage as shown by early differentiating oligodendroglia is poor in ROS
increased membrane lipid peroxidation and detoxification systems and enables a peroxide
decreased Na+ ,K+-ATPase activity, irrespective of accumulation and OH Ì generation by the Fenton
reoxygenation. High levels of isoprostane-8, another reaction. 152,168
marker of oxidative stress, also suggest responsibility Several observations also suggest ROS
of ROS in brain damage during asphyxia 161, while involvement in brain injury during hyperoxia.169,170
electron spin resonance spectroscopy has shown that Decreases in cerebral blood flow in response to O2
tissue hypoxia results in increased free radical administration have been detected in human
generation in the cerebral cortex. 162 Levels of studies170 and reduced blood flow was observed in
conjugated dienes and fluorescent compounds, premature newborns treated with high O2 concen-
markers of lipid peroxidation, have also been trations. 171 However, animals kept in hyperoxia
detected in the brain of newborn animals with showed a reduction in blood flow which was not
asphyxia, particularly during recovery from single statistically significant.172
or repeated episodes.163 Histochemical studies of Considering the interaction between ROS and
brains of neonatal rats after hypoxic ischemic injury inflammatory mediators, oxidative stress to the
demonstrated that iron increases rapidly in the first endothelium may play an important role in the
24 hours in regions of ischemic injury, suggesting development of brain damage.173
174 Textbook of Perinatal Medicine

Relationships between ROS and brain damage are antioxidant power.181 However, plasma antioxidants,
suggested by the link between increased markers of if measured in conjunction with other parameters,
oxidative stress and clinical observations.. may be useful in the detection of imbalance between
Oxidative stress in premature and full term free radicals and antioxidants. Chromatographic
newborns with asphyxia is demonstrated by high profiles of antioxidants in human plasma can provide
plasma levels of lipid hydroperoxides and evidence indications of single component deficiencies which
of the MDA reaction.174,175 Markers of oxidative may be useful to distinguish particular deficiencies
stress, such as HPLC determinations of MDA, 4- or increased consumption of a factor involved in a
hydroxynonenal, total hydroperoxide, and carbonyl particular disease.182
groups, are significantly higher in asphyxiated Lipid oxidation is a complex process and
babies.174-177 It is interesting that markers of oxidative commonly used methods, such as thiobarbituric acid,
stress, such as total hydroperoxides, remain high for are questionable. The TBA test should not be used
weeks in sick babies.177 Isoprostanes, a reliable because most TBA-reactive material in the human
marker of oxidative stress, have been reported to be body is not related to lipid peroxidation. 181
higher in cases of fetal distress.178 Measurement of MDA by HPLC is more indicative
High levels of NPBI in plasma of asphyxiated of lipid peroxidation, although MDA is only one of
newborn are evidence of a role of ROS in the the many aldehydes formed during this process.181
development of brain injury in hypoxia-ischemia. The It is more logical to measure 4-hydroxynonenal.181
reports of Dorrepal et al. 179 indicated that this The best biomarker of lipid peroxidation is
occurrence, which is peculiar to neonates, is isoprostanes which are specific end products of
associated with severe brain damage. Buonocore et peroxidation of polyunsatured fatty acids.181,183 Most
al. 180 recently tested the predictivity of traditional work has been done with F2-isoprostane which arises
indicators of brain damage in relation to neuro- from arachidonic acid peroxidation. Neuroprostane
developmental outcome. They demonstrated that or F4-isoprostane has also been measured.183 They
plasma NPBI is the most reliable marker of severe are best measured by mass spectrometry. 184 It is
outcome in asphyxiated newborns.180 important to remember that isoprostanes are rapidly
metabolized so that increased values may indicate
THE MARKERS OF OXIDATIVE STRESS slower metabolism and not increased production.181
If oxidative damage contributes significantly to Measurement of ethane and pentane in expired
neonatal pathology, it is essential to be able to air were among the first methods of detecting of
accurately measure oxidative stress. Two basic oxidative stress in asphyxiated neonates.185 These
approaches have been suggested: 1) attempting to assays have the advantage of being non invasive and
trap ROS and measure levels of trapped molecules; independent of the complex matrix of blood. 186
2) measuring the oxidative damage done by ROS.181 However, variations in the methods make it difficult
Other frequently used approaches are inaccurate.181 to compare populations.187 Simultaneous measure-
Erythrocyte enzyme activities, which were the first ment of pentane and MDA has been carried out to
indication of the low antioxidant resistance of asses oxidative stress. In studies on human hyperoxia,
newborns, are not fully reliable since the enzyme increased values of both markers were found but no
activities of red cells are age dependent and values correlation between pentane and MDA was
may be expression of young or old red cell observed, probably because they are metabolized
populations.181 Measurement of total antioxidants differently. 188
usually involves major contributions from urate, Profiles of aldehydes pentanal, hexanal, 2-hexanal,
ascorbate, bilirubin and albumin-SH groups which heptanal, 2-heptanal, 2-octenal, 2-nonenal and 4-
are variable and may not accurately reflect hydroxy-nonenal formed during autoxidation of
 Oxygen Toxicity 175
fatty acids, such as oleic, linoleic, á-linoleic, ã-linoleic phagocyte activation in inflammatory processes. 196
and arachidonic , seem to improve the sensitivity of Therefore, nitrotyrosine can also be used as a marker
detection.189 of oxidative stress since total nitration is consistent
Determination of protein carbonyl concentrations with amplified cell levels of O2 ·- in the presence of
provides information regarding protein involvement NO and CO2. 197
in ROS reactions. The carbonyl assay as applied to Allantoin can be measured in body fluids and its
tissues and body fluids measures the average extent plasma levels are high under conditions of oxidative
of protein modification.181 The use of proteomics to stress.198 Assays in urine give reliable results.199
identify specifically oxidized proteins appears to be 8-Hydoxydeoxyguanosine has been reported to
a promising method. 190 Research on plasma of be a reliable a marker of oxidative stress. This
newborns has shown interesting selectively oxidized molecule can be assayed in urine and has been done
proteins during asphyxia.191 in newborns. While no differences in relation to
Total hydroperoxides represents a measure of gestational age have been reported by some
overall oxidative stress, given that they are the authors200, others201 observed a negative correlation
intermediate oxidative products of lipi, peptides and between 8-OHdG and gestational age, confirming
amino acids.176 that premature infants are more subject to oxidative
Percentages of oxidized forms of Coenzyme Q- stress.
10 have also been used to demonstrate oxidative Plasma levels of NPBI appear to be a reliable
stress in asphyxiated newborns.72 marker of oxidative stress and close relationships
A major marker of oxidative stress is the GSH/ between these levels and plasma carbonyls have been
GSSG ratio, which directly reflects alteration of reported.197 At least in neonates, both assays can be
intracellular redox status.192 GSH is a cofactor of regarded as markers of potential risk of pathology
GSH-Px and also has the antioxidant effect of binding due to oxygen toxicity.
Cu2+ , contributing to delivery of copper to the Isolevuglandins (structural isomers and
apoprotein of copper enzymes and decreasing free stereoisomers of cyclooxygenase-generated levo-
metal available for the Fenton reaction. Filomeni et glandins) may be formed via free radical-mediated
al.192 showed a relationship between intracellular pathways and have been proposed as a sensor of
GSH levels and mitochondrial-dependent apoptotic lipid peroxidation initiated by myeloperoxidase.202
pathways. Under oxidative stress, GSSG may be
produced at a high rate and extruded from cells into PREVENTION AND THERAPY
the extracellular milieu.192 Since blood glutathione
Avoiding Oxidative Stress
may reflect GSH status in other less accessible tissues,
measurement of GSH and GSSG in blood has been Reactive oxygen species are normally produced in
considered an essential index of overall oxidative living organisms. Their properties and complex role
status and a useful indicator of risk of disease. in the development of diseases make prevention and
The GSH/GSSG ratio has been used as a measure antioxidant therapy very difficult in newborns as well
of oxidative stress in neonates. Decreased ratios as in adults. Obviously, avoidance of conditions such
were observed in premature infants with severe RDS as asphyxia, hyperoxia and retinal light exposure,
and newborns resuscitated with 100% O 2. 193,194 under which excessive free radical release occurs,
Lower GSH/GSSG ratios were found in very low are the best defense against development of
birth weight infants even when they were breathing imbalances in pro-oxidant and antioxidant factors in
room air.195 the neonate. It is also important to remember that
Levels of nitrotyrosine have been reported to be infections and particularly sepsis may be a severe
a marker of ONOO - production resulting from source of oxidative stress. Frequent reports of NPBI
176 Textbook of Perinatal Medicine

in plasma of neonates suggest that indiscriminate iron above 93% for newborns under 32 weeks of age.
supplementation should be avoided. More recently, comparison of two populations of
The concept of optimal oxygenation of newborns high risk newborns kept at O2 saturations of 88-98%
has recently been revised in order to clarify whether and 70-90% showed a significant reduction in ROP
the optimal oxygen saturation unanimously accepted in the group at lower O2 saturation but no differences
for normal infants and adults is also the best for sick in mortality or poor outcome.210,211
neonates especially if premature. The relationship Hyperoxia and oxidative stress may occur during
between Hb oxygen saturation, risk of oxidative neonatal resuscitation. In an attempt to avoid the
stress and oxygen toxicity is still a problem. Even a risk of tissue damage caused by ROS in the first hours
recent Cochrane review failed to define the target of life, when susceptibility to oxidative stress is
range for maintaining blood oxygen levels in particularly high, the effects of reduction of O2 were
preterm/LBW infants.203 This is presumably due to investigated. Some animal studies demonstrated
the complex mechanism of oxygen toxicity which may identical outcome variables, including bood pressure,
be expressed at different percentages of O 2 lung haemodynamics, acid base status, cerebral blood
saturation under different conditions. Conventional flow and brain oxygenation whether resuscitation
indications suggest that optimal oxygen tension was done with room air or 100% oxygen.212 In other
should be maintained between 50 and 70 mmHg.204 experiments with animals subjected to ischemia and
High O2 saturation seems to be necessary for infants hypoxia, reoxygenation with 100% oxygen was
with CLD and infants with prethreshold retino- followed by better restoration of microcirculation
pathy.205 However, in view of susceptibility of some but no difference in biochemical markers of brain
neonates to oxidative stress, it has been suggested injury.213 Comparison of short and long duration of
that oxygen saturation maintained within physio- oxygen treatment after cerebral asphyxia in newborn
logical limits could result in moderate hyperoxia that piglets confirmed the efficacy of reoxygenation with
could generate an excess of ROS. Experimental room air. 214 Potential risks associated with
studies in animals in the first 24 hours of life resuscitation with 100% oxygen are suggested by the
demonstrated a threshold of oxygen-restricted observation of increased production of ROS with
metabolism at Pa O2 = 40 Torr.206 Shulze et al.207 did respect to room air.215,216 Clinical studies have
not observe signs of mismatch between systemic demonstrated no differences in short term outcome
oxygen delivery and demand in low birth weight between newborns resuscitated with room air and
infants kept at O2 93-96% and 89-92%. saturation. A 100% oxygen.217,218 The same results were observed
significant decrease in CLD and ROP without any in a follow up at 18 and 24 months.219 Vento et al.194
differences in mortality were observed in extremely demonstrated that room air resuscitation was
low birth weight (ELBW) infants kept at less than associated with significantly less oxidative stress. It
95% O2 saturation compared to those kept at more is important to note that they demonstrated
than 95%.208 Important indications on the use of increased oxidative stress following resuscitation
oxygen were recently reported by Cow et al.209 in a with 100% oxygen was demonstrated by the sensitive
5-year study in a tertiary neonatal center where GSH/GSSG ratio which is a marker of generalized
oxygen therapy was adjusted to optimize neonatal oxidative stress.192 The satisfactory results of room
care and decrease the incidence of ROP. They air resuscitation in terms of outcome and avoidance
recommended avoidance of repeated increase and of oxidative stress were recently confirmed by the
decrease in FiO2 in response to the oxygen saturation same authors. 220 A reduction in mortality and no
monitor and maintenance of oxygen saturation within evidence of harm were described in a Cochrane
“acceptable” limits. They also recommended an review.221 However, the authors concluded that there
alarm setting for oxygen saturation below 85% and is insufficient evidence on which to recommend a
 Oxygen Toxicity 177
policy of using room air over 100% oxygen or vice definite results have been obtained by retinol
versa for resuscitation of newborns.221 Although the supplementation. 229 Among the antioxidants,
guidelines do not discourage high FiO2, it seems melatonin has a special place since it has been
reasonable to conclude that 100% oxygen should not reported to have several interesting effects such as
be used routinely. enhancement of antioxidant enzyme activities and
neutralization of H 2O 2 singlet oxygen and
Antioxidants peroxynitrite. 230 Melatonin also appears to scavenge
Much research has recently been carried out to find OH·.231 Administration of melatonin to neonates with
substances with antioxidant activity. 222 These RDS has been reported to lower concentrations of
substances can be divided into those decompart- proinflammatory cytokines. 232 In septic newborns
mentalizing metal complexes, those limiting ROS melatonin also lowers levels of oxidative markers
production, those modifying antiradical defenses and such as MDA and 4-hydroxylalkenals and improves
enhancing intracellular or extracellular antioxidant prognosis.233
levels, those incorporating lipophilic antioxidant into Some drugs commonly used in neonatology, such
membranes and those scavenging superoxide.222 as aminophylline, are reported to have antioxidant
Substances inhibiting phagocyte activation or properties.234 Vitamin E is a powerful, widely tested
xanthine oxidase and arachidonic acid metabolism, antioxidant and although no definite agreement has
or decompartmentalizing free iron and making it been reached on its use, interesting results have been
available for the Fenton reaction, have also been reported even in human newborns. Analysis of nine
investigated, together with those scavenging ROS randomized controlled trials of prophylactic use of
directly or repairing ROS-induced membrane injury, vitamin E supplementation in very low birth-weight
like calcium antagonists and betablockers. infants showed no statistically significant reduction
On the whole, the results obtained in newborns in the incidence of retinopathy and hemorrhage
have been uncertain. Although substances such as confined to the germinal matrix, although a significant
ascorbate are considered to be antioxidants in vitro reduction in the incidence of intraventricular
and in vivo, they may act as pro-oxidant factors by hemorrhage was found.235 Some formulations of
causing metal-induced release of ROS.223 Several vitamin E are poorly absorbed236 and the metabolism
other antioxidant substances have been used in and membrane distribution of the vitamin is
newborn animals and humans in an attempt to uncertain; apart from this, there is no doubt about
improve the worst prognosis of damage, presumed the effectiveness of α-tocopherol in protecting
to be due to ROS. Many, such as SOD, showed the membranes and plasma lipoproteins from lipoperoxi-
same disadvantages in newborns as in adults. 224 dation. In view of the potential activity of α-
Other drugs, such as allopurinol, have shown good tocopherol and its proven deficiency in newborns,
results in animals225, but no advantages in human administration of vitamin E at the commonly
newborns, especially those with hypoxic ischemic recommended doses should be considered in any
encephalopathy.226 Indomethacin, which has been high risk neonates.237,238 Doses from 10 to 25 mg/
shown to have antioxidant effects in humans, reduces kg/day in the first 3 days of life should protect
the incidence and severity of intraventricular premature infants in the first weeks239 Serum levels
hemorrhage but it is not known whether this effect should be monitored in order to avoid levels
is due to antioxidant activity. 227 Involvement of exceeding 3 mg/dl. Subsequently, human milk or
metal-induced ROS in brain damage suggested formula should be sufficient to maintain adequate
treatment with chelating agents. Desferrioxamine vitamin levels.239 Conclusions of a recent Cochrane
seemed to have a protective effect in animals which review are that vitamin E supplementation to preterm
has not yet been demonstrated in humans.228 No infants reduces the risk of intracranial hemorrhage
178 Textbook of Perinatal Medicine

but increases the risk of sepsis; in very low birth 5. Halliwell B, Gutteridge JMC, Cross CE. Free radicals,
antioxidants, and human disease: where are we now? J
weight infants it seems to reduce the risk of
Lab Clin Med 1992; 1 19:598-620.
retinopathy and blindness.240 There is no evidence 6. Halliwell B. Free radicals, antioxidants, and human
to support the use of vitamin E at high doses or the disease: curiosity, cause, or consequence? Lancet
aim of keeping serum tocopherol levels above 3.5 1994;344:721-4.
7. Gutteridge JMC. lipid peroxidation and antioxidants as
mg/dl.240 biormarkers of tissue damage. Clin Chem 1995;41:1819-
Peroxidation products in stored lipid emulsions 28.
have been shown to increase lipid peroxidation in 8. Fridovich I. Superoxide dismutase: an adaptation to a
vivo in newborns and adults.241 Since parenteral paramagnetic gas. J Biol Chem 1989; 264:7761-4.
9. Turrens JF. Mitochondrial formation of reactive oxygen
nutrition has been associated with increased species. J Physiol 2003;552:335-44.
formation of ROS, it is necessary to protect intralipid 10. Radi R, Cassina A, Hodara R et al. Peroxynitrite reactions
from light and add vitamins.242 However, adaptation and formation in mitochondria. Free Rad Biol Med 2002;
33:1451-64.
to factors responsible for oxidative stress has been
11. Wink DA, Miranda KM, Effey MG Effects of oxidative
demonstrated by Pitkanen et al. 242 who found and nitrosatide stress in cytotoxicity. Semin Perinatol
attenuated lipid peroxidation in preterm infants after 2000;24:20-23.
repeated doses of intravenous lipids. 12. Beckman JS, Viera L, Estevez A et al. Nitric oxide and
peroxynitrite in the perinatal period. Semin Perinatol
Micronutrients also play a role in protection 2000;24:37-41.
against oxidative stress. Selenium is part of the GSH- 13. Granot E, Kohen R. Oxidative stress in childhood in
Px molecule, and a close correlation exists between health and disease states. Clin. Nutr. 2004;23:3-11.
selenium and GSH-Px.243 Very severe RDS has been 14. Balavoine GG, Geletii YV. Peroxynitrite scavenging by
different antioxidants. I. Convenient assay. Nitric Oxide
reported in selenium-deficient human babies. 244 1999;3:40-54.
However, while the deficiency of GSH-Px has been 15. Halliwell B. Superoxide, iron, vascular endothelium and
demonstrated in premature infants deficient in reperfusion injury. Free Rad Res Commun 1989;5:315-
selenium 245 , the quantity of selenium supple- 18.
16. Weiss SJ. Tissue destruction by neutrophils. N.Engl.J
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Finally, the protective effects of bilirubin against to oxidative stress in mammalian cells. Arch Biochem
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186 Textbook of Perinatal Medicine

15
Pathology of the Neonate

Beáta Hargitai, Tamás Marton, Zoltán Papp

INTRODUCTION GROWTH ABNORMALITIES AND

INTRAUTERINE GROWTH RESTRICTION.
Obstetrical care of high standard and regular
ASSESSMENT OF IUGR DURING PERINATAL
ultrasound scanning usually leads to prenatal
diagnosis of developmental abnormalities and often POST MORTEM EXAMINATION
prevents perinatal pathologists to encounter those Massive cell division and differentiation takes place
in term or near-term neonates. Therefore dysmor- in the developing fetus and result in a linear growth
phology and congenital abnormalities are more and until the 38th week of gestation. Any failure of the
more the subject of the fetopathology whilst growth complicated biochemical routes and control system,
abnormalities, hypoxic injuries, preterm birth, shortfall in nutritional agents or oxygen supply may
infection remains a major problem in neonatal lead to growth abnormalities. In obstetric practise
medicine. Congenital tumour and genetic metabolic ultrasonographic assessment of biparietal diameter
disease is rare in general, but may have a great impact (BPD), femur length and other fetal measurements
on the life of the family especially when it is part of were found to be useful to date the pregnancy.2 To
a syndrome and has a high recurrence risk. Stillbirth estimate the duration of the pregnancy, the most
and early neonatal death rate, due to birth-related
frequently used method is to count the gestational
events, have significantly decreased in the last 40
weeks from the first day of the mother’s menstrual
years (from 7.9 to 0.5 per 1000 total births) in the
period. Although many charts of fetal and neonatal
United Kingdom1 and similar trend can be observed
measurements are available in textbooks, most of
in many other European countries. The number of
these have been created decades ago.3-5 Perinatal
litigation cases following intrapartum neonatal death
pathology centres have to update these data,
is increasing, and thus potentially the post mortem
especially to reflect characteristics of a given
report has medico-legal importance. It is highly
geographical and ethnical population.
recommended for obstetricians to ask for a post
During perinatal necropsy the appropriate
mortem examination and to encourage the parents
measurements of the body (weight, crown-rump
to give permission for a full autopsy. It is a good
length, crown-heel length, foot length, head
practice to have regular discussions with the perinatal
circumference) and organ weight always have to be
pathologist and to provide the pathologist with
detailed clinical information prior post mortem taken and should be compared with the normal
examination. values, apt for the counted gestational age.
 Pathology of the Neonate 187
Neonates, born between the 37th to 41st due to placental dysfunction or maternal under-
gestational weeks are term neonates and those born nutrition, reduced uteroplacental perfusion related
before the 37th week are preterm neonates, to maternal hypertension, pre-eclampsia, diabetes
expressing signs of prematurity. Both term and mellitus or maternal smoking. In late onset IUGR
preterm babies can be of appropriate weight for the the infant’s body is disproportional, the head
gestational age or may weigh less than the expected circumference is relatively large, and the brain
normal value. Babies who weigh 2500g or less are weight/ liver weight ratio is elevated.
called low birthweight neonates and those under Pathological and histological assessment of IUGR
1500g are designated as very low birthweight. Small- requires accurate measurement of body weight,
for-date or small-for-gestational-age (SGA) infants crown-heal length, crown-rump length, head
measure less than 3rd, 5th, or 10th centile or less circumference, foot length, organ weights, and
than 2 standard deviations below the mean. Small- microscopic examination of the parenchymal organs.
for-dates infants are not necessarily growth Elevated brain weight/liver weight ratio [Mean 2.8
restricted and babies suffering from intrauterine (range 1.7-4.1)]6,7, lower crown-rump length than
growth restriction are not always small-for-date! head circumference, immature brain gyral pattern8,
Intrauterine growth restriction (IUGR) is usually decreased nephron counts and presence of
detected during the third trimester of pregnancy. In nephrogenic zone of the kidney after the 36th week
case of an early onset growth restriction the fetal of gestation9, bone growth plate abnormalities and
organs are smaller but proportionally developed. The specific placental findings are sensitive markers of
serial BPD measurements are lower and parallel with IUGR.10
the normal values from the early pregnancy. This Infants, who weigh more than the normal value
type of IUGR is usually associated intrauterine for a particular gestational age, are called heavy-for-
infections, chromosome abnormalities – e.g. Down’s dates babies. This condition can be constitutional and
syndrome, triploidy (Fig. 15.1.) - and many other usually is associated with high maternal body weight
malformation syndromes. Late onset IUGR is usually or higher parity. Maternal diabetes mellitus and
caused by environmental factors such as malnutrition gestational diabetes are often complicated with
increased somatic size (macrosomia) when the
diabetes of the mother is not sufficiently controlled.
Macrosomia, unilateral hyperplasia, or single organ
overgrowth can be seen in so called overgrowth
syndromes. This group includes Beckwith-
Wiedermann syndrome, characterised by hemihyper-
plasia, macroglossia, omphalocele, and increased risk
of pediatric neoplasms, most frequently Wilm’s
tumour. Simpson-Golabi-Bernel syndrome, an X
chromosome linked disorder, is associated with
macrosomia, congenital heart defects among other
abnormalities. 11 Perlman syndrome, autosomal
recessive, is characterised by macrosomia at birth,
cardiac malformation, hypertrophy of the islets of
Langerhans, bilateral renal hamartomas and
sometimes nephroblastomatosis. 12 Weawer syn-
Fig. 15.1: Triploidy: note the relatively large head and atrophic drome is characterised by accelerated growth and
body, small jaw and low set ear of this fetus. osseous maturation, bears considerable overlap with
188 Textbook of Perinatal Medicine

Soto’s syndrome, both of them associated with

congenital heart defects and higher risk of malig-
nancy.13

PATHOLOGICAL SEQUELS OF
INTRAUTERINE ASPHYXIA
Intrauterine asphyxia is a common cause of fetal death
and may lead to severe organ failure such as long
term neurodevelopmental injuries in the surviving
infant. During the last two decades it has become
evident that only a minority of cerebral palsy and
severe neurological damage begins at labour. In
contrast, chronic or subacute intrauterine asphyxia Fig. 15.2: Squamous cells in the alveoli of a stillborn fetus
is responsible for about 80% of cases.14,15 In case of
acute intrauterine asphyxia, pathological events lead There are usually no petechial haemorrhages in
to fetal demise or major damage within 24 hours, subacute asphyxia/hypoxia. Microscopically
while in chronic intrauterine asphyxia the estimated shrinking of the cortex, prominent Hassal’s corpuscles
time course is 3 weeks or more. Specific causes of and histiocytosis can be observed in the thymus, with
intrauterine asphyxia and associated pathological lymphocytolysis, the depletion of lymphocytes results
events can be identified in 50-80% of stillbirth cases.16 in a typical “starry sky” pattern (Fig. 15.3). In the
Clinical data and pathological examination may help adrenals lipid depletion and re-accumulation is
to clarify the mechanism of damage and reveal present in the middle fetal cortex (Fig. 15.4).
maternal, placental or fetal causes such as maternal Chronic intrauterine hypoxia leads to fetal growth
disease, haemorrhage, placental malfunction, fetal retardation with asymmetric or disproportionate
malformation, second trimester loss of a twin in
monochorionic pregnancy, or infection.
During the course of the post mortem of a fetus
or a neonate who underwent intrauterine asphyxia,
a combination of features associated with the
predisposing causes as well as symptoms related to
intrauterine hypoxic stress can be seen.
Acute intrauterine asphyxia is characterised by
petechial haemorrhages on the epicardium along
coronary arteries and at base of aorta and pulmonary
trunk, visceral pleura, meconium in the airways,
massive intrapulmonary haemorrhage, subcapsular
haemorrhage of the liver, interstitial corticomedullary
haemorrhage of the kidney and subcapsular
haematoma of the adrenal glands. Microscopic
examination reveals aspirated meconium, squames
in the airways (Fig. 15.2), myocardial contraction
band changes, cortical histiocytosis in the thymus and
Fig. 15.3: Starry sky reaction in the thymus of a neonate. The whitish
cystic degeneration of the adult cortical zone in the small areas represent missing thymocytes as a result of subacute
adrenals. stress.
 Pathology of the Neonate 189
hypoxic- ischaemic changes in thalamus, midbrain,
pons, and basal ganglia. Angulation of the neurons,
karyorrhexis, and karyopicnosis are characteristic
signs of neuronal apoptosis (Fig. 15.6) Late
consequences of hypoxic- ischaemic brain damage
may include massive loss of brain tissue causing
porencephaly, hydrocephaly, cystic changes, and
subsequent microcephaly.

PREMATURITY, IMMATURITY
Neonates, delivering before 37 completed weeks of
gestation are called preterm neonates. The direct
causes of preterm labour are not entirely understood
Fig. 15.4: Severe lipid reaccumulation in the adrenal cortex although many associated pathological events have
been studied such as maternal diseases, socio-
pattern, reduced muscle and subcutaneous fat. economic factors, previous reproductive events,
Microscopically, re-accumulation of lipid and fatty effect of twinning and fetal factors. Structural and
change in the outer fetal cortex of the adrenal gland functional immaturity of preterm babies causes major
is characteristic. The thymus shows severe problems in postnatal life during adaptation.
involutional changes with thin or diminished cortex
Hypoglycaemia, hypothermia, high blood potassium
and crowding of the Hassal’s corpuscles (Fig. 15.5).
level, and anaemia are frequent complications.
In the enchondral growth plate of the bones irregural
Pathological appearance of organ specific alterations
costo-chondral junction can be observed.
have been changed due to technical development of
Intrauterine hypoxia leads to congestion in the
neonatal intensive care and new therapeutic
central nervous system. Grossly, flattening of the gyri
methods.
and compression of lateral ventricles can be seen.
Microscopically, different stages of neuronal
degeneration, necrosis and apoptosis are typical for

Fig. 15.5: Atrophic cortex of the thymus, Fig. 15.6: High number of apoptotic figures in the hyppocampus of
prominent hassal’s corpuscles a neonate with hypoxic-ischaemic encephalopathy
190 Textbook of Perinatal Medicine

Pathology of the Respiratory System in visible. Hyaline membrane (Fig. 15.7) is strongly
Premature Infants associated with IRDS, but can be present in acute
asphyxia, in some infections (e.g. group B strep-
Infantile Respiratory Distress Syndrome (IRDS)
tococcus infection) and in pulmonary haemorrhage.
and Hyaline Membrane Disease (HMD)
The incidence of IRDS and HMD has been
IRDS is a frequent condition in preterm infants and significantly reduced with surfactant administration
is characterised by a well defined clinical picture: and especially the preventive use of natural surfactant
rapid increase in oxygen requirement and demand is proved to be useful. Steroid administration before
for ventilation, cyanosis, tachypnoe, intercostal and preterm labour is a common practice, the benefits
sternal recession, increasing expiratory pressure and and complications of which are still investigated.19,20
a typical grunting noise at expiration. Radiological
staging is possible but not always consistence with Changing Morphology of Chronic Lung
the degree of respiratory failure. In an advanced Disease (CLD)
stage the picture of “white lungs” appears on X-ray.
Clinical definition of chronic lung disease requires
The underlying cause behind the acute respiratory
demand for assisted or supported ventilation after
failure of preterm neonates is the functional and
structural immaturity of the lung. The reduced 28 days of life, radiological signs, and previous acute
number and incomplete formation of airways, respiratory failure of the infant, most frequently
inefficient production of surfactant factor, lack of IRDS-HMD. The classical morphology of chronic lung
antioxidant defence lead to a number of immuno- injury has changed and is rarely seen today.
pathological processes similarly to diffuse alveolar Therefore, the term “bronchopulmonary dysplasia”
damage syndromes. The exact mechanism of the is not appropriate for the majority of the cases and
initial epithelial injury is not known but ischaemia, “chronic lung disease” is preferred currently.
volu- and baro-trauma, oxygen toxicity are likely to Traditionally, three stages could be distinguished
play major role.17 Most babies survive IRDS and in in BPD based on histology of the lung.
about 50% of cases there are no significant
complications in the respiratory system. The outcome
is less favourable with younger gestational age. The
incidence is higher in males, and symptoms can be
more severe in infants of diabetic mothers, in multiple
pregnancies and after intrauterine asphyxia.18
In pretem babies who die in the first week of life
with symptoms of IRDS, the lungs are heavy, purple
coloured and have a liver-like texture due to
atelectasia. Microscopically, most airways are
collapsed, but terminal airways are distended, the
bronchial epithelial lining is necrotic. As soon as at
an hour after birth, hyaline membrane starts to
develop lining the primitive airways that consists of
nuclear debris of epithelial cells as well as necrotic
cell mass and exudates from inflammatory cells. A
few hour later polymorphonuclears, macrophages
migrate into the septa and after two days Fig. 15.7: Eosinophilic membrane lines the inner
regenerative changes in the epithelium become surface of the airway.
 Pathology of the Neonate 191
• In acute exudative- early reparative stage (1-9 there is an increased level of inflammatory cytokines.
days) persisting hyaline membrane, lack of type It is suggested, that the current morphology of
II. pneumocytes, bronchiolar epithelial necrosis, chronic lung disease might be the consequence of an
obliterative bronchiolitis, interstitial oedema, alveolar developmental abnormality due to the lack
congestion, and initial septal fibrosis can be seen. of physiological signal during lung remodelling in
• In subacute fibroproliferative stage (10-30 days) the highly immature infants. 21,22
increasing interstitial and perialveolar fibrosis,
necrotising tracheobronchitis, smooth muscle Pulmonary Air Leak and Pulmonary Haemorrhage
proliferation, dilated bronchioli and terminal Positive pressure ventilation may result in alveolar
airways are present. over-distension and rupture. The air can be pressed
• In the late stage (after one month) prominent into the pleural cavities leading to pneumothorax.
septal fibrosis, reduced number and anatomical Air leakage into the pulmonary tissues results in
distortion of terminal airways, metaplastic pulmonary interstitial emphysema. Pneumoperi-
changes in bronchial epithelium, pulmonary cardium is usually associated with other air leaks
hypertensive changes in pulmonary arterioles are and is a severe complication threatening with
typical findings. pericardial tamponade. Systemic air embolism is a
The changing morphology of chronic lung disease very rare complication of ventilation and may lead
might be a result of the longer survival time of the to sudden death.
very immature, very low birth weight preterm infants Intraalveolar and interstitial haemorrhage is
and the technical improvement of intensive care, frequently associated with HMD. Massive haemorr-
especially ventilation. Characteristic morphological hage is occasionally a terminal event while alveolar
changes include less exudative- fibroproliferative and subpleural haemorrhage are rather associated
signs but a dramatic fall in the number of airways’ with acute asphyxia.
and gas exchange surface (Fig. 15.8). The proximal
airways are collapsed and in contrast, the terminal Pathology of the Central Nervous System in
structures are dilated. Patchy fibrosis may be present Premature Infants (Germinal Matrix
but is not dominant. Inflammatory morphological Haemorrhage, Intraventricular Haemorrhage
changes are not common, although, significant and Periventricular Leukomalacia)
inflammatory response is associated with CLD and
A reasonable improved prognosis has been
documented in the last decade, the incidence of
intracerebral haemorrhage and ischaemic white
matter damage in preterm infants is still high and
may be responsible for long term neurodevelop-
mental sequels such as hydrocephalus, spastic
diplegia, hemiplegia, quadriplegia, learning
difficulties, and behavioural problems.23,24
The pattern of neuropathological changes in
preterm brain differs from those that can be found
in term neonates. Most frequent pathological find-
ings in preterms are germinal matrix/intra-
ventricular haemorrhage and perivenricular
Fig. 15.8: Simplified airways, widened interalveolar septa leukomalacia, and in contrast with the term brain
are present in chronic lung disease. tissue, the most vulnerable areas are the
192 Textbook of Perinatal Medicine

periventricular germinal matrix and white matter. can be seen with a chalk white rim, usually within
Although basal ganglia are far more frequently the paraventricular white matter, in the temporal lobe
affected in term babies, pontosubicular necrosis has and in the tapetum. The lesion tends to be multifocal
been observed in a high ratio of preterm infants.25 and bilateral. Histologically, signs of coagulative
The fetal brain is characterised by an active necrosis, microglial and astrocytic reaction, groups
neurogenesis, dense aggregation of precursor cells of macrophages and mineralised neurons can be
in the subependymal germinal layer, and a paucity present. In later stage, cystic changes develop in the
of myelin. Neuronal precursors migrate from the injured sites leading to the typical picture of
germinal layer into the cortex, where later also glial multicystic periventricular leukomalacia (Fig. 15.9).
cells are produced, and by the 36th week of gestation
only residual foci of the germinal matrix can be seen. Necrotising Enterocolitis, NEC
The germinal matrix bears a delicate vascular pattern, The onset of the NEC is usually during the first two
consisting of vulnerable capillaries, having no weeks for preterm infants. Although the exact initial
muscular wall. Sudden changes in the blood pressure, cause is not known, alimentary and iatrogenic aspects
disturbed autoregulation, higher fibrinolythic are investigated. Immaturity is strongly associated
activity, increased permeability of vessel walls, with this condition but the etiological role of early
caused by hypoxia contribute in pathogenesis of enteral feeding is now challenged.30,31 In contrast,
germinal matrix haemorrhage. Bleeding may occur perinatal asphyxia, and respiratory distress syndrome
in one focus but can be multiple, unilateral or were not among the risk factors in the study of
bilateral. According to Papile’s grading system, Kanto32, but umbilical cord catheterisation increased
bleeding restricted to the germinal matrix represent the chance of NEC.33 An infectious component has
grade 1; Haemorrhage, breaking into the lateral also been suspected by many investigators but no
ventricle is regarded as grade 2; In more severe cases pathogenic organism has been found yet.34,35 Breast
dilatation of ventricles follows the haemorrhage milk proved to have a protective role.36
(grade 3) and parenchymal damage (grade 4) can be The clinical picture of NEC is characterised by
observed in about 10% of the cases.26 Germinal matrix lethargy, pale skin tone, abdominal distension,
and intraventricular haemorrhage usually develop bloody stool and vomits. Radiology shows
in the first three days of life. High grade intraventri- distended, gas containing bowels and occasionally
cular haemorrhage, associated with respiratory gas perforation into the abdominal cavity. The
distress syndrome, is a leading cause of death, and outcome is less favourable for very low birthweight
grade 1-4 haemorrhage is present in as many as 83% infants, and for cases complicated with perforation,
of very low birthweight preterm infants in our post peritonitis, sepsis and intravascular coagulopathy.
mortem examinations. On histology, extravasation
of red blood cells, tissue damage, a few days later
many haemosiderin laden macrophages and petrified
neurons can be seen.
Periventricular leukomalacia is related to sudden
drop of the blood pressure and the most vulnerable
sites are the vascular watershed areas, where the
decreased perfusion leads to ischaemia. 27 Recent
studies have revealed relationship between
intrauterine infection, acute high grade chorio-
Fig. 15.9: Post ischaemic change in the brain. The ventricles are
amnionitis- funisitis and white matter injuries.28,29 dilated, and there are multiple cysts in the white matter (post necrotic
On macroscopical examination whitish- yellowish foci porencephaly).
 Pathology of the Neonate 193
Post mortem or post operative examination of the PERINATAL INFECTIONS
bowels reveals distended, thin or paper like bowel
Frequent Pathological Sequels of
wall, sites of perforation, greenish- brownish exudate Intrauterine Infections
on the visceral peritoneum. The number of the villi
of the small intestine is diminished and the wall is The incidence of the intrauterine infection reaches a
showing different degree of oedema, haemorrhagic peak in the second trimester. The two most frequent
necrosis and gangrenous inflammation. The picture mechanisms are the ascending genital tract infections
and the transplacental haematogenous spread. The
can be similar in the lower part of the intestinal tract.
pathogenesis of intra-amniotic infections and the
Retinopathy of Prematurity, ROP and Other most common pathogenic agent are summarised in
Pathological Conditions Associated with Table 15.1.
Prematurity Table 15.1: Mechanism and common pathogens of
intrauterine infections
Retinopathy of preterm infants was described in the
Virus Bacteria Fungi Protozoa
early 40s, and was regarded as retrolental fibroplasia
Transcervical Herpes Group B Candida
(Terry 1942). The frequency dropped when the
Genitalis, Strepto- albicans
adverse effect of concentrated oxygen was HIV-1 coccus
recognised, but rose again with the increasing (infection E. coli
during H. influen-
survival time of very low birthweight infants.
labour!) zae
According to the current practise, high-risk babies CMV Group B Toxo-
(less than 1500 g and/or born before 32nd week of Parvo- Streptoco- plasma
virus ccus Chlamydia
gestation) are monitored in order to prevent retinal
Transplacental Rubella Listeria psittaci
detachment and blindness, as total retinal detachment HIV-1 monocyto- Treponema
being the most severe stage of this condition.37 The genes p. Borrelia
site of the changes is the junction of the vascularised
and avascular retina, where demarcation, fibro- The consequences of intrauterine infection include
vascularisation and neovascularisation develops as early, spontaneous, preterm labor and premature
a pathological reaction of the immature tissue for rupture of membranes,38 and occasionally genera-
angiogenetic signals. The detailed pathway of this lised fetal infection. Developmental abnormalities
procedure is not yet entirely understood. and other clinical features related to particular
There are other, clinically important consequences intrauterine infections are well described in
of the altered metabolic functions, which do not have paediatric pathology. 4 CMV infection is known to
characteristic morphological appearance, such as be associated with severe central nervous system
hypothermia, hypoglycaemia, and higher blood damage, microcephaly with multifocal calcification,
potassium level. Anaemia of preterm infants presents chorioretinitis, hearing loss, neonatal hepatitis, while
with extensive extramedullary haemopoesis and Rubella infection may lead to cardiac malformation,
occasionally fatty changes of the adrenal cortex. deafness, and eye defects. The incidence of Syphilis
The risk of sudden infant death syndrome is higher infection is very low and the vertical transmission
for preterm babies. rate for HIV showed a decreasing trend in the
Preterm birth is very frequently complicated with industrialised countries during the recent years.39,40
perinatal infections, which are discussed under a The statistics is less favourable in the developing
separate subtitle. countries.41
194 Textbook of Perinatal Medicine

The patho-morphological signs of intrauterine rate increases for preterm infants and those born to
infection have to be carefully looked for in case of mothers with infections or prolonged rupture of the
stillbirth or neonatal death. Symmetric type of IUGR fetal membranes. Group B streptococci and
is a common association. Frequent macroscopic and enterobacteriaceae are the main causes of early-onset
microscopic features of viral and bacterial infections sepsis in more developed countries.42
are summarised in Table 15.2. Late-onset neonatal sepsis (>72 hours) is usually
Table 15.2: Typical macroscopic and microscopic features
caused by gram-positive agents, especially coagulase-
of intrauterine infections in the fetus and in the placenta negative staphylococci.43,44
Macroscopic signs Microscopic signs Rarely, other Streptococci, Haemophilus
Bacterial Placenta Placenta influenzae, Serratia marcescens, Malassezia furfur,
Infection – Opaque or greenish- – Transcervical infection Salmonella, Pseudomonas aeruginosa, Campylobacter
brownish membranes Acute, high grade cho- and Listeria monocytogenes leads to neonatal
in transcervical rioamnionitis, fetal
infection. Candida albicans is the most common
infection chorionic vessel vas-
– Placental abscesses culitis, and funisitis among fungal infections, which often colonises the
in case of trans- – Transplacental infec- baby from birth, and sometimes causes pneumonia
placental spreading tion in infants treated with antibiotics.
Fetus Acute villitis, deciduitis
– Macroscopic features Microabscesses,
The costs and benefits of intrapartum antibiotic
of septic shock microgranulomas e.g. prophylaxis therapy should be carefully evaluated
– Leptomeningeal in listeriosis and the therapeutic policies reconsidered in the light
purulent exudate and Fetus of the new data on increasing frequency of
congestion in menin- – Intrauterine pneumo- nosocomial infections.45,46
gitis nia infiltration with The most severe complications of early and late-
– Occasionally periven- polymorphonuclear onset infections are pneumonia and meningitis, but
tricular leukomalatia leukocytes in the air-
enteral and urogenital infections, conjunctivitis and
ways, interstitial
inflammatory reaction
skin rushes may be also present. Pathological signs
– Microabscesses of the are frequently poor and non-specific. Macro-
parenchymal organs scopically, skin rushes, congestion of the parenchymal
Viral Fetus Placenta organs, petechiae, adrenal haemorrhage, rarely
Infection – hepatosplenomegaly – Subacute or chronic leptomeningeal purulent exudate can be observed.
– icterus, petechiae villitis, specific virus Microscopically, inflammatory infiltrate of the
– hydrops inclusions e.g. Parvo- airways is present in the congested, edematous lung
– IUGR virus B19, CMV, HSV tissue, with interstitial reaction. Special stains may
– developmental mal- – haemolysis- haemo-
help to visualise fungi. Samples for microbiological
formation siderin deposition
– focal necrosis, dystro- lab test should be taken during post mortem
phic calcification e.g. examination.
HSV
CONGENITAL TUMOURS AND
Neonatal Infection TUMOUR-LIKE LESIONS

Neonatal infection is frequent in preterm infants, with Epidemiology, Biological Behaviour and
a higher risk and worse prognosis for low birthweight Aetiology of Congenital Tumours
infants. Neonatal tumours, (including congenital tumours)
Sepsis occurring in the first three days of life, is occurring within the first 28 days of life represent an
called early-onset neonatal sepsis, can be a age specific group of neoplastic lesions. The reported
devastating neonatal problem, with high mortality incidence (2003) ranged between 1 per 12,500-27,500
rate. Although neonatal sepsis is not very frequent live births in the UK and USA and varied from 17-
(2-4 per 1000 live births) in developed countries, the 121 per million births worldwide.47
 Pathology of the Neonate 195
Abnormal tissue swellings and masses present at Beckwith-Wiedermann syndrome, a higher risk of
birth are often regarded as congenital tumours, nephroblastoma, hepatoblastoma and adrenal cancer
although many types of them do not fulfil the criteria can be observed, or in Hirschsprung’s disease, which
of true neoplasias. These tumour-like lesions, is occasionally associated with neuroblastoma. There
traditionally called hamartomas and choristomas, are is a long list of many other inherited syndromes
probably due to tissue developmental abnormalities, including metabolic disorders, phacomatoses, DNA
differentiation and migration defects off cells repair defects, immune deficiency syndromes,
resulting in a pathological architecture. carrying a higher risk of different malignant tumours,
Benign and tumour-like lesions are reasonably but most of these develop only in later childhood.
frequent and usually harmless–such as infantile Neonates with structural chromosomal anomalies
haemangioma, most small congenital nevi- but may present with congenital tumours, trisomy 18 and
occasionally bear more clinical significance and 13 can be associated with teratomas, trisomy 18 with
complications e.g. Kaposiform haemangioendo- nephroblastoma and hepatoblastoma. 52 Acute
thelioma associated with Kasabach-Merrit syndrome megakaryocytic leukaemia is a well known
and fetal hydrops.48 The biological behaviour of complication of Down’s syndrome in early neonatal
neonatal tumours can not always be predicted based age.53
on their morphological appearance. Benign On the other hand, frequency of congenital
congenital lesions may have a risk of malignant abnormalities- spina bifida, abnormalities of ribs,
transformation e.g. malignant melanoma can develop eyes- was higher in children with solid tumours
in giant congenital nevus.49-51 Infantile haeman-gioma (Wilm‘s tumour, Ewing sarcoma, hepatoblastoma)
may show spontaneous regression, however lesions than in population based controls. This observation
of large size may cause cardiac failure or directs future studies in underlying gene disorders.54
consumptional coagulopathy. The histologically Enviromental factors including ionizing radiation,
benign cardiac fibroma or cardiac rhabdomyoma may particular drugs taken during pregnancy, and
represent poor prognosis for its unfavourable maternal CMV, varicella, influenza and HIV virus
location. In contrast, some tumours of malignant infections have been implicated in the aetiology of
histological appearance tend to show significantly neonatal (and paediatric) tumours.55-57
better prognosis in early life, e.g. neuroblastoma,
hereditary retinoblastoma, congenital fibrosarcoma. Common Types of Solid Neonatal Tumours
A unique group of true congenital neoplasias are
The incidence of neonatal tumours is similar in
regarded as embryonal tumours. These are
different reports, teratoma and neuroblastoma being
characterised by a uniformly primitive histological
the most common, followed by soft tissue tumours,
picture resembling embryonal- fetal appearance of
renal and CNS tumours and leukaemias.47
the organ in which they arise. This group include
neuroblastoma, nephroblastoma (Wilm’s tumour),
Congenital and Neonatal Teratoma
hepatoblastoma, retinoblastoma, embryonal
rhabdomyosarcoma and medulloblastoma. Some Fetal and neonatal germ cells tumours have different
embryonal tumours are familial, such as 40% of clinical course and morphology from those occurring
retinoblastomas and familial Wilm’s tumours, while in older children or adults. Congenital teratoma has
others associate with inherited syndromes, e.g. been described in numerous sites, most frequently
glycogenosis type I. and hepatocellular carcinoma, in sacrococcygeal location, but ovarial, testicular,
or α-1 antitripsin deficiency and hepatoblastoma. mediastinal, cervico-facial, retroperitoneal,
In a few sporadic malformation syndromes there is abdominal and intracranial location has also been
a higher risk of neonatal tumours, for example in documented (Figs 15.10A to D). There are published
196 Textbook of Perinatal Medicine

A B

C D
Figs 15.10A to D: Sacrococcygeal teratoma in a fetus of 23 rd weeks of gestation. A. Macroscopic picture of the large, mainly praesacral
tumour. B., C., D Microscopic examination reveals immature neural elements, squamous epithelium with a hair follicule, and hyaline cartilage
tissue

cases of teratoma developing in the placenta or amount of immature tissue,62 however, immature
umbilical cord. Prenatal diagnosis, recognition of risk neural elements do not indicate malignancy in this
factors, and intrauterine therapeutic interventions age group. True malignant tumours, most frequently
improved the outcome, although maternal compli- yolk-sac tumour, was present in 5.8 % of teratomas
cations, polyhydramnios, fetal cardiac failure, fetal with the highest incidence (10%) in sacrococcygeal
hydrops, tumour rupture are not uncommon.58-60 teratoma and a tumour recurrence rate of 5% was
Macroscopically, teratoma presents as a solid and reported in a recent review.61
cystic mass, potentially containing well-formed Presacral sacrococcygeal teratoma has a worse
organoid structures. The traditional histological prognosis than those in postsacral location, gastric
definition requires presence of tissues from all three teratoma has a good prognosis, while the outcome
germ layers and most teratomas fulfil these criteria. of the intracranial teratomas is poor, with few
Immature tissue is usually present in 20-50% of exceptions.63-66 The main prognostic factors of fetal
cases4,61 and the histological grading is based on the and neonatal teratoma are the size and location, the
 Pathology of the Neonate 197
completeness of surgical excision, and presence of characterised by small primary tumour, disseminated
malignant tumour (yolk-sac tumour). spreading, and low N-myc copy numbers is termed
as Stage IV-S neuroblastoma. Spontaneous regression
Congenital Neuroblastoma is not an uncommon finding in this stage.75-77 Only
The incidence of congenital neuroblastoma is similar a small proportion of congenital neuroblastomas
to the teratoma thus it is the most frequent malignant require aggressive therapy. Life threatening
tumour of the neonatal period. Ultrasonographic respiratory complication might be related to massive
features of the tumour have been described and hepatomegaly.
prenatal diagnosis gives opportunity for appropriate
Soft Tissue Tumours
planning and management.67,68
Congenital neuroblastoma usually presents with Fibromatosis: This is a unique group of tumours with
an abdominal or adrenal mass but extraadrenal diverse clinicopathologic features.
location, disseminated form, massive liver involve- The histological picture varies according to the
ment, and metastasis of the skin and placenta can specific types, but shares common features, like
occur.69-72 presence of intersecting bands of spindle cells in
The morphological features are not different from variably collagenised stroma. The lesions might be
those in older children, and the same histological more cellular than the similar adult type alterations
criteria are used for classification. 73 Immuno- and show an aggressive growth. In contrast with
histochemistry and electron microscopy confirm the the occasionally formidable picture the outlook is
histological diagnosis. Molecular genetics is a useful favourable. Spontaneous regression is not
aid to detect prognostic factors. N-myc amplification, uncommon, although local recurrence may occur.78
expression of bcl-2, an apoptosis suppressing protein, Congenital myofibromatosis may present as a
are associated with unfavourable histology and bad solitaer lump and show spontaneous regression,
prognosis. 74 The outcome of congenital neuro- while in its generalised form carries a poor prognosis
blastoma is generally favourable. A special pattern, due to visceral involvement (Figs 15.11A and B).
Fibromatosis colli is a palpable mass in the
sternocleidomastoid muscle, occurs in young infants,

Figs 15.11A and B: Soliter infantile myofibromatosis in a term baby. A. CT scan shows soft tissue swelling around the second rib, on the right,
suggesting infiltrative growth. B. Characteristic microscopic appearance, with bindles of spindle cells, and small round primitive looking cells.
The soliter lesion bears an excellent prognosis
198 Textbook of Perinatal Medicine

while infantile digital fibromatosis may present on at birth. The circumscribed type is more common,
the fingers and toes. Cranial fasciitis and fibrous with superficial location, while the diffuse type
hamartoma of infancy are both rapidly growing (lipoblastomatosis) originates from deep soft tissue,
lesions of the subcutaneous soft tissue, the former has an infiltrative growth pattern and recurs more
localised on the skull. frequently. Characteristic clonal karyotypic changes
Sarcoma: Congenital infantile fibrosarcoma is a can be demonstrated and help to distinguish from
fibroblastic-myofibroblastic proliferation, a rapidly childhood and adult lipomas as well as from myxoid
growing lesion resulting in massive tumour. The liposarcoma.86
histological appearance is sarcoma-like but the
prognosis is good, with five-year survival of more Intracranial Tumours
than 90% and metastases are very rare.78 Some cases Most frequently diagnosed intracranial tumour is
have a characteristic chromosomal translocation with teratoma, primitive neuroectodermal tumour,
t(12;15)(p13;q25) and an ETV6-NTRK3 gene fusion medulloblastoma, astrocytoma, glioblastoma
or ETV6 gene rearrangement. 79 Embryonal multiforme and ependymoma. Plexus choroideus
rhabdomyosarcoma shares similar features in young papilloma, ganglioglioma and low grade astrocytoma
infants and children, having a five-year survival of have the best prognosis, but the overall survival rate
66%. Embryonal rhabdomyosarcoma displays loss of perinatal brain tumours was only 28% in a recent
of heterozygosity on chromosome 11p15.5, a tumour review. Stillbirth is frequent and hydrocephalus-
related locus at 11q, numerical abnormalities, trisomy macrocephaly is often diagnosed prenatally.87-90
8 and other abnormalities. However, these findings
do not, as yet, have diagnostic or prognostic Congenital Tumours of the Kidney
significance.80,81 Congenital mesoblastic nephroma is a benign tumour,
occasionally leads to fetal hydrops and polyhydram-
Neural/Neuroectodermal Tumours
nios. Although the tumour mass can be huge and
Neural tumours in young infants are usually extend beyond the kidney, surgical treatment is
associated with neurofibromatosis type 1 (NF1). usually curative. Histologically, the tumour consists
Plexiform neurofibromas are histologically benign of spindle cells of myofibroblastic origin. A more
lesions with premalignant potential as in about 10 % cellular variant is known which carries the same
of the NF 1 patient malignant peripheral nerve-sheath t(12;15)(p13;q25) and ETV6-NTRK3 gene fusion as
tumour (MPNST) develops from it. Congenital infantile fibrosarcoma.91
peripheral/ primitive neuroectodermal tumour Rhabdoid tumour of the kidney is an aggressive
(PNET) have been reported in several sites.82-84 PNET tumour with bad prognosis and distinct morpho-
and Ewing sarcoma are now considered the same logical features. It is characterised by deletion of the
entity, based on their shared genetic abnormalities, hSNF5/INI1 gene, which links it to other rhabdoid
being consistently associated with chromosomal tumors of infancy that arise in the soft tissue and
translocation and functional fusion of the EWS gene brain.92
to any of several structurally related transcription Congenital and infantile Wilm‘s tumour is rare
factor genes (EWS-FLI-1, EWS-ERG, EWS-ETV1, and shows a strong association with presence of
EWS-E1AF etc.).85 nephrogenic rests (persistent metanephric blastema)
in the kidney.93 Recent molecular genetic findings
Adipose Tumours of the Neonate
suggest a multi-step model of the pathogenesis in
Lipoblastoma, a typical benign tumour of fat tissue Wilm‘s tumour and supports the precursor role of
of the early childhood, occasionally may be present nephrogenic rests.94 Nephrogenic rest as well as
 Pathology of the Neonate 199
nephroblastoma may present in bilateral location. 15. MacLennan A. A template for defining a causal relation
between acute intrapartum events and cerebral palsy:
Nephroblastoma of the early infancy has a good
international consensus statement. BMJ 1999;
prognosis. 95,96 319(7216):1054-1059.
16. Magee JF. Investigation of stillbirth. Pediatr Dev Pathol
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 SECTION 3
Ethical and Legal Dimensions
FA Chervendak, LB McCullough
 16
Ethics : An Essential Dimension
of Perinatal Medicine

Frank A Chervenak, Laurence B McCullough

INTRODUCTION obligations of physicians and health care

organizations to patients, as well as the obligations
Ethics is an essential dimension of perinatal
of patients.4 Medical ethics should be distinguished
medicine.1,2,3 In this chapter we develop a framework
from the many sources of morality in pluralistic
for clinical judgment and decision-making about the
societies. These include law, our political heritage as
ethical dimensions of perinatal medicine. We will
a free people, the world’s religions, ethnic and
emphasize a preventive ethics approach that
cultural traditions, families, the traditions and
anticipates the potential for ethical conflict and
practices of medicine (including medical education
adopts ethically justified strategies to prevent those
and training), and personal experience. Medical ethics
conflicts from occurring. Preventive ethics in
since the eighteenth century European and American
perinatal medicine helps to build and sustain a strong
enlightenments has been secular. 5 It makes no
physician–patient relationship.
reference to God or revealed tradition, but to what
This chapter has five parts. First, we define ethics, rational philosophical discourse produces. Therefore,
medical ethics, and the fundamental ethical principles ethical principles and virtues should be understood
of medical ethics; beneficence and respect for to apply to all physicians, regardless of their personal
autonomy. Second, we show how these two religious and spiritual beliefs.6
principles should interact in perinatal medicine, with The traditions and practices of medicine constitute
emphasis on the clinical ethical concept of the fetus an important source of morality for physicians,
as a patient. Third, we describe different concepts because they are based on the obligation to protect
of the ethical principles of justice. Fourth, we examine and promote the health-related interests of the
ethical issues in managed care, with particular patient. This obligation tells physicians what morality
attention to the virtues of the physician as a in medicine ought to be in very general, abstract
professional. Fifth, we describe a new formal tool terms. Providing a detailed, clinically applicable
for critically appraising the literature of medical account of that obligation is the central task of
ethics, including perinatal ethics. medical ethics, using ethical principles.4

ETHICS AND MEDICAL ETHICS Ethical Principles

Ethics is understood to be the disciplined study of The Principle of Beneficence

morality. Medical ethics is therefore the disciplined The ethical principle of beneficence requires one to
study of morality in medicine, and concerns the act in a way that is expected reliably to produce the
206 Textbook of Perinatal Medicine

greater balance of benefits over harms in the lives of There is an inherent risk of paternalism in beneficence-
others.6 To put this principle into clinical practice based clinical judgment. By this we mean that
requires a reliable account of the benefits and harms beneficence-based clinical judgment, if it is
relevant to the care of the patient and of how those mistakenly taken by the physician to be the sole source
goods and harms should be reasonably balanced of moral responsibility, and therefore moral authority
against each other when not all of them can be in medical care, invites the unwary physician to
achieved in a particular clinical situation. In medicine, conclude that beneficence-based judgments can be
the principle of beneficence requires the physician to imposed on the patient irrespective of her autonomy.
act in a way that is reliably expected to produce the Paternalism is a dehumanizing response to the patient
greater balance of clinical benefits over clinical harms and, therefore, should be avoided in the practice of
for the patient. 4 perinatal medicine.
Beneficence-based clinical judgment has an The preventive ethics response to paternalism is
ancient pedigree, with its first expression found in for the physician to explain the diagnostic,
the Hippocratic Oath and accompanying texts. 7 therapeutic, and prognostic reasoning that leads to
Beneficence-based clinical judgment aims to interpret his or her clinical judgment about what is in the
reliably the health-related interests of the patient interest of the patient and her pregnancy so that the
from a rigorous clinical perspective which is provided patient can assess that clinical judgment for herself.
by accumulated scientific research, clinical experience, The physician should first explain to the patient the
and reasoned responses to uncertainty. Such a major factors of this reasoning process, including
rigorous clinical perspective is thus not the function matters of uncertainty. In neither medical law nor
of the individual clinical perspective of any particular medical ethics does this require that the patient be
physician and therefore should not be based merely provided with a complete medical education.8 The
on the clinical impression or intuition of an individual physician should then explain how and why other
physician. On the basis of this rigorous clinical clinicians might reasonably differ from his or her
perspective, which should be based on the best clinical judgment. The physician should then present
available evidence, beneficence-based clinical a well-reasoned response to this critique. The
judgment identifies the clinical benefits that can be outcome of this process should be that beneficence-
achieved for the based on the competencies of based clinical judgments take on a rigor that they
medicine. The benefits that medicine is competent sometimes lack, and the process of their formulation
to seek for patients are the prevention and includes explaining them to the patient. In complex
management of disease, injury, handicap, and areas such as perinatal medicine, beneficence-based
unnecessary pain and suffering and the prevention clinical judgment will frequently result in the
of premature or unnecessary death. Pain and identification of a continuum of clinical strategies that
suffering become unnecessary when they do not protect and promote health-related interests.
result in achieving the other goods of medical care, Awareness of this feature of beneficence-based
e.g., allowing a woman to labor without effective clinical judgment provides an important preventive
analgesia.4 Non-maleficence means that the physician ethics antidote to paternalism by increasing the
should not, on balance, cause harm, and is best likelihood that one or more of these medically
understood as expressing the limits of beneficence. reasonable, evidence-based alternatives will be
This is also known as “Primum non nocere” or “first acceptable to the patient. This feature of beneficence-
do no harm.” This commonly invoked dogma is based clinical judgment also provides a preventive
really a Latinized misinterpretation of the Hippocratic ethics antidote to “gag” rules that restrict physician’s
texts which emphasized beneficence while avoiding communications with the managed care patient.9 All
harm when approaching the limits of medicine. 4 beneficence-based alternatives must be identified and
 Ethics : An Essential Dimension of Perinatal Medicine 207
explained to all patients, regardless of how the 1. absorbing and retaining information about her
physician is paid, especially those that are well condition and alternative diagnostic and
established in evidence-based perinatal medicine. therapeutic responses to it,
One advantage for the physician in carrying out 2. understanding that information (i.e., evaluating
this approach to communicating with the patient and rank-ordering those responses and
would be, we believe, to increase the likelihood of appreciating that she could experience the risks
compliance. 10 This is an especially pertinent of treatment), and
consideration in perinatal medicine, e.g., self- 3. expressing a value-based preference. The
observation for unusual weight gain, bleeding, or physician has a role to play in each of these. They
signs of premature labor. Another advantage would are, respectively,
be to provide the patient with a better-informed 1. to recognize the capacity of each pregnant
opportunity to make a decision about whether to patient to deal with medical information (and
seek a second opinion. The approach outlined above not to underestimate that capacity), provide
should make such a decision less threatening to her information (i.e., disclose and explain all
physician, who has already shared with the patient medically reasonable alternatives, i.e.,
the limitations on clinical judgment. supported in beneficence-based clinical
judgment), and recognize the validity of the
The Principle of Respect for Autonomy values and beliefs of the patient,
To complement the principle of beneficence, there is 2. not to interfere with but, when necessary, to
emphasis in the literature of medical ethics on the assist the patient in her evaluation and ranking
principle of respect for autonomy. 6 This principle of diagnostic and therapeutic alternatives for
requires one always to acknowledge and carry out managing her condition, and
the value-based preferences of the adult, competent 3. to elicit and implement the patient’s value-
patient, unless there is compelling ethical justification based preference. 4
for not doing so, e.g., prescribing antibiotics for viral
Beneficence and Respect for
respiratory infections. The pregnant patient
Autonomy in Perinatal Practice
increasingly brings to her medical care her own
perspective on what is in her and her pregnancy’s The ethical principles of beneficence and respect for
interest. The principle of respect for autonomy autonomy play a central role in perinatal practice.
translates this into autonomy-based clinical judgment. There are obviously beneficence-based and
Because each patient’s perspective on her interests is autonomy-based obligations to the pregnant patient:
a function of her values and beliefs, it is impossible the physician’s perspective on the pregnant woman’s
to specify in advance the benefits and harms of the health-related interests provides the basis for the
patient’s autonomy-based clinical judgment. Indeed, physician’s beneficence-based obligations to her. Her
it would be inappropriate for the physician to do so, own perspective on those interests provides the basis
because the definition of her benefits and harms and for the physician’s autonomy-based obligations to
their balancing are the prerogative of the patient. her. Because of an insufficiently developed central
Autonomy-based clinical judgment is strongly nervous system, the fetus cannot meaningfully be
antipaternalistic in nature.4 said to possess values and beliefs. Thus, there is no
The responsible practice of perinatal medicine basis for saying that a fetus has a perspective on its
depends on an operationalized concept of autonomy interests. Hence, there can be no autonomy-based
to make it relevant to clinical practice. We therefore obligations to any fetus. The language of fetal rights
identify three sequential autonomy-based behaviors has no meaning, and therefore, no application to the
on the part of the patient: fetus in perinatal clinical judgment and practice,
208 Textbook of Perinatal Medicine

despite its popularity in public and political discourse about when the fetus acquires independent moral
in the United States and other countries. The status. Some take the view that the fetus has
physician does have a perspective on the fetus’s independent moral status from the moment of
health-related interests, and the physician can have conception or implantation. Others believe that
beneficence-based obligations to the fetus, but only independent moral status is acquired in degrees,
when the fetus is a patient.4 thus resulting in “graded” moral status. Still others
hold, at least by implication, that the fetus never
Clinical Ethical Concept has independent moral status so long as it is in
of the Fetus as a Patient utero.11,12
The clinical ethical concept of the fetus as a patient Despite an enormous amount of theological and
is essential to perinatal clinical judgment and practice. philosophical literature on this subject, there has been
Developments in fetal diagnosis and perinatal no closure on a single authoritative account of the
management strategies to optimize fetal outcome independent moral status of the fetus. This outcome
have become widely accepted, encouraging the should be expected, because, given the absence of a
development of this concept. This concept has single method that would be authoritative for all of
considerable clinical significance, because when the the markedly diverse theological and philosophical
fetus is a patient, directive counseling, that is schools of thought involved in this sometimes
recommending clinical management for fetal benefit, acrimonious debate, closure is impossible. For closure
is appropriate, and when the fetus is not a patient, ever to be possible, debates about such a final
nondirective counseling, that is offering, but not authority within and between theological and
recommending, a form of management for fetal philosophical traditions would have to be resolved
benefit, is appropriate. However, these seemingly in a way satisfactory to all, an inconceivable
straightforward roles for directive and nondirective intellectual and cultural event. Claims about the
counseling are often difficult to apply in actual independent moral status of the fetus as the basis
perinatal practice, because of uncertainty about when for claims about the fetus as a patient have no stable
the fetus is a patient. This concerns moral status, i.e., or clinically applicable meaning. We therefore
whether others have an ethical obligation to the fetus abandon these futile attempts to understand the fetus
to protect and promote its interests. as a patient in terms of independent moral status of
One prominent approach for establishing whether the fetus and turn to an alternative approach.
or not the fetus has the moral status of being a patient Our analysis of the clinical ethical concept of the
has involved attempts to show whether or not the fetus as a patient starts with the recognition that being
fetus has independent moral status. Independent a patient does not require that one possess
moral status for the fetus means that one or more independent moral status. Rather, being a patient
characteristics that the fetus possesses in and of itself, means that one can benefit from the applications of
and therefore, independently of the pregnant woman the clinical skills of the physician. More precisely
or any other factor, generate and therefore ground stated, a human being is properly regarded as a
clinical obligations to the fetus on the part of the patient when two conditions are met: that a human
pregnant woman and her physician. being (1) is presented to the physician, and (2) there
Many fetal characteristics have been proposed as exist clinical interventions that are reliably expected
the basis for such independent moral status, including to be efficacious, in that they are reliably expected
moment of conception, implantation, central nervous to result in a greater balance of clinical benefits over
system development, quickening, and the moment harms for the human being in question.13 We call
of birth. It should come as no surprise that there is this the dependent moral status of the fetus as a
considerable variation among ethical arguments patient.
 Ethics : An Essential Dimension of Perinatal Medicine 209
The authors have argued elsewhere that or delivery in a tertiary care center when indicated.
beneficence-based obligations to the fetus exist when Non-aggressive obstetric management excludes such
the fetus is reliably expected later to achieve interventions. Directive counseling for fetal benefit,
independent moral status as a child and person. The however, must always take account of the presence
fetus is a patient when the fetus is presented for and severity of fetal anomalies, extreme prematurity,
medical interventions, whether diagnostic or and obligations to the pregnant woman.
therapeutic, that reasonably can be expected to result The strength of directive counseling for fetal
in a greater balance of goods over harms for the child benefit justifiably varies according to the presence
and person the fetus can later become during early and severity of anomalies. As a rule, the more severe
childhood. 4 The clinical ethical significance of the the fetal anomaly, the less directive counseling should
concept of the fetus as a patient, therefore, depends be for fetal benefit. In particular, when lethal
on links that can be established between the fetus anomalies such as anencephaly can be diagnosed with
and its later achieving independent moral status. certainty, there are no beneficence-based obligations
to provide aggressive management. Such fetuses are
The Viable Fetus as a Patient dying patients, and the counseling, therefore, should
One such link is viability. Viability is not an intrinsic be nondirective in recommending between non-
property of the fetus because viability should be aggressive management and termination of
understood in terms of both biological and pregnancy, but directive in recommending against
technological factors. It is only by virtue of both aggressive management for the sake of maternal
factors that a viable fetus can exist ex utero and thus benefit.15 By contrast, third-trimester abortion for
achieve independent moral status. It is important to Down Syndrome or achondroplasia is not ethically
appreciate that these two factors do not exist as a justifiable, because the future child with high
function of the autonomy of the pregnant woman. probability will have the capacity to grow and
When a fetus is viable, that is, when it is of sufficient develop as a human being.16,17
maturity so that it can survive into the neonatal period Directive counseling for fetal benefit in cases of
and achieve independent moral status given the extreme prematurity of viable fetuses is appropriate.
availability of the requisite technological support, and In particular, this is the case for what we term just-
when it is presented to the physician, the fetus is a viable fetuses, those with a gestational age of 24 to
patient. 26 weeks, for which there are significant rates of
Viability exists as a function of biomedical and survival but high rates of mortality and morbidity.
technological capacities. These differ in different parts These rates of morbidity and mortality can be
of the world. As a consequence, there is no increased by non-aggressive obstetric management,
worldwide, uniform gestational age to define whereas aggressive obstetric management may
viability. In the United States, we believe viability favorably influence outcome. Thus, it appears that
presently occurs at approximately 24 weeks of there are substantial beneficence-based obligations
gestational age.14 to just-viable fetuses to provide aggressive obstetric
When the fetus is a patient, directive counseling management. This is all the more the case in
for fetal benefit is ethically justified. In perinatal pregnancies beyond 26 weeks of gestational age.
practice, directive counseling for fetal benefit involves Directive counseling for fetal benefit is therefore
recommending against termination of pregnancy, justified in all cases of extreme prematurity of viable
recommending against non-aggressive management, fetuses. Of course, such directive counseling is
or recommending aggressive management. Aggres- appropriate only when it is based on documented
sive obstetric management includes interventions efficacy of aggressive obstetric management for each
such as fetal surveillance, tocolysis, cesarean delivery, fetal indication. For example, such efficacy has not
210 Textbook of Perinatal Medicine

been demonstrated for routine cesarean delivery to previable should be nondirective in terms of
manage extreme prematurity. continuing the pregnancy or having an abortion if
All directive counseling for fetal benefit must she refuses to confer the status of being a patient on
occur in the context of balancing beneficence-based her fetus. If she does confer such status in a settled
obligations to the fetal patient against beneficence- way, at that point beneficence-based obligations to
based and autonomy-based obligations to the her fetus come into existence, and directive
pregnant woman. Any such balancing must recognize counseling for fetal benefit becomes appropriate for
that a pregnant woman is obligated only to take these previable fetuses. Just as for viable fetuses, such
reasonable risks of perinatal interventions that are counseling must take account of the presence and
reliably expected to benefit the viable fetus or child severity of fetal anomalies, extreme prematurity, and
later. A unique feature of perinatal ethics is that the beneficence-based and autonomy-based obligations
pregnant woman’s autonomy influences whether, in to the pregnant woman.
a particular case, the viable fetus ought to be For pregnancies in which the woman is uncertain
regarded as presented to the physician. about whether to confer such status, the authors
Obviously, any strategy for directive counseling propose that the fetus be provisionally regarded as a
for fetal benefit that takes account of obligations to patient. This justifies directive counseling against
the pregnant woman must anticipate the possibility behavior that can harm a fetus in significant and
of conflict between the physician’s recommendation irreversible ways, e.g., substance abuse, especially
and a pregnant woman’s autonomous decision to the alcohol, until the woman settles on whether to confer
contrary. Such conflict should be managed the status of being a patient on the fetus.
preventively through the use of the informed consent In particular, nondirective counseling is
process as an ongoing dialogue throughout a appropriate in cases of what we term near-viable
woman’s pregnancy, augmented as necessary by fetuses, that is, those that are 22 to 23 weeks of
negotiation and respectful persuasion.18 gestational age, for which there are anecdotal reports
of survival. In our view, aggressive obstetric and
The Previable Fetus as a Patient neonatal management should be regarded as clinical
The only possible link between the previable fetus investigation (i.e., a form of medical experimen-
and the child it can become is the pregnant woman’s tation), not a standard of care.14 There is no clinical
autonomy, because technological factors cannot result obligation on the part of any pregnant woman to
in the previable fetus becoming a child. The link, confer the status of being a patient on a near-viable
therefore, between a previable fetus and the child it fetus because the efficacy of aggressive obstetric and
can become can be established only by the pregnant neonatal management has yet to be proven.
woman’s decision to confer the status of being a
The In Vitro Embryo as a Patient
patient on her previable fetus. The previable fetus
has no claim to the status of being a patient A subset of previable fetuses as patients concerns
independently of the pregnant woman’s autonomy. the in vitro embryo.19 It might seem that the in vitro
The pregnant woman is therefore free to withhold, embryo is a patient because such an embryo is
confer, or, having once conferred, withdraw the presented to the physician. However, for
status of being a patient on or from her previable beneficence-based obligations to a human being to
fetus according to her own values and beliefs. The exist, it must also be the case that medical
previable fetus is presented to the physician as a interventions are reliably expected to be efficacious.
function of the pregnant woman’s autonomy.4 Whether the fetus is a patient depends on links
Counseling the pregnant woman regarding the that can be established between the fetus and its
management of her pregnancy when the fetus is eventual independent moral status. Therefore,
 Ethics : An Essential Dimension of Perinatal Medicine 211
whether medical interventions on the in vitro embryo that in the distribution of resources, each should
should be reliably expected to be efficacious for the receive what is due to him or her. Different concepts
child later depends on whether that embryo later of justice define “due” in different ways. Each strives
becomes viable. Otherwise, no benefit of such to result in a fair distribution of benefits, i.e., access
intervention can meaningfully be said to result. An to resources, and burdens, the risks that could follow
in vitro embryo becomes viable only when it survives from lack of such access.
in vitro cell division, transfer, implantation, and Utilitarianism is a theory of justice that makes
subsequent gestation to such a time that it becomes central the obligation to produce the greatest good
viable. The process of achieving viability occurs only for the greatest number in the management of scarce
in vivo and is therefore entirely dependent on the resources. To be successful in guiding practical, day-
woman’s decision regarding the status of the to-day decisions about the allocation of resources,
fetus(es) as a patient, should assisted conception utilitarianism requires an account of the greatest
successfully result in the gestation of the previable good. For society overall, it has been difficult, if not
fetus(es). Whether an in vitro embryo will become a impossible, to define what the greatest good is. The
viable fetus, and whether medical intervention on value of utilitarianism is the balance it seeks to achieve
such an embryo will benefit the fetus and future among benefits and burdens of scarce resources, so
child, are both functions of the pregnant woman’s that inequalities do not become inequities, i.e. unfair.
autonomous decision to withhold, confer, or, having Critics of utilitarians have pointed out that sometimes
once conferred, withdraw the moral status of being utilitarianism results in inequities, i.e., shared
a patient on the previable fetus(es) that might result distributions of benefits and burdens.21
from assisted conception. Two other concepts of justice have been developed
It therefore is appropriate to regard the in vitro to address this problem. The first of these is a
embryo as a previable fetus rather than as a viable libertarian concept of justice. This concept of justice
fetus. As a consequence, any in vitro embryo(s) should was developed to correct for tyrannical burdens that
be regarded as a patient only when the woman into pure utilitarianism could create. In particular,
whose reproductive tract the embryo(s) will be libertarianism was developed to give priority to
transferred confers that status. Thus, counseling individual freedom and property rights, as
about preimplantation diagnosis should therefore be correctives to the potential excesses of utilitarianism
nondirective, just as it should be for previability and, in the political realm, of state power.
counseling. One additional justification is that the Libertarians argue that in a market that places
woman may elect not to implant abnormal embryos. different values on different services and products,
These embryos will not become patients, and so there and in which there is an equal opportunity to develop
is no basis for directive counseling regarding them. one’s talents, those who provide more highly valued
Information should be presented about prognosis for services rightly earn more than those who provide
a successful pregnancy and the possibility of less valued (though not necessarily less intrinsically
confronting a decision about selective reduction, valuable) services. Everyone should get to keep what
depending on the number of embryos transferred. he or she earns through these marketplace exchanges,
Counseling about how many in vitro embryos should reflecting the strong emphasis of the libertarian
be transferred should be rigorously evidence- concept of justice on property rights. Libertarian
based.20 theories emphasize fairness of process, rather than
equality of outcomes.
JUSTICE AND PERINATAL MEDICINE
The other concept of justice that has been
Ethical concerns about justice arise when economic, developed is an egalitarian concept of justice. This
clinical, or other resources are scarce. Justice requires concept was developed to protect vulnerable and
212 Textbook of Perinatal Medicine

disadvantaged members of society, who may lose interests rather than pursue his or her own interests.
out in a utilitarian distribution of scarce resources. Virtues are those traits and habits of character that
This concept of justice corrects for unfair outcomes routinely focus the concern and behavior of an
in the form of undue burdens on those least able to individual on the interests of others and thereby
protect themselves. habitually blunt the motivation to act on self-interest
These three and other concepts of justice remain one’s primary consideration. We believe that four
in unresolved competition in ethics generally, in virtues constitute the physician–patient relationship
medical ethics,22 and in perinatal ethics. It is fair to based on the physician as fiduciary.4
say that the medical ethics literature is strongly The first virtue is self-effacement. This professional
influenced by a concept of justice that calls for fair virtue requires the physician not to act on the basis
equality of opportunity (an element of libertarian of potential differences between the patient and the
justice) and protection of the least well off (an element physician such as race, religion, national origin,
of egalitarian justice). However, it is also fair to say gender, sexual orientation, manners, socioeconomic
that no single concept of justice shapes health care status, or proficiency in speaking English. Self-
policy in the United States. This lack of a conceptually effacement prevents biases and prejudices arising
coherent health care policy is a long-standing feature from these differences that could adversely impact
of American health care policy. In particular, unlike on the plan of care for the patient.
many other developed countries, the United States The second professional virtue is self-sacrifice. This
has yet to create a universal right to health care, requires physicians to accept reasonable risks to
though there are selective entitlements. themselves. As one example, perinatologists manifest
this virtue in their willingness to perform a cesarean
MANAGED CARE AND THE delivery for an HIV+ patient, following accepted
PROFESSIONAL VIRTUES standards. In both fee-for-service and managed care,
the professional virtue of self-sacrifice obligates the
The practice of perinatal medicine is coming under
physician to blunt economic self-interest and focus
managed care, which involves a set of strategies used
on the patient’s need for relief when the two are in
by both private and public payers to control the cost
conflict.
of medical care. Two main business tools are used to
The third professional virtue, compassion,
achieve this goal: motivates the physician to recognize and seek to
1. creating conflicts of interests in how physicians alleviate the stress, discomfort, pain, and suffering
are paid, diplomatically called “sharing economic associated with the patient’s disease and illness. Self-
risk;” and effacement, self-sacrifice, and compassion provide
2. increasingly strict control of clinical judgment and the basis for a powerful ethical response to the
practice through such means as practice business tool of conflicts of interest by the physician.
guidelines, critical pathways, physician report This response is strengthened by the fourth
cards, and retrospective chart review. These professional virtue, integrity. This virtue imposes an
business tools generate ethical challenges to intellectual discipline on the physician’s clinical
perinatologists that seriously threaten the virtues judgments about the patient’s problems and how to
that define the fiduciary character of medicine as address them. Integrity prescribes rigor in the
a profession.23 formation of clinical judgment. Clinical judgment is
In medicine, the physician is the patient’s rigorous when it is based on the best available
fiduciary. The physician should be competent and scientific information or, when such information is
use clinical competence as a matter of routine and lacking, consensus clinical judgment and on careful
habit primarily to protect and promote patients’ thought processes of an individual physician that can
 Ethics : An Essential Dimension of Perinatal Medicine 213
withstand peer review. Integrity is thus an antidote The professional virtue of self-sacrifice prohibits
to the pitfalls of bias, subjective clinical impressions, the physician from making the avoidance of such
and unexamined clinical “common sense” that can financial risk the primary consideration. Avoiding
undermine evidence-based practice. Integrity financial risk as one’s primary consideration involves
provides the basis for the physician’s ethical response an ethically pathologic process that leads naturally
to the business tool of control of clinical judgment and quickly to the abandonment of self-effacement
and practice. (economically driven managed care for some patients
None of these four virtues is absolute in its ethical but not for others), compassion (patients’ health-
demands. The task of medical ethics is to identify related concerns do not matter but are only a means
both the application and the limits of these four to maximize revenues), and integrity (the standard
virtues. The concept of legitimate self-interest of care is sacrificed to maximize revenues).
provides the basis for these limits. Legitimate self- Importantly, physicians are not sanctioned by society
interest includes protecting the conditions for to engage in the destruction of medicine as a fiduciary
practicing medicine well, fulfilling obligations to profession, because it is a public trust, not a private
persons in the physician’s life other than the patient, fiefdom.
and protecting activities outside the practice of Physicians should not assume that managed care
medicine that the physician finds deeply fulfilling. organizations (MCOs) are unwilling to negotiate
Managed Care and the Physician as Fiduciary contracts to reduce the severity of economic conflicts
of interest. Physicians should therefore make a good
The fee-for-service practice of medicine uncons-
faith effort to negotiate these matters. If the MCO
trained by fiduciary obligations could and did in the
refuses to negotiate and the economic risk of not
past lead to harm to patients from non-indicated
signing the contract is very significant, then the
over-utilization of resources. It is a violation of the
physician should voluntarily accept the ethical
standard of care to subject patients to unnecessary
responsibility to be alert to and manage these
active intervention in order to achieve personal
conflicts of interest well. First, integrity requires that
economic gain. Managed care unconstrained by
the physician avoid the self-deception of
fiduciary obligations puts patients at risk of harm by
denying access to the standard of care. This will occur underestimating any potential influence on clinical
if patients are subjected to unnecessary risk from judgment and practice by the conflict of interest.
withholding appropriate care and intervention in Second, once these contracts are signed, the
order to achieve reduced cost.23,24 professional virtues add an important dimension to
Financial incentives to the physician and total quality management: diligent monitoring of
supervision of clinician decision making with strict conflicts of interest to prevent them from resulting
controls over utilization are the business tools in substandard care should be among the physician’s
managed care uses. Forms of payment by managed “accountabilities.” Third, the realities of managed
care plans, such as capitation and withhold, care mean that, for the near term at least, increasing
deliberately impose an economic conflict of interest financial sacrifice may be required to protect the
on the physician.25 Every time the physician uses a integrity of medicine as a fiduciary profession.
resource, e.g., consultation, diagnostic testing, or Fourth, in group practice, there should be a fair
surgical procedures, the physician pays an economic sharing of economic self-sacrifice. In particular,
penalty. The ethical challenge occurs when the individual efforts to tune the system to one’s
patient’s interests are subordinated to the pursuit of economic advantage in a group, for example, avoiding
financial rewards and thereby harmed by this the care of high-risk pregnancies, and to the
underutilization. disadvantage of colleagues should be avoided.
214 Textbook of Perinatal Medicine

The second business tool of managed care, There is no conclusive evidence that preserving
increasingly strict control of clinical judgment and medicine as a fiduciary profession is impossible, even
practice, is a heterogeneous phenomenon. Some given the enormous economic power of managed care
managed care plans are poorly capitalized and poorly organizations. Ethics teaches us that business and
managed. They compete by price, with little or no economic power are not absolute and should always
attention given to the quality of their services. A be called to account for their consequences. Society
“bottom line” mentality dominates, with economic has not given MCOs the moral authority or
savings and net revenue maximization the overriding permission to destroy the fiduciary character of
values. These poorly managed companies have little medicine as a consequence of the pursuit of economic
or no understanding of or interest in the fiduciary interest and power. Nor has society given physicians
nature of medicine, and so their controls of clinical moral authority or permission to cooperate willfully
judgment and practice are driven almost entirely by with this destruction. Quite the opposite, society
economic considerations. counts on physicians because ultimately society can
Physicians subject to management controls by such count on no one else to preserve and advocate for
companies face the very difficult challenge of trying the fiduciary character of the medical profession.
to get such companies to constrain their economic
Argument-based Ethics
interests by their fiduciary obligations, a daunting
task but not, we believe, an impossible task. The Before turning to the presentation of a formal tool,26
concerns of ethics, especially to protect the integrity for critically appraising the ethics literature, it is
of the fiduciary enterprise, may frequently be swept important to distinguish descriptive from normative
aside when they are not ignored altogether. medical ethics. The proposed formal tool is designed
However, as the fiduciaries of patients, physicians to be applied to the latter. Descriptive medical ethics
in such managed care organizations are the ultimate uses empirical methods to obtain data that describe
bulwark on which patients and society must be able the actual ethical judgments, practices, and policies
to rely at the present time to protect patients from of physicians and health care organizations, of patient
management’s unbridled pursuit of economic self- and their families, and of the larger society. These
interest. Physicians, therefore, should strenuously articles also report the results of ethically justified
resist and seek to change management controls interventions for their clinical effects. Descriptive
driven solely by economic considerations. Adhering ethics articles use accepted methods of empirical
to evidence-based medicine of perinatal practice research, such as interviews analyzed with
becomes a powerful tool for achieving this goal. If qualitative methods and questionnaire research
physicians refused to cooperate with such poorly analyzed with quantitative methods. 27,28 Such
managed companies, systematic dissociation would empirical studies are common in the medical literature
result in a loss of market share or, more and should be critically appraised using appropriate
optimistically, better management. methodology that has already been well
Being a physician-controlled, managed care described.29-37
organization provides no immunization against the The literature of normative medical ethics is
ethical challenges of the business tools of managed argument-based. It therefore uses the tools of ethical
care. These new physician-owned provider entities analysis and argument to explore the implications of
will not provide a solution in and of themselves to ethical concepts for what clinical practice and
the ethical threats of conflict of interest and control organizational and health care policy ought to be, as
of clinical judgment and practice. The virtue-based we did above with respect to the clinical ethical
arguments we made will apply to these new entities concept of the fetus as a patient. Normative ethics
without exception. scholarship offers reasoned conclusions about what
 Ethics : An Essential Dimension of Perinatal Medicine 215
clinical judgment, decision making, and behavior The importance of the issue should be explained,
ought to be, rather than empirically based which can be theoretical or clinical. The issue may be
descriptions of what these are. important for research or for organizational and
public policy. The importance of the issue should be
Formal Assessment Tool justified. It is important that the article should identify
The new critical appraisal tool presented here is the perspective from which importance of the issue
adapted from recent work on critical appraisal of is claimed, whether that of physicians, scientific
the medical literature reporting the results of investigators, patients, patient’s families and other
qualitative research (Fig. 16.1).26 support networks, payers, health care organization
leadership, and scholars and public officials
1. Does the article address a focused ethics question? concerned with health policy. The target audience
a. Does the article address a clearly stated and focused
ethical issue or problem?
for the article should be made clear.
b. Is the issue important and why?
c. Is justification for the importance presented? Are the Arguments that Support
d. From whose perspective is importance claimed? the Results of the Article Valid?
2. Are the arguments that support the results of the article
valid? This question concerns whether the results of the
a. Is the literature search complete? article, i.e., the conclusions that it draws about what
b. Are the analysis and argument of cited papers morality in medicine ought to be, are supported by
reported clearly and accurately?
c. What is the quality of the paper’s ethical analysis high quality ethical analysis and argument. The
and argument? literature of normative ethics in perinatal medicine
3. What are the results? is now quite extensive, making it increasingly unlikely
a. What are the conclusions of the paper’s ethical that there is no prior relevant literature that should
analysis and argument?
be considered. Relevant literature should be cited
4. Will the results help me in clinical practice?
a. Will the help be practical? and analysis and arguments from this literature
b. Will the help be theoretical? should be presented clearly and accurately. In the
c. How should the reader change his or her thinking, basic and clinical science literature investigators are
attitudes, practices or policies? increasingly expected to elucidate the search
Fig. 16.1: Formal assessment tool. strategies, including key words, databases,
bibliographies, and other sources used. The same
Does the Article Address a
standard should begin to be met by the normative
Focused Ethics Question?
ethics literature. In assessing the search of an article,
Normative ethics articles in perinatal medicine should the critical reader should first ask, how adequate is
have a clear, well-defined focus. This focus should the article’s search strategy? Inasmuch as all are major
be reflected in the title and made explicit in the forms of scholarship in bioethics, are articles, book
introductory section of the paper. There are a number chapters, and books cited?
of possible domains for the focus of normative ethics Is the literature carefully reviewed? By this we
literature, including theoretical issues (such as mean that major positions on the issue should be
whether the fetus is a patient or a person), clinical presented in a clear and unbiased fashion. How these
issues for a specific patient population (the positions have developed and their critical interaction
management of pregnancy in a diabetic patient), should be explained, so that the reader is provided
research issues for a specific population (surgical with a reliable account of the best thinking on the
management of fetal spina bifida), organizational subject. Major positions should be critically appraised
management issues (quality improvement and cost for their strengths and weaknesses and how well
control of IVF services), and public policy issues they have responded to criticisms that advanced
(partial-birth abortion). against them.
216 Textbook of Perinatal Medicine

What is the quality of the paper’s analysis and the reputation of the author(s) or of the journal. Just
argument? Quality turns on both validity and as in the basic and clinical sciences, the standing of
soundness. Validity concerns the formal qualities authors in journals in obstetrics and gynecology or
of ethical analysis and argument. Are relevant in the field of bioethics is no guarantee of quality in
clinical and other facts clearly identified and normative medical ethics.
supported? Are key concepts and ethical appeals
clearly stated and reasonably related to clinical What are the Results?
information? Are these concepts and appeals used The results of normative ethics are the conclusions
with consistent meaning throughout the argument? of ethical analysis and argument. These conclusions
Do the reasons given for the position, the premises should be clearly stated and easy to find in the article.
of the argument, fit together into a coherent whole?
Is the conclusion that follows from those premises Will the Results Help Me in Clinical Practice?
clearly stated? Normative ethics in perinatal
The results of normative ethics articles and books
medicine is not an “ivory tower” enterprise; it
can be helpful in at least three ways. First, they may
concerns issues of vital importance in clinical practice
have important practical implications, especially if
and research and in organizational management and
the paper incorporates evidence to support the
health policy. Physician readers are therefore
clinical utility of acting on the conclusions of the paper.
entitled to expect authors of normative medical
The quality of the empirical evidence cited should
ethics scholarship to take a clinically relevant and
be assessed in the same way as evidence should be
applicable stand that is supported by the argument
assessed in any medical or scientific article.29-37 The
presented.4,41
results for clinical practice, research, organizational
Soundness concerns the substance of the ethical
management, or policy should be assessed as well.
analysis and argument, including especially whether
Second, they may have important theoretical
the conclusion should be regarded as reliable, i.e.,
implications, which do not depend on whether an
one on which the physician can act with confidence
intervention was performed and evaluated.
that patient care will be improved as a result.
Identifying such theoretical implications results in
Reliable arguments are those in which a clear warrant
critical assessment and revision of ethical frameworks
of defense is given for each premise or reason offered
and appeals based on them. Finally, readers of the
in support of the conclusion.
normative ethics literature should ask themselves
In preventing readers’ bias, 42 it is helpful to
identify the disciplines represented among the how they should change their thinking (clinical
authors. The normative medical ethics literature is judgment and reasoning), attitudes (toward patients,
distinctive in that work of high quality by non- their families, and legal institutions), clinical practice,
clinicians should influence the clinical judgment and or organizational policies. This is a crucial step in the
decision making of physicians, just a work on literature on evidence-based medicine and is similarly
infectious diseases of the reproductive tract by crucial here.
microbiologists or on pharmacokinetics of
CONCLUSION
gynecologic cancer chemotherapy by pharmacologists
rightly influences clinical judgment and practice. In this chapter we have provided a general ethical
Normative ethics work, therefore should not be framework for perinatal clinical judgment and
dismissed when only some or even none of the practice. Implementing this framework on a daily
authors are physicians. basis is essential to creating and sustaining a
At the same time, the reader should beware professional physician–patient relationship in
positive or negative bias toward an article, based on perinatal medicine. This framework emphasizes
 Ethics : An Essential Dimension of Perinatal Medicine 217
preventive ethics, i.e., the recognition that the 15. Chervenak FA, McCullough LB. An ethically justified,
clinically comprehensive management strategy for third-
potential for ethical conflict is built into clinical
trimester pregnancies complicated by fetal anomalies.
practice and the use of such clinical tools as informed Obstet Gynecol 1990;75:311-6.
consent and negotiation to prevent such conflict from 16. Chervenak FA, McCullough LB. Campbell S. Is third
occurring. This framework comprehensively appeals trimester abortion justified? Brit J Obstet Gynaecol
1995;102:434-35.
to the ethical principles of beneficence, respect for
17. Chervenak FA, McCullough LB. Campbell S. Third
autonomy, and justice, and the professional virtues trimester abortion: Is compassion enough? Brit J Obstet
of self-effacement, self-sacrifice, compassion, and Gynæcol 1999;106:293-96.
integrity. Finally, a formal tool can now be used to 18. Chervenak FA, McCullough LB. Clinical guides to
preventing ethical conflicts between pregnant
critically evaluate the literature of ethics in perinatal women and their physicians. Am J Obstet Gynecol
medicine. 1990;162:303-307.
19. Chervenak FA, McCullough LB, Rosenwaks Z. Ethical
considerations in newer reproductive technologies.
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1. American College of Obstetricians and Gynecologists. 20. Chervenak FA, McCullough LB, Rosenwaks Z. Ethical
Ethics in Obstetrics and Gynecology. Washington, DC. dimensions of the number of embryos to be transferred
American College of Obstetricians and Gynecologists, in in vitro fertilization. J Assist Reprod Gentet
2002. 2001;18:583-87.
2. Association of Professors of Gynecology and Obstetrics. 21. Sterba JF, Justice. In: Reich WT, ed. Encyclopedia of Bioethics,
Exploring medical-legal issues in Obstetrics and 2nd ed. New York: Macmillan, 1995:1308-15.
Gynecology. Washington, DC. APGO Medical Education 22. Chervenak FA, McCullough LB. Professionalism and
Foundation, 1994. justice in the leadership of academic medical centers. Acad
3. FIGO Committee for the Study of Ethical Aspects of Med 2002;77:45-47.
Human Reproduction. Recommendations of Ethical Issues 23. Chervenak FA, McCullough LB, Chez R. Responding to
in Obstetrics and Gynecology. London. International the ethical challenges posed by the business tools of
Federation of Gynecology and Obstetrics, 1997. managed care in the practice of obstetrics and
4. McCullough LB, Chervenak FA. Ethics in obstetrics and gynecology. Am J Obstet Gynecol 1996;175:524–27.
gynecology. New York: Oxford University Press, 1994. 24. Council on Ethical and Judicial Affairs of the American
5. Engelhardt HT Jr. The foundations of bioethics, 2nd ed. New Medical Association. Ethical issues in managed care. JAMA
York: Oxford University Press, 1995. 1995;273:330–35.
6. Beauchamp TL, Childress JF. Principles of biomedical ethics, 25. Spece RG, Shimm DS, Buchanan AE. ed. Conflicts of
5th ed. New York: Oxford University Press, 2001. Interest in Clinical Practice and Research. New York: Oxford
7. Hippocrates. Oath of Hippocrates. In Temkin O, Temkin CL, University Press, 1996.
eds. Ancient Medicine: Selected Papers of Ludwig Edelstein. 26. McCullough LB, Coverdale JH, Chervenak FA.
Baltimore: Johns Hopkins University Press, 1976:6. Argument-based medical ethics: A formal tool for critically
8. Faden RR, Beauchamp TL. A History and Theory of appraising the normative medical ethics literature. Am J
Informed Consent. New York: Oxford University Press, Obstet Gynecol 2004; 191:1097-1102.
1986. 27. Sulmasy DP, Sugarman J. The many methods of medical
9. Brody H, Bonham VL Jr. Gag rules and trade secrets in ethics (or thirteen ways of looking at a blackbird). In:
managed care contracts: ethical and legal concerns. Arch Sugarman J. Sulmasy DP. eds. Methods in Medical Ethics.
Intern Med 1997;157: 2037-43. Washington, DC: Georgetown University Press, 2001:3-
10. Wear S. Informed Consent: Patient Autonomy and Clinician 18.
Beneficence within Health Care, 2 nd ed. Washington, DC: 28. Sugarman J, Faden R, Weinstein J. A decade of empirical
Georgetown University Press, 1998. research in medical ethics. In: Sugarman J. Sulmasy DP.
11. Callahan S, Callahan D. eds. Abortion: Understanding eds. Methods in Medical Ethics. Washington, DC:
differences. New York: Plenum Press, 1984. Georgetown University Press, 2001:19-28.
12. Annas GJ. Protecting the liberty of pregnant patient. N 29. Oxman AD, Cook DJ. Guyatt GH. Users’ guides to the
Engl J Med 1988;316:1213–1214. medical literature. VI. How to use an overview. JAMA
13. Chervenak FA, McCullough LB. Ethics in obstetrics and 1994;272:1367-71.
gynecology: an overview. Euro J Obstet Gynecol Reprod 30. Guyatt GH. Sackett DL. Cook DJ. Users’ guides to the
Med 1997;75:91-94. medical literature. II. How to use an article about therapy
14. Chervenak FA, McCullough LB. The limits of viability. J or prevention. A. Are the results of the study valid? JAMA
Perinat Med 1997;25:418-20. 1993;270:2598-601.
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31. Guyatt GH, Sackett DL, Cook DJ. Users’ guides to the 36. Drummond MF, Richardson WS, O’Brien BJ, Levine M,
medical literature. II. How to use an article about therapy Heyland D. Users’ guides to the medical literature. XIII.
or prevention. B. What were the results and will they help How to use an article on economic analysis of clinical
me in caring for my patients? JAMA 1994;271:59-63. practice. A. Are the results of the study valid? Evidence-
32. Wilson MC, Hayward RS. Tunis SR. Bass EB. Users’ guides Based Medicine Working Group. JAMA 1997;277:1552-57.
to the medical literature. VIII. How to use clinical practice 37. O’Brien BJ, Heyland D, Richardson WS, Levine M,
guidelines. A. Are the recommendations valid? JAMA Drummond MF. Users’ guides to the medical literature.
1995;274: 570-74. XIII. How to use an article on economic analysis of clinical
33. Wilson MC, Hayward RS, Tunis SR, Bass EB. Users’ guides practice. B. What are the results and how do they help
to the medical literature. VIII. How to use clinical practice me in caring for my patients? Evidence-Based Medicine
guidelines. A. What are the recommendations and will Working Group. JAMA 1997;277: 18027-1806.
they help you in caring for your patients? JAMA 38. Brody BA. Life and Death Decision Making. New York:
1995;274:1630-32. Oxford University Press, 1988.
34. Giacomini MK, Cook DJ. Users’ guides to the medical 39. Brody BA. Taking Issue: Pluralism and Casuistry in
literature. XXIII. Qualitative research in health care. A. Are Bioethics. Washington, DC: Georgetown University Press,
the results of the study valid? Evidence-Based Medicine 2003.
Working Group. JAMA 2000;284:357-62. 40. DeGrazia D, Beauchamp TL. Philosophy. In: Sugarman J,
35. Giacomini MK, Cook DJ. Users’ guides to the medical Sulmasy DP, eds. Methods in Medical Ethics. Washington,
literature. XXIII. Qualitative research in health care. B. DC: Georgetown University Press, 2001:31-46.
What are the results and how do they help me care for 41. Chervenak FA, McCullough LB. What is obstetric ethics?
my patients? Evidence-Based Medicine Working Group. J Perinat Med 1995;23:331-41.
JAMA 2000;284:478-82. 42. Owen R. Reader Bias. JAMA 1982;247:2533-34.
 17
Ethical Committees

Joseph G Schenker

INTRODUCTION exchange views on topics of immediate concern,

unhampered by administrative, political, or other
In the last two decades, ethical issues in medicine
considerations was needed. They are intended
have come to the forefront of public consciousness,
especially for the discussion of the scientific and
with concern focusing on several important areas.
technical bases of advances in biology and medicine
Advances in scientific and technological knowledge
and other related areas and their social, economic,
have created ethical dilemmas about what is right
ethical, administrative, and legal implications forums
and wrong, about life and death issues, as well as
in which scientists and lay people can exchange views
issues of equality, justice and personal preferences.
on topics of immediate concern, unhampered by
Biomedical ethics also raised issues on patients’
administrative, political, or other considerations was
rights, which required steps to be taken to protect
needed.
patient’s welfare and to promote patients’ autonomy.
The range of ethical questions raised by new
Society’s concern for ethical issues in medical
scientific achievements in the life science and methods
practice has led to a growing need for the medical
of taking care of women’s health, especially assisted
profession to become fully aware of the public view
reproduction, have been debated by international
not only on individual patient–physician relation-
political and professional bodies. Within international
ships, but also on how medical developments affect
committees, diverse geographic, ethnic, cultural,
social structure and health policies. Health policy
linguistic, and religious backgrounds are
makers as well must examine the ethical basis of
represented.
decision-making, prioritization, and conflicts of
interest as they influence health care locally, nationally
THE NUREMBERG CODE
and internationally.
Biomedical ethical issues, guidelines, principles The first international code of ethics for research
and regulations cut across national boundaries and involving human subjects—the Nuremberg Code—
often have universal implications. Although cultures was a response to the atrocities committed by Nazi
differ, certain values are common to all. In this research physicians that were revealed at the
context, the most important is respect for human Nuremberg War Crimes Trials. Many of their
dignity, and this should not be negotiable. The experiments had entailed the deliberate killing of,
establishment of international and interdisciplinary or infliction of grievous injuries on, prisoners whose
forums in which scientists and lay people can rights to consent or refuse were ignored. Thus, it
220 Textbook of Perinatal Medicine

was to prevent repetition by physicians of such e. No experiment should be conducted where there
attacks on the rights and welfare of human beings is an a priori reason to believe that death or
that human-research ethics came into being. The disabling injury will occur, except, perhaps, in
Nuremberg Code, issued in 19471 laid down the experiments where the experimental physicians
standards for carrying out human experimentation, also serve as subjects.
emphasizing the subject’s voluntary consent. f. The degree of risk to be taken should never
a. The voluntary consent of the human subject is exceed that determined by the humanitarian
essential. This means that the person involved importance of the problem to be solved by the
should have legal capacity to give consent; should experiment.
be so situated as to be able to exercise free power g. Proper preparations should be made and adequate
of choice without the intervention of any element facilities provided to protect the experimental
of force, fraud, deceit, duress, over-reaching, or subject against even remote possibilities of injury,
other ulterior form of constraint or coercion; and disability, or death.
should have sufficient knowledge and h. The experiment should be conducted only by
comprehension of the elements of the subject scientifically qualified persons. The highest degree
matter involved as to enable him to make an
of skill and care should be required through all
understanding and enlightened decision. This
stages of the experiment of those who conduct or
latter element requires that before the acceptance
engage in the experiment.
of an affirmative decision by the experimental
i. During the course of the experiment, the human
subject there should be made known to him the
subject should be at liberty to bring the
nature, duration, and purpose of the experiment;
experiment to an end if he has reached the physical
the method and means by which it is to be
or mental state where continuation of the
conducted; all inconveniences and hazards
experiment seems to him to be impossible.
reasonably to be expected; and the effects upon
j. During the course of the experiment, the scientist
his health or person that may possibly come from
his participation in the experiment. The duty and in charge must be prepared to terminate the
responsibility for ascertaining the quality of the experiment at any stage if he has probable cause
consent rests upon each individual who initiates, to believe, in the exercise of the good faith,
directs, or engages in the experiment. It is a superior skill, and careful judgment required of
personal duty and responsibility that may not be him, that a continuation of the experiment is likely
delegated to another with impunity. to result in injury or death to the experimental
b. The experiment should be such as to yield fruitful subject. All research involving human subjects
results for the good of society, unprocurable by should be conducted in accordance with three
other methods or means of study, and not basic ethical principles, namely: respect for
random and unnecessary in nature. persons, beneficence, and justice.
c. The experiment should be so designed and based The Nuremberg Code document was criticized
on the results of animal experimentation and because it does not distinguish between different
knowledge of the natural history of the disease types of biomedical experimentation. The Nuremberg
or other problem under study that the anticipated Code makes the subject’s legal capacity to consent a
results will justify the performance of the prerequisite to experimentation, thus excluding from
experiment. participating in research many people who might
d. The experiment should be so conducted as to benefit from the results obtained, including children,
avoid all unnecessary physical and mental the mentally ill, and others who are unable to give
suffering and injury. legal consent.
 Ethics : An Essential Dimension of Perinatal Medicine 221
UNESCO - THE UNITED NATIONS has set technical standards and proposed guidelines
EDUCATIONAL, SCIENTIFIC AND and codes of good practice in virtually all its fields
CULTURAL ORGANIZATION of activity, including the widely publicized areas of
organ transplantation, breast-milk substitutes,
The United Nations Educational, Scientific and
essential drugs, the marketing of pharmaceuticals,
Cultural Organization (UNESCO) was established on
and, more recently, reproductive health, environ-
November 16, 1945.2 The main objective of UNESCO
mental health, and emerging diseases. The WHO also
is to contribute to peace and security in the world
contributes to harmonizing legislation and
by promoting collaboration among nations through
terminology and fosters the dissemination and
education, science, culture, and communication to
exchange of information on these subjects. Ethics
further universal respect for justice, for the rule of
continues to provide the basis for the WHO’s
law, and for the human rights and fundamental
activities and functions. Several WHO programs have
freedoms that are affirmed for the peoples of the
their own ethical review committees; additional
world without distinction of race, sex, language, or
activities are carried by consultation on ethics and
religion. At the international level, UNESCO has been
health at global level.
one of the principal promoters of the reflection on
ethics of living. In 1993, UNESCO created the
THE DECLARATION OF HELSINKI
International Bioethics Committee (IBC). The IBC 3
is a forum for debate and reflection and for the The Declaration of Helsinki, promulgated in 1964 by
elaboration of UNESCO’s normative actions, the World Medical Association, is the fundamental
particularly with regard to the implementation of document in the field of ethics in biomedical research
the Universal Declaration on the Human Genome and has had considerable influence on the
and Human Rights. It is up to the IBC to keep up formulation of international, regional, and national
with progress in genetics while taking care to ensure legislation and codes of conduct. The Declaration,
respect for the values of human dignity and freedom revised in Tokyo in 1975, in Venice in 1983, and again
in view of the potential risks of irresponsible in Hong Kong in 1989, 5 is a comprehensive
attitudes in biomedical research. The IBC has drafted international statement of the ethics of research
statutes and published reports on the ethical aspects involving human subjects. It is the mission of the
of human embryonic stem cell research and its use physician to safeguard the health of the people. The
in therapeutic research; ethical issues on genetic physician’s knowledge and conscience are dedicated
screening and the testing, treatment, storage, and to the fulfillment of this mission. Medical progress
use of genetic data on genetic screening; and human is based on research that ultimately must rest in part
gene therapy. on experimentation involving human subjects. In
current medical practice, most diagnostic,
WHO – WORLD HEALTH ORGANIZATION therapeutic, or prophylactic procedures involve
The Health Organization of the League of Nations hazards.
was set up in Geneva in 1919. In 1945, the United The purpose of biomedical research involving
Nations Conference on International Organization human subjects must be to improve diagnostic,
established a new, autonomous, international health therapeutic, and prophylactic procedures and the
organization – the World Health Organization understanding of the etiology and pathogenesis of
(WHO). The objective of the WHO is the attainment disease. In the field of biomedical research, a
by all peoples of the highest possible level of health.4 fundamental distinction must be recognized between
The WHO’s constitution affirms fundamental medical research in which the aim is essentially
ethical principles, such as the equality of rights and diagnostic or therapeutic for a patient and medical
the unalienable dignity of all human beings. The WHO research, the essential object of which is purely
222 Textbook of Perinatal Medicine

scientific and without implying direct diagnostic or The spirit of the Declaration of Helsinki is that,
therapeutic value to the person subjected to the in medical research, the interests of science and
research. society should never take precedence over
In 1992, International Ethical Guidelines for considerations related to the well-being of the
Biomedical Research Involving Human Subjects were subject. Only a minimal level of risk may be allowed
introduced by The Council for International for volunteers to subject themselves for the benefit
Organizations of Medical Sciences and WHO based of others. However, it remains a problem to decide
on ethical principles.6 All research involving human what sorts of levels of risk are acceptable in the case
subjects should be conducted in accordance with three of pregnant women and where the subjects of non-
basic ethical principles: respect for persons, therapeutic research are not autonomous (e.g,
beneficence, and justice. Respect for persons premature and newborn babies).
incorporates at least two fundamental ethical It is generally accepted that pregnant and nursing
considerations: women are not suitable subjects of clinical trials other
i. respect for autonomy, which requires that those than those that are designed to respond to the health
who are capable of deliberation about their needs of such women or their fetuses or nursing
personal choices should be treated with respect infants. Clinical trials for conditions associated with
for their capacity for self-determination; and or aggravated by pregnancy and to test the safety
ii. protection of persons with impaired or diminished and efficacy of drugs, methods, and devices for
autonomy, which requires that those who are detecting fetal abnormalities and well-being are of
dependent or vulnerable be afforded security primary importance in the medical field of
against harm or abuse. perinatology. The justification for the participation
For all biomedical and clinical research involving of pregnant women in clinical trials is that they
human subjects, the investigator must obtain the should not be deprived arbitrarily of the opportunity
informed consent of the prospective subject. Informed to benefit from investigational drugs, vaccines, or
consent is based on the principle that competent other agents that promise therapeutic or preventive
individuals are entitled to choose freely whether to benefit. In all cases, risks to pregnant women, fetuses,
participate in research. Informed consent protects the and newborns should be minimized, as far as sound
individual’s freedom of choice and respects the research design permits. As a general rule, pregnant
individual’s autonomy. In the case of an individual or nursing women should not be the subjects of
who is not capable of giving informed consent (eg, clinical trials except when such trials as are designed
a fetus, a newborn, or a small child), the proxy to protect or advance the health of pregnant or
consent of a properly authorized representative nursing women or fetuses or nursing infants and for
should be obtained. In all human research, ethical which women who are not pregnant or nursing
guidelines have differentiated between beneficial would not be suitable subjects. Such research may
(therapeutic) and non-beneficial (non-therapeutic) have a differential impact on the pregnant woman
research. The therapeutic research subject stands to and the fetus, with one benefiting while the other
gain as much from the research, whether it be a does not. At the extreme, the research that is
procedure or a drug, as to lose from it. In the non- beneficial to the one may actually be harmful to the
therapeutic research, the subject cannot possibly other.
benefit himself, and any benefits can therefore only Some therapeutic research on fetuses in-utero
add to others. The risks of a non-beneficial research must be allowed. It contributes to the discovery of
fall solely on the research subject, whereas the new methods for treating fetal health problems.
benefits may extend beyond the research subject to There is a consensus that research on fetuses in-utero
the population as a whole. should be treated as human subjects research, and
 Ethics : An Essential Dimension of Perinatal Medicine 223
governed by the policies for human subjects research. research, whereas in the British guidelines there is
Because fetuses in-utero and pregnant women are no such specific provision. In Britain it is proposed
linked to each other, research on one may affect the that non-beneficial research is to be done on the fetus
other. Such research may have a differential impact in utero or the viable fetus, whereas in United States
on the pregnant woman and the fetus, with one it may be done if there is minimal risk.
benefiting while the other does not, and may be
harmful to the other. The fundamental COUNCIL OF EUROPE
presupposition of all ethical policies is that the In 1985, the Council of Europe created a
independent review process for human subjects multidisciplinary body with experts appointed by
research must consider the interests and rights of each member country. This committee has already
both parties in reviewing research protocols. Most produced documents on reproduction research on
guidelines have also imposed additional human subjects, prenatal diagnosis and screening,
requirements on the acceptable level of risk to the and genetic testing. Once the Committee of Ministers
fetuses involved in the research protocol. It is approves these documents, they become
assumed that fetuses have some moral standing so recommendations for the national parliaments, which
that some concern must be devoted to their interests may or may not decide to follow them. The European
and rights. assembly and other committees have also issued
Sir John Peel’s report, published in 1972, 7 reports related to bioethical problems. The Council
presented governmental guidelines concerning the of Europe, which represents all the democratic
ethics of fetal research. The recommendations were countries of Europe, has organized a European
as follows: Convention on Bioethics. The Committee published
• Viable fetuses should not be subjected to non- protocols regarding human experiments and organ
beneficial research. transplantation.9
• Research is permitted on the whole alive previable
fetus, dead fetus, or its organs. FIGO COMMITTEE FOR THE
• Dead fetuses or tissues may be used in accordance STUDY OF ETHICAL ASPECTS
with the provisions of the Human Tissue Act, OF HUMAN REPRODUCTION
which governs the postmortem use of human In 1985, the FIGO Committee for the Study of Ethical
tissue. Aspects of Human Reproduction was established.10
• Parental informed consent should be obtained. Its main objectives were the recording and study of
• The validity of the research should be assured. general ethical problems emanating from the research
The National Commission for the Protection of and practice of human reproductive medicine, with
Human Subjects in Biomedical and Behavioral the aim of providing guidelines to the attention of
Research was established in July 19748 and issued its physicians and the public in developed and
recommendations. The guidelines have certain things developing countries
in common the British guidelines but differ on some From its inception this committee was not
grounds. They have in common that dead fetuses intended to solve these ethical dilemmas, but rather
and their tissues are to be afforded the respect of to raise discussion by suggesting perspectives that
other dead human bodies and tissues. Fetuses with this group of health professionals, lawyers, and
a chance of survival are to be treated like children. ethicists came to in carefully crafted analysis and
Willful damage to the fetus in- utero may not be debate over these issues. Given the rich field of
caused, presumably lest a mother change her mind ethical issues in women’s health that derive from not
about abortion. Significant differences are that in the only the reproductive life cycle, but the economic
United States, regulations fathers can veto the and political status of women internationally – this
224 Textbook of Perinatal Medicine

committee will always confront new issues and even support their advocacy for improvements in the
new aspects of old issues that challenge ethical health and status of women internationally. In the
perspectives and practice. There are continual face of rapid cultural and scientific change, this is a
variations on themes the committee has raised in the critical role of ever-greater need. Women are clearly
past through new medical developments. The social vulnerable in countries where their health care rights
status of women, the constraints on health care are either non-existent or threatened, and thus, these
dollars, and the health status of women have also guidelines can be a powerful force to support the
increased the need for the committee to address the rights of women.
broader set of rights and economic issues that The work of the Committee: In its first Congress
directly influence the health of women and the ethical as a standing committee, the Ethics Committee
setting of their care. presented three seminars: medical ethics and
The committee was composed of a range of medically assisted reproduction, AIDS with emphasis
international members who represented developing on ethical aspects, and refusal of obstetrical care
and developed countries and had a significant interest (maternal health, fetal health, and neonatal health),
and expertise in medical ethics. The members of the which were published in the proceedings of the Rio
FIGO Committee are obstetricians, gynecologists, Congress.
oncologists, lawyers, and public health workers, all The early focus of the Committee, from 1985 to
of whom represent diverse geographic, ethnic, 1991, was clearly in areas central to obstetrics and
cultural, linguistic, and religious backgrounds. gynecology practice, with a focus on such areas as
Among the 14 members, 13 were chairs of leading sterilization, research on pre-embryo, and elective
obstetric and gynecologic departments. reduction of multiple pregnancies. In that same time
The initial task of the FIGO Committee for the period, however, the committee began to explore
Study of Ethical Aspects of Human Reproduction was what the ethical responsibilities of societies of
to identify and study the important ethical problems gynecology and obstetrics were for the broader issues
confronting health care practitioners in human of provision of reproductive health care and women’s
reproduction. The identified ethical problems were health in general. This led to a seminar during the
to be brought to the attention of physicians and the FIGO Singapore Congress focusing on issues such
public in the developed and developing countries to as:
provide ethical guidelines where appropriate. This • How much are mothers worth?
task has assumed greater importance with the • Distribution of resources between primary and
continuing challenge of ensuring that women are tertiary reproductive care
granted human and reproductive rights worldwide. • Availability of resources for newborn care
Furthermore, the complexity of incorporating the • Macro-ethical issues in obstetrics and gynecology
many ethical aspects of reproductive issues in This key seminar was chaired by Profs. Sureau and
differing societies for issues such as cloning, or Schenker, and marked an important expansion of the
patenting of the human genome, argue for the need thinking of the Committee beyond that of the
for such a consensus body. common bioethical analysis of the time, which
There is no other body internationally that focused on principals such as benefit (beneficence),
confronts these issues with a view towards the harm (maleficence), and patient autonomy in the area
impact on the health care of women. Because of this, of human rights and justice. During this time, the
the opinions of the committee are used by women’s Committee also began to align its meetings with
health practitioners internationally to assist them in regional meetings that paralleled the focus of the
setting national or local standards, to expand the committee on ethical aspects of human reproduction.
depth of discussion of these issues locally, and to The first of these took place in Cairo in 1991 and
 Ethics : An Essential Dimension of Perinatal Medicine 225
focused on bioethics in human reproduction research discussed and provided guidelines on general issues
in the Muslim World. The committee meeting in women’s health and advocacy, issues on genetics,
foreshadowed an area of ongoing controversy in embryo research, contraception, abortion, and
medicine – that of transplantation. At that time the reproductive endocrinology issues regarding
group considered whether research on pre-embryos pregnancy, maternal-fetal health, and neonates. The
was required in order to broaden our knowledge of first bound publication of the collated Issues and
the developmental process, to improve the treatment Guidelines appeared in 1994, 1997, and 2000, and by
of infertility and the control of reproduction, and to 2003 had grown to a body of work that encompassed
permit genetic screening with its potential for the such that with the translations into Spanish and
prevention and treatment of birth defects. The French, covers 232 pages.11
Committee recognized and tried to incorporate the The method of analysis adopted by the committee
diverse spectrum of ethical, cultural, and religious evolved early on and consisted of position papers
values regarding the status of the pre-embryo. on a topic identified by the committee that were
However, agreement was reached on some key areas circulated prior to committee meetings in the working
even with these divergent views: language of the committee, English.
a. First, research on pre-embryos was only ethically These research papers explicated the problem, the
acceptable when its purpose is for the benefit of present status of knowledge, and the various ethical
human health and only if animal models would stances or issues that were identified in the literature.
not suffice. At times, the committee invited outside experts in
b. The Committee felt that no developing human areas where there was not felt to be adequate depth
pre-embryo might be kept alive beyond 14 days of expertise or where there were other FIGO
after fertilization (not including any time during Committees working on the medical or rights aspects
which the embryo had been frozen). of the same issue. The papers were presented at the
c. Research projects on pre-embryos should be meeting and a consensus about the important
authorized by ethical and /or other appropriate background and ethical issues was identified.
bodies in the country and, if allowed, appropriate Depending on the issues, further work on
informed consent must be obtained before synthesizing these into a set of reflections or
undertaking research on pre-embryos, normally guidelines might take place at the meeting or over
both gamete donors. Furthermore, provision of several meetings, until every word of each document
gametes and pre-embryos should not be subject was reviewed, read, and revised by all the members
of commercial profit. of the committee. Proposed statements were read
d. The Committee was unable to reach a consensus line by line and edited by the entire committee to
as to whether research should be limited to assure that not only the content was acceptable to
surplus pre-embryos or should also include the committee, but that the translations to French
preembryos specifically generated for research, and Spanish would not contain errors because of the
a debate that continues worldwide. The discussion likely translation from English.
over this issue established the precedent that The committee statements, opinion are
committee statements required consensus, and independent from FIGO member societies or
where that was not possible, debates were either executive board. The documents represent the result
not included or included with the caveat that there of that carefully researched and considered
was no consensus. discussion. This independence has been particularly
The deliberations are made public through helpful to FIGO in providing ethical guidance
committee statements published in scientific journals regarding the relationship of the federation to
and in specific reports. The FIGO Committee has industry, initially formulated as internal ‘Guidelines
226 Textbook of Perinatal Medicine

for Relations between Industry and FIGO’ in 1991. have issued reports on ethical and legal aspects,
The committee collaborates with international especially in the fields of perinatal care, assisted
organizations – such as the World Health reproduction technologies, and human experimen-
Organization – on various aspects of women’s health tation. Scientific progress is ahead of what society is
to ensure that the ethical aspects are fully covered. willing to accept, and the reports of the bioethical
The committee members represent a wide committees protect the public by monitoring and,
spectrum of religions and countries, and numerous when necessary, regulating scientific practice. There
members have co-coordinated with multiple is no single solution to a moral problem. A committee
international committees to encourage and ensure must incorporate a number of different moral ideals
inclusion of these ethical aspects in regular and and reach a workable compromise. The law that these
extraordinary meetings. committees create must be in step with moral beliefs,
or it will not be implemented. It is the task of the
WAPM – WORLD ASSOCIATION ethics committee to try to produce some consensus,
OF PERINATAL MEDICINE based on all considerations, and to recommend it
In 1999, the World Association of Perinatal Medicine for practice. Several problems arise in the setup of
established an Ethical Committee. The main the committees. Who should make moral decisions
objectives of the committee are:12 in controversial public issues? How is the committee’s
• To study the ethical problems that emanate from membership to be determined? In a pluralistic, mainly
practice and research in perinatal medicine secular society there are no moral experts per se.
• To provide guidelines for the practice of obstetrics Committees who serve public morality must conform
and neonatology to certain specifications of expertise. The committee
• To bring the ethical issues to the attention of members must be capable of understanding the
physicians, nurses, paramedical staff, and the scientific background of the subject matter of the
public issue. They must be acquainted with moral
philosophy and understand the nature of ethics. The
NATIONAL ETHICS COMMITTEES members must be intelligent and creative and not
National ethics committees are set up by dogmatic. It is imperative that people who hold
governments to advise on regulations or proposed particular moral or religious views that make them
legislation concerning moral bioethical programs that impervious to the language of consensus are not
raise controversy among professionals and the public. included in the committee’s team. They may be
National committees were originally created due to incapable of sympathy and flexibility and thus not
an increasing demand among doctors and researchers be of use. The members must also be readily available
for some authoritative guidance as to what was to perform this extremely time-consuming task. One
permissible in issues where no law exists. The nature major disadvantage of these committees is that
of the membership of such committees is of even sometimes the advent of new technologies is ahead
greater importance. The chairman must be unrelated of committee deliberations. If a previous committee
to the medical or research profession. The members decision was opposed to specific new advances, their
of national ethics committees must represent a broad use may be delayed until the committee changes its
range of values and professional expertise in the original decision. It is imperative that people who
fields of medicine, law, administration, media, hold particular moral or religious views that make
economics, public policy, and moral philosophy. them impervious to the language of consensus are
Within committees dealing with reproductive health, not included in the committee’s team. In most
for example, at least 50% of the members must be western countries, committees are set up ad hoc to
women. Governmental or non-governmental bodies address specific subjects of public bioethical concern.
 Ethics : An Essential Dimension of Perinatal Medicine 227
The Warnock Committee on Human Fertilization and concern, unhampered by administrative, political, or
Embryology (1984) had a great influence on other considerations, was needed. They are intended
subsequent legislation in the United Kingdom.13 In especially for the discussion of the scientific and
the United States, legislation that seems to reinforce technical bases of advances in biology and medicine
ethical conduct may actually replace the exercise of and other related areas and their social, economic,
ethical judgment with unreflective obedience to law. ethical, administrative, and legal implications.
They may be incapable of sympathy and flexibility. Commissions appointed by institutions, governm-
The Belmont Report (1979) identified the basic ethical ents, and international bodies serve to alleviate the
principles that should emphasize the conduct of medical profession from making ethical decisions and
biomedical and behavioral research involving human to protect human subjects from any harm. The
subjects and developed guidelines that should be deliberations of these committees are usually
followed to assure that such research is conducted followed by guidelines of operation, which in many
in accordance with those principles.14 The guidelines cases have become abiding law. For these committees
provided by national committees are usually to be of full advantage, they must convene promptly
converted into laws by legislation that introduces as issues arise so as not to delay medical advances
criminal punishment for violation. Legislation that from being implemented.
seems to reinforce ethical conduct may actually
REFERENCES
replace the exercise of ethical judgment with
unreflective obedience to law. The experience of 1. The Nuremberg Code. In: Anna GJ, Grodin MA, eds. The
Nazi doctors and the Nuremberg Code: human rights in human
Assisted Reproductive Technology (ART) practice experimentation. New York: Oxford University Press 1992.
demonstrated that countries with voluntary 2. Constitution. London: UNESCO 1945.
guidelines seem to enjoy public confidence, and public 3. International Bioethics Committee. Statutes of the
International Bioethics Committee. London: UNESCO
pressure for a change seems minimal. Countries with 1998.
legislative surveillance seem to agree that it works 4.. WHO. From small beginnings. World Health Forum. 1988;
well, although there are understandable complaints 9:29-34.
about the slowness of the legislative process and the 5. World Medical Association. Declaration of Helsinki. In:
Anna GJ, Grodin MA, eds. The Nazi doctors and the
difficulty of having regulations changed once they Nuremberg Code: human rights in human experimentation.
are in place, and thus, not be of use. New York: Oxford University Press 1992:311-343.
6. International ethical guidelines for biomedical research
involving human subjects. In: Bankowski Z, Levine RJ,
CONCLUSION eds. Proceedings of the 26th CIOMS Conference, Geneva,
The range of ethical questions raised by new scientific Switzerland 5-7 February 1992. Geneva: CIOMS 1993:1-36.
7. Department of Health and Social Security, Scottish Home
achievements in the life science, and methods of and Health Department, Welsh Office. The use of fetuses
taking care of women’s health especially, has been and fetal material for research: report of the advisory group.
debated by international political and professional London: Her Majesty’s Stationery Office 1972.
8. US Department of Health, Education, and Welfare, Office
bodies. Biomedical ethical issues, guidelines,
of the Secretary. Protection of human subjects: proposed
principles, and regulations cut across national amendments concerning fetuses, pregnant women, and
boundaries and often have universal implications. in vitro fertilization. Federal Register 42, no. 9. January
Although cultures differ, certain values are common 13, 1977. p. 2792–93.
9. The Council of Europe. Principles concerning medical
to all. In this context, the most important value is research on human beings. WHO Int Digest Health
respect for human dignity, and this should not be Legislation. 1990; 41:3-6.
negotiable. The establishment of international and 10. Schenker JG, ed. Recommendations on ethical issues in
obstetrics and gynecology by the FIGO Committee for the Study
interdisciplinary forums in which scientists and lay of Ethical Aspects of Human Reproduction. London: FIGO
people can exchange views on topics of immediate 1994;11: 7-8.
228 Textbook of Perinatal Medicine

11. Recommendations on ethical issues in obstetrics and 13. Warnock DM. Report of the Committee of Inquiry into Human
gynecology by the FIGO Committee for the Study of Fertilization and Embryology. London: HMSO 1984.
Ethical Aspects of Human Reproduction. London: FIGO, 14. National Commission for the Protection of Human
1994, 1997, 2000, 2003. Subjects of Biomedical and Behavioral Research. The
12. Schenker JG. Report from the Ethical Committee of the Belmont Report: ethical principles and guidelines for the
World Association of Perinatal Medicine. J Perinat Med. protection of human subjects of research. United States: Office
2000;28:3-6. for Protection from Research Risks 1979:1-8.
 18
Education in Perinatal Ethics

Gordon M Stirrat

INTRODUCTION The 21st century will bring further advances in

what can be done, but the prevailing ethical climate
Amazing advances, in for example, genetics,
suggests that there will continue to be much less
reproductive technologies, and perinatal medicine,
critical consideration of what “ought” to be done.
occurred in the latter part of the 20 th century. As
How then can we as individuals and as a community
Radcliffe-Richards 1 has said “Science keeps on
of physicians reduce the risk of Radcliffe-Richards’s
throwing up new situations which, in some ways
“strains and cracks” from causing the edifice of our
resemble familiar ones but in others are utterly unlike professional practice from crumbling around us? If
them; and we try to solve the resulting problems by you ask an architect, builder or constructional
stretching our old familiar categories to fit, but with engineer that question their answer will be “Get the
ever increasing strains and cracks appearing foundations right!”3 Would it not, therefore, seem
everywhere.” Those of us who practice Perinatal prudent that those training to be perinatal physicians
Medicine are required to consider a wide range of be properly grounded in the theories and principles
ethical questions, sometimes on a daily basis. Some behind the increasingly complex ethical decisions in
of them relate to our specialty while others are which they will inevitably be closely involved in their
generic (e.g. consent, confidentiality, and resource subsequent career?
allocation). The problems can be complex and true This chapter is based on several fundamental
dilemmas where the choices are between equally premises:
undesirable alternatives. Over 30 years ago, 1. Each one of us is required to think ethically and
Campbell2 wrote, “moral dilemmas will continue to act morally (i.e., we are all “moral agents”). This
occur in medicine as long as choices have to be made is not an optional extra.
which involve putting one set of values against 2. Ethics is about individuals living and working in
another.” Unfortunately ready-made answers cannot community.4 It is not just about “me” and “mine.”
be found in textbooks (not even this one!), because As Campbell5 states “there can be no possibility
the situations in which the problems arise and the of freedom for any one individual if that person
stories of the people involved are all different from acts without reference to all other moral agents.”
any other. The desired goals may also be different. 3. Medical ethics is not solely a matter of moral
For example, the prevention of disease and health theory: it is “an ethics of relation and practice.”4
promotion tends to raise different issues and require Thus ethsics is for something and must be
different solutions than the relief of symptoms, pain translatable into moral action. It has to work in
and suffering, or the cure of disease. real life.
230 Textbook of Perinatal Medicine

4. The dominant individualistic version of 6. Ethics is a necessary part of good clinical practice.
autonomous choice is fundamentally (and, in the Ethical judgments must take full account of all
long-run, potentially fatally) flawed.6,7 Stirrat and the circumstances of the case and be based on
Gill,7 among others, have suggested a principled sound principles. Decisions must be consistent,
version of patient autonomy that involves the free from contradiction, and clinically relevant.
provision of sufficient and understandable Exercise by physicians of their clinical judgment
information and space for a patient, who has the is frequently attacked as paternalism. While, in
capacity to make a settled choice about medical some instances, this can be so, it may also be the
interventions on herself and to do so responsibly doctor fulfilling his or her duty to the patient by
in a manner considerate to others. A lifetime in exercising his or her own autonomy, and as such,
clinical practice strongly suggests that this model may be entirely justified. Indeed, there will be
best fits the optimal patient/doctor relationship some occasions, particularly in perinatal medicine,
in which there is a mutual, unspoken agreement in which acquiescence to a requested intervention
between the parties that recognizes the duties and against one’s clinical or ethical judgment will be
obligations each to the other with bilateral trust abrogation of one’s duty as a doctor!
at the heart of this relationship. This is discussed 7. The patient-physician covenant relationship
further below. depends totally on the trust of the former that
5. The discipline of Medical Ethics is not qualitatively the latter will act at all times with the highest
different from ethics in general. The fundamental ethical standards. Indeed, not only is trust “the
ethical principles underpinning medical practice fundamental virtue at the heart of being a good
should be shared by society in general. However, doctor,” it also allows us all to function socially
by virtue of being a profession, we clearly have as individuals in a complex society,11 and “every
special obligations to the patients we serve. In genuine moral community is built on the trust that
the United Kingdom the “Duties of a Doctor” are its members will look beyond personal interests
clearly laid down by the General Medical Council and individual concerns towards a truly common
(GMC)8 whose primary roles are “To protect the good.”12 The words “trust” or “trustworthy” can
public by setting standards for professional be found on several occasions in the GMC’s
practice, overseeing medical education, keeping
“Duties of a Doctor” (Table 18.1) and it is implicit
a register of qualified doctors and taking action
in the AMA’s Code of Ethics ( Table 18.2).
when a doctor’s fitness to practice is in doubt.”
(Among other authors, Draper and Sorell10 argue
Table 18.1 outlines the duties of a doctor as set
that the patient has reciprocal duties but it is not
down by the GMC.8
appropriate to discuss this further here.)
The Code of Medical Ethics of the American
Medical Association (AMA)9 states, “a physician
THE BASIS FOR ETHICS
must recognize responsibility not only to patients,
but also to society, to other health professionals, Since at least the time of Socrates (470-399BC) people
and to self.” The two main items on the agenda have asked questions like, “How do we know what
of the first meeting of the Association in 1847 is good?” “How should I live?” “How can we know
were the establishment of a code of ethics and which decision is right?” and “What is justice?” Ethics
the creation of minimum requirements for medical or moral philosophy addresses these fundamental
education and training. Table 18.2 shows the questions in order to establish a basis for moral
Principles adopted by the AMA as “standards of judgments. Morals are the specific judgments, codes,
conduct which define the essentials of honorable or beliefs of particular groups or societies and the
behavior for the physician.” actions that follow from these.
 Education in Perinatal Ethics 231
Table 18.1: Duties of a Doctor (UK General Medical Council)7

“Patients must be able to trust doctors with their lives and well-being. To justify that trust, we as a profession have a duty
to maintain a good standard of practice and care and to show respect for human life.”
As a doctor you must:
• Make the care of your patient your first concern. • Recognize the limits of your professional competence.
• Treat every patient politely and considerately. • Be honest and trustworthy.
• Respect patients’ dignity and privacy. • Respect and protect confidential information.
• Listen to patients and respect their views. • Make sure that your personal beliefs do not prejudice
your patients’ care. Act quickly to protect patients from
• Give patients information in a way they can risk if you have good reason to believe that you or a
understand. colleague may not be fit to practice.
• Respect the rights of patients to be fully informed • Avoid abusing your position as a doctor.
in decisions about their care. • Work with colleagues in the ways that best serve
• Keep your professional knowledge up to date. patients’ interests.

In all these matters you must never discriminate unfairly against your patients or colleagues. And you must always be
prepared to justify your actions to them.

Table 18.2 : American Medical Association Principles of Medical Ethics8

The medical profession has long subscribed to a body of ethical statements developed primarily for the benefit of the
patient. As a member of this profession, a physician must recognize responsibility not only to patients, but also to society,
to other health professionals, and to self. The following Principles adopted by the American Medical Association are not
laws, but standards of conduct which define the essentials of honorable behavior for the physician.
I. A physician shall be dedicated to providing competent medical service with compassion and respect for human dignity.
II. A physician shall deal honestly with patients and colleagues, and strive to expose those physicians deficient in character
or competence, or who engage in fraud or deception.
III. A physician shall respect the law and also recognize a responsibility to seek changes in those requirements which
are contrary to the best interests of the patient.
IV. A physician shall respect the rights of patients, of colleagues, and of other health professionals, and shall safeguard
patient confidences within the constraints of the law.
V. A physician shall continue to study, apply and advance scientific knowledge, make relevant information available to
patients, colleagues, and the public, obtain consultation, and use the talents of other health professionals when indicated.
VI. A physician shall, in the provision of appropriate patient care, except in emergencies, be free to choose whom to
serve, with whom to associate, and the environment in which to provide medical services.
VII. A physician shall recognize a responsibility to participate in activities contributing to an improved community.

The relationship between ethics and morals has “neoplastic” and may become malignant, ultimately
been compared to that between DNA and cell causing the demise of the body. What this might
proteins. 13 Within the DNA (ethics) lies the suggest about the long-term consequences of the
fundamental information for the cell to function. The dominance of the primacy of the individual – “I,”
proteins (morals) produced by the cell interpreting “me,” and “mine” – in today’s society is among the
and following that information do two things – they factors that leads to my concern about the potentially
express both the nature and character of the cell and fatal flaw in this view of autonomy.
also perform its specific function. In addition, cells
must work together within and among bodily DIVERSITY OF MORAL THEORY
structures and organs. The cell that expresses its In 1972 Campbell [2] wrote, “The essence of morality
individuality at the expense of its neighbors is is that there is uncertainty.” As a young obstetrician
232 Textbook of Perinatal Medicine

wrestling with a whole series of ethical dilemmas at into consideration as the passage from moral question
that time, I found this very threatening. I was like to moral answer is navigated.”
Montaigne who said, “Tell me of your certainties; I It is, perhaps, not only inevitable, but also
have doubts enough of my own.” Indeed, I venture appropriate that a multiplicity of theoretical
to suggest that we all find uncertainty difficult to approaches to ethics should have arisen. Campbell
deal with. We would much prefer “meanings that has suggested, “The diversity of ethical theories is
are completely clear” and “truths that are completely about as wide as the diversity of ways of
certain.”14 Campbell2 stated, “Many people seek to understanding the relationship between man and his
handle situations of uncertainty by elevating their environment.”2
personal convictions to the status of inherent and The first of the two main theories is deontology or
all-embracing rules, which must apply to every “duties in action.” The best example is found in the
situation, whatever its complexities and ambiguities. writing of the philosopher Immanuel Kant in the 18th
Others try to reduce all moral dilemmas to questions century. The essence of Kant’s ethics is:
of technical skill.” He considered that both of these • Certain kinds of acts are intrinsically right and
reactions were commonly found among physicians others intrinsically wrong determined by a set of
and nurses, “many of whom may feel that there is rules.
little to be argued about in medical ethics, either • The rules must be universally applicable, coherent
(i.e., not contradictory) within what Kant called
because they do not themselves see any moral
“a rational system of nature” and capable of being
ambiguities in their professional practice or because
freely adopted by “a community of rational
they consider all the decisions taken to be purely
beings.”
matters of clinical judgment.” Personal experience
• Among the rules are “do not kill, cause pain,
suggests that, although such individuals still exist,
disable, deprive of freedom or pleasure;” and “do
the vast majority of health care professionals are
not deceive, break promises, cheat, break laws,
anxious to learn how to make more reflective and
or neglect one’s duty.”
consistent ethical judgments in the face of the
• Each of us has a set of duties to our fellow men
problems that they face day by day.
and women. One of the most important duties is
Of course, “moral philosophy does not attempt
to “act so that you treat humanity, whether in
to ‘solve’ moral dilemmas.”2 Rather, “it attempts to
your own person or in that of any other, always
provide a rational framework for understanding the as an end, and never as a means only.” It is this
complexities of moral judgment.”2 It is entirely maxim that has, for example, contributed to
appropriate that we try to make sense out of concerns about so-called “savior sibling”
uncertainty, and we do so by classification and procedures in which a child is conceived with the
codification of what we think we know. We need primary intention of being a source of compatible
frameworks as reference points to allow us to tissue for a seriously ill sibling.
progress through our lives as individuals in society, • An action should not be judged to have been right
much as a ship traveling across the ocean. Indeed, or wrong by its consequences in individual
Jonsen 15 suggests that “moral principles are not situations.
unlike the sky-marks used in celestial navigation: a No theory is without problems, and the main
position is determined and a course marked by difficulties with this theory are defining the meaning
continual reference to fixed points – sun, stars, and of “rational” and agreeing on universally applicable
planets. At the same time the navigator must look rules.
not only to the sky-marks but also to any visible The second main theory, developed in the 19th
landmarks and to the wind and waves. Thus while century by Jeremy Bentham and John Stuart Mill, is
principles provide an indispensable general guiding consequentialism, in which the rightness or wrongness
direction, other features of the problem must be taken of an action is based solely on consequences.16 They
 Education in Perinatal Ethics 233
named their theory Utilitarianism, and argued that Critics say, with some justification, that these are
the maximization of pleasure or happiness was what merely a checklist without an underlying theory, are
made acts right. This has been summarized as “The often in conflict with one another (with no internal
greatest happiness of the greatest number.” resolution), and do not deal with emotional aspects
Consequentialist theories can be further divided – or relationships. In particular, as has already been
act consequentialism states that the right action is the noted, the concept of autonomy is widely
one that produces the most good. In rule misunderstood. It does not necessarily mean doing
consequentialism the test is whether an action accords what someone requests or demands at one point in
with a set of rules whose general acceptance would time. It implies a settled view of the individual
result in the most good. In each case “good” is reached by deliberation as to what is in his or her
determined solely by the beneficial consequences. own long-term best interests. It is also to be balanced
The problem with consequentialism is that, although with the autonomy of others, including, in this
consequences are undoubtedly important in moral context, medical staff. Regrettably, the four principles
judgments and actions, happiness is highly subjective, are all too often used as a mantra to be applied by
and what is good (let alone the greatest good) is not the lazy to every ethical issue without thought or
always easy to determine. Moreover, benefiting the discrimination. If, however, one recognizes their
majority could result in ignoring vulnerable shortcomings and incorporates some other insights
minorities. Where do the seriously disadvantaged
such as those discussed below, the four principles
in our society such as the very pre-term infant, the
can provide a useful framework for analyzing ethical
severely disabled child, the terminally ill, or the
problems (Table 18.4a).
elderly with dementia fit with this philosophy? A
rule to protect the vulnerable could be set aside if it Other useful perspectives can be found in:
did not promote general happiness. Narrative ethics18 – this takes account of the patient’s
Clearly these theories are not, of themselves, and the physician’s context, emotions and
sufficient for the resolution of clinical problems in relationships. Indeed, whatever one’s approach, the
real life and several other views have been developed patient’s story must be part of the ethical relationship
to try to deal with their inherent problems. The Four and one’s own feelings are relevant to the moral
Principle Approach, otherwise known as “Principlism,” choices. It is important that the latter be recognized,
shown in Table 18.3 (and see Beauchamp17 ) was if only to ensure that one’s feelings do not
formulated as a basis for working out practical inappropriately influence the choice of the patient.
solutions for problems in Medical Ethics. Virtue ethics – Instead of asking, “How should I act?”
this asks “How should I live?”19 This system tried to
Table 18.3: The Four Principles (‘Principlism’)17
define excellence of character or behavior to which
Principle The Obligation/Duty individuals or groups should aspire. One aspect is
Beneficence – To do what is in the patient’s best caring about someone, rather than just caring for him
interests
– To provide benefits balanced against
or her, and it can provide a useful perspective in, for
risks example, those faced with chronic and/or serious
Non-maleficence – Not to cause harm and, indeed, seek to illness or disability.
prevent it.
Autonomy (“self – To respect the right of the individual to Feminist approaches to ethics20 – One form of feminist
-rule”) make choices about her own life in the ethics attempts to balance the dominant masculine
context of equal respect for everyone ethos of traditional ethics with a more feminine
else involved.
perspective. The ethics is one of caring for individuals
Justice – To treat patients fairly and without
unfair discrimination. and, although caring resolutions may be different in
– Fairness in the distribution of benefits their outcomes, they are linked by personal regard
and risks. and respect given to individuals.
234 Textbook of Perinatal Medicine

Table 4a: Making Ethical Judgements – 1. Analysis

Analyze the problem(s)

• What are its elements? – e.g. medical, ethical, legal, etc.
• What parties are involved? – such as the patient, her family, one or more fetus, statutory authorities (e.g. social workers,
police), health care professionals etc.
o Who is the appropriate advocate for the fetus?
• How do their perspectives fit together or conflict and, if the latter, what are the appropriate mechanisms for resolution?
• What is its context? – e.g., social, ethnic, economic (within this may be issues about rationing).
Consider the underlying principles involved
• It may be useful to start with the four principles (beneficence, do no harm, autonomy and justice).17
o What is in the patient’s best interests?
o How can I balance this with the avoidance of harm?
o Is the patient competent? If so:
• Is she expressing her settled view on what she wants?
• Am I respecting her right to make choices about her own life?
• Does this conflict with the autonomy of others and, if so, how is this to be resolved?
o If she is not competent (e.g. a minor or an unconscious adult), or if this is open to question (e.g. a child aged
12-13), how is this to be dealt with?
o Are there any issues of justice? e.g.
• Is the patient being unfairly discriminated against?
• Is there any conflict between what I consider to be in the patient’s best interest and what can be provided?
• What other perspectives could assist in resolution?
o Have the patient’s social context, emotions and relationships been adequately considered?
o Am I sure that I am treating the patient as a person?
o Are we both caring for and caring about the patient?

However, “formal frameworks, for all their value, “templates” for different sorts of approaches to
need to be supplemented with other ethical problems. She suggests that we use competing
approaches, based more on interpretation and theories as a set of lenses through which we can get
judgment than on formal deduction or algorithm”18 a clearer view of complex moral problems. Some
and “Any particular theory, when applied lenses will provide clearer understanding than
deductively, is shown to be inadequate sooner or others.
later.”21 Dunstan’s4 criteria for the practice of ethics in
Sherwin22 suggests, “No moral theory can do the medicine are: good moral theories, the elucidation
work normally expected of it, because none provides of principles to which implicit or explicit appeal can
reliable grounds for resolving all moral complexities be made, the discipline of logic for the framing of
through deductive application of its central good arguments and the exposure of bad ones,
principles” and “Doing bioethics well requires appeal learning the “art of moral reasoning,” discipline in
to the insights provided by multiple theories.” the use of words without clichés, and “wisdom above
Ethical reflection depends on having a set of core all.”
ethical beliefs that describe clear cases of morally
objectionable or praiseworthy behavior which MAKING ETHICAL JUDGMENTS:
contribute the prototypes of ethical deliberation.” There are two main ways in which ethical issues arise.
Rather than trying to force us to choose a single, The first is while dealing with patients and their
comprehensive theory to apply to all cases, she finds clinical problems. The second is when faced with an
it preferable to view different theoretical perspectives issue in abstract [e.g., “what do you think of
as providing alternative “frameworks” or cloning?”]. Dealing with the former tends to inform
 Education in Perinatal Ethics 235
one’s approach to the latter and, incidentally, how to use common sense to advantage.” Thomas
provides valuable insights not given to the non- Huxley’s aphorism that “Science is nothing but
clinician. trained and organized common sense.” 23 applies
How then do we go about making ethical equally to ethics. He suggests that the former differs
judgments in the clinical context? McCullough and from common sense “only as a veteran may differ
Chervenak21 advocate five individually necessary from a raw recruit: and its methods differ from those
and jointly sufficient criteria for rigorous analysis. of common sense only as far as the guardsman’s cut
These are: and thrust differ from the manner in which a savage
• Clarity: terms and concepts must have precise wields his club.” To change the metaphor, no one
meaning. expects the child with an innate musical ability to sit
• Consistency: those terms must always be used down at the piano and immediately play Beethoven
with that precise meaning and reasoning must be sonatas. The talent needs to be developed both by
free of contradiction. understanding the theory underpinning the music
• Coherence: ethical deliberations must be and also by practicing increasingly complex
internally consistent and non-contradictory. compositions. It must also be rewarding for the
• Applicability: the results of ethical deliberations student! Thus it is with ethics.
can be applied in the clinical and research settings. I believe that far more is achieved if a teacher
• Adequacy: the judgments allow ethical conflicts starts from where the students are and builds on
to be identified, managed, or, preferably, their inherent abilities, rather than start from where
prevented. the teacher is and expect the students to soak up
It has to be emphasized that there is no magic facts and opinions that do not necessarily relate to
formula, and indeed, Dan Callahan has suggested their own experiences. In the United Kingdom the
(personal communication, 2002) that “ethical theory majority of students come to medical school from
ultimately doesn’t matter very much – 90 per cent is high school at about 18 years of age. Teaching in
educated common sense.” ethics in medicine in the University of Bristol begins
My own approach to making ethical judgments shortly after the students commence their course and
involves consideration of a series of questions under follows several weeks working with family
five task-orientated headings as outlined in tables practitioners meeting patients, learning about their
18.4a and table 18.b that move from ethical analysis problems and discerning the ethical issues involved.
to clinical action. It subsequently runs as a vertical theme through all
five years of the course. We never cease to be amazed
THE PURPOSE AND PROCESS at the maturity with which these talented young
OF EDUCATION IN ETHICS people address complex ethical issues often from their
If Callahan is correct that 90 per cent of ethics is own experiences. This develops as the course
educated common sense, why should anyone need progresses. They have the talent; it is our task to let
training in ethics? The key is in the qualifying it flourish.
adjective, “educated.” I once bought a wooden Not long ago I had one of the most rewarding
plaque on Cape Cod that read, “The one thing about teaching experiences of my life at the other end of
common sense is that it is not so common!” Josh the age spectrum. I was asked to speak to an older
Billings (the pen name of Henry Wheeler Shaw), the women’s group on a reproductive ethics topic. Instead
renowned 19th century humorist, said two wise things of lecturing them on the subject (on which, if truth
on the subject: “Common sense is the knack of seeing be told, I was not an expert) I had prepared four
things as they are, and doing things as they ought hypothetical cases of increasing ethical complexity.
to be done.” and “Learning is the art of knowing Members of the group presented each case, the facts
236 Textbook of Perinatal Medicine

Table 18.4b: Making Ethical Judgements – 2. Action

Move towards recommending actions that best meet the above criteria
• What are the proposed objectives? e.g. cure, relief of symptoms (e.g. pain and suffering), or prevention of disease?
- Which objectives are essential and which desirable?
- What alternatives are available (including doing nothing)?
- What are the risks of acting (or failing to act) and what is their probability and severity?
- Do the expected benefits outweigh the potential risks?
• Has the patient been properly informed of the available options?
- Is she competent to give consent?
— If so, has the consent being obtained properly?
— If yes, put chosen option into effect.
- If she is not competent whom, if anyone, can legally give consent?
Dealing with potential or actual conflict:
This difficult area cannot be dealt with comprehensively here, but examples include:
• The patient refuses to accept the recommended interventions.
- If competent, she has the right to do so, even if it leads to harm of herself (or unborn child). Do not coerce her.
Among the things to do are:
— If junior, inform more senior colleagues: if senior, seek advice through clinical governance channels.
— Make sure that full contemporaneous notes are made.
• She requests intervention that informed medical opinion suggests is not justified or in her best interests.
- You are not bound to do as she asks, particularly if it is contrary to your principles.
- Offer referral for another opinion or, if needs be, transfer care to another team. (In the UK, if the patient is
requesting termination of pregnancy you are obliged to refer to another practitioner).
- (Then as above).
• Another party tries to intervene inappropriately, e.g.
- The family or another third party asks for confidential information.
— The presumption is that confidentiality must be kept.
— Any breach can only be justified in exceptional circumstances.
- It is preferable that this be with the knowledge of the patient.
- However, if, for example, it is judged that the patient would be seriously harmed by knowing that her illness is
terminal, but that it would be in her best interests that a close relative should know about it, information may be
divulged without consent.
- The family asks that the patient be not told the truth of her illness.
— The assumption (possibly rebuttable with good grounds –see example above) must be to tell the truth at all
times.
— Not to do so can have regrettable consequences, e.g., who is she to trust when she discovers any deception?
— Remember that your primary duty of care is to your patient and not her family.
Good communication skills in general, and knowing how to impart bad news in particular, are central to being a good
doctor
Review the outcome
– Ethical issues do not lend themselves easily to audit, but it may be useful to record and review major cases from
time to time.
– In individual cases, remember that a good or bad outcome does not necessarily mean that the intervention was
right or wrong.
 Education in Perinatal Ethics 237
of the matter were discussed and questions increasing emphasis on this course being inter-
addressed. We then began to consider the ethics of professional, involving students from a variety of
each case. In a very short time, the key ethical issues health care professions. The confrontation of some
had been raised and debated, and by the time the issues will be traumatic for some students. Teachers
fourth case had been completed, we had discussed must be sensitive to it. The earlier this is recognized
a range of issues that would not have disgraced a and dealt with, the better. In addition, having been
textbook of ethics. Of course we did not come up Dean of a medical faculty, I realize that the problem
with many firm answers, but these women not only of the failing student is more often a problem in
discovered that they could think (something their attitude rather than ability. This too must be
families had probably told them implicitly or recognized early for remedial action to be instituted
explicitly that they could no longer do), but also that and, if necessary, the student encouraged to join an
their opinions were meaningful. What is more, they alternative course of study for which he or she is
were not only thinking ethics on that day, but had more suited. It is too late for this to be recognized
been doing so all their lives! They also learned that for the first time after qualification, perhaps as a result
there were few absolute answers, but had derived of an event that resulted in harm to a patient.
the principles to address the dilemmas by their own 3. A core generic course for health care professionals: It is
efforts. It was gratifying to see their self-esteem rise suggested that these practice-based modular courses
as the session progressed, and they left rejoicing in be designed for doctors working in hospitals, family
the experience. Henry Brook Adams, the historian, practice, and public health, nurses, midwives, allied
wrote in 1907 “a teacher affects eternity: he can never health professionals, and health care managers. The
tell where his influence stops.” Our objective in courses would be an integral part of their continuous
education in ethics is no less! professional development. The design would have
to recognize that not all participants are starting from
PHASES OF EDUCATION IN ETHICS the same point in their understanding of basic
The most effective way to achieve proper education Bioethics. A “core and options” design would allow
in ethics is to begin early and build on it through this to be the first part of a specialty specific program
school, college, medical school, and continuing (in our case Perinatal Medicine). Among the proposed
professional development. objectives of these courses would be:
1. Education in human relationships: This should begin • To provide an introduction to (or revision of)
early in school days and become a more formal study basic theory in bioethics and to the relationship
of ethics for all students in high school and college, between ethics and the law.
where it should be part of the examined curriculum. • To develop consistent, critical, and reflective
The objective is for the student to learn how to think, attitudes to ethical decision making in the
not what to think. healthcare setting.
• To increase awareness of ethical dilemmas faced
2. Introduction to Bioethics: This should commence in
in different healthcare settings.
medical school, concentrating on a patient-centered
• To understand better the ethical problems facing
approach to medicine, and be part of the examined
colleagues in different disciplines.
curriculum. This has been emphasized by the GMC
• To reinforce best practices in clinical and research
in “Tomorrow’s Doctors – recommendations on
governance.
undergraduate medical education.” 24 The focus
should not only be on knowledge, but also skills and The desired learning outcomes would include:
attitudes as shown in table 18.5. Both clinical and • A working knowledge of basic concepts and
research governance should be included. There is theories in clinical ethics.
238 Textbook of Perinatal Medicine

Table 18.5: Introduction to Bio-ethics in Medical Schoola

Objective Key issues

Increasing knowledge - In ethics there are very few cut and dry solutions to problems. In part this is because the
problems themselves are so varied.
- As a practical discipline, ethics involves fitting general principles to specific circumstances
in a way that respects these variations, but this does not mean deciding arbitrarily or with
prejudice.
- The course should cover the main principles of ethics in medicine (e.g., respect for
autonomy, beneficence, justice) and ethical concepts to be used in making morally
reasonable judgments (e.g., duty, rights, virtue, consequences).
- The students should learn:
- the relevant law and professional codes of conduct that determine specific obligations owed
by doctors to patients, society and each other.
- how best to determine what is morally important and relevant in a given medical situation:
without this moral understanding it is impossible to apply rules or concepts in a sensitive
and constructive way.
- the centrality of the patient’s narrative in determining what is important for her and her
medical care.
Developing skills The course should aim to develop skills of analysis, judgment and rational argument about moral
issues in medicine. The context should always be their relevance to the practice of medicine and
good patient care
Improving attitudes The student should be become aware of the wide variety of patients’ attitudes to health, illness,
doctors and society, the ways in which these impact on the medical relationship, and the ways in
which their own attitudes play a part in this relationship.
The ways in which ethical issues in medicine are not only about hard decisions for doctors, but
about making decisions with patients in personal, social, and institutional contexts should be
explored.
This approach to patients’ attitudes will inevitably involve the students confronting and rethinking
their own, and this can be threatening for some.
Problematic attitudes should be identified, acknowledged by the student and, if possible, remedied.

a: Based on the Ethics and Law in Medicine Vertical Theme Course in the University of Bristol Medical School, 2003/4

• A greater confidence in confronting ethical issues a master’s degree in bioethics.

encountered in clinical practice. 4. Specific course in Perinatal Medicine: In this model,
• A more consistent approach to dealing with participants would have completed and gained
similar ethical issues as they affect individual credits in the generic course. This too could benefit
patients. from being interdisciplinary. Table 18.6b is a guide
• A better understanding of the social and to the possible subjects to be included in the
institutional context of decision making in curriculum for such a course. Tables 18.7a and 18.b
healthcare. lists some suggested texts relevant to both the generic
• Improved inter-professional communication, and specific curriculum. It is for the users to adapt
learning, and decision-making. these suggestions to their requirements.
• Improved communication of ethical issues with
the patients and their families. DOES EDUCATION IN ETHICS MAKE ANY
Table 18.6a outlines some suggested modules for DIFFERENCE?
such a course in basic bioethics. Formative and It is not sufficient to assert that education in ethics
summary assessments would be incorporated and is a good thing. Evaluation is required in support of
candidates could gain credits towards, for example, the program to justify the commitment and expense,
 Education in Perinatal Ethics 239
Table 18.6a: Suggested Basic Bioethics Modules for a Core Generic Course for Health Care Professionals

Module 1: Overview of bi ethics – “What ought I do?” Dealing with uncertainty, etc.
Module 2: Competing theories, e.g., duties v. consequences.
Module 3: Other important concepts, e.g., principlism, virtue and narrative ethics, autonomy, paternalism.
Module 4: Ethics and the law.
Module 5: Ethics and the professions: e.g., confidentiality, informed consent, and the vulnerable and failing doctor.
Module 6: Making ethical judgments.
Module 7: Methods of ethics support in practice.
Among the suggested core topics might be:
– Patients’ rights, expectations and reality – Quality of life issues
– Consent, confidentiality, communication – Decision making, to include:
– Legal framework in relevant countries. — Partnerships in decision making e.g.- interdisciplinary
– Economics, to include resource allocation and career perspectives; patient/parental perspectives.
prioritization — Dealing with uncertainty
– Refusal of treatment — “Futile” treatment
– Conflicts of interest: — Withdrawing or withholding treatment
— e.g., commercial enterprises in medical practice — Religious and secular influences on decision-making
– Clinical Governance, e.g. – Generic issues at the beginning and end of life
— Managing and reducing risk, clinical error: – Research governance, e.g.
poor performance; support structures — Evidence based medicine
— Clinical ethics committees — Properly informed consent
— Innovative interventions
— Fraud and misconduct
— Research ethics committees

Table 18.6b: Indicative Curriculum for a Specific Course in Perinatal Medicine:

– Human genetics – Screening, antenatal diagnosis and counseling

– Conception & birth – Sex selection for medical and non-medical reasons
– New reproductive technologies; pre-embryo – Termination of pregnancy
research; stem cells and cloning
– The law and perinatal medicine – Feticide
– Non-selective embryo reduction
– The fetus as person and patient – Antepartum management of fetal anomalies
– Patient choice and the maternal - fetal relationship – Drug dependency in pregnancy
– Obstetric interventions ‘on demand’ – Critical care obstetrics
– HIV infection in pregnancy
– Prematurity (particularly the very pre-term infant – Ethical aspects of the care of the newborn
at or near the threshold of viability)
– Ethical aspects of the care of the malformed or
brain damaged infant

and to provide an evidence-base for future work. made to measure the general effectiveness of ethics
But what outcomes can be used? Among those training,33-36 the work lacks substantial investigation
suggested are ethical sensitivity, attitudes, reasoning and discussion of different methods of moral
ability, and decision-making. There is some literature education. One study has attempted to evaluate the
on promoting ethical sensitivity in modern medical effects of an intensive ethics course on health care
practice,25-30 but the main focus has been on medical professionals, including physicians and nurses.37 It
students. 31-32 Although some attempts have been was carried out during an open conference. Only
240 Textbook of Perinatal Medicine

Table 18.7a: A Guide to a Bibliography for Core Ethical Subjects

Medical Ethics Today- The BMA’s handbook of BMJ Publishing Group, A comprehensive, concise
ethics and law London, 2004 and authoritative guide to
Medical Ethics
Medical Ethics 2nd edition Campbell A, Oxford University Press, An invaluable primer for the
Charlesworth M, New York/Oxford, 1997 subject accessible to the non-
Gillett G, Jones G. expert
Clinical Ethics 5th edition Jonsen AR, Siegler M, McGraw-Hill, New York A ‘must read’ in this context.
Winslade WJ 2002 “Facilitates solutions to
everyday ethical problems”.
Principles of Health Edited by Gillon R John Wiley, Chichester/ A detailed in depth analysis of
Care Ethics New York 1994 the field
Principles of Bio-medical Beauchamp TL & Oxford University Press, Another excellent source
ethics 5th edition Childress JF New/York/Oxford, 2001 book
Bioethics – an Introduction Jecker NS, Jonsen AR, Jones & Bartlett Publishers, It does as it says
to the History, Methods Pearlman RA Boston 1997
and Practice
Medical Ethics – a Schwartz L, Preece PE, Saunders, Edinburgh/ A useful guide
Case-based Approach Hendry RA New York 2002
Medicine, Patients and the Brazier M Penguin Books, A scholarly work by an
Law 3rd edition London 2003 eminent legal authority
Medical Ethics and the Hope T, Savulescu J, Churchill Livingstone, A useful guide
Law - the Core Curriculum Hendrick J. Edinburgh/New York 2003
Autonomy and Trust in O’Neill O Cambridge University Press, A must for anyone who
Bioethics Cambridge, England 2002 wishes to understand the true
nature of autonomy.
Three Methods of Ethics Baron MW, Pettit P, Blackwell Publishers, Oxford/ For those who wish to
Slote, M. Malden/Mass. 1997 consider more deeply and
contrast Kantian Ethics,
Consequentialism and Virtue
Ethics.
The Health Care Edited by Thomasma DC Georgetown University This book builds on the work
Professional as Friend & Kissell JL Press, Washington DC, 2000 of Edmund Pellegrino. A
and Healer ‘must-read’ in this context

about half of the participants provided direct patient • It is a public system rather than a private activity,
care, and there were no data on the proportions of and no one can act morally without reference to
health care professionals taking part, so no real other individuals.
conclusions can be drawn from it. More rigorous • The fundamental ethical principles underpinning
work is required. medical ethics are those of society in general.
• Ethical analysis must be clear, consistent,
SUMMARY internally consistent, and free of
Ethics is the system of thought that analyzes and contradiction.
provides a rational framework for moral judgments. • The judgments made must allow ethical conflicts
Among the key features of ethics are: to be identified, managed, or, preferably,
• It must be translatable into moral action. prevented.
 Education in Perinatal Ethics 241
Table 18.7b: A Guide to a Bibliography for Perinatal Ethics

Ethics and Perinatology Editors Goldworth A, Oxford University Press, A required text for this field.
Silverman W, New York/Oxford, 1995
Stevenson DK,
Young EWD.
Ethics in Obstetrics McCullough LB, Oxford University Press, Another valuable reference
and Gynecology Chervenak FA New York/Oxford, 1994 for this field.
Ethics in Obstetrics American College of ACOG, Washington DC, A compilation of the subjects
and Gynecology Obstetricians and 2002 considered by the ACOG
Gynecologists Ethics Committee and
another invaluable source of
material.
Recommendations on The FIGO Committee for FIGO, 2000 A compilation of the subjects
Ethical Issues in the Ethical Aspects of considered by the FIGO Ethics
Obstetrics & Gynecology Human Reproduction and Committee and also an
Women’s Health invaluable source of material.
Ethical Issues in Editor Dickenson DL Cambridge University Contains succinct but deep
Maternal-Fetal Medicine Press, Cambridge, analyses of many relevant
England 2002 issues
Crucial Decisions at the McHaffie H Radcliffe Medical Press, A descriptive account of
Beginning of Life Oxford, 2001 parents’ experiences of
treatment withdrawal from
their infants.
Should the Baby Live? Kuhse H, Singer P Oxford University Press, A controversial book that
The Problems of New York/Oxford, 1985 discusses issues that must be
Handicapped Infants addressed in this context.
Selective Non-treatment Weir RF Oxford University Press, A necessary source book in
of Handicapped New York/Oxford, 1988 this context for understanding
Newborns: Moral how better to deal with
Dilemmas in Neonatal clinical and ethical dilemmas.
Medicine
The Worth of Child Murray TH University of California A deep and compassionate
Press, Berkeley 1996 analysis of many of the
relevant issues

The most effective way to achieve proper education REFERENCES

in ethics is to begin early and build on it through 1. Radcliffe-Richards J. Maternal-fetal conflict. In: Bewley S
school, college, medical school, and continuing and Ward RH editors. Ethics in Obstetrics &Gynaecology.
professional development. Among the purposes of London RCOG Press 1994;34- 42.
education in ethics are the development of consistent, 2. Campbell AV. Moral dilemmas and ethical theories. In:
critical and reflective attitudes to ethical decision Moral Dilemmas in Medicine. Edinburgh: Churchill
Livingstone 1972 p1-13.
making, increasing awareness of ethical dilemmas in 3. Stirrat GM. Education in Ethics. Clin Perinatol 2003;30:1-
one’s own practice and that of others, and reinforce- 15.
ment of best practices in clinical and research 4. Dunstan G. Should philosophy and medical ethics be left
governance. to the experts? In: Bewley S and Ward RH editors. Ethics
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in Obstetrics &Gynaecology. London RCOG Press 1994;3- Press 1994;3-81.

8. 22. Sherwin S. Foundations, frameworks and lenses. In: The
5. Campbell AV. The freedom that is health. In: Health as role of theories in Bioethics. Oxford. Blackwell 1999;198-
Liberation. Cleveland, Ohio: The Pilgrim Press. 1995;1- 24. 206.
6. O’Neill O. Gaining autonomy and losing trust? In: 23. Huxley TH. Collected Essays (1893-4) ‘The Method of
Autonomy and Trust in Bioethics. Cambridge, Zadig.’ London, Macmillan 1893.
Cambridge University Press. 2002;1-27. 24. General Medical Council. Tomorrow’s Doctors –
7. Stirrat GM, Gill R. Autonomy in medical ethics after Recommendations on Undergraduate Medical Education.
O’Neill. J Med Ethics 2004 [in press]. London, GMC 1993.
8. General Medical Council. Duties of a Doctor: GMC, 25. Andre J. Learning to see: moral growth during medical
London 1998. training. J Med Ethics 1992;18:148-52.
9. American Medical Association. Council on Ethical and 26. Herbert P, Mesline EM, Dunn EV, et al. Measuring ethical
Judicial Affairs. Principles of Medical Ethics. In: Code of sensitivity in medical students: using vignettes as an
Medical Ethics. 2000-2001 edition Chicago. p. xii. instrument. J Med Ethics 1990;16:141-45.
10. Draper H, Sorell T. Patient’s responsibilities in medical 27. Herbert PC, Meslin EM, Dunn EV. Measuring the ethical
ethics. Bioethics, 2003;16:335-52. sensitivity of medical students: a study at the University
11. O’Donovan LJ. A profession of trust: reflections on a of Toronto. J Med Ethics 1992;18:142-47.
fundamental virtue. In: Thomasma DC, Kissell JL editors: 28. Savulescu J., Crisp R., Fulford KWM, Hope T. Evaluating
The Health Care Professional as Friend and Healer. ethics competence in medical education. J Med Ethics
Washington. Georgetown University Press 2000;1-9. 1999;25:367-74.
12. Pellegrino ED. Being a physician: does it make a moral 29. Walker RM., Miles SH., Stocking CB, Siegler M. Physicians
difference? Advances in Otolaryngology – Head and and nurses perceptions of ethics problems on general
Neck Surgery 1992;6:1-10. medical-services. J Gen Int Med 1991;6(5):424-29.
13. Stirrat GM. How to approach ethical issues. The 30. Zalewski Z. What philosophy should be taught to the
Obstetrician & Gynaecologist (RCOG) 2003;5:214-17. future medical professionals? Medicine, Health Care and
14. Westphal M. Post-modern theology. In: Concise Philosophy 2000;3:161-67.
Routledge Encyclopaedia of Philosophy. London and 31. Goldie J, Schwartz L, McConnachie A, Morrison J. Impact
New York. Routledge 2000;699. of a new course on students’ potential behaviour on
15. Jonsen A (1994). Clinical ethics and the four principles. encountering ethical dilemmas. Medical Education
In: Gillon R, editor. Principles of Healthcare Ethics. 2001;35:295-312.
Chichester and New York. John Wiley & Sons 1994;13- 32. Green B, Miller PD, Routh CP. Teaching ethics in
21. psychiatry: a one-day workshop for clinical students. J
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perspective. In: Three methods of ethics. Oxford, 33. Bebeau MJ. Designing an outcome-based ethics
Blackwell,92-174. curriculum for professional-education-strategies and
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R, editor. Principles of Healthcare Ethics. Chichester and 35. Holm S, Nielsen GH, Norup M, et al. Changes in moral
New York. John Wiley & Sons 1994;207-15. reasoning and the teaching of medical ethics. Medical
19. MacIntyre A. After virtue: a study in moral theology (2nd Education 1995;29(6):420-23.
edition). London, Duckworth 1985. 36. Self DJ, Davenport E. Measurement of moral
20. Tong R. Feminist ethics. In: Concise Routledge development in medicine. Cambridge Quarterly of
Encyclopaedia of Philosophy. London and New York. Healthcare Ethics 1996;5(2):269-77.
Routledge 2000;278. 37. Malek JI, Geller G, Sugarman J. Talking about cases in
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Gynecology. New York and Oxford. Oxford University
 19
Words Matter: Nomenclature
and Communication in
Perinatal Medicine
Lachlan de Crespigny

LANGUAGE clamor of the mob. In other words, when the majority

of Australians agreed with him, they represented
The general public now accepts of the importance of
the “mainstream,” but when most disagreed, it was
using appropriate language. Their acceptance
“the mob” talking.1
contrasts with to the attitude of many doctors who
People now take care to avoid sexist and
are quick to dismiss the importance of word choice
discriminatory language. Racist language, in
in treating patients. The goal of this chapter is first
particular, is acknowledged as being offensive and
to demonstrate that word choice by professionals
inappropriate. It is hurtful to, and places stress on,
involved in prenatal diagnosis is important, and
other people. Nobody working in prenatal diagnosis
second to consider ethically appropriate word choices
could fail to be aware of the unique stresses placed
in our speciality.
on a couple who are given bad news following a
Sexist and discriminatory language is now
prenatal test. Despite this, however, there is
recognized to be unacceptable. This is because we
remarkably little literature analysing what word
are aware that such language impacts negatively on
choice in prenatal diagnosis leaves couples feeling
others. As long ago as 1977 the United States
most comfortable. The importance of language has
Department of Labor revised 3,000 of its
had very little focus in medicine generally – indeed
approximately 30,000 titles for occupations.
discussions on word choice may be perceived as
Advertisers are well aware of the importance of
trivial.
language and spend huge resources choosing names
for products and developing phrases to describe
LANGUAGE, REALITY,
them. Language is also the tool of trade of politicians.
AND MORAL JUDGMENT
When there was an outcry over the government’s
harsh treatment of asylum-seekers, the Australian Language makers and users of language are in a
Prime Minister, John Howard, recently declared that position to influence reality; language is a vehicle
his party was endeavoring to govern in the interests for them to construct, reinforce and reproduce their
of the mainstream of the Australian community. particular bias or view of reality.2 People’s language
Shortly afterwards, when the majority of Australians can influence opinion: for example, a group might be
believed that he should dismiss the Governor General called “freedom fighters” if we support their cause,
who had failed to act on child sexual abuse claims, others may call the same group “terrorists” if they
he indicated he would not be succumbing to the wish to present them as evil.3
244 Textbook of Perinatal Medicine

Doctors practicing in prenatal diagnosis are did the wording of questions to watchers of the
language makers in their specialist field. By their crash film. In prenatal diagnosis there is the added
language they can subtly influence how their patients factor that the doctor is seen as “the expert.”
perceive a problem. We know that doctors have the Following the diagnosis of fetal abnormality,
potential to influence a patient’s decision of what to patients will often ask their doctor what is the best
do when a fetal anomaly is diagnosed. They can do course of action. They will even attempt to read
this both by their choice of what information to impart into a doctor’s words or manner whether he or she
and in the way that they impart it. One group found thinks an abortion is warranted. It is not the role
that the proportion of women choosing pregnancy of the doctor to make a moral judgment about what
termination following the diagnosis of a facial cleft is best for any particular patient. However patients
was 50%. It dropped to 5% following the introduction may be highly influenced not only by what the
of “emergency counseling by the clef team.”4 Women doctor says, but also by inferences from the doctor’s
feel vulnerable and are susceptible to influence from word choice. The use of words such as “baby” and
their doctor following the diagnosis of fetal “mother” when the doctor means “fetus” and
abnormality. There are few, if any, areas of medicine “pregnant woman” may result in the patient
in which the language used by doctors is more thinking that her doctor considers that her fetus
important than in communicating with women has the status of a baby and she is already a mother.
having prenatal testing. Women are feeling stressed It might be expected that such a word choice may
and may need to make one of the biggest decisions influence the patient’s decision about abortion. In
of their lives – to consider whether to have an the crash film the questioner’s language influenced
abortion if a major abnormality is found. the subjects’ perception. Following detection of a
Loftus and Palmer,5 who summarized their results fetal abnormality, the doctor’s language at the time
as follows, demonstrated the impact of language on of diagnosis could affect the woman’s decision on
memory: abortion. If her doctor, either directly or by word
Two experiments are reported in which subjects choice, infers that the fetus is a baby, this might
viewed films of automobile accidents and then also impact in the woman’s ultimate ability to come
answered questions about events occurring in the to terms with her decision.
films. The question, “About how fast were the
cars going when they smashed into each other?” MEDICAL LANGUAGE.
elicited higher estimates of speed than questions In a field closely allied to prenatal testing, Bowker2
which used the verbs collided, bumped, contacted, explores the level of gender insensitivity in specialist
or hit in place of smashed. On a retest one week language in the field of infertility. She cites examples
later, those subjects who received the verb smashed demonstrating that the language used for similar
were more likely to say “yes” to the question, problems leading to male and female infertility is
“Did you see any broken glass?” even though often gender insensitive. For example, “sperm
broken glass was not present in the film. These antibodies” are described as being present in a male,
results are consistent with the view that the while a woman whose cervical mucus develops such
questions asked subsequent to an event can cause antibodies is described as having “hostile mucus.”
a reconstruction in one’s memory of that event. She claims that the choices of language are not always
The unique emotive experience suffered by innocent and may be determined by belief systems
women given a diagnosis of fetal abnormality far that underlie them. Language may attempt to portray
exceeds that of people watching a film. It is men in a more positive light and women in a negative
reasonable to assume that the doctor’s language one. She also notes that the term “expected date of
would have at least as much impact on patients as confinement” suggests punishment and imprison-
 Words Matter: Nomenclature and Communication in Perinatal Medicine 245
ment reflecting the male doctor’s control over the LANGUAGE IN OBSTETRICS
place of birth and birthing practices. The terms
Although doctors are often dismissive of “politically
“expected date of delivery” or “due date” are more
correct” language, our journals have over time
gender sensitive. Bowker concludes that even when
reduced discriminatory language. The use of
a doctor claims not to have a bias against women,
“husbands and wives” when the author means “men
the language that he uses to communicate to patients
and women” would no longer be accepted, although
may be based on such a bias and may therefore have
these terms are used in a leading journal as recently
a harmful effect, even in the absence of a malicious
as 1984.8 Similarly, one would not now expect to find
intent.
in a standard medical text a quote such as “it has
A detailed analysis of the terms commonly used
been said that bad girls get babies but good girls get
in obstetrical ultrasound practice would be valuable.
myomata.”9 While this may have been presented as
Some language is clearly gender insensitive, such as
a joke, it helps perpetuate sexism by suggesting
cervical incompetence and the labeling of a woman
“good girls comply with the stereotypical portrayal
as a “recurrent aborter.” Some language is simply
of women as chaste and passive.”10
insensitive, such as intrauterine growth retardation
The RCOG Study Group on Problems in Early
(instead of restriction, to avoid a perceived
Pregnancy: Advances in Diagnosis in Management11
association with intellectual retardation) or a fetal
has recommended that in early pregnancy loss, the
anomaly scan (instead of a fetal normality scan, to
term “abortion” be replaced by “miscarriage.” It is
focus on the normal).
recommended that “spontaneous miscarriage”
Doctors also use terms that could lead to
replace “spontaneous abortion,” “early embryonic
misconceptions in the eyes of colleagues as well as
demise” and “fetal demise” replace “blighted ovum”
the public. It has been suggested that “myocardial
and “missed abortion” respectively, and “incomplete
infarction” should be replaced by “coronary
miscarriage” be used instead of “incomplete
occlusion” since the goal of current treatment is to
abortion.” 12 The general community has long
prevent the myocardial death that follows coronary
accepted that our language is important in influencing
occlusion.6 The same author also proposed replacing
the way people see reality; this is also starting to be
the term “hypertension” which falsely suggests that
accepted in our specialty.
the condition is related to tension or stress, and
replacing “cardiac failure” with “cardiac LANGUAGE IN PRENATAL DIAGNOSIS
insufficiency.”
The medical profession has been slow to Ethical dilemmas pervade the specialty of prenatal
acknowledge the importance of language, diagnosis. However, there has so far been little
dismissing it as being “politically correct.” The attempt to review the language we use and the
term “political correctness” is now used as a slogan impact it may have on other professionals, and even
of opprobrium, referring to someone who is an more importantly on our patients. It is time doctors
ideological monster. 7 Doctors dislike linguistic were more considered and considerate in their word
change and find it threatening, suggesting that choice. The terms “fetus” and “pregnant woman”
there is something more acceptable about their own are grammatically more correct than “baby” and
linguistic preference. 7 Why is it that the Right to “mother.” The latter names are used by some
Life movement long ago learned to use “killing of (including anti-abortionists) euphemistically with a
babies” instead of “abortion,” while doctors often more sinister motivation – namely to blur reality.
still speak as if language is mere political Anti-abortionists use baby and mother as “linguistic
correctness and does not impact on peoples’ fig leaves” to suggest that abortion must be wrong;7
opinions? while the motivation of doctors using these terms is
246 Textbook of Perinatal Medicine

likely to differ from anti-abortionists, it may be Another study suggested that some patients
misinterpreted by patients. preferred the term “baby” to “fetus.”15 Researchers
How do we determine the most appropriate in Canada examined the results of a questionnaire
terminology for the language of our specialty? Should sent to women who had been informed of ultrasound
we survey our patients and let them decide findings of “serious anomalies,” soft markers of
terminology? One such survey showed pregnant aneuploidy, or obstetric complications. Approxi-
women had a strong preference to be called “patient” mately 900 patients were seen in the study year, the
rather than “mother,” “client,” “consumer,” number who declined to participate was not
“customer,” “lady,” “woman,” or “pregnant recorded, but 117 agreed to participate in the survey.
woman.”13 Another study surveyed women in an Surveys were returned by 65% of the 117. This shows
antenatal clinic in an attempt to decide whether to the difficulty in both performing and analysing the
use the term “mother-to-be,” “pregnant woman,” results of such a survey – questionnaires were
“maternant,” “patient,” “client,” or “consumer.”14 analysed from only 76 (8%) of the original
The authors concluded, “Simple softer terms like approximately 900 eligible women.
mother-to-be please a vast majority.” While we do More women felt strongly that they preferred to
not know the gestation of these women, given that have their health care provider use the word “baby”
most women have healthy pregnancies, it must be when giving them bad news. A smaller number felt
assumed that most of these women believed they it important to hear the word “fetus.” There was a
had, and in fact had, healthy pregnancies. How significant minority who considered the terms used
would their answers have changed if, immediately to be unimportant. There was great diversity of
after filling out this questionnaire, their doctor had opinion among the women.
told them that their fetus had a major abnormality? It is not clear from this paper how many women
The softer pleasing term of “mother-to-be” suddenly had chosen pregnancy termination following
seems inappropriate – the patient will probably diagnosis of a serious anomaly. It might be expected
choose not to be a mother this time. Would the doctor that many women who continue their pregnancy,
using the term “mother-to-be” have an impact on who have made the decision that they are going to
their patient’s decision whether or not to continue have a baby, would prefer the term baby to be used.
with the pregnancy? Would the patient think that This would apply particularly to the women in this
the doctor is insinuating that since she is a mother- study who completed the survey up to 9 months after
to-be and not a pregnant woman that the doctor their ultrasound visit, so would by then either have
therefore opposes an abortion? If the woman has an a baby or be very late in pregnancy.
abortion, might her grief be prolonged because of In our use of language in the specialist field of
her concern that the doctor had implied that she prenatal testing we have a number of goals:
should have become a mother? 1. To maximize the information provided to
Mothers, and presumably mothers-to-be, do not pregnant women: the words we use should be
kill their children/fetuses. Pregnant women, descriptive and easily understood by the majority
however, do have a right to abortion in some of pregnant women.
circumstances in most Western societies. We cannot 2. Be respectful of women’s choices. While some
expect patients in an outpatient survey to think have suggested that prenatal diagnosis is a “select
through these issues. Sometimes word choice is better and destroy” mission, most support the concept
resolved by reflection and discussion, because the of prenatal diagnosis enhancing autonomous
appropriate survey cannot be easily carried out. Word choices of pregnant women. The enhancement of
choice is not always best resolved by surveying autonomy should apply not only to choice of tests,
patients – just as medical treatments are not. Doctors but also to what information they receive from
have a role in patient and community education. these tests (does the woman wish to know
 Words Matter: Nomenclature and Communication in Perinatal Medicine 247
“everything” including all low risk markers of detection and that a mid-trimester scan is the final
aneuploidy?), and the decision whether to prenatal test. Although women anxiously await the
continue the pregnancy or have an abortion.16 results of any prenatal test, the defining moment for
3. Reduce risks of long-term psychological pregnant women has become the news of a normal
maladjustment: Since we have few data on the mid-trimester ultrasound examination. It is rare that
impact of language on psychological adjustment subsequent events or testing cause a pregnant woman
to adverse pregnancy outcome, we must theorize to rethink pregnancy termination.
on its impact. Surveying healthy women at an Our language should support and enhance the
antenatal clinic does not answer this question. autonomy of pregnant women.18 It is a normal mid-
4. Promote bonding in normal healthy pregnancies: trimester ultrasound examination that indicates to
This is not only through our language, but also most pregnant women that their fetuses will become
by the use of technology, for example offering of babies. They will become mothers after the birth.
3D and 4D ultrasound when available. They are now unlikely to request abortion – a fetal
At times points 3 and 4 may appear to be in anomaly is now unlikely to be found. Our word
conflict. In showing pregnant women ultrasound choice should acknowledge that our language is
images, we may promote bonding only to discover focused on the woman, and not on the views of the
later in the examination that there is a fetal doctor.
abnormality. The bonding itself is not necessarily a The Oxford English Dictionary defines “mother”
problem if the patient later chooses pregnancy as a female parent, one who has borne a child. It is
termination. Indeed, counselors go to great lengths therefore grammatically incorrect to use the term
to support bonding by offering photographs, “mother” for a pregnant woman. Pregnant women
footprints, etc., following termination for fetal and mothers have contrasting rights and
abnormality, and such a policy is supported by patient responsibilities. Pregnant women have the right to
groups. We should not shield women from the fact abortion in certain circumstances in most western
that the fetus they aborted looks human, but we can countries, while it is illegal for a mother to kill or fail
use language that indicates that even though it looks to care for her child.
human, it does not have human characteristics such The definitions of “baby” are more variable. The
as a conscious life and an ability to plan. Careful use Oxford English Dictionary includes both unborn and
of language can support this message. newly born human beings as a baby while the Collins
Rothman has coined the phrase “tentative Dictionary defines a baby as a child in the first year
pregnancy”17 to describe the state of limbo that or two of life. It is proposed that “fetal patient” (or
women are in prior to completion of prenatal testing. the lay terms “child” or “baby”) should be used when
Women cannot say with confidence that “I am going it is unlikely that termination of pregnancy would
to have a baby” until after the completion of prenatal be requested.18 For most women this is after normal
testing. Those of us in prenatal diagnosis know that results of prenatal testing. An exception is the woman
most women in whom a major fetal abnormality is who in early pregnancy clearly indicates that she
diagnosed will choose pregnancy termination. would not consider termination of pregnancy for fetal
Women who have had a previous pregnancy abnormality; she has given the status of a fetal patient
terminated because of fetal abnormality are uniquely to her pre-viable fetus. She is free to withdraw that
aware of their “tentative pregnancy.” Their relief and status at any time.18
excitement at the completion of a normal mid- The goal should be to remain as neutral as possible
trimester ultrasound examination is plainly visible. in the choice of words prior to the completion of
Women are increasingly aware that a mid-trimester prenatal testing in an attempt to avoid inadvertent
ultrasound examination is primarily for fetal anomaly directive counseling. The term “fetus” is neutral in
248 Textbook of Perinatal Medicine

that it does not imply the fetus has the status of a care have good reason for being confident that
baby; it implies that pregnancy termination is still “they are going to have a baby” after completion
considered acceptable. Following completion of of testing; it would be a pity if our language
prenatal testing the term “fetal patient” is advocated diminished that confidence. Very few women
with “child” or “baby” as the analogous lay term.18 have reason to request abortion after standard
The term “mother” is clearly defined, and should tests are completed. There is little reason not to
be used when grammatically correct. “Mother” is enhance such confidence by using the lay term
appropriate when describing a woman who has borne “baby” late in pregnancy.
a child and is inappropriate when describing a 2. Those opposing abortion following potential fetal
pregnant woman who has not borne a child. viability may argue that from viability the term
What alternative proposals for word choice might “baby” should be used. Given a normal mid-
be suggested? trimester ultrasound examination, few women
1. In an earlier paper the author argued that the will have further prenatal tests in the few weeks
terms “pregnant woman” and “fetus” should prior to potential viability. Even fewer women
replace “mother” and “baby” throughout suddenly change their mind at this late stage and
pregnancy.19 Such language supports the claim that decide that their apparently normal pregnancy is
“a pregnant woman…should have the right to unwanted and they wish to have abortion. To
make decisions about her own body up until the propose viability as being decisive in determining
time of birth…In a difficult decision, the woman’s word choice would result in the doctor
present right to bodily integrity should prevail prolonging the tentative pregnancy to support his
over the rights of the potential person.”20 or her ethical position. For the patient, the
The law puts great importance on the moment completion of prenatal testing is the more critical
of birth. Late abortion is legal in many parts of time.
the world, especially in the presence of a major 3. Finally, even after reflection, some doctors may
fetal abnormality. In most western countries late choose to call the fetus a “baby” from conception.
abortion is available for lethal abnormalities. This is the position of the Right to Life movement,
Using the term “fetus” throughout pregnancy since it enhances their view that abortion is
supports the philosophy that women late in tantamount to killing babies. These doctors are
pregnancy may put their rights above those of using word choice to deliberately promote their
the fetus in the unusual situation when these are personal views on the status of the fetus. Others
in conflict. may claim that they use the term “baby”
There are good reasons for reserving the term throughout pregnancy because it is more patient-
“baby” for after birth and “fetus” before birth. friendly – better understood by some women.
This word choice is consistent with the definition However, the term “fetus” is now widely used
of baby in at least some dictionaries. It supports and understood in the lay context, few adults find
the autonomy of the pregnant woman throughout this term confusing. Young children and some
pregnancy. adults may be more comfortable with “unborn
On balance, however, the author suggests the baby” and “mother-to-be” – these are acceptable
use of “baby” is preferred following completion alternatives to “baby.”
of prenatal testing. A disadvantage of using the Some might claim that the language proposed
term “fetus” late in pregnancy is that it might contradicts the language used by many pregnant
potentially prolong the “tentative pregnancy” in women who prefer to think of their child as a
the eyes of the pregnant woman. Women baby. The doctor participating in such baby talk
benefiting from modern obstetrical and neonatal may please some pregnant women and may be
 Words Matter: Nomenclature and Communication in Perinatal Medicine 249
preferred by many, or even most, women who in pregnancy. Doctors would be less tempted to
will proceed to have a baby. However, the long- indulge in baby talk if they perceived there was
term interests of the patient may be better served any risk that this could result in more prolonged
by more neutral language, particularly if the psychological sequelae for a woman who
outcome to the pregnancy is adverse. It would subsequently chose pregnancy termination in the
be unfortunate if patients interpreted the doctor’s presence of a fetal abnormality. The principle
participation in baby talk as the euphemistic guiding the physician should be respect for the
language of an anti-abortionist. patient.
It is important to consider the impact of our Our respect for the patient also extends to others
language on women continuing the pregnancies. But in the family. The term “father” should be avoided
the life-long distress felt by many women following during pregnancy. A male partner or husband
pregnancy loss means that this group deserves our becomes an expectant father following normal
special attention. These women are at greatest risk prenatal test.18 If the partner is a woman, she becomes
– and they will not have a baby. The critical issue is the expectant parent at that time.
how language impacts on women who are
considering pregnancy termination. The author’s CONCLUSION
proposition is that by using neutral language, such
The best interests of our patients are served by using
as “fetus” and “pregnant woman,” these terms are
language that supports patient autonomy and is
not only more accurate, but assist in ensuring that
neutral. While it remains a “tentative” pregnancy,
the pregnant woman does not misinterpret the health
i.e., prior to the completion of normal prenatal tests,
care provider as having an anti-abortion bias.
the term “fetus” should be used. Following normal
We need to be sensitive that women who give
prenatal testing, only in rare situations will the
the status of a patient to the fetus, in other words
pregnant woman request an abortion. It is
women who have made a prior decision to continue
appropriate that the term “fetal patient,” or lay terms
the pregnancy, might prefer the use of “baby” to
“child” or “baby,” be then used. To be a mother,
“fetus.” We should use whatever language is most
however, one must have borne a child.
supportive of our patients.
Our language should support the autonomous
After a miscarriage or pregnancy termination,
views of the patient. The language proposed is not
some couples like to think of and refer to their fetus
intended to be rigidly adhered to in all situations,
as a baby. They may even name the fetus. Even
women having a pregnancy termination may wish but rather is an appropriate starting point, after which
the fetus to be considered as a baby, and that pre- we as health providers need to be responsive to the
term labor is being induced in the best interests of position of the pregnant woman. It is important to
the baby. It is important that our language is individualize language to accommodate the views
supportive of our patients and flexible, so enhancing of individual patients. It is, however, time for doctors
their best interests. No rigid framework is correct to acknowledge that their language can influence
for all situations. This is not to say, however, that reality, particularly since they are frequently
the doctor should support the “baby talk” of a considered experts, not only in prenatal diagnosis,
woman early in pregnancy, excited by the first but also in morality. Doctors’ language has a powerful
images of her fetus on the ultrasound screen. Not influence not only on the way patients think, but
all pregnant women appreciate that prenatal testing potentially also on the decisions that they make.
may mean that they withdraw the status of a baby
from their fetus. We as professionals need to be REFERENCES
aware that we should, in general, support neutral 1. Henderson G. When the mainstream becomes a mob,
language, even when caring for excited couples early blame the dingo pack. “The Age” 2002;11.
250 Textbook of Perinatal Medicine

2. Bowker L. Terminology and Gender Sensitivity; a corpus- 12. Hutchon DJR. Understanding miscarriage or insensitive
based study of the LSP of infertility. Language in Society abortion: Time for more defined terminology ? Am J
2001;30:589-601. Obstet Gynecol 1998;179:397-98.
3. Schulz MR. The Semantic Derogation of Women. In Barrie 13. Denning AS, Tuttle LK, Bryant VJ, Walker SP, Higgins
Thorne and Nancy Henley (eds), Language and Sex: JR. Ascertaining women’s choice of title during pregnancy
Difference and Dominance 1975:64–75. and childbirth. Aust N Z J Obstet Gynaecol 2002;42:125-
4. Moss A. Controversies in cleft lip and palate management. 29.
Ultrasound in Obstetrics and Gynecology 2001;18:420-21 14. Batra N, Lilford RJ. Not clients, not consumers and
5. Loftus EF, Palmer JC. Reconstruction of automobile definitely not maternants. European J Obstet Gynecol and
destruction: an example of the interaction between Reproductive Biology 1996;64:197-99.
language and memory. J Verbal Learning and verbal 15. Alkazaleh F, Thomas M, Grebenyuk J, Glaude L, Savage
behaviour 1974;13:585-89. D, Johannesen J, Caetano M, Windrim R. What women
6. O’Rourke MF. What’s in a Name? Would that which we
want: women’s preferences of caregiver behavior when
call “cardiac failure,” by any other name threaten less?
prenatal sonography findings are abnormal. Ultrasound
MJA 1997;166:372-73.
Obstet Gynecol 2004;23:56-62
7. Burridge K. Polcor-Big Brother, Thomas Bowdler or June
16. de Crespigny L, Savulescu J. Is paternalism alive and well
Dally-Watkins. In Style in context: language at large,
Proceedings of Style Councils 1996,1997 and 1999 ed in obstetric ultrasound? Helping couples choose their
Peters PH. children. Ultrasound Obstet Gynecol 2002; 20:213-16
8. Stray-Pedersen B, Stray-Pedersen S. Etiologic factors and 17. Rothman BK. A tentative pregnancy: Prenatal diagnosis
subsequent reproductive performance in 195 couples with and the future of motherhood, Viking, New York 1986.
a prior history of habitual abortion. Am J Obstet Gynecol 18. de Crespigny L, Chervenak F, McCullough L. Mothers
1984;148:140-44. and babies, pregnant women and fetuses. BrJ Obstet
9. Llewellyn-Jones D. Fundamentals of Obstetrics and Gynaecol 1999;106:1235-37.
Gynaecology Volume 2. London: Faber & Faber.1982. 19. de Crespigny L. What’s in a name – is the pregnant
10. Harres A. The representation of women in three medical woman a mother? Is the fetus a baby? Aust NZ J Obstet
texts ARAL Series S number 10 1993;35-53. Gynaecol 1996;36:435-36.
11. Grudzinskas JG, O’Brien PMS. Problems in early 20. Special project, Legal rights and issues surrounding
pregnancy: Advances in Diagnosis and Management. conception, pregnancy and birth “maternal rights v’s fetal
London: RCOG Press; 1997. rights.” Vanderbilt Law Review 819 at 1986;849;39.
 20 The Beginning of Human Life-
Scientific and Religious
Controversies
Asim Kurjak, Jose Maria Carrera

INTRODUCTION themselves in trying to contribute to the solution of

the human life puzzle. They are led by the idea that
One of the most controversial topics in modern
each newborn child will only reach its full potential
bioethics, science, and philosophy is the beginning
if its development in utero is free from any adverse
of individual human life. In the seemingly endless
influence, providing the best possible environment
debate, strongly stimulated by recent technologic
for the embryo/fetus. Considering the embryo/fetus,
advances in human reproduction, a synthesis between
it should be always kept in mind the amazing aspect
scientific data and hypothesis, philosophical thought,
of these parts of human life in which the pregnant
and issues of humanities has become necessary to
woman and the embryo/fetus, although locked in
deal with ethical, juridical, and social problems. 1
the most intimate of relationships, are at all times
Furthermore, in this field there is a temptation to
two separate individuals. Accepting the embryo/
ask science to choose between opinions and beliefs
fetus as a person opens a new set of questions about
that tend to neutralize one another. Indeed, the
its personality and human rights.
question of when human life begins requires the
essential aid of different forms of knowledge. Here THE DEFINITION OF LIFE
we become involved in the juncture between science Proper answers to the question of how to define
and religion, which needs to be carefully explored.2 human life are complicated. Nowadays, dilemmas
Obviously, the beginning of human life is seen consider the respect of human life from the birth to
differently by different individuals, groups, cultures, death involving not just biology, but other sciences
and religions. Fundamental to productive debate and also. Philosophy, theology, psychology, sociology,
reconciliation between minority and majority groups law and politics evaluate this topic from different
is an understanding of the ill-defined concept of “the point of views. Integration of all could result in a
beginning of human life.”3 useful answer.
Entering this field, scientists have been remiss in Some authors say that that life as such does not
failing to translate science into the terms that allow exist – no one has ever seen it. Szent-Gyorgy says
mankind to share their excitement of discovering life that the noun “life” has no significance because there
before birth. Regardless of the remarkable scientific is no such thing as “life.” Le Dantez holds that the
development, curiosity, and speculations dating back expression “to live” is too general, and that it is better
to Hippocrates, life before birth still remains a big to say a dog “dogs” or a fish “fishes” than a dog or
secret. Different kinds of intellectuals involved a fish lives.4
252 Textbook of Perinatal Medicine

When defining life, it should be considered not Although we should not forget that in the same
just as it is today, but as it might have been in its way today’s research is tomorrow’s benefit, 6
primordial form and as it will be in the future. All concerning human life, conclusions should not be
present forms of life appear as something completely treated one-sidedly – from one perspective. This
new. Life, then, is transferred and not conceived in reality should be regarded in all its richness: the
each new generation. Furthermore, the phenomenon embryo gives the biologist and geneticist substance
of life has existed on Earth for approximately 3.5 for consideration, but talking about the beginning
billion years. Consequently, although the genome of of a human life requires philosophical/anthro-
a new embryo is unique, the make-up of an embryo pological consideration, as well as theological and
is not new. If life is observed through the cell, then social sciences. In its protection, we have to include
every life (and human also) is considered as a ethics and law. This approach leads to the conclusion
continuum. Human cells and mankind have existed that it is necessary to reject reductionism as well as
on Earth continuously since the appearance of the integrism, and to find a “golden middle” between
first man. However, if the definition refers to a single these two methodologies.1
human being or the present population, the statement HAT DOES BIOLOGY SAY?
that “human life is a continuum” is not acceptable.5
Life, in a true sense of the word, begins when Biology characterizes human beings by the dynamics
of the system and its self-control (homeostasis),
the chemical matter gives rise, in a specific way, to
excitability (response to stimuli of different nature
an autonomous, self-regulating, and self-
and origins), self-reproducibility, the heredity of the
reproducing system. Life is connected with a living
characters, and the evolutionary trend. 1 For
being, and it creates its own system as an indivisible
biologists it is important to specify which form of
whole – it forms its individuality. One of the most
life phenomena we are referring to: cell, organism
important characteristics of living beings is
population, or species. The basic level of organization
reproduction. Reproduction is a means of creating
and the simplest form of life is the cell. Biologically
new life by transferring forms of an old one into
speaking, human cellular life never stops – or if it
newly formed human being. Therefore, variability,
did, the extinction of the human species would result
individual development, and harmony characterize
– and is passed on from one generation to another.
human beings. Individuality is the most essential
Human individual organismic life is defined within
characteristic of human beings consisting of new its life cycle, which is temporarily limited; i.e. it has
life, but also all human life forms through evolution, a beginning and an end.7 It is obvious that life is a
characterized by phenotype, behavior and the highly dynamic phenomenon that could be described
capability to recognize and adapt. Human embryo and explained through the careful study of life
and fetus gradually develop into these processes and interactions by interdisciplinary
characteristics. approach. In human spermatozoa and oocyte are two
“Human life” poses a semantic problem. The essential cells involved in creating human life. (Fig.
placenta is “human life,” as is every individual cell 20.1 and 20.2) It is clear that biologists are most
or organ of the human body, but “human life” is qualified to render judgment on the structure and
clearly not equivalent to “human being.” It is function of cells. To quote Scarpelli,8 the very broad
therefore mandatory to differentiate between scope of biological science (from molecular to
organic or vegetative human life and “potential behavioral biology, and from unicellular to
personal human life.” The latter term allows various multisystem forms) brings with it the justifiable
groups to identify a point of the continuum between understanding that the biological scientist knows and
abortion and birth to which they can ascribe is able to define the state of being alive or “life.” If
appropriate values and rights.3 not, the science fails.
 The Beginning of Human Life- Scientific and Religious Controversies 253
question of when the life cycle of a human individual
starts. Therefore, in the following text the main steps
of the human developmental process are going to be
briefly described, primarily during the first 15 days
following fertilization.
A human being originates from two living cells:
the oocyte and the spermatozoon, transmitting the
Fig. 20.1: Schematic presentation of spermatozoa and
oocyte. torch of life to the next generation. The oocyte is a
cell approximately 120 µ in diameter with a thick
membrane, known as the zona pellucida. The
At the moment of conception?
spermatozoon moves, using the flagellum or tail, and
the total length of the spermatozoon including the
tail is 60 µ. 10
After syngamy, the zygote undergoes mitotic cell
division as it moves down the fallopian tube toward
At the moment of implantation?
the uterus. A series of mitotic divisions then leads to
the development of the preembryo. The newly
divided cells are called blastomeres. From one to
When heart activity begins? three days after syngamy, there is a division into
two cells, then four cells. Blastomeres form cellular
aggregates of distinct, totipotent, undifferentiated
cells that, during several early cell divisions, retain
Fig. 20.2: Some possible questions on the beginning of the capacity to develop independently into normal
human life.
preembryos. As the blastocyst is in the process of
The biological scientist, who may specialize within attaching to the uterine wall, the cells increase in
one or another domain of the broad scope, has number and organize into two layers of cells.
particular and definitive knowledge and under- Implantation progresses as the outer cell layer of the
standing of the living individual that is his specialty. blastocyst, the trophectoderm, invades the uterine
If not, disorder will rise above failure. wall and erodes blood vessels and glands. Having
Understanding of the beginning of human life and begun five or more days after fertilization with the
development of the embryo/fetus could provide attachment of the blastocyst to the endometrial lining
definitive resolution. However, with the recent of the uterus, implantation is completed when the
possibility of visualizing early human development blastocyst is fully embedded in the endometrium
virtually from conception, perinatologists should be several days later. Even during these 5-6 days,
those who by study, training, practice and research modern medicine introduces the possibility of
are singularly qualified.9 making preimplantation genetic diagnosis.
While science provides us data about physical However, at this time, these cells are not yet
development of the human being, it does not provide totally differentiated in terms of their determination
information about its personality and personhood. to specific cells or organs of the embryo. The term
These are philosophical, rather than scientific topics. preembryo, then, includes the developmental stages
from the first cell division of the zygote through the
HUMAN EMBRYOGENESIS morula and the blastocyst. By approximately the 14th
Only proper understanding of the process of human day after the end of the process of fertilization, all
embryogenesis enables answering scientifically the cells, depending on their position, will have become
254 Textbook of Perinatal Medicine

parts of the placenta and membranes or the embryo. The newly conceived preembryo presents itself
The embryo stage, therefore, begins approximately as a biologically defined reality. However, the status
16 days after the beginning of the fertilization process of the preembryo as an individual remains a great
and continues until the end of 8 weeks after mystery. In the present scientific scene especially with
fertilization, when organogenesis is complete.11 the progress of ultrasound technologies, prenatal
The preembryo is the structure that exists from psychology and therapeutics opened a window into
the end of the process of fertilization until the prenatal life of embryo and fetus confirming the
appearance of a single primitive streak. Until the evidence that the embryo/fetus is a true subject
completion of implantation, the preembryo is capable itself. 12,13
of dividing into multiple entities, but does not contain
enough genetic information to develop into an PERSONALITY
embryo: it lacks of genetic material from maternal Defining personality is very complex. There is still
mitochondria and of maternal and parental genetic no clear definition of personality. One dictionary
messages in the form of messenger RNA or proteins. offers “what constitutes an individual as distinct
Therefore, during the preembryonic period it has person,” but does not define what the “what” is.
not yet been determined with certainty that a Another dictionary asserts “the state of existing as
biological individual will result, or would be one or a thinking intelligent being.” This definition might
more (identical twins forming), so that the assignment lead to the inference that personality increases pro
of the full rights of an individual human person is
rata with intelligence, or that some people may not
inconsistent with biological reality.
have a personality at all if we followed Bertrand
One conclusion from this is that the preembryo
Russell’s dictum that “most people would rather die
requires the establishment of special rules in the
than think and many, in fact, do!” Kenneth
society: it cannot claim absolute protection based on
Stallworthy’s Manual of Psychiatry is more help with
claims of personhood; although meriting respect, it
the definition that “personality is the individual as
does not have the same moral value that a human
a whole with everything about him which makes him
person has. Today, one largely accepted opinion is
different from other people,” because we can
that until the 14th day from fertilization or at least,
certainly distinguish fetuses from each other and
until implantation – the human embryo may not be
from other people. With the next sentence –
considered, from the ontological point of view, as
“personality is determined by what is born in the
an individual.
Genetic uniqueness and singleness coincide only individual in the first place and by everything which
after implantation and restriction have completed, subsequently happens to him in the second” – we
which is about 3 weeks after fertilization. Until that are really in the field.1,3
period, the zygote and its sequelae are in a fluid Viewpoints on the nature of “personhood” and
process, are not physical individual, and therefore what it means ethically and legally vary widely. In
cannot be a person. his proposed Life Protection Act, Sass acknowledges
It is well known that high percentages of oocytes that a fetus with formed synapses is not a “person”
which have been penetrated never proceed on to in the usual sense of the word, connoting
further development, and that many oocytes which consciousness and self-consciousness.14 Veatch sees
do, are thwarted so early in their development that the problem as defining the life that has full moral
their presence is not even recognized. It is suggested standing,15 while Knutson16 has noted that “those
that 30% of conceptions detected by positive reactions who employ spiritual or religious definitions of when
to human chorionic gonadotropin (HCG) tests abort life begins tend to place the beginning of life earlier
spontaneously before these pregnancies are clinically than those who employ psychological, sociological,
verified. or cultural definitions.”
 The Beginning of Human Life- Scientific and Religious Controversies 255
Led by the truism, “No insignificant person was Human society created several standards in
ever born,” human beings should be valued from defining “person” or “human being” based on what
birth to natural death. It is hard to establish proper is familiar and easy recognizable.1 For example: a
values and exact definitions. This becomes especially human speaks, understands, and laughs. Absence of
problematic when prenatal life is considered. The these characteristics (mutism, autism, and stoicism)
above stated truism opens an important question: does not disqualify. To the contrary, the conclusion
“Is the person-unborn a person in the first place and, is that the characteristics we have come to associate
if so, is the person-unborn a ‘significant’ person?”1 with being a person may not be applicable to each
Let us evaluate further present controversies. individual person. Therefore, it is necessary to
There is no doubt that the embryo and fetus in utero establish criteria for a definition of “person” in society
are biologically human individuals prior to birth. The and in time (Fig. 20.3 and 20.4). Some prominent
child who is born is the same developing human Italian professors12 committed themselves to caring
individual that was in the mother’s womb. Birth for the embryo in such a way; giving the same dignity
alone cannot confer natural personhood or human to every patient, and the human conditions to grow
individuality. This is confirmed by preterm deliveries and develop, to educate others inside and outside
of babies who are as truly human and almost as viable the specialty, and to carry out research involving all
as those whose gestation goes to full term. All the the components of society.
known evidence supports the human fetus being a
true ontological human individual and consequently
When becoming a person?
a human person in fact, if not in law. A human person
cannot begin before the appropriate brain structures are
When a person is recognised
developed that are capable of sustaining awareness. The in a society?
same applies to a grossly malformed fetus. It would
Does science know the answer?
answer?
still be a human individual even if its human nature
was not perfect or its functions quite normal. Nobody
questions the humanity of a Down’s syndrome fetus Is the answer metter of religion?

or child. A fetus or child with severe open spina bifida

is not less of a human being. The same should be
Fig. 20.3: Some questions about
said for the live anencephalic fetus or infant with
the definition of a person.
only brain stem functions. It is a human individual
even if it lacks a complete brain and usually survives
birth by only a few hours or a day.
“Person” and “personhood” are the legally
operational terms in the United States and many
other countries. Alternatively, “person” and
“personhood” are replaced by terms such as “viable
outside the uterus,” “a woman’s right to privacy,”
and “a woman’s right to choose.” In each case, viable,
privacy and choice, the life-support provider may
legally order transfer of the dependent individual
into a morbid environment. For this group, dilemma
(which includes the stem cell, abortion and cloning
Fig. 20.4: Different behavioral patterns of the fetuses in
debates) is abated, but not resolved. 3 second half of pregnancy. Are they different personalities?
256 Textbook of Perinatal Medicine

EMBRYO AS A PATIENT: pregnant woman or any other factor, generate, and

BIOETHICAL ASPECTS therefore ground obligations to the embryo/fetus
The idea of the embryo/fetus as a miniaturized infant on the part of the pregnant woman and her physician.
or adult is true to the extent that the embryonic/ A wide range of intrinsic characteristics has been
fetal physiologist must be able to apply knowledge considered for this role, e.g., moment of conception,
of every system after birth, yet quite untrue in failing implantation, central nervous system development,
to recognize the many ways in which life before birth quickening, and the moment of birth.20 Given the
differs fundamentally from life after birth. 6 The variability of proposed characteristics, there are many
newly conceived form presents itself as the views about when the embryo/fetus does or does
biologically defined reality: it is an individual that is not acquire independent moral status. Some take the
completely human in development that view that the embryo/fetus possesses independent
autonomously, moment by moment without any moral status from the moment of conception or
discontinuity, actualizes its proper form in order to implantation. Others believe that the embryo/fetus
realize through intrinsic activity, a design present in acquires independent moral status in degrees, thus
its own genome (Fig. 20.5 to 20.10).12 The embryo as resulting in “graded” moral status. Still others hold,
a patient is best understood as the subset of the at least implicitly, that the embryo/fetus never has
concept of the fetus as the patient. These two independent moral status so long as it is in utero.19
concepts opened a whole set of questions regarding Being a patient does not require that one
ethical problems. The embryo as the patient is possesses independent moral status.21 Being a patient
indivisible from its mother. However, balance is means that one can benefit from the application of
needed in protecting the interests of the embryo/ the clinical skills of the physician. 22 Put more
fetus and the mother. One prominent approach to precisely, a human being without independent moral
understanding the concept of the embryo/fetus as a status is properly regarded as a patient when the
patient has involved attempts to show whether or following conditions are met: that a human being is
not the embryo/fetus has independent moral status, presented to the physician for the purpose of
or personhood.17,18,19 Independent moral status for applying clinical interventions that are reliably
the fetus would mean that one or more of the expected to be efficacious, in that they are reliably
characteristics possessed either in, or of the embryo/ expected to result in a greater balance of goods over
fetus itself, and therefore independently of the harms in the future of the human being in question.20

Fig. 20.5: Transvaginal sonography of the Fig. 20.6: Color Doppler visualization of entire embryonic
8 weeks embryo with yolk sac. circulation.
 The Beginning of Human Life- Scientific and Religious Controversies 257

Fig. 20.7: Ten weeks gestation. Intrauterine content with early Fig. 20.8: Nine week embryo with vitelline duct and yolk
fetus. Many anatomical landmarks are visible. sac seen in three dimensions.

When the brain

activity starts?

Fig. 20.9: Eleven week embryo with entire peripheral and Fig. 20.10: The earliest detection of brain circulation at 7
central vascularization visualized by 3D power Doppler. weeks and 4 days of gestation.

In other words, an individual is considered a patient LEGAL STATUS OF THE EMBRYO

when a physician has beneficence-based ethical When discussing law, it should be always kept in
obligations to that individual. mind that medicine is international, but law is not.
To clarify the concept of the embryo/fetus as the Before the era of Aristotle, who taught that human
patient, beneficence-based obligation is necessary to life begins when the fetus is formed, human life was
be provided. Beneficence-based obligations to the considered to begin at birth. Prior to birth, the fetus
fetus and embryo exist when the fetus can later was not an independent human being but, like an
achieve independent moral status.22 This leads to the organ, part of the mother.23 Thus the birth of a full-
conclusion that ethical significance of the unborn child term infant has been used in the laws of various
is in direct link with the child to be born – the child countries to signify the beginning of the human life
it can become. that is to be protected.
258 Textbook of Perinatal Medicine

Indeed, the status of the human embryo is not into an embryo, a fetus, a child and an adult. By this
juridically defined and relies on the political, social, account, the zygote is an actual human individual
and religious influences in each country. and not simply a potential one, in much the same
Interestingly, nearly all countries of the Western way as an infant is an actual human person with
world use the twelfth week of pregnancy as the limit potential to develop to maturity and not just a
for legal abortion. It is not the end of the first potential person. As Scarpelli pointed out, outside
trimester, which is 13.3 weeks, and there is no other the realm of religious dogma, there has been no one
particular biological event to justify this limit. whose existence can be traced back to any entity
It is hard to answer the question when human other than the fertilized egg. The biological line of
life should be legally protected. At the time of existence of each individual, without exception,
conception? At the time of implantation? At the time begins precisely when fertilization of the egg is
of birth? In all countries (except Ireland and successful.9
Liechtenstein) juridical considerations are based on The process of fertilization actually begins with
Roman law. Roman civil law says that the fetus has conditioning of the spermatozoon in the male and
rights when it is born or if it is born-nasciterus. female reproductive tracts. Thereafter, fertilization
Few countries agree with the definition of the involves not only the egg itself, but also the various
beginning of human personality at the time of investments which surround the egg at the time it is
conception. The majority does not grant legal status released from the ovary follicle. Fertilization,
to the human embryo in vitro (i.e., during the 14 therefore, is not an event, but a complex biochemical
days after fertilization). Thus, even in the absence of process requiring a minimum of 24 hours to complete
legal rights, there is no denying that the embryo syngamy, that is the formation of a diploid set of
constitutes the beginning of human life, a member chromosomes. During this process, there is no
of the human family. Therefore, whatever the commingling of maternal and paternal chromosomes
attitude, every country has to examine which within a single nuclear membrane (pre-zygote); after
practices are compatible with the respect of that this process, the parental chromosomes material is
dignity and the security of human genetic material.24 commingled (zygote).
Among the many other activities of this new cell,
ARGUMENTS FOR BEGINNING OF HUMAN most important is the recognition of the new genome,
LIFE AND HUMAN PERSON AT FERTILIZATION which represents the principal information center for
The fundamental approaches of biomedical and social the development of the new human being and for all
(secular) practice must begin with the understanding its further activities. For the better understanding
that the subject before birth is a person and that of the very nature of the zygote, two main features
“personhood” is conferred by successful fertilization are to be at least mentioned here. The first feature
of the egg. To hide from this in silence or ignorance is that the zygote exists and operates from syngamy
should be unacceptable to all, as stressed by on as a being, ontologically one, and with a precise
Scarpelli.9 identity. The second feature is that the zygote is
The view that human life begins when sperm and intrinsically oriented and determined to a definite
eggs fuse to give rise to a single cell human zygote, development. Both identity and orientation are due
whose genetic individuality and uniqueness remain essentially to the genetic information with which it
unchanged during normal development, is widely is endowed. That is why many do believe that this
supported. Because the zygote has the capacity to cell represents the exact point in time and space where
become an adult human individual, it is thought it a new human individual organism initiates its own
must be one already. The same zygote organizes itself life cycle.1

ARGUMENTS AGAINST THE BEGINNING

 The Beginning of Human Life- Scientific and Religious Controversies 259
OF HUMAN LIFE AT FERTILIZATION necessary condition for an embryo belonging to
the human species, and this condition can be
Today, one largely accepted opinion is that until the
obtained only at implantation.19 However, there
14 th day from fertilization – or at least, until
is evidence that development of a human embryo
implantation – the human embryo may not be
in vitro can continue well beyond the stage of
considered, from the ontological point of view, as
implantation, and that mouse embryos implanted
an individual. There are at least five main reasons in
under the male renal capsule can reach the fetal
favor of this opinion:
stage. It is also argued, or at least implied, that
1. Before the formation of the embryonic disc, the
so many human embryos die before or after
embryo is “a mass of cells, genetically human,”
implantation that it would be lacking in realism
“a cluster of distinct individual cells,” which are
to accept that the human individual begins before
each “distinct ontological entities in simple contact
implantation.
with the others”.25 The genetically unique, newly It is well known that high percentages of
developed DNA, a genome, is not established oocytes which have been penetrated never
until 48 hours after sperm penetration. The ovum proceed on to further development, and that many
and sperm lie side by side for more than 48 hours oocytes which do, are thwarted so early in their
before they finally merge. In biological terms, this development that their presence is not even
renders conception as a process that occurs over recognized. Up to 50% of ovulated eggs and
time and not a specific point in time.3 zygotes recovered after operations were found
2. Until approximately the 14th day after fertilization, so grossly abnormal that it would be very unlikely
all that happens is simply a preparation of the that they would result in viable pregnancies. It is
protective and nutritional systems required for also suggested that 30% of conceptions detected
the future needs of the embryo. Only when the by positive reactions to human chorionic
entity called embryonic disc is formed can the gonadotropin (HCG) tests abort spontaneously
embryo develop into a fetus. 26 before these pregnancies are clinically verified.
3. The monozygotic twins phenomenon or chimeras The scientific literature is not unanimous on the
can occur. In fact, this seems to be the strongest incidence of natural wastage prior to, and during,
reason why the embryo is denied the quality of implantation in humans, varying from 15% to as
individuality, and as a proof that the zygote cannot much as 50%. The vast majority of these losses
be an ontologically human being. In are due to chromosomal defects caused during
approximately one-third of cases the embryo gametogenesis and fertilization. 27
divides at about the two cells stage, and in the Genetic uniqueness and singleness coincide
other two-thirds, the inner cell mass divides only after implantation and restriction have
within the blastocyst from day 38. Occasionally, completed, which is about 3 weeks after
the division takes place from day 8-12, but usually fertilization. Until that period, the zygote and its
it is not complete, thereby forming conjoined sequelae are in a fluid process and are not a
identical twins or two-headed individuals. physical individual, and therefore cannot be a
The chimera, resulting from the recombination person.
of two individua to become one individuum (and Although in a set of twins one individuum can
detectable through genetic testing), provides disappear, genetic and individual identities are
another argument against the equivalence of now more or less equivalent. Many eminent
conception and the beginning of human life: no Catholic writers, among them the Australian priest
individuum has died, yet one has ceased to exist. Norman Ford, author of When Did I Begin?
4. Co-existence of the embryo with its mother is a consider implantation to mark the beginning of
260 Textbook of Perinatal Medicine

human life; they maintain that the preembryo has individual is already constituted.29,30
only intrinsic potential and must be protected only In Western Europe and in North and South
from the time of implantation.28 America these opinions are mostly based on Judeo-
5. The product of fertilization may be a tumor, a Christian theology, in Arabian Countries, in Africa,
hydatidiform mole, or chorioepithelioma. Though and in Asia prevail the influences of the Islamic and
the mole is alive and of human origin, it is Buddhist religions. Although their approach to the
definitely not a human individual or human being. beginning of human life is impressively similar, each
It lacks a true human nature from the start and of these religions has different attitudes to the
has no natural potential to begin human problem of embryo research, infertility and its
development. therapy. In a fact, while the Jewish attitude towards
A teratoma is another clear instance of cells infertility is expressed in the Talmud sayings and in
developing abnormally that results from the the Bible (synthesized in the first commandment of
product of fertilization, but which could not be God to Adam “Be fruitful and multiply”), the
considered to be a true human individual with a Christian point of view establishes no absolute right
human nature. It has no potential to develop into to parenthood. According to the Islamic views,
an entire fetus or infant. Clearly, the fetus with attempts to cure infertility are not only permissible,
the teratoma would be a human individual, but but also a duty.
not the attached teratoma itself. Obviously, not Islamic teaching is based on prophet Mohammed
all the living cells that develop from the conceptus, description: “The creation of each of you in his
the early embryo, or the fetus form an integral mother’s abdomen assumes a “nufta” (male and
part of a developing human individual.1 female semen drops) for 40 days, then becomes
“alaga” for the same (duration), then a “mudgha”
DIFFERENT RELIGIOUS TEACHINGS (like a chewed peace of meat) for the same, then God
AND HISTORICAL ASPECTS sends an angel to it with instructions. The angel is
The Catholic Church’s teachings are clearly described ordered to write the Sustenance, life span, deeds and
in the Introduction Donum Vitae: “A human creature whether eventually his lot is happiness or misery,
is to be respected and treated as a person from then to blow the Spirit into him” (Human
conception and therefore from that same time his developments as described in Khur’an and Sunnah;
(her) rights as a person must be recognized, among Moore et al. In: Some evidence for the truth of Islam,
which in the first place is the invaluable right to life 1981). The summary of this poetic and sacred
of each innocent human creature.” description is: Soul breathing “ensoulment” occurs
In 1997 the Third Assembly of the Pontifical at 120 days of gestation from conception.
Academy for Life was held in Vatican City. It has To make this religious principle applicable to the
been concluded that “at the fusion of two gametes, practice, the Islamic Jurisprudence Council wrote a
a new real human individual initiates its own FATWA in 1990 that said: “Abortion is allowed in
existence, or life cycle, during which – given all the the first 120 days of conception if it is proven beyond
necessary and sufficient conditions – it will doubt that the fetus is affected with a severe
autonomously realize all the potentialities with which malformation that is not amenable to therapy, and
he is intrinsically endowed.” The embryo, therefore, if his life, after being born, will be a means of misery
from the time the gametes fuse, is a real human to both him and his family, and his parents agree.”
individual, not a potential human individual. It was so that there is no difficulty for either the prenatal
even added that recent findings of human biological diagnosis, or for the possible termination of
science recognize that in zygotes resulting from pregnancy within the exposed limits.
fertilization, the biological identity of a new human Buddhism has imposed strict ethics on priests,
 The Beginning of Human Life- Scientific and Religious Controversies 261
but it has relatively lenient attitudes toward lay and it greatly depends on the individual’s
people, so if medical treatment for infertility is philosophical principles. Those two, more or less
available, people should make use of it. autonomous intellectual disciplines have very often
For about two thousand years the opinions of tried dominating one another, or ignoring each other.
Aristotle, the great Greek philosopher and naturalist, It is only recently that the majority of scientists and
on the beginning of the human being were commonly some theologians have come to realize that the
held. He argued that the male semen had a special separate meanings of scientific and religious “truths”
power residing in it, pneuma, to transform the complement each other, thus representing
menstrual blood, first into a living being with a methodologically independent entities. Current
vegetative soul after seven days, and subsequently science is not interested in what Nature is, but in the
into one with a sensitive soul 40 days after contact facts that could be stated regarding it, thus trying to
with the male semen.31 explain the term, rather then inventing it. The main
Aquinas adopted Aristotle’s theory, but specified difference between science and religion can be seen
that rational ensolement took place through the in the fact that scientific “truths,” unlike religious
creative act of God to transform the living creature postulates, can and must be experimentally verified
into a human being once it had acquired a sensitive and the methods of scientific cognition can be easily
soul. The first conception took place over seven days, explained and learnt. Whereas religion favors
while the second conception, or complete formation
irrationality, science prefers an entirely rational
of the living individual with a complete human
approach to matters of importance. Intellectual
nature, lasted 40 days.32
cognition, when scientifically expressed, usually is
Hippocrates believed that entrance of the soul into
in a form of mathematical formulas and presented
the male embryo occurred on the thirtieth day of
quantitatively. Contrarily, religion tends to keep its
intrauterine life. It entered into the female embryo
truths in a form of metaphoric expressions, preferring
on the fortieth day. Actually, this idea was a
qualitative. Today, there is a tendency, on a higher
considerable improvement on the scheme found in
level, to reopen the dialogue between the science
the Book of Leviticus, where it is suggested that the
and religion, which was present at the very beginning
soul does not enter the female until forty days after
of our culture. Religion had existed long before
the conception.33
science came to life, but science is not to be thought
In short, the rational soul enables the matter to
become a human being, an animated body, an of as a continuation of the religion. Each discipline
embodied soul, a human person. should preserve its principles, its separate
Harvey’s experiments with deer in 1633 proved interpretations and its own conclusions. In the end,
Aristotle’s theory of human reproduction wrong, both of them represent different components of the
without himself finding a satisfactory explanation of one and indivisible culture of mankind.
human conception. After modern scientists
CLINICAL CONTROVERSIES
discovered the process of fertilization, most people
took for granted that human beings, complete with There are some clinical controversies pertinent in any
a rational soul, began once fertilization had taken discussion of when life begins. Spermatozoa are living
place. cells. They present evidence that they are living by
It is clear that the answer to the question “When their motility. They are equipped with an effective
has the human being actually come to life?” could mechanism for movement in the form of a tail that
only be given by combining the cognition of different beats under the control of the cytoplasmic droplets
religions, philosophies, and various biological within the head. These living cells, which have been
scientific disciplines. There is a very fine line between manufactured in the testes, are released into the
the competence of science and the one of metaphysics,
262 Textbook of Perinatal Medicine

environment provided by the male reproductive described as the complete expulsion of a fetus of 1000
tract. They are not yet capable of fertilization. The g or 28 weeks of pregnancy. With advances in
spermatozoon must first come under the influence perinatal and neonatal intensive care, the line was
of the male reproductive tract, where it acquires the drawn at 500 g, or approximately or 22 weeks of
ability to function in fertilization. Even after gestation, some years later. This meant that a 20-
ejaculation, it is capable of penetrating the egg, and week-old-fetus was not born by definition, even if
it is modified further by exposure to the female it was viable. This concept has changed. The same
reproductive tract, taking on the ability or capacity logic applies to a live fetus being accorded the term
to fertilize. The decision must be made as to whether “life,” if we use such definitions as the beginning of
the spermatozoon is a being (i.e., living and human brain activity or ultrasonic proof of heartbeat and
with the potential for continued life once fertilization movement. The establishment of each of these
has occurred); albeit in another form, it is entitled to parameters is shifted to an earlier stage year by year
the right of protection as a person. Those who deny by improving technological refinements in electronic
right for life to the spermatozoon might argue that and ultrasonic equipment. This leads us to the
it is not a complete human cell chromosomally – it conclusion that to follow this line of reasoning means
contains only the haploid number of chromosomes. to give life, birth, and viability definitions
Paradoxically, those who take that point of view determined by technology. The more advanced the
would insist that an individual born with fewer or technology, the earlier life begins.
more chromosomes than normal is human and In any consideration of the beginning of human
entitled to all the rights of “personhood.” As life, it helps to think about when life ends. Let us
Mastroianni stressed, the decision to base the consider the following: A two-week-old-newborn
definition of “human life” solely on the number of is hospitalized with massive brain injury suffered in
chromosomes in a given cell has far-reaching an automobile accident. Despite all measures, no
implications.34 electrical or other brain activity can be detected
Furthermore, life has been defined as being during the next two days and the child is pronounced
terminated when brain activity ends. If we were to dead. Its body parts may survive after its death, as
say that life begins when brain activity starts, we after the death of every person of whatever age. Hair
would be admitting that the definition of the and nails grow for days. Kidneys, heart, liver and
beginning of life is dependent upon technology and other organs may go on living for years if
not upon ethics or morality. transplanted into another individual. Cells taken
Some suggested that the beginning of human life soon after death and cultured in a laboratory might
requires the neural fusion of the periphery with the live well beyond the 72 or more years this child might
center, as well as sufficient development of the brain have lived, although the life of the infant has ended.
itself. 35 Brody formulated the so-called symmetry The conclusion reached in this case – that death of
concept: if the death of a human being requires the the brain means the end of life – is generally accepted
death of the brain, the beginning of human life shall by physicians, courts, and the public.4
correspond with the beginning of the life of the brain, Returning to the question of when life begins, it
considered to be at day 32 pc.36 However, Sass has is true that the DNA of the fertilized egg has the
correctly pointed out that fusion is not established information necessary to form an individual, but so
anatomically without neurons which form synapses, does virtually every other cell in the body. Nobody
which would be expected from embryological would claim full rights for the living cells of the infant
development at 70 days (8 weeks) pc.37 killed in the accident, although each has a complete
In this light, let us take for example the accepted library of DNA. Nor would they for thousands of
definition of birth, which some years ago was living skin cells we loose every time we wash our
 The Beginning of Human Life- Scientific and Religious Controversies 263
hands and faces. Is there some stage in the vascular changes in the former follicular wall. Color
development of the brain that is critical? Or is it the Doppler studies of the luteal blood flow velocities
time at which the fetus can survive outside the womb, enable evaluation of the corpus luteum function in
with or without the support of medical technology? second phase of menstrual cycle and early pregnancy.
Should we revert to a criterion used for many years, When the placenta takes over the role of production
the time of quickening, when one can feel the fetus of progesterone, the corpus luteum starts regressing.
moving? These are questions still to be answered. After ovulation there is a short period during
which the endometrial receptivity is maximal. During
VISUALIZATION OF EARLY these few days a blastocyst can attach to the
HUMAN DEVELOPMENT endometrium and provoke increased vascular
Significant advances have been made in recent years permeability and vasodilatation at the implantation
in visualizing and analyzing the earliest human site. Trophoblast-produced proteolytic enzymes
development. Most of them have been done by cause the penetration of the uterine mucosa and erode
introduction of three-dimensional static and color adjacent maternal capillaries. This results in formation
Doppler and 4D sonography. Many new parameters of the intercommunicating lacunar network – the
about early human development are now studied intervillous space of the placenta. A small
directly by new ultrasound techniques. intradecidual gestational sac can be visualized by
Considerable number of biochemical, morpho- transvaginal sonography between 32 and 34 days.39
logical and vascular changes occur within the follicle The secondary yolk sac is the earliest
extraembryonic structure normally seen within the
during the process of ovulation and luteinization and
gestational sac in the beginning of the 5th gestational
most of them can be studied by transvaginal
week. The yolk sac volume was found to increase
ultrasound with color Doppler and 3D facilities.38 If
from 5 to 10 weeks’ gestation. When the yolk sac
the oocyte is fertilized, the embryo is transported
reaches its maximum volume at around 10 weeks, it
into the uterus where under favorable hormonal and
has already started to degenerate, which can be
environmental conditions, it will implant and develop
indirectly proved by a significant reduction in
into a new and unique individual. The introduction
visualization rates of the yolk sac vascularity. 25
of transvaginal color Doppler improved the
Therefore, a combination of functional and
recognition of blood vessels enabling detailed
volumetric studies by 3D power Doppler helps to
examination of small vessels such as arteries supplying
identify some of the most important moments in early
preovulatory follicle, corpus luteum and human development.
endometrium.26 The embryonic heart begins beating on about day
Perifollicular vascularization can help in 22-23, accepting blood components from the yolk sac
identification of follicles containing high quality and pushing blood into the circulation. The
oocytes, with a high probability of recuperating, embryonic blood begins circulating at the end of the
fertilizing, cleaving and implanting, while 3D 4th week of development.
ultrasound enables accurate morphological inspection The start of the embryo-chorionic circulation
and detection of cumulus oophorus. Follicles without changes the source of nourishment to all
visualization of the cumulus by multiplanar imaging intraembryonic tissues. The survival and further
are not likely to contain fertilizable oocytes. This development of the embryo become dependent on
information is especially useful in patients the circulation of embryonic/fetal blood. If the
undergoing ovulation induction. embryo-chorionic circulation does not develop, or
Following ovulation, the corpus luteum is formed fails, the conceptus is aborted. The embryo cannot
as the result of many structural, functional and survive without the chorion (placenta) and the
264 Textbook of Perinatal Medicine

chorion will not survive without the embryo. and behavior.45 With four-dimensional ultrasound,
Avascular degenerated chorionic villi constitute the movements of head, body, and all four limbs and
hydatidiform mole. extremities can be seen simultaneously in three
Within the embryo, there are three distinct blood dimensions.46 Therefore, the earliest phases of the
circulatory systems:10 human anatomical and motor development can be
1. Vitelline circulation (from yolk sac to embryo) visualized and studied simultaneously. It is clear that
2. Intraembryonic circulation neurologic development – early fetal motor activity
3. Two umbilical arteries (from embryo to placenta and behavior needs to be re-evaluated by this new
- fetoplacental circulation) technique.47-49 Our group studied the development
It is possible to visualize and assess them virtually of the complexity of spontaneous embryonic and
from conception.40-44 fetal movements. 50 With the advancing of the
At five weeks from the maternal side of placenta, gestational age, the movements become more and
it is possible to obtain simultaneous three- more complex. The increase in the number of
dimensional imaging of the developing intervillous axodendritic and axosomatic synapses between 8 and
circulation during the first trimester of pregnancy. 10, and again between 12 and 15 weeks51 correlates
Three-dimensional power Doppler reveals intensive with the periods of fetal movement differentiation
vascular activity surrounding the chorionic shell and with the onset of general movements and
starting from the first sonographic evidence of the complex activity patterns, such as swallowing,
developing pregnancy during the 5 th week of stretching and yawning, seen easily by 4D technique.
gestation. By seven to eight weeks of pregnancy, gross body
At seven weeks, three-dimensional power movements appear. They consist of changing the
Doppler images depict aortic and umbilical blood position of the head towards the body. By nine to
flow. Initial branches of umbilical vessels are visible ten weeks of pregnancy, limb movements appear.
at the placental umbilical insertion. They consist of changing the position of the
During the 8th and 9th week, developing intestine extremities towards the body without the extension
is being herniated into the proximal umbilical cord. or flexion in elbow and knee. At ten to twelve weeks
At nine to ten weeks, herniation of the mid-gut
is present. The arms with elbow and legs with knee
are clearly visible, while feet can be seen approaching
the midline.
At eleven weeks, three-dimensional power
Doppler imaging allows visualization of the entire
fetal and placental circulation.
During the 11 th -12 th week of pregnancy
development of the head and neck continues. Facial
details such as nose, orbits, maxilla and mandibles
are often visible. Herniated mid-gut returns into the
abdominal cavity.

NEW POSSIBILITIES FOR STUDYING Fig. 20.11: Integrated slide showing continuity of scientific
EMBRYONIC MOVEMENTS AND BEHAVIOR visualization of the beginning of early human development
from genetic material to oocyte, morphology of embryo, its
The latest development of 3D and 4D sonography vascularization and fetal behavioral pattern assessed by
enables precise study of embryonic and fetal activity 4D sonography.
 The Beginning of Human Life- Scientific and Religious Controversies 265
of pregnancy, complex limb movements appear. They 5. Godfrey J. The Pope and the ontogeny of persons
(Commentary), Nature 1995,273:100.
consist of changes in the position of limb segments 6. Liggins Graham (Mont). Foreword. In Nathanielsz P.W.
towards each other, such as extension and flexion in “ Life before birth and the time to be born.” Promethean
elbow and knee (Fig. 20.11) . Press Ithaca, New York, 1992.
7. Gilbert SF. Developmental biology. Sunderland, Mass.
Between twelve to fifteen weeks of pregnancy,
Sinauer Associates 1991; 3.
swallowing, stretching and yawning activities 8. Scarpelli EM. Postnatal through adult human life and the
appear. In addition to these activities, it is now scientific deception. In: Atti del I Congresso Nazionale
feasible to study by 4D ultrasound a full range of della Societa Italiana di Medicina Materno Fetale, Rome,
March 17-21, 2003. Medimond (International
facial expression including smiling, crying and eyelid Proceedings): Bologna, Italy, 2003, 29-36.
movement. 9. Scarpelli EM. Personhood: a biological phenomenon. J
It is hoped that the new 4D technique will help Perinat Med 2001; 29:417-26.
10. Jirasek JE. An Atlas of the human embryo and fetus.
us have a better understanding of both the somatic NewYork-London: Parthenon Publishing 2001.
and motoric development of the early embryo. It 11. ACOG Committee Opinion: Committee on Ethics:
will also enable the reliable study of fetal and even Preembryo research: history scientific background, and
ethical considerations. Int J Gynecol Obstet 1994; 45: 291-
parental behavior. 46 301.
12. Declaration of Professors from Five Faculties of Medicine
CONCLUSION and Surgery of the universities of Rome, organizers of
the Conference: The Embryo as a Patient.
The question of when a human life begins and how 13. Kurjak A, Azumendi G, Stanojevic M, Carrera JM. An
to define it, could be answered only through the attempt to study fetal awareness by four-dimensional
inter-connecting pathways of history, philosophy, ultrasonography, (submitted).
14. Sass HM. Brain life and brain death: a proposal for
medical science and religion. It has not been easy to
normative agreement. J Med Philos 1989;14:45-59.
determine where to draw the fine line between the 15. Veatch RM. The beginning of full moral standing. In: The
competence of science and metaphysics in this delicate beginning of human life, FK Beller, RF Weir (Eds).
philosophical field. To a large extent the drawing of Dordrecht, Kluwer, 1994, p 19.
16. Knutson AL. When does human life begin? Viewpoints
this line depends on one’s fundamental philosophical of public health professionals. Am J Publ Health
outlook. To quote Beller: “The point at which human 1967;57:2167.
life begins will always be seen differently by different 17. Engelhardt HT. Jr. The foundation of bioethics. New York
individuals, groups, cultures, and religious faiths. In Oxford University Press 1986.
18. Dunstan GR. The moral status of the human embryo. A
democracy there are always at least two sides, and tradition recalled. J Med Ethics 1984;10 :38-44.
the center holds only when the majority realizes that 19. Chervenak FA, McCullough LB, Kurjak A. Ethical
without a minority, democracy itself is lost. The implications of the embryo as a patient. In: Kurjak A,
Chervenak FA, Carrera JM. The embryo as a patient.
minority in turn must realize its best chance lies in Parthenon Publishing Group New York London 2001;226-
persuasion by reason and thoughtfulness rather than 30.
fanaticism.”3 20. Curran CE. Abortion: Contemporary debate in
philosophical and religious ethics. In Reich WT(ed).
REFERENCES Encyclopedia of Bioethics. New York Macmillan 1978, 17-
26.
1. Serra A, Colombo R. Identity and status of the human 21. Ruddick W, Wilcox W. Operating on the fetus. Hastings
embryo: the contribution of biology. In: de Dios Vial Cen Report 1982;12:10-14.
Correa, Sgreccia E. (eds). Identity and statute of human 22. McCullogh LB, Chervenak FA. Ethics in Obstetrics and
embryo. 1998;128. Gynecology. New York. Oxford University Press, 1994.
2. Kurjak A. The beginning of human life and its modern 23. Connery JR Jr. The ancients and medievals on abortion.
scientific assessment. Clin Perinatol 2003;30:27-44. In: Abortion and Constitution, DJ Horan, ER Grant, PC
3. Beller FK, Zlatnik GP. The beginning of human life. Cunningham (Eds). Washington DC, Georgetown
Journal of Assisted Reproduction and Genetics University Press, 1987, 124.
1995;12(8):477-83. 24. Pierre F, Soutoul JH. “Medical and legal
4. Kurjak A. When does human life begin? Encyclopedia complications.”[Article in French] J Gynecol Obstet Biol
Moderna 1992; 383-90. Reprod (Paris) 1994;23(5):516-9.
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25. Ford NM. When did I begin? Conception of the human 41. Kurjak A, Predanic M, Kupesic S. Transvaginal color
individual in history, philosophy and science, Cambridge: Doppler study of middle cerebral artery blood flow in
Cambridge University Press 1991, 137-46. early normal and abnormal pregnancy. Ultrasound
26. McLaren A. Prelude to embryogenesis, in the Ciba Obstet Gynecol 1992;2:424-28.
Foundation, Human Embryo Research, Yes or No? 42. Kurjak A, Kupesic S. Doppler assessment of the
London, New York: Tavistock 1986:5-23,12. intervillous blood flow in normal and abnormal early
27. Abel F. Nascita e morte dell’uomo: prospettive della pregnancy. Obstet Gynecol 1997;89:252-256.
biologia e della medicina, in S. Biolo, ed. Nascita e morte 43. Kurjak A, Kupesic S, Hafner T. Intervillous blood flow in
dell’uomo. Problemi filosofici e scientifici della bioetica, normal and abnormal early pregnancy. Croatian Med J
Genova: Marieti 1993:37-53. 1998;39(1):10.
28. McCormick KA. Who or what is the preembryo? 44. Kurjak A, Kupesic S. Three-dimensional transvaginal
Kennedy Instit Ethics J 1991;1:24. ultrasound improves measurement of nuchal
29. Mahoney SJ. Bioethics and belief. London, Sheed and translucency. J Perinat Med 1999;27:97-102.
Ward, 1984, 80. 45. Kurjak A, Kupesic S, Banovic I, Hafner T, Kos M. The
30. Johnson M. Delayed hominization. Reflections on some
study of morphology and circulation of early embryo by
recent Catholic claims for delayed hominization.
three-dimensional ultrasound and power Doppler. J
Theological Studies 1995, 56: 743-63.
Perinat Med 1999;27:145-57.
31. Congregation for the Doctrine of the Faith, Instruction
on respect for human life in its origin and on the dignity 46. Lee A. Four-dimensional ultrasound in prenatal diagnosis:
of procreation “Donum Vitae” (February 12, 1987), Acta leading edge in imaging technology. Ultrasound Rev
Apostolicae Sedis 1988, 80: 70-102. Obstet Gynecol 2001;1:144-48.
32. Ford NM. When did I begin? Cambridge University Press, 47. Campbell S. 4D, or not 4D: that is the question.
1991. Ultrasound Obstet Gynecol 2002;19:1-4.
33. Beazley JM. Fetal assessment from conception to birth. 48. de Vries JI, Visser GH, Prechtl HF. The emergence of fetal
In: Kurjak A, ed. Recent advances in ultrasound diagnosis behaviour. I. Qualitative aspects. Early Hum Dev
2. Amsterdam: Excerpta medica 1980;128. 1982;7:301-22.
34. Kurjak A. Kada pocinje zivot. In: Kurjak A, ed. Ocekujuci 49. de Vries JI, Visser GH, Prechtl HF. The emergence of fetal
novorodjence, Zagreb: Naprijed, 1987;18-28. behaviour. I. Qualitative aspects. Early Hum Dev
35. Mastroianni Jr L. Ethical aspects of fetal therapy and 1985;12:99-120.
experimentation. In: Schenker JG, Weinstein D, editors. 50. Kurjak A, Vecek N, Hafner T, Bozek T, Funduk-Kurjak
The intrauterine life: management and therapy. B, Ujevic B. Prenatal diagnosis: what does four-
Amsterdam: Excerpta Medica; 1986, 3-10. dimensional ultrasound add? J Perinat Med 2002;30:57-
36. Beller FK, Reeve J. Brain life and brain death: the 62.
anencephalic as an explanatory example. J Med Philos
51. Kurjak A, Azumendi G, Vecek N, Kupesic S, Solak
1989;14:5-20.
M, Varga D, Chervenak F. Fetal hand movements
37. Brody B. Abortion and the sanctity of human life: A
and facial expression in normal pregnancy studied
philosophical view. Cambridge, MIT Press, 1975, p 109.
38. Sass HM. The moral significance of brain-life-criteria. In: by four-dimensional sonography. J Perinat Med
The beginning of human life, FK Beller, RF Weir RF (Eds). 2003;31:496-508.
Dordrecht, Kluwer, 1994, p 57-70. 52. Okado N, Kojima T. Ontogenity of the central nervous
39. Kupesic S. The first three weeks assessed by transvaginal system: neurogenesis, fibre connection, synaptogenesis
color Doppler. J Perinat Med. 1996;24:310-17. and myelinization in the spinal cord. In Prechtl HFR, ed.
40. Kupesic S, Kurjak A, Ivancic-Kosuta M. Volume and Continuity of neural functions from prenatal to postnatal
vascularity of the yolk sac. J Perinat Med 1999;27:91-96. life. Oxford: Blackwell Scientific 1984, 46-64.
 21
Preimplantation Diagnosis

Lawrence J Nelson

INTRODUCTION 19% in women of 40 or more years of age.3 One study

found aneuploidy to be 52% in women aged 40 to
Preimplantation genetic diagnosis (PGD) is a
47.4 PGD of aneuploidy has been shown to reduce
technique devised within the last 15 years used
the risk of children with trisomies, increase
primarily to identify genetic disorders or defects in
implantation rates, and decrease spontaneous
human embryos created by in vitro fertilization (IVF)
prior to their implantation for gestation. The two abortions.5
dominant methods of PGD currently in use are polar Finally, in cases of parents who have children with
body biopsy and blastomere biopsy on cleavage stage bone marrow disorders who are in need of HLA-
embryos, though fluorescence in-situ hybridization matched stem cell transplantation (e.g., acute
has been used for PGD of common aneuploidies. PGD lymphoid leukemia) and who wish to conceive
is an “attractive means of preventing heritable another child to serve as a donor of stem cells, PGD
genetic diseases” which, as an alternative to can be employed to test embryos for causative gene
traditional prenatal genetic diagnosis following mutations and simultaneously for HLA alleles with
chorionic villus sampling or amniocentesis, can avoid the goal of selecting and transferring only those
the need for selective abortion of affected fetuses, unaffected embryos which are HLA matched to the
even though “it is strongly recommended that sick child. A recent report documents this process as
normality be confirmed by subsequent CVS or resulting in five singleton pregnancies and the birth
amniocentesis.”1 According to the National Society of five HLA-matched healthy children.6
of Genetic Counselors, the primary reason for More than 1,000 unaffected children have been
electing PGD over traditional prenatal diagnosis “is born following PGD; this suggests that the procedure
the couple’s objection to pregnancy termination.”2 is both accurate and safe. 7 Even thought PGD was
PGD is also used to detect aneuploidy (the major described as experimental as recently as 1998,8 it is
cause of inherited diseases) and to select now considered “an established technique with
chromosomally normal embryos for implantation specific and expanding applications for standard
mostly in women of advanced maternal age clinical practice” that is “a viable alternative to post-
undergoing in vitro fertilization. The only known conception diagnosis and pregnancy termination.”1
risk factor for aneuploidy is maternal age: while This chapter will review and comment upon the
trisomies appear in 2% of recognized pregnancies of central ethical issues raised by PGD. These fall into
women 25 years old, this number increases to up to three major categories:
268 Textbook of Perinatal Medicine

1. ethics and the provision of PGD, including the While advertising health care services is by no means
ethics of marketing PGD services, shared risk or inherently unethical, the traditional professional
refund programs, and disclosure and patient values of beneficence and loyalty to the patients’
consent; interests indicate that the provision of medical
2. the moral status of the extracorporeal human services ought not to resemble a common commercial
embryo (those outside a woman’s body) and their transaction between strangers. Clinicians are in a
destruction following embryo selection; and fiduciary relationship with their patients and are
3. the ethically appropriate uses of PGD, including obligated to act so as to deserve and maintain the
its use to prevent the birth of disabled persons patient’s trust and confidence that their wishes and
and to select for sex and other traits for best interests are being faithfully served.
nonmedical reasons. The last section examines the Consequently, the marketing of infertility services
importance of each individual clinician making a ought to place the good of patients above other
personal decision, based upon the exercise of an interests (especially a clinician’s or clinic’s own
informed conscience, about the ethical propriety economic interests), should not induce patients to
of his or her involvement in the provision of PGD accept excessive, unneeded, or unproven services,
services, whether for the prevention of genetic and should adhere to high standards of honesty and
disease and disability or for the selection of sex accuracy in the information provided to prospective
or some other trait unrelated to health. patients.10
For example, one infertility clinic that used
ETHICS AND THE PROVISION OF PGD advertisements to entice persons to undergo IVF
with language suggesting that “the dream of having
Marketing
a child might still come true for you” can be criticized
Most of the utilization of IVF and, by implication, as selling profitable services at the expense of
PGD, services is not covered by health insurance in vulnerable people suffering from the anguish and
the United States8, and this is likely true elsewhere disappointment of childlessness. Another IVF clinic
in the world as well. Consequently, most individuals used chemical rather than clinical pregnancies in
pay for these services directly out of their own private calculating its “success” rate, a misleading number
resources. With the average cost for an IVF cycle in as only a relatively small portion of chemical
the U.S. being $12,400,9 the financial commitment for pregnancies result in live birth.10 The “success,” that
the individuals involved is substantial. Receiving is, healthy live-birth, rate of IVF and PGD varies by
direct payment from patients’ appeals to clinicians center, and the staff of each is ethically obligated to
who are not required to wait weeks or months for be scrupulously careful in calculating and disclosing
insurer reimbursement, or to expend large amounts its rates of success – and its rates of error as well.
of time and effort in submitting reimbursement This is particularly important as many PGD centers
forms, or obtaining pretreatment authorization. have not reported their experience, and there
These factors make the provision of IVF and PGD an currently is no systematic approach to presenting
attractive and potentially profitable form of errors. Informal reports suggest an error rate in the
professional practice. The utilization of PGD adds range of 1% to 10%, depending on the disease and
several thousands of dollars in cost over and above assay being evaluated.1 The European Society for
those incurred for IVF. Human Reproduction and Embryology PGD
Clinics providing IVF, PGD, and other consortium has reported clinical pregnancies in 17%
reproductive health services often advertise in the of cases after testing for structural chromosomal
mass media and make other efforts to attract patients abnormalities, 16% after sexing, and 21% after testing
(e.g., free informational seminars, internet sites). for monogenic diseases, while the International
 Preimplantation Diagnosis 269
Working Group of Preimplantation Genetics has plans reviewed by the ASRM Ethics Committee were
reported a pregnancy rate of about 24%.11 The former found to meet this standard.12
also noted an error rate of 2-3%. The objection to shared risk plans as an unethical
contingency fee is likewise misplaced. The AMA
Shared Risk Programs Code of Medical Ethics states that “a physician’s fee
In addition to traditional fee-for-service pricing, should not be made contingent on the successful
outcome of medical treatment.” 13 First, this
some assisted reproduction programs offer IVF on
prohibition is primarily aimed at physicians treating
a shared risk basis by refunding the patient(s) a
patients who are seeking compensation for their
portion of, or even all, specified fees (pretreatment
injuries through the legal system. A contingent fee
screening and drug costs are typically excluded from
arrangement would strongly tend to bias the
refund) if the patient does not have a live birth or
physician’s opinion in favor of more treatment and
achieve an ongoing pregnancy. However, patients
more expensive treatment than might be warranted.
electing shared risk pay a significantly higher initial
This concern is absent in assisted reproduction.
fee. These alternative payment plans have been
Second, the prohibition is aimed at dispelling the
criticized as being “exploitative, misleading, and
implication that a good outcome is guaranteed and
contrary to long-standing professional norms against
avoiding unrealistic patient expectations that follow
charging contingent fees for medical services.” 12
from it. However, shared risks plans are offered
There is also the objection that shared risk plans precisely because the outcome of the procedure is in
create a conflict of interest in which the clinician is serious doubt and the provider is willing to accept
induced to take steps to achieve pregnancy some of the financial risk of failure with the patient
regardless of the impact on the patient in order to at the latter’s own election.
avoid paying the refund. Assuming fair and adequate The final objection based on conflict of interest
disclosure of terms, defenders of the practice point focuses on the likelihood of a clinician preferring
out that it is a legitimate alternative payment plan 1. utilization of egg stimulation procedures that will
given the usual absence of insurance coverage which not only produce more oocytes but also pose more
addresses patient concerns about the high cost of risks to the woman’s health, and
many cycles of IVF that fail to achieve pregnancy, a 2. transfer of a larger number of embryos in order
not uncommon outcome. to enhance the chances of pregnancy occurring
The claim that all such programs are misleading but simultaneously increasing the chances of
or exploiting those who are desperate to have a multiple gestation which poses well known risks
genetically related child by inducing them to to both offspring and parents. This objection has
purchase a more expensive set of services is not some merit. These dangers do exist, but they exist
persuasive. While persons contemplating the equally for IVF services provided on a fee-for-
utilization of expensive IVF services may well suffer service basis. The solution is not to prohibit
greatly from their infertility and may feel some shared risk payment plans, but for clinicians both
degree of desperation in their efforts to conceive a to carefully monitor their own behavior for strict
child, it is wrong to assume that they are inherently conformance with the patient’s best interests and
unable to determine their own best interests and to fully disclose to patients all of the risks and
make decisions with significant economic benefits, both to health and wealth, of the
consequences. The clinicians involved are, of course, different financing arrangements. Also, the ASRM
obligated to provide patients with sufficient Ethics Committee found no evidence that either
information to make an informed choice of a shared danger mentioned here has actually
risk plan rather than fee-for-service. The shared risk materialized. 12
270 Textbook of Perinatal Medicine

Disclosure and Informed Consent afford to pay for them on their own. But the lack of
broad availability of PGD for the less economically
All clinicians should be scrupulous about the accuracy
advantaged does become ethically problematic to the
and truthfulness of the methods they use to attract
extent PGD satisfies fundamental human needs but
and secure patients who are dependent on
remains unavailable to them (like basic preventive
professionals for knowledge about the health care
and acute health care services) or produces
services they receive. Likewise, all information
“additional social advantages for the well-to-do” by
provided by clinicians to patients wanting to utilize
enhancing their offspring to which others cannot get
PGD should be complete, accurate, and devoid of
access. 8 Insofar as PGD can be legitimately
ambiguity – in contrast with typical commercial
considered something owed as a matter of social
information which is often deliberately incomplete
justice to all persons in need, then it is the duty of
and ambiguous, and at least sometimes inaccurate.
the society in question to make PGD available to all.
In particular, the risks, burdens, benefits, pro-
Finally, it is worth noting that it is seriously ethically
babilities of success, and the limits of PGD and IVF
questionable for public funds to be used in the
should be presented in a matter-of-fact manner and
development of PGD services when they are largely
in terms easily accessible to persons unskilled in
available only to persons of high socioeconomic
medical and scientific terminology. In particular, it
status.
is “imperative that patients be aware of potential
diagnostic errors and the possibility of currently MORAL STATUS OF THE
unknown long-term consequences on the fetus [and EXTRACORPOREAL EMBRYO
subsequently born child] of the embryo biopsy PGD is intended to result in the selective destruction
procedure.”1 (or the limbo of indefinite freezing) of extracorporeal
While the persons seeking PGD will almost human embryos following genetic analysis. Some
certainly be competent adults with an above-average consider PGD to be morally preferable to traditional
amount of education, they are also very likely to be prenatal genetic diagnosis because it precludes the
struggling with the reproductive decisions they face need of an abortion to avoid the birth of a genetically
and seriously worried about outcomes. Clinicians abnormal child. This moral advantage to PGD can
providing PGD – and all other infertility and be understood in one of two ways. First, the woman
reproductive services-should be especially careful to who would have to undergo the abortion may find
avoid intentionally exploiting the anxiety and it morally preferable from her personal point of view
apprehension (or even desperation) of persons who to discard embryos prior to implantation rather than
know they are at risk for transmitting a genetic undergoing a surgical or medical abortion with its
disease to their offspring. attendant physical and psychological risks. Second,
one could claim that discard is not morally wrong
Justice and Ability to Pay
because extracorporeal embryos either lack moral
Marked discrepancies in the use of prenatal genetic status altogether or have less moral status than
diagnosis already exist between affluent white gestating embryos or fetuses, either of which makes
women and other women in the United States.8 As destroying them in utero via abortion more morally
PGD becomes more available, this pattern will problematic.
undoubtedly continue. It is certainly not inherently For many, the ethical acceptability of the
unethical for clinicians to offer health care services- destruction of human embryos turns much more on
such as cosmetic surgery, full body scans for the inherent moral status or standing of the (gestating
detection of abnormalities, LASIK vision correction, or extracorporeal) human embryo than on someone’s
or PGD-that are available only to those who can moral preference for discard over abortion given that
 Preimplantation Diagnosis 271
both end in the death of the human entity. If, as some to preserve the pregnant woman’s life or health, but
contend, all human embryos have the same moral it may not totally ban previability abortions or
status as live-born persons,14 then they are entitled otherwise place an undue burden on a woman’s right
to basic rights, including the right not to be killed to terminate her pregnancy.16 In the absence of a state
arbitrarily or for the purpose of advancing the statute prohibiting the practice (and none exist at
interests of other persons. In this view, PGD that present), the discarding of embryos following PGD
resulted in the destruction of extracorporeal with the informed consent of the gamete sources
embryos, as well as abortion following traditional cannot be considered a violation of the embryo’s legal
prenatal genetic diagnosis, would be seriously rights or be a form of criminal homicide in the United
morally wrong. The opposing view would hold that States. Whether the state could constitutionally ban
embryos lack any moral status whatsoever as they PGD and IVF because they result in embryo discard
lack any properties, such as sentience or other is uncertain. Such a ban implicates not only the legal
cognitive traits that determine moral standing and status of extracorporeal embryos, but also the
so can be destroyed at will. constitutionally protected right of the persons whose
Perhaps the more commonly held-and more gametes constitute the embryo to reproduce.17
ethically defensible – position is that human embryos However, the legal status of human embryos is
deserve some modest moral status because they are not uniform around the world. Recently the European
alive, have some degree of potential to become Court of Human Rights ruled that the unborn are
human persons, and are in fact valued by moral not human beings entitled to full human rights under
agents whose views deserve at least some respect applicable human rights conventions and that each
and deference from others, but they nevertheless do national government must settle this legal issue for
not possess the full and equal moral standing of itself. 18 The legal status of embryos and the legal
persons because they lack interests and other moral propriety of PGD varies in Europe. For example, PGD
claims to personhood. Having a modest level of moral is currently illegal in Germany and Switzerland,
status does not preclude the destruction of embryos although a recent study shows that a majority of
for a morally serious reason or purpose, and the Germans think the technique should be permitted
informed and conscientious choice of the persons who for detecting genetic diseases. 19, 20 The German
created the embryos to prevent the birth of a child Embryo Protection Law protects embryos from
with a serious genetic disease or abnormality is “improper use” and forbids genetic analysis of an
widely (though by no means universally) considered embryo at the eight-cell stage or before. 21 One
to be such a reason. Austrian clinician has reported that the legal
This ethical position roughly parallels that of permissibility of PGD in Austria is unclear.20 PGD
current American constitutional law which does not has been authorized in France since 1994, but is strictly
recognize embryos or fetuses as legal persons with limited to cases in which there is a strong probability
rights (including the 14th Amendment rights not to of the presence of a severe genetic disorder known
be deprived of life, liberty, or property without due to be incurable at the time of diagnosis.22 The Human
process of law and to have the equal protection of Fertilisation and Embryology Authority in the United
the laws), but recognizes considerable value in these Kingdom has licensed PGD for certain severe or life-
entities through the State’s substantial interest in threatening disorders at a limited number of clinics.23
preserving potential human life, an interest that PGD is legally permitted in the Netherlands and
becomes particularly compelling at viability.15 This Spain as well.20
interpretation of constitutional personhood means Returning to the ethical analysis, the persons most
that the State may ban post-viability abortions (40 humanly and ethically connected to human embryos
states have done so) unless an abortion is necessary are the individual men and women whose gametes
272 Textbook of Perinatal Medicine

wholly constitute the embryo. Almost all persons care human entities are entitled to the very same moral
deeply if their gametes or embryos are used for respect owed to born persons. Moreover, the
reproduction, and being a genetic parent is linked in objection considers the benefits to the parents of a
profound ways to the individual’s identity and the child born free of a serious, even devastating, genetic
meaning he or she gives to life. Embryos ethically disease and to the child herself to be morally
“belong” to the people who created them, even if irrelevant, a conclusion that seems myopic and
they are not property like inanimate objects.24 incomplete.
Consequently, even though embryos themselves The use of PGD for HLA testing and selection of
have only modest moral status, it is nonetheless embryos who, when born, can serve as stem cells
seriously morally wrong to use the extracorporeal donors for their seriously ill siblings is certainly more
embryos of persons for any purpose without their controversial than PGD used for the detection of
informed consent. A corollary to this view is that aneuploidy. The most commonly heard objection here
the discarding of embryos secondary to PGD with is that the child to be conceived is being used as a
the informed consent of the persons whose gametes means to benefit the already existing diseased child
created them is morally proper. In other words, the and her parents and is not being brought into the
persons who created an embryo have the right of world for her own sake, a violation of the Kantian
exclusive control over the disposition of those principle of respect for persons. For this same reason
embryos, a right grounded in their interest in making the parents’ motives for conception of a child are
the intimate, personal decision of when and how to considered ethically improper. Some critics would
reproduce. As no one else has a more significant moral also claim that the child will be harmed
connection to the embryos than the persons who psychologically once she finds out that she was
created them, no one else has the moral authority to brought into the world for the purpose of saving a
overrule their decision about the disposition of their sibling.
embryos. Yet this right of disposition does not render The moral objection to the child being conceived
embryos morally insignificant or allow them to be as a means to an end really has force only if the
used for a morally trivial purpose; human embryos parents actually have this specific intent and treat
retain their modest moral status in any event.24 the child in a manner consistent with it by, e.g.,
putting the child up for adoption immediately after
ETHICS AND THE CURRENT USES OF PGD stem cell harvesting or abandoning her. No public
Before considering the ethics of the dominant use of report could be located that documents such a state
PGD (the prevention of heritable genetic diseases), of affairs; in fact, the children born in this manner
let us consider the other major uses mentioned appear to be loved and valuable members of the
previously: the identification (and discard) of family just as their ill sibling is. People conceive
chromosomally abnormal embryos in IVF and testing children for a wide variety of reasons and motives
for HLA compatibility with an existing child. A moral – to have help in their old age, to fulfill cultural
objection to the former is actually an objection to the expectations, to make grandparents of their parents,
entire IVF process insofar as it results in the discard to honor a command of God, to fulfill their own
or indefinite cryopreservation of any human embryos dreams of parenthood, and so on – not all of which
which have the moral status of persons with full and are morally admirable or accepted as legitimate by
equal basic rights because this status would preclude most persons. The real moral test is not the purity
their destruction or suspended animation. The of parental motives, but the quality of their behavior
objection to the intentional destruction of during pregnancy and after birth, which should show
extracorporeal embryos for any purpose rests upon love, concern, and dedication to their child.
the very controversial conclusion that such immature Moreover, as existing children can properly serve as
 Preimplantation Diagnosis 273
bone marrow donors for sick siblings, then it follows retardation) is plainly a morally legitimate goal. If it
by analogy that it is ethically acceptable for parents were not, then it would make no sense to encourage
to make a child who will serve in the same role, pregnant (or pre-pregnant) women to avoid smoking
assuming all children involved are loved and not tobacco or consuming large amounts of alcohol, to
subjected to procedures that are clearly contrary to obtain competent prenatal care, or to take folic acid.
their best interests.11 Finally, it is implausible to But the prevention of such births is at least morally
assume that psychological harm will come to children permissible, even if it is not morally obligatory.
who serve as donors when they areas likely to benefit There are two fundamental moral objections that
from knowing they assisted in preserving their can be levied at this particular goal:
sibling’s life. 1. the means taken to avoid the birth-the intentional
The most common utilization of PGD is by a discarding of embryos in the case of PGD – is
particular woman who wishes to avoid bearing a morally wrong (this objection, based on the moral
child with a genetic disease or abnormality that she status of the embryo, was discussed above), and
(and commonly a spouse or partner) finds 2. the conception of “disease or disability” being
unacceptable. Actually, the risk of bearing such a child utilized by prospective parents and the clinicians
is reduced, but not eliminated, because PGD can only assisting their reproduction is morally deficient.
detect diseases or conditions with an identified In addition, strong moral objections have been
genetic basis (such as certain single gene defects and made to the use of PGD to determine conditions
translocations), and it has an estimated error rate in that cannot plausibly be called “diseases,” such
the range of 1% to 10%, depending on the particular as sex and the absence of desirable physical,
disease and assay being evaluated. 1 Errors are mental, or social characteristics.
particularly bothersome when testing autosomal
recessive or dominant conditions due to the Disease and Disability
phenomenon of allele specific dropout.25 Historically, medicine has offered prenatal diagnosis
While the key purpose of traditional, nondirective as a means of preventing the birth of children with
prenatal diagnosis is to provide persons with so-called serious inherited disorders such as Tay
information about the genetic constitution of the Sachs, Trisomy 13, 18 and 21, cystic fibrosis, muscular
pregnancy and not to render any opinion on its dystrophy, Huntington’s, Lesch-Nyhan, and
termination, the same cannot be said of PGD. “The neurofibromatosis. To one degree or another, each
purpose of PGD is not simply to inform couples about of these conditions may entail the imposition of pain,
the genetic nature of their embryos. The explicit suffering, shortened life span, and/or significant
purpose is also to transfer healthy embryos and to inability to engage in typical activities of daily living
discard those destined to be affected. Once a couple on the individual with the condition. They also may
has chosen PGD, nondirectiveness is no longer place personal and economic burdens of one degree
relevant.”8 Therefore, the very purpose of PGD is to or another on the individual’s parents, family, and
avoid the gestation and birth of a child who will even the society in which they live. These
have, or is likely to have, an identifiable genetic considerations lead some individuals to conclude that
disease or disability of some sort. Nevertheless, they would rather not give birth to a child with such
clinicians remain ethically obligated not to impose a disorder; they then turn to medical professionals-
on the prospective parents the values they bring to such as those who provide PGD – to assist them in
the assessment of a given embryo’s genetic condition. effectuating this decision. Embryo selection then
As a matter of general principle, prevention of prevents disability by avoiding the gestation of
the birth of a (genetically or otherwise) diseased or individuals who would (or likely) be significantly
disabled child (such as one with profound mental disabled or diseased if born.
274 Textbook of Perinatal Medicine

Recently disability activists have strongly public’s perception that disability is a tragic mistake
challenged what they deem to be the basic (that could and should have been avoided) and that
assumption underlying PGD and traditional prenatal disabled people are therefore justifiably
diagnosis: reducing the incidence of disease and marginalized.”26
disability is an obvious and unambiguous good. They Some commentators within the disability
rightly criticize certain views that can-and frequently community acknowledge that disability itself is not
do-support this assumption: that the disabled’s inherently a neutral condition, that it may limit some
enjoyment of life is necessarily less than for non- options and impose real health problems and
disabled people; that raising a child with a disability diminished human capacities. But they also
is a wholly undesirable thing; and that selective emphasize that “oppressive social conditions have
embryo discard or abortion necessarily saves so distorted the public’s perceptions [of disability
mothers from the heavy burdens of raising disabled and disabled persons], as well as how disabled
children.26 Not all disabled persons are barred from individuals themselves might internalize these
having a satisfying life by their disability (although perceptions, that it is difficult to assess the true impact
the social disadvantages and discrimination they of disability on the individual’s life experiences.”26
encounter do decrease their quality of life), nor is it In other words, the real negative impact of disability
the case that raising a disabled child is always terribly in and of itself is exceedingly difficult to isolate
burdensome or unrewarding. because of deep and pervasive social discrimination
However, the ethical critique of the disability against disabled individuals and widely shared,
activists goes much deeper than this quite proper strongly negative social views on the meaning and
debunking of broadly drawn and inaccurate personal impact of disability.
assumptions about life with any disability. First, they Insofar as individual clinicians do, in fact,
contend that the medical system tends to exaggerate exaggerate the problems and burdens of living as an
the “burden” associated with having a disability and individual with a disability or of living with a
underestimates the functional abilities of the disabled person as a parent or family member, then
disabled. “Conditions receiving priority attention for they are doing a moral disservice to the people they
prenatal [genetic testing] are Down syndrome, spina are duty bound to be helping. Adults who wish to
bifida, cystic fibrosis, and Fragile X, whose clinical reproduce are ethically obligated to do so in a
outcomes are usually mildly to moderately disabling. responsible manner, and this means (insofar as it is
Individuals with these conditions can live good possible in a world about which we have imperfect
lives.”26 The activists also point out how medical knowledge) gathering and assessing fair and accurate
language reinforces the negativity associated with information about what the future might hold for
disability by using such terms as “deformity” or them and the child they might produce. Clinicians
“defective embryo or fetus.” (especially genetic counselors) should endeavor to
Second, and more importantly, the disability provide this kind of information, supplemented – if
activists claim that the promotion and use of PGD at all possible – by the firsthand information that
and traditional prenatal diagnosis “sends a message” comes from those who have actually lived with
to the public that negatively affects existing disabled disabilities of various kinds as parents of the disabled
people and fosters an increase in the oppression and or from the disabled individuals themselves. For
prejudice from which they regularly suffer. The so- example, it is certainly true that not all individuals
called “message” of PGD – that the birth of disabled with Down syndrome or their parents live painful,
persons who are defective or deformed ought to be frustrated, or tragically diminished lives. The same
prevented – “may have the effect of triggering is true for individuals with spina bifida, cystic
additional oppression, reinforcing the general fibrosis, Fragile X, and other genetic disorders.
 Preimplantation Diagnosis 275
On the other hand, these conditions are simply the child born to them may not be “perfect” or not
not utterly benign or neutral as each may – and often as healthy as they would like. Unlike an embryo that
does – involve what can fairly be described as an has only modest moral status whose very existence
“undesirable event such as pain, repeated can properly be controlled by the persons who
hospitalizations and operations, paralysis, a created it, a live-born child is an independent
shortened life span, limited educational and job individual with full and equal moral status who has
opportunities, limited independence, and so forth.”27 now joined the human community and who cannot
Even though not all instances of such disorders will be arbitrarily discarded or destroyed by its parents
involve the experience of such problems, a significant without a serious moral wrong being done. Rejecting
risk that an individual may encounter them always or not loving a child solely because he or she has a
exists. A prospective parent who chooses to act on disability is reasonably considered morally arbitrary
his or her conclusion that it is better for a child not and wrong because the child has full and equal moral
to have, or to be at significant risk to have, such status while an extracorporeal embryo does not.
serious disorders is acting reasonably. “We do no Society does not utilize PGD or traditional
one – not disabled individuals, not women, not prenatal diagnosis, whatever “society’s” views on
families – a service by minimizing the physical, mental, disability might be. Individual persons utilize such
and emotional burdens that may result from services with the assistance of individual clinicians,
parenting children with disabilities.”27 and they do so in order to make deliberate choices
The claim of certain disability advocates that those about their personal reproduction and about their
who utilize PGD as patients or who offer it as particular lives rather than leaving these entirely to
clinicians are necessarily “sending a message” to the chance. A choice that each individual makes about
public that it is ethically right to oppress or his or her own reproduction has no moral implication
discriminate against the disabled, or that the birth for how a similar choice ought to be made by another
of any disabled child is a tragic mistake which ought person: a choice not to implant an embryo with the
to have been avoided, is simply untenable. “From gene for cystic fibrosis, while morally permissible,
the fact that a couple wants to avoid the birth of a does not (indeed cannot) mean that the opposite
child with a disability, it just does not follow that choice by a different person is morally wrong. Nor
they value less the lives of existing people with does such a choice mean that the individual must
disabilities, any more than taking folic acid to avoid therefore devalue persons living with cystic fibrosis.
spina bifida indicates a devaluing of the lives of However, some commentators have argued that
people with spina bifida.”27 The attempt on the part under certain circumstances persons have a positive
of a prospective parent to avoid the conception and ethical duty not to reproduce.28
birth of child with a disability through PGD (and it Suppose PGD reveals the presence of a genetic
is always just an attempt as there are no guarantees) abnormality, Down syndrome, in an embryo.
does not mean that he or she would surely reject or Someone could say that an individual woman who
fail to love a child born with a disability – or show chooses not to have that embryo transferred into
disrespect to an existing disabled person. her uterus is rejecting persons with Down syndrome,
While it is morally permissible for a prospective but there is another, more plausible interpretation
parent to discard an embryo with a genetic disease, as well. “What I would say is ‘I do not want my
it would be seriously wrong for him or her to child to be born with Down syndrome,’ meaning ‘if
“discard” or reject a live-born child with the same I have a choice, I want the person who will be my
disease. Adults who reproduce must take moral and child to be born into a body without such potentially
legal responsibility for their reproductive decisions, significant limitations’.... That’s all [I am expressing].
and this necessarily includes accepting the risk that For a person with a disability to take this as a personal
276 Textbook of Perinatal Medicine

rejection seems unreasonable to me.”29 The claim of 2. PGD with transfer of embryos of the desired sex;
the disability activists that the meaning of PGD must and
be that “people like us will never be born” is 3. traditional prenatal diagnosis and selective
unfounded: of course “they will [be born], they just abortion. However, given that IVF with PGD is
won’t have the disability. To me, this objection only expensive, technologically daunting, and imposes
really make sense if people with disabilities are their significant burdens on women, it has only limited
disabilities” which they are not.29 usefulness as a method for sex selection, though
In sum, discrimination against persons with it currently works much better than sperm
disabilities is just as morally repugnant as sorting.30 This may change as more reports of
discrimination against persons based on race, clinical experience with Microsort are made
religion, or sex, but it is not at all clear that PGD publicly available.
reinforces or contributes to this in any manner. Interestingly, the Ethics Committee of the
Regardless of how society might change (as it surely American Society for Reproductive Medicine has
ought to change) its attitudes and practices to decrease opined that “policies to prohibit or condemn as
or, better, eliminate the socially created unethical all uses of nonmedically indicated
disadvantages wrongly placed on the disabled – and preconception gender selection are not justified,” 1
regardless of how individual persons might change yet it has also held that “initiation of IVF and PGD
their views on the prospect of knowingly having a solely for sex selection...holds even greater risk of
child with a serious disability, other persons “will unwarranted gender bias, social harm, and the
prefer not to have a child with a serious disability, diversion of medical resources from genuine medical
no matter how wonderful the social services, no need. It should therefore be discouraged.”31 The
matter how inclusive the society. [T]his is a perfectly National Society of Genetic Counselors has flatly
acceptable attitude, one that does not impugn their stated that couples wanting “sex selection for
ability to be good parents. Nor does this attitude personal preference are not candidates for PGD.” 2
imply a devaluing of the lives of existing people with The primary ethical distinction between sperm
disabilities, any more than do programs to vaccinate sorting and PGD rests on the fact that the latter
children against polio or ensure that pregnant involves the creation and destruction of embryos
women get enough folic acid.”27 It is this individual which have some moral status and are therefore
choice that PGD preserves, although the clinicians entitled to some moral respect, while gametes have
who offer PGD have a moral obligation to explore no moral status.
their own and their patients’ attitudes about, and The selection of an embryo’s sex via PGD is done
understanding of, disability so these individual for two basic reasons:
decisions can be made fairly and responsibly with 1. preventing the transmission of sex-linked genetic
accurate information about the real world of life with disorders such as hemophilia A and B, Lesch-
and without disability. Nyhan syndrome, Duchenne-Becker muscular
dystrophy, and Hunter syndrome; and
PGD and Selection for Sex and 2. choosing sex to achieve gender balance in a family
other Desirable Characteristics with more than one child, to achieve a preferred
Three methods for prepregnancy or prebirth sex order in the birth of children by sex, or to provide
selection are available: a parent with a child of the sex he or she prefers
1. prefertilization separation of X-bearing from Y- to raise. 31 While little extended ethical debate
bearing sperm with selection of the desired sex exists regarding the former, sex selection for the
for artificial insemination or IVF (Microsort); purpose of preventing the transmission of sex-
linked genetic disease, the latter is the subject of
 Preimplantation Diagnosis 277
heated ethical disagreement. To insist [that the experience of parenting a boy
The ethical objections to sex selection for is different from that of parenting a girl] is not
nonmedical reasons can be grounded both in the very the case seems breathtakingly simplistic, as if
act of deliberately choosing one sex over the other gender played no role either in a person’s
and the untoward consequences of sex selection, personality or relationships to others. Gender may
particularly if it is performed frequently. Sex selection be partly cultural (which does not make it less
can be considered inherently ethically objectionable “real”), but it probably is partly biological.... I
because it makes sex a determinative reason to value see nothing wrong with wanting to have both
one human being over another when it ought to be experiences.30
completely irrelevant: females and males as such Thus, gender differences in fact exist and appear
always ought be valued equally and never to be both cultural and biological in origin; actual
differentially. physical and psychological differences exist between
Sex selection can also be ethically criticized for male and female children that affect parental child
the undesirable consequences it may generate. Choice rearing experiences in important ways.34 Even one
by sex supports socially created assumptions about noted feminist author has asserted that gender
the relative value and meaning of “male” and Asimilarity and complementarity are morally
“female,” with the latter almost universally being acceptable reasons for wanting a child of a certain
considered seriously inferior to the former. By sex.35
supporting assumptions that hold femaleness in The defender of sex selection for family balancing
lower social regard, sex selection enhances the can also point out that parents who desire this
likelihood that females will be the targets of different experience can do so without believing or
infanticide, unfair discrimination, and damaging acting as if one sex is better than the other and
stereotypes. The experience in India and China without imposing harmful gender roles (e.g., females
indicates that sex selection is commonly used to are emotional, not rational) upon their children. As
ensure the birth of males over females.32 At one point persons having such a preference may do without
in China there were 153 boys for every 100 girls.30 believing that one sex is superior to another and with
A more recent report indicates that in parts of China, respect for the equal rights and status of females,
there are 140 boys for every 100 girls (in contrast to proponents would argue that their preference should
the U.S. and world average of 105 boys for every be respected incident to the exercise of their right to
100 girls) and suggests that this will likely result in reproduce, especially in the absence of empirical
an increase in prostitution and the outright selling evidence showing that the practice of sex selection
of women. 33 A preference for males as first-born actually harms females. Moreover, it can be argued
could also disadvantage females as research that the modest moral respect due embryos is not
consistently shows that first-born are more offended by a parental choice made on the basis of
aggressive, more achieving, and of higher income sex.
and education than later-born children.30 It also seems very unlikely that sex selection
Proponents of the ethical acceptability of sex would significantly skew the male-female balance in
selection would argue that a parent’s desire for family the United States population or that of other
balancing can be – and typically is – morally neutral. developed Western nations. One U.S. study has
The defense of family balancing rests on the view shown that among the respondents who would use
that once a parent has a child of one sex, he or she sex selection, 81% of the women and 94% of the men
can properly prefer to have a child of the other sex would want their first-born to be a boy, which would
because the two genders are different and generate result in more males receiving the advantage of being
different parenting experiences. first-born. But given that this same study found that
278 Textbook of Perinatal Medicine

only 25% of all respondents would use sex selection are – and should be – self-sacrificing) are not.
methods, it appears unlikely that this would Consequently, given that sex selection is inevitably
dramatically add to the number of first-born males. gendered and most gender roles and expectations
“Nevertheless, if sex selection became widely restrict the freedom of persons to be who they wish
available, it might change the American family, to be regardless of gender, sex selection is at least
making older sisters to younger brothers somewhat strongly ethically suspect, if not outright wrong.
less common than they otherwise would be. Whether Some would claim that choosing the sex of our
this change would be harmful enough to justify children is not the most morally worrisome
constraining choice [of sex], however, remains hard application of PGD or other forms of medical
to say.”30 Overall, the predictions of potential bad intervention in reproduction; it is rather the prospect
consequences due to sex selection seem too of our ability to choose the characteristics of our
speculative to be determinative of its moral offspring. “[T]he real threat comes from the
propriety.31 identification of an increasing number of genetic
An opponent of sex selection for family balancing markers associated with conditions that are not life-
can argue that good parents-whether prospective or threatening, but impairing or socially undesirable,
actual-ought never to prefer, favor, or give more such as hyperactivity, homosexuality, and obesity.”36
love to a child of one sex over the other. For example, Botkin notes that the moral reluctance to discard an
a morally good and admirable parent would never embryo or abort a fetus for a less than serious
love a male child more than a female child, give the medical condition already conflicts with the value of
male more privileges than a female, or give a female honoring parental autonomy “in this most intimate
more material things than a male simply because of of enterprises.” 8
sex or beliefs about the child’s “proper” gender. A This conflict will be “exacerbated by the rapid
virtuous and conscientious parent, then, ought not increase in genetic tests for a wide range of
to think that, or behave as if, a child of one sex is conditions, including late-onset conditions,
better than one of the other sex, nor should a good conditions with a limited impact on health, and,
parent believe or act as if, at bottom, girls are really possibly, behavioral or physical characteristics that
different than boys in the ways that truly matter. A fall within the normal range.”8 Despite the apparent
virtuous and conscientious parent, then, ought not falsity of strict genetic determinism, “we may only
to think that, or behave as if, a child of one sex is need a popular perception of genetic determinism,
better than another. fueled by creative marketing and weak regulation,
The argument in favor of sex selection for family to move poorly predictive tests from the lab into the
balancing has to assume that gender and gender roles clinic... [T]hese tests need not be very predictive to
exist and matter in the lived world. For if they did be adopted by some couples who want the very best
not, then no reason would exist to differentiate the that their sperm, eggs, and money can buy.”8 In this
experience of parenting a male child from that of a regard, it is also worth recalling the ASRM’s
female. However, it is precisely the reliance upon characterization of PGD as “an established technique
this assumption to which the opponent of sex selection with specific and expanding applications for standard
objects: accepting – and perpetuating – gender roles clinical practice.”34 (emphasis added)
inevitably both harms and wrongs both males and Sex selection by PGD or traditional prenatal
females, although females clearly suffer much more diagnosis is already available, although one recent
from them than males. While some gender roles or study shows that a majority of physicians who offer
expectations are innocuous (e.g., men don’t like PGD are not willing to do so for sex selection.37 The
asking for directions), the overwhelming majority existence of genetic tests linked (even tenuously) to
(e.g., males are – and should be – aggressive, women certain desirable or undesirable social, psychological,
 Preimplantation Diagnosis 279
or behavioral characteristics is highly likely to undoubtedly disagree, but this is the same situation
generate at least some demand from people who will with other controversial areas in medicine such as
pay the going rate for such tests up front in cash and futility, the propriety of treatment in the absence of
who will be more than capable of giving informed “medical indications,” physician assisted suicide, and
consent to the procedure. The critical ethical question physician performed euthanasia.39
will be: should medical professionals provide any Little true consensus exists regarding when
such tests (or sex selection for that matter) on request physicians and other clinicians ought to refuse to do
or, more likely, on demand? certain interventions because they do not benefit
patients, harm patients or others, are inconsistent
The Role of the Individual with the healing nature of medicine, disrespect the
Clinician’s Conscience value of human life, or are outside the legitimate
It is quite common for bioethicists to call for a “social” scope of medicine which should be devoted to
resolution of thorny questions like this that arise in promoting human health, not human happiness or
medicine.8,38 One type of social resolution comes from simple human preference. As a result of this
the law. However, an answer to the ethical and variability in ethical interpretation, each individual
practical question of which genetic tests clinicians clinician has to make a personal decision, in light of
should offer will almost surely not come from the his or her own conscience and understanding of the
law which is (at least in the United States) a typically ethical requirements of responsible professional
politically charged, slow (it is consistently behind practice, about which genetic tests he will and will
developments in science), expensive (for both not perform incident to PGD.
lobbying and litigation), uncertain, and cumbersome Conscience is a form of self-reflection on, and a
method for regulating what physicians and other judgment about, whether a particular act (or
clinicians do, especially when it comes to human omission) is morally right or wrong, good or bad,
reproduction. A true social consensus about matters but it is never self-certifying from the moral point of
involving embryo destruction is even less likely, as view.40 Conscience has to be properly informed by
witnessed by the current debate over therapeutic the pertinent moral principles and rules as well as
cloning and stem cell research, not to mention relevant professional values as well. But conscience
abortion. Some semblance of an answer may come must, at some point or another, lead the individual
from professional medical organizations in the form to take a stand on pressing ethical issues – like which
of “recommendations” or “guidelines,” but they genetic tests of offer incident to PGD. And the stand
probably will be quite general and in need of must at least sometimes be “this I will not do.” The
interpretation and application to specific cases. very meaning and integrity of an individual as a
Professional guidelines may also be intentionally moral agent turns on this: the good things any person
ambiguously worded in order not to create a does can be made complete only by the things she
standard of care that could be legally enforced refuses to do.39
through civil lawsuits. When conscientiously refusing to do PGD for sex
What then is a clinician involved in PGD to do? or a new marker associated with homosexuality or
Should she perform PGD for sex selection for increased height, a clinician is not necessarily
nonmedical reasons or for roughly determining, say, adopting the position that it is unethical for any other
IQ (which probably has some genetic basis)? There clinician to act in this manner, although she may
undoubtedly will be coherent and serious ethical believe this to be so and may attempt to persuade
arguments on both sides of the question, as the brief others to exercise their consciences in the same
review of the debate over sex selection (above) manner. An individual clinician who refuses to
indicates. Thoughtful and conscientious clinicians will perform PGD for some specific purpose is primarily
280 Textbook of Perinatal Medicine

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integrity and expresses her need to assume personal Reproductive Medicine and Society for Assisted
moral responsibility for her actions. Clinicians cannot Reproductive Technology. Preimplantation genetic
diagnosis 2001. Available at www.asrm.org, Accessed June
control the behavior of other professionals in their
2002.
field, but they can and should choose to conform 2. National Society of Genetic Counselors. Preimplantation
their own behavior to the ethical standards they genetic diagnosis. Available at www.nsgc.org/
personally embrace, even if the field as a whole as pr_diagnosis_10_01.asp, Accessed 23 June 2002.
3. Bahce M, Escudero T, Sandalinas M, Morrison L, Legator
not taken a firm stand on the relevant issue. M, and Munne S. Improvements of preimplantation
Each and every clinician involved in assisted diagnosis of aneuploidy by using microwave hybridi-
reproductive medicine (whether physician, nurse, zation, cell recycling and monocolour labeling of probes.
genetic counselor, or technician) should practice as Molecular Human Reproduction 2000; 6(9):849-54.
4. Marquez C, Sandalinas M, Bahce M, Alikani M, Munne S.
a responsible individual moral agent who has Chromosome abnormalities in 1255 cleavage-stage
developed an informed conscience and not as a human embryos. Reproductive BioMedicine Online 2000;
vending machine of professional services operated 1:17-26.
5. Munne S. Preimplantation genetic diagnosis and human
on patient demand. Every clinician should recognize
implantation – a review. Placenta 2003; 24:S70-S76.
that not all of her colleagues may come to the same 6. Verlinsky Y, Rechitsky S, Sharapova T, Morris R, Taranissi
conclusion as she and that her professional M, Kuliev A. Preimplantation HLA testing. Journal of the
organizations may waffle on certain issues and issue American Medical Association 2004. 29(17):2079-85.
7. Kuliev A, Verlinsky Y. Thirteen years’ experience of
only vague1 or ambiguous ethical exhortations. But preimplantation diagnosis: report of the Fifth
the lack of agreement or consensus on ethical issues International Symposium on Preimplantation Genetics.
does not permit a morally conscientious individual Reproductive BioMedicine Online 2004; 8(2):229-35.
to follow the path of least resistance and simply do 8. Botkin J. Ethical issues and practical problems in
preimplantation genetic diagnosis. Journal of Law
whatever can technologically be done and whatever Medicine and Ethics 1998; 26(1):17-28 .
a willing patient will pay for. 9. American Society for Reproductive Medicine. Available
at www.asrm.org/Patients/FactSheets/invitro.html. Accessed
CONCLUSION 13 July 2004.
10. Nelson LJ, Clark HW, Goldman RL et al. Taking the train
PGD is a valuable addition to the repertoire of to a world of strangers: health care marketing and ethics.
reproductive medicine as it gives individuals with a Hastings Center Report 1989; 19(5):36-43.
11. Sermon K, Van Steirteghem A, Liebaers I.
documented history of a genetic disorder the Preimplantation genetic diagnosis. The Lancet 2004; 363:
opportunity to begin a wanted pregnancy with little 1633-41.
or even possibly no fear that they are transmitting 12. American Society for Reproductive Medicine Ethics
Committee. Shared-risk or refund programs in assisted
this disorder to their offspring. An outstanding
reproduction. Available at www.asrm.org/Media/Ethics/
example of this is the recent report of PGD being shared.html. Accessed 8 July 2004.
successfully used to avoid the conception of a child 13. American Medical Association, Council on Ethical and
that could have inherited a predisposition to early- Judicial Affairs. Code of medical ethics 1997; 94-95.
14. President’s Council on Bioethics. Human cloning and
onset Alzheimer disease.41 But if this service becomes human dignity: the report of the President’s Council on
embroiled in the detection of conditions having little Bioethics 2003. New York, Public Affairs: 174-75.
or nothing to do with health and disease in order to 15. Nelson LJ, Marshall MF. Ethical and legal analyses of three
satisfy patient demand or be a profitable business, coercive policies aimed at substance abuse by pregnant
women. Report to the Substance Abuse Policy Research
its practitioners deserve will get-and deserve-serious Program of the Robert Wood Johnson Foundation, award
ethical criticism. #030790, 1998.
 Preimplantation Diagnosis 281
16. Planned Parenthood of Southeastern Pennsylvania v. 28. Purdy L. Genetics and reproductive risk: can having
Casey, 505 U.S. 833 (1992). children be immoral? In Mappes T and DeGrazia D (eds):
17. Robertson J. Children of choice 1994. Princeton, Princeton Biomedical Ethics 2001: Boston, McGraw Hill: 520527.
University Press: 22-42. 29. Baily MA. Why I had amniocentesis. In Parens E, Asch A
18. European Court of Human Rights. Case of Vo v. France, (eds): Prenatal Testing and Disability Rights 2000;
2004. Application no. 53925/00. Washington DC, Georgetown Univ. Press: 64-71.
19. Preimplantation genetic diagnosis should be allowed in 30. Steinbock B. Sex selection: not obviously wrong. Hastings
Germany, study reveals. Available at Center Report 2002; 32(1): 23-28.
www.medicalnewstoday.com/news.php?newsid=10048. 31. Ethics Committee of the American Society for
Accessed 8 July 2004. Reproductive Medicine. Sex selection and preimplantation
20. Feichtinger W. Preimplantation diagnosis (PGD) – a genetic diagnosis. Fertility and Sterility 1999; 72(4): 595-
European clinician’s point of view. Journal of Assisted 98.
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21. Mueller S. Ethics and the regulation of preimplantation Assisted Reproduction and Genetics 2002. 19(9): 411-16.
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International Bioethics 1997; 7:5-6. San Jose Mercury News 2004; 8 July: 1A, 13A.
22. Comite Consultatif National d’Ethique. Reflections 34. Ethics committee of the American Society for
concerning an extension of preimplantation genetic Reproductive Medicine. Preconception gender selection
diagnosis. Available at www.ccne-thique.fr/english/pdf/ for nonmedical reasons. Fertility and Sterility 2001; 75(5):
aviso72.pdf. Accessed 8 July 2004. 861-64.
23. Human Fertilisation and Embryology Authority and 35. Overall C. Ethics and human reproduction 1987. Boston,
Advisory Committee on Genetic Testing. Consultation Allen and Unwin, 27.
document on preimplantation genetic diagnosis. Available 36. Wachbroit R, Wasserman D. Patient autonomy and
at http://www.publications.doh.gov.uk/pub/docs/doh/ value-neutrality in nondirective genetic counseling.
preplant.pdf. Accessed 8 July 2004. Stanford Law & Policy Review 1995; 6(2):103-10.
24. Meyer MJ, Nelson LJ. Respecting what we destroy: 37. Benson K, Udoff L, Escallon C. Physician attitude toward
reflections on human embryo research. Hastings Center controversial applications of preimplantation genetic
Report 2001; 31(1):16-23. diagnosis. Journal of Genetic Counseling 2003; 12(6): 543-
25. Findlay I, et al. Allelic drop-out and preferential 44.
amplification in single cells and human blastomeres: 38. Callahan D. Medical futility, medical necessity. Hastings
implications for preimplantation diagnosis of sex and Center Report 1991; 21:30-35.
cystic fibrosis. Human Reproduction 1995;10(6):1609-18. 39. Nelson LJ. Medical futility and the clinician’s conscience.
26. Saxton M. Why members of the disability community In Misbin R, et al. (eds): Health Care Crisis? The Search
oppose prenatal diagnosis and selective abortion. In for Answers 1995. University Park, University Publishing
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27. Steinbock B. Disability, prenatal testing, and selective 41. Verlinsky Y, Rechitsky S, et al. Preimplantation diagnosis
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282 Textbook of Perinatal Medicine

22
Genetic Counseling

Akos Csaba, Zoltan Papp

INTRODUCTION avoided with absolute certainty. The requirement

of living up to this expectation more
In the past decades, genetic counseling has assumed
comprehensively has led to establishing and launching
an increasingly significant role in medical science.
genetic counseling centers that have become an
Deep changes in societal expectations coupled with
integral part of the maternity care system. It has
the transforming social structure have led a growing
become virtually the first priority for families to
number of married couples to make use of services
expect the health care system to prepare and inform
offered by genetic counseling. Whereas at the time
them and thus make it possible for them to accept
of Semmelweis, the saving of mothers' lives had
pregnancy as a result of a well-informed and well-
constituted a breakthrough in obstetrical practice,
considered decision. Society has also recognized that
the 20th century development of neonatology and
for a number of reasons (healing, psychological,
perinatology leading to improved survival chances
financial, societal, etc.) it is preferable to prevent
in fetuses and newborn babies, brought further
diseases than treat them after their emergence.
significant progress. As birthrates decreased and
families tended to be founded at older age, more
and more pregnant women chose to take advantage
of genetics. It became a more important, if not the
most important, objective to enable families burdened
with inheritable and accumulating problems to have
healthy children. The natural selection process that
works on a large scale was no longer acceptable for
families desiring to have one or two children;
therefore, the demand emerged in developed
countries for the safest possible pregnancy care. As
part of this development, genetic counseling
developed and continues to assume an increasingly
significant role. The recent, explosive progress in
genetic research has made people believe that now
every hereditary disease can be screened in time and
prevented, that is, the birth of a sick baby can be Fig. 22.1
 Genetic Counseling 283
The roots of genetic counseling go back a long their problems. Those asking for advice had to make
time in history. The correction of the undesirable do with mere information, the rigid percentage
qualities of the human race and the curing of its numbers of the risk of repetition, on the basis of
diseases has preoccupied us since prehistoric times. which they could make their decision on whether to
In one of his works, The State, Plato (427-347 B.C.) have a child. In many cases, however, the high risk
described the way to improve people in "selective of occurrence and/or recurrence communicated by
breeding." English scientist Francis Galton was the the physician forever deterred the couple from having
first to be engaged more thoroughly and more another child. To be sure, in other cases it was useful
seriously in eugenics. (It was he that introduced the for the couple to know that with the knowledge
word eugenics in 1883.) In a book written in 1869 about the heredity of the given problem, they could
(Hereditary Genius), he proposed that outstanding safely have another pregnancy without having to
men be married by a plan to well-to-do women in dread the recurrence of the disease that they had
order for a talented race to emerge. In the first half feared. In that period there could occur such a
of the 20th century, certain forces disgracefully used situation (due to a lack of assisted reproduction
the science of genetics and its achievements as a techniques) when genetic counseling shed light on a
distorted means of eugenics to underpin their racial disease inherited in a recessive manner, which might
theories (for the extinction of Jews, blacks, and have led the couple to the conclusion that their
homosexuals) and also in the early 20th century this descendents were exposed to an heightened risk.
culminated in political dictatorships ordering This could, unfortunately, result in the deterioration
sterilization for individuals with high genetic risk. of the relationship, and even in their divorce, in order
As a result, the application of genetic achievements that they both could increase their respective chance
was long stigmatized and it had a hard time regaining to have a healthy child. At last, the physician
the appreciation it deserves. performing genetic counseling was also in a difficult
Before discovering genetic rules, genetic position, since in many cases he was aware that he
counseling was based on empirical observations. In could not give the assistance that was needed, and
this process it was important to recognize that certain he must have sensed the tension generated by the
diagnoses were more frequent in certain couples’ puzzlement in the couple seeking advice. (In certain
descendents. cases, this feeling has, unfortunately, remained
The 20th century witnessed revolutionary progress known to physicians providing genetic counseling.)
in the science of genetics that coincided with
increasing societal demands and therefore became THEORETICAL AND PRACTICAL
an integral part of modern genetic counseling. In the MEANS OF GENETIC COUNSELING
beginning, in the age of “classic genetic counseling”, Genetic counseling is centered on close interactive
our means were quite limited. Genetic diseases were communication between those requesting and those
Mendelian disorders or diseases that were giving advice. Genetic counseling centers operate in
inheritable through one gene. Then counseling numerous countries of the world. Their task
extended merely to clarifying the genetic, i.e., everywhere is to give information about hereditary
hereditable nature of a certain disease and informing diseases, to let patients know about the possible
the patients about the risk or recurrence. This was cures, and not least to define the method of heredity.
the time when society’s demand for the prevention Knowing the type of heredity is indispensable for
of diseases emerged, but our scientific and technical figuring out the risk of occurrence and/or recurrence,
possibilities were still rather restricted. Regrettably, which is the most frequently asked and most
we were in no position to offer a reassuring important question for pregnant women or couples
“alternative” to the couples that approached us with wanting babies, and therefore seeking counseling.
284 Textbook of Perinatal Medicine

Thus, genetic counseling can basically be divided into started the decision-making process. The physician
two major branches: leaves it to the patients to use the intensive interactive
a. Finding out if the disease of a new-born baby, process to arrive at their final decision. Various
older child or adult is hereditary, making prenatal screening and diagnostic methods have
diagnosis, and providing information about the demonstrated revolutionary progress and have been
possible treatment. made indispensable parts and means of modern
b. Counseling during pregnancy concerning the genetic counseling.
occurrence and/or recurrence of hereditary Often screening tests could at least lower the
(genetically determined) diseases in a family or excitement and nervousness, but it was prenatal
those materializing in pregnancy, using prenatal diagnostics that made the real breakthrough in the
diagnostic tools with the aim of ensuring the birth practice of genetic counseling. At this point during
of a healthy offspring. counseling one has to mention the inevitable necessity
Although the two branches obviously focus on to explain the differences between screening tests
the same diseases, they require different approaches. and diagnostic tests. Society mistakenly confuses the
All over the world, genetic counseling is primarily two examinations and attributes to them equal
done by biologists, geneticists, and various medical importance. In the daily practice, this can result in
specialists, mainly paediatricians and obstetricians.1- erroneous decisions because many regard the
3
Pregnant women and their partners facing various reassuring results of the screening tests as a safe
genetic problems can base their decision on diagnosis. Too often we can hear the following
information and advice made available by these statement from a 40-year old pregnant woman and
professionals’ knowledge and expertise.4 Counseling her 50-year old husband: “As the biochemical
can follow two principles: the more widely used markers (triple-quadro test) are normal, and the
nondirective genetic counseling and the so-called genetic ultrasound examination has not detected any
directive genetic counseling.5 Because the current era visible abnormalities either, we can rest assured, for
is dominated by legal claims against physicians, the we cannot have a child with chromosome
nondirective method is more acceptable and more abnormalities. We do not want amniocentesis.”
easily defendable, even though in many cases patients Screening tests are performed to help us detect and
expect and demand a decision-shaping process “take out” those who face a higher than average risk
closely guided by the physicians. When applying the in certain pathological conditions of concern. Some
nondirective method, the genetic counselor is ready procedures may serve a screening purpose in some
to share information in a nondirective manner cases while they can have a diagnostic value in
without committing to any potential alternative. It association with another disease. Sonography is one
is very important that having thoroughly described of these procedures, but it is only of a screening
the disease in question, the consultant should also nature in the case of Down Syndrome, while it has
inform the patient about the risk of occurrence and/ a diagnostic value in the case of anencephaly, spina
or recurrence. After that, diagnostic alternatives bifida, and hydrocephalus.
should be described and offered – if there are any. Among prenatal diagnostic tools we distinguish
This has to be done in a fashion so that the patients between non-invasive and invasive methods.
seeking counseling can understand the basic facts, Sonography, one of the most frequently and widely
and it may vary with the given circumstances. The used, dynamically developing examination procedure
patient’s fear and anxiety must not be worsened by belongs in the first group. In the non-invasive group
giving an opinion expressed in mystical, complicated we also find the tests using maternal blood, from
sentences that are incomprehensible to ordinary which tests with fetal cells obtained from maternal
people. By this point, the couples have already circulation deserve more and more attention. The
 Genetic Counseling 285
arsenal of invasive prenatal diagnostics is also steadily even fearful, because they are apt to treat machine-
broadening, but those applied first in the practice of made images virtually as facts, and to interpret them
genetic counseling remain its most frequent as serious threats to the fetus. It is then a daunting
procedures. These are genetic amniocentesis (GAC) task to dispel anxiety or fear because the patients
and chorionic villus sampling (CVS). Invasive tend to believe the “objective” computer. Here too,
procedures, unfortunately, carry certain risks for the the nondirective method is advisable, and it is
fetus and the pregnant woman. Their complications important to point out not only the possible
have a considerable influence on the patients’ pathologic conditions, but also the possibility of a
decision, since in many cases they perceive their reassuring outcome. For this reason it is essential to
situation as a choice between bad and worse. In this follow closely any abnormalities detected during
context it is understandable that the essential factor ultrasound examinations in later stages of the
on which they base their decision is the intention to pregnancy and after delivery. This approach can lead
opt for the less risky examination if they are given us to a stage when images currently interpreted as
a choice. The pain and tension caused by the “suspicious signs” will not result in groundless
examination also appear as a problem in invasive tension and fears for the pregnant woman.
examination, but this does not have a decisive Practice standards regarding ultrasound
influence when making the final choice. While these examinations during pregnancy vary from country
procedures are not painless, the pain is not extensive to country. In some countries one or two
either. examinations are deemed sufficient without
This strong inter-relatedness between genetic providing much detail as to how these should be
counseling and prenatal diagnostics is largely timed. Nearly a decade ago, we introduced in
determined and driven by ultrasound examinations Hungary a carefully designed system that pays due
that, as a result of rapid technological advancements, consideration to the interests of pregnant women
allow the physician to follow more closely the life of and to professional rationality. Our protocol advises
the embryo and the fetus.6-8 Ultrasound is biologically four plus one examinations for the pregnant woman,
harmless, so undergoing an ultrasound examination with the first taking place during the first call (usually
cannot pose a serious dilemma for pregnant women. in the fifth to eighth week), the others after in the
However, despite the accumulation of an increasingly tenth to twelfth, the eighteenth to twentieth, the
significant amount of expertise and knowledge, it is twenty-eighth to thirtieth, and the thirty-sixth to
often difficult to evaluate and interpret the results thirty-eighth week. If necessary, we advise an
of the examination. Modern medical examination intrauterine examination of the fetus’s heart
equipment with largely improved detection (echocardiography). 10 The pregnant woman must
capabilities makes even tiny “suspicious signs” understand that these examinations are part of a series
recognizable.9 Nevertheless, these signs can lead to of screening tests meant to check on the intrauterine
differing interpretations, thereby causing development of the fetus. Countries advising or
unwarranted concern among patients. The sonograph performing fewer examinations partly cite high costs
can record even tiny divergences from normal and question the efficiency of the examinations. There
conditions that cannot be ignored, because written are also skeptical opinions about whether ultrasound
documents can later serve as legal evidence. examinations can significantly improve morbidity and
Frequently we are in no position to perform further mortality indicators.11 Some others, arguing against
noninvasive examinations to reassure the patients. ultrasound examinations, also point to the
This often renders invasive examinations advisable, misleading, wrongly reassuring effects of “false
potentially putting the patients in a difficult decision negative” diagnoses. Well-elaborated and organized
making situation. Patients can become anxious or sonographic training can, however, minimize such
286 Textbook of Perinatal Medicine

risks. It is imperative that examinations be carried decision has to come from the woman. The genetic
out and interpreted by trained and experienced counselor must not assume a “divine role” and cannot
professionals. be familiar with all relevant aspects of another
Such invasive genetic examinations as person’s life. Even in cases that seem identical, the
amniocentesis, chorionic villus sampling, and fetal final decisions can be different. A 37-year-old couple
blood sampling have become indispensable means who already have three healthy children and where
of prenatal diagnostics and genetic counseling. These the woman can conceive without difficulty is likely
examinations allow us to obtain genetic information, to request karyotyping, whereas a couple having
leading to major breakthroughs in the development tried in vain to conceive a child for fifteen years can
of genetic counseling. Samples obtained during be very concerned about the threat of miscarriage
invasive procedures are helpful in performing several and may choose not to have such an invasive act
examinations, and the number of diseases that can performed.
be detected this way is steadily increasing. Beyond During genetic counseling, certain “semi-invasive”
detecting chromosome irregularities, these are now examinations can also be of assistance; these are
important means of diagnosing monogenic widely used in screening because of their minimal
inheritable diseases (Mendelian inheritance) as well. level of invasiveness. Nevertheless, as a result of their
From the samples we can also perform microbiological being a screening test, they can produce false positive
and serological examinations. The newest molecular results, generating serious concern in pregnant
genetic techniques are opening a previously women. Biochemical marker tests done from samples
unhoped-for dimension in prenatal diagnostics. of the mother’s blood (AFP, BHCG, E2, PAPP-A,
Beyond dangers arising from the invasive nature of Inhibin) constitute one sort of these genetic screening
such examinations (due to the higher risk of examinations. Besides false positive results, there are
miscarriage), their more widespread use has raised some false negative test results as well, which makes
numerous ethical questions as well. Even when we it essential to explain to patients that screening
face increased risks of genetic, inheritable diseases, examinations do not provide the basis for
we must try our best to make sure that no sick establishing a diagnosis. In view of the existing risk
children are born, while giving couples a realistic factors of invasive examinations, one has to aim at
chance to have a healthy newborn. Here we have a putting together as reliable a screening examination
reverse situation: contrary to ultrasound exami- protocol as possible. There are ongoing efforts to
nations, in this case the interpretation of examination examine an increasing number of serum markers that
results leaves very few questions owing to diagnostic can be combined with ultrasound examinations (e.g.
accuracy from the principle of methods applied. In nuchal translucency) to improve results. Because of
these cases, however, the examination carries fears of being held accountable and exposed to
dangers that create significant tension, concern, and malpractice claims, the drawing of the point will
complicated decision situations. There can emerge a regrettably increase the number of false positive
peculiar and difficult contradiction because the cases, which, in turn, will demand a larger capacity
patients would like to have a healthy child, but the for intrauterine chromosome analysis.
examination necessary to make this happen might
endanger the further development of the fetus. When DECISION-MAKING: RIGHTS AND
the woman makes this decision, the physician must RESPONSIBILITIES
stick with nondirective counseling, which allows him Physicians who have provided genetic counseling for
to inform patients about the benefits and drawbacks, an anxious married couple have faced their distress
but has him answer any further question about what and feelings of defenselessness. The very uncertainty
decision to make in a nondirective fashion. The final shadowing the health of their desired offspring puts
 Genetic Counseling 287
a considerable burden on the expectant woman and make a decision nor the responsibility resulting from
her spouse. Add to that the further risk of various that decision can rest with the genetic counselor. This
other special circumstances, and the result can be an point is important because it makes many legal claims
effectively unbearable load. Those couples seeking avoidable. The non-directive counseling process can
genetic counseling almost always carry the “extra be easily violated, because patients can be
burden,” that being the very reason why their manipulated by carefully determining the sequence
physician sends them to consult a specialist. of sentences. It must be our objective to be as neutral
Many decision-making situations crop up during as possible, while providing comprehensive and
genetic counseling. In certain cases the first question honest information to patients. Our words ought not
to answer is whether or not the patient is ready for to give away which decision we might favor.
pregnancy, knowing the genetic risk. The individual Although it is true that we cannot exist without
seeking counseling must decide if she wants to have having certain ideals, values, and views, and that
the proffered diagnostic test. Another decision may we are bound to form an opinion about what we say
have to be made with regard to the patient’s wish in a counseling situation, the patients should not
to carry on with or terminate pregnancy in the case sense that we might disagree with their decision or
of a positive result (indicating disease).2,12,13 that we might judge them negatively as a result. For
The diverse nature of genetic problems the pregnant woman and her partner to accurately
necessitates separating the following branches in feel the weight of their decision it is necessary to
order to better understand decision-making stress that they can choose freely from the alter-
mechanisms: natives described to them. They have to see clearly
a. Those cases requiring invasive, high-risk the consequences of whatever decision they opt for.
intervention (chromosome defects). It would be very difficult to conceive of any other
b. Monogenic diseases with a high risk of occurrence counseling mechanism and decision-making process
and/or recurrence. in democratic states where the wide-ranging rights
c. Low-risk genetic situations (taking medicine, of the individual are safeguarded. In democratic
diagnostic X-ray examinations). systems, however, one should not forget about
d. Uncertain conditions for which diagnostics are obligations and responsibilities. Systems that
limited (certain infections and anatomical defects exclusively emphasize rights, but not the obligations,
detectable by serology or ultrasound where the are moving towards anarchy. This anarchy would
outcome cannot be predicted). obviously apply to the field of genetic counseling as
One important consideration is whether the well. For free choice to be preserved, it is crucial
available means can result in a rock-solid diagnosis, that the decision made by the patients in no way
or the problem in hand cannot be diagnosed during influences further pregnancy care, and that the
pregnancy, although certain results may indicate physicians continue to provide the broadest range
pathological conditions. The decision-making of services possible.
mechanism seems to be affected by a couple of factors, The weight of the decision requires that pregnant
including risk of recurrence, seriousness of the women be given sufficient time to ponder the various
disease, risk of the procedure, maternal age, previous dimensions of their choices. In most cases, the
pathological pregnancies (malformations, pregnant woman finds it reassuring to discuss her
miscarriages), number of healthy offspring, level of situation with her partner or physician and to seek
education, religious faiths, and convictions of the advice of her family before committing to one of
conscience. the alternatives. It is highly possible that the patient
The kind of genetic counseling we prefer lets the and the counselor will have to see each other more
patients have the final word. Neither the right to than once.
288 Textbook of Perinatal Medicine

During counseling, the physician should be counselor is aware of the problem’s serious and
understanding and patient – one cannot occasionally hopeless prognosis. The recurrence of
overemphasize the role empathy plays in the process. this mental burden can pose a serious challenge for
Dramatic statements, gestures, and other forms of the physician. In cases of possible abortion, the
nonverbal communication are equally impermissible genetic counselor’s role goes beyond merely sharing
during nondirective genetic counseling. A written information. From the moment that patients are
report must be prepared about the counseling session confronted with the problem, we have to provide
and the patient’s decision. them with support. Besides the bare facts, we also
The complex nature of genetic counseling and its need to point out the potential remedies. We must
relatively short history are bound to raise several convey positive messages to the couple so that they
moral and ethical questions. Although there is an can more easily deal with a tragedy. The description
emerging consensus on the older problems, the new of the problem is never meant to deter; therefore,
possibilities and achievements have caused significant calm, a human voice, and compassion are the most
rifts among physicians and scientists. These important qualities of a genetic counselor. We stand
developments are increasingly prevalent in our a much better chance to achieve cooperation if, instead
everyday life, and their divisive effects can be felt in of telling the facts in a cold matter-of-fact manner,
the society as well. When it comes to genetics and we act kindly, and do not conceal the problem. The
our endeavors to influence heredity, society tends patients must never sense frustration and exhaustion
to be sharply divided. In these situations the on the part of the genetic counselor.
individual’s freedom and need to decide are at play It is essential that the decision possibly reflect the
simultaneously. common will of the couple, but at a minimum be
The counselor is not in an easy situation either. preceded by a consultation between the partners.
In these complicated and often very difficult decision- The couple frequently wishes to request the advice
making situations the consultant’s room for of the woman’s gynecologist before making the final
maneuver is rather limited due to the non-directive decision. This reinforces the strong bond of
principle of counseling. One can feel every now and confidence that develops between the pregnant
then that the advice-seeker counts on the consultant’s woman and her physician. This is especially true when
help when making her decision. Limited though the genetic counseling is done by an obstetrician/
consultant’s opportunities may be, he is still able to gynecologist who may also be in charge of the
help by supplying clear and direct information patient’s pregnancy.
relevant to the case. He is not to use either verbal or The woman usually desires the most
metacommunicative means that might suggest he is comprehensive information possible so she can make
taking a firm stand on either side of the dilemma. At an educated final decision. Questions like “How
the same time, the verbal and metacommunicative would you decide in my place?” are often put to the
behavior he does perform must not contradict each genetic counselor. When responding, one has to
other, because that may confuse the other party. He follow the rules of nondirective counseling and
must be patient and compassionate, but focussed on accordingly give information about how the majority
the issues in hand, and should not let the advice- of other couples decide in similar situations. It needs
seeker’s attention wander. He must dissipate fears to be pointed out to the patients that every
raised by “rumors” and “horror stories,” but must individual’s and every family’s life is different, and
never gloss over or retouch actual facts and dangers. therefore it is impossible to give a generalized
The consultant must always be prepared and set forth answer. The decision is influenced, among other
possible alternatives along with their advantages, factors, by whether the family already has a healthy
drawbacks, and consequences.14 In many cases, the child, how many pregnancies the woman has had,
 Genetic Counseling 289
how old the couple are, and how long they have them available. However, HGP and our ever-
been trying to conceive a child. Religion and beliefs deepening knowledge also mean that the genetic
certainly also play an important role. After the final background of more and more “conditions” can be
decision is made, the couple must be given assistance examined, which conceals ethical dangers. Does
to be able to deal with the consequences as smoothly humankind not try to implement positive eugenics
as possible. A guilty conscience and the shadow of when unearthing the genetic (hereditary)
an irresponsible decision are difficult to dispel in a background of intelligence and physical features? Is
family, but proficiently executed counseling can there not a strange “preordination,” “innate
prevent them from developing. predestination,” or “special selection” for those who,
because of their financial status, are able to take the
ETHICAL AND MORAL ASPECTS opportunity provided by science, however costly it
OF GENETIC COUNSELING may be in the beginning? Will it be possible to acquire
or “purchase” favored social status even before
The Diagnostics of Monogenic Diseases
childbirth? Will these sayings come true: my child
(Heterozygote Screening, Human
was born to be a banker, a doctor, a lawyer, a teacher
Genome Project, Eugenics)
or an athlete, an artist? Utopian as this assertion may
The molecular genetic research brought to a high stage seem, it is not unimaginable.
of development in the last years of the 20th century Let us play with the idea, and assume that the
resulted in an ever more detailed knowledge of the genetic code of every human disease and human
human genetic material. The Human Genome Project quality, including physical and mental endowments
(HGP) has established that the sequence of 3.1 billion as well as appearance, has become detectable through
letters of DNA show that humans are made up of the HGP. In the present social environment, science
about 30,000 to 40,000 genes.15,16 This may generate and technology provide for the possibility of
erroneous beliefs in society, because many think that choosing and creating the socially most
any hereditary gene defect can be detected today, “competitive,” healthy descendants. If at the
and therefore any given disease can be screened in beginning it is doable through costly procedures, we
the embryonic stage. True, more and more monogenic have already reached the eugenics envisioned by
diseases may be diagnosed by polymerase chain Plato and Sir Francis Galton. Further, there could
reaction (PCR) or other molecular genetic techniques, emerge in society castes firmly embedded for several
but science has yet to enable us to detect every generations, for with the help of genetic advantages,
genetic defect. These examinations, combined with the descendants of the wealthier would become the
assisted reproduction techniques, in certain cases leading stratum, while those with no access to these
make possible the detection of diseases in the pre- advantages would constitute the stratum of the
embryo conceived by IVF. This doubtlessly important subordinates and the employees. Would it be
fact can be a strong propaganda factor for the “healthy,” socially useful, or beneficial if everybody
unconditional supporters of this method and can wished to be endowed with Einstein’s IQ and
contribute to solidifying it in practice and making its Schwarzenegger’s or Marylin Monroe’s appearance?
application more widespread by pushing its In our view, this vast acceleration of evolution’s long
disadvantages into the background and making use and slow process could lead to unforeseeable tragic
of the media’s help. Given that these are costly consequences.
examinations, it is necessary to bring about a well- A more delicate and much more topical aspect of
established international network of research. If the this line of thinking is very much alive today: What
disease in question is serious, every effort is morally are the pathological conditions that justify the
justifiable to organize prenatal diagnostics and make induction of premature delivery as they exhaust its
290 Textbook of Perinatal Medicine

scope of indication? Who is to decide on these? If serious disease is inevitable in a later stage of one’s
certain conditions (e.g., depression, rheumatoid life could put a heavy burden on his everyday
arthritis, schizophrenia, arteriosclerosis, certain existence and might even change an individual’s
tumors, autoimmune diseases) are proven to be personality. Surviving in the knowledge that one is
inherited monogenically, is the pregnancy to be to expect to develop a malignant tumor by age 30 to
terminated if the fetus carries the faulty gene(s) and 40 is difficult. By the same token, possessing the
there is no known therapy? It is of paramount relevant information might result in more careful
importance that the scope of therapy be extended so diagnostic examinations, which should have a
that more and more detected diseases can be treated. substantial effect on the life expectancy.
In order to prevent this, it is urgently necessary to At the same time, this raises the question of who
create the proper legal framework of regulations and is entitled to know the information, i.e.
to introduce rational restrictions instead of outright confidentiality. 18,19 The individual affected and his
prohibitions. Historical examples show that whatever relatives? One might think that only the individual
can conceivably be done by man will be created sooner affected should, but with the disease in question
or later. We, therefore, cannot lull ourselves into being a genetic one, are the relatives not affected,
illusions that mere prohibitions can prevent human too? Do they not have the right to know their risk?
cloning or that irrational restrictions can prevent the Is the parent obliged to tell his or her child? Can the
above vision from materializing. child request the performance of a predictive test?
Can the parent make a decision on whether the
Presymptomatic Diagnostics examination should be performed for her minor
(Confidentiality of Genetic Data – child?.20 Presymptomatic and susceptibility testing
Relatives, Insurance Companies, in the absence of therapeutic options should be
Employers, the Family and the Individual) available if certain conditions are met. It is important
Presymptomatic diagnostics and so-called that the individual be provided thorough information
“susceptibility testing” are gaining increasing salience about the limits of testing, and the information
with reference to an increasing number of diseases.17 contribute to enhancing the pathography and
Presymptomatic testing refers to identification of informing the family because, in many cases, it is
healthy individuals who may have inherited a gene impossible to predict the onset and seriousness of a
for a late-onset disease, and if so will develop the particular disease and its symptoms. Awareness of
disorder if they live long enough (e.g., Huntington susceptibility could induce a change in lifestyle that
disease). Susceptibility (predictive) testing identifies could prevent or prolong the development of a
healthy individuals who may have inherited a disease. And if a disease is inevitable, the individual
genetic predisposition that puts them at increased will have a possibility of planning for his or her short
risk of developing a multifactorial disease (e.g., heart life, as in the case of Huntington disease. Such genetic
disease, Alzheimer disease, or cancer), but who may information can influence plans for marriage and
never develop the disease in question. Do we have having children. Preimplantation genetics could
the right to inform the patient about the existence of possibly prevent the development of a particular
untreatable diseases before symptoms appear? Is it disease in their children. But the basic question
necessary to do so? Are we obliged to do that? Is remains: Is it good or useful to know what for
this individual ill at all? Can or need populations be millennia mankind has had no way of knowing – the
screened for certain diseases? Indeed, the ultimate end of life, the number of years, the
development of some diseases might be slowed sequence of probable diseases? Is society prepared
down if changes in lifestyle were implemented. The for this? Is the human soul strong enough to carry
knowledge, however, that the development of a this burden? Do such examinations make sense as
 Genetic Counseling 291
long as we lack adequate therapies? Do we have to burdens for insurance companies and could lead to
do everything just because we can? The problem is the total collapse of the insurance system.
further complicated by the shortcomings of available Environmental or occupational (e.g., miners and
predictive genetic tests that still carry a factor of chemical industry workers, pilots) hazards can play
serious uncertainty about whether a disease will a significant role in the development of certain
develop, and if it does, when exactly and to what conditions (e.g., asthma, allergies, heart disease, or
extent. Given the onus of this information, if there cancers); therefore, by applying for such jobs, people
is no medical advantage concerning prevention or jeopardize their own health, which can become
treatment, these examinations had best be postponed starting points of future lawsuits. (The employer
until adulthood, when the individual is able to make could propose that the individual should work in a
decisions on crucial aspects of his own life. different department, since the desired job could
accelerate the development of the disease. If the
Stigmatization, Discrimination employee would still choose the job not
Society tends to single out “other-than-average” recommended, which he should have a right to do,
individuals, in many cases stigmatizing them. Given then he or she would lose his or her right to sue his
the sensitive nature of issues such as reproduction, company on these grounds.)
heredity, child-rearing skills, and the fact that society Considering the likely rapid dissemination of
considers calculable and predictable health defects a predictive tests, there is an urgent need to develop
serious drawback, exposing information about such a well thought-out, detailed legal framework.
issues is unethical. It is for the individual to decide Prohibition cannot be allowed, because it would
whether or not his genetic profile ought to be made deprive the individual of rather important
public. Employers, insurance companies, government information. The proper regulation would eliminate
administrations, and schools are prone to gather the the situation of diametrically opposed interests among
widest possible spectrum of information about their the parties and would make them interested in wide-
associates.21-23 The results of presymptomatic and ranging examinations. (For instance, at birth
susceptibility tests are beginning to become central everyone should be genetically screened for
issues for these institutions. These organizations “susceptibility” and the resulting information should
would like to have unrestricted access to these data. be made available to those concerned, but at the same
The individual is essentially interested in the time, discrimination and the possibility of abuse by
opposite, since the insurance company would surely the examined individual should be prohibited;
demand a higher premium if it will be ready to offer emphasis should be placed on prevention, and
insurance at all. adequate sets of incentives should be elaborated.)
Similarly, an employer would be disinclined to Apparently avoiding stigmatization and
employ someone of whom it is known that in a few discrimination makes a very important goal, but the
years he or she cannot do his or her job. At the same problem itself is highly complex. It is unacceptable
time, the fear of insurers and employers is also to discriminate against anybody at school, work, or
understandable, because the individual can also when taking out an insurance policy because of one’s
abuse such genetic information. Those declared genetic background. It must not be allowed either,
“healthy,” who will not have to reckon with the that individuals misuse this information. Therefore,
development of a serious disease in the course of it is crucial to bring about well-considered, detailed
their lives, would not pay for insurance, and even regulation and legislative background. At present,
the “ill” would wait almost until the likely the individual’s and the family’s personal rights must
development of the disease before they would buy not suffer damage, and genetic information may be
insurance. This could generate unmanageable made public only with their consent.
292 Textbook of Perinatal Medicine

Sex selection and Sex Determination interventions that on the surface would be “done
Both the prenatal and the preimplantation diagnostic for genetic reasons,” but in reality would serve a
procedures are suitable for the determination of the sex manipulated selection of human qualities. At a later
of the preembryo/embryo or the fetus. The majority point, this logic could namely have us argue that the
of society does not prefer one sex to the other. In decreasing population could be expanded if legal
certain communities, however, the offspring’s sex is regulations allowed selection on the basis of
very important; therefore sex determination presents intelligence or physique, or where the opposite is
itself as a problem in this controversial moral field. needed, the “high-quality,” “efficient,” and
Many civilized societies do not allow carrying out “productive” descendants could just as well slow
invasive genetic examinations merely to select or population growth.
determine sex, but loopholes exist in many countries.
Where a pregnancy may be terminated at the married In our view, to avoid abusing information about sex
couple’s request, the decision to do so is often made revealed by carrying out karyotyping for other
in the knowledge of the fetus’ sex (as a result of reasons, careful regulation is needed that effectively
karyotyping or an ultrasound examination). In these makes it impossible to terminate pregnancy just
cases we speak of sex determination done for non- because the fetus belongs to one or the other sex.28
medical reasons. Those in favor of this try to rely on Individual (personal) rights must be curtailed, and
demographic/statistical data arguing that in certain those uncritically embracing them should not ignore
cases it would be favorable to permit it. There are the rights of the fetus. Individualism is not identical
certain research groups and countries where sex to exemption from obeying rules and laws.
determination is permitted if a couple already has a Today sex determination may be justifiably
child, and would like to next one to be of the other indicated only if a family is affected by a hereditary
sex. Some claim that in countries with decreasing disease connected to a sex chromosome, and when
populations this could even become an instrument special molecular diagnostic tools making use of
in stopping the declining numbers. In other countries genetic engineering are not yet available. In such a
(in Asia), this possibility is seen as one of the factors case, if the test reveals that the fetus is male, the
slowing down population growth.24,25 They point out couple has the right to ask for the termination of
previous European experience when the selection of pregnancy so that the disease will be avoided. In
the descendant’s sex was possible on the basis of the this case we speak of sex determination done for
sperms, and practice showed that this did not change medical reasons. If the preferred method of
the proportion of the sexes in the population. In 2001, conception is IVF-ET and the disease in question is
The American Society for Reproductive Medicine an X-determined, recessive one, the so-called
ruled that it is proper and ethical to help couples to praeimplantation diagnostics is a possible option,
choose the sex of their babies.26 which may ensure that only healthy female pre-
By the same token, sex determination done for embryos get implanted.29
non-medical reasons also has several opponents. The
The Definition of Illness and Health
most frequently heard argument against the use of
PGD for non-medical sexing is that a medical method Differentiating between illness and health presents
should not be used for non medical reasons.27 We an increasingly complex problem. According to the
are even more concerned that by legalizing this kind WHO’s definition, health is a state of complete
of sex determination, we will cross the Rubicon, for physical, mental, and social well-being, and is not
it would be classifying the sex of an individual as merely the absence of disease or infirmity.30 Holding
“abnormality.” This would be the first step towards the assertion that the absence of disease (an organic,
the above described, apparently utopian human physical decrease in or failure of function) does not
 Genetic Counseling 293
in itself constitute health makes it difficult to define so bad that termination on a genetic basis may be
the conditions that ought to be regarded as healthy. proffered. Even in this case, the goal of nondirective
Late-onset diseases, deviations from the statistical counseling is to inform the patient about this option.
norm and increased susceptibility to cancers are The woman is about to resolve one of the most
questionable states. These men and women are not difficult situations of her life. The weight of the
ill for a long time, but they are handicapped from a decision depends on the gestational age of the
certain point of view. Shall or shall we not treat these pregnancy and other factors. Decisions on serious
states as diseases until we are able to cure already conditions detected in the first trimester are made
detected genetic predispositions? At the same time, easier. Given that most diagnoses are made in the
millions of people live happy lives with certain second trimester, when the fetus has already made
diseases (blindness, absence of fingers, color- its first movement, a very close relationship has
blindness, deafness) presuming they are healthy. A sometimes developed between fetus and expectant
number of geniuses would not have been born had mother by decision-time. She may have seen its face
they been fallen victim to procured abortion because during an ultrasound examination, and she may even
of conditions considered by society as illnesses. know her offspring’s sex. Realizing her widening
There is another serious ethical challenge here. waistline, the people around her may learn about
Do parents have the right to decide whether or not the pregnancy, and this knowledge and having to
an obvious infirmity they carry is one that needs wait, make it even more difficult for her to cope.
The necessity to make a decision presents a major
screening that might help avoid it in their children?
state of crisis, the extent of which depends, among
And if they do not, who can decide? If it is left to
other things, on the obstetrical anamnesis.
the parents to make decisions, then strange situations
In such a case, the task is to give the relevant
should be expected. A good example is reported by
facts, help the patient to consider them thoughtfully
Green. 31 A deaf-mute couple sought genetic
and calmly, and to encourage her to develop positive
counselling their disease’s nature being
prospects for the future. It is important to outline
monogenically hereditary. Having been informed
the possible short-term and long-term consequences
about their prospects, they asked for a molecular
of the decisions, the risk of the defect being recurrent,
genetic diagnosis to be made on the 13-week-old
and the details of its heredity. If the woman opts to
fetus. To the pleasure of their consultant, the result
continue her pregnancy, she needs to be briefed on
was homozygote-recessive, meaning they could
what sort of aid she can rely upon from the fields of
expect a healthy offspring. Surprisingly, however, medicine and social services, as well as family care.
the couple was disappointed by the result, indicating, Those deciding to terminate the pregnancy must be
“We can’t carry on with the pregnancy. How could informed about the procedure to relieve tension and
we bring up a child totally alien to us, able to hear distress. In any case, this should ease the anxiety
and communicate, while our friends and we live in regarding the operation itself. It must be stressed
a different way? We aren’t capable of establishing that if the couple opts to terminate the pregnancy,
the appropriate circumstances.” the procedure must be initiated as early as possible.
The methods used for mid-term abortions vary from
Terminating Pregnancy
country to country. Regardless of the method, the
Because of Genetic Indications
objective is to get the procedure over with in the
The most challenging moments of genetic counseling shortest possible time and in the least intrusive way.
arise when a decision has to be made on the The patient ought to get back to her home as soon
disposition of a pregnancy. From the consultant’s as possible to be able to deal with the tragedy with
point of view, those situations are the most difficult her loved ones. Access must be made available to
when the problem is so severe and the prognosis is post-termination counseling.
294 Textbook of Perinatal Medicine

The Woman’s and Partner’s Freedom of the last minute.” Our era is burdened with lawsuits
Choice and Representing the Fetus’ and brought against thousands of doctors, and many tend
the Newborn’s Interest:. Considerations to give in to patients’ request as self-defense. There
Relating to Faith and Religion are cases of minor problems whose long-time
One basic feature of modern genetic counseling is prognosis is not known for certain. In such cases the
that the final decision is always made by those seeking question is frequently asked, “But surely our child
assistance. 1 The justification for this appeals to will be healthy? You know we don’t want a sick
individual rights of freedom and people’s right to baby.” Well, this question is difficult to answer. One
decide issues affecting their own lives. Obstetrics and must not yield to pressure by irresponsibly allowing
genetics, however, are fields where a decision often termination in such cases. The freedom of choice must
has to do with another individual (ie, the embryo, be kept in focus, but between reasonable boundaries,
fetus, or newborn); therefore, it must not be practiced too. Regulation established to protect fetal life
without limitations and relevant regulation. The enables us to do our job, living up to the principles
problems of fetal life have often been put in the center of modern medicine, and actually protect life and
of debates, not only in professional circles, but also health.
as a political issue. The rigid attitude of the Roman
Preimplantation Diagnostics; Gene-Therapy
Catholic Church is well known and stirs a lot of
debates even within that faith community. The Assisted reproductive techniques are becoming more
church turns a deaf ear to the issue of termination and more sophisticated, contributing to the expertise
and does not accept contraception as a legitimate that makes it possible to subject the fertilized egg to
option (with a few exceptions). Thus, it is difficult to ever more detailed genetic examinations still outside
provide the opportunities offered by the the mother’s body. In the course of the procedure,
achievements of prenatal diagnosis to Catholics. In blastomer, blastocyst, and polar-body biopsy take
some liberal circles’ view, parents must be assured place while the genetic analysis is performed with
to have the widest possible sphere of authority. This two major molecular genetic techniques, polymerase
cannot be readily accepted by a physician or an chain reaction (PCR) and fluorescence in-situ
obstetrician-geneticist. In the United States, it is hybridization (FISH). The high cost of practice and
legally possible that termination be carried out until the low pregnancy rate achieved are still considered
the twenty-fourth week of pregnancy at the request the two major drawbacks of this new procedure. As
of the patient and without any medical indication. our knowledge of the genetic background of diseases
The test is whether an individual physician accepts expands, the number of those for whom these
the pregnant woman’s decision to terminate her examinations may be indicated is also increased. In
pregnancy. the future, in vitro fertilization may become more
The WHO’s position is that after the twenty- widespread, because it would prevent numerous
fourth week, an end to a pregnancy has to be terminations from happening: pre-embryos carrying
considered as childbirth and as such, everything has disease would not be implanted in the first place.
to be done to save the life of the premature infant. Regulation must not be neglected in this field,
Therefore, there are cases where several doctors and because within a short time, society would be
nurses make superhuman efforts for weeks to rescue confronted with a deluge of unwarranted
a 490-gram premature baby born after the twenty- examinations. The financial and moral burden of this
fourth week, whereas the life of another baby, would surely prove unbearable. Positive eugenics
perhaps with a little better initial life-expectancy, must not be allowed to be realized this way.
perhaps even weighing a little more, is taken in Currently, the number of gene-therapy
minutes because the parents changed their mind “at procedures is negligible, but intensive research may
 Genetic Counseling 295
make some treatments possible soon. This will herald ago have come close to being realized. While ancient
a new age of genetics and, indeed, the whole of Sparta used exposure of infants on Mount Taigetos
medicine. On the one hand, many couples as yet as a means of creating a healthy society, today we
unable to rear children will have the opportunity to try to prevent the birth of ill children by examing
do so; on the other hand, one or another of these and improving tiny DNA spirals and base pairs. The
therapeutic methods might become a way of question is indeed whether mankind is ripe enough
retrieving health, indeed, a new lease of life for many to use this knowledge for choosing the right way
people. ahead and utilizing the achievements for society’s
benefit. It is crucial that the relevant regulation be
Financial Considerations designed. The center of the ethical questions is
Science is capable of much more today in the fields occupied by the treatment of important personal
of genetics and prenatal diagnostics than the health information and the method of its being made public.
care system is able to offer to society. It is those costly The way the problems are dealt with is always
interventions that make the difference. When setting changing, just as society is in a constant process of
priorities, their social usefulness must always be kept change. It is important, however, that we always be
in mind. The needs of the wide social strata must ready to offer proper help to those in need when
never be sacrificed for the sake of a relatively narrow they need it.
stratum. This principle will be there to be confronted
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in the past 25 years. In: Chervenak FA, Kurjak A, Papp
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2. Sjogren B, Uddenberg N. Decision making during the
available which are advantageous to the masses of
prenatal diagnostic procedure. A questionnaire and
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(insurance, work, pensions) are beneficial. The cost- diagnosis. Prenat Diagn 1988;8(4):263-73.
benefit principle may not be accepted without 3. Marteau T, Drake H, Bobrow M. Counselling following
diagnosis of a fetal abnormality: the differing approaches
reservation, but it defines what sort of examinations of obstetricians, clinical geneticists and genetic nurses. J
can be routinely carried out in a health care system Med Genet 1994;31:864-7.
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testing: implications for clinical practice. Nurs Clin North
Am 2000;35:615-26.
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6. Berkowitz RA. Should every pregnant woman undergo
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counseling is of momentous consequences and has the routine obstetric scan. Ultrasound Obstet Gynecol
1991;1:18-20.
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Am J Obstet Gynecol 2001;185:1021-27. information and the workplace: legislative approaches and
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 23
Selective Reduction

Mark I Evans, David W Britt, Doina Ciorica, John C Fletcher

INTRODUCTION 99% of higher order multiples are initiated by them

(Table 23.2). With increasing public and professional
Millions of babies have been born benefiting from
attention, some of the very high order multiples have
infertility therapies including more than 1,000,000 IVF
diminished, particularly secondary to lower transfer
babies over the past 25 years. These fulfilling
numbers of embryos in IVF. There are some
outcomes, however, have been accompanied with
suggestions that the incidence of triplets and higher
serious side effects. The twin pregnancy rate, has
is slowly diminishing, but the incidence is still very
doubled to more than 1 in 45. Multiple pregnancies
high.
have continually risen. Prematurity and related
sequelae closely correlate with fetal number (Fig.
Table 23.1: Multiple births in the United States
23.1) (Table 23.1).1 Infertility treatments have become
so pervasive that more than 70% of all twins and Year Twins Triplets Quadruplets Quintuplets
& Higher
Multiples
RISKS OF PREMATURITY
2002 125,134 6898 434 69
AS A FUNCTION OF FETAL NUMBER
90
2001 121,246 6885 501 85
2000 118,916 6742 506 77
80
1999 114,307 6742 512 67
70
1998 110,670 6,919 627 79
1997 104,137 6,148 510 79
60
1996 100,750 5,298 560 81
50 1995 96,736 4,551 365 57
1994 97,064 4,233 315 46
P T <3 2
B W <1 5 00
40

1993 96,445 3,834 277 57

30
1992 95,372 3,547 310 26
20
1991 94,779 3,121 203 22
1990 93,865 2,830 185 13
10
1989 90,118 2,529 229 40
0
S i ng l e to n T w i ns Tr i p le ts Q ua d s Q u i nt s+
% Change
from
Fig. 23.1: 2002 United States Centers for Disease Control 1989–2002 38.9% 172.8% 89.6% 72.5%
Data. Diagonal lines Pre-term birth <32 weeks. Data taken from National Vital Statitics Report, Volume 52,
Shaded area Birth Weight < 1500 grams. #10, p22, 2003.
298 Textbook of Perinatal Medicine

Table 23.2: Ratio of Observed to Expected Multiples occurrence. Despite this, clearly some cases might
Births Observed Expected Ratio
have been prevented if increased vigilance had been
used.11-13
Twins 125,134 44,686 2.80:1
Triplets 6,898 496 13.9:1
PATIENT ISSUES
Quadruplets 434 6 72.3:1
Quintuplets & higher multiples 69 0.07 985.7:1 The demographics of patients considering
Total Births in 2002 – 4,021,726
multifetal pregnancy reduction (MFPR) have evolved
considerably over the past 10-15 years.11,12 The most
Perceived pregnancy losses in multiple dramatic change has been the introduction of donor
pregnancies are mostly correlated to how early in eggs which has opened the door to “older women.”
pregnancy one establishes the denominator.2,3 Some Over 10% of all patients seeking MFPR that we see
perinatal reports are overly optimistic because these are over 40 years of age; nearly half of them are using
physicians don’t start counting until they begin to donor eggs. As a consequence of the shift to older
see patients at nearly 20 weeks, at which time most patients, many of whom already had previous
losses have already occurred.23,4 Many other articles relationships and children, there is an increased
have addressed those issues and will not be repeated desire by these patients to have only one further
here.4-6 child. The number of experienced centers willing to
In the 1980’s, about 75% of multifetal pregnancy do 2 to 1 reductions is still very limited, but we
patients seeking reduction had pregnancies initiated believe it can be justified in the appropriate
with ovulation induction agents such as Pergonal.47 circumstances.11,13 We expect the proportion of all
However, even with the first month of the lowest patients with multiples reducing to a singleton to
dose of Clomid, quintuplets have occurred. Over the continually rise.
years, cases induced by assisted reproductive For patients who are “older” particularly using
technologies (ARTs), such as IVF have become their own eggs, the issue of genetic diagnosis comes
increasingly common. Currently, about 70% of into play. By 2001, more than 50% of patients in the
patients we see seeking reduction have pregnancies United States having ART cycles were over 35 (Table
generated by ARTs. 8 23.3) 1,9,10,14 In the 80’s and early 90’s, the most
Despite the increased utilization of ART’s,58 the common approach was to offer amniocentesis at 16-
proportion of cases significantly hyper-stimulated, 17 weeks on the remaining twins. A 1995 paper
and resulting in quintuplets or more has dramatically suggested an 11% loss rate in these cases, which
decreased to less than 10% of all cases seen by us. caused considerable concern.15 However, the issue
Regardless, the 2000 report of the Society of Assisted was settled by a much larger collaborative series in
Reproductive Technologies (SART) suggested that, 1998 that showed that loss rates were no higher than
of all pregnancies achieved by Assisted Reproductive
Table 23.3: Maternal Age and ART (SART Data – 2001)
Technologies (ARTs), in the United States 58.5% are
singletons, 28% twins, 7.5% triplets or higher, & 5.9% All Cases 81,915
were unknown 9,10 In our experience with referred Fresh Non Donor 60,780
<35 28,778
cases of ovulation stimulation, the proportion of cases 35-37 14,416
that are quintuplets or more has likewise fallen but 38-40 11,301
not as remarkably.11 41-42 4,365
The vast majority of multifetal cases occur to 42+ 2,190

physicians with the best of equipment and with the Wright VC, Schieve LA, Reynolds MA, Jeng G: Assisted
reproductive technology surveillance
best of intentions who have an unfortunate and
reasonably unpredictable or unpreventable mal- Pub Med, MMWR Surveill Summ. 2003, Aug 29;52:1-16.
 Selective Reduction 299
comparable controls of MFPR patients who did not the best approach was to know what was in the basket
have amniocentesis. 16 The collaborative data before reducing the other embryos.11,12 In these cases
demonstrate a loss rate of 5%, which was certainly we performed a CVS on usually all the fetuses or
no higher than the group of patients post MFPR who one more than the intended stopping number, and
did not have genetic studies. performed a fluorescent in situ hybridization (FISH)
Since the centers with the most MFPR experience analysis with probes for chromosomes 13, 18, 21, X,
also happened to be the ones who also had the same and Y (Fig. 23.2). Whereas about 30% of overall
accomplishments with chorionic villus sampling, anomalies seen on karyotype would not be
combinations of the procedures were very logical. detectable by FISH with these probes, 18 there is
There are two main schools of thought as to the best always residual risk19 The absolute risk given both
approach to first trimester genetic diagnosis, i.e. a normal FISH and a normal ultrasound including
should it be before or after the performance of nuchal translucency20 is only about 1/500. We believe
MFPR? Published data in the early 90’s doing the that risk is lower than the increased risk from the
CVS first followed by reductions suggested a 1-2% two week wait necessary to get the full karyotype.
error rate as to which fetus was which, particularly We have now commonly extended this approach to
if the entire karyotype is obtained before going on all patients who are appropriate candidates for
to reduction.17 Therefore, for the first 10-15 years, prenatal diagnosis regardless of the fetal number.
the approach we used was to generally do the Over the past few years, more than half our patients
reduction first at approximately 10.5 weeks in have combined CVS & MFPR procedures. With data
patients reducing down to twins or triplets, followed now suggesting increased risks of chromosomal and
by CVS approximately one week later.11,14 However, other anomalies in patients conceiving by IVF and
in patients going to a singleton pregnancy, essentially especially with ICSI, the utilization of prenatal
putting “all of their eggs in one basket”, we believed diagnosis will likely increase even further 21-26

Fig. 23.2: Transcervical CVS being performed on posterior placenta.

For this patient, anterior placenta can be reached either transcervically or transabdominally.
300 Textbook of Perinatal Medicine

The other approach used by another group was initially tried, but with little success. Some centers also
to perform the CVS and complete karyotype first used transvaginal mechanical disruption, but data
and have the patient come back for the reduction. suggested a significantly higher loss rate than with
Although “mistakes” were common 10 years ago, the trans-abdominal route.1131 Today virtually all
the chance of error has been considerably reduced, experienced operators perform the procedure inserting
and they believed the benefits of the full karyotype needles transabdominally under ultrasound guidance.
justified the wait. The issue as to the better of these
two approaches is currently unsettled and would OUTCOMES
require a very large series to differentiate among Several centers with the world’s largest experience
small risks. have, for more than a decade, collaborated to
leverage their power of their data. In 1993 the first
PROCEDURES
collaborative report showed a 16% pregnancy loss
Multifetal pregnancy reduction (MFPR) is a rate through 24 completed weeks.17 While by today’s
clinical procedure developed in the 1980’s when a standards, that was not a very satisfactory number,
small number of centers in both the United States it did represent a major improvement for higher
and Europe attempted to reduce the usual and order multiple pregnancies. Further collaborative
tremendously adverse sequelae of multifetal papers have shown continued dramatic
pregnancies by selectively terminating or reducing improvements in the overall outcomes of such
the number of fetuses to a more manageable number. pregnancies. (Table 23.4)11 The 2001 collaborative
The first European reports by Dumez,27 and the first data demonstrated that the outcome of triplets
American report by Evans, et al.,28 followed by a reduced to twins, and quadruplets reduced to twins
further report by Berkowitz, et al., 29 and later now perform essentially as if they started as twins11.
Wapner, et al.,30 described a surgical approach to Even with the tremendous advances in neonatal care
improve the outcome in such cases. for premature babies, the 95% take home baby rate
Even these early reports appreciated the ethical for triplets and the 92% take home baby rate for
dilemma faced by couples and physicians under such quadruplets clearly represent dramatic improvements
difficult circumstances.13 In the mid 80’s, needles were over natural statistics. Not only has the pregnancy
inserted transabdominally and maneuvered into the loss rate been substantially lowered, but so has the
thorax for the injection of KCL or mechanical rate of very dangerous early prematurity. Both
disruption of the fetus by either mechanical continue to be correlated with the starting number.
destruction, air embolization, or potassium chloride Data from the past few years show that the
injections despite relatively mediocre ultrasound improvements are, not surprisingly, greatest from
visualization. Transcervical aspirations were also the higher starting numbers (Fig. 23.3).

Table 23.4: Multifetal Pregnancy Reduction – Losses by Years

Losses (weeks) Deliveries (weeks)

Total % < 24 % > 24 % 25-28 % 29-32 % 33-36 % 37+
1986-90 508 13.2 4.5 10.0 21.1 15.7 35.4
1991-94 724 9.4 0.3 2.8 5.4 21.1 61.0
1995-98 1356 6.4 0.2 4.3 10.2 31.5 47.4

Evans MI, Berkowitz R, Wapner R, Carpenter R, Goldberg J, Ayoub MA, Horenstein J, Dommergues M, Brambati B, Nicolaides
K, Holzgreve W, Timor-Tritsch IE. Multifetal pregnancy reduction (MFPR): Improved outcomes with increased experience.
American Journal of Obstretrics and Gynecology, 184:97-103, 2001
 Selective Reduction 301
g

MULTIFETAL PREGNANCY REDUCTION

% Losses & Premature Delivery Losses and Very Prematures
by Starting Number

20
18 < 24 wks
16 15.4 25-28 wks
14
12 11.4
9.6
10
7.3
8 6.2
6 4.9 4.5
4 3.8 3.5
2
0 0.0
Starting # 6+ 5 4 3 2

Fig. 23.3: Adapted from: Evans MI, Berkowitz R, Wapner R, Carpenter R,

Goldberg J, Ayoub MA, Horenstein J, Dommergues M, Brambati B, Nicolaides K, Holzgreve W,
Timor-Tritsch IE. Multifetal pregnancy reduction (MFPR): Improved outcomes with increased experience.
American Journal of Obstretrics and Gynecology, 184:97-103, 2001

The lowest pregnancy loss rates are for those cases to triplets. The data from the most recent collaborative
reduced to twins with increasing losses for singletons series suggest that pregnancy outcomes for cases
followed by triplets. However, the rate of early starting at triplets or even quadruplets reduced to twins
premature delivery has been, not surprisingly, do fundamentally as well as starting as twins. These
highest with triplets followed by twins and lowest data therefore support some cautious aggressiveness
with singletons. Mean gestational age at delivery was in infertility treatments to achieve pregnancy in difficult
also lower for higher order cases. Birth weights clinical situations. However, when higher numbers
following MFPR decreased with starting and occur, good outcomes clearly diminish. A 2001 paper
finishing numbers reflecting increasing prematurity.32 suggested that reduced triplets did worse than
While data in the literature are conflicting, our continuing ones.34 However, analysis of that series
experiences suggest that triplets reduced to twins showed a loss rate following MFPR twice that seen in
do much better in terms of loss and prematurity than our collaborative series11 and poorer outcomes in every
do unreduced triplets. We believe that if a patient’s other category for remaining triplets Several other
primary goal is to maximize the chances of surviving recent papers have likewise shown higher risks for
children, that reduction of triplets to twins achieves “unreduced” triplets than for reduced cases.35-38. It is
the best live born results. More recent analyses clear that one must use extreme caution in choosing
suggest that while mortality is lowest with twins, comparison groups.(Table 23.5). An ever increasing
morbidity is lowest with remaining singletons. situation involves the inclusion of a monozygotic pair
There has continued to be a debate in some circles of twins in a higher order multiple39. Our experience
over whether to reduce triplets or not. Yaron, et al.,33 suggests that provided the “singleton” seems healthy,
compared triplets to twins data to unreduced triplets that the best outcomes are achieved by reduction of
with two large cohorts of twins. The data show the MZ twins. Obviously, if the singleton is not healthy,
substantial improvement of reduced twins as compared then keeping the twins is the next choice.
302 Textbook of Perinatal Medicine

Table 23.5. Reduced vs “Unreduced” prematurity, or uterine abnormality. 11 In recent

Triplets Comparison years, however, the demographics are changing, and
Years MFPR CASES the vast majority of such cases are from women in
their 40’s, or even 50’s, some who of whom are using
Deliveries (weeks)
donor eggs and who, more for social than medical
Losses 24-28wk 29-32 33-36 37+ reasons, only want a singleton pregnancy.42,44 New
<24wks
data suggest that twins reduced to a singleton do
1980s 6.7% 6.1% 9.1% 36.9% 47.9%
better than remaining as twins.13 Consistent with the
90-94 5.7% 5.2% 9.9% 39.2% 45.2%
above, more women are desiring to reduce to a
95-98 4.5% 3.2% 6.9% 28.3% 55.1%
singleton. In a recent series of triplets, we found
98-02 5.1% 4.6% 10.8% 41.8% 37.6%
the average age of outpatients reducing to twins to
Mean GA 35.5PMR 10.0/1000)
be 37 years and to a singleton 41 years.43 While the
98-02 8.0% 4.0% 12.0% 4.0% 72.0%
(3->l) reduction in pregnancy loss risk for 3-1 is not as
Mean GA 39.5PMR 0/1000 much as 3-2, (15% to 7% & 15% to 5% respectfully),
the gestational age at delivery for the resulting
NON REDUCED TRIPLETS
singleton is higher, and the incidence of births <
98(Leondires) 9.9% Mean GA 33.3 PMR 55/1000
1500 grams is 10 higher for twins than singletons. 1
99(Angel) 8.0% Mean GA 32.3 PMR 29/1000
These data have made counseling of such patients
99(Lipitz) 25.0% Mean GA 33.5 PMR 109/1000
far more complex than previously. (Figs. 23.4 and
02(Francois) 8.3 % Mean GA 31.0 PMR 57.6/1000
23.5). Not surprisingly there are often differences
Evans MI, Krivchenia EL, Kaufman M, Zador IE, Birtt DW,
between members of the couple as to the
Wapner RJ. The optimal management of first trimester
triplets: reduce. The Central Association of Obstetricians desirability of twins or singleton.45 There are also
and Gynecologists. Annual Meeting, Las Vegas, Nevada, profound public health and financial implications
October 27-30, 2002. to these decisions, as 2000 United States Data show
that of $10.2 billion spent per year on initial
Pregnancy loss is only one of the deleterious newborn care, 57% of the money is spent on the 9%
outcomes. Very early preterm delivery correlates of babies born at < 37 weeks46. This progress is much
with the starting number. However it has not been more likely to rise than fall.
well appreciated that about 20% of babies born at
less than 750g develop Cerebral Palsy.40 In Western R IS K R E D U C T IO N
Australia, Peterson et al showed that the rate of
Cerebral Palsy was 4.6 times higher for twins than
50
singletons per live births, but 8.3 times higher when 45
calculated per pregnancy. 41 Pharoah & Cooke 40

calculated Cerebal Palsy rates per 1000 1 st year 35

survivor at 2.3 for singletons, 12.6 for twins, and 30

B E F ORE
44.8 for triplets.42 25 A F TE R

In the 2001 collaborative report the subset of 20

patients who reduced from two to one, (not for fetal 15

anomalies) included 154 patients. These data 10

suggested a loss rate comparable to three to two, 5

but, in about one third of the 2 → 1 cases, there was

0
Q UINTS Q UA D S TRIP LE TS TW INS

a medical indication for the procedure - e.g. maternal

cardiac disease or prior twin pregnancy with severe Fig. 23.4: Risk Reduction as a function of starting number
 Selective Reduction 303
RISKS STARTING WITH TRIPLETS

40

35

30

25
TR IP LE TS
20 TW I NS
SI NG L ETO N
15

10

0
M is carriag e G A at d el <1 50 0g ram s Inf m ortality

Fig. 23.5: Reduction of triplets to twins has lower loss rates but higher incidence
of prematurity, low birth weight and infant mortality than reducing to a singleton.

SOCIETAL ISSUES justice to the subject other than to state that most
There will never be a complete societal consensus proponents do not believe this is a frivolous
on MFPR. Opinions have never followed the classic procedure, but see it terms of the principle of
“pro-choice/pro-life” dichotomy.2,7,11,14. We believe proportionality, i.e. therapy to achieve the most good
that the real debate over the next 5-10 years will not for the least harm.13,47-49
be whether or not MFPR should be performed with How patients “hear” and internalize data and
triplets or more. A serious argument will be put forth make decisions with respect to reduction have been
over whether or not it will be appropriate to offer a subject of our investigation for several years. Much
MFPR routinely for twins, even natural ones for of the literature on medical decision making has
whom the outcome has commonly been considered emphasized a rational choice model in which
“good enough”.43 Our data suggest that reduction, emotions, feelings and values are treated as
of twins to a singleton actually improves the outcome complications that must be considered as a second
of the remaining fetus. 43 No consensus on stage of an analysis that puts hard data regarding
appropriateness of routine 2→1 reductions however, relative risks center stage.50-51 Even the literature that
is ever likely to emerge. We do, however, expect the talks about genuine alternative models of decision
proportion of patients reducing to a singleton to making (systematic versus heuristic, for example), a
steadily increase over the next several years. central assumption is that these are individual
The ethical issues surrounding MFPR will also differences in style that can be identified through
always be controversial. Over the years, much has what people say.52-53
been written on the subject. Opinions will always We have investigated this problem from a
vary substantially from outraged condemnation to different direction, arguing that where controversial,
complete acceptance. No short paragraph could do high-anxiety decisions are concerned, patients treat
304 Textbook of Perinatal Medicine

these decisions as an ongoing part of the social reality and their implications. And they will be likely to
that they are creating to live in and raise a family.54 choose a final number for reduction that maximizes
These realities, composed of supportive people and the chances of a “take-home” baby.
institutions together with complexes of supportive The lens of scientific objectivity is not the only
values, norms and attitudes, are the source of frames frame through which women who have gone through
that the patients use to view the data. 47-49 The IVF in order to have a child will examine these data.
decisions they make and how they justify those For those who have immersed themselves in a social
decisions may help resolve incompatible elements in reality that has a strong emphasis on norms against
the realities in which they find themselves enmeshed. abortion and/or reduction – such that they
The one thing in common for all such patients is themselves have such normative beliefs and are
a very strong desire to have a family (Table 23.6). heavily involved in churches who reinforce similar
But there does not appear to be a single set of beliefs – a detached examination of the “facts” is
supportive institutions, people and norms that is simply not possible. These “facts” hold no special
conducive to going through the pain, stress and moral authority. Their beliefs and those of the
resource expenditure of IVF and then consider partial individuals and social institutions in which they have
reduction as a pregnancy-management strategy. selected themselves have a moral authority as well.
Rather, we think there are three viable alternative The balance that such women will likely seek is one
resolutions. The first of these, a rational Medical that reduces their relative risk to acceptable limits.
Model, looks superficially like what one would expect So, unless the consequences are dire, they will not
from the rational analysis model. But the commitment reduce or choose to reduce only to three. We labeled
to factual analysis comes from their having selected such a resolution a Fundamentalist Model.
themselves into the hard sciences, medicine, Finally, there are those for whom the demands
dentistry, engineering or the law – disciplines in of career and/or existing children constitute
which the “facts “are crucial. Such women will want powerful elements in their constructed realities. For
to see the numbers regarding the relative risk such women – and this includes many of the older
associated with different reduction choices and will patients we encountered – the essential balance that
want to engage in a rigorous discussion of the data they seek is a more secular one, a Lifestyle Model,

Table 23.6: Frame Comparison

Medical Frame Fundamentalist Frame Lifestyle Frame

Intensity of Commitment High High High
to having children
Intensity of training in High Low Modest
medicine, dentistry, hard
sciences and the law
Intensity of commitment Modest High Modest
to belief that life begins
at conception
Intensity of commitment High Low High
to career
Source of moral Relative survivability Minimization of damage Having a “normal” life in
authority for resolution of fetuses to moral beliefs though a culture that values both
a “barely sufficient” careers and family for
reduction women
 Selective Reduction 305
one that emphasizes creating a family situation in to patients for the procedure performed by an
which having a family can be balanced with having experienced operator. Our own experience and
a career. Such women will more than likely choose anecdotal reports from other groups suggest that less
reduction to two or even one embryo, depending experienced operators have worse outcomes.
on the number of other children they have and the Pregnancy loss is not the only poor outcome. The
level of resources that the family has. other main issue with which to be concerned is very
Where women have selected themselves into and/ early preterm delivery and the profound
or been trained to accept the legitimacy of rigorously- consequences to such infants. Here again there is an
determined statistics regarding relative risk (a increasing rate of poor outcomes correlated with the
Medical Frame), reduction choices can be starting number. The finishing numbers are also
straightforward – or at least they can appear to be critical, with twins having the best viable pregnancy
relatively straightforward. This is usually not the outcomes for cases starting with three or more.
case, however, for women who must forge a Triplets and singletons do not do as well. However,
resolution amongst potentially incompatible elements, an emerging appreciation that singletons have
as for women who are struggling to reconcile the prematurity rates less than twins is making the
potentially oppositional elements of religious beliefs counseling far more complex. We continue to hope,
and involvement with risks associated with higher- however, that MFPR will become obsolete as better
level pregnancies (Fundamentalist Frame) or those control of ovulation agents and assisted reproductive
who are struggling to reconcile he potentially- technologies make multifetal pregnancies uncommon.
conflicting identities of home and career (Lifestyle
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18. Evans MI, Henry GP, Miller WA, et al. International, an increased risk of intrauterine growth restriction, except
Collaborative Assessment of 146,000 Prenatal Karyotypes: for very high order multiples. Am J Obstet Gynecol
Expected Limitations if only Chromosome-Specific Probes 1998;(179):221-25.
and Fluorescent In Situ Hybridization were used. Human 33. Yaron Y, Bryant-Greenwood PK, Dave N, et al: Multifetal
Reproduction 1999;14(5):1213-16. pregnancy reduction (MFPR) of triplets to twins:
19. Homer J, Bhatt S., Huang B and Thangavelu M: Residual Comparison with non-reduced triplets and twins. Am J
risk for cytogenetic abnormalities after prenatal diagnosis Obstet Gynecol 1999;(180)(5):1268-71.
by interphase fluorescence in situ hybridizatio (FISH) 34. Leondires MP, Ernst SD, Miller BT, et al. Triplets:
Prenatal Diagnosis 2003;23:556-571. outcomes of expectant management versus multifetal
20. Greene RA, Wapner J, Evans MI: Amniocentesis and reduction for 127 pregnancies. Am J Obstet Gynecol
choironic villu sampling in triplet pregnancy In, Keith LG, (United States), 1999; 72p257-60.
Blickstein I, Oleszcuk JJ (eds.) 35. Lipitz S, Shulman A, Achiron R, et al. A comparative study
Triplet Pregnancy. Parthenon Publishing Group, London, of multifetal pregnancy reduction from triplets to twins
New York , ppgs 73-84. in the first versus early second trimesters after detailed
 Selective Reduction 307
fetal screening. Ultrasound Obstet Gynecol; 2001;(18):35- 46. St. John EB, Nelson KG, Oliver SP, Bishno, RR,
38. Goldenberg RL. Cost of Neonatal care according to
36. Angel JL, Kalter CS, Morales WJ, et al. Aggressive gestational age at birth and survival status. Am J. Obstet
prerinatal care for high-order multiple gestations: Does Gynecol 2000;(182):170-75.
good perinatal outcome justify aggressive assisted 47. Britt DW, Risinger ST, Mans M, Evans MI. Devastation
reproductive techniques? AM J Obstet Gynecol, and relief: conflicting meanings in discovering fetal
1999;(181):253-59. anomalies. Ultrasound in Obstetrics and Gynecology.
37. Sepulveda W, Munoz H, Alcalde JL. Conjoined twins in a 2002;20:1-5.
triplet pregnancy: early prenatal diagnosis with three- 48. Britt DW, Risinger ST, Mans M, Evans MI. Anxiety among
dimensional ultrasound and review of the literature. women who have undergone fertility therapy and who
Ultrasound Obstet Gynecol., 2003;22(2):199-204. are considering MFPR: Trends and Scenarios. Journal of
38. Francois K, SEARS C, Wilson R, Elliot J. Twelve year Maternal-Fetal and Neonatal Medicine (In press).
experience of triplet pregnancies at a single institution. 49. Britt DW, Evans WJ, Mehta SS, and Evans MI. Framing
Amer J Obstet Gynecol 2001;(185):S112. the decision: Determinants of how women considering
39. Yakin K, Kahraman S, Comert S. Three blastocyst stage MFPR as a pregnancy-management strategy frame their
embryo transfer resulting in a quintuplet pregnancy. moral dilemma. Fetal Diagnosis and Therapy
Hum Reprod., 2001;16(4):782-84. 2004;(19):232-40.
40. Neonatal Encephalopathy and Cerebral Palsy: defining 50. Redelmeier, DA, Rozin, P, Kahneman, D. (1993)
the pathogensis and pathophysiology. Task Force of Understanding patients’ decisions: cognitive and
American College of Obstetricians and Gynecologists, emotional perspectives. Journal of the American Medical
ACOG Washington DC, 2003. Association, 270, 72-76.
41. Petterson B, Nelson K, Watson L et al. Twins, triplets, and 51. Chapman, GB, and Elstein, AS. (2000) Cognitive pro-
cerebral palsy in births in Western Australia in the 1980s. cesses and biases in medical decision making. In Chap-
British Medical Journal, 1993;(307), 1239-43. man, GB, and Sonnenberg, FA (Eds.). Decision Making
42. Pharoah PO, Cooke T. Cerebral Palsy and Multiple Births. in Health Care: Theory, Psychology and Applications.
Archives of Disease in Childhood. Fetal and Neonatal Cambridge University Press: New York. Pp. 183-210.
edition 1996;(75), F174-77. 52. Steginga, SK and Occhipinti, S. (2004) The application of
43. Evans MI, Kaufman MI, Urban AJ, Krivchenia EL, Britt the heuristic-systematic processing model to treatment
DW, Wapner RJ. Fetal Reduction from Twins to a decision making about prostate cancer. Medical Decision
Singleton: A Reasonable Consideration. Obstetrics and Making, 24.
Gynecology, 2004 (In press). 53 Hamm, RM (2004) Theory about heuristic strategies
44. Templeton A. The multiple gestation epidemic: The role based on verbal protocol analysis: The emperor needs a
of the assisted reproductive technologies. shave. Medical Decision Making, 24, 681-86.
45. Kalra SK, Milad MP, Klock SC, Crobman WA: Infertility 54. Britt, D.W. and Campbell, E.Q. (1977) Assessing the
patients and their partners: differences in the desire for Linkage of Norms, Environments and Deviance. Social
twin gestations. Obstet Gynecol 2003;102:152-55. Forces, (December), 532-49.
308 Textbook of Perinatal Medicine

24
Neonatal Ethics

Subramaniam

BACKGROUND gestational age groups (Vohr BR, 2000, Botting N,

1998, Ment LR, 2003).
Neonatal medicine has undergone significant changes
With increased survival and an increase in the
over the last four decades. The increasing survival
total number of handicapped infants, society is
of smaller and younger infants is possible because of
confronted with the need for special assistance for
medical and technological innovations, such as
antenatal steroid administration to a pregnant these children. Decisions regarding resuscitation at
mother in preterm labor, the availability of surfactant the lower ends of gestational age (<24 weeks) and
to the premature infants, ventilators of different birth weight (<400g) become increasingly difficult.
kinds (conventional, high frequency, etc.), inhaled Decisions regarding the congenitally malformed or
Nitric Oxide (iNO), and Extra Corporeal Membrane infants with chromosomal problems (like trisomy 13
Oxygenation (ECMO) to name a few. The mortality and 18), identified during pregnancy, pose an ethical
rate has improved over time in USA (Lemons, JA and moral challenge for the various participants. The
2001, Stevenson, DK 1998) and rest of the world pregnant woman and the father of the fetus, along
(Horbar, JD, 1997, Wood B, 1989) and it has with the family and physicians and other health care
significantly declined in all weight categories. But providers, struggle with these decisions at times of
there also is a need to have uniformity in the extreme vulnerability and uncertainty. Numerous
denominators we use for defining mortality and publications and guidelines by professional and legal
morbidity of these infants. Currently, the mortality organizations attempt to clarify the issues and guide
rates are expressed as deaths per 1000 live born babies the parents, health care providers, and hospitals.
born, deaths per all premature infants, by specific Management of these issues compels the clinicians
weight categories, by admissions to Neonatal to make decisions “in the moment of clinical truth”
Intensive Care Units (NICUs), or by deliveries in (Pellegrino ED, 1987).
one hospital, geographic region, or country. The rates Significant medical and technological innovations
vary significantly depending upon which terminology have invaded the NICU. Thoughtful use of such
is used. Although rates of significant morbidities or advances might help to save more lives but attention
serious handicaps have reduced or have remained should be paid whether these advances decrease
steady across many gestational ages or weight groups morbidity over time. Surfactant use from 1990 has
over the years (O’Shea 1997), there is still a high rate significantly increased survival and reduced
of handicaps in lower birth weight or early morbidity. Administration of antenatal steroids to
 Neonatal Ethics 309
pregnant mothers with preterm labor has increased dismal in terms of survival of infants < 500 g (Allen
both pulmonary maturity and survival. Short-term MC, 1993, Costeloe K, 2000).
outcomes of those infants appear to be favorable but In a prospective study from England and Ireland
long term outcomes are being evaluated. On the other (Costeloe K, 2000), the survival rates expressed as a
hand, the introduction of ECMO and ventilators percentage of live births in 1995 for infants at 23, 24,
occurred without any controlled studies in NICUs. and 25 weeks of gestation were 11%, 26%, and 44%
Later studies suggested limited benefit for some of respectively. Expressed as a percentage of the
these therapies. It is critical we evaluate any new admission to NICUs, the survival rates improved to
medical or surgical therapies before implementing 20%, 34%, and 52% respectively. For the same cohort
them on a widespread basis in NICUs. of infants, the survival rates expressed by birth
In this chapter some of these issues, such as the weight for <500g, 500 to 749g, and 750 to 999g infants
lower limit of viability (or how small is too small?), were 6%, 32%, and 55% respectively.
withdrawal and/or withholding life support Birth weight-specific statistics of admissions to
including nutrition and fluids, economics, role of NICUs in the USA have shown higher survival rates.
parents and health care providers, global The NICHD network (Stevenson DK, 1998) reported
perspectives, and a common framework for neonatal survival rates for infants at 23, 24, and 25 weeks of
ethical issues, will be reviewed. gestation were <20%, 47%, and 68% respectively. In
the same report, survival rates from birth until
THRESHOLD OF VIABILITY OR discharge for infants born between January 1993 and
HOW SMALL IS TOO SMALL? December 1994 with birth weights of 501 to 750 g,
The current published statistics about survival and 751 to1000g, 1001 to 1250g, and 1251 to 1500 g were
morbidity rates of extremely low birth weight 49%, 85%, 93%, and 96% respectively. Among those
(ELBW) and very low birth weight (VLBW) babies survivors, chronic lung disease developed in 19%,
will be presented to assist in addressing the issue of intra ventricular hemorrhage in 32 % (with 11%
viability. Survivability of infants correlates with having severe grades), and periventricular
gestational age and birth weight. African American leukomalacia in 6%. The incidence of necrotizing
infants comprise of 36.8% of the ELBW (< 1000 g) enterocolitis ranged from 3% to 9% and that of late
babies born in the USA but account for only 15.5% onset sepsis varied from 9% to 34 % inversely related
of all live births. Biomedical and biopsychosocial to birth weights. Infants in these weight groups
factors may be contributing to this disproportionate stayed in the hospital on an average of 2 to 4 months.
increase in ELBW in African American births, and The report also notes that the mortality rate declined
these dynamics need further investigation. by 42% from 1988 to 1994 in all weight groups but
It is important to know the outcomes of these with no significant drop in the morbidity rates of
ELBW and VLBW infants, especially below 25 weeks infants <750 g (38% in 1988 and 37% in 1994).
of gestation, to assist in decision making regarding In 1997, a report compared the survival and
withholding or withdrawing support. Infants born morbidity rates of infants weighing 501 to 800g born
and admitted to the NICU at or < 23 weeks have a in North Carolina, USA (O’Shea, 1997) during three
less than 10 % chance of survival. Less than 1% time periods from 1979 to 1984, 1984 to 1989, and
survival was reported in ELBW infants with birth 1989 to 1994. Survival rates increased from 20% to
weights < 400 g. In a large multi-center review in 36% to 59% respectively. On the other hand, the
USA, the survival rate from birth until discharge for major neuro-sensory impairments at 1 year of age
infants born between 1996 and 2000 and with birth stayed relatively the same, at 25%, 28%, and 21%,
weights of 401 to 500 g was 17% (Lucey JF, 2004). during the same three periods. Hussain and
Earlier reports by other investigators were more Rosenkrantz (2003) reported, in a 2003 composite of
310 Textbook of Perinatal Medicine

many studies from developed nations, a survival rate 2003). Saigal (1999) reported that when presented
of <3.5% at 22 weeks, 21% at 23 weeks, 46% at 24 with hypothetical clinical vignettes, health care
weeks and 66% at 25 weeks of gestation. providers in NICU were significantly more negative
The cohort of infants born in 1995 in England and than the parents or the teenaged ELBW children.
Ireland at < 25 completed weeks were prospectively The parents rated the quality of life as good for their
followed for >6 years. The report in 2005 suggested children even though they acknowledged their
that the cognitive and neurological deficits were children have a greater burden than other normal
common at school age (21%) (Marlow N). A birth weight children. These studies suggest parents
comparison with their classroom peers showed even are appropriate decision makers in most cases.
more impairment (41%). The rates of mild, moderate, It is evident from the available data that the
and severe disabilities were 34%, 24% and 22% mortality and morbidity rates are high for infants
respectively in these survivors. Twelve percent had born < 24 weeks and/or <500 g. At 23 and 24 weeks
cerebral palsy. Even more sobering were the rates even though survival has improved, reported
of survival with no disability among this group at 6 handicaps of survivors should give a pause to those
years of age: 1%, 3%, and 8 % for those born at 23, in NICU in pursuing a course of aggressive action in
24, and 25 weeks of gestation respectively. the delivery room and subsequently in the unit. It is
While this information will keep changing in the important to have the global, national, regional, and
future as mortality and morbidity rates change, one institutional data on not only survival but also
can attempt to address the issue of how small is too outcomes of these ELBW infants so the information
small. Biologically, at <22 weeks of gestational age, can be shared with the parents to assist in decision
the physiological and anatomical maturity of the lung making. Because the statistics differ depending upon
will unlikely support extra-uterine function and hence which denominators are used, one should be clear
survival (Barbet JP, 1988, DiMaio M, 1989, deMello and consistent in the communication.
DE, 2000). Over the last 10 years there seems to be The issue of sanctity of life versus quality of life
a leveling of improvement in survival in these is a running debate in neonatal and obstetric
gestational age groups. This leveling suggests that specialties, as well as with the prospective parents.
we may have reached the threshold of viability with Those who believe in sanctity of life may suggest
the current technology and support. Sharing this that it is worth intervening with aggressive support
information and institutional, regional, national, and for any live product of conception. Many have
global mortality and morbidity reports with parents difficulty in accepting this notion as necessarily
will be the first step in addressing the issue of directing anyone to initiate or sustain treatments
viability. regardless of the mortality and morbidity. They
suggest that it may be preferable to assess
PARENTS ROLE intervention after birth so that the decision can be
In USA, parents are generally considered appropriate made with more information at hand. On the other
surrogate decision makers for their children. They hand, the slippery slope argument about the quality
are also considered to have the required authority of life judgment is well-known. This issue remains a
and best interests of the infant in their minds when continuing debate in society and adds to the
making decisions about medical care for their uncertainty in decision making.
children.
ECONOMICS
Attitudes of parents and health care providers
regarding outcomes of ELBW infants, including As a result of advancing technology hospital bills
quality of life have been evaluated in many reports have increased dramatically, and the total lifetime
(Streiner DL, 2001, McHaffie HE, 2001, Hansen MB, costs may go up even higher if the infant needs any
 Neonatal Ethics 311
type of rehabilitation or follow-up care. The cost of the burdens outweigh the benefits, the withholding
care in NICUs in the USA is now reported as or withdrawal of support to adults, children, or
exceeding four billion dollars. A 2003 California study neonates is acceptable. Currently, most reports
(Gilbert WM, 2003) reported an average hospital cost suggest that for adults with terminal conditions it is
of $224,000 for an infant with birth weight between appropriate for the patient to request WH/WD of
500 to 700 g compared to $4300 for infants between nutrition and fluids as well (Winter S, 2000, Hastings
2250 and 2500 g and $1000 for those with birth Center 1987, JAMA 1990). Most agree that
weights of greater than 3000 g. In the same study, appropriate family members, especially if authorized
hospital costs averaged $202,400 for an infant born to make medical decisions, can request WH/WD of
at 25 weeks compared to $2600 for an infant born at nutrition and fluids for a terminally ill adult patient.
36 weeks and $1100 for 38 week infant. Similarly, Increasingly, pediatric patients are also reported as
another study (Rogowski J, 2003) reported a median appropriate candidates for requests for WH/WD in
cost of $103,600 for infants born between 501 and terminal conditions (Burns JP, 2001, Cranford RE,
750 g going down to $31,200 for those between 1251 1995, Johnson J, 2000). The premise behind such
and 1500 g. The hospital costs were highest for infants requests is that tube feeding or intravenous
born at 25 to 26 weeks of gestation with a median alimentation should be considered a medical
of $101,600 dropping to $18,700 for infants born at intervention just like intubation or other treatments.
>32 weeks. Another 1987 California study calculated Others would argue that withdrawal of nutrition and
that the average cost per first-year survivor in infants fluids, especially from neonates, should not be
in NICUs with birth weights less than 750 g was recommended.
$273,900; for those who weighed 750-999 g the In an excellent review by Carter and Leuthner
average cost was $138,800. In a May 16, 1988 article (2003), the authors hold that WH/WD of nutrition
Newsweek quoted the total cost for a surviving fetal and fluids in newborn infants is also appropriate.
infant as $366,480 with additional costs during They state that the “medical facts such as underlying
rehabilitation. However, the aggragate cost of NICU diagnosis, response to previously given treatments,
is still far less than the cost of adult intensive care likely response to appropriate treatments or
units providing care for those at the end of life. interventions not yet offered and ultimate prognosis
This brief discussion of the economics of caring for the infant’s condition” should be considered and
for critically ill infants in the NICU is necessary to discussed in detail with the team, parents, and
understand the full impact on families, society, and extended family. In addition, parents’ expectations,
the surviving infant with special needs. The infant’s culture, religion, traditions, and other social values
family undergoes severe emotional and financial should be brought to bear on this decision for their
stress with the birth of an extremely premature infant. The health care team should not usurp the
infant, and they often are confused, angry, and authority of the parents without documentation
frustrated by resulting issues. This concern needs to (from independent experts) that they are not capable
be understood by the medical team, and the public of making such decisions. The institution’s policies
and society needs to address it in an open forum. and state legal statues should be reviewed and taken
in to account. Offering oral feeding in infants should
WITHHOLDING/ WITHDRAWAL be acceptable as well as pain medications as part of
OF NUTRITION AND FLUIDS: palliative care. Hospice care, if available, for such
The benefits and burdens of any medical intervention infants when the WH/WD of care including nutrition
should be assessed so that a determination can be and fluids is indicated is a good alternative. More
made regarding the withholding/withdrawal (WH/ discussion by physicians, the health care community,
WD) of nutrition and fluids. Most will agree that if parental groups, and society is necessary to guide
312 Textbook of Perinatal Medicine

the decision making about WH/WD of nutrition and infants born at tertiary centers with neonatal and
fluids in newborn in the future. perinatal specialties had a better survival rate at these
gestational ages. Those transferred in utero to
GLOBAL PERSPECTIVES tertiary centers at 23, 24, and 25 or 26 weeks of
It is clear that ethical decision making does not take gestation showed lower morbidity and had a better
place in the abstract. Societies, nations, cultures and prognosis. Globally, the viability limit seems to be
traditions, and religions play an intricate part in such slowly but steadily converging around 22 to 24 weeks
decision making. In developing nations, and now in based on biological and experiential data.
developed nations as well, the economy also plays
COMMON FRAMEWORK FOR
a role in such decisions at the macro level of national
PERINATAL AND NEONATAL ETHICS
health care policy and micro level in the decision
making of a patient (the principle of justice). In many Attempting to create a common framework for
countries, such as India, Nepal and Sri Lanka, neonatal and perinatal ethics is a daunting task. We
(Subramanian KN, 1995) quality of life and economy proposed in 1987, a model (Subramanian KN,
clearly play a crucial role in parental and societal McCullough LB, 1987) based on the ethical principles
decisions regarding WH/WD of support. In of beneficence and respect for autonomy,
Singapore (Ho NK, 1995) using an individualized incorporating the families, religion, culture and
prognostic strategy, “a consensual decision that traditions, societies, and nations as part of the fabric
respects parental authority and promotes physician of decision making (Fig 24.1). With minor
beneficence with the best interest of the infant placed modifications it probably still holds as an anatomical
in the center of analysis” is being reached. In Israel framework for clinicians to work through difficult
(Hammerman C, 1997) the maternal birth place and ethical dilemmas.
level of religious observance were associated with The principles of beneficence and respect for
aggressive intervention in hypothetical cases. In autonomy are clearly addressed in the model. The
neonatal care, specific guidelines, such as those in fetus and future neonate along with the pregnant
Netherlands and Japan (Oishi M, 1997, Nishida H, woman are at the center of this schema generating
1992), led to infants at 22 or <25 weeks of gestation both beneficence and autonomy related obligations.
being resuscitated, but resulted in significant Even though there are ethical obligations generated
mortality and morbidity. Similarly, a study in towards the parent/s, the neonatologist’s primary
California, USA requiring resuscitation of all infants patient is the neonate. The future parent/s is included
>22 weeks of gestation or >450 g resulted in at the top of the model to reflect the relationship in
significant mortality and morbidity, leading to a the neonatal period. The physician is at the base of
recommendation of providing other than comfort the model generating ethical obligations to
care as exceptional for infants <23 weeks or <500 g. prospective parents, the pregnant woman, and the
A report from Scotland (McHaffie HE, 1999) outlined fetus during the perinatal period and to the neonate
that 8 European countries compared the “legal, ethical and the parents in the postnatal period and beyond.
and professional settings within which decision It is recognized that these ethical dilemmas are
making for neonates took place.” Overly aggressive affected by the context in which they occur and hence
treatment was discouraged and comfort care the schema recognizes the need to add religious
recommended. Most of the countries prohibited beliefs, traditions, family beliefs and values, cultures,
“active intentional ending of life” except Dutch societies, and nations as the very fabric on which
pediatricians. Reports from USA (Yeast JD, 1998, this model is built. There are primarily beneficence-
Bode MM, 2001), Australia (Doyle LW, 2001) and based ethical obligations to the fetus and neonate,
Austria (Hohlagschwandtner M, 2001) suggest that but the model included autonomy-based obligations
 Neonatal Ethics 313
PARENT/S

Prospective Parent/s

FAMILY BELIEFS RELIGIONS

TRADITIONS
Pregnant
Woman

BENEFICENCE RESPECT
?
- ----------------------------- For
Fetus
AUTONOMY
?
Neonate -----------------------------

CULTURES SOCIETIES/NATIONS

Physician
Nurses & others

Fig. 24.1: Common framework for Perinatal/Neonatal Ethics, modified

from Seminars in Perinatology, 1987,
“The Ethics of Perinatal and Neonatal Care

as a secondary in the model because some may The four “C”s of clinical ethical decision making
believe they exist. This structural guidance could be include
applied to ELBW infants, infants with congenital 1. communication
anomalies such as Trisomy 13, Trisomy 18, 2. clarification
anencephalic and other terminally ill infants. 3. consistency and
This model extends Pellegrino’s proposed 4. caring. Maintaining a high level of communication
framework (1987) for clinical ethical dilemmas to the between parents and health care providers is
complex perinatal and neonatal areas. This model necessary in the NICU where issues are extremely
complex and highly charged with emotions.
recommends a collaborative approach to decision
Clarification of issues that arise among health care
making between the parent/s, physician, and other
givers and between parents and medical and
health care providers acting in the best interest of
nursing staff is crucial for problem solving even
the baby. Parents should be able to make those
before a dilemma arises. Providing consistent
decisions for their infant unless they are shown to
information available to date by all care givers
be incompetent or incapable as assessed by
(provided good communication exist between
independent specialists such psychiatrists or, of
providers) will allow for trusting environment in
course, the courts. Obtaining the opinion of ethics which decision making is encouraged. An attitude
consult or ethics committee will help the clinician and of caring from the very beginning provides the
family in guiding the decision making. Many families necessary environment in which parents feel
have found the objective view of another expert or comfortable in discussing any and all issues about
group of people helpful in facilitating the discussion their infants. All four of these facilitate decision
and clarification of the facts of the ethical dilemma making by the parents and health care providers
being faced and the options available. during difficult times.
314 Textbook of Perinatal Medicine

GUIDELINES age or birth weight at this edge of viability should

Currently, there exist guidelines from various be avoided because the prognosis for the individual
organizations including the American Academy of infant remains uncertain in terms of both mortality
Pediatrics(AAP), AAP Committee on Fetus and and morbidity. Parents who understand the high
Newborn, (1995), AAP Committee on Bioethics risks involved in aggressive interventions at the
statement (1996), American College of Obstetricians borderline gestational ages should be given the
and Gynecologists (ACOG), ACOG committee on option of assessment at birth and resuscitation.
Obstetric statement, Canadian Pediatric Society, Further action will depend on the infant’s condition
Thames Regional Perinatal Group (2000), Colorado and NICU course. Even prior to delivery, one should
Collective for Medical Decisions, International discuss with parents that, if assessment after birth
Guidelines for Neonatal Resuscitation (Niermeyer indicates a significantly poor prognosis, withdrawal
2000), NY State Task Force on Life and Law, (1988) of support should be an option. There should always
and from other countries. At 22 weeks or <23 weeks be room for individual decision making based on
or <400 g, most guidelines recommend giving only the specifics of the situation, such as a parent with
comfort or compassionate care, which is consistent infertility, advanced age, multiple pregnancy losses
with available data about mortality and morbidity etc. Even though ethically there is no difference
and biological information. Most guidelines will also between withholding and withdrawing care,
suggest comfort care at 23 weeks unless parents, after emotionally the latter may be harder for parents or
understanding the high risks, want to initiate some health care providers. For some, withholding
aggressive attempts. At 24 weeks, resuscitation will may be preferable than withdrawing, but clear
depend upon the assessment of the baby’s condition communication before and throughout the hospital
at birth and the parents’ understanding of the course will help in making the right decision.
mortality, morbidity, and prognosis; choosing to Collaborative or consensus decision making
intervene to give a trial of life is an appropriate between the parents, physician, and team with
alternative. In some of the recommendations (Italy careful, clear communication and discussion is the
2004, NY 1988), 24 weeks or >500 g are used as cutoff best way to resolve any ethical dilemmas. In situations
points for resuscitation. At 25 weeks and beyond, where disagreement exists between the health care
most guidelines recommend full resuscitation. team and parent(s), additional consultations with a
However, some maintain that a parental request not colleague and other specialists and/or ethics consults
to resuscitate should be followed even at 25 weeks. and committee meetings should help clarify the issues
Most guidelines base the recommendations on and resolve the differences. In those difficult
gestational age. Because growth-restricted mature situations where differences remain, one or the other
infants are included in the statistics presented by birth party can seek legal action. Usually courts are not in
weight, a hard birth weight cutoff is more difficult the best position to resolve these difficult moral and
to use in deciding viability. ethical issues except on narrow legal grounds. In
All guidelines consistently recommend the need many situations Law and Ethics may not see eye-to-
for clear communication among physicians, nurses eye in resolving the dilemma.
and parents both before delivery and afterwards.
CONCLUSION
Collaborative decision making between parents and
physicians, along with other health care providers, In summary, the tremendous advances made in the
is the best way to chart a course that is appropriate last 4 decades in neonatal medicine have also
for the individual baby and parents, especially in brought difficult ethical dilemmas for health care
infants expected to be <24 weeks of gestation or <500 providers and parents. Over these years the lower
g in birth weight. Any strict cutoff by gestational limit of viability dropped from 28 to 32 weeks to 22
 Neonatal Ethics 315
to 23 weeks of gestation. As we reach the the decision making. The physician has beneficence
physiological and anatomical limits of lung generated obligations towards the fetus and
development and extra-uterine survival we also neonate. The neonatologist has both beneficence
reach a natural barrier of lower limit of viability. and autonomy generated obligations towards the
Of course this can change if there are some additional pregnant mother and father during antenatal
advances in existing treatments such as liquid consultations and subsequently to the parent/s
ventilation or providing nutrition in a novel way, when the neonate comes into the NICUs.
or new interventions such as artificial placenta or Collaborative/consensus/shared decision making
uterus. But this ‘medical miracles around the corner’ with parents, physicians and others, applying the
argument or outliers in terms of survival of <23 ethical principles outlined in the model, will result
weeks gestation infants cannot be used for decision in the best practice in NICU for these infants.
making occurring now. Advances in technology and Judicial uses of the ethics consultant or committee
the ability to prolong life should be tempered with and other experts may facilitate better
the benefits and burdens to the patient. Principles communication and clarification in difficult
of beneficence and respect for autonomy obligations circumstances. Providing communication in a clear,
weigh heavily in neonatal ethical dilemmas in the consistent and caring way (4 ‘C’s) and sharing all
milieu of principle of justice and cultures, traditions, the information about mortality, morbidity, and
religions, and nations. Weighing the benefits/ prognosis before and after delivery of a high risk
burden to the patient should guide every one in infant facilitates decision making.

Table 24.1: Guidelines for Care of Extremely Preterm Infants.

Canadian Pediatric Society, 1994

• 22 weeks’ gestation: Treatment should be started only at the request of fully informed parents or if it appears that
the gestational age was underestimated.
• 23 to 24 weeks’ gestation: There is a role for parental wishes, the option of resuscitation, and a need for flexibility
in deciding to start or withhold resuscitation, depending on the infant’s condition at birth.
• 25 weeks’ gestation: Resuscitation should be attempted for all infants who do not have fatal anomalies.
Colorado Collective for Medical Decisions, 2000
• 22 weeks’ gestation: Comfort care is the only appropriate choice.
• 23 weeks’ gestation: Most participants would advise comfort care, but if parents understood the high risks, they
would be willing to initiate a course of intensive care.
• 24 weeks’ gestation: Participants are able to support either decision, as long as a collaborative process with good
sharing of information occurred.
• 25 weeks’ gestation: Most participants were uncomfortable with withholding care, but some were willing to support
a parental request for comfort care if there had been good education and an effort at collaboration.
American Academy of Pediatrics/Americal Heart Association Neonatal Resuscitation Program, 2000
• Non-initiation of resuscitation in the delivery room is appropriate for newborns who had confirmed gestation of
less than 23 weeks or birthweights of less than 400 g
Thames Regional Perinatal Group, 2000
• Less than or equal to 22 weeks’ gestation: Compassionate care only
• 23 to 24 weeks’ gestation: Resuscitation depends on infant’s condition at birth.
• 25 to 27 weeks’ gestation: Full resuscitation and supportive care
From: Boyle RJ, c472 NeoReviews vol.5 No. 11 November 2004
316 Textbook of Perinatal Medicine

ACKNOWLEDGEMENTS 12. deMello, D. E., & Reid, L. M. (2000). Embryonic and early
fetal development of human lung vasculature and its
My thanks to Ms. Ninian Kring for preparing the functional implications. Pediatr Dev Pathol, 3(5), 439-49.
tables and figures and Ramya Sivasubramanian, J.D. 13. Doyle, L. W., & Casalaz, D. (2001). Outcome at 14 years
of extremely low birthweight infants: a regional study.
for reviewing the manuscript and providing valuable Arch Dis Child Fetal Neonatal Ed, 85(3), F159-64.
suggestions. 14. Doyle, L. W., Cheung, M. M., Ford, G. W., Olinsky, A.,
I also thank all the infants that I had the privilege Davis, N. M., & Callanan, C. (2001). Birth weight <1501 g
and respiratory health at age 14. Arch Dis Child, 84(1),
of taking care over the years and their parents for
40-44.
the opportunity to serve and learn from and all the 15. Ethics and the care of critically ill infants and children.
staff, residents, fellows and colleagues at American Academy of Pediatrics Committee on Bioethics.
(1996). Pediatrics, 98(1), 149-52.
Georgetown University Hospital NICU.
16. Gilbert W, M., Nesbitt, T. S., & Danielsen, B. (2003). The
cost of prematurity: quantification by gestational age and
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Cognitive and educational outcome of very-low- 22. Horbar, J. D., Badger, G. J., Lewit, E. M., Rogowski, J., &
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Neurol, 40(10), 652-60. associated with variation in 28-day mortality rates for
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(2001). End-of-life care in the pediatric intensive care unit: Pediatrics, 99(2), 149-56.
attitudes and practices of pediatric critical care physicians 23. Hussain, N., & Rosenkrantz, T. S. (2003). Ethical
and nurses. Crit Care Med, 29(3), 658-64. considerations in the management of infants born at
7. Carter, B. S., & Leuthner, S. R. (2002). Decision making in extremely low gestational age. Seminars in Perinatology,
the NICU—strategies, statistics, and “satisficing”. Bioethics 27(6), 458-70.
Forum, 18(3-4), 7-15. 24. The initiation or withdrawal of treatment for high-risk
8. Colorado Collective for Medical Decisions. Neonatal newborns. American Academy of Pediatrics Committee
Guidelines and Video, Colorado Collective for Medical on Fetus and Newborn. (1995). Pediatrics, 96(2 Pt 1), 362-
Decisions, 777 Grant Street, Suite 206, Denver, CO 63.
9. Costeloe, K., Hennessy, E., Gibson, A. T., Marlow, N., & 25. Johnson, J., & Mitchell, C. (2000). Responding to parental
Wilkinson, A. R. (2000). The EPICure study: outcomes to requests to forego pediatric nutrition and hydration. J Clin
discharge from hospital for infants born at the threshold Ethics, 11(2), 128-35.
of viability. Pediatrics, 106(4), 659-71. 26. Lantos, J. D., Tyson, J. E., Allen, A., Frader, J., Hack, M.,
10. Cranford, R. E. (1995). Withdrawing artificial feeding Korones, S., et al. (1994). Withholding and withdrawing
from children with brain damage. Bmj, 311(7003), 464-65. life sustaining treatment in neonatal intensive care: issues
11. DiMaio, M., Gil, J., Ciurea, D., & Kattan, M. (1989). for the 1990s. Arch Dis Child Fetal Neonatal Ed, 71(3), F218-
Structural maturation of the human fetal lung: a 23.
morphometric study of the development of air-blood 27. Lemons, J. A., Bauer, C. R., Oh, W., Korones, S. B., Papile,
barriers. Pediatr Res, 26(2), 88-93. L. A., Stoll, B. J., et al. (2001). Very low birth weight
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outcomes of the National Institute of Child health and Newborn. American College of Obstetricians and
human development neonatal research network, January Gynecologists Committee on Obstetric Practice. (1995).
1995 through December 1996. NICHD Neonatal Research Pediatrics, 96(5 Pt 1), 974-76.
Network. Pediatrics, 107(1), E1. 40. President’s Commission for the Study of Ethical Problems
28. Lucey, J. F., Rowan, C. A., Shiono, P., Wilkinson, A. R., in Medicine and Biomedical and Behavioral Research.
Kilpatrick, S., Payne, N. R., et al. (2004). Fetal infants: the Deciding to Forego Life-Sustaining Treatment: A Report
fate of 4172 infants with birth weights of 401 to 500 on the Ethical, Medical, and Legal Issues in Treatment
grams—the Vermont Oxford Network experience (1996- Decisions. Washington, DC: US Government Printing
2000). Pediatrics, 113(6), 1559-66. Office, 1983, pp171-92.
29. Management of the woman with threatened birth of an 41 .Rogowski, J. (2003). Using economic information in a
infant of extremely low gestational age. Fetus and quality improvement collaborative. Pediatrics, 111(4 Pt 2),
Newborn Committee, Canadian Paediatric Society, e411-18.
Maternal-Fetal Medicine Committee, Society of 42. Stevenson, D. K., Wright, L. L., Lemons, J. A., Oh, W.,
Obstetricians and Gynaecologists of Canada. (1994). Cmaj, Korones, S. B., Papile, L. A., et al. (1998). Very low birth
151(5), 547-53. weight outcomes of the National Institute of Child Health
30. Marlow, N., Wolke, D., Bracewell, M. A., & Samara, M. and Human Development Neonatal Research Network,
(2005). Neurologic and developmental disability at six January 1993 through December 1994. Am J Obstet
years of age after extremely preterm birth. N Engl J Med, Gynecol, 179(6 Pt 1), 1632-39.
352(1), 9-19. 43. Streiner, D. L., Saigal, S., Burrows, E., Stoskopf, B., &
31. McHaffie, H. E., Cuttini, M., Brolz-Voit, G., Randag, L., Rosenbaum, P. (2001). Attitudes of parents and health care
Mousty, R., Duguet, A. M., et al. (1999). Withholding/ professionals toward active treatment of extremely
withdrawing treatment from neonates: legislation and premature infants. Pediatrics, 108(1), 152-57.
official guidelines across Europe. J Med Ethics, 25(6), 440- 44. Subramanian, K. N., & McCullough, L. B. (1987). A
46. common framework for perinatal and neonatal medical
32. McHaffie, H. E., Laing, I. A., Parker, M., & McMillan, J.
ethics. Semin Perinatol, 11(3), 288-90.
(2001). Deciding for imperilled newborns: medical
45. Subramanian, K. N., & Paul, V. K. (1995). Care of critically
authority or parental autonomy? J Med Ethics, 27(2), 104-
ill newborns in India. Legal and ethical issues. J Leg Med,
09.
16(2), 263-75.
33. Ment LR., Vohr, B., Allan, W., Katz, K. H., Schneider, K.
46. Task Force on Ethics of the Society of Critical Care
C., Westerveld, M., et al. (2003). Change in cognitive
Medicine: Consensus report on the ethics of foregoing
function over time in very low-birth-weight infants. Jama,
life-sustaining treatments in the critically ill. Crit Care
289(6), 705-11.
Med, 18:1435-39, 1990
34. Niermeyer, S., Kattwinkel, J., Van Reempts, P., Nadkarni,
47. Thames Regional Perinatal Group. Guidelines relating to
V., Phillips, B., Zideman, D., et al. (2000). International
Guidelines for Neonatal Resuscitation: An excerpt from the birth of extremely immature babies (22-26 weeks
the Guidelines 2000 for Cardiopulmonary Resuscitation gestation). March 2000, Available at http://
and Emergency Cardiovascular Care: International www.gapm.org/publication.php
Consensus on Science. Contributors and Reviewers for 48. Tyson, J. E., & Stoll, B. J. (2003). Evidence-based ethics and
the Neonatal Resuscitation Guidelines. Pediatrics, 106(3), the care and outcome of extremely premature infants.
E29. Clin Perinatol, 30(2), 363-87.
35. Nishida, H., & Sakamoto, S. (1992). Ethical problems in 49. Vohr, B. R., Wright, L. L., Dusick, A. M., Mele, L., Verter,
neonatal intensive care unit—medical decision making on J., Steichen, J. J., et al. (2000). Neurodevelopmental and
the neonate with poor prognosis. Early Hum Dev, 29(1- functional outcomes of extremely low birth weight infants
3), 403-06. in the National Institute of Child Health and Human
36. Oishi, M., Nishida, H., & Sasaki, T. (1997). Japanese Development Neonatal Research Network, 1993-1994.
experience with micropremies weighing less than 600 Pediatrics, 105(6), 1216-26.
grams born between 1984 to 1993. Pediatrics, 99(6), E7. 50. Winter, S. M. (2000). Terminal nutrition: framing the
37. O’Shea, T. M., Klinepeter, K. L., Goldstein, D. J., Jackson, debate for the withdrawal of nutritional support in
B. W., & Dillard, R. G. (1997). Survival and developmental terminally ill patients. Am J Med, 109(9), 723-26.
disability in infants with birth weights of 501 to 800 grams, 51. Wood, B., Katz, V., Bose, C., Goolsby, R., & Kraybill, E.
born between 1979 and 1994. Pediatrics, 100(6), 982-86. (1989). Survival and morbidity of extremely premature
38. Pellegrino, E. D. (1987). The anatomy of clinical-ethical infants based on obstetric assessment of gestational age.
judgments in perinatology and neonatology: a Obstet Gynecol, 74(6), 889-92.
substantive and procedural framework. Semin Perinatol, 52. Yeast, J. D., Poskin, M., Stockbauer, J. W., & Shaffer, S.
11(3), 202-09. (1998). Changing patterns in regionalization of perinatal
39. Perinatal care at the threshold of viability. American care and the impact on neonatal mortality. Am J Obstet
Academy of Pediatrics Committee on Fetus and Gynecol, 178(1 Pt 1), 131-35.
318 Textbook of Perinatal Medicine

25
Medicolegal Aspects of Perinatal
Medicine: European Perspective

James Walker

INTRODUCTION This has meant that the fetus is increasingly seen as

an individual that has access to medical care and is
A pregnant woman has similar rights to any other
a factor in medical decision making. This has led to
patient and these are protected by the normal human
the concept of the “Fetus as a Patient” and by
rights assigned to her by society. Therefore, her
definition, medical rights.1 Generally, what is good
informed consent is required before intervention and
for the baby is good for the mother, so there is no
her right to refuse treatment accepted. However,
conflict. It is when the mother disagrees with her
there is a complication, she carries another potential
carers about what is best for the baby that conflict
individual, therefore, her rights and her control over
appears 2, 3
her pregnancy is influenced by the rights assigned
With advances in medical technology and the
to the fetus and how much of these rights are
ability to salvage pregnancies that previously failed,
allocated to the mother to hold.
society has begun to believe that medicine can achieve
Irrespective of the rights the child has in utero,
anything. This means that if damage occurs, there
after birth, its rights are paramount, and although
has to have been error and negligence. Since the fetus
the parents may control these rights to a degree, this
is usually the one that is damaged, it is the baby, or
is not absolute and their control can be removed in
its guardian, that will proceed with litigation, even
the best interests of the baby. Also in some situations,
though the fetus may not have had rights at the time
the rights of the newborn baby can be considered to
of the event. If a neonatal death occurs, increasingly
be present in retrospect, in other words, damage done
this may lead to potential criminal proceedings4, 5
prior to delivery that results in problems after birth,
but this can depend on the legal rights of the fetus
can give rights of complaint to the baby that were
and whether it is born alive or not. It is in these
not there at the time of the event. Therefore,
areas of litigation and fetal rights that there is so
potentially, the rights of this one individual, the child,
much difference between countries.
and the rights of others over it, can change at the
moment of birth and, in some instances, these change
THE RIGHTS OF THE FETUS
of rights can then be applied retrospectively.
This has caused increasing ethical dilemmas over There is no universal truth and that is never more
the years because of the increasing knowledge of true than for ethical and legal issues. Perinatal doctors
pregnancy physiology and, more importantly, the in different countries work within different
increasing ability to assess and visualise the fetus. environments. What is acceptable in one country may
 Medicolegal Aspects of Perinatal Medicine: European Perspective 319
not be in another, not because it is right or wrong, he may never be born at all; but it is nonetheless real and
but because of differences of ethical, legal or social present ownership. A man may settle property on his wife
mores.5 In medicine, we are taught to “first do no and the children to be born of her. Or he may die intestate
harm”, but in the case of perinatal medicine, to and his unborn child will inherit his estate.”
whom? The problem is that there can conflict This is traditional called “present ownership,”
between the concept of the “Fetus as a Patient” and that is, a right possessed by the unborn child at that
the rights of the mother. time, but conditional on being born alive. If the child
This situation is covered by the term beneficence.1 is stillborn, the inheritance (or rights) will revert to
Beneficence is the moral principle that one should someone else. The is referred to as the “born alive
aim to help and failure to do this when one is in the rule.”7
position to do so is morally wrong. However, one Therefore, any right the fetus has in English
is obligated to act to benefit others when one can do common law is dependant on being born alive. This
so with minimal risk, inconvenience or expense. In means that actions leading to death of the baby before
perinatal medicine there is potentially two patients birth are not subject to the normal crimes against the
to consider. How much of a conflict this is depends person but if the baby is born alive and then dies
on both legal and moral belief. In general, the life of then the baby’s existence, and therefore rights, exist
the mother takes precedent since there is a logic that and action can be taken. Overall, the legal situation
the health of the mother is important not only to the in Europe is somewhat confused and is constantly
health of that baby but of any siblings. However, evolving as will be described. Within the European
the main governor of the decision making process is Community, there is a further complication since the
the legal rights of the fetus. countries are governed by similar European laws on
If the fetus has the same rights as a newborn human rights, although there still differences with
baby, decisions can be made on behalf of the baby the application due to local law in each country.
against the wishes of the mother, so called court
ordered care. 2 There is also the potential of the The Right to Life
newborn suing for any damage sustained in utero When the European Human Rights Act came into
from maternal or other’s actions, so called Wrongful force in 2000, it was felt by many that the “Right to
Life decisions.6 Life” stated in Article 2 could be extended to the
However, where the fetus has no legal rights, the unborn fetus. This would protect it from termination
mother’s wishes are paramount. It is only variations of pregnancy and give it equal rights to the mother
in law or ethical constraints that will restrict her and when considering medical decisions. However, a case
her carers’ actions. However, this maternal control based on this belief, has recently been heard in the
exists only up to the moment of birth when full European Court of Human Rights and it was decided
neonatal rights exist and the control transfers to the that the rights of the fetus are not covered by Article
baby or its guardians. This change in legal status 2. This is an important landmark decision not based
occurs in a matter of minutes and can be confusing on law but more on lack of consensus of what is right.
to the mother, attendant staff and society as a whole. The case involved Mrs Vo, one of two women of
Generally, in European law, the starting point is that the same name admitted to the same hospital at the
a child en ventre sa mere is a part of its mother and same time, one for a medical examination when six
therefore its rights are held by the mother.7 months pregnant, the other to have a coil removed.
However, in English common law an unborn child The wrong Mrs Vo went for coil removal. In an
has rights to inherit property as follows:- attempt to remove the non-existent coil, Mrs Vo’s
“There is nothing in law to prevent a man from owning amniotic sac was pierced and the pregnancy
property before he is born. His ownership is contingent, for terminated. The doctor was charged with
320 Textbook of Perinatal Medicine

unintentional homicide, the French equivalent of setting a precedent on the legal status of unborn
involuntary homicide. He was initially acquitted, but babies that will be applied across European countries.
then convicted on appeal and sentenced to six months
in prison and fined 10,000 francs. He then appealed WRONGFUL LIFE AND WRONGFUL BIRTH
to the Court of Cassation - France’s highest court - After the baby is born, it has equal rights to the
which overturned the ruling on the grounds that the mother and the rest of society. To some extent these
fetus was not a human being and not entitled to the rights can be applied retrospectively and the events
protection of criminal law. that occurred or did not occur prior to birth can, in
Mrs Vo then took the case before the Grand theory, be litigated against if it adversely affects the
Chamber of the European Court (application no. baby after birth. There are two particular situations,
53924/00). She accused that France’s failure to extend Wrongful Life and Wrongful Birth, where the plaintiff
the law on unintentional homicide to the unborn claims that the baby would rather not have been
violated the State’s Article 2-based obligation to born, i.e. be terminated. Since this usually involves
respect life. However, the court found in favour of failure of prenatal diagnosis and termination of
France by fourteen votes to three. pregnancy, this can produce conflict with the various
The Court felt that the decision of when the right legal and moral arguments.
to life begins was a question to be decided at national
level. They noted that there was no European Definitions
consensus on the scientific and legal definition of the
beginning of life, particular France, where the issue Wrongful life is when the child takes the action against
had been the subject of public debate. At best, it could another party for allowing it to be born in a deformed
be said that the consensus was that the embryo/ or harmed way caused by actions or inaction prior
foetus belonged to the human race. Its potential and to birth. In other words, it would rather have been
capacity to become a person required some protection terminated and litigates for damages to help it live
in the name of human dignity, without making it a as comfortably as possible.
person with the right to life for the purposes of Wrongful birth is when the mother sues other
Article 2 or legal status in conflict with the mother. people for being burdened with a disabled child
Therefore, the Court was convinced that it was something she could have avoided.
neither desirable, nor even possible as matters stood, In essence these suits are genetic or prenatal
to answer the question whether the unborn child was diagnosis litigation cases where termination could
a person for the purposes of Article 2 of the have been offered. Again much of the debate has
Convention. The main judgment of the Court was to occurred in France but affects all countries.
accord each State a degree of autonomy, or a “margin
The Nicholas Perruche Case
of appreciation” as it is called, to work out the right
legal position for itself. So on this view Article 2 did In 1982, when Josette Perruche was early pregnancy,
not apply. A minority of the judges felt that there her 4 year old daughter developed rubella. She told
was no issue; since “even if one accepts that life begins her doctor that, if she had been infected, she wanted
before birth, that does not automatically and a termination rather than risk giving birth to a
unconditionally confer on this form of human life a handicapped child. She had two blood tests, two
right to life equivalent to the corresponding right of weeks apart, which gave contradictory results. Mrs
a child after its birth.” Perruche was reassured that all was well. However,
Therefore, by a majority of thirteen to four, the Nicholas was born with the rubella syndrome and,
court was in favour of the inapplicability of Article after investigation, it was discovered that the
2, implying a lack of rights for the unborn child and laboratory had made an error. A case was brought
 Medicolegal Aspects of Perinatal Medicine: European Perspective 321
on behalf of Nicholas against the doctors alleging when they were unsure about the normality of the
that failure by doctors to diagnose the condition in fetus. Some started to refuse to carry out routine
the womb had prevented a termination of pregnancy antenatal scans as they were worried that they would
and led to Nicholas being born with deformity. The be sued if a disabled baby was born that they had
French Court found in his favour stating in its ruling8 failed to diagnose. The doctors threatened strike
‘since mistakes committed by the doctors and the action.
laboratory while carrying out their contract with Mrs Ethicists and legal specialists also attacked the
Perruche prevented her from exercising her choice rulings. “To allow a child to be born cannot be considered
to end the pregnancy to avoid the birth of a as a mistake - that must be written into law,” said Laurent
handicapped child, the latter can ask for Aynes, a professor in civil law at Paris’ Sorbonne
compensation for damages resulting from this University. Many called on the government to change
handicap.’ the law on the subject. Initially they held out against
There was great upset to the court ruling. Cathrine legislation, but were forced to act by public pressure
Fabre, of the Federation of French Families, said at and by the decision by some medical staff to stop
the time ‘we cannot approve the idea of claiming for carrying out prenatal scans. The bill was passed that
compensation for being alive.’ states that nobody can claim to have been harmed
Further cases were brought where families argued simply by being born. By doing this, the govern-
that if doctors had detected the disabilities prior to ment’s ruling brought to an end a year’s legal and
birth, they would have had the pregnancies moral debate. 8
terminated.9 This case went on appeal to the highest However the new parliament bill prohibited
court in France, the Cour de Cassation. The court wrongful life cases only not wrongful birth suits. This
ruled that disabled children were entitled to means that the obstetrician or technician can still be
compensation if their mothers were not given the sued, but the parents - not the affected child - will
chance of an abortion. The court stated that the be able seek damages, but only on the grounds of a
Perruche precedent remained “as long as a causal link “blatant error” by doctors, the argument being that
can be established with an error committed by a doctor”. the birth of the disabled child is damaging the life
Following this doctors and campaigners for the of the mother.
disabled reacted furiously, describing the decision
by the court as an incitement to eugenics. The case The Dutch Experience
was widely described as establishing in French law After a court awarded damages to a severely
a disabled child’s “right not to be born.” The Collective disabled girl for the fact that she was born, MPs called
To Stop Discrimination against the Disabled (CCH), for the Netherlands to follow France and ban damage
which was set up after the Perruche case, feared that claims for Wrongful Life. Doctors fear the judgment
parents would be attacked for giving birth to a could lead to a sharp increase in defensive prenatal
handicapped child as a result of the decision. “This testing.
is a real act of phobia. Now parents are going to be attacked The case was of 9 year old Kelly Molenaar whose
and seen as irresponsible because they gave birth to a parents had informed a midwife at the Leiden
handicapped child,” it said. “The ruling means that the University Medical Centre that a relative of the father
handicapped have no place in our society,” said Yves was disabled because of a chromosomal abnormality.
Richard, a lawyer representing the medical The midwife reassured them and did not carry out
profession. “There is a real risk of this starting a process further prenatal diagnostic tests or refer the case to
that ends with the search for the perfect child.” a clinical geneticist. The abnormality was not
Doctors expressed increasing concern that the detected early enough to intervene and Kelly was
verdict would push doctors to terminate pregnancies born with multiple mental and physical disabilities.
322 Textbook of Perinatal Medicine

She cannot walk, talk, or properly recognise her amount of damages to assist the woman in the raising
parents; has deformed feet; is believed to be in of the child. A spokesman for the Leeds Teaching
constant pain; and has had several heart operations. Hospitals NHS Trust said: “This was an extremely
By the age of 21 months, she had been admitted to complex case and one which was defended by the trust
hospital nine times due to “inconsolable crying.”10 because it raised important clinical questions.”
The court accepted that damage to Kelly resulted
from the midwife’s error. The appropriate referral Summary of the European Situation
would have resulted in a termination and Kelly As can be seen, the European situation is confused,
would not have been born. Damages against the but it would seem that Wrongful Life cases are not
hospital amounting to the cost of Kelly’s care and being allowed, not only because of the litigation fears
upbringing until her 21st birthday were awarded to it brings, but also the moral aspects deciding that a
her parents. But the court went further, ruling that disabled child is better off not being born. However,
Kelly herself was liable to damages. The court judged Wrongful Birth cases are increasing. These cases,
that the damage experienced by Kelly was in a legal unlike the usual litigation case, which relates to
sense a predictable consequence of the midwife’s damage sustained, centre round the doctor or
mistake. Therefore, the court accepted the possibility technician’s failure to diagnose a pre-existing
of a claim for Wrongful Life. The amount of the abnormality and therefore prevented the mother
damages is still to be decided. from having the opportunity to terminate the
The hospital’s lawyers are considering an appeal pregnancy. This produces major problems and
to the Supreme Court to quash the judgment and concern for obstetric units because any scan potential
MPs are urging the ministries of health and justice to will “miss” an abnormality. Also, which abnormalities
respond to the decision. Boris Dittrich (MP) has called “merit” consideration for termination? This is
for Dutch law to be changed to prohibit wrongful accentuated by a case currently under consideration
life claims as has happened in France. in the UK where a member of the public has asked
Joseph Hubben, Professor of Health Law at the for a judicial review on a case of a late termination
Free University of Amsterdam, said: “To recognise a of pregnancy for a cleft lip and palate.
disabled life as a source of financial damages gives the wrong The upper gestational limit of termination varies
signal to society. Disabled people should be fellow citizens from country to country, in France the law allows
not someone who should have been aborted.” He also termination of pregnancy with no upper gestational
argued that the decision would increase pressure for age limit; in Italy, termination of pregnancy after the
more prenatal diagnostic testing not just from parents time of viability may be legally carried out only when
but also from doctors. continuation of pregnancy represents, either for
physical or psychological reasons a danger to the
The UK Experience
mother’s life. In the UK, the most recent abortion
In 2004, a UK mother was successful in suing her act states that a termination of pregnancy can be
hospital after giving birth to a child with genetic carried out for a serious handicap right up until term
abnormalities. She claimed damages, saying that if as long as the baby is born dead.
she had been informed of the child’s disability, she What, however, is a serious handicap? A paper in
would have had him killed before birth. The baby 2001, demonstrated that of the 270 children born with
had had extensive scanning but no abnormality was cleft lip and/or palate, 23 were positively diagnosed
detected. The baby boy was born in 1999 with a by ultrasound prior to birth.11 Out of that 23, two
genetic abnormality that causes bladder, bowel and ended up having termination of pregnancy, which is
genitalia defects. The Hospital, Leeds Teaching just under 10%. The assumption from this and other
Hospitals NHS Trust, had to pay an undisclosed studies is that, if the diagnosis was available to more
 Medicolegal Aspects of Perinatal Medicine: European Perspective 323
couples, then more terminations for cleft lip and palate rising litigation cost, medical malpractice insurance
would be requested. It also implies that there are for obstetricians has escalated. This has led to the
many causes of fetal abnormality that parents may UK government bringing in “Crown Indemnity”
wish to terminate and which are not currently meaning that the National Health Service (the
universally diagnosed or termination offered. In a Crown) will cover the cost of litigation.14 Therefore,
European survey, only 2% of doctors would offer a it is the health authority that is sued not the
termination for cleft lip/palate, 12 Do we need to individual doctor. Also, all cases brought against
extend the screening of babies to cover a wider range hospitals are defended in England by lawyers
of abnormalities and offer all termination of working for the National Health Service Litigation
pregnancy. If we do not offer them termination and/ Authority (NHSLA), a centralized body. Any costs
or the abnormalities are missed, will litigation follow up to £100,000 are paid by the individual Hospitals
to cover any surgical and other care costs? Who is to but above that, the costs are met by the Clinical
decide what a serious handicap is and whether a Negligence Scheme for Trusts (CNST) which was set
termination is justified? up in 1995 to indemnify acute NHS Trusts against
litigation. CNST grade hospitals according to risk
LITIGATION – THE EUROPEAN PERSPECTIVE and, when a Trust undergoes this assessment, it can
This problem relating to Wrong Birth cases is adding earn a rebate of up to 30% of its indemnity payments,
to the already increasing litigation culture in Europe. if it can demonstrate significantly good performance
There are significant differences between Europe and in terms of certain risk management processes.15 This
the US. In Europe:- can be a 6 figure sum.
1. The litigation is usually brought by claimants Therefore, litigation in Europe is becoming an
paying for the legal costs. However, this is often increasing drain on health care resources and
supported by government grant (Legal Aid in the governments are stepping in to provide the financial
UK) although some “No Win, No Fee” cases are cover in various ways. However, this does not come
beginning to appear. without strings, Although individuals are no longer
2. The cases are heard in front of judges, not juries targeted for litigation, the government agencies are
which mean that the cases are usually less emotive wielding increasing power to insist on risk
but lead to law of precedent. management procedures and the appropriate training
3. The awards are largely for cost of care required, and supervision of staff. So although individuals are
not suffering. This means that the cost of an award no longer responsible to reduce the litigation threat,
for a child with Cerebral Palsy may in the region the hospitals themselves have financial gains to be
of 4 million UK pounds but if the child dies, the made if their staff follows the necessary guidelines
award may only be 20,000. and practices. This can be an important driver of
The cost of litigation is mounting and, at present, improved care. 15
the total potential payouts for litigation in the UK is
OBSTETRIC DECISION MAKING
more than the total cost of running three London
teaching hospitals or providing all maternity care for Decision making by doctors is a complex business.
England for a year. However, this is a misleading Influenced by training, culture and knowledge of
statistic, as the total amount paid out in settling claims outcome. An good example of this is decision to
each year is only about 1% of it’s the total NHS deliver by CS for the premature fetus. Obstetricians
budget, not a huge sum.13 In 1998, the rate of litigation in the different European countries were asked what
was 0.81 closed claims per 1000 finished consultant would be the earliest gestation they would intervene
episodes. The problem is that 65% of the cost, but by Caesarean section in the fetal interest in three
not the numbers, are obstetric cases. Because of the different scenarios.
324 Textbook of Perinatal Medicine

1. when parents wanted everything possible done fetus is allowed but it is not minutes later after birth,
to save this baby, adds to the confusion.
2. when parents were against aggressive However, Dr. Eduard Verhagen, of the
management Groningen Academic Hospital and Dr Louis Kollée
3. When it was your child of Radboud University Medical Centre in the
In the first situation, the median lowest Netherlands, have asserted that euthanasia of infants
gestational age at which obstetricians would be is occurring worldwide. They called on the Dutch
willing to perform an emergency Caesarean section government to regularize the killing of handicapped
for fetal indication varied from 24 completed weeks newborn babies by providing guidelines that will
in Sweden and Germany, to 26 in Netherlands, UK, protect physicians from murder charges. They felt
Italy and Spain. Knowledge that parents were against that there should be a panel to consider guidelines
aggressive management would increase this figure for euthanasia for people with “no free will”, i.e.
by one week in Spain, France, Netherlands, severely handicapped infants. The practice varies
Luxembourg and Sweden. Interestingly the most throughout Europe most commonly in the
conservative approach, i.e. the latest gestation, was Netherlands and France but doctors are divided in
found in scenario 3 where it was your own child.12 whether it should be controlled by law. 18
These results imply that it you want to achieve a life Interestingly, nurses are more in favour that doctors.
birth, then going early can be justified but it is not An associated problem is when to initiate and/or
if the best interests of the parents and the baby are withdraw care from an infant with a severe
taken into account. The recent GRIT study would abnormality or gross prematurity. This problem was
tend to confirm the rightness of that view since highlighted by the “Baby Messenger” case in the US
delayed delivery reduced long term disability.16 where a severely ill preterm infant was resuscitated
against his parents wishes and was removed by his
NEONATAL DECISION MAKING parents from ventilator support and allowed to die
As previously stated, at birth, the baby takes on in their arms. The father was initially charged with
individual rights which may initially rest with the manslaughter although subsequently acquitted. 19
parents but ultimately can be practiced indepen- The approach to the resuscitation of premature babies
dently through an appointed guardian. This can varies between countries with many producing clear
cause confusion since before birth, sometimes just guidelines of when small or abnormal babies should
minutes before, the maternal rights were paramount, be treated or when treatment should be withdrawn.20
now the baby rights can be in conflict. The different approaches are based on various
Here again, retrospective rights pertain. In methodologies including
English law, termination of pregnancy is allowed • the “statistical” approach whereby treatment is
right up until term for significant fetal abnormality, withheld from infants defined as underweight
however, the baby must be born dead. If the baby and/or immature,
is born alive and then dies due to the result of • the “initiate and reevaluate” approach whereby
prematurity or of the procedure itself, the doctor aggressive treatment is begun and then
who carried out the procedure which led to the reevaluated relative to the infant’s progress and
baby’s death can be charged with manslaughter. This parents’ wishes,
means that late termination usually requires feticide. • a “treat until certainty” approach whereby each
This adds to the stress and unpleasantness of the infant is treated until death or discharge.
procedure for the parents and the staff carrying out Each of these approaches has advantages and
the procedure although others find feel that it is more disadvantages. The Danish Council of Ethics
humane.17 The fact that the killing of a handicapped produced a protocol that combines a minimum
 Medicolegal Aspects of Perinatal Medicine: European Perspective 325
gestational age, maturity and parental wishes. In a survey in different European countries,
Generally, infants younger than 24 or 25 weeks will doctors were asked how they would care for a
not be aggressively treated but this can be modified case of extreme prematurity (24 weeks’ gestational
if the infant looks mature and can be resuscitated age, birth weight of 560 g, Apgar score of 1 at 1
using “low technology modalities” and minimal minute). Most physicians in every country but the
handling. 19 Also the approach can be modified by Netherlands would resuscitate this baby and start
considerations of parental wishes. The long term intensive care.20 On subsequent deterioration of
outcome for the baby is greatly influenced by the clinical conditions caused by a severe
ability of his parents to provide the care it requires. intraventricular hemorrhage, attitudes diverge:
Therefore the threshold can be moved down by most neonatologists in Germany, Italy, Estonia,
parents wishing to care for a child that fails to meet and Hungary would favor continuation of intensive
the criterion or up by parents requesting to withhold care, whereas in other countries some form of
treatment from a newborn that meets the threshold limitation of treatment would be the preferred
requirement. Under these guidelines, baby choice. Parental wishes appear to play a role
Messenger would not have been resuscitated. Even especially in Great Britain and the Netherlands.
had the neonatologist decided that the gestational Interesting, again nurses are more likely than
threshold had been met, the baby’s immediate doctors to want to withhold resuscitation in the
condition following birth did not meet the maturity delivery room and to ask parental opinion
criterion. This, together with the parent’s refusal of
regarding subsequent treatment choices. Among
ventilator support, should have meant that he should
doctors who would resuscitate, only in Great
not have been resuscitated. The council’s
Britain and the Netherlands would a substantial
recommendations are based on two main factors; the
percentage change the decision, knowing that
infant’s best interests and economic justice: “The basis
parents were against resuscitation. In Estonia,
for the [modified threshold] recommendation is that the panel
Hungary, Italy, Germany, and Spain, most doctors
considers the 35% occurrence of severe handicaps in children
would withhold treatment in case of emergencies,
born after a pregnancy term of 24-25 full weeks to be high
such as cardiac arrest whereas doctors in Great
in relation to the number of surviving infants; the panel
Britain, the Netherlands, and Sweden would
also takes into account the comparison of the expenditure
withdraw mechanical ventilation. Only in France
incurred with the possible alternative applications for that
and the Netherlands would definitive actions be
amount.”9 Therefore the infant’s best interests and
the cost to society is considered not just survival. A taken to end life. Therefore, the range of care
35% risk of severe impairment may be too high for throughout Europe, in the same clinical situation,
a parent, physician or policy-maker to accept. varied from active care until there was no hope to
However, there is also a chance that the child may positively ending life.
lead a relatively normal life. While this may seem a Interestingly, the parents responses to these
reasonable decision for parents to make, it does result decisions are varied, partly depending on outcome
in large numbers of healthy infants being allowed to with 22% of the parents expressing reservations about
die to avoid a smaller number of handicapped the length of the dying process. Some reported that
infants. One benefit of targeting care it to benefit this had taken from three to 36 hours. Deaths that
those who would gain most. “It seems reasonable to medical teams had predicted would be quick had,
exercise reticence in the treatment of extremely preterm according to the parents’ recollections, taken from
infants in order to benefit the slightly less premature, since 1.5 to 31 hours. When a baby died swiftly, this
the prospects of better results increase with age and fewer seemed to confirm the decision to stop but, when
resources are consumed, allowing more to be helped.”10 babies lingered, doubts were raised.20
326 Textbook of Perinatal Medicine

CONCLUSIONS 4. Molenaar JC. The legal investigation of a decision not to

operate on an infant with Down’s syndrome and a
So there is no pan-European perspective, each duodenal atresia: a report from the Netherlands. Bioethics.
country has its own approach. The Danes have a Jan 1992;6(1):35-40.
5. McHaffie HE, Cuttini M, Brolz-Voit G, et al. Withholding/
varied statistical approach to what should and should withdrawing treatment from neonates: legislation and
not be done, the Dutch similarly have a definite cut official guidelines across Europe. J Med Ethics. Dec
of point, with a pragmatic approach towards 1999;25(6):440-46.
6. Bottis MC. Wrongful birth and wrongful life actions. Eur
withdrawal of treatment and even active ending of J Health Law. Mar 2004;11(1):55-59.
life, the British wait and see, discuss the case with 7. Wellman C. The concept of fetal rights. Law Philos. Jan
their colleagues and the parents and largely let nature 2002;21(1):65-93.
take its course but will withdraw treatment when 8. Spriggs M, Savulescu J. The Perruche judgment and the
“right not to be born”. J Med Ethics. Apr 2002;28(2):63-
clear possibilities of a successful outcome has gone 64.
and the Germans will work to save the baby until it 9. Dorozynski A. Highest French court awards
dies. This does not appear to be influenced by compensation for “being born”. Bmj. Dec 15
2001;323(7326):1384.
religious factors but by the social norms of the society 10. Sheldon T. Court awards damages to disabled child for
that the doctors work. having been born. Bmj. Apr 12 2003;326(7393):784.
Similarly the approach towards termination is 11. Shaikh D, Mercer NS, Sohan K, Kyle P, Soothill P.
Prenatal diagnosis of cleft lip and palate. Br J Plast Surg.
extremely liberal and uninfluenced by religious
Jun 2001;54(4):288-89.
prejudice. This is helped by the largely pan-European 12. Cuttini M. The European Union Collaborative Project on
legal position that the fetus has no rights before birth Ethical Decision Making in Neonatal Intensive Care
as this is the main pillar of the right of life battle. (EURONIC): findings from 11 countries. J Clin Ethics. Fall
2001;12(3):290-96.
The recent findings in the European Courts has 13. Walsh P. Editorial. The AVMA Medical & Legal Journal.
ended that fight for the foreseeable future. 2003;9:108.
However, there is an increasing European 14. Palmer RN. United Kingdom ‘Crown’ indemnity for
medical negligence—an overview of the first 18 months
problem of litigation with the number and cost of of the new scheme. Med Law. 1992;11(7-8):623-27.
cases increasing. The UK leads the way in this 15. Wood L. Clinical Negligence Scheme for Trusts and
situation and has tried to solve the insurance costs maternity care: let’s redesign services, not patch up
outdated systems. CLINICAL RISK. 2003;9:86-88.
by the government footing the bill. This has just led
16. Thornton JG, Hornbuckle J, Vail A, Spiegelhalter DJ,
to spiralling costs. The newer Wrongful Birth cases Levene M. Infant wellbeing at 2 years of age in the
has opened up what appears to be an endless source Growth Restriction Intervention Trial (GRIT): multicentred
of new cases which can be of significant cost. Again randomised controlled trial. Lancet. Aug 7 2004;364
(9433):513-20.
Governments have had to intervene to legislate in 17. Dommergues M, Cahen F, Garel M, Mahieu-Caputo D,
these situations, not because of the rights or wrongs Dumez Y. Feticide during second- and third-trimester
but for the social good. termination of pregnancy: opinions of health care
professionals. Fetal Diagn Ther. Mar-Apr 2003;18(2):91-97.
18. Cuttini M, Casotto V, Kaminski M, et al. Should
REFERENCES euthanasia be legal? An international survey of neonatal
1. Chervenak FA, McCullough LB. The fetus as a patient: intensive care units staff. Arch Dis Child Fetal Neonatal Ed.
an essential concept for the ethics of perinatal medicine. Jan 2004;89(1):F19-24.
Am J Perinatol. Nov 2003;20(8):399-04. 19. Gross ML. Avoiding anomalous newborns: preemptive
2. Draper H. Women, forced caesareans and antenatal abortion, treatment thresholds and the case of baby
responsibilities. J Med Ethics. Dec 1996;22(6):327-33. Messenger. J Med Ethics. Aug 2000;26(4):242-48.
3. Harris LH. Rethinking maternal-fetal conflict: gender and 20. De Leeuw R, Cuttini M, Nadai M, et al. Treatment choices
equality in perinatal ethics. Obstet Gynecol. Nov 2000;96(5 for extremely preterm infants: an international
Pt 1):786-91. perspective. J Pediatr. Nov 2000;137(5):608-16.
 26 Malpractice Issues in Perinatal
Medicine: The United
States Perspective
Barry S Schifrin,

INTRODUCTION
medicine or its numerous schools of practice. There
It was probably inevitable that the law and medicine was no need: patients generally were fatalists,
would come into conflict, irrespective of the fact that believing that any adverse medical outcome was the
despite some obviously different approaches, these will of God. It became an issue after 1848 only
learned professions share more than they conflict. because allopathic physicians, to eliminate other
While medicine is fundamentally inductive and law “schools of medicine” created objective standards
deductive, both fields are centered in advocacy for of practice, created national medical societies and
the client. When it comes to medicine, the law tries national standards, elected to support litigation under
to reconcile a body of science with the art of clinical tort law rather than contract law, and established
practice. When it comes to the law, medicine tries to the “deep pockets” of malpractice insurance – a
reconcile a body of laws with notions of fault and profitable industry for attorneys.
accountability. The relationship is abetted when the But it was only with the beginning of the 1960’s
goals of better, more efficient care and prompt and that more educated, informed and assertive patients
effective methods of dealing with error and adverse began to question their physicians in the same manner
outcome are agreed upon. On the other hand, when that they evaluated their other goods and services.
each profession deems the other side to hold some In general, this was poorly accepted by physicians,
unscrupulous advantage, when the “playing field is who for the most part maintained a traditional
perceived to be not level,” and when myth and authoritarian stance in the care of their patients. The
misdirection are rampant and malpractice premiums legislative crises of the1970’s and subsequent crises
have become excessive or insurance coverage of the 80’s, 90’s, and present, brought with tort
unavailable, then the worst of the relationship comes reform HMO’s increasing regulation, decreasing
to the fore, and political and legislative resources autonomy, strained relations with hospital
are recruited to help control the dialogue and the administrations and allied healthcare providers, and
invective, and define or create new rules of decreased physician and patient satisfaction.
engagement. In the end, care is compromised as are Although much has changed from the mid 1800’s
notions of justice and access to the law. there is one historic consistency; the major litigen is
not outcome, but is physician behavior.
HISTORIC PROSPECTIVE OF
MALPRACTICE IN THE UNITED STATES MALPRACTICE LAW
Malpractice suits were unheard of until 1848. Prior Malpractice law is part of tort, or personal-injury,
to that there was no control over the practice of law that affects large segments of society, including
328 Textbook of Perinatal Medicine

product liability, automobile accidents, airplane “What complaints do you have about physicians?”
crashes, etc. and other examples of unintended harm. patients respond rather specifically (Table 26.1).4 As
As mentioned above, it was the physicians underscored by these data, the attorney is often the
themselves, who determined that due to their last person who is contacted, not the first. Indeed,
superior status, were not subject to contract law with most often patients are directed to an attorney by a
patients, who were not their equal, and set the higher member of the medical community.
civil law standard of tort law. The objectives of Indeed many are amazed when looking at medical
malpractice litigation are straightforward: malpractice cases, by the cold-blooded attitude so
1. To resolve disputes fairly with equal opportunity many defendants have taken toward patients who
for “justice” on both sides, have been seriously, and sometimes grotesquely,
2. to compensate persons injured through harmed. Inhumanity and indifference to the suffering
negligence, and of others is in itself another form of injury. When
3. to deter unsafe practices – i.e., raise the standard patients file suit, they are often made to feel as though
of care1 — all without resorting to armaments or they had done something wrong, as if seeking legal
fisticuffs. redress and compensation was in some sense an
A plaintiff prevails in a lawsuit by proving the 4 affront to the system, a personal assault on the
D’s: that the defendant physician. Many plaintiffs feel pressured by all the
1. owed a Duty of care to the plaintiff, parties involved to agree to a settlement. In some
2. that there was a Deviation from an acceptable instances, such advice may come from the plaintiff
standard of care, attorney or even the sitting judge. Indeed, on occasion
3. that there was a non-trivial injury to the plaintiff extraordinary amounts of offered settlement are
(Damages) that was Directly caused by the turned down, not because of the size of the award,
deviation from the standard of care.1 A failure to but because all the details of their case would then
demonstrate any one of the four means that the come out publicly – they would have their day in
requirements, under the law, are not met. To begin court.
the process, a patient approaches a lawyer. The Physicians believe themselves to be operating in
reasons patients sue are many.2-5 an environment of zero tolerance for error. It is
For patients and family members, the physical and embedded in their oath and dedication to “do no
emotional devastation of medical error cannot be harm,” in their professed desires help others, and
easily overcome. As a rule, however, this magnified by a historic paternalistic tendency to
circumstance has been made even more difficult extend unrealistic expectations to their patients.
because there was no satisfactory explanation to the (Moore) The physician who has erred is wounded,
patient of the reason for the adverse outcome, there and suffers the consequences of guilt, fear of reprisal
was no admission of negligence, no opportunity for
questions, and no consolation for loss.6,7 In reality, Table 26.1 :Malpractice Induced Activities
the patients want a forthright explanation of what Modality Percent
happened - want to understand if they played a role Testing 76.2
in it. And if, just if, a mistake had been made, they Monitoring 73.3
expect an apology and an offer to compensate for Documenting 72.2
the expense and aggravation. They are real people, Informed Consent 61.6
Consulting MDs 58.0
and whether the injury was the result of negligence Patient Information 51.2
or not, they, not the physicians burdened with a Referrals 47.2
lawsuit, are the real victims. When asked, “What was Staff Presence 21.8
ACOG - 1990
wrong with the care you or your child received?” or
 Malpractice Issues in Perinatal Medicine: The United State Perspective 329
(from the patient, hospital, and regulatory agencies), Ideally, medical witnesses will be readily available
embarrassment (peer), and sorrow for having and forthright, and medical standards will be
harmed someone. (Levinson) Because medicine, for determinable from readily available medical records
centuries, has been loathe to identify negligent care that are well documented, readable and responsive
(even in closed, protected settings) this system of to questions of whether or not the medical conduct
justice has enfranchised the plaintiff’s attorney, not met a reasonable standard of care. The medical
especially trained for the purpose, to determine the consultant/potential expert witness will possess both
medical and the legal merits of the case (they are not current knowledge and experience with the issues
the same!). Under the contingency-fee relationship at hand, but, at any time in the review process, is
prevalent in the United States, the attorney takes a honor bound to use all available relevant information
percentage of the award as a fee (often around 35 and to apply broadly understood, minimal,
percent) to compensate for the costs, expenses and standards of care – not their own personal standards.
time absorbed in pursuing the case irrespective of An expert witness must elaborate the standard for
the outcome; they take nothing if the defendant medical care at the time of the plaintiff’s injury and
prevails. These expenses are not trivial; bringing a give an opinion on whether the defendant’s conduct
“bad baby” case to court, for example, may easily met this standard. The standard is not unique to the
cost $100,000 of up front expenses. It is not expert, but rather must reflect general principles
undertaken lightly. 8 applicable to all practitioners, at the same time specific
But before the attorney can proceed, one of his to the individual patient’s circumstances. Ideally, it
first expenses will involve consultation with a should be supported by scholarly literature. While it
medical expert (a physician) to determine whether need not prescribe a single course of action, it must
the potential case satisfies two most critical criteria either (for the plaintiff) proscribe the defendant’s
of the 4D’s: Was there a Deviation from a reasonable conduct or (for the defense) endorse the defendant’s
standard of care and was there a Direct causal conduct as an acceptable alternative. Therein lies the
relationship between that failure and the adverse conflict.
outcome? Damages and Duty, generally, are self- While the courts expect that medicine, as a learned,
evident. Traditionally, the “standard of care” is science-based discipline, will have articulated
defined as the quality of care (customs and behavior) standards for practice in most circumstances, they
that would be expected of a reasonable practitioner also recognize that not all standards are formalized
in similar circumstances. These standards are drawn or even well defined, not all clinical circumstances
from members of the profession itself as well as can be circumscribed in some obvious standard of
documents that reflect a consensus on appropriate car, and that there is “art” to the practice of medicine.
standards (plural) of care. To overcome these hurdles the courts, using their
It should be emphasized that there is no single own legal (not medical) standards of witness
standard of care. Satisfying the need to do something acceptability, allow appropriately qualified expert
“reasonable under the circumstances,” indeed, may witnesses to express expert opinions. Indeed, the
permit mutually exclusive choices to be within the expert witness is the only party in the lawsuit who
standard of care. Because the law holds the arcane may express opinions; everyone else is only entitled
nature of medicine “a learned profession” to be to the “facts” of the case. Ideally the expert will not
beyond the grasp of common citizens, it requires the be an advocate, except perhaps of his own opinion,
testimony of experts in the same field as the and will honestly present his or her understanding
defendant.9,10 Neither the courts nor the legislatures of the applicable standards without tailoring his
can reasonably establish detailed conduct for responses to serve the single-minded ends of the
professional practice without “practicing medicine.”11 lawyer engaging the expert.
330 Textbook of Perinatal Medicine

Obtaining expert testimony has always been the and urban physicians will have the same training and
most difficult part of medical malpractice litigation. exercise the same level of judgment and diligence.
Historically, experts were readily available to testify The rule does not require that the rural physician
against competing medical disciplines including have the same medical facilities, consultants or other
homeopathic physicians and chiropractors, although resources available. If the community does not have
they were expected to remain silent about the facilities for an emergency cesarean section, for
misconduct of members of their own profession example, the physician cannot be found negligent for
(omerta). To abolish these vituperative, economic failing to do this surgery within the 15 minutes that
rivalries, the courts established the doctrines of might be the standard in a well-equipped urban
“school of practice” and “locality rule” as bases for hospital. However, to comply with the standard of
qualifying expert witnesses. care, the physician must inform the patient of the
The school of practice rule permits the limitations of the available facilities and recommend
differentiation of physicians into self-designated prompt transfer if indicated. He must also make
specialties depending upon whether the case concerns reasonable efforts to deal with the inevitability of
procedures and expertise that are intrinsic to the requiring an emergency section – even in a rural
specialty or general medical knowledge and community. Proper informed consent allows patients
techniques that are common to all physicians. Thus, to balance the convenience of local care against the
obstetrical cases may involve family practitioners, risks of inadequate facilities.
midwives, ob-gyn as well as members in training; At trial, judges and jurors (the triers of fact) have
the potentially significant differences in their no alternative but to judge the testimony of witnesses
individual standards may indeed require expert whether expert or percipient (fact) on the personal
witnesses from each of these specialties. credibility of the witness. For the experts and the
Before the standardization of medical training defendants, positive factors such as academic degrees,
and certification that prevails today, there was a specialty board certification, and publications
tremendous gulf between the skills and abilities of influence credibility. So do factors such as physical
university-trained physicians and the graduates of appearance, race, gender, command of English, and
“less reputable” schools issuing diplomas. Thus, in personality. For each of these, the objective is to be
many parts of the country, a physician’s ability to believed. The defendant also has to be believed, but
serve as an expert would be determined by his role is much more focused; he has but one chore:
comparison with the other physicians in the to convince anyone who will listen (judge, juror,
community, or at least in similar neighboring attorney, stenographer, bailiff, passerby) that he/
communities. For obvious reasons, this rule she is a thoughtful, caring, concerned human being
essentially precluded injured patients from finding who did what was reasonable under the
supportive expert testimony – effectively preventing circumstances. The defendant has no other job.
most medical malpractice litigation. Reasonably, there Performing research, providing expert opinion or
is no longer a justification for any rule that impedes combating the opinions of the opposing expert are
evaluation of what have become national standards all some else’s function. As mentioned above, his
of care on the sole basis that it is the norm for a demeanor in deposition or trail (as well as with his
given community. While most states have explicitly patients) has a great deal to do both with the
abolished the locality rule, it is being reinvigorated likelihood of lawsuit and its resolution. For the expert
in some states as a tort reform measure (and omerta) witness, the foremost requirements are effective
to deal with the problems of access to care and presentation and teaching ability. The expert must
facilities in rural areas. educate the judge and jury in the technical matters
A national standard of care implies that the rural at hand.
 Malpractice Issues in Perinatal Medicine: The United State Perspective 331
Until 1993, federal courts had used the “general defendant’s care followed customary medical
acceptance” test, set forth in Frye v. United States, practice. The court must determine for itself the
to assess the admissibility of expert scientific appropriateness and the logic of the professional
testimony.12 In 1993, the United States Supreme Court opinion and find reassurance that the body of opinion
modified the standard for determining the relied upon was not created for defensive purposes
admissibility of expert scientific testimony in federal (see below). It is a curiosity that an expert’s position
trials. In Daubert, the court stated that Frye test did may fail a Daubert challenge in one case, but may
not comport with the Federal Rules of Evidence and continue to be offered in other cases! It seems
that “a rigid ‘general acceptance’ requirement would counterintuitive that a lay judge is qualified be asked
be at odds with the `liberal thrust’ of the Federal to determine the qualifications and credibility of an
Rules and their `general approach to relaxing the expert. Some believe that the selection of medical
traditional barriers to opinion testimony.” 12 experts be the purview of medically trained peers.
Accordingly, the court emphasized that a trial judge Indeed, there is an argument to be made that the
must screen the proposed scientific testimony to specialty societies develop a list of “true” experts
ensure that the testimony is relevant and reliable that are available to either side or the judge himself.
before allowing the testimony to be presented at trial. At least in Federal Court the expert’s legal
Rule 702 reflects the need for screening.12-14 activities over the last five years must be listed with
If scientific, technical, or other specialized the court prior to his appearance. Federal rules also
knowledge will assist the trier of fact to understand give a judge the authority to
the evidence or to determine a fact in issue, a witness 1. limit cumulative evidence, i.e., more than one
qualified as an expert by knowledge, skill, expert testifying to the same issues unrelated to
experience, training, or education may testify thereto qualifications, or
in the form of an opinion or otherwise. It is a judicial 2. retain experts to assist the court, or
decision, not a medical one.14,15 3. with mutual consent appoint a single expert
The court set forth four factors that may be used witness. Despite these available options,
to assist the trial judge in determining “whether the especially in “bad baby cases,” there is an
expert is proposing to testify to scientific knowledge increasing tendency to line up a broad array of
that will assist the trier of fact to understand or qualified experts on both sides including an
determine a fact in issue.” The factors that may be obstetrician, perinatologist, placental pathologist,
considered when determining the validity of a neonatologist, neurologist, nurse, economist,
scientific theory or technique are: neuroradiologist, etc. There is at least some
1. whether the theory or technique can be tested, evidence that this proliferation of experts (and
2. whether the theory has been subject to peer costs), more likely driven by the defense, is
review and publication, counterproductive. Bors-Koffelt, et al, found that
3. the rate of error, and the use of multiple defense expert witnesses
4. the acceptance of the theory of technique within decreased the chances of a successful defense.16
the community. The court cautioned that “[t]he Many jurisdictions have attempted to insinuate
focus ... must be solely on principles and the expert witness into the proceedings prior to the
methodology, not on the conclusions that they case being filed. In several states a report or affidavit
generate.” The court emphasized that these of merit from the expert is required to launch the
factors are not exclusive. suit, in others only the testimony by the lawyer that
Thus, under Daubert, a defendant doctor may be he has contacted an expert is required. By and large
considered negligent for treatment and diagnosis there is no standard format for expert reports, and
even though he presents evidence from a number of they are normally quite minimal and non-specific.
medical experts genuinely of the opinion that the There is also no requirement that the “expert” who
332 Textbook of Perinatal Medicine

gave an affirmative opinion to the attorney, whether interview with the patient or secondarily on the basis
he signed the letter of merit or not, will subsequently of the review by the consulting expert. It is not
be involved in the case, a deplorable circumstance as widely appreciated but the vast majority of patients
will be discussed below. Even if he/she were later that approach lawyers with complaints about their
involved, there are no mechanisms short of physicians are turned down (probably in excess of
deposition or interrogatory to amplify on the experts’ 90%). Some patients are actually grateful to know
allegations. In some states, the expert cannot be that they did not receive substandard care, and
deposed before trial and indeed his identity is equally important, that they themselves did not
unknown to the opposing side until he is called to contribute to the adverse outcome. Despite any anger
the stand – widely referred to as “trial by ambush.” or frustration they may have with the conduct or
While the expert’s opinion is normally protected deportment of the physician they often harbor
by the doctrine of witness immunity, this does not notions of their own complicity in an adverse
protect the witness from fraud or from professional outcome, especially when there has been a brain-
malpractice liability 17 or from other forms of damaged baby – if they had only not skipped an
harassment. “The goal to insuring that the path to appointment, not used the hot tub, not gained so
truth is unobstructed and the judicial process is much weight, etc. Being turned down in a request to
protected, by fostering an atmosphere where the sue a physician may have positive benefits of closure.
expert witness will be forthright and candid in It may indeed help them to forgive themselves. While
stating his or her opinion, is not advanced by it is quite uncommon to pursue a lawsuit based solely
immunizing the expert witness from…negligence in on an emotional misdemeanor by the physician, it
forming the opinion.”17 In one instance, a consulting becomes a powerful incentive to bring a lawsuit if
expert was sued for failing to testify on behalf of the the care has also been negligent. As will be seen in
plaintiff in trial. The expert believed that causation the statistics below, many negligent physicians are
could not be satisfactorily proven. exculpated or avoid lawsuits entirely not because of
It is perhaps instructive here to deal with the the facts of the case, but by a becoming demeanor to
terms, “meritorious” and “frivolous” as applied to the patient or to the jury. Other physicians have been
malpractice cases. As a short-hand, whether the case found negligent, not because of their care, but by
is meritorious or not is a function not of the result, their indifference toward the patient. It is this author’s
but of whether there is a substantive question about experience that the minute the jury perceives that
the standard of care and its relationship to the the physician doesn’t care vindication of his medical
outcome. In a frivolous case, there is no substantive conduct is not possible.
question, the 4 D’s cannot be shown or linked, or Thus, to label as “frivolous”, as many physicians
any question of negligence is readily answered in have, all cases that plaintiffs lose, or are settled “for
the negative simply with the most cursory economic reasons” or are dismissed, trivializes the
examination of the evidence. Often, the complaints tort system, the lawyers, the patients, the opposing
that prompt the visit to the attorney derive from expert witness, and in its way, impedes the solution
actual or perceived slights by the physician related of the malpractice problem and foments more error.
to a poor “bedside manner,” a disputed bill, a lack This posture reveals an inadequate understanding
of timely response, etc. In this respect, it is important of the dynamics of expert allegations, settlements,
to understand how, given the unrequited emotional jury verdicts, and even the process of peer review.
needs associated with adverse outcomes, malpractice Given the affirmative report by his expert, the
litigation serves the purpose of emotional attorney is legally obligated to pursue discovery – the
vindication. 18, 19 Such complaints are usually accession of all the relevant clinical data from the
dismissed out of hand by the attorney in the first medical records or other sources. To flesh out the
 Malpractice Issues in Perinatal Medicine: The United State Perspective 333
records and to understand something of the both defensive medical practice practices and
personality of the defendants, depositions are taken spurious claims – after all it is the medical profession
of the relevant treating or factual witness – and not the juries that establishes the standard of
sometimes including the custodian of records, etc. care; the jury just attempts to find out what were the
and the various medical experts. standards that the medical profession had set for
The defense against the allegation of failing to itself in any given situation and then to determine
meet the standard of care of a malpractice case whether those guidelines were appropriately and
centers around issues of customary practice, clinical reasonably followed. There are several problems
practice guidelines, informed consent, and with the use of “guidelines”. First, they may not be
differentiating error from complication. In judging usable (admissible in evidence) at all. Because of the
the conduct of the physician in a court of law the wide range of reasons for creating guidelines (care,
court is guided by a notion called “reasonable costs, medico-legal protection) in many states such
conduct.” Indeed, it is sufficiently vague as to require guidelines constitute “hearsay” in great measure
the participation of an expert witness to state what because their author isn’t in Court to be cross-
is and what is not “reasonable” conduct. At least examined. Finally, having followed the guidelines
theoretically, the creation of clinical practice may not mean malpractice was not committed.
guidelines would simplify and implement broadly Scrupulous adherence to the relevant Guidelines for
understood practices subscribing to a quality care an amputation, for example, avails nothing if the
that could be objectively measured. At the same time wrong leg has been amputated. Thus it is that the
the quality of care would be improved and iatrogenic notion that compliance with guidelines renders the
injury diminished. clinician immune from lawsuit has not been upheld.
There has been a broad implementation of Consensus, after all, is not necessarily wisdom, or
“clinical practice guidelines” from various hospitals, applicable in all cases!
professional organizations and the government itself. When the opinions of the opposing experts conflict
A clinical practice guideline is any guide to the clinical irreconcilably over this issue the jury comes face to
management of a patient. These guidelines vary face with the logical conundrum. Is the disagreement
widely according to the purpose for which they are related to lack of awareness of the standards or is
written and who has been selected to write them. one of the experts lying? The jury assesses the
They may be driven by medico legal issues, by the credentials and the credibility and various other
cost of care, or by the quality of care. While great sources of information to help them decide which
emphasis has now been placed on the process of expert is more credible in relating the individual
writing guidelines, many providers have become patient’s care to the prevailing standards.
concerned with the basic precepts of guidelines, One of the most widely quoted and
including the possible emergence of “cookbook” misunderstood guidelines require that institutions
medicine, the effect of patient variability, and the be capable of instituting an emergency cesarean
need to keep guidelines flexible, current, and section within 30 minutes of decision. 22 Some
credible.20, 21 institutions cannot meet these guidelines reliably
Clearly, one impetus for the creation of clinical while others maintain a standard that can result in
practice guidelines for specific medical conditions and an emergency cesarean section in 10 minutes or less.
their treatment was the notion that they would help While several studies have attempted to determine
avoid or defend malpractice claims. Indeed, someday the reasonableness of “the 30 minute rule,” neither
they might replace the “reasonable conduct” the “studies” nor the “guidelines” take into account
standards and their dependence upon expert certain realities or certain remedies.22 The “30 minute
testimony in medical cases and thereby discourage rule” is shorthand designation for a more
334 Textbook of Perinatal Medicine

encompassing principle that, under certain conditions thoughtful, alternative choice of care – that is
performance of a cesarean section should be carried annotated!
out as quickly as possible consistent with concern
for the health and well-being of the mother and fetus, INFORMED CONSENT
preferably within 30 minutes. But what is the Similarly, the patient has rights, no matter how
standard if there is already one cesarean section in appropriately they may be exercised, to influence
progress, or two? Under these circumstances, a delay decisions about her care. In dealing with matters of
becomes “reasonable under the circumstances,” informed consent, most courts in the United States
notwithstanding the fact that standard of care look to what a reasonable patient would want to
required earlier cesarean section. However, if a know, not what a “reasonable physician” would have
physician is late in realizing the need for Cesarean said. The courts have on several occasions been asked
section or is ready to operate within 20 minutes but to intervene in circumstances involving the refusal
fritters away 10 minutes beforehand, his conduct of treatment by a pregnant woman, refusal which
cannot possibly comport with a reasonable standard nominally threatens the life and well being of her
of care, even if the patient is delivered within 30 fetus and herself. While the courts’ responses have
minutes. Further, it stands to reason, that institutions been varied there is general consensus amongst the
normally unable to consistently meet the 30-minute specialties that these ethical (not legal) issues should
rule must modify their practices and exhibit a not be resolved in court and that considerable ethical
willingness to prepare for cesarean sections early weight should be given to the mother’s decision as
(even if it proves unnecessary) in anticipation of long as the consent has been proper and there been
problems and make special arrangements for unique no coercion. Lawsuits based entirely on informed
situations such as VBAC. Thus, the failure to meet consent are quite uncommon, but most such cases in
the 30-minute rule is rarely by itself a telling plaintiff’s obstetrics seem to involve vaginal birth after cesarean
allegation. Much more frequently, the plaintiff’s (VBAC), the use of operative delivery and the
allegation is that the failure to properly interpret the decision to induce labor with a previous history of
fetal monitoring tracing or to properly estimate the shoulder dystocia. If the “informed consent”
feasibility of safe vaginal delivery hopelessly delayed document in such cases is to truly represent
the decision in the first place, irrespective of the “informed consent” it must reveal the patient’s
“decision to incision” interval. understanding that she may either undergo an
There is frequent debate over whether “official” elective repeat Cesarean section or, if she is a suitable
pronouncements such as the “30-minute rule” are to candidate, attempt a VBAC. She must understand
be construed as monolithic “standards of care.” that not all patients are candidates for VBAC and
More reasonably, it seems, that irrespective of that not all VBAC attempts will result in successful
whether these writings are entitled practice vaginal delivery. She must be aware that some of
parameters, guidelines, standards, apocrypha, hints, the determinable clinical factors that affect the success
clues, etc., the imprimatur of an official body, gives of VBAC become apparent only in labor. The patient
any statement about care the force of a “standard”. must also understand that all pregnancies carry a
Indeed during litigation, both sides are opt to offer small risk to both mother and fetus, whether or not
these professional publications as standards to the mother has had a previous Cesarean section. In
support their case irrespective of the disclaimer that patients with a previous Cesarean section, the risk
these recommendations are guidelines rather than of uterine rupture during a VBAC is approximately
standards of care. Thus, guidelines, whatever their 1% and that this occasionally may result in serious,
provenance, are never “medico-legally binding” and potentially life-threatening complications for the
can be directly and reasonably contravened by a mother or the baby. If the patient initially agrees to
 Malpractice Issues in Perinatal Medicine: The United State Perspective 335
attempt VBAC, she needs to understand that she is two or more medically acceptable options for
entitled to an updating of the likelihood of success treatment are present,” the court held, “the competent
and to change her mind at any reasonable time and patient has the absolute right to select from among
to obtain a Cesarean section, even during labor. those treatment options after being informed of the
Finally, the patient should understand that no relative risks and benefits of each approach. But
decision, however thoughtfully made, or how consent, once given, is not categorically immutable
reasonably pursued, guarantees a normal outcome and the patient was entitled to withdraw her consent
for the mother or the infant. to VBAC. That indisputable withdrawal placed the
The reader may now compare this approach with patient and her physician in their original position –
the deliberations in an “informed consent” case that a blank slate on which the parties must again diagram
was decided by the Wisconsin Supreme Court and their plan which in this case would have resulted in
that stretched the limits to which some physicians cesarean section.” It was foreseeable that as a
would go to reduce their cesarean delivery rate. In backlash to the alarm generated by this verdict along
this case (Schreiber) a patient presented with a history with other reports and settlements, many hospitals
of two previous Cesarean sections, the first no longer permit VBAC deliveries and an increasing
undertaken for arrest of labor after 17 hours (the number of malpractice insurers are limiting their
second was elective); she had agreed prior to labor indemnification of physicians performing VBAC
to attempt VBAC.23 During labor, in the face of slow deliveries! (ob-gyn news, vol 40 no.3 feb, 1, 2003)
progress and severe abdominal pain, she changed
her mind and repeatedly requested a cesarean section. COMPLICATION OR ERROR?
Just as often the obstetrician maintained that it was The “recognized risk defense”, asserts that the
unnecessary. The obstetrician commented, “if I undesirable outcome or injury in question is nothing
performed cesarean section on every woman who more than an unavoidable complication — an
wanted one that all deliveries would be by cesarean understandable and acceptable risk of a properly
section.” Intimidated, the patient no longer considered and provided treatment. Accordingly, so
requested cesarean section. Ultimately, the uterus long as the patient is reasonably apprised of the more
ruptured and the child was hopelessly injured despite serious and the commonplace risks and participates
delivery within 30 minutes. The physician defended in the decision then in theory there can be no issue
his conduct on the ground that the original informed of negligence. A typical example is subgaleal or
consent should prevail throughout the labor and that intracranial hemorrhage in the newborn following
the standard of care had been met by the “timely” vacuum assisted delivery. Indeed, every obstetrical
delivery within 30 minutes. He noted that the patient text devotes significant space to such complications
had reaffirmed upon admission her earlier willingness but only rarely do they include a full discussion about
to undergo a trial of labor and he maintained that preventability or even the distinction between
labor continued “without objection.” complication and negligence. Is intracranial /
The court (inviting the implication that the patient subgaleal hemorrhage following vacuum extraction,
had been coerced) rejected the defense position that for example, an unavoidable risk or, in some
the patient’s resignation implied acceptance of a instances, the result of negligence and how would
continued trial of labor.23 The court did not comment that be determined?24 Similarly, is brachial plexus
on the change in the medical situation (dysfunctional injury after shoulder dystocia a foreseeable event
labor, unexplained abdominal pain) that required related to excessive lateral traction on the fetal neck,
medical reconsideration of the case and updating of anticipated by multiple risk factors, or is it a totally
the informed consent. The court did, however, unpredictable, unpreventable injury always unrelated
conclude that the legal situation had changed. “Where to the care of the physician during delivery. In the
336 Textbook of Perinatal Medicine

courtroom, the plaintiff’s attorney will use the In practice, this theoretically balanced system falls
statistics on complications as follows: A “recognized short of its objectives as illustrated in the “ire and
complication” does not preclude that the angst” of contemporary malpractice litigation.11 This
“complication” was caused by negligence. Indeed, chapter, therefore, being written at the end of 2004,
none, all, or only a part of such complications may will attempt to review some of the competing, nay
represent negligence. For example, if 2% of all drivers dueling, agendas that are being brought to bear in
run red lights, running red lights is a known the medical, legal and political arenas. The enterprise
complication of driving, but it is also negligent. The redounds with myth and divisive and often
most likely situation is that some of the injury is contradictory data — sometimes of dubious
potentially avoidable. Thus, that a given adverse provenance. The dust of the latest in these,
outcome is a known complication of a procedure, increasingly disagreeable, epochal skirmishes for the
tells an attorney nothing. The attorney wants to know malpractice “high road” has not yet settled and is
why the complication occurs and, more importantly, unlikely to be settled to everyone’s satisfaction in
why it occurred in this particular case. the near future. In the authors’ view, this situation
prevails because each side, for its particular, reasons,
PURSUING THE CASE is unwilling to make the tort system work as it was
If the case is pursued, it may be settled by an designed to. Indeed some of the issues raised are
agreement of the parties or go to trial. While the ethical in nature, beyond the purview of the courts
physician believes himself disadvantaged in this and the legislature.
system of finding fault, in reality the law gives health
MALPRACTICE MYTHOLOGY –
care providers considerable advantage. They are
THE FAILURE OF MEDICOLEGAL EDUCATION
advantaged by the presumption of non-negligence.
They do not have to be right in their care, just An enduring feature of the malpractice upheaval in
reasonable. The law denies the jury the right to decide the United States (and almost nowhere else) is the
medical issues and even requires ‘expert witnesses’ ignorance of malpractice doctrine in the medical
from the profession itself. After an agreement to community and beyond. Not only is there
settle the case or after an adjudication that finds the widespread fear of being sued, but there is a great
defendant negligent, his insurance company bears misperception about the requirements for proof of
the costs of both economic losses (lost earnings and malpractice, the outcomes of lawsuits, and the
medical bills) and the non-economic losses, so-called reasons patients sue. There is little appetite to deal
“pain and suffering.” The system is maintained in with the major litogen (a factor promoting lawsuit)
balance by the provision of insurance for both – physician behavior.
hospitals and physicians based on a pooling of risk, Some current mythology: “Malpractice relates to
historically through separate lines of insurance11,25 the incompetence of a few bad physicians.” “Anyone
This minimizes the risk of bankruptcy by a single can sue, everyone wins.” “Every case resulting in
large pay out and that resources are available to CP will come to lawsuit.” “The system is unfair and
compensate patients. The cost of insurance coverage favors the plaintiff.” “Patients who sue are greedy,
for hospitals is typically linked to the history of claims ingrates.” “Judges and juries cannot understand
from year to year, an arrangement known as medicine.” “Losing a lawsuit raises premiums and
“experience rating.” Physicians, on the other hand, besmirches the physician’s name in the community.”
unless their experience is extreme, are generally are “The plaintiff’s attorney and the expert are the enemy,
not risk rated, a potentially contrived actuarial along with the judge, jury, and insurance company.”
practice.26 “Malpractice doesn’t make care better.” “The
 Malpractice Issues in Perinatal Medicine: The United State Perspective 337
majority of suits in medicine are frivolous whether recognized the importance of legal medicine and have
they are settled, dropped, go to jury trial or lose.” repeatedly recommended its study by physicians in
“We’re living in a time when people have a higher training – with minimal success. In 1952 the AMA
expectation from physicians—that until proven advised that “No medical student should be
otherwise, it’s the doctor’s fault.” “The system is permitted to receive his medical degree without
overrun with runaway juries and jackpot justice, with instruction in legal duties.” Four decades later less
sinister lawyers and opportunistic plaintiffs preying than 50% of medical schools had medico legal courses,
on virtuous corporations, hospitals and doctors in considering the subject too unimportant to teach.
search of that big pay out from the lawsuit lottery.”27 Even fewer schools have any formal instruction on
There is almost universal belief that the injured communication and dispute management skills. Many
child’s appearance in the courtroom elicits sufficient medical schools feel that the intense curriculum leaves
sympathy from the jury for the plaintiff to win the no room for such instruction, and that the ability to
case. Physicians, however, win about 80% of lawsuits communicate and deal with conflict is part of the
that do go to court. It is naïve to believe that these student selection process, that is to be refined
were the cases in which the plaintiff’s attorney forgot following their didactic medical school training,
to bring the affected child into the courtroom. More during their apprentice/mentor training of internship
reasonably, it is the thoughtful, compassionate and residency.
physician who manifests his sympathy and Kollas in 1997 studied the medico legal knowledge
compassion that most easily obtains the jury’s favor base of senior residents in internal medicine. Only
and a favorable verdict. 28% felt they had been adequately trained in the
The defendant is often unaware of the statistics subject. Only 26% could list the requirements for
that about 40% of cases are dropped, about 50% proof of malpractice, i.e., the 4 D’s.28,29
settle, sometimes as befitting the merits of the case A national survey of physicians in 1999 revealed
and sometimes as a calculated strategy that limits that 58% had faced malpractice charges and that more
exposure of assets. The physician who is terrified by than 20% had been sued at least three times. Almost
an ad damnum clause (demand for damages) that 70% expected to be sued during their career. Despite
greatly exceeds his insurance policy limits is rarely the fact that physicians win the vast majority of cases
in our experience reassured by his own attorney that that go to court, more than 75% of physicians polled
the risk to a physician’s assets is essentially nil. The felt that lay juries were not capable of deciding
author is unaware of any malpractice suit involving malpractice cases! While ready to admit that everyone
an obstetrician who was covered by a reasonable makes mistakes and that they had made mistakes in
policy and who, despite a verdict that exceeded the other cases, virtually all physicians believe that the
policy limits, had to pay any money out of his own cases filed against them have no merit.{., 1999 #1367.
pocket. Despite counseling, the frightened Something (read tort reform) must be done,
obstetrician does “not want to be the first one.” To physicians cry, to stem the tide, to eliminate the reign
some extent the defense attorney may be excused of terror by the plaintiff’s attorneys. Plaintiff’s
for failing to understand how impoverished the attorneys and some consumer groups also want to
physician’s medico-legal education is. As one stem the tide as they see it – the tide of medical error,
physician put it: “I fought in the battle of the bulge the tide of unsympathetic, unapologetic, and ill-
in World War II. We were trained, we were fighting informed physicians.
a good cause and we were armed. I felt safer then When all of these myths are wiped away, the most
than I do in a malpractice suit.” devastating myth or fiction about malpractice, the
Education is the antidote to disabling myth. one that resides deepest beneath the surface, is that
Medical and legal organizations have long the allegation of malpractice represents the allegation
338 Textbook of Perinatal Medicine

of incompetence, or misanthropy, or malice. In fact, with pregnancy and under the best of circumstances,
it simply represents an allegation of fallibility – being considering the stakes, not all outcomes are perfect.
human and being capable of error. Imagine the As with all medical care, there is always an element
response of the physician who believes that he or of uncertainty – about care, and about outcome. Are
she is being accused of malice – the intention to do lawsuits generated by those patients who fail to
harm. The allegation of malice is precluded by the understand this principle, or by the physician who
precepts of tort law and is rendered improper by confronted with a bad outcome fails not only to
the Hippocratic Oath in which the physician swears educate such a patient but also fails to respond
to, “First, do no harm,” and by implication, to “intend compassionately?
no harm, i.e., malice. Judges and jurors understand With regard to the notion that the presentation
that the physician, like the speeding driver, did not of the handicapped child in the courtroom dooms
intend harm. But the physician’s good intentions are the defense case because of sympathy for the child,
not the test of reasonable performance and the the author has witnessed the following situation in
profession will be unlikely to regulate itself without the courtroom in the case of a neurologically
first understanding that the rules of negligence handicapped infant. After their deliberations, the jury
exclude malice. Indeed Institute of Medicine’s (IOM), returned to the courtroom to announce their verdict
“To Err is Human”, and Chaudry’s, uncovered an before the judge and the various parties. When the
alarming incidence of medical errors within judge asked for the decision of the jury, the foreman
institutions, which was associated with a high arose and asked the judge if he could first make a
resistance, among physicians, to report errors. (IOM, preliminary statement on behalf of each of the jury.
Chaudry) The “culture of secrecy” may in fact With tears in his eyes, the foreman acknowledged
represent a “culture of fear.” that over the course of the trial the members of the
I will attempt, in passing, to deal with these jury felt that they had come to know and care for
notions, but perhaps the following experiences will the parents and the afflicted child. He further stated
assist the reader to focus on the issue of patients’ that he wanted to extend from each member of the
expectations of a perfect outcome. I delivered my jury both their best wishes for the future and their
first baby as a medical student about 1963. After the considerable concerns about the future support of
delivery, the first words out of the mother’s mouth the child. They did not find the physician negligent.
were, “Is my baby alright?” I would deliver my last In medicine today there is considerable
baby about 40 years later and the first question this enthusiasm for “evidence-based medicine;”
mother asked me was exactly the same as the epidemiologically-driven decisions; and structured
question asked by the mother 40 years earlier. In the reimbursement. There seems much less appetite for
intervening 40 years the ultrasounds, computers and “evidence-based law”. The initiatives derived from
monitors of every description have allowed us to “evidence-based medicine” seem driven as much by
visualize the fetus, characterize its genetic motives of cost control as by the hope for better
composition, and determine its behavior, its growth health care services. Similarly, the avoidance of error
and its tolerance to hypoxia. As a result there has such as the use of automated medication ordering
been a dramatic reduction in the risk of fetal anomaly and dispensing, and the efforts of risk management
or death, especially during labor. Labor rooms have (safeguarding assets) while contributory may not
become intensive care suites with remote surveillance directly enhance the quality of care. The
capabilities. Indeed it has never in history been safer extraordinary response to the IOM study, has led to
to deliver a baby, or perversely, to be sued for a nation wide movement to find ways to reduce error
negligent care. Everyone, patients and physicians and increase patient safety. The foundation of these
included, understand that there are no guarantees efforts is based on increasing the ease and
 Malpractice Issues in Perinatal Medicine: The United State Perspective 339
confidentiality for error reporting, as well as the departure or impact on the offending physician are
facilitation of root cause analysis systems, team inconstantly applied and haphazardly administered.
approach techniques, and improved communication Peer review requires the presence of the physician -
and dispute management techniques, all with the goal an overt acknowledgment of the fact that medical
of improving patient care. Legislative bills such as records are often silent about important questions
HR663 are aimed at such lofty goals, but to date no whose understanding is necessary to determine the
proposed legislation has answered all the needs, and standard of care. Despite the physician’s presence, the
the one’s that have been endorsed by medical deliberations of the peer review committee are not
associations only given tepid support. backed up by systemic reviews of the physician’s
In this way, the avoidance of error and the efforts conduct with similar cases. The system is not designed
of risk management (safeguarding assets) have to promote either patient education or an apology.
become as important, if not more important than Peer review in obstetrics is especially problematic.
assuring the quality of care. The breadth of The medical records of the infant may not be present,
malpractice mythology and the detestation and fear nor may there be anyone (neonatologists/
of the malpractice system by the physicians and pediatrician) present to discuss the infant’s course
organized medicine has distracted our attention from and the impact of the obstetrical care on that course.
the public’s concern about the ineffectual efforts to The patient, moreover, is rarely, if ever, questioned
improve outcome whether by the adoption of higher about her perceptions of the care! Invariably, there
standards, improved educational processes or the is no long-term follow-up, especially if the infant is
meaningful activities of peer review committees and transferred to another hospital. Imagine, therefore,
professional societies. a discussion at a Peer Review Meeting of the medical
conduct in a case of shoulder dystocia and brachial
Peer Review plexus injury. The medical record is silent about the
In 1973, the United States Congress enacted use of fundal pressure – as it should be – fundal
legislation requiring physicians to initiate Peer pressure should not be used to relieve shoulder
Review Organizations to monitor the utilization and dystocia. As a result the physician who had carefully
the quality of hospital and physician services in the documented a normal sequence of maneuvers was
federally funded Medicare program. Now more than exonerated. During the malpractice case, however,
30 years later we must acknowledge the lack of a incontrovertible evidence was produced that the 263
gold-standard, medical or legal, for reviewing pound anesthesiologist was exerting sufficient force
allegations of negligence and dealing meaningfully on the top of the patient’s abdomen to produce
with medical error. Peer reviews produce considerable pain and broad ecchymoses. The case
inconsistent agreement and operate without formal settled in behalf of the plaintiff!
rules or guidelines for review {Morris, 2003 #524}. Other complaints of lack of due process and poor
They are left to the local hospital30 although the reproducibility plague discussions of the peer review
ACOG has attempted to provide outside review to process. There is evidence that the knowledge of an
individual hospitals, there is no analysis of such adverse outcome (hindsight bias) may cause the peer
efforts.31 The majority of “true” peer review exercises review committee, like the expert in a malpractice
are driven by adverse outcomes and do not represent case, to criticize retrospectively the decisions of the
systemic reviews of the numerous latent processes treating doctor. 32,33 While it might be better to
promoting adverse outcome. These are left to the withhold outcome information in both circumstances,
occasional review of a “sentinel event. With peer this seems neither practical nor enforceable.
review the rules for reviewing records and for Peer reviews are conducted by people from the
obtaining agreement about either the severity of any same department of the hospital and in many states
340 Textbook of Perinatal Medicine

are safeguarded from legal scrutiny under the review is a parochial matter; only rarely does it obtain
common law privilege of self-critical analysis, a information from the patient or review from bona
privilege that protects and encourages quality fide experts in the field. These potential sources of
assessment, but that secrecy, in the final analysis, enlightenment are available in the courtroom.
may be counterproductive for the ultimate objective Gawande, in an article in The New Yorker, describes
of improved patient care and better transparency of a surgical peer review exercise and the limitations of
medicines self-governance34,35 At its most collegial, this process. He admits that he made a serious medical
colleagues of the physician being reviewed are likely error, but he was not obligated to face the peer review
to minimize error on the notion that when my turn committee directly, and the committee did not deal
comes, similar cordiality and extenuation will prevail. directly with the error itself in any remedial way.37
Sometimes, however, peer review meetings may Under the heading of “the banality of injury,”
not be cordial and the meeting may be the Gawande acknowledges that medial error is
appropriate venue for criticism, removal of privileges ubiquitous and makes the point that medical error is
or dismissal. Sometimes, the purpose is not strictly NOT the province of a select few culprits as common
medical, political, economic and administrative, wisdom suggests. There are no “incompetent,
described under such appellations as “economic unethical, negligent few,” no basket of “bad apples”
credentialing” or “sham peer review.” At these times, that conspire to taint all of medicine.
generally, hostility will prevail, the physician will While there are correlations between risk of
hire a lawyer and the battle will be joined. It is the lawsuit and medical school prestige, physician
law, not medicine, that will safeguard due process. intuition, gender and even the apparently perverse
If it can be shown that peer review was being used inverse relationship between current medical
for purposes other than medical care, the knowledge and the likelihood of being sued, the fact
deliberations of the committee may no longer be is that most obstetricians are sued at least once in
protected. In either circumstance, it is an expensive, their professional life. 38 Repeat offenders may
unsatisfying, experience for which physicians have sometimes occur, but are not a common problem. As
little appetite – whatever the outcome. Gawande poignantly asks, “How do we keep good
A study by Cheney, et. al., about agreement physicians from harming patients?” We may also ask,
among anesthesiologists assessing twelve actual what is the value of either peer review or even
malpractice cases whose verdict was known has malpractice suits in improving care?37
implications both for malpractice and peer review.36 A study (generally known as the Harvard study)
They showed a high intra-observer agreement commissioned by New York State in 1986, and
amongst observers (>80%). Of the eight cases with released in 1990, showed that actual malpractice is
complete or virtually complete agreement between relatively rare, it is nevertheless underreported. If
respondent anesthesiologists, three (37.5%) disagreed anything, they believed that there were too few
with the verdict rendered by the actual juries. In lawsuits.39-41Further, they wrote, that “Physicians
addition, anesthesiologists showed significant tended to equate a finding of negligence with a
disagreement (> 30%) among themselves in four of judgment of incompetence. Thus, although willing
the case scenarios, indicating there may not be to admit that ‘all doctors make mistakes,’ physicians
agreement regarding the standard of care in these were often unwilling to label substandard care as
clinical circumstances. Finally, anesthesiologists negligent and were opposed to compensation for
predicted jury verdicts poorly, with success rates of iatrogenic injury.” Given the medicine’s delayed
50% or less in seven of the twelve case scenarios. response to the problem of medical error, including
One wonders what the results would be if this study the limitations of peer review, the public’s only
were performed in cases of peer review. Finally, peer alternative therefore was for individual patients to
 Malpractice Issues in Perinatal Medicine: The United State Perspective 341
try to hold individual practitioners, one at a time, to alternative course of dispute resolution combined
whatever medical standards could be upheld by with improved communication.44 Parenthetically, the
lawyers and expert witnesses. (Mohr, 2000). It may more time the physician spends with a patient the
be true that to “address the problem of iatrogenic greater is the satisfaction of both patient and physician
injuries seriously, we must reform the system of (Woods). In a survey reported by the ACOG,
malpractice litigation.” What seems equally true is physicians reported wholesale changes in their
that the problems of iatrogenic injury and physician practices (Table) and their fees as a result of
conduct cannot be contingent on changing the tort malpractice – including greater consultation with the
system alone. patient.
In 1997, a highly publicized article recommended
The Role of the Physician that when doctors make a mistake that harms a
These complaints about the system also serve to patient, they should tell the patient what happened,
camouflage the physician’s role in the genesis of apologize and do whatever it takes to repair the
malpractice suits. “It has been estimated that, the damage.45 Basic professional ethics aver that patients
risk of lawsuit “seems not to be predicted by patient have a right to know what happened to them. It
characteristics, illness complexity, or even physicians’ seems like the right thing to do as part of the
technical skills.” Instead, risk appears related to physician’s responsibility to his patient and it may
patients’ dissatisfaction with their physicians’ ability be therapeutic for the physician who may feel guilt
to establish rapport, develop trust, provide access, and distress. Telling the truth may also strengthen
administer care and treatment consistent with patient’s faith in the doctor while a cover-up that
reasonable expectations, deal effectively with fails, as many do, may anger patient and make them
conflict,and communicate efectively.”4 In an article by more inclined to sue. Cover-ups also antagonize
Hickson, et al, patients who saw physicians with the juries. Medicine is a human enterprise and error (i.e.,
highest number of lawsuits were more likely to fallibility) is part of being human. “We are
complain that their physicians would not listen or return programmed for error.”
telephone calls, were rude, and did not show respect. 2 Understandably, the notion of admitting error
Such complaints, furthermore, were similar to those has drawn skeptical review from the medical
documented in interviews with families who sued community, the insurance companies and the defense
their physicians. Patients are less likely to sue (about bar.46 They fear that admitting mistakes will “open
50%) less, even for moderate and severe mistakes, the floodgates” to lawsuits and hurt their reputations
if the physician informs them of the mistake and careers. They fear also that without tort reform
(basically, apologizes). to decrease the number of malpractice suits and large
For reasons mentioned above, physicians are settlements, , and to reduce the punitive implications
untrained in the art of apology. It may seem of existing reporting , few doctors could risk owning
counterintuitive for many physicians that one can up to errors. The notion that telling the truth,
accept responsibility for an outcome, without apologizing and reaching out to a family in grief can
admitting blameworthiness.42,43 defuse some the anger and polarization that
In an analysis of 500 claims in obstetrics and characterize a typical lawsuit becomes hostage to the
gynecology by B-Lynch et al show that 46% were notion that every word you uttered in consolation
misguided allegations about half were due to or contrition is an admission that can be used against
incompetent care, an error of judgement, lack of you in a court of law. On top of that, defense lawyers
expertise, poor supervision or inadequate staffing. then order doctors to say nothing until all the facts
The other half were due to poor communication and are in, and then to say nothing. It seems obvious to
“misguided allegations” for which they recommend state that until legislative protections maintaining
342 Textbook of Perinatal Medicine

such admissions are enacted, it is very likely that individuals, departments, and all levels of healthcare
lawyers will continue to order doctors to say nothing providers, such as between physicians and nurses or
until all the facts have been ascertained through physicians and administrators. Most concerning are
discovery, and then to say nothing. But Is this a the attitudinal problems involving the interaction of
medico-legal problem, or is it an ethical nurses and physicians which receive too little
problem? 45,47,48 Baldwin suggests that increased emphasis and are particularly difficult to change.
levels of moral reasoning may diminish the risk of Their potential serious impact on the ability of an
malpractice suit. 49 making legislative protection obstetrical unit to provide “high reliability care” has
unnecessary. been discussed at length by Simpson and Knox.25 Of
The Joint Commission on Hospital Accreditation the many specific types of cases only several will be
(JACHO) standards require the disclosure of sentinel briefly discussed here: the failure to properly
events and other unanticipated outcomes of care to interpret fetal monitoring tracings, poor conduct of
patients and to their family members when operative vaginal delivery, management of the large
appropriate. Hospital administrators, fearing medical infant and shoulder dystocia resulting in either in
liability suits, are reluctant to comply with this brain damage with death or subsequent CP or the
standard. 50 If disclosure is taken a step further to infant with brachial plexus injury (sometimes both).
the offer of an apology, hospitals and physicians are Along with the measures taken by physicians in
even more likely to gravitate to traditional “defend response to the threat of malpractice, the profession,
and deny” behaviors. Apology as it turns out is yet especially obstetrics, has embarked upon a series of
one more control that physicians exert over the risk defensive “scientific” initiatives to modify its
of lawsuit. Thus a prompt explanation of what is vocabulary and its accountability. Defensive medicine
understood about what happened and its probable is a practice designed not for the purpose of
effects; assurance that an analysis will take place to answering clinical questions or directing therapy, but
understand what went wrong; follow-up based on for the purpose of preventing lawsuits or
the analysis to make it unlikely that such an event counteracting plaintiff testimony in court. The ACOG,
will happen again; and an apology will likely reduce for example, has recommended the elimination of
the risk of lawsuit.and heal, rather than harm, the such universally applied terms of art as “fetal
physician-patient relationship.51 In fact, a growing distress,” “perinatal asphyxia” and “stat cesarean
number of hospitals, doctors and insurers have come section” and have modified the definitions of “low-
to accept that genuine disclosure and apology may ” and “mid forceps”57-59 Further articles have created
reduce error-related payouts and the frequency of definitive, unyielding requirements for the diagnosis
litigation.52-55 Further, a growing number of states of birth-related injury and suggest that labor related
are passing (“I’m sorry”) laws that protect an apology injury is rare and perhaps irreducible.60
from being used against a doctor in court.52 Despite Irrespective of motivation, these publications have
the ethical imperatives underlying such disclosure, not been accompanied by any decrease in lawsuits,
it seems likely that more such fundamental any improvement in outcome, or any less defensive
protections will be needed before these practices posture on the part of the obstetrical community.
become commonplace. These efforts to make our specialty “fair of speech”
and litigation proof, discount important mechanisms
Common Areas of Litigation during Labor
of injury, diminish notions of medical judgment,
General problems relating to litigation in medicine inhibit scientific inquiry into the timing and
include documentation, communication, to institute mechanism of fetal injury and delay the testing of
chain of command, or internal systems conflicts, when new paradigms for dealing with adverse outcome.
there is unresolved disagreements between These articles attempt to influence the defense in
 Malpractice Issues in Perinatal Medicine: The United State Perspective 343
these cases in several ways: An inexperienced lawyer advantage over auscultation. Similarly, she argues,
may turn down a meritorious case because, as the EFM provides no protection in the courtroom.
guideline states, “It is not possible to ascertain Though obstetricians believe that they should use
retrospectively whether earlier obstetric intervention EFM because its status as the standard of care will
could have prevented injury or cerebral damage in protect them from liability, Ms. Lent argues that
any individual case where no detectable sentinel given its failings it may in fact expose them to liability.
hypoxic event occurred,” or because the umbilical She further argues that auscultation, at least as safe
artery pH was >7.0 despite obvious injury during and effective as EFM is also more likely to protect
labor or delivery. In addition, by insisting that physicians from liability. Ms Lent concludes that
extreme derangements in pH values are required to obstetricians have an obligation to their patients and
begin to make the correlation between labor events to themselves to adopt auscultation as the new
and subsequent neonatal injury, these criteria modify standard of care. She finds “no excuses left to defend
the level of proof normally required in malpractice the continued use of EFM.” The medical literature,
suits. The burden of proof in these suits requires that can be used to justify any position on monitoring,
the level of confidence in the relationship between including those of Ms. Lent. Thus it may be shown
the events and the outcome be more probable than that CTG increases the risk of CP and that
not. It is well to compare these pronouncements with “substandard care” protects against subsequent CP.
a widely respected authority of neonatal brain injury. While failure on the part of the health care
“Brain injury in the intrapartum [period] does occur, provider to recognize clear FHR abnormalities is
[it] effects a large absolute number of infants frequently alleged in malpractice cases, to isolate the
worldwide… and represents a large source of CTG tracing under these circumstances frequently
potentially preventable neurological morbidity. oversteps its permissive role in obstetrical care. A
Among the many adverse consequences of the normal CTG pattern permits ongoing labor only as
explosion in obstetrical litigation has been a tendency long as the safe vaginal delivery is a reasonable
in the medical profession to deny the importance or option. If the pattern turns abnormal (rising baseline,
even existence of intrapartum brain injury.” (Volpe, decreasing variability along with variable / late
Neurology of the Newborn (3 rd ed. 1995). These decelerations) especially in the second stage then the
issues have also been discussed at some length for questions are several. Can the pattern be ameliorated
the brain-damaged infant61,62 and for brachial plexus (by reducing the oxytocin, moderating the pushing
injury.63 efforts)? If the pattern cannot be ameliorate what is
the feasibility of safe vaginal delivery given the
Fetal Cardiotocography estimated fetal weight, previous obstetrical history,
In part because of the pivotal role they play in position, presentation of the fetal head, and progress
malpractice cases, there have been attacks on fetal in labor to this point? Experience suggests that the
monitoring that have come both from within the vast majority of cases hinge far more on the
profession and from without. In an article in the reasonableness of conduct of the obstetrical care
Stanford University Law Review, Margaret Lent, a (especially the second stage) than on the
young defense lawyer, argues that the widespread interpretation of the fetal monitor. Irrespective,
use of EFM is both medically and legally unsound.64 reviewers of malpractice cases consistently find that
Ms. Lent points to selected clinical trials to the CTG tracing has been frequently misinterpreted
demonstrate that EFM does not reduce fetal in allegations of negligence. 65
mortality, morbidity, or cerebral palsy rates. She
THE LEGAL CLIMATE
argues that because EFM has a very high false positive
rate and its usage correlates strongly with a rise in Most changes in both the medical and legal
cesarean section rates that it offers no medical professions are evolutionary and it is often difficult
344 Textbook of Perinatal Medicine

to define any sea change. The last three decades, however, physician income. The average annual increase in
have witnessed a number of remarkable and epochal health care costs from 2000 to 2004 was 12 to 16
changes in the medico-legal climate in the United percent with predictions (Towers Perrin) that,
States, with doubtless more to come. Many of the whether or not derived from negligent care, will rise
changes derive from periodic surges in malpractice by a further 8 percent in 2005 and with likely little
premiums, reduced availability of insurance coverage containment beyond that.
and the exodus of major insurers from the market It is important to emphasize that premium levels
first in the early 1970’s, again in the mid-1980’s, a are responsive to a variety of factors besides litigation
lesser event in the 1990’s and more recently in the dynamics, including previous losses, past and
new millennium. In each epoch, affected providers expected investment returns, business strategies, and
clamored for policy changes to inhibit litigation.66 In the degree of state regulation of rate changes. 71 A
the 1970s legislatures established joint underwriting January 2004 study found that nationwide, average
associations to serve as insurers of last resort, 67 premiums for all physicians between 2000 and 2002
special state patient-compensation funds were rose by 15 percent – a rate of rise almost twice as
introduced to absolve commercial insurers of fast as per capita total health care spending. Certain
responsibility for specified dollar portions of specialties had even greater increases including:
malpractice payments, and public reinsurance obstetricians/gynecologists (22 percent) and
mechanisms were established to fill gaps in the internists and general surgeons (33 %) 72 Neuro-
underwriting market. By the late 1970s, the surgeons, obstetricans, orthopedists and ER
malpractice crisis had abated – only to recur less than physicians are particularly likely to have premium
a decade later. In Washington State between 1984 rate increases. The rates for obstetricians / gyne-
and 1986, for example, malpractice premiums for cologists vary nationally, but according to ACOG,
obstetrics jumped approximately 100%. As a between 2002 and 2003 about half of obstetricians/
consequence, obstetricians marched on legislatures gynecologists were experiencing increases of 10%-
or joined many family physicians and midwives in 49% in their insurance premiums.
an exodus from obstetric practice. Those remaining Premiums may influence physicians’ decisions to
in practice became more reluctant to care for high- join and leave the labor force, their choice of a medical
risk obstetric patients and less willing to accept specialty, and their decision of where to locate,
indigent patients and reduced fees, irrespective of creating the potential for underserved patient
the fact that indigent patients, in fact, appear less populations in certain specialties or geographic areas.
likely to sue.68 Rising malpractice premiums may also encourage
In many rural locales across the US obstetric care physicians to practice “defensive medicine,”
became virtually unobtainable. Periodically, these performing more tests and procedures than necessary
circumstances galvanize legislative activity in in order to reduce exposure to lawsuits.
virtually every state and lead to further far-reaching Parenthetically, however, “defensive medicine”
reforms of existing tort and insurance law69,70 with (ordering a test not for the purpose of furthering
some stabilization of premiums – at least initially. patient care, but for the legal protection of the
After almost a decade of essentially flat premiums physician) is indefensible in court. Imagine the
premiums are rising exponentially, said to be due to physician-defendant responding to a question about
an increasing size of awards and by insurers leaving the indication for a certain test with the answer: “I
the medical malpractice business because of didn’t want to get sued.” Both rising malpractice
diminishing returns on investment. This has been premiums and defensive medicine practices may
aggravated by rising health care costs ($1.6 trillion contribute to the rising health care costs and thus to
in 2002 and increasing yearly), and efforts to control an increase in health insurance premiums.
 Malpractice Issues in Perinatal Medicine: The United State Perspective 345
The choices for the obstetricians – short of some reduced income from investments to help offset
windfall protection scheme – is 1) leave practice, move underwriting losses.
to a “more compliant” state, give up obstetrics, obtain Another study in 2004 found that hospital
employment where malpractice insurance is professional liability and physician liability claims
provided, raise fees, discontinue seeing patients with costs have increased at a steady 9.7 percent since
restrictive payment structures, or go bare, i.e., not 2000 and are likely to rise at the same rate in 2004.
obtain any malpractice insurance. For many, there is Frequency, or the number of claims, is growing at 3
not a good option and their future will hinge on the percent a year; claim severity (the dollar amount) is
least inimical choice. Beyond physicians, these increasing 6.5 percent annually. Hospital liability
rapidly rising medical malpractice premiums have claim costs for 2004 are expected to reach almost
again become an issue of increasing concern about $150,000 per claim, compared with $79,000 per claim
the health care system for policy makers and the in 1996. The average claim against a physician is
general public. expected to reach $178,000, compared with $120,000
in 1996. (AON Risk Services)
Underwriter Data Claims Payments
Jury Awards and Settlements
The insurance industry also has its problems. In 2003
insurers were paying out in claims and expenses, 1.38 In early 2005 a Towers Perrin study found that over
dollars for every medical malpractice premium dollar the 28 years since 1975, when they were first
collected. (National Underwriter Data Services) identified separately, medical malpractice cost
Results have deteriorated steadily from 1998 when increases have outpaced other tort areas, rising at
the rate of return was 7.6. Medical malpractice an average of 11.8 percent a year, compared with 9.2
insurers’ return on net worth was a negative 7.4 percent for all other tort costs. In 2003 medical
percent in 2002, down from a negative 4.7 percent in malpractice, at almost $27 billion, cost each American
2001 (National Association of Insurance an average $91 a year. This compares with $5 a year
Commissioners) Results in 2002 were worst in the in 1975. (January 2005, Towers Perrin - U.S. Tort
following states: Arkansas, Nevada, Montana, Costs: 2004 Update. Recent data suggests that jury
Mississippi, Illinois, and Missouri, with return on net awards are stabilizing, but the range of awards is
worth ranging from minus 33.7 percent in Arkansas moving upwards. Median medical malpractice jury
to minus 24.4 percent in Missouri. In reality, even in awards have held steady at about $1 million over
good years, premiums rarely cover payouts. The the three years 2000-2002 . (From Jury Verdict
system works in part because premiums are invested Research). However, awards ranged from a low of
and with at least a modest return permit the insurance $11,000, almost double the amount the previous year,
company to make a profit. This is abetted by the fact to a high of $95 million. The average award in 2002
that malpractice suits, especially, take a long time to hit $6.25 million, up from $3.91 million in 2001.
resolve – about 4 years on average. However, only a small fraction of cases go to trial
The average claim payment rose almost 8 percent and very large awards are frequently reduced after
per annum from $95,000 in 1986 to $320,000 in 2002 the fact and after the publicity.
despite the fact that the frequency of claims per 100 The costs of Perinatal injury are quite high, related
doctors has remained more or less constant. Only not only to the costs of settlement, and defense but
about 30 percent of claims result in insurance payouts, also in terms of personal and professional upheaval
but expenses for cases, especially obstetrical (brain- for all concerned. As Simpson and Knox have pointed
injured baby cases) where there is no payout are out56 from the perspective of human and system
considerable (16)}. Concurrently, insurance factors reveals themes, context and conditions
companies, along with the population at large, faced common to accidental injury in other high risk
346 Textbook of Perinatal Medicine

domains. According to the Jury Verdict Research national advisory on the risks of vacuum extractors.73
Series (JVRI 2001), in 2000 the median jury award This was rapidly followed by a nationwide television
for neonatal neurological injury had increased to .$5 program emphasizing some of the disastrous results
million compared to $725,000 in 1994 with 76% of with vacuums. In turn, there has been a dramatic
the jury awards valued at greater than $1 million increase both in the reporting of adverse events
(compared to 40% in 1994). Higher awards were associated with vacuum deliveries to the FDA and
more likely to occur when the hospital was the sole lawsuits alleging negligent care in the use of vacuums.
defendant compared to when both were defendants. Similarly, the methods undertaken to lower the
Conventional wisdom holds several contributing cesarean section rate in the US have perhaps been
factors to account for the increased incidence of achieved at the expense of an increased risk of
malpractice claims: ruptured uterus, shoulder dystocia and lawsuit.74
1. People are more litigious; it is part of our culture While all authorities would agree that any woman
and extends everywhere from lawyers with one previous Caesarean section and no other
themselves to city governments. adverse features may be eligible for an attempt at
2. Given the media coverage and watchdog groups vaginal birth after cesarean section (VBAC) – if she
there has been an increasing understanding of chooses to do so after being carefully explained the
public of the fallibility of physicians. The Public options. Some health maintenance organizations
Citizen Health Research Group, and more recently (HMO) refused to accede to the mother’s choice and
formed groups emphasizing both medical error have required that every patient with a previous
and the need to improve care as part of tort reform cesarean be given a trial of labor – a horrific, medically
have also helped fuel the public’s demand for indefensible recommendation. One institution in
change35 California that adopted this policy was assessed
3. The diminishing intimacy of the patient-doctor almost $25 million as a result of 48 women who
relationship fomented in part by larger changes suffered adverse outcome as a result of this policy.
in the way health care is distributed (HMO’s), by
increasing overhead and by deteriorating Prevalence of Medical Malpractice
reimbursement schedules, A study (generally known as the Harvard study)
4. the increasing availability of medical experts to commissioned by New York State in 1986, and
testify in malpractice cases (the breakdown of released in 1990, showed that actual malpractice is
OMERTA), relatively rare, it is nevertheless underreported. If
5. The increasing assertiveness of the courts and the anything, they believed that there were too few
increasing sophistication of the plaintiff’s bar with lawsuits. When hospital medical records from New
more careful selection of meritorious suits. York State were examined, the incidence of adverse
6. The need to assistance with financing medical events or injuries resulting from medical
bills. Indeed, there is seeming growth in the “interventions” or treatment, was 3.7 percent. The
frequency of lawsuits for the “bad baby”, in part percentage of adverse events due to what the
because of the large verdicts sometimes realized physician team characterized as “negligence” (not
but also because of the increasing incidence of CP necessarily a legal definition) was 1 percent.
related to increasing survival of low birthweight However, only one in eight who suffered from an
infants and the costs thereof. adverse event due to negligence filed a medical
Several clinical practices and media attention malpractice claim, and only one in 15 received
would seem also to be impacting on the frequency compensation. Most adverse events resulted in only
and type of lawsuit. As an example, the United States minimal and transient disability and most of the
Food and Drug Administration (FDA) issued a patients’ medical care expenses were paid for by
 Malpractice Issues in Perinatal Medicine: The United State Perspective 347
health insurance. This helps to explain why only a either by the plaintiff’s attorney or by the courts.
small percentage of patients who are injured as a Eighteen of the remaining 19 claims were settled
result of negligence file medical malpractice claims. before trial, with an average payment to the plaintiff
However, a significant portion (22 %) of patients who of $185,000. The one suit that went to trial resulted
did not file medical malpractice claims suffered in a defense verdict. A review of the case histories
moderate or greater incapacity. In a second phase of demonstrated that in the majority of cases when a
the study, researchers confirmed that some of the payment was made, probable medical negligence had
tort claims filed provided little or no evidence of taken place. Non-meritorious claims were not
medical malpractice or even an adverse event, compensated. For those cases in which a payment
suggesting that the tort system is “very error-prone,” was made, the size of the settlement was
at least in its initial stages (related to the expert) This commensurate with the seriousness of the injury,
inefficiency in both the medical and legal systems, which almost always involved damage to the infant.
notwithstanding, the study noted that, “if anything, Poor physician judgment was the most common
there are too few lawsuits. The inference here is that source of error. 78
more patients with adverse outcomes related to The surviving, handicapped infant, continues to
negligence should be suing.39, 40, 75, 76 represent the highest payout / case. There are
There are several studies of closed claims in numerous representative reviews of closed cases.
obstetrics and their relationship to negligence or the (Table 26.2) In an analysis of 353 closed claims
adherence to guidelines. Julian, et al reviewed the involving obstetrician-gynecologists revealed that the
files of 220 obstetric closed-claim cases to identify 40 highest-paid claims (11.3%) accounted for 88.7%
common factors predisposing to claims and to of the total dollars spent. The majority of these 23
suggest preventative measures. Identification of (57.5%) were obstetrical including the five highest
common obstetric risks and correct management of claims and 17 of the first 20 highest-paid awards.
these risks was poor in these cases. Only 54% of the
risks were recognized; of these, only 32% were Table 26.2 Why Patients Sue {Hickson, 1992 #966}
correctly managed. A high percentage of risks were Cited deficiencies of care:
thought to be directly related to the obstetric Recognizing fetal distress 53%
outcome leading to the claim (66%). The authors feel Managing fetal distress 57%
Timely cesarean section 35%
obstetric closed claims can be studied and suggestions
Physician unavailable 29%
made to aid obstetricians in providing care. They Birth injury (forceps) 28%
concluded that obstetric malpractice closed claims Consultation or transfer 10%
are amenable to study; physicians and their patients What prompted lawsuit?
would benefit from better data collection systems to Person outside family 33%
identify risks in individual pregnancies; along with Medical personnel 23/41 (56%)
available resources to aid their management of Lawyer 8/41 (20%)
Money for long-term care 24%
patients. They felt that suits can be avoided through
Physician deception 24%
modification of physician behavior.77 Child would have no future 20%
In 1990, Rosenblatt and Hurst reviewed all closed Find out what happened 20%
obstetric claims in the records of a major physician- Deter malpractice / Revenge 19%
sponsored malpractice insurer from1982 to 1989. Of Complaints about physicians:
the 54 files closed during the 6.5-year period covered Not informed about injury potential 70%
by this study, 21 (39%) involved physician reports Misled patient 48%
Would not talk or answer questions 32%
of bad outcomes that did not lead to a formal claim.
Would not listen 13
Of the 33 formal claims, 14 (42%) were dismissed,
348 Textbook of Perinatal Medicine

Obstetrical negligence represented over $5 million in a number of cases in which the reviewer thought
(76.5%) of the total expense. Of the 40 cases, 23 (60%) no malpractice had occurred. The authors concluded
were resolved with a compromise settlement, nine that these results suggest that improvements are
claims (22.5%) resolved with indemnity payment on needed in prenatal and perinatal health care as well
the basis of verdict or pre-trial compromise; seven as in the legal system used to address the problem
(17.5%) had no indemnity payment because of a jury of perinatal medical negligence.79
verdict or voluntary dismissal. These seven were in In a study published in 2003, Ransom et al, tried
the highest-paid claims group only because of to estimate whether guideline compliance affected
expenses. 73,78 medico-legal risk in obstetrics and whether
Of the 40 case, none were considered frivolous; malpractice claims data can provide useful
28 (70%) were judged to be meritorious; 12 (30%) information about compliance.80 From the claims
were judged to be non-meritorious. Seven of the experience of a large health system delivering
latter settled without indemnity costs, including four approximately 12000 infants annually, they
that went to trial with a defense verdict and three retrospectively identified 290 delivery-related
that were dismissed, leaving five others in this group (diagnosis-related groups 370-374) malpractice claims
with proper treatment and indemnity costs. Expenses and 262 control deliveries between 1988 and1998.
to defend all 12 cases of proper treatment totaled Clinical pathways for vaginal delivery and cesarean
over $500,000. Irrespective of the absence of strict section, implemented in 1998, were used as a
negligence, each of these “non-meritorious claims” “standard of care.” They compared rates of
illustrated substantial deficits with the medical noncompliance with the pathways in the claims and
record or system failures – inviting the allegation of control groups. They found that noncompliance with
negligence and lawsuit (making the case appear the clinical pathways was significantly more common
meritorious). These analyses clearly reveal that bad among claims than controls (43.2% versus 11.7%, P
outcomes may not be the fault of the physician, but <.001; odds ratio = 5.76, 95% CI 3.59, 9.2). In 81
that physician behavior in the conduct of the case (79.4%) of the claims involving noncompliance with
and the conduct of the medical record contribute the pathway, the main allegation in the claim related
heavily to successful allegations of malpractice. directly to the departure from the pathway. The
Ogburn et al reviewed 153 closed claims involving excess malpractice risk attributable to noncompliance
perinatal injury or death filed from 1980 through 1982 explained approximately one third (104 of 290) of
with the St. Paul Fire and Marine Insurance Company. the claims filed (attributable risk = 82.6%). They
The claims included were those in which an concluded that malpractice data is a useful resource
indemnity was paid or $1,000 or more was expended in understanding breakdowns in processes of care
on the legal defense. Cases were classified as to the and that adherence to clinical pathways might
presence or absence of medical negligence. Most of 1. reduce clinical variation,
the complications leading to claims arose during labor 2. improve the quality of care,
and delivery. Many claims resulted from the failure 3. might protect clinicians and institutions against
to evaluate or treat in a manner consistent with malpractice litigation.
accepted standards of care. Many lacked A study by Greenwood et al from the National
documentation of the physician’s recognition of the Perinatal Epidemiology Unit, Oxford, UK. compared
risk factors involved. In the opinion of the reviewers, the prevalence of criteria suggesting acute
medical negligence occurred in 47% of the cases. intrapartum hypoxia in children with cerebral palsy
Indemnity payment occurred with most (but not all!) according to whether a lawsuit was brought alleging
of the claims judged to be associated with medical obstetrical negligence. The subjects were singleton
negligence. Payment to the claimant was also made children with cerebral palsy born between 1984 and
 Malpractice Issues in Perinatal Medicine: The United State Perspective 349
1993, excluding cases with a recognized postnatal average cost. Thus, while an erroneous decision may
cause for cerebral palsy. Only one-fifth (27/138) of be defensible if the reasons leading to it are recorded
all singleton CP children were the subject of a lawsuit. in the chart, the changed record and the
The greater the number of criteria suggesting contradictory record are almost impossible to
intrapartum insult the more likely was a legal claim defend. Until medical records objectively
(P < 0.01), but 36% (4/11) of those satisfying all communicate the findings, the attention paid, the
required criteria did not make a claim. Of the 27 comprehension that was achieved and offer a
claims, 12 were discontinued, 8 were settled and in reasonable plan followed by appropriate and
7 the legal process is still pending at the time of the consistent action, their appearance in court will
article. Furthermore, the presence of the three continue to be an uphill battle for the physician and
essential criteria for acute intrapartum hypoxia did he /she will get little credit for the thought process
not increase the likelihood of a legal claim being or use to his / her advantage the testimony of “a
settled.81 witness whose memory never dies.”
Other studies have focused on the costs and As an aside, the reader is invited to compare the
outcomes of litigation but not on culpability.16 Closed two enclosed notes regarding a midforceps procedure
claims provide valuable data, but because, on (Table 26.3). In the first example, the note invites
average, a medical liability case takes three to five lawsuit if there is an adverse outcome. The note
years to come to closure.(GAO 7) Opportunities for provides no indication for, or detail about, the
timely intervention in unsafe practices are lost. The procedure. It is more a personal memorandum than
research value is further compromised when the a responsible medical description relevant for
details of cases that reach settlement are suffocated decisions about care in future pregnancies, for
by “gag clauses” that mandate silence not only about example. The second note, on the other hand, would
the amount of award, the allegations and the seem to protect against lawsuit in several ways. The
admission or even acknowledgement of wrong- note
doing, thereby removing an obvious incentive to 1. clearly bespeaks thoughtfulness.
make care better. Hatlie has suggested that gag 2. It bespeaks understanding of the medical issues
orders are counterproductive. 35 and alternatives.
3. It underscores the physician’s efforts to provide
Medical Records forthright explanation to the patient and her
Unfortunately, the opinions that serve to launch husband – all powerful disincentives to lawsuit.
medical or medico-legal proceedings are most often Naked may be the best disguise!
based on a review of medical records that are One can readily blame the plaintiff attorney for
frequently silent on the intentions of the provider or the bringing to suit apparently a frivolous case, but
their exercise of “medical judgment.” They may be who is to blame (i.e., what has been learned?) for
silent, as well, on fundamental details of the the negligent care and adverse outcome in situations
obstetrical care. As a result, medical records, which where no suit is brought despite negligent care or
represent both a medical document and a legal where no award is made despite a suit and the
document, often promote or perpetuate cases and physician’s care is vindicated? Should the plaintiff
confound their defense. A cost analysis of 3205 multi- attorney be blamed for pursuing a case that his
specialty claims showed an average cost per claim of expert has told him, based on a review of the medical
$22,584. 82 Deficits in the medical record, e.g., records only, is negligent care?. Each of the articles
inadequate instructions, delayed entries, inadequate that evaluated closed cases found appreciable
notes, and consent-form issues, more than double amounts of agreed upon negligent care. Each
the average cost. System failures nearly tripled the emphasizes
350 Textbook of Perinatal Medicine

Table 30.3 Operative Delivery Notes

Operative Delivery Note (A) Translation

Op del note: Operative Delivery Note:
MF, OP >> OA, Mid epis, no lac Midforceps, occiput posterior (OP) to occiput anterior
(OA), Midline episiotomy, no lacerations
Apgar 8,9 P and M intact
Apgar scores 8,9 at 1,5 minutes. Placenta and
membranes expressed intact
EBL 400, M and B left DR in good cond.
Estimated blood loss 400 ml Mother and infant left the
delivery room in good condition.

Signature
Operative Delivery Note (B)
Procedures: Trial of forceps, midforceps rotation, episiotomy repaired.
Findings: Gyneocoid pelvis, normal active phase, +3 station, minimal molding, direct OP, epidural anesthesia,
second stage = 2.5 hours, pushing inadequate, patient tired.
EFW = 3000 Prev. baby = 2800
Indications: Persistent occiput posterior, prolonged second stage, secondary arrest of descent, tired patient.
Informed consent: Discussed options with patient and husband who agree and understand that if any difficulty is
encountered, the forceps will be abandoned and cesarean section undertaken. The operating room has
been alerted.
Methods: Midline episiotomy Kielland forceps - Direct application to OP without difficult. Gentle rotation: ROT to
OA. Kiellands removed, Simpson forceps applied. Gentle traction – delivered as OA
Fetal Outcome: 3200 gm male infant APGAR 8, 9 (see individual features in chart).
Resuscitation: Oxygen only, no evidence of trauma to skull forceps marks reveal appropriate placement.
Maternal Outcome: Perineum intact, episiotomy repaired, no lacerations. Placenta and membranes intact Estimated blood
loss:300 cc Mother left delivery room in good condition.

1. the need for better data, specialties and perspectives strongly suggest that it
2. the inculpating role of physician behavior and is not a lottery. Given the non-medical issues that
3. the importance of the review of malpractice claims incite or color a case, physicians squander much of
to identify problem-prone clinical processes and the advantage they have in the system! Thus it is,
suggest interventions that may improve outcome with some justification that critics of malpractice
and reduce negligence.83 litigation point out that it is unrealistic to expect that
It must be readily apparent from even these increased levels of litigation will make compensation
limited studies that not all meritorious suits succeed for injuries more “just” or health care better. A
and not all non-meritorious (not the same as reductio ad absurdum argument suggests that
frivolous) lose. These articles leave open to immunity from lawsuit, perhaps the true goal behind
speculation why patients victimized by obvious physicians’ notion of tort reform, will, by eliminating
medical negligence do not sue or why they are not lawsuits achieve these goals. Some conventional tort
compensated by the system in the face of agreed reforms appear to be effective in reducing litigation
upon negligence. Clearly, patients without costs and stabilizing insurance markets, they are not,
demonstrable evidence of negligence bring suit and however, designed to remedy the fundamental
sometimes they are rewarded in the system. It does failings of the malpractice system – making care better
not work perfectly, but these studies from various and making the physician patient relationship better
 Malpractice Issues in Perinatal Medicine: The United State Perspective 351
Fulfillment of these objectives may not require more of a case prior to the institution of suit, while
sweeping tort reform, perhaps more sweeping others attempted to remove the infant who is
“thought reform,” or alternatively, trying to make brain damaged during birth from the medico legal
the system work as it was supposed to. These reforms arena by the institution of no-fault insurance. Still
may only come from the medical community. other initiatives have attempted to increase the
percentage of any award that goes to the patient
Legal Vulnerability by limiting the attorney’s fees.
The last several decades have also witnessed the The most popular of these, caps on premiums,
development of new bases for lawsuit in reproductive have had the benefit of moderating the increases in
matters including wrongful birth and wrongful life. insurance payments. A publication from the Rand
In the former the parents with an injured child may Corporation has cast doubt on the likely benefit of
bring suit alleging that negligent treatment or advice caps on the high award cases where economic
deprived them of the opportunity to avoid conception damages are large and “pain and suffering” may be
or terminate a pregnancy. The latter, brought on much smaller. It seems axiomatic that caps should
behalf of the child born with birth defects, alleges not apply to frivolous suits where the cap should be
that the child would not have been born but for zero.
negligent advice to, or negligent treatment of, the In the 1970’s 22 states legislated some form of
parents. It should be emphasized that such allegations pre-litigation processes, including screening panels
are actionable in some states but not in others. While and mandatory binding and non-binding arbitration:
not strictly related to malpractice, a mother who only two remain active and neither has been effective.
pleaded with her hopelessly premature infant’s The costs of constitutional battles over due process
caretakers to discontinue resuscitation was not rights for binding processes and the failed reduction
heeded, resulting in the survival of a severely of litigated cases in non-binding processes, led to
handicapped child and a provisional $42 million further soaring legal costs, rather than reductions.
verdict for the plaintiff. The only lasting “tort reform”, although as discussed
later, questionable material impact on malpractice
TORT REFORM MEASURES frequency and awards, has been “Caps” on non-
Most Liability Reform Acts have four major economic damages, with the “gold standard” being
components: that of California’s Medical Injury Compensation
1. reforms directly addressing the size of awards – Reform Act of 1975 (MICRA).
under the heading of caps on damages Tort reform, the mantra of both the ACOG and
2. reforms intended to modify liability rules, to the Bush administration to deal with high medical
control the number of claims and size of payouts malpractice costs, makes sense only from the political
by eliminating joint and several liability for cases aspect. (New York Times Editorial - Malpractice
in which a plaintiff found to be partially at fault Mythology 1/9/2005). Capping awards on
becomes responsible for a disproportionate share malpractice suits may offend trial lawyers, but it helps
of the damages, or holds harmless special interests in the insurance,
3. reforms limiting access to the courts, through drug and health care industries. It provides no
shortening statutes of limitation - a reduction in assistance to patients who suffer grievous harm as a
the length of time during which lawsuit can be result of negligent care nor does it improve the
brought, and delivery of medical care. To many, a $250,000 cap
4. periodic payments — the latitude to pay future (the cap placed on non-economic damages in
economic damages over time. Other initiatives California) is poor acknowledgement indeed for the
have legislated review panels to pass on the merit physical and emotional damage done to people who
352 Textbook of Perinatal Medicine

have suffered total paralysis, permanent blindness The Center for Justice and Democracy, a consumer
or severe brain injury because of medical errors. advocacy group recently commented that, ‘’It may
Indeed, many states burdened with high premiums be hard to understand why ‘tort reform’ is even on
have already set their own caps, but generally at the national agenda at a time when insurance
more reasonable levels. It would seem more useful industry profits are booming, tort filings are
to consider making it harder for insurance companies declining, only 2 percent of injured people sue for
to gain rate increases. compensation, punitive damages are rarely awarded,
Guidelines for judges and juries might be enacted liability insurance costs for businesses are minuscule,
to help determine what compensation is reasonable medical malpractice insurance and claims are both
in a given circumstance. Similar guidelines could help less than 1 percent of all health care costs in America,
ensure that punitive damages, sometimes and premium-gouging underwriting practices of the
masquerading as non-economic damages are high insurance industry have been widely exposed.’’
enough to deter bad conduct; $250,000 would hardly Despite claims by the insurance industry, there is
amount to a wrist slap. no evidence that soaring malpractice premiums are
The problem with frivolous lawsuits is best the result of sharp increases in the amounts of money
addressed by raising the hurdles for filing a paid out for malpractice claims. And, tellingly,
malpractice suit, for example, requiring an expert industry executives have carefully acknowledged
judgment on the merits of a case before it can proceed that tort reforms will not result in substantial
through the courts. As mentioned above, there seems
premium reductions – only an improvement in care
to be no place for the expert witness to certify a case
can do that (BOB HERBERT, Malpractice Myths NYT
as meritorious if that same expert will not appear on
6/21/04 EDITORIAL NYT – Feb 2005).
the record for (public) report, deposition, and trial
Caps do not limit lawsuits. More reasonably, caps
if necessary.
are intended to increase the hurdles to a lawsuit by
The notion that the crisis of escalating malpractice
diminishing the economic value of a suit. In cases
insurance premiums is forcing doctors out of business
where there is little economic loss (irrespective of
remains murky. Insurance companies have
negligence) victims may not be able to find lawyers
substantially raised premiums for malpractice
to take their cases. (www.saynotocaps.org/newsarticles/
coverage for doctors in high-risk specialties like
WSJEffect of Caps.html) Because malpractice cases can
obstetrics and neurosurgery in some states, leading
cost plaintiff’s lawyers hundreds of thousands of
at least some doctors to curtail their services, retire
or move. But when the Government Accountability dollars out of pocket to prosecute, with no guarantee
Office visited five of the hardest hit states in 2003, of recouping those expenses. As pointed out by the
it found only scattered problems and was unable to Rand Corporation study, caps have little impact on
document wide-scale lack of access to medical care.71 lawsuits where there are substantial economic losses,
None of the tort reform proposals deal with the e.g. brain damaged infant, maternal death, etc. A
underlying need to diminish malpractice and to one-size-fits-all cap cannot encompass the unique
identify harmed patients and provide them with fair, facts in any case, and, in fact, more reasonably creates
prompt compensation. or provide tools for healthcare a system of “one size fits none.” It unfairly
providers to properly prepare patients and to deal discriminates against victims with no economic losses,
effectively with unanticipated outcomes. Although, such as children, stay-at-home moms, the elderly,
they do solve the health care industry and the the poor and the mentally handicapped. The media
insurance companies’ desire for fewer big court unflinchingly promulgates numerous cases tragic,
awards, they do not materially impact the frequency ineffable medical error where such arbitrary limits
of suit. But they do act as a roll back of the legal (originally set in 1979) seem inadequate, if not
rights of patients who are injured. inadequate, arbitrary.
 Malpractice Issues in Perinatal Medicine: The United State Perspective 353
Caps will not lower doctors’ malpractice insurance addition, again in Pennsylvania, one of the “red alert
premiums. (www.saynotocaps.org/reports/ Premium states,” there has been a significant increase in the
Deceit.pdf: The Failure of Tort ‘Reform’ To Cut Insurance number of physicians over the past several years
Rates”) Average premiums are actually 16 percent prompting one state legislator to call such claims of
higher in states with caps. In states that have recently a doctor exodus as “scare tactics.”
adopted caps, most notably Texas and Florida, It is far from clear that malpractice costs are
insurance rates are continuing to increase. Indeed driving up the costs of health care. Malpractice costs
the only thing keeping rates down in California - a account for less than 2 percent of the U.S. health-
state often cited as a model for caps - is insurance care budget. The Congressional Budget Office, in a
industry regulation provided by Proposition 103. report released in January 2004, found that legislation
The amount of money awarded on pain and to cap damages in medical malpractice lawsuits
suffering is unknown. In the majority of awards, would “do little to hold down health care spending”
those reached by settlement out of court, no or eliminate the practice of “defensive medicine.”
distinction between economic and non-economic There is little evidence that the threat of malpractice
damages. In jury trials economic and non-economic lawsuits contributes to the practice of “defensive
damages are awarded separately, but there appears medicine.” Rather, it has been suggested that doctors
to be no calculation of either the amount or the order additional tests because it is good medical
propriety. Nor has there been any compilation of practice; doctors make money from additional
those extreme awards that are reduced, sometimes testing; and managed care discourages unnecessary
drastically, by judicial review. In three case where testing, or “bad” defensive medicine. 71
the jury awarded over $220 million, the total Faulty underwriting and misfeasance by
cumulative amount received was $14 million (6 cents malpractice underwriters are additional factors
on the dollar!). There was no publication of the contributing to the rise in premiums. In Pennsylvania
reduction! (www.saynotocaps.org/reports/Public in the late 1990s half dozen major malpractice insurers
Citizen.pdf) When adjusted for the skyrocketing rate became insolvent because of risky premium under-
of health-care inflation, total payouts in malpractice pricing, poor investment strategies and Enron-style
cases remained flat up until 2001. (www.say- malfeasance, leaving doctors to pay for their
notocaps.org/reports/Stable Losses Unstable Rates.pdf) In mismanagement (www.saynotocaps.org/reports/
the three years since, total payouts have declined InsolvencySummary.pdf.)
each year (www.saynotocaps.org/newsarticle/Lower- There is no basis for the notion that insurance
Payouts.htm). Furthermore, data released in March companies routinely settle lawsuits just to make them
2004 by the Pennsylvania Supreme Court show go away. This seems more like a strategy for self-
malpractice case filings have decreased by nearly 30 destruction and is contradicted by the closed-claims
percent statewide since 2000. data presented above. (www.saynotocaps.org/
Many states have enacted legal reforms which factsandfigures/fibsysfacts.html#settle)
have effectively eliminated any lawsuits that could There can be little doubt that there is an
be construed as “frivolous.” By requiring a immediate question of affordability which must be
“certificate of merit” from a physician certified in dealt with acutely. Indeed several states have
the same medical specialty as the doctor being sued. contributed significant amounts of public money to
There have also been laws enacted to prevent “venue subsidize insurance premiums. Physician remain the
shopping” for a more favorable jury has been highest-paid professionals in the state, according to
eliminated. Indeed a Republican state Senator from U.S. Census data, indeed the incomes of obstetricians
Pennsylvania declared that “There is no such thing the physicians most affected by higher premiums –
as a frivolous lawsuit anymore” in Pennsylvania . In are rising. For many, on average, doctors spend 1 to
354 Textbook of Perinatal Medicine

5 percent of their gross revenues on medical It may also discriminate against patients at high-risk
malpractice insurance. It seems obvious also that for injury. It is uncertain how the establishment of
many doctors supplement their incomes with fees a no-fault system will impact cost. Some test
from attorneys for providing “independent medical programs have demonstrated that costs of a general
evaluations” in malpractice cases. no-fault system would exceed that of the present tort
system. Finally, the introduction and administration
Alternative System Reforms of a no-fault medical injury system, whether public
Experts have suggested a number of approaches, or private, will be complicated and likely politically
including special health courts with judges trained encumbered.
to deal with malpractice issues, required mediation, Preventable Events (ACES) represents consensus
mandatory reporting of errors by doctors and on what constitutes an avoidable event {Bovbjerg,
prompt offers of compensation. Some of these will 1991 #195}. These are pre-determined events that
be reviewed briefly here. (JCAHO). Not strictly part should not occur in quality health care delivery. They
of tort reform, alternative dispute resolution has encourage prevention of avoidable events that can
much to recommend it.44 trigger eligibility for early compensation offer. ACE’s
Strict Liability (No-Fault) Administrative System make “avoidability” and therefore, eligibility for
supports creation of a just patient safety culture and compensation, transparent to providers and patients
encourages reporting (and prevention) of adverse alike. They standardize eligibility for compensation
events It has the advantages of dispensing with trial and provide quicker identification of eligible cases.
and supports open disclosure to the patient (not the There is, however, no comprehensive ACE list
public) as the deliberations are administrative. In this currently available, and concern exists as to who is
system the provider is accountable for all avoidable to develop the categories of avoidable events. Brain
medically related losses and the matter can be damaged infants, for example, would not be covered.
resolved promptly. It eliminates the requirement of Development of the list will, of course, require an
proving negligence, but the patient must establish array of expert consensus (selected by whom?) The
that their injury was actually caused by the treatment. use of ACE’s provides a basis to determine eligibility
As a generalization, eligibility is based on for alternative and conventional compensation
avoidability rather than providers being strictly systems. It can also be paired with a standardized
responsible for medically related losses. There is, compensation fee schedule.
unfortunately, the common perception that “no-fault”
MEDIATION
means “no accountability.” Examples include NICA
in Florida and Virginia. Mediation represents a highly efficient option for
Although, the system of No-Fault is modeled after non-adversarial resolution of healthcare conflicts. It
that of Workers Compensation and Automobile No- is a process in which the parties to the conflict,
Fault claims, the complexity of determining causal themselves, not lawyers, craft their own unique
and avoidable injury medical injury claims is very resolution to a conflict. Mediation is essentially
different. And allthough it removes negligence as a facilitated communication and negotiation using a
basis for claim, it does not replace the regulatory neutral third party. The process itself is non-binding
system of reporting and resultant physician fear, nor and does not prevent the patient from moving
does it address the inbred philosophy of the “do no forward to litigation. However, if a resolution is
harm”, “zero tolerance.” Since premiums in any no- reached, it becomes binding under contract law and
fault system are based on injury rates, this creates may even be brought as an order of the court.
an incentive to conceal injuries and reduce the Mediation is highly cost efficient, time sparing in that
admission of high-risk specialtists to medical staffs. it makes response to adverse events and their
 Malpractice Issues in Perinatal Medicine: The United State Perspective 355
resolution more timely and boasts a greater than 90% low utilization and increased litigation costs. Such
resolution rate. It is widely excepted and highly systems intensifies pressure on patients to settle thus
successful in many “industries”such as real estate and reducing or avoiding litigation. It may be used with
education. but has met with much resistance in the current tort system –as well as with no fault and
healthcare “industry”, especially in medical ACEs. Kaiser Permanente, for example, “requires
malpractice. . It intensifies pressure on patients to enrollees to sign a ‘willingness to arbitrate’
settle thus reducing or avoiding litigation. Because agreement. With this approach, the health plan
confidentiality has been stripped from the mediation undertakes to resolve disputes through arbitration
process in medical malpractice disputes by medical than go through the courts. This of course is not the
regulatory boards and reporting agencies, and same as a waiver of liability.
therefore has crippled the successful application of
the mediation process in physician/patient conflicts. Specialized Medical Malpractice Courts
Although, confidentiality in error reporting is a There are three types of specialized courts under
foundation for most of the proposed legislation, it consideration: the Health Court, the Medical Board
has not been extended to the resolution of conflicts Administrative Adjudication System, and Tripartite
arising from alleged medical errors. The statutory Panel.
obligation physicians have to report settlements of Health Court involves the creation of an
disputes involving quality of care issues creates a alternative court system within the federal court
perverse incentive for physicians to move forward system. This proposal will, as touted by the
in litigation, especially when one considers the high consumer advocate group, Common Good,
attrition rate of malpractice claims and the likelihood presumably make judgments more reliable and
of a physician prevailing in those cases that persist. provide clearer lessons for deterrence of adverse
It is likely that even in the face of tort reform, outcome. In theory they can provide more timely
mediation will remain an infrequently used medium access, provide faster resolution of claims along with
for physician/patient dispute resolution. more reliable and standardized compensation. It
requires appointment of special expert courts to hear
Arbitration
medical cases or administer compensation based on
As with mediation, arbitration provides economical avoidable events. Health courts also make the system
and prompt adjudication of adverse events Like more transparent by providing public access to
mediation, it provides prompt, private settlement and settlement and adjudication findings. It will require
compensation, yet is also subject to reporting judges who have special knowledge or training in
requirements and regulatory oversight. The medicine. Although proponents believe that this
processes differ, however, in a few major factors: form of adjudication will offer more consistent and
With arbitration the decision maker is a third party, informed decisions than the traditional trier of fact,
the arbitrator(s), and the process is highly formalistic a lay jury, many studies find that in comparison with
and adversarial. There are two forms of arbitration, expert’s reviews, the present jury system is quite
binding and non-binding. The later is similar to consistent.
mediation in that if either party disagrees with the Health courts may be paired with ACEs and
arbitrator’s decision, they may move on to litigation. standardized compensation schedule –and may even
The former, however, is a binding decision, which add a trial option to an administrative system. There
cannot be appealed. Binding arbitration for are precedents for these types of courts in certain
malpractice claims has met with considerable legal tax and patent infringement and worker’s
opposition and non-binding arbitration has met with compensation laws.
356 Textbook of Perinatal Medicine

Medical Board Administrative Adjudication There is Pre-Hearing Discovery then a Pre-Trial

System - In 1988 the AMA, 31 medical specialty Screening Hearing that follows the format of an
associations, the Physician Insurer’s Association of arbitration. Depositions are admissible, but expert
America (PIAA), and the Counsel of Medical testimony unusual. The panel has prior access to
Specialty Societies created the Medical Liability written briefs, complete medical records, deposition
Project to develop an equitable and efficient method transcripts. The panel then acts as both the trier of
to handle malpractice claims. They proposed a claims fact and law, under the standard used by lay juries,
adjudication process based on fault and suggested “preponderance of the evidence.” It evaluates the
that the states’ medical boards act as the trier of fact case on the basis of the Four D’s of negligence.
in addition to their regulatory and disciplinary roles. Unanimous decisions by the panel on negligence and
This system would initially screen cases, offer free causation are admissible in court, both in favor of
legal counsel for cases passing review, and offer patient or provider. The decision of the panel, like
limited judicial review. In a parallel development, in non-binding arbitration does not bind either party
The AMA considers that the provision of expert from pursuing litigation and trial. Some systems allow
testimony constitutes “the practice of medicine?” and recovery of costs by the losing party, but as stated
that it should be subject to peer review by state previously, if it is the plaintiff, actual recovery is
medical boards. The AMA encourages the state unlikely.
medical associations to work with the licensing
boards to develop effective disciplinary measures for Enterprise Liability
fraudulent testimony.
Enterprise Liability provides incentive for
Tripartite Panel - Also in 1988 PIAA proposed an
prioritization of enterprise- wide safety It shifts
administrative system similar to that used in
liability from individual provider to a provider
Workers’ Compensation. In the hope that patients
organization such as an integrated medical staff, IPO,
would elect this more speedy system through the
offer of incentives. The panel would consist of a large group practice, or hospital capable of influencing
judge, a physician, and a lay person and function care across the systems. Enterprise Liability
much like the few state screening panels that remain essentially makes these organizations “strictly liable”
active. In cases where malpractice was found, all in both a legal and economic sense by their
medical expenses would be paid under a specific responsibility for liability premiums for all staff
method of computation, all non-economic awards involved in the organization, which could potentially
would be based on a fixed schedule of benefits, and impact the present punitive reporting system and
their would be a limit on attorney’s fees. allow for a freer flow of error reporting. Such a
system would promote institutional safety, and
Pre-Trial Screening Panels potentially stabilize liability insurance fees. Legal
This is a system that is modeled after state programs provisions (Stark laws) may prohibit liability
that are presently functioning, with those of Maine insurance coverage of non-employee physicians
and Vermont most recognized. To enlist the Panel, Works equally well with alternatives as well as the
the patient provides written notice to physician and current tort system. ‘The Department of Health and
with the Superior court to be acted upon within 90 Human Services’ Office of Inspector General (OIG)
days. The Superior Court selects a Panel Chair from historically has been concerned that a hospital’s
a pool of retired judges and/or mediators with subsidy of malpractice insurance premiums for
judicial or legal experience. The Chair selects from a potential referral sources, including hospital medical
court issued list, one attorney and one physician staff, may implicate the anti- kickback statute, because
panelist, of the same or relevant specialty. The parties the payments may be used to influence referrals,”
may challenge the selection for cause. There is a particular concern where subsidies are
 Malpractice Issues in Perinatal Medicine: The United State Perspective 357
offered in a conditional or selective manner that Medicine’s “To Err is Human” which claims that
reflects current or anticipated referrals from the between 44,000 and 98,000 hospitalized patients die
subsidized practitioners.” Hospitals may be able to per year as a result of medical error, and subsequent
subsidize the malpractice insurance of local studies such as that of Sarwat Chaudry, et. al , patient
obstetricians without triggering anti-kickback safety has become the mantra of the Joint
sanctions, according to an advisory opinion issued Commission on Accreditation which has now
by the OIG. In the opinion, OIG out- lines a specific embellished the requirements for disclosure of error.
case in which it would not impose anti-kickback (JACHO). Programs for the evaluation of route cause
sanctions against a medical center that provides analyses of reported errors and resulting error
subsidies to four community-based obstetricians who reducing actions have become, as they should, a
hold staff privileges at the medical center but are national priority.
not employees of the facility. OB-GYN NEWS Also potentially threatening to the physician, are
October 15, 2004, p. 25 those tort reforms that are linked (politically) to the
Tort reform in many of its guises, however, has establishment of enhanced physician review panels,
historically not been universally “friendly” to the the creation of “3 strikes and you are out rules,” etc.
physician. In 1988, the US Congress established a In Texas, for example, along with a stringent tort
National Practitioner Data Bank authorizing the reform bill passed in 2003, the Texas legislature gave
collection of data about physicians and dentists from the Texas State Board of Medical Examiners new
authority to regulate medical practice through the
malpractice settlements, awards and disciplinary
passage of S.B. 104. This bill gave the board increased
actions; these data were to be supplied by insurers,
funding for expert consultants and staff. These
hospitals and HMO’s.4 Queries of the Data Bank
resources were used to assess the approximately 6000
might be made by hospitals and physicians, but there
complaints the board receives each year. As a result,
is to be no access by the public or actual or
Board enforcements have increased dramatically.
prospective litigants including patients and attorneys
Before the augmentation, cases were filed against
although expanded access to this information is the
physicians immediately and immediately affected
subject of much debate. This tracking by the Data
their records. The new system provides more due
Base has probably decreased the willingness of
process, but is more far ranging. Opponents of this
physicians to settle cases, but has probably not
feature of Texas Health litigation argue that standard
decreased the frequency of malpractice. The NPDB
of care issues should be left to local community
reporting system is primarily based on the reporting medical societies or hospital peer review and
of any formal written claim of malpractice that results credentialing societies. But when the shoe is on the
in even one penny changing hands, regardless of other foot and these organizations engage in sham
admission of blame or severity of injury. Such reports peer review or economic credentialing physicians
carry great weight in considerations for staff complain about their unfair practices (see below).
privileges, provider contracts, and malpractice Physician groups complaining about S.B. 104 want 1)
premium rates. Hatlie has argued that the NPDB the presumption of innocence, the right to access
should be abandoned. 35 details of the complaints against them, the right of
Even more recently has come the increasing discovery, the right to present witnesses and cross-
attention of the amount of medical error that has examine witnesses and the right to appeal. How
heretofore gone unnoticed and undocumented. The seductive is the illusion of a new idea – all of these
AMA has created a Patient Safety Initiative and the features are present in current malpractice law – the
Federal Government is considering legislation that beneficiary of 200 years of accumulated
will likely reorient the approach to error. Indeed, jurisprudence. Public Citizens’s Health Reasearch
since the publication of the prestigious Institute of Group ranked Texas 23 out of the 50 states.
358 Textbook of Perinatal Medicine

Reviews of the impact tort reform on premiums States Government Printing Office, 519-216/63040,
suggest that while premiums do respond to increases 1988.
in payments, they do not increase dollar for dollar Whether driven by legislation or not, it seems
(http://www.nber.org/papers/w10709). This reasonable that stable malpractice insurance
suggests that other factors may also be important in premiums offered by experienced, reputable
explaining the recent jump in malpractice premiums, companies are important reasons for maintaining
such as a less competitive insurance industry or a physician availability and equilibrium.
decline in insurers’ investment income. There is little There is no evidence that tort reform has resulted
evidence that changes in malpractice premiums are in better care or more realistic confrontation of error.
linked to changes in either the total number of Tort reform simply “tinkers with certain aspects of
physicians or the number of physicians working in the system in a piecemeal fashion without having to
obstetrics/gynecology, surgery, or internal medicine. grapple with fundamental reform of either the health
Weak evidence suggests that the entry decisions of care delivery system, the reimbursement system or
young physicians and the exit decisions of older physician behavior.”
physicians may be affected by malpractice premiums.
Stronger evidence suggests that rural physicians are Tort Reform and Finances -
more sensitive to change in premiums - a 10 percent Litigation and Risk Management
increase in premiums results in a 1 percent decrease There is universal agreement that the medical needs
in rural physicians per capita and a 2 percent decrease of those with adverse outcome need more attention,
in older rural MDs (http://www.nber.org/papers/w10709). whether it is related to negligence or not. There is
Although there is no change in the frequency of also universal agreement that the present functioning
most treatments, some data suggests that physicians of the medico-legal system is an anachronism -
may increase the use of screening procedures in neither efficient nor error-free in reaching settlement
response to higher premiums. Such practices however or that the distribution of money is equitable. In the
have had little effect on total Medicare expenditures, United States, only about 28 cents of every premium
suggesting that the costs associated with defensive dollar goes to injured patients after an average delay
medicine practices may be small, at least for this age of 4.9 years to dispose of a case.
group. Thus it is far from clear that state tort reforms Is no fault insurance better? To determine
will avert local physician shortages or lead to greater whether Florida’s implementation of a no-fault
efficiencies in care. The stabilization of premiums, system for birth-related neurological injuries reduced
the initial response to most rounds of tort reform, lawsuits and total spending associated with such
may not indeed be the result of the tort reform injuries, and whether no-fault was more efficient than
legislation. Normally it takes years before legislative customary tort procedures in distributing
tort reform has a direct impact on malpractice compensation, Sloan et al compared claims and
premiums and several, but not all, state courts have payments before and after implementation of a no-
invalidated the cap on damages, the component of fault system in 1989.6 They found that the number of
the law with the greatest potential to reduce tort claims for permanent labor-delivery injury and
premiums. (Zuckerman et al. 1989) Malpractice death indeed fell by about 16-32%. However, when
premiums are affected by a constellation of additional no-fault claims were added to tort claims, the total
factors, including the general investment climate, claims frequency rose by 11-38%. Further, of the
interest rate cycles, and insurance regulations. estimated 479 children suffered birth-related injuries
Department of Health and Human Services. Report annually, only 13 were compensated under no-fault.
of the Task Force on Medical Liability and Total combined payments to patients and all lawyers
Malpractice, August 1987. Washington, DC: United did not decrease, but under no-fault, a much larger
 Malpractice Issues in Perinatal Medicine: The United State Perspective 359
portion of the total went to patients. Thus, less than claims. Analyses of these claims have, for example,
3% of total payments went to lawyers under no-fault revealed patterns in patient injury in the use of
versus 39% under tort — a new equilibrium. Some regional anesthesia, in the placement of central
claimants with birth-related injuries were winners, venous catheters, and in chronic pain management.
taking home a larger percentage of their awards than Results of these analyses are published in the
their tort counterparts. Lawyers clearly lost under professional literature to aid practitioner learning and
no-fault, but so did many many children with birth- promote changes in practices that improve safety and
related neurologic injuries who did not qualify for reduce liability exposure.
coverage because of the narrow statutory definition. Closed claims data analysis is the one way in
which the current medical liability system helps to
SOLVING THE MALPRACTICE PROBLEM inform improvements in care delivery. However,
While the focus of clinical risk management intuitively reliance on closed claims for information related to
rests on the analysis of adverse events, it seems clear error and injury is cumbersome at best. It may take
that this is a most inefficient way of reducing or years for an insurance or malpractice claim to close.
eliminating harm to the patient. In the current climate These are years in which potentially vital information
risk management tends to deal more with avoidance on substandard practices remains unknown.
of blame and litigation than in the avoidance of harm Providing patient safety researchers with access to
to patients. open claims, now protected from external
One of health care’s principal patient safety success examination, could vastly improve efforts aimed at
stories is anesthesiology. In the 1980s, in the midst identifying worrisome patterns in care and designing
of a separate medical liability crisis, the rate of appropriate safety interventions.
anesthesia-related deaths was one in 10,000; 6,000 In addition to anesthesiology’s early work in
people per year who had undergone anesthesia died identifying the human factors and system failures
or suffered brain damage, and anesthesiologists’ that cause error, anesthesiology has also promoted
liability insurance premiums had sharply escalated.68 reliance on standards and guidelines to support
Following a national news magazine broadcast which optimal anesthesiology care. Anesthesiology has also
pilloried the field for these outcomes, the American been at the forefront in the use of patient simulation
Society of Anesthesiologists (ASA) decided to seize for research, training and performance assessment.
the opportunity presented by the crisis to improve With simulation, no patients are at risk for exposure
anesthesiology safety. to novice caregivers or unproven technologies.70
It started with the hiring of a systems engineer. Anesthesiology is still far from perfect. But, its
Through close scientific examination of 359 anesthesia “institutionalization of safety,”71 continues to serve
errors, every aspect of anesthesia care – equipment, the field well as it tackles the continuing threats to
practices, and caregivers – was analyzed. Eventually, patient safety that are endemic to modern medicine.
with the commitment of leadership and resources Medicine is different from industry in that the
towards the task, the many system failures revealed medical system has not adjusted to the realities of
by the study were re-engineered, and anesthesia- human fallibility. The circumstances of contemporary
relat-ed death rates fell to one in more than 200,000 malpractice situation continue to compromise both
69 cases. the provision and safety of health care as well as our
The American Society of Anesthesiologists uses notions of justice of access to the law and to health
case analysis to identify liability risk areas, monitor care. This state of affairs benefits neither the patient,
trends in patient injury, and design strategies for nor in the long run, the physician. While in some
prevention. Today, the ASA Closed Claims Project instances the fear of lawsuit has increased the amount
– created in 1985 — contains 6,448 closed insurance of surveillance and may have even had a salutary
360 Textbook of Perinatal Medicine

effect on outcome, there is little argument that the Chaumeton N, Levinson W. Surgeons’ tone of voice: a
clue to malpractice history. Surgery 2002;132(1):5-9.
present format for dealing with allegations of
6. Sloan FA, Whetten-Goldstein K, Hickson GB. The
negligence provides any incentive to the profession influence of obstetric no-fault compensation on
to practice better medicine, to provide better peer obstetricians’ practice patterns. Am J Obstet Gynecol
review or in the occasional instance, restrict the 1998;179(3 Pt 1):671-76.
7. Gibson S. Wall of Silence.
future practice of the physician whatever his conduct. 8. Kritzer H. The justice broker: lawyers and ordinary
True reform will require a systemic approach to error litigation. New York: Oxford University Press; 1990.
in medicine as elsewhere and some refinement of 9. Hyams AL, Shapiro DW, Brennan TA. Medical practice
our ethics and an appreciation of the paradoxes of guidelines in malpractice litigation: an early retrospective.
J Health Polit Policy Law 1996;21(2):289-313.
contemporary malpractice. To lower the risk of 10. Peters K. The role of the jury in modern malpractice law.
malpractice we must continue to attempt to raise the Iowa Law Rev 2002:909-69.
standards of care. We need this more than we need 11. Studdert DM, Mello MM, Brennan TA. Medical
malpractice. N Engl J Med 2004;350(3):283-92.
the identification of the “bad apples” of our specialty.
12. Fry v. United States F. In.
We must increase communication with the patient 13. Shea vs. Esensten F, 3d 625m 629 (8th Cir.). In; 1997.
and remain their advocate. We must address the 14. Daubert v. Merrell Dow Pharmaceuticals I, 509 U.S. 579.
formal teaching of communication skills, conflict 1993.
15. Kumho Tire Co. LVC, 119 S. Ct. 1167. In; 1999.
management, and team development techniques 16. Bors-Koefoed R, Zylstra S, Resseguie LJ, Ricci BA, Kelly
throughout medical school and residency. We must EE, Mondor MC. Statistical models of outcome in
construct effective error reporting and systems malpractice lawsuits involving death or neurologically
analyses programs that promote error reduction, impaired infants. J Matern Fetal Med 1998;7(3):124-31.
17. LLMD of Michigan IvJ-C, Co. In; 1999.
while protecting physicians from being punished by 18. Ross BK. ASA closed claims in obstetrics: lessons learned.
arbitrary and ineffective reporting systems. We must Anesthesiol Clin North America 2003;21(1):183-97.
not squander our greatest asset - the medical record, 19. Meyers AR. ‘Lumping it’: the hidden denominator of the
medical malpractice crisis. Am J Public Health
and stop acting the role of victim. Often the ultimate
1987;77(12):1544-48.
failure is often not the individual provider but the 20. Meeker CI. A consensus-based approach to practice
latent, systemic errors, errors for which our systems parameters. Obstet Gynecol 1992;79(5 (Pt 1)):790-3.
are programmed, but which are functionally immune 21. Meeker WC. The future impact of clinical practice
guidelines. J Manipulative Physiol Ther 1995;18(9):606-10.
from lawsuit. A law suit cannot make “the system” 22. Lavery JP, Janssen J, Hutchinson L. Is the obstetric
a defendant. Finally, we must be willing to participate guideline of 30 minutes from decision to incision for
in the process of uncovering error and make the Cesarean delivery clinically significant? J Healthc Risk
patients our allies in these efforts. Manag 1999;19(1):11-20.
23. Schreiber v. Physicians Insurance Company of Wisconsin
223 Wis. 2d 417. In; 1996.
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30. Spaeth RG, Pickering KC, Webb SM. Quality assurance ethical duty to admit mistakes? Healthc Financ Manage
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34. Donohue SK. Health care quality information liability & State Med Assoc 2004;97(6):245-47.
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39. Brennan TA, Hebert LE, Laird NM, et al. Hospital 56. Simpson KR, Knox GE. Common areas of litigation
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to know? Acad Emerg Med 2002;9(11):1156-61. fetal neurological injuries. Best Pract Res Clin Obstet
43. Witman AB, Park DM, Hardin SB. How do patients want Gynaecol 2004;18(3):437-56.
physicians to handle mistakes? A survey of internal 62. Dear P, Newell S. Establishing probable cause in cerebral
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1996;156(22):2565-9. 2000;320(7241):1075-76.
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45. Finkelstein D, Wu AW, Holtzman NA, Smith MK. When 807 April, 1999: 51 Stan. L. Rev. 807 April, 1999; 1999.
a physician harms a patient by a medical error: ethical, 65. Ennis M, al: e. Obstetric accidents: a review of 64 cases
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68. Burstin HR, Johnson WG, Lipsitz SR, Brennan TA. Do the sectional study of litigation, quality assurance, and
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69. Sloan FA, Whetten-Goldstein K, Githens PB, Entman SS. 77. Julian TM, Brooker DC, Butler JC, Jr., et al. Investigation
Effects of the threat of medical malpractice litigation and of obstetric malpractice closed claims: profile of event. Am
other factors on birth outcomes. Med Care J Perinatol 1985;2(4):320-24.
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70. The effects of medical professional liability on the delivery malpractice claims. Obstet Gynecol 1989;74(5):710-14.
of obstetrical care. Washington, DC: Institute of Medicine, 79. Ogburn PL, Jr., Julian TM, Brooker DC, et al. Perinatal
National Academy Press; 1989. medical negligence closed claims from the St. Paul
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74. Sachs BP, Kobelin C, Castro MA, Frigoletto F. The risks 81. Greenwood C, Newman S, Impey L, Johnson A. Cerebral
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75. Brennan TA, Leape LL, Laird NM, et al. Incidence of 82. Richards BC, Thomasson G. Closed liability claims
adverse events and negligence in hospitalized patients: analysis and the medical record. Obstet Gynecol
results of the Harvard Medical Practice Study I. 1991. Qual 1992;80(2):313-36.
Saf Health Care 2004;13(2):145-51; discussion 51-2. 83. Kravitz RL, Rolph JE, McGuigan K. Malpractice claims data
76. Brennan TA, Localio AR, Leape LL, et al. Identification of as a quality improvement tool. I. Epidemiology of error
adverse events occurring during hospitalization. A cross- in four specialties. JAMA 1991;266(15):2087-92.
 SECTION 4
Evidence Based Medicine
and Epidemilogy
Z Alfirevic, L Cabero-Roura
 27
Epidemiology in
Perinatal Medicine

L.S. Bakketeig

DEFINITIONS onwards.2-4 The increasing attention being paid to

perinatal mortality was caused by the observation
For a long time, it has been recognized that events
that the fall in infant mortality (death during the 1st
during pregnancy and childbirth influence the health
year of life) in the first half of the 20th century derived
and development of the newborn. This recognition
mainly from the reduction in mortality of infants
has led to the establishment of perinatology as a
surviving beyond the 1st week of life.5 It appeared
medical specialty which bridges the gap between the
that the progress made was mostly a result of the
obstetrician’s concern for the pregnant woman and
success in combating deaths due to infectious
the pediatrician’s care of the newborn.
diseases in early infancy. Mortality among infants
Population-based studies of these phenomena are
shortly after birth, as well as fetal mortality, had
labelled ‘perinatal epidemiology’, which has evolved
decreased far less.5
into a major subspecialty of epidemiology,
Perinatal mortality is the most commonly-used
representing an important contribution to perinatal
death rate as an indicator of perinatal health. The
medicine. Traditionally, perinatal epidemiologists
other death rates used in perinatal epidemiology are
have focused on exposures and outcomes occurring
stillbirth, neonatal, postneonatal and infant death
in the perinatal period which most commonly covers
rates, illustrated. The death rates are defined as the
the time from conception through to birth and the
number of deaths per 1000 births, or per 1000
first part of life (1 week, 1 month or the 1st year of
livebirths for the latter three rates.
life). In recent years, though, it has been realized
that events or exposures that take place in utero, or
PERINATAL SURVEILLANCE
shortly after birth, can also affect development and
health even into adult life. We also have come to Perinatal surveillance can be based on the perinatal
realize that even events occurring long before and infant death rates, but also on other health
pregnancy, sometimes intergenerationally, can affect indicators such as the frequency of different
our reproduction. congenital anomalies or the frequency of preterm
An Austrian pediatrician suggested nearly 75 births or low-birth-weight births. Some countries,
years ago that stillbirths and deaths during the 1st for example, the Scandinavian countries, have
week of life should be treated as one statistical entity established medical birth registries where all births
in the analysis of causes of death.1 The term ‘perinatal in the country are monitored. Thus, the occurrence
mortality’ was increasingly used from the 1940s of different adverse outcomes can be monitored and
366 Textbook of Perinatal Medicine

changes in frequencies can be detected and further association between the use of diethylstilbestrol in
investigated. The thalidomide disaster in the early pregnancy to prevent miscarriages and the risk of
1960s was the main reason why such a medical cancer vaginalis in the female offspring of these
registration system was established in Norway in women when they reach their early reproductive
1967. This was the first national population-based years.7
registration of births ever established.6 Later, similar The other approach in studying associations
registration systems were established in Denmark, between exposures and adverse outcomes is the use
Sweden and Finland. of cohort studies, where two groups of women are
The medical registration of births contains selected, one being and one not being exposed to
information on the parents (a few items on civic and the suspected risk factor, and then comparing the
medical information), the course of pregnancy and outcomes in the groups. In Table 27.1, an example is
delivery and, finally, some information about the shown of such a cohort study which focuses on the
newborn baby. Therefore, the medical birth risk of small-for-gestational-age (SGA) births for
registration information can be used for perinatal groups of women with established risk factors at the
audit purposes beyond the surveillance of congenital start of their pregnancies, and evaluates the
anomalies. Perinatal audit represents a current additional risk associated with cigarette smoking.
assessment of the quality of perinatal care, based on The data shown in the table are based on a
the structure of care, the process of care and the longitudinal study of fetal growth.8 For women with
outcome of care. The information collected through no known risk factors at the beginning of the
the medical birth registration represents a valuable pregnancy, 6.5% will have a SGA birth. If the women
basis for assessing at least the process and the smoke cigarettes, the risk increases to 11.8% (relative
outcome of care, while data on the structure of care risk (RR) = 1.8). If the women have had a previous
will have to be collected separately. low-birth-weight (LBW) birth (birth weight below
The medical birth registration forms the basis of 2500 g), then the risk of a SGA birth is more than
the Medical Birth Registries in the Nordic countries. doubled (RR = 2.4), and if they smoke cigarettes,
The child and its parents are identified by unique there is a further doubling of the risk (RR = 5.4).
identification numbers. This facilitates the linkage Case-control and cohort studies are both observa-
of the information with other data sources, like the tional studies. Furthermore, within perinatal
death registry, the census data and the education epidemiology as well as other areas of epidemiology,
registry. Also, the identification number makes it observational studies are the dominant tools in
possible to link the medical birth registries with other addition to more descriptive and even hypotheses -
morbidity registries, such as the cancer registries, generating studies. The more powerful experimental
which represent high-quality data sources in the approaches are obviously less suitable. However, in
Nordic countries. evaluating perinatal care, one can use randomized
controlled trials, applying either individual or cluster
RISK FACTORS randomization. This approach can also be applied in
Perinatal epidemiology focuses on different risk the evaluation of preventive programs. Here, the
factors associated with pregnancy and childbirth. cluster randomization approach ought to be used
Births with an adverse outcome are compared with more often. For example, in evaluating a new
controls and whether one group has more often been program for antenatal care, instead of randomizing
exposed to the risk factor under study than the individuals, one could randomize areas, counties,
controls (case-control study). An outstanding municipalities or clinics to alternative programs and
example of such a study is the discovery of the strong then compare the results.9
 Epidemiology in Perinatal Medicine 367
Table 27.1: The frequency of small-for-gestational-age (SGA) births in cohorts of women with different risk factors,
including cigarette smoking, at start of pregnancy. Derived from reference 8
SGA births
Risk factor Women (n) n % Relative risk 95% Confidence interval
None*
non-smoker 3190 208 6.5 1.0
smoker 1515 179 11.8 1.8 (1.5, 2.2)
Previous low-birth-weight birth
non-smoker 286 44 15.4 2.4 (1.7, 3.3)
smoker 238 84 35.3 5.4 (4.2, 7.0)
Low prepregnancy weight (< 50 kg)
non-smoker 164 20 12.2 1.9 (1.2, 3.0)
smoker 175 45 25.7 3.9 (2.9, 5.4)

*Defined as the absence of the following risk factors: previous low-birth-weight birth, low prepregnancy weight, previous
perinatal death, or chronic maternal diseases (essential hypertension, heart disease, or renal disease)

RECURRENCE RISKS The first births included in the Norwegian

Medical Birth Registry from 1967 onwards have now
The feasibility of linking parents and child in the
since long started to reproduce themselves, which
medical birth registries makes it possible to study
facilitates the study of intergenerational effects. As
the recurrence of pregnancy and childbirth events it turns out, birth weight correlates across
within sibships. This has been done extensively, based generations, but gestational age correlates to a lesser
on the Norwegian Medical Birth Registry data over extent. 11 A recent analysis is based on 105 104
the last 20 years, starting with a paper in 1977 which mother/child pairs recruited from females in the
demonstrated the strong tendency to repeat preterm, Norwegian Medical Birth Registry born since 1967
low-birth-weight and small-for-gestational-age births and reproducing through 1995. Based on 101 579
in successive pregnancies in the same woman.10 single mother/child units, the recurrence risks across
As it turned out, as shown in Table 27.2, low birth generations are shown in Table 27.3. The recurrence
weight (LBW) was the best predictor of subsequent risk for low birth weight is of the same magnitude
LBW, preterm birth was the best predictor of later as the recurrence within sibships.10 However, for
preterm birth, and small-for-gestational-age (SGA) gestational age, the recurrence risk across generations
birth was the best predictor of subsequent SGA births. is much weaker compared to the recurrence within
These and later analyses have indicated that women sibships. This could indicate that genetic factors affect
are ‘programmed’ to have births of a similar size in fetal growth more than the duration of pregnancy
subsequent pregnancies. and that gestational age might be more affected by

Table 27.2: Prediction of low-birth-weight (LBW), preterm and small-for-gestational-age (SGA) second births based
on birth weight and gestational age of first birth (76 398 mothers with first two births 1967-73). From reference 10
Risk of second birth
LBW Preterm SGA
First birth % Relative risk % Relative risk % Relative risk
LBW 15.2 5.6 15.4 3.7 20.5 4.1
Preterm 11.8 4.1 16.4 4.0 11.5 1.5
SGA 7.7 2.8 6.6 1.4 22.1 3.9
368 Textbook of Perinatal Medicine

environmental factors. Further studies of paternal ACKNOWLEDGEMENT

effects and the association among paternal and
I wish to thank Liv Knurvik for skillful technical
maternal half-siblings might help to clarify these
assistance in preparing this manuscript.
relationships.
REFERENCES
FUTURE PERSPECTIVES OF
1. Peller S. Proper delineation of the neonatal period in
PERINATAL EPIDEMIOLOGY perinatal mortality. Am J Public Health 1965;55:1005-11.
2. Wallgren A. The neonatal mortality in Sweden, from a
The idea that health in adult life may reflect
pediatric point. Acta Paediatr Scand 1942;29:372-86.
circumstances in childhood, or even earlier in life, 3. Baird D, Thomson AM, Duncan, EHL. The causes and
dates back many years.12 The notion that at least prevention of stillbirths and first week deaths. J Obstet
some adult diseases may originate in utero has Gynaecol Br Emp 1953;60:17-30.
4. World Health Organization. Epidemiological and Vital
recently captured attention across a wide range of Statistics. Report 57, 1957:506-11.
biomedical sciences. Editorial comments have ranged 5. Taylor W. The changing pattern of mortality in England
from being enthusiastic, claiming a ‘paradigm shift’13 and Wales. I. Infant mortality. Br J Prev Soc Med 1954;8:
1-9.
to being more critical and septical.14
6. Bjerkedal T, Bakketeig LS. Surveillance of congenital
Barker has introduced a series of hypotheses of malformations and other conditions of the newborn. Int J
relationships between perinatal events and later Epidemiol 1975;4:31-6.
health.15 For example, Barker and colleagues have 7. Schlesselman JI. Case-Control Studies. New York: Oxford
University Press, 1982.
examined the association between blood pressure 8. Bakketeig LS, Jacobsen G, Hoffman HJ, et al. Pre-
and measures of size and shape at birth, indicating pregnancy risk factors of small-for-gestational age births
that the ratio of birth weight to placental weight is among parous women in Scandinavia. Acta Obstet
Gynaecol Scand 1993;72:273-9.
an important predictor of subsequent blood
9. Bakketeig LS. Methodological problems and possible
pressure, where men who were light at birth, but endpoints in the evaluation of antenatal care. Int J Technol
with a relatively heavy placenta, had the highest Assess Health Care 1992;8(Suppl. 1);33-9.
blood pressure.16 10. Bakketeig LS. The risk of repeated preterm or low birth
weight delivery. In Reed DM, Stantey FJ, eds. The
Most of these associations will require more Epidemiology of Prematurity. Baltimore-Munich: Urban
sophisticated studies before the issues can be and Schwarzenberg, 1977.
resolved. In the Nordic countries we have some 11. Magnus P, Bakketeig LS, Skjærven R. Correlations of birth
weight and gestational age across generations. Ann Hum
advantages in approaching some of these challenges,
Biol 1993;20:231-8.
particularly since we have relatively homogeneous 12. Kuh D, Davey Smith G. When is mortality risk
populations where the individuals can be traced over determined? Historical insights into a current debate. Soc
time due to our identification number system, which Hist Med 1993;6:101-23.
13. Robinson RJ. Is the child father of the man? (editorial). Br
thus facilitates longitudinal studies with follow-up Med J 1992;304:789-90.
over a long time.17 14. Paneth N, Susser M. Early origin of coronary heart disease
Epidemiology certainly has an extremely (“the Barker hypothesis”) (editorial). Br Med J
1995;310:411-12.
important role to play in perinatal medicine, and
15. Barker DJP, ed. Fetal and Infant Origins of Adult Disease.
genetic and molecular epidemiology are likely to Br Med J 1992.
introduce new and more effective analytical 16. Barker DJP, Bull AR, Osmond C, et al. Fetal and placental
methods, which will provide the basis for improved size and risk of hypertension in adult life. Br Med J
1990;301:259-62.
prevention of adverse outcomes of perinatal events, 17. Bakketeig LS. Perinatal epidemiology - a Nordic challenge.
regardless of when these outcomes occur. Scand J Soc Med 1991;19:145-7.
 28
Structure of Perinatal
Care Systems

G.A. Little

Pregnancy outcomes are clearly dependant upon the THE PROBLEM

availability and effective delivery of reproductive
Throughout the world, disease associated with
care. Advances in knowledge and technology have
reproduction represents a dominant portion of
resulted in improvement in national perinatal
medical need and is a major contributor to mortality
statistics such as survival of low birth weight infants
and long-term morbidity. Even if that portion of
but the degree of improvement is dependant upon
reproductive system pathology not necessarily
the care enviornment. Structure, the systematic
associated with pregnancy, such as infertility and
organization of perinatal care, is a primary determi-
sexually transmitted diseases, is removed, the human
nent of the degree of success in meeting the needs of
and economic cost of pregnancy-related disease
a population
remains very high in both developed and less
Constant improvement of pregnancy outcomes is
a logical objective. The optimal state of health involves fortunate countries.
functioning at full individual potential, without The disparity between developed and developing
disease or abnormality. The ultimate positive regions is especially dramatic in the area of reproduc-
expression of reproductive health would be preg- tive health. Thirty-nine of 50 million yearly deaths
nancies without adverse medical outcomes occurring worldwide (approximately four-fifths) occur in the
as intended events within a healthy emotional and developing countries where maternal, perinatal and
social environment. A zero adverse outcome rate may communicable causes are said to be responsible for
not seem attainable at this time, but there is no reason 40% of deaths as compared to 5% in developed
to believe that there is an irreducible minimum of poor countries. Pregnancy-related conditions are estimated
outcome that cannot eventually be overcome. to be responsible for 18% of the burden of disease in
This chapter discusses organization of perinatal women between 15 and 44 years of age, and in
care in the effort to improve outcomes of pregnancy. children under 5 years of age about 19% of loss of
While each geopolitical entity-population, region or healthy life is said to be due to perinatal complica-
country-must be analyzed and subject to individua- tions.1 Of five essential groups of clinical interventions
lized planning and intervention, there are common for developing countries identified in a world
concepts that apply. development report-prenatal and delivery care,
370 Textbook of Perinatal Medicine

family planning services, management of the sick evident that improvement in infant mortality in some
child, treatment of tuberculosis and case-management countries such as Egypt has exceeded the rate of
of sexually transmitted diseases-three involve improvement in neonatal mortality, suggesting that
perinatal and reproductive health.2,3 advances in perinatal care for the fetus and neonate
Within developed countries there have been may lag behind advances in care for conditions of
remarkable advances in outcomes over recent decades infancy, as programs such as oral rehydration for
but persistent differences between countries. Further- diarrheal diseases make an impact.6
more, expenditure of greater resources per capita and The low-birth-weight rate and birth-weight-specific
availability of proportionately more providers does mortality provide information about the general health
not necessarily result in better outcomes. The United of a population and relative success of intervention,
States despite greater application of resources to especially for the population of prematurely born
neonatal intensive care does not appear to have better babies (< 37 weeks’ gestation). Within the United
birth-weight specific mortality than some other States, for example, the low-birth-weight rate varies
countries.4 by a factor of 3 or 4 times for various subpopulations
and has not responded favorably to interventions,
INDICATORS while birth-weight-specific mortality has improved
Perinatal systems of care have traditionally used vital considerably, probably due to neonatal intensive care
statistics indicators to quantify relative magnitude of and regional programs. The result is a situation where
outcomes. The following are illustrative of indicators individual low-birth-weight babies do relatively well
that are based upon events that are relatively easy to and birth-weight-specific mortality is perhaps the best
define and record such as death, birth weight and in the world, but the number of low-birth-weight
gestational age. babies per thousand births remains higher than in
Maternal mortality, usually defined as death of a many other countries.
woman during or within 42 days of pregnancy of any Fig. 28.1 serves to illustrate the breadth of possible
cause other than accidental or incidental, remains a perinatal outcome indicators. Identified values can be
problem in the industrialized world where deaths used to derive indicators. Traditional outcomes based
approximate 10-20 per 100,000 live births. This on vital statistics address a small portion of the value
indicator is said to document the widest disparity of and outcome spectrum. The clinical value compass
human reproductive outcomes yet reported, with model can be applied to all aspects of a care delivery
some sections of the world, notably Sub-Saharan process including parent perspective of the neonatal
Africa and South Asia, apparently experiencing an intensive care experience.7 Perinatal care systems in
incidence as much as 200 times higher than the safest all stages of development will rely on vital statistics
areas.5 based indicators. Those in complex environments that
Fetal, neonatal or infant mortality serve as valuable are complex and market-driven with a strong interest
indicators by themselves or when included in various in consumer or family-centered care may also employ
rates and ratios. Perinatal mortality, including all a variety of indicators.
newborns, live and stillborn, of 1000 g and greater
and up to 168 hours or 7 days (early neonatal), is used RISK ASSESSMENT, NEED IDENTIFICATION
frequently. Neonatal mortality, deaths up to 28 days, AND RESOURCE ALLOCATION
is part of infant mortality (deaths in the 1st year) and Risk assessment is a key concept in perinatal care
the two, independently or when analyzed together, systems. The process of evaluating the possibility that
give valuable insights into the health of a population a patient has or will have a specific problem is an
and availability of care. For example, it has become integral part of all medical practice including
 Structure of Perinatal Care Systems 371
Functional Health Status
• • Physical
• • Mental
• • Social/Role
• • Risk Status

Clinical Status Satisfaction

• • Mortality • • Care experience
• • Morbidity • • Perceived Health Benefit
• • Complications

Total Costs
• • Direct medical care costs
• • Indirect social costs

Fig. 281: The Clinical Value Compass model has been used to derive the four parental neonatal intensive care outcome groupings.
A wide range of outcome indicators can be developed for each of these groupings. (Derived from Conner JM and Nelson EC,
Reference 7)

perinatal medicine. Needs are identified and quanti- all forms of risk, inadequate preparation or training
fied for both individual patients and populations. of personnel, lack of complete understanding of
Resources can then be allocated to meet identified or determinants of risk including cultural factors, and
anticipated needs. inability to achieve balance between preventive and
Risk assessment has furthered care and improved curative services.9,10
outcomes through identification of populations and
individuals at increased risk for specific conditions. PATIENT CARE AND THE NEED
It also can result in false positives and negatives . FOR STRUCTURE
Furthermore, there is legitimate concern that the
concept of risk has meant to some that pregnancy is The individual perinatal patient has benefited greatly
never normal except retrospectively. These short- from advances in care. For example, if access to
comings must be managed. preventive and acute care is available and timely, all
A method entitled the risk approach has been of the five main causes of maternal mortality -
developed to improve availability and use of existing hemorrhage, unsafe abortions, hypertensive dis-
health-care resources and systems especially in orders, sepsis and obstructed labor - can be managed
resource poor areas. Health problems, including their successfully. Most of the common causes of fetal and
associated risk factors and populations, are identified, neonatal mortality and morbidity, such as peripartum
the status of function of the existing health-delivery asphyxia, prematurity and infections, respond to
system is assessed, interventions to deal with risk and assessment of fetal well-being, obstetric intervention,
performance are put in place, and these are followed neonatal resuscitation and intensive care. Although
by monitoring and evaluation.8 This process has been there are many diagnostic and therapeutic challenges
applied to construct programmatic approaches to that remain such as prevention of permaturity, the
population-based maternal and child health care. simple fact is that most of the world’s perinatal
Shortcomings have been discussed, including pathology can be detected and treated successfully
inability in some situations to recognize or evaluate with available knowledge and structured care.
372 Textbook of Perinatal Medicine

Because it is not possible to meet all needs in all A problem associated with improving pregnancy
places a structured system that allows for efficient use outcomes is the need for both comprehensive
of resources and maximizes outcomes is a logical preventive and acute care for an entire population.
objective. One without the other will not be successful. As the
health-care pyramid suggests, an effective and
THE HEALTH-CARE PYRAMID efficient framework or structure of component
activities is necessary.
The World Health Organization (WHO) has presented
an ideal health-care pyramid with three levels: PERINATAL SYSTEMS
family/community, health center and district
hospital.3 With slight modification, this model can Systems consist of components functioning together
serve as a conceptual framework for the structure of for common goals and objectives. Understanding of
perinatal health care in countries and societies at all the complexity and breadth of activities associated
stages of development. The basic importance of the with perinatal care is essential if systems are to be
family/community sector is emphasized; it is here effective.
that the need for clinical intervention arises and
Perinatal System Activities
moves to health center and hospital when necessary.
The arrow on the right pointing down suggests a Table 28.1 provides an overview of the basic activities
family/community objective for supervision in the associated with systematic efforts to improve
WHO model; the guidance and management terms pregnancy outcomes of a population. Patient care is
were added to this illustration to suggest proactive essential and must be facillitated by administration
clinical and educational interventions that originate and management. If standards of care and outcomes
in health-care institutions. are to be maintained and improved, ongoing data
Table 28.1: Perinatal system activities
Date acquisition,
Patient Care evaluation and research Administration Education
Primary (basic) Vital statistics Clinical services Public
pregnancy planning Pregnancy outcomes System development and Patient
preconception maternal maintenance prevention
prenatal neonatal/infant Institutions preparation
peripartum Technology assessment clinics training and
postpartum Professional/provider hospitals continuing
maternal Medical and social Quality assessment and System (outreach)
infant science improvement
Specialty (consultative, referral) Fiscal
genetics
high-risk obstetrics
(maternal-fetal)
neonatal (medical and surgical)
psychological and social
ancillary services
radiology/imaging
anesthesia
laboratory
Transportation
(interhospital care)
maternal-fetal
neonatal
 Structure of Perinatal Care Systems 373
collection, evaluation and research must take place many countries in Europe and elsewhere. Neonatal
to provide the substrate for quality improvement. intensive care in particular was emerging, as was the
Training and education of personnel must be available concept of interhospital transfer, including care
either from within the system itself or available from instituted prior to and during movement to estab-
a cooperating resource. lished centers. Perinatal providers and their organi-
zations, including the American Academy of
System Development Pediatrics (AAP) and the American College of
Obstetricians and Gynecologists (ACOG), became
Much of the effort of system development in
convinced that a systems or programmatic approach
technically-advanced nations has focused on hospital
to perinatal care could improve outcomes. With the
inpatient services. The hospital is usually the
assistance of a private foundation, The National
community institution where knowledge and
Foundation-March of Dimes, the AAP and ACOG,
technology are concentrated, with individual
joined by the American Medical Association and
members of the community coming to that location.
American Academy of Family Physicians, formed an
In developing and less fortunate environments, a
ad hoc Committee on Perinatal Health.
single regional institution such as a district hospital
Toward Improving the Outcome of Pregnancy:
receives designated governmental support, while in
Recommendations for the Regional Development of
more affluent areas there may be multiple hospital
Maternal and Perinatal Health Services was formally
alternatives that, in fact, may compete.
released in 1976.11 The first sentence states that to
Perinatal systems and their patients originate from
make optimal care available for each person, ‘a
communities and families. The focus on hospitals as
systems approach is essential’.
an identified community resource and site of a many
The publication, now known as TIOP I, while
if not most births leads to a challenge for systems to
directed broadly at maternal and perinatal services,
adaquately address needs in the ambulatory and
focused heavily on the third trimester and neonatal
education sectors. Preconception and prenatal care
period and on the hospital or inpatient sectors
tends to be less well addressed in many systems as
primarily. Central to the recommendations and
inpatient services.
subsequent influence of TIOP I was a three-level
In the ideal situation, need assessment followed
categorization of perinatal services. The level
by resource allocation to guide initial development
framework was promoted to introduce co-operative
of a basic perinatal system for a defined population
interaction and organization into a system having as
is a relatively uncomplicated exercise. As previously
its only objective the improvement of pregnancy
discussed, vital statistics and perinatal indicators can
outcome.11,12
help to quantify the magnitude of the need and
By the mid-1980s, perinatal regionalization,
support solutions that direct resources towards
including the level concept of organization, had been
systems and comprehensive program activities. The
implemented throughout the United States with most
reality of perinatal systems development is complex,
authorities agreeing that it had been responsible for
with each situation involving different medical,
improvement in outcomes.13 The degree of govern-
economic, social and political determinants.
mental involvement in the form of leadership and
regulation varied widely across the 50 states. The
Perinatal Regionalization in the United States:
three-level categorization was broadly accepted,
Evolution of a Systems Approach
although some argued for a four-level system with a
During the 1960s and early 1970s, significant advances few perinatal centers, usually academic, to provide
in perinatal care, especially in hospital-based services, the most technologically demanding care as another
were occurring in the United States, Canada and level. Others argued for a two-level system involving
374 Textbook of Perinatal Medicine

primary, routine or specialty care and a referral level factors must be addressed. TIOP II is also not a laissez-
for subspecialty care. Some felt that the level system faire document; it recommends that community
inappropriately centralized care, although the TIOP resources as well as professionals should play a role
documents clearly state that that is not intended. in a system that includes a forum, usually government
Recently the American Academy of Pediatrics led, for addressing accountability, access and
released, after considerable collection of practice data progress.16
and debate, a new categorization of levels of newborn Thus, in the United States, the need for structure
care that maintained a basic three level framework in delivery of perinatal care that includes risk
with subcategorization based upon functional identification, patient referral and possible transport
capabilities.14 The rationale utalized, while applied to a site of available service, and categorization of
to neonatal care, is seemingly also applicable to levels of care has been debated and largely accepted.
obstetric units. As perinatal services in hospitals and Agreement on specifics of system implementation and
within systems are interrelated, assigning level of management is not as universal. In some states,
perinatal service is an important aspect of structure. structure has evolved informally, while in others,
By the late 1980s, a great deal of concern was being considerable structure has been mandated. The care-
expressed by US professionals and health planners related activities presented in Table 28.1 are largely
that so-called ‘deregionalization’ was occurring and in place, while some, such as continuous quality
that outcomes might be worsening or at best the rate improvement involving an entire geopolitical unit
of improvement was inadequate. Some argued that such as a state, are not. The current movement
the levels categorization had outlived its usefulness. towards managed care and competition on one hand
It is important to place this concern into a context of supports the development of systems of care that are
a nationwide deliberation about the entire system of internally structured and largely self-contained, while
care and health-care reform. A movement to review on the other hand urging freedom to compete and
and revise TIOP I emerged. limited external structure and review. In many areas,
TIOP II, Toward Improving the Outcome of Pregnancy, there are regionalized perinatal networks that
The 90s and Beyond was released in 1993 by a function in parallel, with limited interaction including
reconstituted and expanded Committee on Perinatal assessment.
Health.15 Included is a review of past development In this millineum the US perinatal system
of US prenatal services, consideration of indicators continues to evolve while there is ongoing question-
of outcome, and recommendations for improvement ing of resource allocation. The dominence of hospital
that are broad and strongly state that successful based services including obstetric high-risk and
interventions such as intensive obstetrical and neonatal intensive care is being debated from the
neonatal hospital-based interventions must be perspective of whether it improves outcomes. 17
maintained, while a newly engerzied focus on Availability of neonatal intensive care capacity is
ambulatory care, especially in the preconception, thought be be responsible for a significant portion of
prenatal and postpartum intervals, should be improvement in outcomes such as low birth weight
instituted. The level categorization is supported but survival with obstetric care contributing a smaller but
with a recommendation that review and revision on definite portion.18 There is research that supports a
a local or state basis should be undertaken as part of concern that neonatal intensive care capacity may be
an emphasis on the need for regional systems to be excessive and not able to contribute further to
community focused. Also stressed are health aware- improved pregancy outcomes.19
ness and promotion, universal access to care, and a A cross-national study of reproductive care
recognition that social and fiscal, as well as medical, involving the US, Australia, Canada and the United
 Structure of Perinatal Care Systems 375
Kingdom determined that the US has more neonatal measures of acuity21,22 and the growing worldwide
intensive care capacity with 6.1 neonatologists per presence of collaborative networks such as the
10,000 live births compared with 3.7, 3.3 and 2.7 for Vermont-Oxford Neonatal Network23 with its inter-
the others respectively. Neonatal bed capacity was national cumulative database of 400-1500-g-birth-
also greater in the US. Birth-weight specific mortality weight babies from over 400 units provide oppor-
outcomes were not the best in the US where proportio- tunity for evidence based collaborative research.24
nately less resources are allocated to such efforts as These tools need to be supported, developed further
preconception, prenatal and other maternal and child and used by perinatal systems.
health services.4 This study questions the effectiveness
of current distribution of reproductive care resources, Quality Improvement
as did TIOP II,15 and should serve as resource for other The concept of continuous quality improvement
perinatal systems in development and evolution. employed with success in business and in health care
is not foreign to perinatal care. In fact, an emphasis
PRESENT AND FUTURE CHALLENGES on measurement and improvement of outcomes has
always been a fundamental part of perinatal care, as
Access to Clinical Care
evidenced by the Apgar Score and neonatal follow-
Implementation and improvement of perinatal up efforts. Perinatal systems can benefit from
systems remains challenging across the spectrum of advances in quality management being championed
economic development and political structure. In the in other sectors, including competitive business. Data
less developed situations, certain key system acquisition and analysis is essential in this effort and
components, such as the first referral level for the productive linkage of data with quality improve-
emergency obstetric care and the ability to perform ment is a systems function.25
operative interventions like Cesarean sections, are yet
to be made universally available. In others access may Expectations and Accountability
be less than optimal due to organizational or
Perinatal systems, their institutions and personnel are
economic factors. System structure may have to be
formally and informally considered to be accountable
modified or individualized to meet priortized acute
for their actions and outcomes. Accountability is well-
care needs. In situations where care is readily available
defined in some areas such as procedures on patients
and perhaps even oversubscribed, such as neonatal
in hospitals and less evident in other concerns such
care, there are challenges related to relative priority
as who is responsible for patients who receive
of technologies and services. Dissemination of
inadaquate prenatal care. Problems such as maternal
evidence-based innovations has been pointed to as a
mortality in developing countries and infant mortality
challenge in all industries including health care.20
in subpopulations of some advanced countries may
become part of a political process that asks for
Data Acquisition and Analysis
identification of responsible party and improvement.
The ability now is available to perinatal system In such situations the media my become involved by
management to use existing computer technology to publicizing issues and asking for accountability and
provide data about events and outcomes in a practical change.
and real-time fashion. Individual providers, centers Families and communities in this era of patient or
or hospitals and systems can record data economi- consumer involement in health care have expectations
cally, and through analysis derive information to effect . They can profoundly influence care. For example,
improvement and change. Efforts such as the Oxford perinatal parents have successfully advocated for
Database for Perinatal Trials, the emergence of change leading to presense of fathers at operative
376 Textbook of Perinatal Medicine

delivery and increased involvement in decision- 11. Committee on Perinatal Health. Toward Improving the
Outcome of Pregnancy (TIOP #1): Recommendations for
making in the neonatal intensive care unit.26
the Regional Development of Maternal and Perinatal
A basic principle of public health is to involve the Health Services. White Plains, NY: National Foundation-
entire population in analysis and efforts for improve- March of Dimes, 1976.
ment. Many perinatal systems across the economic 12. Frigoletto FD, Little GA, eds. Guidelines for Perinatal
Care, 2nd edn. Elk Grove, Washington: American
and political spectrum of countries study portions of
Academy of Pediatrics, American College of Obstetrians
the total population. Accountability or responsibility and Gynecologists, 1988.
for less than the total cohort is inadequate. If more 13. Phibbs CS, Bronstein JM, Boxton E, et al. The effects of
than one perinatal network, program, or system exists patient volume and level of care at the hospital of birth on
neonatal mortality. J Am Med Assoc 1996;276:1054-59.
within a population, then responsibility must rest
14. American Academy of Pediatrics, Committee on Fetus and
somewhere, often with the government, for total Newborn, Policy Statement, Levels of Neonatal Care,
cohort accountability. Pediatrics, 2004, 114, 5, 1341-47.
15. Committee on Perinatal Health. Toward Improving the
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in the Health Sector: Disease Burden, Health Expenditures
16. Little GA, Merenstein GB. Toward improving the outcome
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Organization, 1994.
(commentary). Pediatrics 1993;92(4):611-12.
2. The World Bank. World Development Report 1993:
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Much of a Good Thing, New Eng J of Med, 2002, 346, 1574-
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3. World Health Organization. Care of Mother and Baby at
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Working Group, WH0/FHE/MSM/94.2. Geneva: World
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Intensive Care Always Better? Insights From a Cross- Between the Availability of Neonatal Intensive Care and
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2002; 109: (6): 1036-1043. 15442.
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Neonatal Care Program: a practical strategy to improve index for babies) score: a tool for assessing initial neonatal
neonatal outcomes. Int Child Health 1996;VII:31-8. risk and comparing information of neonatal intensive care
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Satisfaction Measured From a Parent’s Perspective, 22. Richardson DK, Gray JE, McCormick MC, et al. Score for
Pediatrics, 1999, 103, 1, 336-349 (supplement) Conner JM neonatal acute physiology: a physiology severity index for
and Nelson EC, Neonatal Intensive Care: Satisfaction neonatal intensive care. Pediatrics 1993;91(3):617-23.
Measured From a Parent’s Perspective, Pediatrics, 1999, 23. Horbar JD. The Vermont Oxford Neonatal Network:
103, 1, 336-349 (supplement). integrating research and clinical practice to improve the
8. World Health Organization. The Risk Approach in quality of medical care. Semin Perinatol 1995;19:124-31.
Maternal and Child Health. (WHO Offset Publication No. 24. Lucey JF, Rowan CA, Shiono P, et al. Fetal Infants: The Fate
39). Geneva: World Health Organization, 1978. of 4172 Infants with Birth Weights of 401-500 Grams – The
9. McCarthy BJ, Kowal D. The risk approach in maternal and Vermont-Oxford Network Experience (1996-2000)
child health. In Wallace HM, Giri K, Serrano CV, eds. Health Pediatrics, 2004, 113, 6, 1559-1566.
Care of Women and Children in Developing Countries, 2nd 25. Horbar JD, Rogowski JD, Plsek P, et al. Collaborative
edn. Oakland: Third World Publishing, 1995. Quality Improvement in Neonatal Intensive Care.
10. Backett EM, Davies AM, Petros-Barvazian A. The Risk Pediatrics 2001; 107: (1), 14-22.
Approach in Health Care, Public Health Papers, No 76. 26. Harrison H. The Principles for Family-centered neonatal
Geneva: World Health Organization, 1983. care. Pediatrics, 92, 5, 643-650.
 29
Perinatal Quality Indicators
and Perinatal Audit

Gunilla Lindmark, Jens Langhoff-Roos

INTRODUCTION themselves as subjects and part of the process and

not as objects of scrutiny or criticism.
Health care services should be evaluated not only in
To define quality as the extent to which the care is
quantitative terms, which is still often the case, but
meeting the expectations and needs of the patient is
also with respect to the quality. The qualitative
attractive, and implies that also other outcomes than
dimensions of health care are fundamental for its
the strict medical ones must be considered. However,
impact on health. Clients, not least in maternal health
the expectations on the health care do not come only
care, increasingly demand to be considered as
from the patient but also from society and from the
individuals and not only as objectives of the health
agencies that cover the cost of the care. Therefore, not
care activities. Resources are restricted even in the
only individual but also public health outcomes must
most affluent parts of the world and do not allow
be considered, and the effective use of available
unlimited use of health care interventions. Critical
resources will therefore be a quality aspect of great
scrutiny and assessment of the quality of health care
interest. When comparisons of quality of perinatal
is therefore mandatory.1
care are performed, it is common to relate only to
In maternal and perinatal health care, survival of
indicators of outcome or process and not mention
mother and baby without short or long term
indicators of structural input. Also, single process or
morbidity are the first and fundamental needs.
outcome indicators – like rates of Caesarean section
However, in childbearing there are other needs related
and perinatal mortality – have been used to measure
to social, cultural and existential dimensions, which
quality without considering the relation with other
also have to be considered in the care of mothers and
important aspects of care.
infants. One obvious reason to acknowledge these
It will be increasingly important to define quality
dimensions is their importance for acceptance of and
also as cost-effectiveness, in any case if the ambition
compliance with care.
is to offer universal high-quality care to all mothers
To maintain and improve quality in health care, it
and newborns
is necessary to clearly define goals and objectives
related to patient’s needs, and assess available
INDICATORS OF QUALITY
resources.2 For such a process to be possible, good
communication and collaboration must be present. It A weighted sum of all essential indicators, including
is also essential that health workers at all levels feel fetal and maternal, short term and long term
378 Textbook of Perinatal Medicine

outcomes, as well as maternal satisfaction and the These quality indicators are useful for constructive
impact on future pregnancies and deliveries, would discussions about the content and quality of perinatal
be the ideal measure of quality. This will imply that health care. The variations in outcome are not related
an unrealistic high amount of resources are spent to to physical resources in a simplified way, but must
collect quantitative as well as qualitative data - at least be discussed in the wider context of attitudes,
in the same population. The most important source practices and training of health staff at all levels.
for quality improvement activities is the routinely Assessment of results of care should not be limited to
collected indicators at the local and regional level. intermediate variables such as results of tests or
However, we still need to supplement with results examinations, but focus on essential patient-related
from other and larger regions. Published descriptive- indicators. In perinatal care, it is common that a
analytical clinical research will also in the future screening procedure or an intervention during
constitute one of the backbones of regional quality pregnancy is validated by parameters that are
assessment activities. indirectly related to actual health outcome of mother
Decisions on the best indicators must consider not or infant or even to the result of another test or
only the relevance for assessment of the objectives of examination. Variables that are indirectly related to
the care, but also their feasibility. For an indicator to health outcome, such as low birth weight and preterm
be useful it must be constructed from data that are birth and to some extent low Apgar score, may be
possible to collect within the available resources, and useful, however, if there is a direct relationship with
both these variables and the indicator itself must be short- and long-term morbidity.
clearly defined. The usefulness of quality indicators
for comparisons over time or between regions is DATA COLLECTION
depending on agreement on these definitions and Since quality assessment includes both the general
continuous data collection by all the participating level of care in all cases as well as serious adverse
health facilities. events, variables and indicators must include both
Quality assessment of the structure of care includes information about all mothers and newborns and
organisation, resources, qualifications of staff, and special information in selected cases of special interest.
availability of structured and adequate programs of The data collection system must therefore include
care. The process or utilisation of resources in the both routine registration of basic information and
provision of health care can be assessed so that each more detailed information on complicated events -
activity for screening, prevention, diagnosis or usually to be retrieved from the medical record.
therapy is correctly applied and used for the intended Existing routinely collected data, for example from
or appropriate purpose. Assessment of process quality medical birth registers should be used whenever
should ascertain that the care is carried out according possible, in order to limit resources needed.3 Studies
to evidence-based guidelines or recommendations. show that the quality of routine data in maternity
In perinatal care the result of the health-care services can be adequate for quality control.4
process in terms of mortality and morbidity traditio- In some countries, routine data may be retrieved
nally has been discussed most often. Nowadays, from clinical information systems in hospitals or
patient satisfaction and provision of relevant and primary care, or civil registers of births and deaths.
reliable information are products of care generally In the Scandinavian countries, national medical birth
appreciated as important not just in cases with registers provide important information. In some
perinatal complications but also in the majority of countries, routine surveys of reproductive health
cases in which everything is normal from a strictly outcomes are performed at regular intervals and data
medical perspective. from routine child health care may be used for quality
 Perinatal Quality Indicators and Perinatal Audit 379
assessment purposes. However, register data and The validity of the data registration must therefore
standard data collected without a specific purpose or be given attention before the data registration begins
unrelated to specific quality improvement activities as well as regularly over time. Also it is important
may be of questionable validity. Registers may also that definitions and indications are not changed too
be unreliable regarding causes of death, diagnoses of often. A change should not be considered unless a
complications or autopsy data. Terms such as hypoxia, significant improvement is foreseen to follow,
placental dysfunction or pre-eclampsia are frequently considering both the initial rather poor validity of
used without clear and uniform definitions of the data during the first phase and the loss of longitudinal
variables. aspects of data collection.
For comparisons - not only of trends over time in In order to secure valid registration of indicators
one specific region, but also, between regions or using it is important that health personnel is provided with
the data compiled for international comparisons - it regular and immediate feedback based on registered
is essential that all variables are defined according to data and that regular proper validation based on
international standards. internal registry analyses and external studies based
Definitions of basic concepts such as perinatal on case notes are performed.
mortality, gestational age, and diagnoses describing Validation of reported indicators depend on
maternal and infant condition must be uniform. It is whether the data are aggregated, anonymous case-
particularly important that all extremely preterm based, or case-based linked to a personal ID. At an
deliveries and infants with the lowest birth weight aggregated level validation may be achieved by logic
are included, because of their high risk of mortality checks for outliers, at a case-based anonymous level
and morbidity. by logic checks for relations between indicators (such
The patient record is an important quality as compatibility – caesarean section vs. sphincter
instrument if it is standardized and contains specified rupture), whereas at a case-based level where case
and well defined data. It is nowadays often in a notes are traceable a proper external validation may
computer format and can be used directly to produce be carried out.
data for special purposes. However, there must be
specified definitions for registration to make a Sets of Indicators for Quality Assessment
variable useful for quality assessment. All data that Many quality assurance projects have used process
are the result of a subjective interpretation are also indicators in the health care, often recorded as
less reliable than absolute values of test results. proportions of cases subject to various interventions.
Specific surveys and interviews, as well as Several national and international agencies and
observations of the process of care, are valuable scientific societies have developed lists of essential
instruments for assessment of quality, but cannot quality indicators for maternal and perinatal care.5 An
usually be routinely used since they are more resource example of a set of clinical quality indicators for
demanding and also require training and skills of the monitoring results have been developed by the
data collectors. Thus, these methods will be limited American College of Obstetrics and Gynaecology2
to specific, short-period projects. (Table 29.1). Other sets reflect a more public health
oriented perspective. Usually they are a mix of imput
Validity of Data
from clinicians (obstetricians or midwives) and public
The most common problem in the initial discussions health professionals. Clinicians usually focus more on
about choice of indicators is that people under- indicators of specific areas to be improved by clinical
estimate the difficulties to perform continuous data interventions (process-outcome indicators), indicators
collection in routine care over long periods of time. such as caesarean section, sphincter rupture, and
380 Textbook of Perinatal Medicine

Table 29.1: Obstetric clinical indicators developed by the American College of Obstetricians and Gynecologists
Maternal indicators
• Maternal mortality
• Unplanned readmission within 14 days
• Cardiopulmonary arrest
• In-hospital initiation of antibiotics 24 hours or more after term vaginal delivery
• Unplanned removal, injury, or repair of organ during operative procedure
• In-hospital maternal red blood cell transfusion or haematocrit < 22 vol% or haemoglobin of <7.0 g or decrease in haematocrit
of 11 vol% or haemoglobin of 3.5 g or more.
• Maternal length-of-stay more than 5 days after vaginal delivery or more than 7 days after cesarean delivery.
• Eclampsia
• Delivery unattended by the “responsible” physician*
• Postpartum return to delivery room or operating room for management
• Induction of labour for an indication other than diabetes, premature rupture of membranes, pregnancy-induced hypertension,
post term gestation, intrauterine growth retardation, cardiac disease, isoimmunization, fetal demise, or chorioamnionitis.
• Cesarean delivery required:
• Primary cesarean delivery for fetal distress.
• Primary cesarean delivery for failure to progress
• Delivery of an infant with a birth weight <2,500 g or respiratory distress syndrome following induction of labour
• Delivery of an infant with a birth weight < 2,500 g or respiratory distress syndrome following induction of labour
Neonatal indicators
• Perinatal mortality of a fetus or infant surviving less than 28 days and weighing 500 g or more at delivery
• Intrapartum death, in hospital, of a fetus or infant weighing 500 g or more.
• Neonatal mortality of an inborn infant with a birth weight of 750-999 g in an institution with a neonatal intensive care unit**
• Delivery of an infant weighing <1,800 g in an institution without a neonatal intensive care unit.
• Transfer of an neonate to a neonatal intensive care unit inanother institution.
• Term infant admitted to a neonatal intensive care unit.
• Apgar score of 4 or less at 5 minutes.
• Birth trauma (#767 in ICD-9 directory), such as shoulderdystocia, cephalohaematoma, Erb palsy, and clavicular fracture but
not caput.
• Diagnosis of fetal “massive aspiration syndrome (#770.1 in ICD-9-CM”)
• Inborn term infant with clinically apparent seizuresrecorded before discharge.
* To be defined by each institution
** An inborn infant is one born in this hospital rather than transferred from another institution.

asphyxia at delivery. Public health professionals focus of perinatal health for health professionals, policy
more on areas that are public health issues (structure- makers, researchers and health service users who wish
outcome indicators) such as maternal age, marital to monitor and evaluate perinatal health. The aim of
status, congenital malformations, length of hospital this project, which included 13 countries, was to
stay for childbirth etc. facilitate monitoring and comparison by harmonising
By comparison these sets of indicators are quite indicator definitions and encouraging the collection
heterogeneous and show a considerable amount of of comparable data based on the following priorities:
diversity, reflecting differences in interest, but also • Assess maternal and infant mortality and mor-
characterized by a number of common indicators that bidity associated with events in the perinatal
were found to be essential such as maternal, perinatal period.
and infant death. • Describe the evolution of risk factors for perinatal
A recent European collaborative effort, PERISTAT, health outcomes in the population of childbearing
– a part of the European Commission’s Health women, including demographic, socio-economic
Monitoring Programme – has developed indicators and behavioural characteristics.
 Perinatal Quality Indicators and Perinatal Audit 381
• Monitor the use and consequences of medical Analyses also depend on the level at which data
technology in the care of women and infants are reported. Aggregated data merely provide a basis
during pregnancy, delivery and the postpartum for frequencies and predefined tables, whereas case-
period. based data allow ad hoc analyses involving all
In 2003 a list of recommended indicators (Table variables or indicators recorded. When cases have an
29.2) was published on the Internet together with the ID-number with a link to the newborns personal ID,
figures for year 2000 from most of the participating longitudinal follow-up of maternal and infant
countries.6 morbidity and mortality, and even intergenerational
studies are possible.
ANALYSIS OF INDICATORS When data are reported at a case-based level
Differences in quality indicators are usually inter- regional differences may be adjusted by multivariate
preted as mainly related to the care itself, but it is analyses. This is often used in epidemiological
important to consider also differences in the popula- analyses for a scientific purpose. Multivariate analyses
tion. Even when comparing area-based populations, have the advantages that adjustment may be made
differences in maternal characteristics such as parity, in a model that considers several variables/risk
multiple pregnancy, preterm birth rate etc. influence factors and ends up in a single Odds ratio with
the rates of interventions and outcome. Differences confidence intervals. The disadvantages are that the
in social and economic conditions may be important analysis only considers very simple mathematical
for outcomes, but are difficult to assess in reliable way. relations, that the procedure is not easy to explain,

Table 29.2: PERISTAT 6 working list of indicators

Category Core Recommended Future development
Neonatal health Fetal mortality rate Prevalence of congenital Causes of perinatal death
Neonatal mortality rate anomalies Prevalence of cerebral palsy
Infant mortality rate Distribution of APGAR Prevalence of hypoxic-
Distribution of birth weight score at 5 minutes ischemic encephalopathy
Distribution of gestational age
Maternal health Maternal mortality ratio Maternal mortality by Prevalence of faecal
cause of death incontinence
Severe maternal morbidity
Prevalence of trauma to
the perineum

Population Multiple birth rate by Percent of women who Distribution of mothers’

characteristics or number of foetuses smoke during pregnancy country of origin
risk factors Distribution of maternal age Distribution of mothers’
Distribution of parity education
Heath care services Distribution of births by Percent of all pregnancies Indicator of support
mode of delivery following fertility treatment to women
Distribution of timing of Indicator of maternal
1st prenatal visit satisfaction
Distribution of births by
mode of onset of labour
Distribution of place of birth
Percent of infants breast-
feeding at birth
Percent of very preterm
births delivered in units
without a NICU
382 Textbook of Perinatal Medicine

and that the analysis often is perceived as something group. With this method it could be demonstrated
happening in a black box. that neonatal morbidity was increased in centres
where the Caesarean section rates were either higher
STANDARD POPULATIONS or lower than average.
OR RISK STRATIFICATION
AUDIT OF PERINATAL DEATHS
Another way to adjust for differences in maternal
characteristics is to apply “standard populations”. Perinatal audit can be performed at different levels:
One of the first standard populations used in perinatal local, regional and national. The levels are of
quality assessment is the “standard primipara”.7 The importance when discussing the methodology and
standard primipara is a 20-35 year old parturient outcome of an audit.
without pregnancy complications, admitted in Audit at local level is often performed on materials
spontaneous labour at term with vertex presentation. that cannot be compared in a quantitative way
This “standard primipara” is only one of several because of the small sample sizes. However, they are
possible standard populations that adjust for clinically very useful for improvement in structure and process.
relevant preconditions, and – not least – reflect a risk Depending on whether the audit is performed by a
of interventions and complications that occur in a selected group (leaders) or by all involved in the care
specific group of mothers. Thus, the results from these (all midwives, all obstetricians, a keen pathologist, all
analyses are relevant for that specific group of women neonatologists), the audit process will be perceived
when informed to choose mode of delivery. as a superior control or as constructive discussion how
It is possible to construct a structure of mutually to improve within the team. It is very important that
exclusive standard populations that constitute the audit meetings of the latter type are supervised in a
whole population.8 In this way the variables primi/ permissive way to underline the fact that by
multiparity, preterm/term, vertex/breech-transverse, discussing our mishaps openly we share with each
singleton/multiple pregnancy, and elective delivery other experience that probably will reduce the risk of
(induction of labour/caesarean section) have been repetition. This can also reduce the guilt that many
used to define standard populations. carry subsequent to a more or less preventable
National birth statistics stratified by place of birth adverse outcome.
and standard population may be useful for clients For practical reasons audit at a regional level will
choosing place of birth and midwives and obstetri- not take place very close to the obstetrical or neonatal
cians as a basis for discussions on quality improve- department where the event took place. Regional
ment issues.9 audits, however, can work as a forum for discussion
To compare regional differences of Caesarean of guidelines and attitudes. Also, since the distance
section rates in a population with an average rate of from the auditors to the local department where
23%, a specific low risk standard population was implementation should take place is not very far, often
defined and used for comparison.10 The low risk at least one participant in the activity will represent
standard population, which constituted 49% of the the local department or hospital. Quantitative
population, consisted of women of all parities without analyses of common events will sometimes be
previous caesarean section, spontaneous labour at possible at a regional level, and comparisons between
term, vertex presentation and without specific regions are often valuable for initiating quality
pregnancy complications or fetal malformations. The improvement activities. The results of qualitative
average rate in this standard population was 5.8%. activities, such as auditing in different regions,
Places of birth were categorised by a higher, lower or however, may be difficult to compare unless audit
average rate of Caesarean section in the low risk procedures are identical and the auditors are well
 Perinatal Quality Indicators and Perinatal Audit 383
matched. In addition, historical comparisons in the Perinatal Death Classification11 (Table 29.3). Perinatal
same region imply that criteria are explicit and deaths with fetal malformations were placed in a
identical and that auditors do not change their sense separate category, and subsequently the rest were
of judgment over time. categorized by time of death (before, during or after
At a national level epidemiological analyses of delivery), gestational age, Apgar score, plurality and
clinical indicators and well defined categories can be birth weight (considering intrauterine growth
used for surveillance and provision of subgroups for restriction, IUGR) in mutually exclusive groups.
audit, in order to identify health care structures or This classification can be applied both to medical
processes that should be changed to improve perinatal records data and, because of the simple structure, to
health care on a national level. register data.
The premise for a valuable international audit is
that indicators and categories are similarly defined. Qualitative Audit
The major advantage of the higher level is the larger It is possible to continue the analysis of cases in
sample sizes that in many cases reach a magnitude subgroups in a qualitative way. Applying the Nordic-
suitable for statistical analyses with confidence Baltic perinatal death classification, a panel from
intervals that allow differences to be detected and Denmark and Sweden found that there were signi-
addressed. ficantly more intra partum deaths of non-malformed
infants in Denmark than in Sweden. By subsequent
Classification of Perinatal Deaths
qualitative audit on case notes blinded by nationality,
One of the main objects of perinatal care is to avoid a panel of Nordic obstetricians concluded that there
serious adverse outcomes. Most perinatal audit was more insufficient care and a higher rate of
activities have focused on perinatal deaths, which is potentially avoidable deaths among the Danish cases.
the most important fetal adverse outcome to be It was proposed that a cardiotocographic (CTG)
avoided. However, perinatal deaths are hetero- recording should be done on admission, and that
geneous, and chains of events and causes of death
Table 29.3: The Nordic-Baltic Perinatal
differ widely. Clearly, some deaths are potentially
Death Classification (ref)
more avoidable than others. A perinatal death
Thirteen mutually exclusive groups
classification, which stratifies the perinatal deaths in
appropriate groups aiming for quality improvement, I Fetal malformation
II Antenatal death. Single growth restricted fetus >=28
including qualitative analyses by audit, and compari-
weeks of gestation.
son between regions may be helpful as a basic tool. It III Antenatal death. Single fetus >=28 weeks of gestation.
should rely on simple, routinely recorded variables IV Antenatal death. Before 28 weeks of gestation.
for allocation into mutually exclusive groups, which V Antenatal death. Multiple pregnancy.
VI Intrapartum death. After admission. >=28 weeks of
should be associated with specific areas for health care gestation.
interventions. VII Intrapartum death. After admission. Before 28 weeks
In an investigation that analyzed the differences of gestation.
in perinatal mortality rate between Denmark and VIII Neonatal death. 28-33 weeks of gestation. Apgar score
>6 after 5 min.
Sweden, a new perinatal death classification was IX Neonatal death. 28-33 weeks of gestation. Apgar score
proposed in order to categorize the perinatal deaths <7 after 5 min.
in relevant groups for further qualitative audit. This X Neonatal death. >33 weeks of gestation. Apgar score
>6 after 5 min.
classification was discussed and evaluated at a Nordic
XI Neonatal death. >33 weeks of gestation. Apgar score
Baltic collaborative workshop with obstetricians, <7 after 5 min.
pediatricians and perinatal epidemiologists. The final XII Neonatal death. Before 28 weeks of gestation.
classification system was named the Nordic-Baltic XIII Unclassified.
384 Textbook of Perinatal Medicine

more swift intervention during delivery should be working even if there is a structure proposed. The
implemented in Denmark.12 most common situation is that the regional centre with
its better resources is overloaded with fairly normal
Register-based Sub Analysis deliveries whereas the complicated cases may not
When comparing Lithuania with the Nordic even reach the first level of care. The denominator for
countries, the higher perinatal mortality in Lithuania any area-based assessment of outcome is therefore
was mainly explained by a doubled rate of malformed very uncertain and also the process-related indicators
infants, a threefold increase in intra partum, and two- will reflect only what happens to a minor part of the
to-fivefold increase in neonatal deaths of non- obstetric population. Still, there is an agreement that
malformed infants.13 Since qualitative audit by case especially in settings with limited resources and large
notes was not feasible a register based sub analysis health problems, quality assessment of care is even
of the type of malformation was performed. The more important than in affluent regions. It is essential
higher rate of malformed perinatal deaths was that quality assessment activities in low-income
explained by a four times higher mortality from countries are focused and their results implemented
neural tube defects. to improve quality of care.
The baseline registration of data in low-income
Perinatal Deaths in Europe countries is usually limited to a delivery book in
which all mothers who are coming for delivery are
In the Euronatal Study, a research project contracted
noted. This registration is done on admission, and the
by the European Union for the period 1996 – 2000,
information about complications and interventions
factors related to differences in populations and
that occur later is usually not complete. Usually, the
health care were studied to explain the differences
outcome of the baby is not registered beyond a
in perinatal death rates. To determine whether sub
notation of stillbirth. In uncomplicated cases the
optimal factors were present in the cases of perinatal
neonatal observation time is very short and can be a
deaths, a regional case-based audit was performed
few hours. If the newborn baby needs special care, it
in 10 European regions.14 Using the Nordic-Baltic
is separated form the mother and the information is
perinatal death classification. The groups in which
not available in her file.
care and treatment were most likely to have a
Therefore, routine registration needs to be
significant impact on the outcome were audited:
improved at several levels before it is valid for
singleton fetal deaths and intrapartum deaths of
regional quality assessment activities. Until then local
28 weeks of gestation or more, and neonatal
and focused quality improvement activities are
deaths in children born after 34 weeks of gestation
needed to motivate staff for relevant routine regist-
or more.
rations.
Suboptimal factors were mostly identified in the
Perinatal audit is such an activity, which is suitable
antenatal care period, often related to professional
for all levels irrespective of the standard of care and
care delivery, with failure to detect severe intrauterine
has been found to increase motivation in staff and
growth retardation as the most prominent factor.
quality of care. The introduction of this process,
Maternal smoking was also a significant suboptimal
however, needs good leadership and careful intro-
factor among potentially avoidable deaths.
duction to overcome initial suspicion and cultural
barriers.
Perinatal Quality Assessment and
Audit in Low-income Countries
REFERENCES
In low-income countries, regions are not always 1. Meeker CI. Quality improvement: then and now. Clinical
clearly defined and referral systems are often not Obstetrics and Gynecology, 1994; 37: 115-121.
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2. Loegering L, Reiter RC, Gambone JC. Measuring the quality 10. Gould JB, Danielsen B, Korst LM, Phibbs R, Chance K, Main
of health care. Clinical Obstetrics and Gynecology, 1994; E, Wirtschafter DD, Stevenson DK and the California
37: 122-136. Perinatal Quality Care Collaborative. Cesarean Delivery
3. Hall M. Audit of antenatal care. Fetal Maternal Med Rev Rates and Neonatal Morbidity in a Low-Risk Population.
1993; 5:19-27. Obstet Gynecol 2004; 104: 11-19.
4. Cleary R, Beard RW, Coles J, Devlin HB, Hopkins A, Roberts 11. Langhoff-Roos J, Borch-Christensen H, Larsen S, Lindberg
S, Schumacher D, Wickings HI. The quality of routinely B, Wennergren M. Potentially avoidable perinatal deaths
collected maternity data. Br J Obstet Gynaecol. 1994; 101: in Denmark and Sweden 1991. Acta Obstet Gynecol Scand
1042-7. 1996; 75: 820-5.
5. Zeitlin J, Wildman K, Breart G, Alexander S, Barros H, 12. Westergaard HB, Langhoff-Roos J, Larsen S, Borch-
Blondel B, Buitendijk S, Gissler M, Macfarlane. Selecting Christensen H, Lindmark G. Intrapartum death of
nonmalformed fetuses in Denmark and Sweden in 1991. A
an indicator set for monitoring and evaluating perinatal
perinatal audit. Acta Obstet Gynecol Scand 1997; 76: 959-
health in Europe: criteria, methods and results from the
63.
PERISTAT project. Eur J Obstet Gynecol Reprod Biol. 2003
13. Langhoff-Roos J, Larsen S, Basys V, Lindmark G,
Nov 28;111 Suppl 1:S5-S14.
Badokynote M. Potentially avoidable perinatal deaths in
6. PERISTAT Monitoring and evaluating perinatal health in
Denmark, Sweden and Lithuania as classified by the
Europe. http://europeristat.aphp.fr. Nordic-Baltic classification. Br J Obstet Gynaecol 1998; 105:
7. Cleary R, Beard RW, Chapple J, Coles J, Griffin M, Joffe M, 1189-94.
Welch A. The standard primipara as a basis for inter-unit 14. Richardus JH, Graafmans WC, Verloove-Vanhorick SP,
comparisons of maternity care. Br J Obstet Gynaecol. 1996; Mackenbach JP, The EuroNatal Audit Panel, The EuroNatal
103: 223-9. Working Group. Differences in perinatal mortality and
8. Robson MS. Can we reduce the caesarean section rate? Best suboptimal care between 10 European regions: results of
Pract Res Clin Obstet Gynaecol 2001; 15: 179-94. an international audit. Brit J Obstet Gynecol 2003;110:97-
9. Danish Medical Birth Statistics http://www.dsog.dk. 105.
 30
Audit in Perinatal Medicine

JM Thomas MRCOG, S Paranjothy

DEFINITION Measure of Structure or Service Provision

Research is concerned with discovering the right thing Audit can provide an overview of service provision.
to do, audit is concerned with ensuring that the right For example, research evidence shows that the
thing is done.1 Clinical audit aims to improve patient outcome for patients with ovarian cancer is better if
care and outcome by reviewing the care provided to they are operated on by an appropriately trained
patients against explicit quality criteria and imple- gynaecologist and managed within the framework of
mentating change to improve the quality of care as a a multidisciplinary team.3–9 An audit of the referral
result. The structure, processes and outcomes of care and management of patients with ovarian cancer can
can be selected and systematically evaluated against provide an overview of service provision in this area.
explicit criteria. Where indicated, changes are Good quality healthcare services need to be patient-
implemented at an individual, team or service level centred and acceptable to those who use them.
and further monitoring is used to confirm improve- Measuring the views of those who use services
ment in healthcare delivery.2 enables healthcare providers to assess the service
delivered from the patient’s perspective.
IS AUDIT EFFECTIVE AT IMPROVING
Process Measure
A review of the evidence by NICE concluded that
Process measures are clinical practices that have been
audit is an effective method for improving the quality
evaluated in research and shown to have an influence
of care. The same review also described the audit
on outcome. For example, research evidence shows
methods associated with successful audit projects.2
that the use of antenatal steroids has improved
These findings are drawn upon in this document to
perinatal outcome. Evaluation of this process of care
give practical advice for undertaking audit.
would entail measuring the proportion of appropriate
women who received antenatal steroids. Process
WHAT CAN BE AUDITED?
measures may be used to assess the quality of care
Audit may evaluate the structure (organisation or and have some advantages over outcome measures:
provision) of services, the process of care or the • they provide a more direct measure of the quality
outcome of care against an agreed standard. of care provided
 Audit in Perinatal Medicine 387
• they occur more frequently, so smaller samples are (CEMD), the Confidential Enquiry into Stillbirths and
needed Deaths in Infancy (CESDI) and the National Confi-
• the findings are easier to interpret dential Enquiry into Perioperative Deaths (NCEPOD).
• as smaller audits are needed, they cost less to These are examples 6 of outcome reporting. However,
achieve. only adverse events are reported.

Outcome Measure THE AUDIT CYCLE

Outcome measure is the physical or behavioural Audit can be considered to have five principal steps,
response to an intervention; for example, the health commonly referred to as the audit cycle
status (dead or alive), cure following surgery for stress 1. selection of a topic
incontinence, level of knowledge or satisfaction (e.g. 2. identification of an appropriate standard
users’ views on the care they have received). 3. data collection to assess performance against the
Outcomes can be desirable; for example, improve- prespecified standard
ment in the patient’s condition or quality of life, or 4. implementation of changes to improve care if
undesirable, e.g. adverse effects of a treatment. The necessary
assessment of outcomes such as cancer survival rates 5. data collection for a second, or subsequent, time
is fundamental to measuring quality of care but the to determine whether care has improved.
use of outcomes alone in assessing quality of care has Audit projects require a multidisciplinary
limitations: approach with the involvement of stakeholders
• outcomes are not a direct measure of the care (including consumers or users of the service provided)
provided; ascribing causal factors to and the local audit department at the planning stage.
• variation in care may be problematic, e.g. social Good planning and resources are also necessary to
and health inequalities may contribute to ensure its success.
• variation in mortality rates
• not all patients who experience substandard care Selecting a Topic for Audit
will have a poor outcome It is essential to establish clear aims and objectives at
• many factors contribute to eventual outcome (e.g. this stage so that the audit is focused and addresses
disease severity, health status and social specific issues within the selected topic. A key
• and health inequalities); therefore, mechanisms to consideration is ‘how will we use the results of this
account for these differences are audit to change or improve practice?’.
• required (e.g. case-mix adjustment for co- In selecting a topic for audit, priority should be
morbidity) given to common health concerns, areas associated
• outcomes may be delayed with high rates of mortality, morbidity or disability,
• research evidence about the impact of some care and those where good research evidence is available
processes on outcome is limited to inform practice or aspects of care that use
• adverse outcomes occur less frequently so larger considerable resources. It is important to involve those
samples will be needed. who will be implementing change at this stage of the
Despite all the difficulties associated with the audit process.
interpretation of outcome measures, mortality and
morbidity measures are important and this is a major Identifiying an Appropriate Audit Standard
justification for regular monitoring. ‘Critical incident’
or ‘adverse event’ reporting involves the identification Review Criteria
of patients where an adverse event has occurred, such These are defined as ‘systematically developed
as the Confidential Enquiries into Maternal Deaths statements that can be used to assess specific
388 Textbook of Perinatal Medicine

healthcare decisions, services and outcomes’. In audit, women with dysfunctional uterine bleeding who
review criteria are generally used for assessing care; were offered transcervical resection of the
this approach is sometimes referred to as criterion- endometrium or endometrial ablation). Information
based audit. The criterion is the reference point about the levels of performance that can be achieved
against which current practice is measured. High- may be helpful when making plans for improvement.
quality evidence-based guidelines can be used as the Target levels of performance should be examined
starting point for developing criteria. Where this is periodically. The most common approach for setting
not possible, criteria should be agreed by a multi- target levels of performance is informal agreement
disciplinary group including those involved in among the group leading the audit or among health
providing care and those who use the service. Where professionals. In some settings, external standards can
criteria are based on the views of professionals or be useful. However, in many audits no explicit targets
other groups, formal consensus methods are prefe- are set and the aim is to improve upon current
rable. Review criteria should be explicit rather than performance.
implicit and need to:2 Target levels of performance have been most used
• lead to valid judgements about the quality of care, in screening programmes. For example, in screening
and therefore should be based on research for cervical cancer there are quality criteria to be met,
evidence about the importance of those aspects of such as the proportion of cervical smears that have
care endocervical cells.
• relate to aspects of care that are important either The term ‘standard’ has been used to refer to
to patients or in terms of clinical outcome different concepts, sometimes as an alternative word
• be measurable. for ‘clinical guidelines’ and ‘review criteria’, either
with or without a stated target level of performance
Table 30.1: Examples of audit and review criteria
and, somewhat confusingly, also to refer to the
Audit topic Review criteria observed or desired level of performance. However,
Induced abortion Screening for lower genital tract orga- it has been defined as ‘the percentage of events that
nisms and treatment of positive cases should comply with the criterion’ in the interests of
among women undergoing induced
clarity.
abortion should be carried out to reduce
post-abortion infective morbidity
Benchmarking
Caesarean section A thromboprophylaxis strategy should
be part of the management of women This is the ‘process of defining a level of care set as a
delivered by caesarean section goal to be attained’. There is insufficient evidence to
Hysterectomy Transcervical resection of the endo-
metrium or endometrial ablation should
determine whether it is necessary to set target levels
be available and offered to women with of performance in audit. However, in some audits,
dysfunctional uterine bleeding as an benchmarking techniques could help participants in
alternative to hysterectomy audit to avoid setting unnecessarily low or unrea-
listically high target levels of performance. Reference
Standard and Target Level of Performance
to the levels achieved in audits undertaken by other
This is defined as ‘the percentage of events that should professionals is useful. National audits may provide
comply with the criterion’ (e.g. the proportion of data for benchmarking. For example, the National
women undergoing induced abortion who were Sentinel Caesarean Section Audit Report7 gives
screened for lower genital tract organisms, the regional and national data for comparison on topics
proportion of women delivered by caesarean section such as the use of regional anaesthesia in women
who received thromboprophylaxis, the proportion of having caesarean section.
 Audit in Perinatal Medicine 389
Data Collection to Assess Performance Data Collection
Against the Pre-specified Standard
Sources of data include:
Data collection in criterion-based audit is generally • routinely collected data if available (e.g. birth
undertaken to determine the proportion of cases registers); this enables repeated data collections
where care is in accordance with the criteria. In with the minimum of extra effort
practice, the following points need to be considered. • clinical records
• data collection through direct observation or from
What Data Items to Collect? questionnaire surveys of staff or patients.
Consideration needs to be given to which data items Routinely collected data can be used if all the data
are needed in order to answer the audit question. For items required are available. It will be necessary to
example, if undertaking an audit on caesarean section check the definitions for data items that are used
rates, collecting information on the number of within the routine database to ensure its usefulness
caesarean sections alone will not give sufficient for the aims of the audit. Also, the completeness and
information to measure the caesarean section rate. coverage of the routine source needs to be known.
Data on the number of other births that took place is Where the data source is clinical records, training
also required. In general, for audit projects with clear of data abstractors and use of a standard pro forma
aims, objectives and well-defined review criteria, it can improve accuracy and reliability of data collec-
is easier to identify those data items that require tion. The use of multiple sources of data may also be
collection. Definitions need to be clear so that there is helpful. However, this can also be problematic, as it
no confusion about what is being collected. The will require linking of data from different sources with
definitions will depend upon the review criterion that common unique identifiers.
is being assessed. For example, if collecting data on Questionnaire surveys of staff or patients are often
rupture of membranes, it may need to be specified used for data collection. There are several validated
whether this is spontaneous or artificial. Data questionnaires on a wide range of topics that may be
collectors should always be aware of their legal adapted to a specific audit project. There is also
responsibilities regarding confidentiality and having literature on developing these (see Appendix).
electronic patient data such as under the Data
Developing a Questionnaires
Protection Act in the UK and the Caldicott Principles8.
Under the Data Protection Act 1998, it is an offence to There is a large amount of literature on how to
collect personal details of patients such as name, develop questionnaires. 11,12 Some of the general
address, or other items that are potentially identifiable principles involved are presented here. Question-
for the individual without consent. It is rarely naires are often used as a tool for data collection.
necessary or acceptable to use patient identifiers, such Questions may be open or closed. Generally, question-
as names and addresses, but some form of pseudo- naire design using open questions; e.g., “What was
anonymised identifiers may be used. Clinical audit the indication for caesarean section?” (Followed by
may be considered part of direct patient care and space for free text response) is easier. However,
therefore consent to use of data for audit can be analysis of these data is difficult, as there will be a
implied through consent to treatment, provided that range of responses and interpretation can be prob-
information is given to patients that their data may lematic. Open questions may be more difficult and
be used in this way. Audit project protocols should time consuming to answer and can lead to non-
be submitted to the local research and development response, which results in loss of data.
committee and ethics committees to seek approval if Questionnaires can be composed entirely of closed
necessary. Guidance on how to do this is can be questions (i.e. with all possible answers predeter-
obtained from the respective bodies. mined). More time is needed to develop this type of
390 Textbook of Perinatal Medicine

questionnaire but the analysis is generally easier. An data abstraction. However, for larger projects, e.g. a
example of this type of questionnaire is: prospective audit on induction of labour practices
Which of the following statements most accurately within a maternity unit, it may be more appropriate
describes the urgency of this caesarean section? for those involved in the care of the woman giving
A. Immediate threat to the life of the fetus and the birth (e.g. midwives or obstetricians) to fill in standard
mother. data collection sheets. Where available, audit support
B. Maternal or fetal compromise that is not imme- staff should be involved.
diately life threatening. Data that are collected on paper forms are usually
C. No maternal or fetal compromise but needs early entered on to electronic databases or spreadsheets
delivery. such as Microsoft Access®, Epi Info® or Microsoft
D. Delivery timed to suit the woman and staff. Excel® for cleaning and analysis. Data entry may be
Closed questions assume that all possible answers done by optical character recognition (OCR) software,
to the question are known but not the distribution of optical mark readers (OMR) or manually. OCR is most
responses. Time and consideration needs to be given accurate for questionnaire data using tick boxes but
to the options available for response as, if a desired less accurate for free text responses. The method of
response is not available, the question may just be data entry needs to be taken into account when
missed out and it may put people off completing the designing the questionnaire or data collection sheet.
rest of the questionnaire. For some questions, the For manual data entry, accuracy is improved if double
‘other’ category can be used with the option ‘please data entry is used. However, this can be a time
specify’, which gives an opportunity for the respon- consuming exercise. If the facilities and resources are
dent to write in a response. However, if this is used, available, electronic collection of data can be
thought must be given a priori as to how these freetext considered. In this case, data are entered immediately,
responses will be coded and analysed. In some at source, into a computer and saved to disk. While
situations, not having a category of ‘other’ may lead this is quick and requires minimal storage space, it
to the question not being answered at all, which can be difficult to handle unexpected responses. As
means that data will be lost. information is entered directly into a computer it
If questionnaires are developed for a specific cannot be verified or double-entered.9
project, they need to be piloted and refined to ensure Consideration also needs to be given to the coding
their validity and reliability before use as a tool for of responses on the database. For ease of analysis of
data collection. While those who developed the closed questions it is generally better to have numeric
questionnaire understand the questions being asked, codes for responses. For example, yes/no responses
the aim of piloting is to check that those who have to can be coded to take the value 0 for no and 1 for yes.
fill in the questionnaire are able to understand and Missing data will also need to be coded; for example,
respond with ease. Questionnaires that are not user with the number 9. The code assigned for missing data
friendly are associated with lower response rates, the should be distinguished from those where the
quality of data collected will be poor and hence results response is ‘not known’ (if this was an option on the
will be of little value. questionnaire).
It is advisable to incorporate consistency checks
Data Management as data are being entered, in order to minimise errors.
For example, if there are two questions:
Thought needs to be given to who will collect the data, a. How many previous pregnancies of at least 24
as well as the time and resources that will be involved. weeks of gestation has this woman had?
In small audit projects it may be feasible for the b. How many previous caesarean sections has she
principal investigators to go through clinical notes for had?
 Audit in Perinatal Medicine 391
A consistency check will highlight entries with These simple statistics can be easily done using
responses other than 0 to question (b) if the response Microsoft Excel spreadsheets and Microsoft Access
to question (a) is 0. databases. Other useful statistical software packages
include Epi Info, SAS, SPSS, STATA and Minitab.
Data Analysis
Implementation of Changes to
Simple statistics are often all that is required.
Improve Care if Necessary
Statistical methods are used to summarise data for
presentation in the form of summary statistics (means, Data analysis and interpretation will lead to the
medians or percentages) and graphs.10 identification of clinical areas that should be
Statistical tests are used to find out the likelihood addressed. There are many methods by which this can
that the data obtained has arisen by chance and how be done. The feedback of audit findings is most
likely it is that a real difference exists between two commonly used; for example, presentation at regular
groups. Before data collection has started it is essential audit meetings will stimulate discussions and
to know what data items will be collected, whether solutions may be agreed. The NICE review2 identified
comparisons will be made, and the statistical methods several audits in which change in care had occurred.
that will be used to make these comparisons. Simple methods were occasionally effective, for
Data items that have categorical responses (e.g. example:
yes/no or A/B/C/D) can be expressed as percen- • feedback of data collected
tages. Some data items are collected as continuous • provision of clear data, perhaps using modern
variables; for example, mother’s age, height and information systems, supported by active team-
weight. These can either be categorised into relevant work
categories and then expressed as percentages or, if • support from the organisation for teamwork
they are normally distributed, the mean and standard • use of several methods together within the context
deviations can be reported. These summary statistics of an implementation plan.
(percentages and means) are useful for describing the Change does not always occur in audit and
process, outcome or service provision that was consideration of the reasons for failure may take place
measured. after the second data collection. Resistance to change
Comparisons of percentages between different among local professionals or in the organisational
groups can be made using a chi-square test; t tests environment or team should be considered. Patients
can be used to compare means between two groups, themselves may have preferences for care that make
assuming that these are normally distributed. change difficult.
Nonparametric statistical methods can be used for The significance of teamwork, culture and
data that are not normally distributed. These resistance to change has led several authors to propose
comparisons are useful in order to determine whether frameworks for planning implementation. These
there are any real differences in the observed findings; usually include analysis of the barriers to change and
for example, when comparing audit results obtained use of theories of individual, team or organisational
at different time points or in different settings. In some behaviour to select strategies to address the barriers.
situations a sample-size calculation may be necessary For some topics, such as adverse incidents,systems
to ensure that the audit is large enough to detect a for continuous data collection may be justified.
clinically significant difference between groups, if one
exists. In this situation, it is important to consult a ORGANISATION OF AUDIT
statistician during the planning stages of the audit The NICE review 2 found that some methods of
project. organising audit programmes were better than others.
392 Textbook of Perinatal Medicine

The following features are associated with successful learn. Barriers identified in the literature include
audit: a lack of training in evidence-based audit skills and
• structured programmes with realistic aims and the failure to apply what has already been
objectives established.
• leadership and attitude of senior management • Cost.
• nondirective, hands-on approach It must be recognised that audit requires appro-
• support of staff, strategy groups and regular priate funding and that improvements in care
discussions resulting from clinical audit can increase costs.
• emphasis on teamworking and support
• environment conducive to conducting audit. REFERENCES
1. Smith R. Audit and research. [see comments]. BMJ
Common Reasons Why Audits Fail 1992;305:905.
2. NHS, National Institute for Clinical Excellence, Commis-
• Failure to participate and attitudes to audit. sion for Health Improvement, Royal College of Nursing,
Involving all stakeholders (including service users) University of Leicester. Principles for Best Practice in
Clinical Audit. Oxford: Radcliffe Medical Press; 2002.
in the project can encourage participation. It is [www.nelh.nhs.uk/BestPracticeClinicalAudit.pdf]
important to recognise the attitudes of those whose Accessed 11 September 2003.
behaviour is being audited, and to modify the 3. Junor EJ, Hole DJ, Gillis CR. Management of ovarian cancer:
audit process to accommodate these views. referral to a multidisciplinary team matters. Br J Cancer
1994;70:363–70.
• Failure to continue and complete the audit cycle. 4. Woodman C, Baghdady A, Collins S, Clyma JA. What
This makes it impossible to determine whether the changes in the organisation of cancer services will improve
audit has led to any improvements in care. the outcome for women with ovarian cancer? Br J Obstet
Gynaecol 1997;104:135–9.
• Failure to provide a supportive environment for
5. Department of Health. The NHS Cancer Plan. London:
audit. Department of Health; 2000.
Perceived lack of support at all stages, together 6. Penney GC. Audit. In: O’Brien PMS, Broughton Pipkin F,
with a range of structural and organisational editors. Introduction to Research Methodology for
Specialists and Trainees. London: RCOG Press; 1999. p. 95–
problems, is associated with poor progress in 106.
conducting audit. Research has pointed to a 7. Royal College of Obstetricians and Gynaecologists, Clinical
theory–practice gap for clinicians carrying out Effectiveness Support Unit. The National Sentinel
audit, one solution being to change the organi- Caesarean Section Audit Report. London: RCOG Press;
2001.
sational culture to one in which clinical audit is 8. Department of Health. Data Protection Act 1998. Protection
supported and actively encouraged. and Use of Patient Information. London: Department of
• Lack of resources, especially time. Health; 1998.
9. McKenzie-McHarg K, Ayres S. Data management. In:
This includes lack of protected time to investigate
O’Brien PMS, Broughton Pipkin F, editors. Introduction to
the audit topic, collect and analyse data, and the Research Methodology for Specialists and Trainees.
time to complete an audit cycle. It follows that London: RCOG Press; 1999. p. 140–6.
audit should be recognised as an important part 10. Brocklehurst P, Gates S. Statistics. In: O’Brien PMS,
Broughton Pipkin F, editors. Introduction to Research
of clinical practice and those directly involved in Methodology for Specialists and Trainees. London: RCOG
audit need to be allocated protected time. Press; 1999. p. 147–60.
• Lack of training in audit methodology and 11. Gillham B. Developing a Questionnaire. London: Conti-
evidence-based skills. nuum; 2000.
12. McColl E, Jacoby A, Thomas L, Soutter J, Bamford C, Steen
Health professionals and audit support staff N, et al. Design and use of questionnaires: a review of best
require adequate knowledge and skills for practice applicable to surveys of health service staff and
undertaking audit, and they should be keen to patients. Health Technol Assess 2001;5(31):1–256.
 31
Systematic Reviews in
Perinatal Medicine
Zarko Alfirevic

INTRODUCTION more worryingly, it took more than 15 years for this

evidence to start appearing in medical textbooks and
The principles of evidence-based medicine are not authoritative review articles. In perinatal medicine,
disputed. What constitutes the evidence, however, is the evidence that antenatal corticosteroids can not
hotly debated. Traditionally, medical textbooks and only reduce neonatal respiratory distress syndrome,
review articles written by experts and opinion leaders but also reduce the risk of neonatal intracranial
have been the main sources of evidence. Recommen- haemorrhage and perinatal death was available from
dation on diagnostic and therapeutic interventions in early 1970s. Even if early studies could have been seen
such material was predominantly based on personal as hypothesis generating, the reluctance to consider
clinical experience and easily accessible literature. the totality of evidence on this topic in the late eighties
Although there has always been some concern about was inexcusable.
possible biases inherent in this traditional approach Systematic reviews have emerged as one of the
to teaching and information sharing, a more formal most effective ways of bridging the gap between
criticism gathered momentum in the early nineties. already available evidence and clinical recommen-
For example, Antman et al published in JAMA a dations. The main differences between traditional and
comparison between treatment recommendations for systematic reviews are summarised in the Table 31.1.
myocardial infarction extracted from review articles Numbers of published systematic reviews have risen
and textbook chapters on one hand and randomised quite considerably in the last decade (Fig. 31.1) and
clinical trials on the other. 1 The evidence that such reviews are now considered not only an integral
thrombolytic therapy saves lives had been available part of clinical guidelines, but also a prerequisite for
in early 1970’ when a combined reduction in deaths any planned research on diagnostic and therapeutic
from 10 clinical trails with around 2,500 enrolled interventions. The term meta-analysis is often used
patients reached statistical significance. Unfortu- as a synonym for a systematic review in this context
nately, there were no attempts to analyse the results because of the misconception that systematic review
from the different studies together and further clinical must always include a quantitative synthesis of the
trials continued well into 1990’s with tens of data to yield a summary statistics (meta-analysis).
thousands of patients exposed unnecessarily to This is clearly not the case, as systematic reviews may
placebo and many more to no treatment at all. Even fail to identify studies suitable for statistical pooling.
394 Textbook of Perinatal Medicine

Table 31.1:
Narrative reviews Systematic reviews
Defined clinical questions Rarely Common
Reproducible, clearly defined literature search No Mandatory
Defined exclusion criteria for potentially eligible studies Rarely Common
Pre-specified comparisons and outcomes of interest No Common
Statistical pooling of the results (meta-analysis) No Common
Peer review before publication Rarely Common

500
new review, significant input from consumers and
400 consumer advocates throughout the reviewing
300 Randomised trials
process 3 and a commitment to keep Cochrane
Reviews regularly updated. The main criticism of
200
Meta-analysis Cochrane Reviews is a limitation of any evidence
100 based solely on randomised trials.
0 The criticism that systematic reviews of rando-
1983 1993 2003
mised trials ignore the wealth of knowledge generated
Fig. 31.1: Progressive increase in the number of randomised by observational studies and basic science is valid.
trials and meta-analyses related to pregnancy included in the However, the restriction of Cochrane Reviews to
PubMed (number of hits for 3 separate 12 month periods using
randomised trials is primarily pragmatic. The
keywords: pregnan* OR labor OR labour)
methodology for systematic searches of observational
studies is nowhere near as sophisticated as searches
COCHRANE REVIEWS restricted to randomised trials. The current register
Major advances in the scientific rigour and availability of randomised trials compiled by the Cochrane
of systematic reviews in perinatal medicine have come Pregnancy and Childbirth Group contains more than
from the Cochrane Collaboration - an international, 10,000 trial reports the majority of which are yet to be
not for profit organisation established in 1993.2 The included in the Cochrane Reviews. It is anticipated
aim of the Cochrane Collaboration is to facilitate the that any similar register of all literature relevant to
preparation, maintenance and dissemination of up- the evaluation of health interventions related to
to-date systematic reviews of the effects of healthcare pregnancy could contain more than million records.
interventions. The Cochrane Collaboration Pregnancy
OTHER TYPES OF SYSTEMATIC REVIEWS
and Childbirth Group (CCPC) was the first registered
review group within the Cochrane Collaboration and Two other types of systematic reviews have gathered
was subsequently joined by around 50 other topic- momentum recently as a welcome addition to the
based groups, each of them working under the already established analyses of aggregate data from
guidance of an international editorial team. The CCPC randomised trials – systematic reviews of diagnostic
remains the largest and most productive Cochrane and screening tests and individual patient data
Review Group with more than 400 registered analysis.
reviewers from 27 countries. Systematic reviews of diagnostic tests differ from
The distinguishing features of the Cochrane standard reviews in the assessment of study quality
Reviews published quarterly in the electronic and statistical methods used to combine results
publication The Cochrane Library are transparent peer- (pooled sensitivities, specificities, likelihood ratios
reviewed protocols published in anticipation of each and summary receiver operating curves). 4 Most
 Systematic Reviews in Perinatal Medicine 395
published systematic reviews of diagnostic tests are knowledge. The challenge for the future is to provide
hindered by the poor quality of the included studies. regularly updated unbiased summaries of obser-
It is also important to note that the evaluation of vational, randomised and qualitative data in a format
diagnostic accuracy of a test is only one aspect of that is understandable to both patients and health
clinical usefulness; the most accurate test can still be professionals. We have nothing to fear. The time
clinically useless or, even worse, harmful. currently spent on information gathering and the
Methods of undertaking a meta-analysis of several haphazard critical appraisal of incomplete evidence
studies may involve collecting either aggregate data will be much better spent talking with our patients
or data on each patient individually. The advantages and helping them to achieve perinatal care and
of the latter approach, described as the ‘yardstick’5 outcomes that truly suit their needs.
include a more complete analysis of ‘time of event’
outcomes and a more powerful analysis of whether REFERENCES
treatment is more or less effective in particular 1. Antman EM, Lau J, Kupelnick B, Mosteller F, Chalmers TC.
subgroups. The drawbacks can include the increased A comparison of results of meta-analyses of randomized
control trials and recommendations of clinical experts.
use of time, staff and financial resources and the lack
Treatments for myocardial infarctions. JAMA 1992; 268:
of availability of the original data for some trials 240-8.
2. Sakala C, Gyte G, Henderson S, Neilson JP Horey D.
CONCLUSION Consumer-Professional Partnership to improve research:
the Experience of the Cochrane Collaboration’s Pregnancy
Systematic reviews in perinatal medicine have made and Childbirth Group. Birth 2001; 133-137.
an important contribution to perinatal medicine by 3. Chalmers I. The Cochrane Collaboration: preparing,
maintaining and disseminating systematic reviews of the
reinforcing the evidence about effective therapies like effects of health care. Annals of the New York Academy of
antenatal corticosteroids in threatened preterm labour Science 1993; 703: 156-165.
and highlighting ineffective interventions like 4. Deeks JJ. Systematic reviews of evaluations of diagnostic
and screening tests. BMJ 2001; 323:157-162
thyreotropin-releasing hormone in the same clinical
5. Stewart LA, Parmar MKB. Meta-analysis of the literature
scenario. Equally important has been the role of or of individual patient data: is there a difference? Lancet
systematic reviews in identifying gaps in our 1993; 341: 418-422.
 32
Cost Benefit in
Perinatal Medicine
Z. Stembera

INTRODUCTION The approach to preparation of these studies and

to their exploitation exhibits considerable variations.
Greatly increased advances in medicine lead on one
It is different in the professionals within the perinatal
hand to a high quality of care expected and demanded
field who wish to make optimal use of the budgets
by both the health care professionals find the patients,
and resources that are available to them, than in the
but on the other hand the resources available for
planners who must decide on the appropriate level
responding to the expectations and demands are
of funding for the maternity care. There are also
becoming increasingly stretched. Even in the high-
differences between the views of the patient, of the
income countries, the available resources are scarce
hospital, as well as of the government or a community
in relation to these demands.
at large.
Because of this, more and more has appeared in
the expert medical literature of these countries in the METHODS OF ECONOMIC EVALUATION
last two decades trying to solve the disproportion When discussing the already classical studies of
between the increasing investments in health care and Drummond and colleagues 1 and Mugford and
the principal factors that have led to basic improve- Drummond2, it is necessary first to quote some basic
ments in health by means of methods of economic considerations related to the role of economics in the
evaluation. evaluation of care:
The key question on how best to choose between 1. The first consideration must be that the care for
the different and competing ways of using the which the resources are used is likely to do more
resources that are available has considerable impor- good then harm. Only afterwards comes the
tance in perinatal medicine, whose share in the costs consideration of both the most cost-effective or
of health care is quite high. This has three reasons. efficient use of the resources available for perinatal
First, the number of users pregnant and childbearing care, and the extent to which the society’s resources
women and their infants is quite high. Second, the should be allocated to perinatal care.
number of preventive screening examinations and 2. Economic evaluation requires a contrast between
preventive hospitalizations in the course of pregnancy alternative courses of action, in term of both costs
is increased. Third, the number of special, sometimes and consequences.
very expensive, examinations using technological 3. There are three main stages of economic
advances in medicine increases. evaluation. First, the likely costs and benefits must
 Cost Benefit in Perinatal Medicine 397
be enumerated; second, they must be measured; decreases the costs of postnatal care, this change
third, they must be expressed in comparable units. opens new concerns:
4. To the most important methods of economic 1. A deteriorated satisfaction of Czech women
evaluation of perinatal care programs belong the (predominantly primiparae) in consequence of the
cost-minimalization, or marginal, cost-effective- shorter spell of rest after delivery and the early
ness, cost-utility and cost-benefit analyses. care of the newborn at home.3
The nature and scale of any economic evaluation 2. A choice of the optimal method for cord care
will vary according to the question that is being asked. associated with a reduction of the number of home
While all approaches involve to some extent deriving visits by midwives.4 However, these types of
a balance sheet of the costs and benefits of the different studies fall within other methods of economic
strategies compared, some approaches are more evaluation.
complex than others.
MARGINAL ANALYSIS
COST-MINIMALIZATION ANALYSIS
Such analysis would be particularly useful in the case
This probably most simple analysis comes from the of routine and repeated testing that is so common in
presumption that benefits of treatments that are the care of women during pregnancy and childbirth.
compared are equal, which makes it possible to But the key question is: How many of them should
compare the resource costs without any need to we use? There may be a general agreement that
measure benefits. A different length of hospitalization certain screening tests should be applied to high-risk
of a woman subsequent to a spontaneous delivery and pregnancies. But should they be applied routinely to
physiological pregnancy, who delivered a healthy, all pregnant women and possibly also repeatedly?
term newborn, whose adaptation to extrauterine life When analyzing the majority of screening tests
was normal in the first hours of life, could serve as an performed in the course of pregnancy, it should be
example. This is the problem that is being solved at first taken into account that there exist complex factors
present in the Czech Republic. Before the transfor- affecting the mother’s health. It is consequently
mation of health care to the conditions of market extremely difficult to evaluate the effectiveness of the
mechanism, that is, before 1990, hospitalization after analyzed test, because many other variables that
delivery in the given case lasted for 5-6 days, whereas influence maternal and fetal health are interacting at
in the majority of high-income countries with the same time and confound the findings. These
advanced perinatal care, such hospitalization lasts for variables are considerably different in developing and
half that time on average without adversely influenc- industrial countries, where the most important ones
ing the health condition of the woman or her child. influencing the outcome of pregnancy include
From the given example concerning the calculation socioeconomic factors, level of education, desire for
of decreased costs with the same benefit, it explicitly pregnancy and maternal age. Taking into account the
emerges that it is possible to save the costs of above background information and limitations, we
hospitalization for 2-3 days. On the other hand, shall try to ascertain the effectiveness of these
however, new costs arise for visits of every mother screening tests and subsequent measures from the
and infant at home when women are discharged following two aspects:
earlier from hospital after delivery. This has to last at 1. Biological. Each intervention is considered in
least until the time of separation of the umbilical terms of what it intended to achieve.
stump in the child, and healing of the perineal wound 2. Programmatic. Do the maternal health programs
in the woman. Even if, in comparison with the more successfully deliver the biologically effective
expensive hospital care, the cheaper home care clearly intervention to the intended target population?
398 Textbook of Perinatal Medicine

The widely used practice of ultrasound imaging successively eliminate anencephaly out of the
of the fetus during pregnancy can be employed as a population of newborns by means of routine ultra-
typical example. From the biological point of view this sound screening, which is performed in 94% of all
method routinely performed up to the 20th week of pregnant women before the 20th week of pregnancy.6
pregnancy since it: In an effort to limit some relatively expensive and,
1. Defines more precisely the expected date of in the majority of cases, invasive tests connected with
confinement, hence reducing the induction rate in a certain, albeit very small, physical risk, but enabling
pregnancies mistakenly diagnosed as post-term; a reliable and timely diagnosis of a serious patho-
2. Allows an earlier diagnosis of twin pregnancies, logical condition, the procedure was divided from the
leading to a reduced premature labor connected programmatic point of view into two levels. The
with an increased mortality and morbidity of these timely diagnosis of some chromosomal or genetic
newborns; and disorders in the fetus can be taken as an example. By
3. Improves the detection of malformed fetuses, means of a routine screening program using relatively
which is followed by termination of pregnancy if cheap and non-invasive tests, a high-risk group is
the pregnant woman agrees, thereby reducing the selected from the total population of women on the
number of impaired babies. first level. Only in the small group of women selected
Repeated routine ultrasound examinations at the in this way are reliable diagnostic methods allowing
beginning of the third trimester improve a timely a timely identification of the disease used. Here
diagnosis of fetal growth retardation and placenta belong, for example, chorionic villus sampling or
previa leading to reduced mortality and morbidity examination of fetal cells after obtaining a sample of
in newborns. amniotic fluid by amniocentesis. Over the past few
In a series of studies, the routinely and repeatedly years in the Czech Republic, such a programmed
performed ultrasound examinations in the course of procedure has decreased the incidence of neural tube
pregnancy were compared with only selective defects and Down Syndrome to a half, similar to the
examina-tions for predicting the expected date of majority of high-income countries.7
delivery and for assessing subsequent measures upon
the occurrence of adverse outcomes. From the COST-EFFECTIVENESS ANALYSIS
programmatic point of view, the health resources
Cost-effectiveness analysis of any intervention
implications of such screening programs between the
requires calculation of the change in costs divided by
two strategies of care can be considered on the basis
the change in outcome of the intervention; the
of costs which include equip-ment, trained staff, and
outcomes are measured in units of health (for
clinic accommodation. These then vary with the
example, survival rates, or life-years saved).
number of cases treated and differ between the two
types of care offered. Of the mentioned studies
Change in Cost
concerning the effectivity of ultrasound screening
programs, only a few refer explicitly to health resource The best economic analysis will consider all costs,
implications.5 However, since several of the above- regardless of who has to pay: the health insurance
mentioned pregnancy complications are studied at the company, the hospital, the patient, the family, or the
same time in the course of one ultrasound exami- community at large. A distinction has to be made
nation, it is very difficult, if not impossible, to earmark between charges and costs. Only in some cases will
out of the total cost of this examination, the partial the charge for a service equal the cost, and only under
cost of diagnosing only one of these conditions. For such circumstances can charge be substituted for
instance, in the Czech Republic, it was possible to costs.
 Cost Benefit in Perinatal Medicine 399
Change in Survival Rates or quality-adjusted life-years saved. From the point
of view of utility, the outcome is also the satisfaction
A differentiated approach to the change in survival
gained from consumption of a service.
rate can be demonstrated with the example of care
for newborns of a very low birth weight. When
Change in Quality-adjusted
evaluating the effectivity of the care for these
Life-years or Survival Rate
newborns in the sense of their survival, the following
considerations are taken into account: The major difficulty is the inability to define what
1. Birth weight of the newborn. The lower the birth constitutes a normal quality of life, and what is the
weight, the longer the time of hospitalization in possibility of measuring the health status and health-
the neonatal intensive care unit (NICU) and the related quality of life. The broad definition of health
higher the costs of the treatment, because the two as formulated by the World Health Organization
factors are combined. (WHO) is: ‘a state of complete physical, mental and
2. Whether the evaluation concerns a country-wide social well-being and not merely the absence of
or regional program, all livebirths, or only neonatal disease or infirmity’. WHO has also developed a
intensive care in the hospital. classification of impairment, disability and
3. Whether the newborn was delivered in a peri- handicap.10 Conventionally, an outcome with normal
natologic center where there is a NICU, or whether health and quality of life is allotted a utility of 1, and
the newborn was transported to the NICU only death is allotted a utility of 0.11 Any outcome of less
after delivery, because out-born newborns have a than normal health or quality of life has a value of
different prognosis. less than 1. But many handicapped children lead
4. Whether all liveborns are evaluated, or whether productive lives, and their health-related quality of
certain newborns are excluded, for example, those life might be fairly good. In this respect, measurement
with lethal malformations, whose death is not of health-related quality of life adds a different,
influenced by the quality of intensive perinatal additional and important dimension to the standard
care. description of cognitive and motor functioning in
The results of this deliberation determine which outcome studies. It is therefore clear that the available
newborns must be accounted for in the denominator adult measures cannot be applied directly to children,
of any calculation of survival rate. whose life experiences and daily activities differ
An internationally recommended objective substantially from those of adults. Therefore, the six-
criterion for the intensive care for newborns of a very component multi-attributable system known as the
low birth weight differentiated in this way is the birth- Health Utilities Index (HUI) was worked out to
weight-specific neonatal death rate (potentially after describe the quality of life of children, and this
exclusion of lethal malformations), which can be includes sensory and communication ability,
further differentiated into death during the first 7 days happiness, self-ability, freedom from moderate to
after delivery (early neonatal death) or during the severe pain, learning and school difficulty and
subsequent 3 weeks (late neonatal death).8,9 physical ability.12 In spite of this, there still remains
series of factors that may influence the measurement
COST-UTILITY ANALYSIS of the health-related quality of life of these children,
In cost-utility analysis, the social value of the outcome for example:
is determined. The analysis requires calculation of the 1. Children of different ages have varying capa-
change of costs, which is the same as for cost- bilities, and with increasing age they develop new
effectiveness analysis, divided by the change in and more advanced skills and challenges. There-
outcome adjusted for the quality-adjusted life saved, fore, the dimensions of any measure of health-
400 Textbook of Perinatal Medicine

related quality of life have to take these changes be performed in the second trimester. On the other
into consideration.13 hand, the examination by means of chorionic villus
2. Health status measured by health professionals, sampling can be performed earlier, in the first
self-assessment and parental score might not be trimester.
consistent.14 However, routine ultrasound screening also has a
3. Children with the same disability might view their psychosocial benefit in some cases. A mother’s
quality of life very differently. attitude to her pregnancy can be positively affected
A particular problem represents the justification by the observation of first fetal movements on the
of estimating the health status at the time of a striking screen of the ultrasound apparatus, even more than
decline in neonatal monitoring of very immature by their perception.16 It is, in this way, possible to
newborns, although improvements in morbidity of create a relationship with the child before it is born.
these children have not been significant. Offering Another example of utility to women represents
intensive care to all newborns of borderline viability the lower satisfaction of women in connection with
without having the possibility to predict reliably the the shortened time of hospitalization after delivery
quality of life gained in every individual case is being that is mentioned in the section ‘Cost-minimalization
questioned by both parents and health-care providers. analysis’.
It is well recognized that parents, health professionals
and members of society may have different views on COST-BENEFIT ANALYSIS
both the dimensions of importance and the values
placed on different health states.15 The fundamental This method of economic analysis in perinatal care,
question, however, is whose values are important for the last one to be mentioned, similarly allows the
consideration of allocation of health-care resources outcome to be converted into monetary terms. The
and for decision making. cost-benefit analysis of perinatal intensive care
Another criterion for analogous decision making, requires the subtraction of additional costs per
for example between neonatal intensive care versus livebirth from additional earnings per livebirth; the
other programs, is the probability of the length of life results can be expressed in units of currency and
gained by means of intensive care. Most surviving would be termed the net economic benefit, or net
adults admitted to intensive care will be dead within economic loss if negative.
a shorter time than the neonates admitted to the The data used for the change in cost are the same
NICU, out of whom the surviving ones may well live ones as mentioned in the section ‘Cost-effectiveness
for 70 years or more. analysis’. The major difficulty is to estimate the
However, cost-utility is also used from the point lifetime earnings of a survivor, when such impon-
of view of utility to women. For example, pregnant derables as life expectancy, career choice (including
women may be anxious about their genetic history, the possibility of unemployment) and inflation have
or because of their age that they may be carrying a to be predicted so far into the future. Affected children
fetus with one or more abnormalities. It is precisely may have different skills and capacities than
the above-mentioned two-level screening performed unaffected children, different health care, education
in these women that will affect an unnecessary and other needs throughout their lives.
prolongation of their anxiety up to the time of Another important point of view when taking into
assessment of the correct diagnosis on the second account the timing of costs and benefits is a gene-
level, since there exists a certain percentage of false- rational view, when, for example, the favorable result
positive results on the first level. The anxiety of the of treatment of a pregnant woman 40 years ago may
women will be also prolonged if the correct final have an adverse effect on the fertility of her offspring,
diagnosis is made by amniocentesis, which can only as happened in the case of diethylstilbestrol.17
 Cost Benefit in Perinatal Medicine 401
The already classical randomized trial of capita on the basis of per capita gross national product
MacDonald and associates18 concerning the economic and health. From the results of this comparison, it
evaluation of electronic fetal heart monitoring versus emerged that for high-income countries, the marginal
intermittent auscultation, achieved the same outcome return of health expenditure per capita as measured
of care. Since, however, the whole course of labor in by mortality is negligible. This means that improve-
every individual woman was always followed by one ment in health and reduction in mortality can be
midwife, and if, rather than her salary bill, the time expected to arise not from further increases in costs,
necessary for such a follow-up should be measured, but from greater efficiency in the use of resources,
we would find that hardly any workplace would have more reliance on preventive measures, advances in
sufficiently numerous staff for such a procedure. lifestyle, behavior and medical technology.20
Costs and benefits arise from changes in uses not It was the preventive measures to which a
only of a community’s, but also of a family’s, comparative epidemiological study was devoted,
resources. Returning back to the example of early concerning the effect of bed rest during pregnancy
postnatal discharge from hospital, it is likely that more upon two internationally accepted indicators of
family resources will be needed for informal home maternal morbidity: rate of eclampsia and neonatal
care and support for a mother who comes back home rate of low birth weight. 21 Incidence of these
very soon after delivery. indicators in the Czech Republic was compared with
the incidence in Hessen (one of the federal states of
INTERNATIONAL COMPARATIVE STUDIES the Federal Republic of Germany), where there is a
The cost-effective analysis for better health outcome lower rate of prenatal hospital admissions, while the
is also solved in the form of international comparative system of perinatal care and the perinatal mortality
studies. To some above-mentioned problems, for rate is similar. From the economic point of view, it
example that the costs have to be standardized if was calculated under the conditions of the Czech
different areas are compared, further sources of Republic that:
confusion arise when comparing different countries 1. The increase of expenses for hospitalization of
due to the fluctuations in the respective currency rates women is higher by 7% in the Czech Republic
over time. (predominantly because of hospitalization for
Out of these studies, the World Bank data19 on different lengths of time for preventive reasons)
infant mortality and life expectancy in 21 high-income (Table 32.1).
and 27 low-income countries are meaningful. For each 2. There is a decrease of expenses for specialized care
country, the differences between actual and predicted in the NICU due to a 0.5% lower incidence of low-
values were calculated for health expenditure per birth-weight infants in the population (further

Table 32.1: Increase of costs for hospitalization of pregnant women. The data are based on a comparison of two
groups of pregnant women: Czech Republic (n = 106 680) and Hessen (58 430) in 1994. The costs are calculated in
accordance with the rate table of the Czech Health Insurance Company in Czech crowns
Hospitalization of pregnant women in population
Cost increase
Length of hospitalization Czech Republic Hessen Difference (Czech
(days) (%) (%) (%) crowns millions)
1-7 10.9 10.1 0.7 0.8
8-21 9.8 7.6 2.2 10.4
> 21 6.6 3.1 3.5 47.8
Total 27.3 20.8 6.4 59.0
402 Textbook of Perinatal Medicine

Table 31.2: Decrease of costs for the care of low-birth-weight newborns in consequence of their decreased incidence
in the population. The data are based on a comparison of two groups of newborns: Czech Republic (n = 107 721) and
Hessen (n = 59 198) in 1994. The costs are calculated in accordance with the rate table of the Czech Health Insurance
Company in Czech crowns
Incidence of low-birth-weight newborns in population
Cost decrease
Birth weight (g) Czech Republic (%) Hessen (%) Difference(%) (Czech crowns) (millions)
< 1000 0.30 0.37 0.07 69.9
1000-1499 0.55 0.62 0.07 34.1
1500-1999 1.07 1.23 0.16 18.6
2000-2499 3.55 3.82 0.27 7.3
Total 5.47 6.04 0.57 129.9

differentiated into four groups according to birth The application of the methods of economic
weight) (Table 32.2). evaluation in perinatal care cannot overcome the
The two-fold lower sum spared from the NICU moral dilemmas that arise in the choice of different
costs against the sum paid for the higher percentage screening or therapeutic methods or allocation of
of preventively hospitalized women does not include resources. It does, however, provide a framework
the benefit attained in the second analyzed indicator, within which such factors become less easily avoided
that is, the decreased incidence of eclampsia (one case and more readily discussed from the point of view of
per 2556 deliveries/year in the Czech Republic both the care givers and the care receivers.
compared with a more than two-fold incidence in
Hessen, that is, one case per 1328 deliveries/year). REFERENCES
However, it is not possible to express this benefit in 1. Drummond MF, Stoddart GL, Torrance GW. Methods for
the Economic Evaluation of Health Care Programmes.
monetary terms.
Oxford: Oxford University Press, 1986.
2. Mugford M, Drummond MF. The role of economics in the
CONCLUSION evaluation of care. In Chalmers I, Enkin M, Keirse MJ, eds.
Effective Care in Pregnancy and Childbirth. Oxford: Oxford
In the economy at large, the costs and benefits of University Press, 1991:86-96.
activities are made visible through the market system. 3. Goldberg H, Velebil P, Stembera Z, et al., eds. Czech
Republic Reproductive Health Survey 1993. Atlanta, USA:
However, the market mechanism in general either Centers for Disease Control and Prevention, 1995.
does not apply, or works imperfectly in the health- 4. Mugford M, Somchaiwong M, Waterhouse I. Treatment of
care field. This is also true of use of the terms ‘cost’ umbilical cords. Report of a randomised controlled trial.
Midwifery 1986;2:177-86.
and ‘benefit’ during economic evaluation of perinatal
5. Bakketeig LS, Eik-Nes SH, Jacobsen G, et al. Randomised
care. Economists thus have to use other approaches controlled trial of ultrasonographic screening in pregnancy.
in estimating the benefits of health-care programs. The Lancet 1984;2:207-9.
most promising approach appears to be the evaluation 6. Sípek A, Gregor V, Chudobová M. Incidence of birth defects
and effectivity of prenatal diagnosis in the Czech republic
of health improvements not in monetary terms. Also, 1993 (in Czech). Cs Pediatrie 1996;2:114-23.
the monetary cost is often an inadequate measure of 7. International Clearinghouse for Birth Defects Monitoring
the true economic cost. From this point of view, the System. ICBDMS, Annual report 1994. Rome: ISSN 0743-
5703, 1996:52-123.
main methods that economists consider in evaluation
8. Dunn PM, McIlwaine G. Perinatal audit. Prenat Neonat
of health-care alternatives and in comparison of Med 1996;1:160-94.
health-care programs were described. These methods 9. World Health Organization. International Statistical
of economic evaluation should also ensure wise Classification of Diseases, 10th revision. Statistical
presentation. Geneva: World Health Organization,
spending during allocation of resources. 1993;2:124-38.
 Cost Benefit in Perinatal Medicine 403
10. World Health Organization. International Classification of outcomes of neonatal intensive care (abstr). Pediatr Res
Impairments. Disabilities and Handicaps. Geneva: World 1996;39:no. 1654.
Health Organization, 1980. 16. Reading AD, Campbell S, Cox DN, et al. Health beliefs and
11. Bennett KJ, Torrance GW. Measuring health state preference health care behaviour in pregnancy. Psychosom Med
and utilities rating scale time trade-off, and standard 1982;12:379-83.
gamble techniques. In Spilker B, ed. Quality of Life and 17. Herbst AL, Ulfelder H, Postkanzer DC. Adenocarcinoma
Pharmacoeconomics in Clinical Trials. Philadelphia: of the vagina: association of maternal stilbestrol therapy
Lippincott-Raven, 1996:253-65. with tumor appearance in young women. N Engl J Med
12. Torrance GW, Furlong W, Feeny D, et al. Multiattribute 1971;284:878-81.
preference functions: Health Utilities Index. Pharmaco- 18. MacDonald D, Grant A, Sheridan-Pereira M, et al. The
economics 1995;7:503-20.
Dublin randomised trial of intrapartum fetal heart
13. Saigal S, Szatmari P, Rosenbaum P, et al. Cognitive abilities
monitoring. Am J Obstet Gynecol 1985;152:524-39.
and school performance of extremely low birthweight
19. The World Bank. World Development Report 1993:
children and matched term control children at age 8 years:
Investing in Health. New York: Oxford University Press,
a regional study. J Pediatr 1991;118:751-60.
14. Saigal S, Feeny D, Rosenbaum P, et al. Self-perceived health 1993.
status and health-related quality of life of extremely low 20. Shmueli A. Cost-effective outlays for better health
birthweight teenagers: comparison with term controls. J outcomes. World Health Forum 1995;16:287-92.
Am Med Assoc 1996;276:453-9. 21. Stembera Z, Holub J. Hospitalization during pregnancy:
15. Saigal S, Rosenbaum PL, Feeny DH, et al. Comparison of professional versus economic aspect (in Czech). Ces Gynek
preferences of health professionals and parents for health 1996;61:332-7.
 SECTION 5
Ultrasound
A Kurjak, Y Ville
 33
3D-4D Ultrasound Evaluation of the
Embryo and the Early Fetus
F. Bonilla-Musoles, LE Machado, F. Raga, F. Bonilla Jr

INTRODUCTION echoes. They also store transparency systems allowing

immediate visualization an avoiding loss of time. The
Following the USA Food and Drug Administration
smaller and easier to handle transducers and the
(FDA) approval of 3D in November 1997, interest in
better proportionate image quality are also definitive
the technique has soared to the extent that reports on
improvements.
3D in Obstetrics and Gynecology are now in the
But not only 3D has changed and improved in the
thousands. Moreover, any international or national
past only two years, in our opinion two amazing
Ultrasound Congress or Meeting of our specialty
improvements have been introduced:
contains main lectures, courses or workshops
• The combination in “quasi-real time” at the same
dedicated to this issue.
time and in the same frame of the 2D and 3D
Today, 3D is an integrated part of US not only in
images. This advantage allows a rapid and better
Obstetrics and Gynecology but also in other medical
orientation and, for those with scarce experience,
steams.
to a easier identification of structures and planes.
Most important, the FDA with its strict guidelines
• The integration of successive images in only one
has highlighted the importance of this technology for second allowing the visualization of embryonic or
the future of Medicine. fetal movements.
Because of the most recent advances in informatics, But these are not the final consequences of the new
several important innovations have appeared recently. computer’s technology:
The first 3D instruments that appeared in 1991 Recently we used Japanese new prototypes of 3D
took 25 seconds to store an image and minutes to machines which were able to produce 6 images per
hours to reconstruct the 3D rendering. Then the second, with a store capacity of minutes (the
defocused instruments87,88 formed 3D images in real nowadays existing store only 10 seconds) and with
time. Current software have improved to the extent an incredible image quality.
that images are stored in tenths of second and being Today more than 11 Commercial Houses dispose
able to reconstruct spatial images immediately, in one 3D, but not all are good. Many use insufficient “work
second,. In this way images are obtained in quasi-real stations” which obligate to spend time (and money)
time showing embryonic or fetal movements, the so after the exam. These are not real 3D machines and,
called 4D. do not forget, that what the patient, and the
The newest instruments limit the field of vision (a sonographer, wants is to visualize here baby on the
disadvantage similar to 2D) and eliminate distorted frame.
408 Textbook of Perinatal Medicine

In our opinion and until very recently no one of diagnostic possibilities in OB/GYN1,3,13,14,17,19,47,54,55,
58,63,76,77,88,89,111,127,128, 132,139,140,149,150,152, 155,166,170, 178-205,
the “work stations’ were good enough. Recently a new
201, 209,211, 213, 215,217,230,246,250,262,263,266
one has been approved by the FDA (but not yet
approved in the European community) with Sporadic reports of normal3,8,13,14, 17-19, 23,24,26, 27,46,54,
55,63,70, 77,81,82, 85,88,89, 103-105, 144,147,155, 251
important advantages: and malformed
• the software program is cheap (15.000 •). fetuses9,23,24, 26,43,53, 74,88,98, 99,100,104, 105,112,113 116,117, 120-133,
136,144,157, 187,198, 203, 220,254
• adaptable to all ultrasound machines (also the followed.
small ones) and transducer images. Soon after, descriptive images of specific organs
• excellent image quality. and areas were available:
• immediate free-hand 3D rendering image of an • craneum and fontanelles138,151
excellent quality. • central nervous system221,224,257,265,269,275
• no store space limitation, as it occurs with all • head49,139,279
existing 3D transducers. • face49,56,58,100,110,114,131,140,153,188
• very rapid 3D rendering allowing the study of the • lips154,157
heart motion. • forehead176
• adaptable to old stored clinical cases, and not only • eyes175
in ultrasound machines but in videos, PC, DVD, • thorax and vertebral column76,110,138,143,162,163,166,173,
183, 186, 271
etc.
Some problems remain to be solved: • heart44,106,137,142,176,177,214,215,210,222,252-254,256
• There is a shortage of learning centers where • fingers36-38,70,104,146,170,173
interested professionals can learn about new • genitalia, normal or ambiguous7,68,69,135,248,258
techniques, learn how to use the new instruments, Comparative 2D/3D biometric studies of fetal
and become acquainted with the variety of weight 33,34,207, 223,233,242,247,270,274 and organ
equipment that is constantly appearing on the volumes 35,58,141,171,207,223 showed that 3D provides
market. more accurate results.
• Health care professionals must be aware that not Specific organ studies allowed to have available
nomograms regarding:
only all commercial instruments are equipped
• Anatomic structures (e.j., long bones)
with all of the latest technological advantages.
• volumetry of organs (e.j., the gestational sac,
They also must know that every month new
lung)48,51,96,101,147,207,223
machines are being offered with new and better
• functions (e.j., the heart)42-44,106,137,142,176,177,214,215
technology.
• vascularization206,218,219,236,237,244,245,247,272,280
• The three first and more important statistics on
• estimation of the fetal weight or fat content
fetal malformations (Merz, Pretorius, Bonilla-
through the calculation of the muscle circum-
Musoles) need to be reproduced by other
ference.52
investigators. All the recently appeared articles
Extensive casuistics have shown that 3D improves
show isolated cases, superficial malformations, or
the diagnostic accuracy of 2D in more than 70% of
works with few cases.
malformations.23,24,27,120-132,227,228 Also the more recent
As a summary, we would recommend to start working
specific reports on selected malformations, such as
with 3D, IT IS THE FUTURE.
facial, 100,204 lips, 154 head, neck and spine, 23,138
abdominal wall, 118,213 limbs, 99,146 have confirmed
HISTORY OF 3D
these findings.
The 3D reports started 10 years ago. The first Regarding to the first trimester fetus, many either
descriptions were dedicated to emphatice the abdominal or transvaginal descriptions have been
 3D-4D Ultrasound Evaluation of the Embryo and the Early Fetus 409
published. 10,14,17,18,20,23,24,26-29,31,32,54,57,65-67, 79,93,108,
115,134,136,151,201,212,225
The most outstanding are those
related to studies from the cerebral cavities.10,13,18,19,
20-27,257,265,275
Also uterine introduced 10MHz
transducers were used65 without success.
Gestational sac and secundines have been volu-
metrically studied.59,91,181, 184
A new field of publications concerning the early
diagnosis of malformations has appeared. They show
the ability to study important markers of chromo-
somal anomalies such as the nucal translucency,23,27,93
ectopia cordis 108 trisomy 18 afected fetuses212 or
conjoined twins.24,28,74,115
Outside of the Prenatal diagnosis same important
articles have been published related with assisted
reproduction,205,212,216,231,238,249,261,264,267,268,273,281 the
cervix in pregnancy, 208 urogynecology, 214,276,277
gynecological and breast cancer.234,235,239-241,243,260,279
This chapter deals with the appearance chronology
of embryonic and fetal structures up to week 16 based
on our own previous published investigations.13,14,17- Graphic 33.1
20, 23,24,26,27

ABDOMINAL ULTRASOUND
As when using 2D, the transvaginal approach is much
superior than the transabdominal for 3D in the first
trimester. Abdominal 3D should not be recommended
Nevertheless, in this chapter we are showing the
3D schedule images of the abdominal US, because all
machines are equipped with abdominal transducers
but not all dispose of transvaginal transducers. These
are an acquired option.
In our book “Atlas de ecografia obstetrica” of 1988
the schedule of apparition of embryonic and fetal
structures according to the gestational week was
established.
This embryologic-echographic schedule is totally
adaptable still today to the first trimester abdominal
3D (Graphics 33.1 and 33.2).
Because of its low interest and the difficulty in
obtaining good 3D first trimester abdominal images
there is a scarcity of publications However, with a
careful examination exceptional quality 3D images
can be obtained: Graphic 33.2
410 Textbook of Perinatal Medicine

Fifth Week The embryonic growth is of 1 mm per day,

reaching 15 to 17 mm at the end of the sixth week.
The gestational sac can be observed with the following
characteristics:
Seventh Week
• oval or round shaped with limpid boundaries
• homogeneous trophoblastic rim greater than 5 Along with the increasing size of the embryo and sac,
mm. the most important feature is the visualization of the
• no internal contour irregularities cardiac activity. The embryo remains round.
• progressive growth (1 mm per day)
The abdominal 3D gestational sac vision at this age Eight Week
do not result easy, and there is no improvement when The limb buds appear in an embryo that is still
compared with 2D. At the present only the trans- rounded in shape. So called jerky embryonic move-
vaginal route is useful. ments are detectable. We say so called, because the
The sac’s shape is round between the fifth and sixth embryo in fact moves up and down repeatedly within
week and becomes oval later on. Irregular forms such the sac.
as enlarged, comma-like shaped, should not be The yolk sac can be observed in a location near
considered abnormal if not accompanied by other the gestational sac.
anomaly/es, such as:
• irregular growth: no growth, to slow, to rapid Ninth Week
• decidual refringency changes
For the first time the embryo appears elongated with
• contour irregularities
definite cranial and caudal Poles. The limbs are fully
• embryo not visible (vanishing), etc
developed, although the fingers are not yet visible.
Abnormal sac forms in normal evolution preg-
The yolk sac is in a more peripheral location.
nancies are common in cases of myomas, ovarian
From this week on, 3D visualization is superior to
cysts, distended bladder or sigmoid, etc.
2D due to the amount of the existing amniotic fluid
The gestational sac wall thickness decreases as the
(Fig. 33.1)
gestation progresses due to the progressive atrophy
of the deciduas capsularis and parietalis.
Following the visualization of the embryo, the
crown-rump length should be measured. This
measurement should be made from the cephalic pole
to the rump taking care to measure the embryonic
curvature. The crown-rump length should be
measured across the dorsal curvature.

Sixth Week
The most important finding is the embryonic
visualization. It appears as an echorefringent round
structure located in the inferior pole because of its
specific gravity greater than that of the amniotic fluid.
Its length is of approximately 10 mm.
Fig. 33.1: Abdominal 3D US in 9+6 weeks. Observe the profile
The gestational sac grows approximately 1.15 mm
of the embryo lying over the placena, showing well defined
per day, so that at the end of the sixth week it measures cranial and caudal poles. The yolk sac can be seen in the upper
20 mm, up from 10 mm at the beginning of this week. pictures (arrow). The remaining pictures show the lower limbs
 3D-4D Ultrasound Evaluation of the Embryo and the Early Fetus 411
Tenth Week Twin Pregnancy
So called slow and lazy movements appear. They are Twin pregnancy can be diagnosed after week 6, when
characterized by fetal rotations around its two gestational sacs are clearly visible, each one with
longitudinal axis, balancing, and movement of the its own embryo.
extremities. It is not acceptable to miss a diagnosis of twins by
The fetus occupies more than a third of the space transabdominal ultrasound examination after the
in the gestational sac; it can be well defined with 3D eight week of pregnancy. (Fig. 33.11)
along with the yolk sac (Figs 33.2 to 33.4).
TRANSVAGINAL 3D ULTRASOUND
Eleventh Week
Fourth Week (from 4+0 to 4+6 days)
There is fusion of the parietal and capsular decidual
layers, eliminating in this way what is considered a The first structures observed with 3D as with
gestational sac. transvaginal 2D are obtainable between weeks four
The fetus occupies now half of the amniotic cavity. and five.
Structures in the head, abdomen, and limbs are clearly The first suspicious image of a pregnancy is the
visible. persistence proximal to the menstrual days of a
decidual transformed endometrium accompanied by
Twelfth Till Sixteenth Week a vascular active corpus luteum (Fig 33.13).
What is first observed is the gestational sac (day
In week twelve the skull is fully formed (Figs 33.5 31 ± 1), and the visualization threshold is nowaday
and 33.6). Facial and abdominal structures can be established when the β-hCG values have surpassed
observed. Hands and feet are fully developed. Finger the 1000 mUI
and toes are identified. Being able to observe in the three orthogonal
From week thirteenth on the normal fetal develop- planes and with 3D rendering allows observation of
ment can be followed (Figs 33.7 to 33.12). the exact site of implantation in the endometrium
(Figs. 33.14 to 33.21).

Fig. 33.2: Abdominal 3D US first trimester. 10+1 week. The Fig. 33.3: 3D abdominal US. 10+3 weeks. Frontal view of the
fetal head, abdomen and extremities are clearly defined. The fetus showing semi-extended legs. The fetus is resting on the
ossification nuclei of the jaw and the face profile along with placenta (left upper and lower pictures), seen in a frontal view
the four limbs are visible. The physiological herniation is where the face can be observed (bottom right) and the feet
depicted in the two lower pictures already formed (bottom pictures).
412 Textbook of Perinatal Medicine

Fig. 33.4: Abdominal 3D US 10+4 weeks. The extremities are complete. The fetus lies over the placenta.
Fully developed fetus with well formed arms and legs lying over the placenta

Fig. 33.6: Thirteen weeks days. This image shows hands

and feet with fingers and toes

Fig. 33.5: Abdominal 3D US in first trimester. 13 weeks. In this

fully developed fetus the physiological herniation has diameter (day 32 ± 1 day). He is linked through the
disappeared. The orbits, nose, mouth, and limbs with hands omphalomesenteric duct to the embryo.
and feet can be seen. On day 33 (± 1 day) the embryo can be seen,
laminar, small, wide, refringent, and 2 mm in length.
The yolk sac is always visible facing the ventral
The gestational sac appears round or oval in shape, surface of the embryo.
perfectly delimited by an echogenic zone greater than In cases of multiple pregnancies, monochorial or
3 mm: the trophoblastis rim. At this time the bichorial, sacs and embryos can be observed. (Figs.
gestational sac size is of 2-3 mm (Graphic 33.3). 33.22 to 33.26). Two sacs and two embryos in
One day after, the yolk sac appears. It is round, bichorionic or two embryos in one sac in cases of
central, well delimited and measering 3 to 4 mm in monoamnionic twin gestation.
 3D-4D Ultrasound Evaluation of the Embryo and the Early Fetus 413

Fig. 33.7: Fourteen weeks and one day gestation (above). Observe
the frontal view of the fetus with uplifted arms, the superciliary arches,
the nose, ears and hands.
Bottom: Fourteen weeks and four days gestation. Fetal profile,
superfiliary arches, eyes, sutures and fontanelles

Fig. 33.8: Fourteen weeks and five days pregnancy. This lying fetus reveals arms and hands
with clearly defined fingers. The mouth can be seen on the profile view of the face (left)

Fig. 33.9: Fifteen weeks plus one day pregnancy. Frontal view of a fetus. Skull bones along
with sutures, fontanelles, orbital sockets, mouth and lower limb bones. The right figure
shows the profile, forhead, eyes nose and mouth
414 Textbook of Perinatal Medicine

Fig. 33.10: Gestations of fourteen plus four and plus five days. At the left
the fetus shows open eyes. At the right the eyes are closed

Fig. 33.11: Monochorionic twin gestation at 13 weeks and three days. Discordant fetuses are
already evident. The fetus on the left side is already evident. The fetus on the left side is already
smaller

Fig. 33.12: Dichorionic diamnionic twin pregnancy at 14 weeks and five days. Both fetuses are
aligned longitudinally, one in cephalic and the other in breech position. The face, sutures, and
fontanelles of one of them can be observed.
3D-4D Ultrasound Evaluation of the Embryo and the Early Fetus 415

Fig. 33.13: Left images 2D and 3D of the Decidua. To the right, the
corpus luteum with its vascularization. The gestation is not yet defined

Fifth Week
By the end of week 5, all these structures are evident,
the embryo enlarges and is connected to the yolk sac
by a long and slender duct (Figs 33.27 to 33.29).
From week fifth on, different organs and structures
will appear and will be visible according to the
schedule showed in graphics 33.4 and 33.5.

Sixth Week
In only on week, the embryo enlarges, allowing the
observation of two well differentiated poles: the
cranial and the caudal. Also the limb buds can be
visualized, especially the superior, which appear
earlier. This finding occurs earlier than what we have
seen in transvaginal 2D US.
Another interesting finding is that at this age in
the distal portion of the caudal pole the cauda is
visible. This structure is not observable with other
ultrasound techniques.
In this week, it is especially remarkable to study
Graphic 33.3 the secundines:
416 Textbook of Perinatal Medicine

Fig. 33.14: Beginning of pregnancy. Weeks 4 to 5. Round or oval implanted gestational sac and its vascularization

Fig. 33.15: Four weeks and 3 days pregnancy. The decidua and the gestational sac are showed. Observe the rim.

Fig. 33.16: 3D normal gestational sacs. The trophoblastic rim is clearly depicted and
can be measured .Its thickness has to be bigger than 5 mm
 3D-4D Ultrasound Evaluation of the Embryo and the Early Fetus 417

Fig. 33.17: 4D color Doppler of a normal gestational sac vascularization.

Observe the trophoblastic rim

Fig. 33.18: Day 32 .The yolk sac appears. A small segment of the
omphalomesenteric duct can be observed in the left image

Fig. 33.19: 4D pictures of normal yolk sacs, gestational sacs trophoblast and vascularization.

The amnios appears as a very thin membrane in As the cord forms, its anchoring site narrows and
the surface of the dorsum of the embryo, just on the thins out.
opposite side from where the yolk sac is visible. The
amnion will soon surround the entire embryo, leaving Seventh Week
out the extraembryonic mesenchyme and the yolk sac The embryo clearly shows the limb buds. This detail
(Figs. 33.30 to 33.33). is used to establish the gestational age (Figs 33.34 and
The yolk sac remains visible until week 13 to 14. 33.35).
It is always round and grows very slowly: 1 mm a The cephalic pole is flexed. It is very interesting
week. that in the back of the embryo two parallel layers are
418 Textbook of Perinatal Medicine

Fig. 33.20: Day 33 the embryo is visible measuring 2 to 3 mm.The

yolk sac is faced to the abdominal embryonic wall. The embryo
growths very rapid, and only days after is bigger than the yolk sac

Fig. 33.21: Visualization of the embryo. Days 33 to 35. The embryo takes
a laminar form. Two poles are depicted

observable which represent the first vision of what Eight Week

will be the fetal spine. This finding is only visible with The configuration of the embryo is completed. The
2D TV ultrasound in the eight week. cranial pole is large and voluminous. The profile, face,
orbits, mouth, jaw and maxilla can be identified.
 3D-4D Ultrasound Evaluation of the Embryo and the Early Fetus 419

Fig. 33.22: Seventh week monochorionic Fig. 33.23: Eight weeks

monoamniotic twin pregnancy monochorionic twin

Fig. 33.24: Comparison between bichorial biamniotic with lambda sign twin (left)
with a monochorial monoamniotic one (right)

Fig. 33.25: Orthogonal planes and 3D-

rendering of a twelfth week twin pregnancy
420 Textbook of Perinatal Medicine

Fig. 33.27: 5 Weeks pregnancy. Elongated embryo with

two poles. The yolk sac is visible on the left side of the right
image

Fig. 33.26: Different cases of triplets. Above in week

tenth and the bottom pictures in week sixth (left) and thirteenth
(right)

Fig. 33.28: Five weeks pregnancy. These four images show Fig. 33.29: The same case of Fig. 33.10. Five weeks pregnancy
the embryo, still smaller and elongated, and the yolk sac round showing the embryo with a thin omphalomesenteric duct linking
and faced to the embryo the yolk sac
3D-4D Ultrasound Evaluation of the Embryo and the Early Fetus 421

Graphic 4 Graphic 5

Fig. 33.30: Beginning of week 6.The embryo is much bigger

than in week 5, shows clearly two poles, the craneal and the
caudal, and the upper and lower buds of the extremities can
are depicted. The cauda appears between the lower extremities
buds

Fig. 33.31: End of week six. The embryo shows a bigger

size, the cephalic pole is slightly angulated, and the
extremities buds are longer
422 Textbook of Perinatal Medicine

Fig. 33.32: These two figures show the 3D image of the whole omphalomesenteric
duct and the yolk sac in week six

Fig. 33.33: End of week six. The embryo shows in detail the Fig. 33.34: Seventh week pregnancy. Observe the cephalic
curved cephalic pole and an elongated, some times thick some pole, the extremity buds, and a long coiled umbilical cord. The
times thin but very long omphalomensenteric duct yolk sac lies away from the embryo

The caudal pole shows large limb buds with Its refringency is that of the abdominal wall, its
stubby ends that resemble hands and feet. Joints and size is small, less than 7 mm, and always disappears
articulations are visible. between the 11th and 12th week.
The spine is completely formed, and appears as a Although at this week the profile, forehead, nose
white line in the dorsum. The superior portion (axis and mouth are visible they will be clearly defined by
and atlas) still remain separate. the 10th week (Figs. 33.36 to 33.39).
It is important to notice that at this week the
physiologic herniation can be seen. It is a round and Ninth Week
well defined structure, refringent, and linked to the At this week the head appears always flexed
abdominal wall at the site of the umbilical cord anteriorly and the finger and toes buds appear (Figs.
insertion. (Graphic 33.6). 33.40 to 33.42).
 3D-4D Ultrasound Evaluation of the Embryo and the Early Fetus 423

Graphic 33.6

Fig. 33.35: Seventh week pregancy, fetuses showing the

cauda, the buds and a very long omphalomesenteric duct.

Fig. 33.36: Eight weeks pregnancy. The embryo shows full extremities. The
profile can be identified. The umbilical cord is fully formed.
424 Textbook of Perinatal Medicine

Fig. 33.38: This picture shows the ossification nuclei of jaw and
maxilla. The mouth is visible as well as the complete extremities

Fig. 33.37: Frontal and sagittal 4D view of an

eighth week embryo

Fig. 33.39: Eigth weeks twin pregnancy showing the both fetuses the hand and feet

Fig. 33.40: Ninth week pregnancy showing the back with the medullary canal (center), a coiled (left)
and a not coiled cord (right) and the physiological herniation (right)
 3D-4D Ultrasound Evaluation of the Embryo and the Early Fetus 425
Tenth Week
The fetus is completely formed. Generally the head
is flexed over the thorax, but even so, we have been
able to see the face with big orbits, lips mouth, etc.
We can visualize prominent fontanelles and sutures
on the forehead.
On the remainder of the fetal body the arms are
well developed with elbow and knee flexions as well
as hands and feet visible (Figs. 33.43 to 33.46).
The umbilical cord is very long and thick,
proportionally larger and thicker than at the end of
the pregnancy. By using the transparency system, we
can observe for the first time, and identify, the femur,
tibia, fibula, humours, radius and ulna. At the
beginning of the 11th week the superciliar arch, the
orbits, eyes, forehead, nose, ears, and jaw can be
observed (Figs. 33.44 and 33.45).

OTHER ORGANS AND STRUCTURES

Fig. 33.41: These pictures showed different varieties of normal The fingers and toes are clearly observed in the 11th
physiological herniations. Also the fetal profile is crearly
depicted, showing the mouth, yaw and maxilla. See the feet and 12th weeks, and are better defined than what is
seen with 2D TV US. (Figs. 33.48 and 33.49).

Fig. 33.42: Ninth week

pregnancy. The fetus
shows the yolk sac near
the occipital bone. The
profile, eyes, abdominal
wall with the physiologic
herniation, extremities
and umbilical cord are
clearly depicted

Fig. 33.43: 10 weeks

fetuses showing a long
umbilical cord with
physiologic herniation.
Hands and feet are visible
426 Textbook of Perinatal Medicine

Fig. 33.44: 10 weeks. Frontal and sagittal view showing the Fig. 33.45: 10 weeks. The hands are showing the finger
mouth, nose, supercilliary arch, hands and feet. The umbilical boots. Eyes are also visible
cord is very long and coiled

Fig. 33.46: Above, shoulder of a 10 weeks fetus looking at the sky. Observe the ears and the claviculae.
Bottom, ten weeks normal fetus surrounded by the amnion (arrows)
 3D-4D Ultrasound Evaluation of the Embryo and the Early Fetus 427

Fig. 33.48: 11th week fetuses. The herniation

Fig. 33.47: Ten weeks pregnancy. The fetus shows the profile is geeting smaller
and the eyes and it is involved by the amnion (arrows).
Extremities, hands and feet are clearly depicted

Fig. 33.49: 12 weeks. Visualization of the whole fetus, umbilical cord and placenta
428 Textbook of Perinatal Medicine

It is of interest to note how these structures move cation. All of this will be useful to measure the
independently. It is possible to notice that the thumb intervertebral spaces.
apposes the other fingers. The phalanges can be Normally fetuses are flexed, and cover their faces
observed in fingers and toes (Fig. 33.54). with their hands. But after the tenth week they can
Although we have observed movement since the deflex, showing in this manner their faces. The orbits
seventh week, by the eight week we can observe the and eyes are more visible and the lids are evident.
fetus flexing its arms and legs across the abdomen. (Figs. 33.51 to 33.58).
These movements, as well as others like opening and The nose is more protuberant and is completely
closing the mouth, etc, are better observed by using formed between weeks 10 and 13. The mouth, lips,
the 4D system available today (Fig. 33.50). and jaw are perfectly defined. The sutures and
We consider the use of the transparency and X- fontanelles will approximate progressively (Figs. 33.51
ray systems essential for the study of the spine and 33.53 and 33.57).
pelvic bones after week twelve. In this way, the Finally, in some cases we have observed the fetal
medullary canal, vertebrae, the ossification nuclei in sex clearly as early as the 13th week only in male
the ribs can be visualized. It is important to remember fetuses. The labia of female fetuses can occasionally
that the high portion of the spine is not completely be distinguished clearly during the 16th week.
closed until the end of week twelve (axis and atlas).
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Fig. 33.51: Frontal view of 13th week fetuses showing the

Fig. 33.50: Visualization of fetuses of 13th weeks, showing development of the face. Special details can be observed
intense arm and leg movements from the development of the nose, eyes and mouth
3D-4D Ultrasound Evaluation of the Embryo and the Early Fetus 429

Fig. 33.52: 4D 13th week fetus

showing complete developed
arms and legs

Fig. 33.53: 3D and 4D visuali-

zation of 13th week fetuses. The
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visible

Fig. 33.54: 14th weeks fetuses showing the face, the

fingers and the palm, as well as the arm bones
430 Textbook of Perinatal Medicine

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 34
Malformations of the
Gastrointestinal System
D’Addario V, Di Cagno L

INTRODUCTION according to different Authors’ results. This wide

variation is due to the different study designs (mainly
A correct ultrasonic examination of the fetal gastro-
the numbers of scans performed during pregnancy),
intestinal tract includes the visualization of the
inclusion criteria, levels of examination. Since many
following structures:
gastrointestinal malformations appear late in
• the stomach (Fig. 34.1)
pregnancy, the best results are obtained when the
• the small and large bowels (Fig. 34.2)
screening design includes a scan also in the third
• the liver with its main vessels and the gallbladder
trimester.
(Fig. 34.1)
The malformations of gastrointestinal tract and
• the abdominal wall and the insertion of the
abdominal wall can be divided in four groups:
umbilical cord (Fig. 34.3)
1. Anterior abdominal wall defects
• the diaphragm (Fig. 34.4).
2. Diaphragmatic defects
The systematic evaluation of the above mentioned
3. Bowel disorders
structures allows the recognition of several congenital
4. Non-bowel cystic masses.
anomalies of the gastrointestinal system. The reported
sensitivity of ultrasound in diagnosing gastro-
ANTERIOR ABDOMINAL WALL DEFECTS
intestinal malformations varies from 24 to 86%,
The congenital abdominal wall defects include
gastroschisis, omphalocele and body stalk anomaly1.

Fig. 34.1: Transverse scan of the fetal abdomen showing the

stomach, the liver, the intraepatic tract of the umbilical vein
and the gallbladder Fig. 34.2: The echogenic bowel is seen below the liver
 Malformations of the Gastrointestinal System 443

Fig. 34.4: Longitudinal scan on the fetal chest and abdomen

showing the diaphragm between the lung and the liver

Fig. 34.3: Insertion of the umbilical cord Gastroschisis is considered a sporadic event with
into the abdominal wall a multifactorial etiology, but cases of familial
occurrence have been reported. Young maternal age,
The ultrasonic prenatal diagnosis of these defects is
maternal cigarette use and vasoactive drugs
relatively simple and possible in the first half of
consumption during first trimester are considered as
pregnancy. However it must be remembered that
possible etiological factors.
there is a physiological herniation of the small
The malformation results from vascular compro-
intestine outside the abdominal cavity between the
mise of either the umbilical vein or the omphalo-
5th and the 11th weeks of gestation (Fig. 34.5) and
mesenteric artery. The abdominal wall defect is
therefore a prenatal diagnosis of abdominal wall
generally small but the amount of bowel protruding
defect cannot be made in the earliest stage of
from the defect and floating freely in the amniotic
pregnancy.2
fluid may be disproportionately large. The herniated
Gastroschisis organs include mainly bowel loops that are not
protected by a membrane but usually covered by an
This malformation consists in a para-umbilical full inflammatory exudate, possibly resulting from
thickness defect of the anterior abdominal wall which chemical irritation by exposure to amniotic fluid.
is usually located to the right side of the umbilical The ultrasonographic diagnosis of gastroschisis is
cord insertion, associated with evisceration of suggested by the finding of a partly solid, partly cystic
abdominal organs. mass adjacent to the anterior abdominal wall and
The incidence ranges from 1:10.000 to 1:15.000 live freely mobile in the amniotic fluid (Fig. 34.6) which
births. has a cauliflower-like appearance. The differential

Fig. 34.5: Physiological herniation of the Fig. 34.6: Gastroschisis: a cauliflower-like mass protrudes
midgut at 10 weeks of gestation from the abdominal cavity into the amniotic fluid.
444 Textbook of Perinatal Medicine

diagnosis from omphalocele is based on the presence The ultrasonographic appearance of omphalocele
of a normal insertion of the umbilical cord, the lateral varies according to the type of defect, the presence of
location of the mass and the absence of a membrane ascites and the organs herniated. The principal
covering the herniated mass. diagnostic features are: the umbilical cord insertion
In contrast to omphalocele, gastroschisis is rarely into the membrane covering the abdominal wall
associated with other malformations and chromo- defect, the presence of the intrahepatic portion of the
somal anomalies, but additional gastrointestinal umbilical vein coursing through the central portion
abnormalities (malrotation, atresia, volvulus, of the defect, and the presence of a limiting membrane
infarction) may occur in 20-40% of the cases.3,4 An high that can occasionally rupture (Fig. 34.7).
percentage of fetuses with gastroschisis (77%) presents There are different syndromes that include
intrauterine growth retardation and preterm labor omphalocele, such as pentalogy of Cantrell (midline
occurs in one third of cases. The extent of bowel supraumbilical abdominal defect, lower sternum
damage is variable and strictly affects the prognosis defect, deficiency of diaphragmatic pericardium,
Most of the bowel damage is caused by constriction anterior diaphragm defect, cardiac abnormality) and
at the site of the abdominal wall defect: the sono- Beckwith-Wiedemann syndrome (macroglossia,
graphic evidence of small bowel dilatation and mural visceromegaly, omphalocele). Although most cases of
thickening correlates with severe intestinal damage omphalocele are sporadic, a familial occurrence of this
and poor clinical outcome. anomaly with a sex-linked or autosomal pattern of
The mode of delivery of fetuses affected by inheritance has been reported.
gastroschisis is still controversial although there is no The most important prognostic variable is the
striking evidence for Cesarean section over vaginal presence of associated malformations (50-70% of
delivery. Maternal transfer before delivery to a tertiary cases) or chromosomal abnormalities (30% of cases).5
care centre is recommended. The mortality rate ranges Some authors have demonstrated that small defects
from about 8 to 28%. containing only bowel are associated with an
increased risk of chromosomal abnormalities, as
Omphalocele opposed to large defects that have exposed liver. The
Omphalocele is a ventral wall defect characterized by main associated malformations are cardiac anomalies
an incomplete development of abdominal muscles, (up to 47% of cases), genitourinary abnormalities (40%
fascia and skin and the herniation of intra-abdominal of cases) and neural tube defects (39% of cases). Fetal
organs (bowel loops, stomach, liver) into the base of mortality highly depends on associated malfor-
umbilical cord, with a covering amnioperitoneal
membrane. The defect is thought to be caused by an
abnormality in the process of body infolding. The
classic omphalocele is a mid-abdominal defect
although there is also an high or epigastric
omphalocele (typical of the pentalogy of Cantrell) and
a low or hypogastric omphalocele (as seen in bladder
or cloacal extrophy), due respectively to cephalic and
caudal folding defects. The incidence of omphalocele
ranges from 1:4.000 to 1:7.000 live births. It is more
frequent in older women; most cases are sporadic,
although a familial occurrence with a sex-linked or Fig. 34.7: Omphalocele: a round solid mass, covered by a
autosomal pattern of inheritance has been reported. thin membrane, protrudes from the anterior abdominal wall.
 Malformations of the Gastrointestinal System 445
mations but also respiratory complications account 2. Septum transversum defects (defect of the central
for a significant percentage of morbidity and tendon)
mortality. 3. Hiatal hernia (congenital large esophageal orifice)
The mode of delivery of fetuses with omphalocele 4. Eventration of the diaphragm
has been debated in literature. The goal in the 5. Agenesis of the diaphragm
management is to deliver the fetus as close to term as A diaphragmatic hernia is a defect in the
possible in tertiary care centres. Cesarean section may diaphragm, due to failure of the pleuroperitoneal
be necessary to avoid dystocia or sac rupture in large canal to close between 9-10 weeks of gestation thus
omphaloceles. In the case of small defects vaginal determining the protrusion of the abdominal organs
delivery is recommended. into the thoracic cavity.
The incidence of congenital diaphragmatic hernia
Body Stalk Anomaly is 1:3000-1:5000 live births. This entity can be either
sporadic or a familiar disorder but its etiology is quite
The body stalk anomaly is a severe abdominal wall unknown. The most common type of diaphragmatic
defect caused by the failure of formation of the body hernia is the Bochdalek type which is a posterolateral
stalk; it is characterized by the absence of umbilical defect mostly located on the left side (80% of cases),
cord and umbilicus and the fusion of the placenta to less frequently on the right side (15%) o bilateral (5%).
the herniated viscera. The incidence is 1:14.000 births. Stomach, spleen and colon are the most frequently
This malformation is caused by a developmmental herniated organs. When the hernia is on the right side,
failure of the cephalic, caudal and lateral embryonic the main organs involved are the liver and the
folds. gallbladder.
The ultrasonographic diagnosis is suggested by The Morgagni type is usually a very small hernia
the finding of a large anterior wall defect attaching which occurs in 1-2% of cases. It is a parasternal defect
the fetus to the placenta or uterine wall, the absence located in the anterior portion of the diaphragm; it
of umbilical cord, and the visualization of abdominal contains liver, which may limit the degree of erniation.
organs in a sac outside the abdominal cavity (Fig. In the case of eventration of diaphragm, this structure
34.8).6,7 The position of the fetus may lead to scoliosis appears to be weak so that the abdominal contents
and kyphosis. Multiple malformations such as neural are displaced in the thoracic cavity.
tube defects, gastrointestinal and genitourinary Eventration of the diaphragm consists of an
anomalies, may be associated. The body stalk upward displacement of abdominal organs into the
anomaly is a uniformely fatal condition. thoracic cavity secondary to a congenitally weak
diaphragm which has the aspect of an aponeurotic
DIAPHRAGMATIC DEFECTS sheet. It occurs in 5% of diaphragmatic defects and it
is more common on the right side.
The classification of these malformations is based on
Diaphragmatic hernia can be either a sporadic or
the location of the diaphragmatic defect :
a familiar disorder and although the etiology is
1. Diaphragmatic hernia (Bochdaleck and Morgagni
unknown this abnormality has been described in
types)
association with maternal ingestion of drugs such as
thalidomide, quinine and anticonvulsivants. There are
two hypotheses to explain the mechanism responsible
for the origin of a diaphragmatic defect :
1. delayed fusion of the diaphragm and
2. a primary diaphragmatic defect. In addition to this
Fig. 34.8: Body stalk anomaly: a large anterior abdominal classification, another one has been proposed
wall defect attaches the fetus directly to the placenta. concerning a late onset of this anomaly :
446 Textbook of Perinatal Medicine

i. Herniation occurring early during bronchial associated. The poor prognosis mainly depends on
branching causing a severe bilateral pulmonary the severity of pulmonary hypoplasia induced by the
hypoplasia and lately death. prolonged compression of the lungs by the herniated
ii. Herniation at the stage of distal bronchial viscera. For this reason experimental prenatal surgery
branching leading to unilateral hypoplasia, has been suggested to prevent the lung damage. The
with survival depending on a balance between different outcome is related to variation in the timing
pulmonary vascular and ductal resistances; of entry of abdominal organs into the chest (the earlier
iii. Late herniation in pregnancy which causes a is the entrance, the worse is the prognosis). Due to
compression of otherwise normal lung and a the complexity of this malformation and the different
good prognosis; diagnosis and treatment, the ultrasound examination
iv. Postnatal herniation without pulmonary is very essential. Management relies on protecting the
pathology and with good chances of viability. controlateral lung hoping that it is normally formed,
The prenatal sonographic diagnosis of diaphrag- which depends on the gestational age at diagnosis. If
matic hernia is mainly based on the visualization of the fetus is less than 24 weeks’ gestation, parents may
abdominal organs at the same level of the four choose to terminate the pregnancy, to continue the
chamber view of the heart in the trasverse section of pregnancy with postnatal care or even to consider
the fetal chest. The heart is usually shifted on the right repair of the defect in utero. Between 24 and 32 weeks,
side of the chest (Fig. 34.9). parents may choose between conventional postnatal
The visualization of the fluid-filled bowel or the therapy and fetal surgery. Anytime a diaphragmatic
stomach bubble in the thoracic cavity is highly defect is diagnosed, prenatal karyotyping and
diagnostic. The presence of peristalsis of bowel loops detailed ultrasound examination to detect associated
may help making the differential diagnosis with other anomalies are recommended. There are no indications
conditions such as cystic adenomatoid malformation for preterm delivery or for cesarean section. The
of the lung, bronchogenic cysts and mediastinal cysts. delivery should be planned in a tertiary care centre.
Polyhydramnios is common and is secondary to the
bowel obstruction. BOWEL DISORDERS
The rate of associated anomalies is 25-75% Prenatal ultrasound examination allows the detection
increasing to 95% in stillborns. Such anomalies of the majority of gastrointestinal malformations
include central nervous system, cardiac and chromo- because they are often associated with a dilated
somal abnormalities, omphalocele and oral cleft. bowel, cystic masses or intra-abdominal calcifications,
The prognosis for this malformation is still very although the prenatal diagnosis generally does not
poor and becomes poorer if other malformations are influence the mode or the timing of delivery (except
in the cases with polyhydramnios that can cause
premature labor or delivery). Moreover, it allows
maternal referral to a center with appropriate
perinatal, neonatal and surgical expertise which, in
some cases, may improve the outcome.

Esophageal Atresia
This anomaly consists in the absence of a segment of
Fig. 34.9: Transverse section of the fetal chest in a case of the esophagus and is often associated with a tracheo-
diaphragmatic hernia: the heart is displaced to the right side
by the presence of the stomach and bowel loops in the thoracic
esophageal fistula (86-90% of cases). Five types of
cavity. esophageal atresia may be distinguished:
 Malformations of the Gastrointestinal System 447
1. Isolated (type I) anomalies, Tracheo-esophageal fistula, Esophageal
2. Associated with a fistula connecting only the atresia, Renal anomalies, Limb anomalies). Fetal
proximal part of the esophagus and the trachea karyotyping is suggested. The prognosis depends on
(type II) the associated malformations and on the severity of
3. Associated with a fistula connecting the lower part polyhydramnios, which can facilitate preterm
of the esophagus and the trachea (type III) delivery.
4. Associated with proximal and distal fistulas (type
IV); and Duodenal Atresia or Stenosis
5. Tracheo-esophageal fistula without esophageal The incidence of this malformation is 1:10.000 live
atresia (type V) births and its genesis goes back to the 11th week of
Among different types the most common is the gestation due to a failure of canalization of the
esophageal atresia associated with a fistula connecting primitive bowel. In most cases the etiology is
the proximal part of the esophagus and the trachea unknown. Atresia is more common than stenosis (70%
(80% of the cases). The incidence varies between 1:800 of cases) and could be associated with chromosomal
and 1:5.000 live births and the etiology is unknown. abnormalities (trisomy 21), skeletal defects and other
The prenatal diagnosis is possible in only 10% of anomalies.9
the cases and should be suspected in the presence of The most typical sonographic finding is the
polyhydramnios with absent stomach bubble in characteristic “double bubble” sign caused by the
several and repeated ultrasound examinations or simultaneous dilatation of the stomach and the
visualizing a dilated proximal tract of the esophagus proximal duodenum (Fig. 34.11). The diagnosis is
with absent stomach (Fig. 34.10) ; however this usually made in the late second trimester.10 Up to half
malformation can occurr even in presence of a normal of duodenal atresia cases are complicated by
or small stomach, due to the frequently associated polyhydramnios and this can contribute to preterm
tracheo-esophageal fistula8. labor, but the main cause of death are the associated
Associated anomalies are present in 50-70% of the anomalies. This malformation can present late
cases, including cardiac, genito-urinary, chromosomal complications (motility disorders, megaduodenum,
(trisomy 21), additional gastrointestinal and muscolo- gastro-esophageal and duodenal-gastric reflux,
skeletal anomalies. A characteristic association is the gastritis, blind loop syndrome) and late death even
“VACTERL” (Vertebral, Anorectal anomalies, Cardiac months or years after management.

Fig. 34.10: Esophageal atresia: the diagnosis is suspected by

the association of absent stomach and dilatation of the proximal Fig. 34.11: Duodenal atresia: the dilated stomach and
tract of the esophagus proximal duodenum are clearly recognized
448 Textbook of Perinatal Medicine

Bowel Obstruction as well as intraluminal hyperechogenic small areas

referring to meconium (Fig. 34.13).13
The incidence of bowel stenosis and atresia is 2-
The diagnosis of bowel obstruction is usually
3:10.000 births and the most common locations are
made in the third trimester: the lower is the obstruc-
distal ileum (36%) and proximal jejunum (31%). There
tion the later is the appearance of the sonographic
are four types of intestinal atresias:
signs.
1. Type I : presence of a transverse diaphragm of
The prognosis of these malformations mainly
mucosa or submucosa (20%)
depends on the level of obstruction (the lower the
2. Type II: presence of blind ends of bowel loops
obstruction, the better the outcome), the length of
connected by a fibrous bands (32%)
remaining intestine and birth weight. Other important
3. Type III: complete separation of blind ends with a
prognostic factors are the presence of associated
corresponding mesenteric defect (48%); and
malformations (especially gastrointestinal anomalies
4. Type IV: absence of a large tract of small bowel
including bowel malrotation, esophageal atresia,
with the typical “apple peel” deformity, resulting
microcolon and intestinal duplication), meconium
from loss of the superior mesenteric artery.
peronitis and intrauterine growth restriction.
These defects are usually sporadic, although
familial cases have been described.
Meconium Peritonitis
According to the site of the obstruction the defects
are divided in: (1) jejuno-ileal atresia and stenosis, (2) This condition is the consequence of in utero
colonic atresia and (3) imperforate anus. perforation of the bowel with spread of meconium
The sonographic prenatal appearance varies into the peritoneal cavity leading to a local sterile
according to the level of the defect. In the case of chemical peritonitis. The peritonitis may be localized,
jejuno-ileal atresia multiple dilated bowel loops in the with the development of a dense calcified mass or
fetal abdomen may be seen in association with fibrous tissue, or diffuse, with a fibrous reaction
polyhydramnios (Fig. 34.12).11,12 In colon atresia (that leading to bowel adhesions and pseudocyst
usually occurs proximal to the splenic flexure with a formation. Inflammatory reaction leads to an
significant segment of absent colon with distal exudative process and ascites. Its incidence is 1:35.000
microcolon) the sonographic finding is similar to live births. Bowel perforation involves the proximal
distal ileal occlusion and the differential diagnosis tract, with some form of obstruction such as intestinal
may not be possible. In the imperforate anus dilated atresia (65% of cases), meconium ileus, volvulus,
intestinal loops with increased peristalsis may be seen gastroschisis or Meckel’s diverticulum.

Fig. 34.13: Imperforate anus in a third trimester fetus: a dilated

Fig. 34.12: Jejunal atresia: multiple dilated bowel loops are distal colon is seen containing multiple small echogenic foci
present in the fetal abdomen due to meconium
 Malformations of the Gastrointestinal System 449
The prenatal sonographic appearance of 1:2.000. The cysts can be single or, in rare cases,
meconium peritonitis varies according to the multiple involving the intrahepatic or extraehepatic
underlying anatomical finding: main signs are portion of the biliary tree. Choledocal cysts are
intrabdominal calcifications (85% of cases), poly- classified into four types : 1) Fusiform dilatation of
hydramnios, fetal ascites caused by exudate and the common bile duct, 2) Diverticular dilatation of
bowel dilatation. the common bile duct, 3) Intramural dilatation of the
Postanatal management depends on the etiology common bile duct, 4) Intrahepatic biliary duct
of meconium peritonitis; up to 1/3 of all cases have dilatation. Its sonographic appearance is that of a
cystic fibrosis. cystic structure located in the upper right abdomen
Echogenic Bowel with dilated proximal ducts. Differential diagnosis
includes duodenal atresia, hepatic cyst, dilated
Sonographically, “echogenic bowel” is defined as
gallbladder, ovarian cyst and biliary atresia. The cystic
echogenicity of the bowel loops equal to or greater
size and the association with biliary obstruction affect
than the density of the iliac wing (Fig. 34.14). 1:200
the prognosis.17
midtrimester fetuses presents this feature which
might depend on a slow or delayed transit of the
meconium along the bowel. This finding has been Mesenteric and Omental Cyst
considered as a “soft marker” of chromosomal This benign malformations consist in cystic structures
abnormalities but actually the increased risk of located in the small or large bowel mesentery or in
chromosomopaty in the presence of such an isolated the omentum filled with serous or chilous fluid. Its
marker is extremely low.14 The risk increases when sonographic appearance is that of a thin-walled,
further sonographic markers are present. The unilocular or multilocular cystic mass. It is difficult
“echogenic bowel” may also be the first sign of cystic to make a differential diagnosis with other
fibrosis or can be seen in cases of intramniotic intrabdominal cystic conditions such as choledocal,
bleeding.15 However it is important to stress that the
ovarian and hepatic cysts..
recognition of hyper-echogenic meconium does not
always represent a pathological condition but might
Hepatic Masses
be a normal variant and an isolated finding.16
Hepatic masses might origin from a an obstruction
NON-BOWEL CYSTIC MASSES of the hepatic biliary system or might have a tumoral
Choledocal Cysts origin (hemangioma, amartoma, etc...).
Their sonographic appearance changes depending
Choledocal cyst is a rare congenital cystic dilatation
on the origin: mesenchymal hamartomas usually
of the common bile duct. The incidence is about
appear as irregular hyperechoic areas (Fig. 34.15),
while hemangioma appears hypoechoic, hyperechoic
or mixed depending on the degree of fibrosis and
stage of involution.18 Hepatoblastomas and adenomas
have a solid appearance. Polyhydramnios may be
associated; many cases of reduction in volume or even
disappearance in utero have been described.
The management is expectant in terms of moni-
toring the size and evolution of the tumor; for large
Fig. 34.14: Echogenic bowel tumors the cesarean section is indicated.19
450 Textbook of Perinatal Medicine

the role of ultrasonography for evaluation of functional

anatomy. Prenat Diagn. 2002 Aug;22(8):669-74.
9. Sugimoto T, Yamagiwa I, Obata K, Ouchi T, Takahashi R,
Suzuki R, Shimazaki Y. Choledochal cyst and duodenal
atresia: a rare combination. Pediatr Surg Int. 2002
May;18(4):281-3.
10. Lawrence MJ, Ford WD, Furness ME, Hayward T, Wilson
T. Congenital duodenal obstruction: early antenatal
ultrasound diagnosis. Pediatr Surg Int. 2000;16(5-6):342-5.
11. Uerpairojkit B, Charoenvidhya D, Tanawattanacharoen S,
Manotaya S, Wacharaprechanont T, Tannirandorn Y. Fetal
intestinal volvulus: a clinico-sonographic finding.
Ultrasound Obstet Gynecol. 2001 Aug;18(2):186-7
12. Ogunyemi D. Prenatal ultrasonographic diagnosis of ileal
atresia and volvulus in a twin pregnancy. J Ultrasound
Fig. 34.15: Hepatic hamartoma appearing
Med. 2000 Oct;19(10):723-6.
as an isolated intrahepatic area
13. Has R, Gunay S. ‘Whirlpool’ sign in the prenatal diagnosis
of intestinal volvulus. Ultrasound Obstet Gynecol. 2002
Sep;20(3):307-8
REFERENCES 14. Al-Kouatly HB, Chasen ST, Streltzoff J, Chervenak FA. The
1. Martin RW. Screening for fetal abdominal wall defects. clinical significance of fetal echogenic bowel. Am J Obstet
Obstet Gynecol Clin North Am. 1998 Sep;25(3):517-26. Gynecol. 2001 Nov;185(5):1035-8.
2. Kurkchubasche AG. The fetus with an abdominal wall 15. Berlin BM, Norton ME, Sugarman EA, Tsipis JE, Allitto BA.
defect. Med Health R I. 2001 May;84(5):159-61. Cystic fibrosis and chromosome abnormalities associated
3. Oguniemy D. Gastroschisis complicated by midgut atresia, with echogenic fetal bowel. Obstet Gynecol. 1999
absorption of bowel, and closure of the abdominal wall Jul;94(1):135-8.
defect. Fetal Diagn Ther. 2001 Jul-Aug;16(4):227-30. 16. Slotnik RN, Abuhamad AZ. Study of fetal echogenic bowel
4. Morris-Stiff G, al-Wafi A, Lari J. Gastroschisis and total (FEB) and its implications. J Ultrasound Med. 1999
intestinal atresia. Eur J Pediatr Surg. 1998 Apr;8(2):105-6. Jan;18(1):88.
5. Boyd PA, Bhattacharjee A, Gould S, Manning N, 17. Chen CP, Cheng SJ, Chang TY Prenatal diagnosis of
Chamberlain P. Outcome of prenatally diagnosed anterior choledochal cyst using ultrasound and magnetic resonance
abdominal wall defects. Arch Dis Child Fetal Neonatal Ed. imaging Ultrasound Obstet Gynecol. 2004 Jan;23(1):93-4
1998 May;78(3)Cadkin A, Strom C. Prenatal diagnosis.of 18. Macken MB, Wright JR Jr, Lau H, Cooper MC, Grantmyre
body stalk anomaly in the first trimester of pregnancy. EB, Thompson DL, O’Brien MK. Prenatal sonographic
Ultrasound Obstet Gynecol. 1997 Dec;10(6):419-21. detection of congenital hepatic cyst in third trimester after
7. Takeuchi K, Fujita I, Nakajima K, Kitagaki S, Koketsu I. normal second-trimester sonographic examination. J Clin
Body stalk anomaly: prenatal diagnosis. Int J Gynaecol Ultrasound. 2000 Jul-Aug;28(6):307-10.
Obstet. 1995 Oct;51(1):49-52. 19. Tsao K, Hirose S, Sydorak R, Goldstein RB, Machin GA,
8. Shulman A, Mazkereth R, Zalel Y, Kuint J, Lipitz S, Avigad Albanese CT, Farmer DL. Fetal therapy for giant hepatic
I, Achiron R. Prenatal identification of esophageal atresia: cysts. J Pediatr Surg. 2002 Oct;37(10).
 35
Ultrasound Diagnosis of
Urinary Tract Anomalies
Prats P, Maiz N, Rodriguez A, Pedero C, Torrents M, Astudillo F, Carrera JM

EMBRYOLOGY AND ANATOMY OF indiferentiated mesenchyma from the nephrogenic

THE NEPHR-OUROLOGIC SYSTEM crest and that will give place to the future kidneys).
At sacral level there are also some paraspinal
The nephrourologic system has the functions of
structures and of mesodermic origin named ureteral
production and conduction of the urine toward the
gemmae from where some canals arise in caudo-
exterior by means of two independent nephrourologic
cephalad direction address denominated mesone-
tracts, but with the same functions that converge
phric ducts or wolffia ducts that in its ascent penetrate
toward a reservoir that is the bladder, where the urine
inside the metanephric blastemas and ramify in their
produced by the kidneys is stored, and it is excreted
interior until a total of 15 generations.
to the exterior through the urethra.
In the 7th week of the gestation the functional units
Embryology of the kidney, the nephronas, begins to differ thanks
to the inductive influence of the ureteral gemma.
It has their embryonic origin in the intermediate In the 20th week of the gestation the collecting
mesoderm, located to both sides of the dorsal wall of system have already been formed: collecting tubules,
the body, as the embryonic development advances it papillary ducts, calyces, renal pelvis and ureteres and
suffers some transformations and specifications that 30% of the total population of nephrones.
will be translated in the different anatomical parts of Starting from this week and until the 36th week
the urinary tract. of gestation an exponential increment of the total
It would be possible to be said that the embryonic number of nephrones will take place.
development of the nephrourological system happens
in two localizations but in synchronous way that are: Lower Nephrourologic System
(Formed by bladder and urethra)
Superior Nephrourologic System
Both structures are uniques and they take charge of
(Formed by: Kidneys (Nephrons), collecting tubules, deriving the urine produced in the superior nephrour-
papillary ducts, calyces, renal pelvis and ureteres) ologic system toward the exterior.
Toward the 5th week of gestation, the paraspinal They come from the mesoderm and of the
mesoderm differentiates in pronephros and mesone- paramesonephric ducts (that also participate in the
phros wich presents some structural changes to formation of the genital system) that will give place
become the metanephric blastema (that would be at pelvic level to a embryonic structure called cloaca.
452 Textbook of Perinatal Medicine

The cloaca, among the 4th and 6th weeks of like lateral oval masses laterally to the psoas muscles
gestation presents a tabication by means of the and below the suprarenal glands. These look like
urorrectal septum that divides the cloaca in two parts, hypoechoic triangular that delimite the superior pole
a posterior one that will be the rectum and another of the kidneys. In the traverse plane the kidneys like
anterior one that it will be the primitive urogenital round paravertebral structures and the renal pelvis
sinus whose superior portion together to the allantois like anechoic areas medial to the kidneys are seen.
will give place to the bladder that will receive (Figs 35.2 and 35.3) The renal pelvis is measured better
posterolaterally the ureteres from the ureteral anteroposterior projection no matter if the fetus’
gemmae. column is up or down. The superior limit of the
The inferior portion of the primitive urogenital normality is of 4 mm until the 33 weeks of gestation
sinus will give place to the membranous urethra and and 7 mm from this date until the term. The normal
vaginal introitus in the female sex and to the values of the renal dimensions have also been
membranous and prostatic urethra in males. published, including the renal longitude, the
anteroposterior diameter and the renal circumference.
Normal Anatomy and Variants
With the transvaginal ultrasonography the kidneys
and the bladder can be detected in the fetus from the
9th week of gestation. To the 12th week the kidneys
look like bilateral echogenic structures in the
paraspinal region. (Fig. 35.1) The renal pelvises can
be identified as areas central medial hipoecogénicas.
The bladder is in the pelvis and looks like a round
anechoic structure well defined. It can be confirmed
the position with the Doppler technique to identify
the two umbilical arteries that surround it.
To the 18-20 weeks of gestation and using coronal
or sagital sections the kidneys can be defined clearly
Fig. 35.2: Sagital scan of the kidney

Fig. 35.1: Kidneys at ten weeks of gestation.Bilateral

echogenic structures in the paraspinal region Fig. 35.3: Coronal scan of the kidney
 Ultrasound Diagnosis of Urinary Tract Anomalies 453
With high resolution devices the renal pyramids a mistake with the hydronephrosis. If there is only
can be seen as hipoechoic areas in the renal cortex that one cyst it can be considered a simple cyst.
it is not necessary to confuse with renal cysts. The collector system of both kidneys should not
The ureteres doesn’t usually see and if they are only be evaluated regarding the size but also as for
identified it is necessary to think of a renal obstruction the number. If two collector systems are seen it is
or vesicoureteral reflux. necessary to discard a double kidney and to explore
The bladder as in the first trimester looks like the bladder to discard an ureterocele.
round anechoic structure with the rectum behind. The dilatation of the collector system forces us to
Often it is possible to differentiate it of the intestine consider the possibility of a renal obstruction. The
that surrounds it; however to measure the thickness grade of dilatation of renal pelvis, ureter and bladder
of their wall it is better to make it at the umbilical usually suggests the level of the obstruction. When
artery level when this surrounds the bladder. The there is a dilatation of the collector system it is
superior limit of the normality for the bladder wall necessary to value the renal cortex echogenicity and
thickness is 2 mm. the presence or absence of renal cysts to discard a
secondary renal dysplasia.
Ultrasonographic Study
Bladder
The ultrasonographic study of the fetal urinary
system implies the evaluation of the kidneys, the The bladder exploration includes the size evalua-
bladder and the volume of amniotic fluid. It is also tion and, when it is big, the visualization of the
necessary to discart associate anomalies. posterior urethra, because if this it is dilated it is
necessary to think of an obstruction of the vesical exit.
Fetal Kidneys The thickness of the vesical wall can be measured at
First it is imperative to settle down if the two kidneys the level of the umbilical artery. It is necessary to
are present. If a kidney lacks it is necessary to look discard the ureterocele existence, mainly when there
for it in ectopic positions like the pelvis. If it does not is a renal duplicity. In a period of 30-40 minutes it is
found is necessary to consider the possibility of an usually possible to demonstrate the vesical filling and
unilateral renal agenesis. The bilateral renal agenesis drainage.
usually associates to a severe oligoamnios, mainly
Volume of Amniotic Fluid
starting from the 17 weeks of gestation. When a renal
anomaly is detected it is fundamental to explore the This volume can be evaluated in different ways.
contralateral kidney to confirm or to exclude a Most of the echographers carries out a subjective
bilateral renal illness. evaluation first and then they appeal to more objective
The size and echogenicity of both kidneys should approaches if they find that there is much or little. It
be valued. The hyperechoic kidneys can be normal seems that the best technique is the calculation of the
but it is also necessary to think about the possibility index of amniotic fluid from the measures in four
of a cystic renal disease, mainly when they are big. uterine quadrants and its half value. The severe
The presence of macroscopic cysts usually oligoamnios of the second trimester usually has bad
indicates a kidney multycystic, but it is necessary to prognosis and if it discards premature rupture of
make sure that the cysts don’t communicate, because membranes and a severe intrauterine growth
there are cases of multycystic kidneys with a great restriction usually indicates the presence of a severe
central cyst and smaller outlying cysts that can made bilateral renal illness.
454 Textbook of Perinatal Medicine

URINARY TRACT MALFORMATIONS • Transvaginal ultrasound in fetuses in podalic

presentation will help to improve the image,12,13
Renal Agenesis • Other techniques have been proposed as the
The renal agenesis is the absence of one or two of the infusion intramniotic and intraperitoneal of
kidneys. The incidence of unilateral renal agenesis is physiologic salt solution to improve the image
1 per 1.000 births, and the bilateral is 1 per 4.000 quality 14,15
births 5 The etiology is ignored. Some cases of Unilateral agenesis. For the diagnosis a meticulous
unilateral agenesis could be secondary to a intra- evaluation of both renal fossae must be carried out.
uterine regression of a dysplastic multicystic kidney.6 The ultrasound findings will be the following:
The embryological origin of the renal agenesis is the • Kidney absence in renal fossa
lack of union or penetration of the ureteral sprouting • Absence of ipsilateral renal artery renal by means
in the metanephric blastema, so that the primitive of the color Doppler. (Fig. 35.6)
collecting tubules won’t induce the nephrons • Absence of pelvic kidney or renal ectopy, for this
formation starting from metanephric mesoderm.7 the renal pelvis and contralateral kidney it will be
valued it
Diagnosis • The contralateral kidney can be increased of size
Bilateral agenesis: Echographyc diagnosis will carry by a compensatory hypertrophy.16(Fig. 35.7)
out due to:
Differential Diagnosis
• Absence of kidneys in renal fossae that will be
difficult to value because of the oligohydramnios Mainly it will be carried out with other causes of
in many cases severe oligoamnios.
• Severe Oligoamnios • Renal pathology
• Not bladder visualization 8 — Bilateral multicystic kidneys. The kidneys are
• Absence of renal arteries by means of the color usually evident for their cysts.
Doppler study. 9,10 (Fig. 35.4) — Infantile policystic kidney disease. The kidneys
• The renal fossae will be able to be occupied by the are usually big and echogenics.
suprarenal glands, giving place to the “lying down • Uretral obstruction: The bladder is usually very
adrenal sign.” 11 (Fig. 35.5) evident.

Fig. 35.4: Bilateral renal agenesis. Fig. 35.5: Bilateral renal agenesis.
Absence of the renal arteries Note the enlarged adrenal gland.
 Ultrasound Diagnosis of Urinary Tract Anomalies 455

Fig. 35.6: Unilateral renal agenesis. Renal artery in Doppler Fig. 35.7: Unilateral renal agenesis . Notice the large kidney
color. Notice the absence of the renal artery

— Intra-uterine growth restriction (IUGR). The • Associate syndromes

kidneys and the bladder are present. It is — Fraser syndrome
usually accompanied by an alteration in the — Brain-oculo-facial skeletal syndrome
flow wave speed (FWS) of the umbilical artery. — Acrorenal-mandibular syndrome
— Premature rupture of membranes (PRM). it — Branchiootorenal syndrome
usually has an antecedent of loss of vaginal
Unilateral agenesis
liquid. The kidneys and the bladder are
• Anomalies of the contralateral kidney in 48% of
present.
the cases
— Vesicoureteral reflux
Associate Anomalies
— Obstruction of vesicoureteral junction
Bilateral agenesis — Obstruction of pelviureteral junction.
• The Potter sequence (wide and plane nose, ears of
low implantation, hypertelorism, receding chin, Prognosis
deformities of extremities) appears as consequence
• Bilateral agenesis: the prognosis is very bad. All
of the severe oligoamnios.
the newborns die in the first hours or days like
• 50% presents other associate anomalies
consequence of the lung hypoplasia.
— Cardiovascular
• Unilateral agenesis: In general the prognosis of
— VATER (Vertebral defects, Anal atresia,
these newborns is very good, although in good
Tracheo-Esophageal, Radial and renal
measure it will depend on the anomalies associ-
anomalies)
ated in the contralateral kidney.
— Gastrointestinal (anal and duodenal atresia,
omphalocele)
Management
— Phrenic hernia
— Musculoeskeletal: sirenomelus, digital • Bilateral agenesis: It can be offer a pregnancy
anomalies interruption due to the lethal prognosis. If the
— Central nervous system (CNS): neural tube mother decides to continue with the pregnancy it
defects, will be opted by a conservative behaviour, a
456 Textbook of Perinatal Medicine

vaginal delivery will always be attempted, and exploration of the fetal pelvis and the contralateral
reanimation manoeuvres won’t be made in the side in search of a possible ectopic kidney.
neonate. • Localization of the kidney adjacent to the bladder
• Unilateral agenesis: During the pregnancy: normal or the wing of the ilium.18 In occasions it can be
controls. As much during the pregnancy as in the difficult for its echogenicity similar to the adjacent
newborn the appearance of anomalies will be intestine. (Figs 35.8 and 35.9)
watched over in the contralateral kidney.
Differential Diagnosis Unilateral renal agenesis.
The recurrence risk of the bilateral renal agenesis
is approximately of 4%.17 Around 9% of the relatives Associate Anomalies Other anomalies have been
in first grade of the fetuses or newborns affections of described like:
renal impotence, will have asymptomatic renal • Gynecological anomalies
malformations. If the renal agenesis is part of a • Gastrointestinal, cardiovascular anomalies and
syndrome, the recurrence risk will depend on the skeletal (18)
inheritance type of this. • Unique umbilical artery.
• Contralateral kidney anomalies, as vesicoureteral
Renal Ectopy reflux.
Ectopic kidney is called to wich is located outside of Prognosis The prognosis is very good, although it will
the renis fossa. The most frequent localizations are the depend on the associated anomalies of the con-
pelvis (pelvic kidney), crusader of the other side tralateral kidney.
(ectopia renal crusade), and other less frequent ones
as lumbar or thoracic. The incidence is approximately Crossed Ectropic Kidney
of 1/1.200 and 1/1.900.18,19
During the renal ascent a kidney crosses to the other
Pelvic Kidney side, giving place to the crossed renal ectopy.

The lack of ascent of the kidneys originates the pelvic Diagnosis

kidneys and other ectopia forms. • Kidney absence in renal fossa
• Big contralateral kidney and bilobate 20
Diagnosis The echographic signs that we will find will
be: Differential Diagnosis
• Absence of the kidney in the renal fossa. In these • Unilateral renal agenesis with compensatory
cases it is very important to make an important hypertrophy. In these cases the kidney is not

Fig. 35.8: Ectopic pelvic kidney. Between iliac arteries Fig. 35.9: Ectopic pelvic kidney. Between iliac arteries
 Ultrasound Diagnosis of Urinary Tract Anomalies 457
bilobed and it does not present a second collector associated to a bigger incidence of adeno-
system. carcinoma29 and transitional cells tumor.30
• Renal tumor. The contraleteral kidney is present.
A collector system is not identified in the tumor. Prognosis

Associate Anomalies The prognosis is excellent. It will be kept in mind a

• Vertebral anomalies (myelomeningocele, sacral bigger incidence of vesicoureteral reflux, renal stone,
agenesis) infection and hydronephrosis
• Anal Atresia
• Urinary anomalies like ureterovesical reflux, Obstructive Uropathies
hydronephrosis, urinary infections, etc. The fetal kidney responds from different ways to an
Prognosis If it is presented in an isolated way the obstruction depending on the gestational age in which
prognosis is good. it occurs. Very precocious obstructions, in the first
trimester or beginning of the second, will give place
Horseshoe Kidney to polycystic dysplastic kidneys. More later obstruc-
tions (above the 22th week) can produce hydro-
The horseshoe kidney is the union of the lower or
nephrosis.
occasionally the upper extremities of the two kidney’s
An important difficulty in the diagnosis of the
by a band of tissue extending across the vertebral
renal obstruction is the high proportion of false
columnis. The incidence is 1 per 400-600 births.21,22
Due to their proximity the kidneys fuse before positive estimates in 36 to 81%. This is due to the
completing their ascent, so that the root of the inferior named mild hydronephrosis that are solved at the end
mesenteric artery will avoid to complete their ascent. of the pregnancy or in the neonatal stage. To try to
avoid these false positive it have been defined cut
Diagnosis values of the anteroposterior dianeterof the renal
pelvis, above of them the obstruction should be
Because of subtle findings, it is an infradiagnosed
suspected. Unfortunately these court points are
entity. The echographic diagnosis is based on the
varied: of 4 to 10 mm the second trimester and of 7 to
demonstration of the presence of a renal tissue bridge
10 mm in the third trimester.
that connects both kidneys, generally in the inferior
For some authors the best echographic approach
poles, it can be identified both traverse and coronal
to predict postnatal uropathies is the anteroposterior
sections.
diameter of the renal pelvis greater or similar to 7 mm
Associate Anomalies in third trimester with a 69% of positive predictive
• Urogenital Anomalies: hydronephrosis, value.31,32 Other authors calculate echographic false
vesicoureteral reflux, hypospadias, and negatives below 10%33 and negative predictive values
cryptorchidism. of 98%.34
• Extraurological Anomalies: anomalies of central Diameters of the renal pelvis above 15 mm have a
nervous system (neural tube defects, 23 high predictive value of renal pathology that needs
cardiovascular, gastrointestinal anomalies, and postnatal surgery. 35
musculoskeletal defects.24 The group that bearss more problems is those that
• Chromosomal anomalies: Turner’s syndrome,25 18 have pelvic diameters diameters from 4 to 10 mm to
trisomy.26,27 the 20 weeks because 10 to 30% of children will
• Renal tumors. In children it has been associated present a vesicoureteral reflux that could deteriorate
to the Wilms’ tumor,28 and in adults it has been the renal function without follow-up. 31
458 Textbook of Perinatal Medicine

These cases should be re-evaluated toward the 28 nization of the collagen and of muscular fibers in its
weeks of gestation and in the neonatal period to wall. In 69% of the cases a muscular anomaly exists
discard a possible progression of the pyelectasis. so that there is an absence of longitudinal fibers.40
A sign of gravity of the hydronephrosis is the With less frequency there are anatomical causes
presence of caliectasis, so that it bends the surgery of obstruction like fibrous adhesions, bands,
necessity with regard to when the hydronephrosis is anomalous ureteral insertion, and obstruction for
only present.36 double kidneys.
Another aspect is the association between the
Diagnosis In the sonographic scan a dilated renal
dilation of the urinary tract and chromosomal
pelvis will be appreciated with or without dilation of
anomalies. In most of cases they are part from a
the renal calyces and without ureteral dilation neither
multisystemic alteration secondary to a genetic
vesical (Figs 35.10 to 35.13).
alteration. 37 In the case of isolated mild hiydro-
In cases of severe obstructions dilation of the renal
nephrosis the association with chromosomopathies is
chalices takes place with weigh loss of the renal cortex
less clear, according to Nicolaides it would be a 3% in
(Fig. 35.14). In strange occasions an abdominal cyst
isolated hydronephrosis. 38
will take place or it will be able to take place its
rupture with the consequent perirenal urinoma (Fig.
Obstruction at the Pyetoureteral Junction Level
35.15).
It is the more common cause of obstruction at renal The volume of the amniotic fluid is usually normal,
level, with an unknown real incidence, some authors however it can cause polyhydramnios for increase of
calculate it in 1/2000 born alive.39 It is more common urine production. It is strange the appearance of
in the masculine sex, and in 30% it is bilateral, when oligoamnios.
it is unilateral it is more frequently in the left side.
Differential Diagnosis It is necessary to carry out the
It is produced by an stenosis at the pyeloutereral
differential diagnosis with other causes of lower renal
junction level.
obstruction where the ureters appears usually dilated
The obstruction is in most of the cases functional,
like those of the vesicoureteral junction, vesical exit
so it would exist a urine propulsion failure.
and the bilateral vesicoureteral reflux. It will also be
Histologically the ureter frequently shows signs
necessary to value the differential diagnosis with
of chronic inflammation with disruption and disorga-
polycystic kidneys, simple renal cysts or urinomas.
Associate Anomalies In the cases of pyeloureteral
obstruction we should study both kidneys with detail
in search of possible associate anomalies (25-27%) as
agenesis, multicystic dysplasia, vesicoureteral reflux,

Fig. 35.10: Mild dilatation of the renal pelvis. Fig. 35.11: Mild dilatation of the renal pelvis.
 Ultrasound Diagnosis of Urinary Tract Anomalies 459

Fig. 35.12: Moderate dilatation of the collecting Fig. 35.13: Moderate dilatation of the collecting
system and the renal pelvis system and the renal pelvis

Fig. 35.14: Hydronephrosis. Severe dilatation of the renal Fig. 35.15: Urinoma. Notice the thinning of the cortex
pelvis and calices. Enlarged kidney

as well as possible extrarenal anomalies (12-19%) like echography, isotopic renogram and cystourethro-
cardiovascular anomalies, neural tube or digestive graphy. The examinations are delayed about 10 days
anomalies, and chromosomal anomalies.41 except in the cases that present severe bilateral
affectation. 42
Prognosis The postnatal prognosis is usually good In most of the cases the postnatal management is
and the hydronephrosis grade is usually correlated conservative except that an increment of the hydro-
with the renal function.35 nephrosis or decrease of the differential renal function
The prenatal management is usually conservative exists where the pyeloplasty is the surgery of
with the echographic follow-up in the third trimester. elección.43
In the newborn one antibiotic profilaxis is prescribed Although most of the cases are sporadic it has been
and it is carried out a complete evaluation with described family forms of dominant inheritance. 44
460 Textbook of Perinatal Medicine

Obstruction of the Ureterovesical Junction double kidneys where the ureteral dilatation is
produced by an ureterocele, in this situation it is usual
It is the second cause of hydronephrosis, affecting
that the superior pole is hydronephrotic and that the
1/6.500 newborns. 39 It is more common in the
ureterocele is visualized inside the bladder.
masculine sex (ratio 2:1). It can be bilateral in 25% of
the cases. Associate Anomalies The contralateral kidney will
The obstruction is generally due to a regional present anomalies in 16% of the cases, including
malfunction or an estenosis at the ureteral end, pyeloureteral obstruction, multicystic renal dysplasia,
without evidence of vesicoureteral reflux neither pelvic kidney, renal agenesis and vesicoureteral
obstruction of the vesical exit. Also called primary reflux.45
megaureter or megaureter without reflux.
Prognosis It is generally good so that until 40% is
Diagnosis The affected kidney is shown with solved postnatally in a spontaneous way. The ureters
pyelectasis and a tortuous ureteral course (Figs 35.16 with diameters of less than 6 mm are associated with
and 35.17). low surgery incidence, while those that have a
The intravesical urine volume and amniotic fluid diameter above 10 mm have a high incidence of
volume are usually normal, although they can be surgical corrections46,47
diminished in some cases of severe bilateral obstruc- It should be carried out a neonatal follow-up with
tions. the realization of a cystourethrography and a
renogram to evaluate the renal function. Those that
Differential Diagnosis The dilated ureter easily can
present a poor renal function will be candidates to
be differentiated of intestine because the urine is
surgery with ureteral reimplantation.
anechoic while the intestinal content transmits low
It is sporadic with a low recurrence risk.
echogenicity.
It should be carried out the differential diagnosis
Secondary Obstruction to Ureterocele
with the vesicouereteral reflux which can have the
and Ectopic Ureter
same prenatal echographic appearance and not to be
able to exclude until the realization of a cystoureto- The ureterocele is a cystic dilation of the distal ureter
graphy in the neonatal period. It will also be necessary in its intravesical portion.
to carry out the differential diagnosis with strange
cases of obstructions in the exit of the bladder that
produce a massive uretral reflux and in the cases of

Fig. 35.16: Dilatation of the ureters Fig. 35.17: Dilatation of the ureters
 Ultrasound Diagnosis of Urinary Tract Anomalies 461
An ectopic ureter is that is not inserted near the these cases a meticulous echographic study would
posterolateral angle of the trigone. demonstrate a kidney increased of size with two
The ectopic ureter can end in the urethra, in the collector systems. The prenatal diagnosis of double
neck of urinary bladder or in the trigone, in an system is usually carried out during the second half
inferomedial localization regarding the normality, in of the pregnancy with the presence of two or more
girls it can also be inserted in the vestibule of vagina, than the following signs: limited hydronephrosis to a
vagina or uterus and in males in the seminal vesicle, kidney pole, double renal pelvis not communicated,
ductus deferens or ejaculatory ducts. megaureter ipsilateral and ureterocele49 (Figs 35.18
The incidence is difficult to determine. There are and 35.19).
studies that estimate it in 1/9000 newborns.39 When hydronephrosis exists the superior pole is
The ureteroceles frequently associates in girls (until usually affected and the ureterocele can be
80%) to double renal systems being located in these demonstrated if the bladder is full. We can not see
cases the ureterocele in the superior system.48 the ureterocele for different reasons: dysplasia of the
However, in children until 40% drainage to a superior pole that makes excrete little urine, empty
unique collector system. The ureteroceles and the bladder, big ureterocele wich confuses with the own
ectopic ureteres are bilateral in 10 to 15% of the cases. bladder. An ectopic ureter will be suspected when
The double systems take place for the develop- hydronephrosis exists in the superior system of a
ment of two ureteral gemmae starting from the double system, and this dilated ureter seems to end
mesoneprhic duct. In the double systems the place below the base of the bladder without seeing an
where drainage is invert, so the ureter of the superior ureterocele. The utility of the magnetic resonacia has
pole drainage in a more inferior and more medial been described in cases dudosos50 (Figs 35.20 and
place and the inferior pole one in a superior and 35.21).
lateral place. The ureterocele presence will produce The ureteroceles can be big and even to produce
hydronephrosis in the superior pole, which can the obstruction of the exit of the urine from the
produce dysplasia and deterioration of the renal bladder. They can be bilateral in 15% of the cases51
function. In the inferior pole it can also have (Figs 35.22 to 35.24).
hydronephrosis but it is usually due to vesicoureteral The amniotic fluid is usually normal in the cases
reflux. of unilateral affectation.
Diagnosis In absence of hydronephrosis it can be
difficult to diagnose prenatally a double system. In

Fig. 35.18: Duplex kidney. A sagital scan through a duplex Fig. 35.19: Duplex kidney. A sagital scan through a duplex
kidney shows two collecting systems kidney shows two collecting systems
462 Textbook of Perinatal Medicine

Fig. 35.21: Duplex kidney. A sagittal scan through a duplex

Fig. 35.20: Duplex kidney. A sagittal scan through a duplex kidney shows two collecting systems
kidney shows two collecting systems

Fig. 35.23: Ectopic ureterocele in the bladder

Fig. 35.22: Ectopic ureterocele in the bladder

Associate anomalies The vesicoureteral reflux is

presented in the inferior pole in 50% of the fetuses
with ureterocele in the superior pole.52 It does not
exist a higher association with other anomalies.
Prognosis It is better when it have carried out a
prenatal diagnosis, the necessity to carry out second
surgeries is smaller when it has been diagnosed
prenatally.53 The renal function will depend on the
Fig. 35.24: Ectopic ureterocele in the bladder
grade of dysplasia of the superior pole that is usually
bigger in ectopic ureters than in ureteroceles. In cases
Differential diagnosis With the reflux and the of severe reflux in the inferior pole can exist also
vesicoureteral obstruction. Also with posterior dysplasia and worsening of the renal function.
urethral valves in cases of ureteroceles that occlude It will be carried out prenatal follow-up ultra-
the urethra, the posterior urethral valves occur only sounds to value the progression of the hydrone-
in males. phrosis.
 Ultrasound Diagnosis of Urinary Tract Anomalies 463
In the postnatal period it will be re-evalued with secondary way renal dysplasia renal recognized
echography, renogram and cystourethrography. In the echographically for echogenic kidneys accompanied
cases with good renal function the ureterocele can be or not by cortical cysts61 (Fig. 35.25).
punctured through the urethra by cystoscopy that It is usually associated to a variable grade of
although has a risk of increasing the reflux in 30%, it bilateral ureterohydronephrosis.60 (Fig. 35.26) The
doesn’t seem to increase the necessity of second vesical distension can give place to its rupture causing
surgeries.54 The non functional superior poles are urinary ascites, this ascites is considered a sign of good
usually resected.55-56-57 prognosis, since it liberates the kidneys of the pressure
It is sporadic with a low risk of recurrence. taken place by the obstruction and therefore it
diminishes the risk of dysplasia.55-62-63
Posterior Urethral Valves They can also break the renal chalices giving place
It is the most frequent cause in severe obstructive to perirenal urinomas, sing of bad prognosis since it
uropathy in children, constituting 9% of the cases of associates to renal dysplasia.64
fetal urinary obstruction.55 The approximate incidence It can exists an asymmetric hydronephrosis by a
is of one from each 5000 to 8000 children. It only affects massive reflux to a kidney that is practically
the males. destroyed, this can be a protection mechanism for the
It is produced by folds of membranous tissue with contralateral kidney.65
a fibrous estruma that go from the prostatic urethra The amniotic fluid can be diminished, being this
to the external urinary sphincter producing a a sign of bad prognosis.
difficulty more or less severe of the urine exit from Differential Diagnosis Mainly with the severe bilateral
the bladder.59 The etiology is unknown, one of the vesicoureteral reflux. Sometimes it is not easy. It can
theories is an anomalous insert of the mesonephric be useful to observe that in the reflux the bladder wall
conduit in the cloaca.60 is usually thin, the dilatation of the posterior urethra
Diagnosis It is usually diagnosed in the second and won’t also be seen.
third trimester. The characteristical echographic We will also carry out the differential diagnosis
findings will be bladder dilatation with wall with the uretral atresia in wich usually exists a marked
thickening (taken place by a detrusor thikening) and vesical distension, of precocious detection in the first
dilatation of the posterior urethra. It can exist in trimester or second initial trimester usually accom-
panied with oligoamnios.
We will also make the differential diagnosis with
other rare causes of obstruction of the exit of the

Fig. 35.25: Dilated bladder and a “keyhole”

deformity of the posterior urethra Fig. 35.26: The kidney had moderate dilatation.
464 Textbook of Perinatal Medicine

bladder like the congenital megalourethra where A determination of urine electrolytes is used to
exists a distal obstruction in the penile urethra and in evaluate the renal function, with serial determinations
the ultrasound can be observed cystic images among to avoid the stagnated urine (table 1). According to
the fetal legs,66 the cloacal persistence and hydrome- the result it will also be able to classify as of good or
trocolpos associated to a urogenital sinus that only bad prognosis.
take place in girls,67 and the microcolon.megalocysts It will also be convenient to carry out a fetal
syndrome where it can exist bilateral hydronephrosis karyotype.
and vesical dilatation but it can be polyhydramnios In the fetuses diagnosed before the 32 weeks
and stomach distention, it affects more to the females without signs of renal dysplasia but with oligoamnios
and it is of rcesive atosomal inheritance.68-69 the decompression of the urinary tract should be
evaluated by means of the realization of a vesico-
Associate Anomalies They will be associated to a
amniotic bypass.74 After the 32th week it will be
sequence of anomalies in variable grade secondary
necessary to evaluate the finalization of the gestation
to the obstruction: megalo-cysts, megaloureter,
for the decompression of the urinary tract in the
hydronephrosis, para-urethral diverticula and
proximate neonatal period. Nowadays an option of
dilatation of the proximal urethra. Other associate
intrauterine fetal therapy exits, by means of the
urinary anomalies are: megalo-urethra,70 cryptor-
valvular resection with endoscopy. The criteria for
chidism, hypospadias and urethral duplications. It is
this intrauterine surgery will be the absence of
also very frequent to find anomalies in other organs
echographic dysplasia findings, normal karyotype
(until in 43% of the fetuses)71 like: tracheal hypoplasia,
and some appropriate values of electrolytes in the
persisten ductus arteriosus, skeletal anomalies,
vesicocentesis.75-76
imperforate anus, VACTERL syndrome72 and frequent
It is sporadic with a low recurrence risk.
association of chromosomal anomalies.
When a precocious oligoamnios exists it will take
Atresia Urethral
place a lung hypoplasia and the typical findings of
the Potter’s syndrome (low ear implantation, The real incidence is ignored. It affects more to the
micrognathia, hypertelorism, limbs contracture). males.
It can be cause of the Prune Belly syndrome Etiology is ignored. It is characterized by the
(thilening of the abdominal wall muscles, urinary tract complete obstruction from the urethra secondary to
alterations and undescended testes) due to the the obliteration of the membranous urethra.
abdominal distension secondary to the vesical Diagnosis Echographicly it can be seen a very dilated
distension. bladder with oligoamnios. The detection can be
Prognosis The prognosis is variable depending on carried out very precociously in occasions starting
the graveness of the obstruction that in turn will be from the 10 weeks. Frequently an anhydramnios exists
translated in the ultrasound findings, so that the most with such a loosened bladder that it is difficult to
serious cases, diagnosed before the 24 weeks will have explore the fetal anatomy. (Fig. 35.27 to 35.29)
a perinatal mortality or chronicle renal failure in 53%, In some occasions a vesicocutaneous fistula is
while those diagnosed later on have a bad evolution developed being able to be the amniotic liquid
risk of 7%. normal.77
They are signs of bad prognosis the precocious Differential Diagnosis With other causes of vesical
oligoamnios, signs of renal dysplasia as the echogenic exit obstruction: posterior urethral valves, megalo-
kidneys, cortical cysts, the perirenal urinoma, and the urethra, megacystis-micro-colon syndrome, persistent
association with other anomalies. cloaca, and severe vesicoureteral reflux.
 Ultrasound Diagnosis of Urinary Tract Anomalies 465

Fig. 35.27: Axial plane through the fetal abdomen Fig. 35.28: Axial plane through the fetal abdomen
demonstrating fetal megacystis demonstrating fetal megacystis

Due to the possibility of an early diagnosis an

appropriate option is the interruption of the preg-
nancy. In the case of continuing with the gestation the
possibility of the realization of a vesicoamniotic shunt
will be evaluated.80
It is sporadic with a low recurrence risk.

Table 35.1
Bad prognostic values in fetal urine
Sodium > 100mEq/l
Chlorine > 90 mEq/l
Osmolarity >
280mOsm/l
Calcium > 2 mmol/l
Fig. 35.29: The kidney had moderate dilatation Phosphate > 2 mmol/l
B2 microglobuline > 2 mmol/l
Associate Anomalies They are very frequent (more
than 50%) but difficult to diagnose because of the Vesicoureteral Reflux
oligoamnios.Among them they are: heart anomalies, It is the backward flow of urine from bladder into
diaphragmatic hernia, polydactily, VACTERL ureter and the pyeloureteral system.
syndrome, chromosomal anomalies. The reflux happens in around 1% of all the
It is one of the causes of the prune belly synd- children. The fetal vesicoureteral reflux presents a
rome.79 masculine prevalence, of until 80% and a high
Prognosis It is always bad and almost always lethal. frequency (20%) of high grade reflux (III to IV).81,82
Due to the oligoamnios or anhydramnios they Around 60% is bilateral. It represents 11% of the
develop a lung hypoplasia. The development of a prenatal hidronefrosis cases.83
vesicocutaneous fistula can improve the neonatal The etiology seems multifactorial. The neonatal
survival, however, they usually develop a renal failure reflux seems to have its origin in a distortion of the
that makes them need a renal transplantation with a vesicoureteral junction in utero, secondary to the high
bigger surgical reconstruction or hemodialysis.77 casting pressures that some fetuses present.81
466 Textbook of Perinatal Medicine

Pathology Associate Anomalies

• The urinary tract infection wich is more frequent Mainly anomalies of the contralateral kidney.
in this group, is typically associated to parenchy- • Obstruction of the pyeloureteral junction
matous affectation. • Multicystic kidney
• Until 50% of the infants with sterile vesicoureteral • Renal agenesis
reflux can present parenchymatous renal anomal- • Renal or ureteral duplicity
ies, which suggests a congenital etiopath-ology of
renal lesion independent of the urinary in- Prognosis
fection.84,85
• Many are solved for complete spontaneously. A
Diagnosis 60% grade III, 50% grade IV and 28% grade V were
solved in 14 months.(83)
• Hydronephrosis. It is the main echographic
• 30% of these fetuses presents renal scars, and two
finding. It can be unilateral or bilateral (Figs 35.30
thirds of them present widespread renal lesions.
and 35.31).
• The reflux is the cause of 25% of the renal failure
• Hydroureter and a dilated bladder with slendered
in children and 15% in adults.
wall. They are findings that we could find in the
most severe cases. It could confuse us with some
posterior ureteral valves. Management
• The amniotic fluid volume is normal. • If we found ourselves facing an hydronephrosis:
• The moderate pyelectasis (4-10 mm) can also be — Prenatal control: In utero we must make an
associated to vesicoureteral reflux. echographic follow-up of the hydronephrosis
and of the volume of amniotic fluid.
Diferential Diagnosis — Postnatal control:
We will make it with other hydronephrosis causes – Echography starting from the 48 hours of
• Unilateral: obstruction of pyeloureteral or life
vesicoureteral junction. – Antibiotic prophylaxis
• Bilateral: posterior urethral valves. – Serial cystourethrography

Fig. 35.30: Moderate pyelectasis with vesicoureteral reflux Fig. 35.31: Moderate pyelectasis with vesicoureteral reflux
 Ultrasound Diagnosis of Urinary Tract Anomalies 467
• If it is a moderate pyelectasis Defects in terminal maturation are observed in
– Postnatal Echography polycystic kidney disease (PKD). Initial nephron and
– Echography to the 3 months collecting duct formation is unremarkable in these
– Urologic follow-up kidneys, but there is a later cystic dilatation of these
The treatment will be surgical in those cases that structures causing secondary loss of adjacent normal
present new renal scars, a high reflux grade, a structures. The commonest types are autosomal
progressive reflux, or persistent urinary infections. dominant and autosomal recessive PKD. Both may
The recurrence risk in brothers of the affected cases present prenatally.90
is 34%86 and in children of the affected cases is 66%.87
Polycystyc Kidney Diseases
Renal Cystic Diseases
Two forms of PKD will be discussed in this chapter:
Renal cystic disease compromises a mixed group of 1. Autosomal recessive polycystic kidney disease
heritable, developmental and acquired disorders. (infantile) (ARPKD).
Because of their diverse etiology, histology and clinical 2. Autosomal dominant polycystic kidney disease
presentation, no single scheme of classification has (adult) (ADPKD).
gained acceptance.88 Both diseases may present prenatally or during
The Potter classification (Potter 1972),89 does cover infancy.
the most important conditions seen prenatally (Table Cysts only arise from collecting ducts in ARPKD,
35.2). whereas they arise from all area of the nephron or
Table 35.2
collecting duct in ADPKD. In addition, there are
usually numerous small cysts in ARPKD whereas
Potter classification of cystic renal diseases
there are fewer, larger cysts in the dominant disease.
Type I Autosomal recessive (infantile) polycystic renal Associated abnormalities in other organ systems are
disease
Type II Multicystic renal dysplasia
quite different in both conditions.90
Type III Autosomal dominant (adult) polycystic renal disease Autosomal Recessive Polycystic Kidney Disease
Type IV Obstructive cystic dysplasia
(Potter I) The condition is characterized by symmetric
enlargement of both kidneys secondary to renal
Many of the terms used to describe kidney
collecting tube dilatation. This is associated with
malformations, such as the Potter classification, are
varying degrees of hepatic fibrosis and biliary
confusing since they are base on histology and do not
ectasia.91
take account of recent advances in molecular biology
It is an autosomal recessive condition with and
and genetics. A more straightforward approach is to
incidence of 1/40.000-50.000 live births.92
divide the abnormalities into groups based on the
It is likely to be a defect in the collecting ducts
underlying cell biology, such as aberrant early
resulting in the formation of cystic dilatations of the
development or defects in “terminal” maturation.90
collecting tubules.93 The hepatic fibrosis could be due
The aberrant early development group includes
to overgrowth of the biliary epithelium. The gene for
dysplastic kidney90:
ARPKD is located on chromosome 6p.103
1. Large multicystic dysplastic (Potter type IIa).
2. Small organs with a combination of hypoplasia/ i. Pathology: The kidneys are symmetrically enlarged,
dysplasia (Potter tipo IIb). and this is produced by cystic dilatations of the
3. Severely obstructed kidneys (Potter IV). collecting tubules, which are arranged radially
Kidney malformations associated with syndromes throughout the renal parenchyma.93 The earlier-
are also included within this category.90 forming distal collecting tubules are more severely
468 Textbook of Perinatal Medicine

affected than the proximal collecting tubules. There Careful measurements of both kidneys are
is no proliferation of the connective tissue. important to the diagnosis because affected kidneys
Clinically the disease has been classified in 4 have a faster growth profile than normal kidneys.101
subtypes94 (Table 35.3). Molecular genetics studies provide a useful
adjunct to ultrasound for diagnosing ARPKD and
Table 35.3: Manifesations of Arpkd according to the
these should be discussed with high risk families. It
Subclassification of Blythe and Ockenden
is possible to make a prenatal diagnosis at 11-12 weeks
Type Proportion of Extent of
gestation from chorionic villus sampling.
dilated renal portal
tubules (%) fibrosisl Lifespan MRI has also been used to diagnose ARPKD in
utero, but this technique is not in regular use in most
Perinatal 90 Minimal Hours
Neonatal 60 Mild Months centers.102
Infantile 20 Moderate 10 yr
Juvenile <10 Gross 50 yr
iii. Associated anomalies: The main association is
hepatic fibrosis.
ii. Diagnosis: The typical appearance is of enlarged iv. Differential Diagnoses: The differential diagnosis
kidneys showing increased echogenicity associated for ARPKD is quite large. However, one important
with small or absent bladder and oligohy- consideration is autosomal dominant polycystic
dramnios.95,96 (Fig. 35.32) kidney disease (adult), which can look identical except
These sonographic features may not be present that liquor volume is usually normal. The other main
until the third trimester, however, and it is well diagnoses are outlined in Table 35.4.
documented that fetuses with their condition may
look absolutely normal at the 20-week scan. Thus, this v. Prognosis: The outcome is predicted from the
condition cannot be excluded until well into the third severity of the renal disease, with the poorest outlook
trimester.97-99 for the perinatal type. Infants usually die from
It has been reported few cases diagnosed by respiratory failure rather than renal problems,
transvaginal scanning at 12-14 weeks´ gestation.100 although aggressive ventilatory support and
emergency nephrectomy may improve the outcome.
The outcome is progressively better with later
presentation and decreasing severity of renal
involvement.
Long term complications include severe systemic
hypertension, urinary tract infection and hepatic
fibrosis with portal hypertension leading to
hypersplenism and gastroesophageal varices.104
vi. Management: When scanning demonstrates
bilaterally enlarged echogenic kidneys with oligo-
hydramnios and there is family history of autosomal
recessive polycystic reanl disease, the Outlook is likely
to be very poor. In that setting a termination of the
pregnancy could be offered to the mother before
viability.
When there is no family history and the amniotic
fluid is normal, other conditions that have better
Fig. 35.32: Autosomal recessive polycystic kidney disease. The
images show enlarged kidneys with echogenic parenchyma prognosis should be considered. In those cases,
and the oligohydramnios. The bladder is not visible conservative management is more appropriate.
 Ultrasound Diagnosis of Urinary Tract Anomalies 469
Table 35.4: Echogenic Kidney: Antenatal Ultrasound Appearances and Clinical Findings
Condition Renal Cysts Hydronephrosis AF Cysts in Family Associated findings
size present? parents’ History
kidneys
ARPKD Large No No ↓ No Yes, in Hepatic
sibling fibrosis
ADPKD Large Sometimes No Normal Yes>20 yr Yes, in Ocasionallaly cysts
los parent in parents´ liver,
spleen
Obstructive Small Often yes Depends No No Hydronepfrosis
cystic dysplasia on degree usually urethral
of renal obstruction
obstruction
Finnish type Large No No Norml No Yes, in Raised serum AFP
nephrotic Sd. sibling
Beckwith- Large No No Normal o↑ No Occasionally Macrosomia, large
Wiedemann sd. liver, macroglossia,
omf¡phalocele
Perlman sd. Large No Sometimos Normal o↑ No Yes, in sibling Macrosomia,
hepatoespleno-
megaly ascites,
micrognathia,
depressed nasal
bridge
Meckel Grubel sd. Large Sometimes No ↓ No Yes, in sibling Polydactiyiy
encephalocele
Trisomy 13 Large Sometimes No Normal No No Facial clefting,
holoprosencephaly,
cardiac defects,
polydactyly
CMV infection Large No No Normal No No Microcephaly,
hydrocephaly,
Intracranea
calcification, large
liver and spleen,
hydrops
Renal vein Large, No No Normal No No Maternal diabetes,
thrombosis usually maternal
unilateral pyelonephritis
Normal Normal No No Normal No No

The presence of associated abnormalities present prenatally or in early childhood. The ADPKD
recommends karyotype. classically of Both kidneys present cystic dilatation
Follow-up scans are of value to asses liquor of the nephrons.
volume in pregnancy. It is the most common of the hereditary renal cystic
There is a 25% risk of recurrence. disease, with an incidence of 1/1000 life births.105
The condition is caused by a mutation near the
Autosomal Dominant Polycystic Renal Disease (Potter telomere of chromosome 16 in 90% cases.106 5% of
III) This condition is much commoner than ARPKD. cases are caused by abnormality of chromosome 4.107
However, it is much less common or ADPKD to 90% of cases are linked to the PKD1 gene on the short
470 Textbook of Perinatal Medicine

arm of chromosome 16106 and 5% are linked to the probably related to the presence of multiple
PKD2 gene on chromosome 4.107 microcysts within renal cortex.
Prenatal diagnosis is possible by gene probes from Sonographic diagnosis is usually made in the third
chorion sampling.104 trimester with a mean of 28 weeks.114 Some cases of
i. Pathology: It is a systemic disorder characterized earlier sonographic diagnosis have been reported but
by cysts formation in ductal organs, particularly mostly in cases with known family history.115,116
the kidneys and liver. Cysts may also be present Follow-up scans are essential because in the second
within the pancreas, spleen, and central nervous trimester the kidneys can look normal.
system.88 In the kidneys only 5% of nephrons are Very rarely, the condition can be unilateral.117,118
cystic in the early part of the disease. iii Differential Diagnosis: Several conditions may
ii. Diagnosis: In adults, almost all patients present exhibit enlarged hyperechogenic kidneys. This
one cysts, at least, at age of 30 years.108,109 The echographic feature may correspond to different renal
sonographic appearance is well known: enlarged diseases with different outlooks and perinatal
hyperechogenic kidneys, with a mixture of small outcomes: obstructive dysplasia, multicystic renal
and large cysts.110 (Fig. 35.33) dysplasia, autosomal recessive polycystic renal
It has been reported some cases diagnosed disease, genetical syndromes (Perlman sd., Beckwith-
prenatally. The sonographic finding most common is Wiedermann sd., Bardet- Biedl sd., Meckel sd.),
large kidneys.111-113 The sonographic appearance is nefroblastomatosi, renal vein thrombosis, toxic
similar to the ARPKD: symmetrically enlarged and injured, infections (cytomegalovirus), isquemia,
hyperechogenic kidneys. The bladder is generally aneuploydy, and sometimes, normality.
present and the amniotic fluid is normal. The In autosomal dominant polycystic kidney disease
corticomedullary junction may appear accentuated or few cases are diagnosed prenatally. The diagnosis is
be indistinct .114 Some reports described the presence based in family history, amniotic fluid, associated
of macroscopic cysts within the echogenic kidneys.90 abnormalities and genetical analysis.
Brun et al,27 determine a new specific echographic iv: Associated Anomalies: The most important
pattern: moderately enlarged kidneys (1-2 SD>mean) associated anomalies are cysts in the liver, spleen, and
with, in the majority of cases, a hyperechogenic cortex pancreas. Noncysts anomalies include cardiac disease,
and relatively hypoechogenic medulla that occurs in skeletal anomalies, pyloric stenosis and intracranial
the third trimester. This hyperechogenic cortex is aneurysms.88 Tract urinary malformations have also
been described associated with this condition.114
v. Prognosis: The condition is often asymptomatic and
usually presents in the fifth decade with hypertension
and end-stage renal failure.105
The outlook for those cases diagnosed in utero is
difficult to determine because to date only 83 cases
of adult-type polycystic renal disease presenting
prenatally or in the first few months of life have been
reported. MacDermott et al, 104 reported that in
prenatal cases 43% of babies die within the first year
of life and 67% of survivors develop hypertension.
The best indicators for outcome are the presence of
Fig. 35.33: Adult polycystic kidney disease. Brightly echogenic
oligohydramnios and the perinatal outcome from a
kidneys with accentuation of the cortico-medullary junction and
a small bladder with decreased fluid. previously affected sibling.
 Ultrasound Diagnosis of Urinary Tract Anomalies 471
vi. Management: Management of the pregnancy MCDK are attached to atresia of the ureter and
depends in large part on the parents´ knowledge renal pelvis. This may be related to incomplete but
of the condition. severe obstruction to the kidney early in
The diagnosis of this condition requires very nephrogenesis.121
careful counseling as to both the short-term and long-
Pathology: The kidney is replaced by multiple
term outlook.
smooth-walled cysts of varying size .88
Follow-up scans in the third trimester are of value
Between the cysts is a dense stroma but usually
to assess liquor volume.
no normal renal tissue.122,123 Typically, the renal artery
There is a 50% risk of recurrence.
is either absent o very small.
DYSPLASTIC KIDNEYS-MULTICYSTIC Diagnosis: The prenatal diagnosis for the unilateral
RENAL DYSPLASIA (Potter II) condition is variable and depends on its severity. It is
The diagnosis is inferred from the “bright” echogenic usually straightforward at the midtrimester scan.
appearance caused by the lack of normal renal The classical presentation of MCDK is a
parenchyma and structurally abnormal kidneys. multiloculated abdominal mass consisting of multiple
Dysplastic kidneys can be any size, ranging thin-walled cysts, which do not appear to be
between massive distended with multiple large cysts connected. The kidneys are usually enlarged with an
up to 9 cm. In diameter, which are commonly termed irregular outline and no renal pelvis can be
”multicystic dysplastic kidneys” (MCDK), to normal demonstrated. (Figs 35.34 and 35.35). Circumferential
or small kidneys, with or without cysts. Dysplasia cysts may occasionally be detected in kidneys of more
can be unilateral or bilateral. MCKD is one of the normal size, particularly in association with lower
commonest causes of abdominal masses in the tract obstruction. Parenchymal tissue between the
newborn.90 cysts is often hyperechogenic 90 (Figs 35.36 and 35.37).
It is the most common form of renal cystic disease Bladder and amniotic fluid are usually normal in the
in childhood. It has an incidence of 1/3000 live births unilateral condition.120,121
and is more common in boys.119,120 The majority is The bilateral form is usually diagnosed earlier
unilateral, but it can be bilateral up to 23% of cases.119 because oligohydramnios is present and bladder is

Fig. 35.34: Multicystic dysplastic kidney disease. The kidney Fig. 35.35: Multicystic dysplastic kidney disease. The kidney
appear enlarged with multiple cysts. The contralateral kidney appear enlarged with multiple cysts. The contralateral kidney
is normal. is normal
472 Textbook of Perinatal Medicine

Fig. 35.36: Multicystic dysplastic kidney disease. Parenchymal Fig. 35.37: Multicystic dysplastic kidney disease. Parenchymal
tissue between the cysts is often hyperechogenic tissue between the cysts is often hyperechogenic

not seen. MCDK usually affects the whole kidney; and umbilical cord as up to 35% may have extra-renal
however, occasionally, only part of the kidney is anomalies These are more likely to occur in fetuses
involved, usually the upper pole of a duplex kidney.124 with bilateral than unilateral MCDKD (127).
Careful attention should be given to assessment Chromosome analysis should be also be discussed
of the contralateral kidney because the incidence of with the parents, particularly when structural
contralateral renal anomalies is high (39%). A search abnormalities are detected or dysplasia is bilateral.
should be made for nonrenal anomalies.110 Risks of chromosomal defects are low if there is
There is a high association between dysplasia and isolated renal dysplasia.
obstruction: dysplastic kidneys are classically Kazebnik et al ,127 reported 102 prenatally detected
attached to atresic ureter; renal dysplasia is associated cases. In their experience the condition is unilateral
with lower urinary tract malformations.90 in 76 % of cases, 10% have normal karyotype, but in
Colour Doppler assessment may be useful in all cases they found associated nonrenal anomalies.
determining the diagnosis since the renal artery is
Prognosis: Unilateral multicystic dysplastic kidney
always small or absent in MCKD and the Doppler
has a good outcome provided the contralateral kidney
waveform, when present, is markedly abnormal with
reduced systolic peak and absent diastolic flow (Fig.
35.38).
Differential diagnosis includes upper urinary tract
dilatations and other cystic abdominal masses.
Associated anomalies: Associated anomalies are seen
in the contralateral kidney in 30-50% of cases:
vesicoureteric reflux is the most common, followed
by renal agenesis, renal hypoplasia and pelviureteric
junction obstruction.125, 126
Detection of dysplastic kidneys should stimulate
a detailed examination of the fetus for other structural
abnormalities, including heart, spine, gastrointestinal, Fig. 35.38: Multicystic dysplastic kidney disease. Colour
central nervous system, cleft palate, limb anomalies Doppler shows that the renal artery is always small or absent
 Ultrasound Diagnosis of Urinary Tract Anomalies 473
is normal. If an associated renal anomaly is present, This condition is caused by early renal obstruction.
the prognosis depends on the severity of the Unilateral disease can be caused by a pelviureteral
associated abnormality. The presence of multiple or vesicoureteric junction obstruction.
anomalies confers a poorer prognosis. Bilateral obstructive dysplasia is caused by severe
Bilateral multicystic kidneys have a very poor bladder outlet obstruction (urethral atresia or
prognosis, and all babies succumb in the early posterior urethral valves).
neonatal period to pulmonary hypoplasia.
Pathology : The kidney is usually small with
Management: Unilateral multicystic kidney can be disorganized epithelial structures sorrounded by
manager conservatively with follow-up scans in the fibrous tissue. Cortical cysts are often present.129
third trimester to assess both the multicystic and
Diagnosis : The sonographic appearance is small
contralateral kidney.
echogenic kidneys with peripheral cysts. In the
Bilateral multicystic kidney has a very poor
bilateral condition, bilateral hydronephrosis may be
prognosis, and a termination of pregnancy is an
present, bladder with thick walls and usually
appropriate management strategy.
collapsed and severe oligohydramnios.
The risk of recurrence is small, about 2-3%, but it
The renal cortex assessment is very important. The
can be higher if it is associated with a genetical
presence of cortical cysts and hydronephrosis is
syndrome.
suggestive of dysplasia. 129 Although increased
OBSTRUCTIVE CYSTIC DYSPLASIA (Potter IV) echogenicity is a good sign of renal dysplasia, normal
It occurs secondary to obstruction in the first or early renal echogenicity does not exclude this condition.128
second trimester of pregnancy.128 (Figs 35.39 and 35.40)
The incidence of this condition is difficult to Occasionally the obstructive dysplasia can affect
determine because only a small proportion of part of a kidney.130
obstructed kidneys progress to renal dysplasia. There Differential Diagnosis: The differential diagnosis is
is an approximate incidence of 1 in 8000 live births, established between multiple conditions, shown in
with 40% being bilateral dysplasia .92, 129 Table 35.3 and 35.4.

Fig. 35.39: Obstructive cystic dysplasia. Peripheral cortical Fig. 35.40: Obstructive cystic dysplasia. Peripheral cortical
cysts and echogenic parenchima cysts and echogenic parenchima
474 Textbook of Perinatal Medicine

Table 35.4: Syndromes Associated common are hydrocephalus, cloacal malformation,

with Renal Cystic Disease malrotation and ambiguous genitalia.131
Syndrome Clinical features Prognosis: The prognosis depends on whether the
Meckel-Gruber Large echogenic kidneys, poliydactyly, condition is bilateral or unilateral. Bilateral disease
encephalocele has a poor prognosis, and most of newborn succumb
Patau Hyperechogenic large kidneys,
polydactyly, holoprosencephaly, facial
in neonatal period to pulmonary hypoplasia. In
clefting unilateral disease, the outcome depends on the
Jeune Echogenic kidneys, dwarfism, small presence of renal anomalies affecting to the
thorax contralateral kidney and the presence or absence of
Beckwith- Large echogenic kidneys, macrosomia,
wiede-mann hepatosplenomegaly, macroglossia, associated abnormalities.
omphalocele Management: Due to the very poor outcome of the
Short rib Large echogenic kidneys, dwarfism,
bilateral condition, it can be offered to the parents the
polydactyly polydactyly, small thorax
(Majewski type) interruption of the pregnancy.
Laurence-Moon Renal cysts, retinal dystrophy, Unilateral condition can be managed conser-
(Bardet-Biedl sd) polydactyly, mental deficiency, vatively in the absence of contralateral kidney disease
hypogonadism
Zellweger Cystic kidneys, hypotonicity, limb
and associated abnormalities.
contractures, congenital cataracts, The condition is sporadic.
hypoplastic corpus callosum, heterotopia
Perlman Macrosomia, hepatosplenomegaly, Echogenic large kidneys or “bright” kidneys
ascitis, micrognathia, depressed nasal Large “bright”, or hyperechogenic kidneys are
bridge
Tuberosa esclerosis Epilepsy, mental retardation, cutaneous
occasionally seen at the time of a routine ultrasound
lesions, cardiac rhabdomyomas (in utero) scan or indeed later in pregnancy when a woman is
scanned for another clinical indication.132
Associated anomalies: The main anomalies seen They represent a difficult diagnostic dilemma,
however, are cardiac and the VACTERL association particularly in the presence of a normal liquor
(v ertebral anomalies, a norectal atresia, cardiac volume, since their underlying etiologies are relatively
anomalies, tracheo-esophageal fistula, renal anomalies diverse. A list of the commoner underlying
and limb abnormalities). Other associations less pathologies is shown in Table 35.5 .90 Only a few of
Table 35.5: Conditions associated with large, “bright” kidneys
AF Renal Renal Macrosomy Other Heart Inheritance Alternative
cysts pelvis abnormalities abnormalities prenatal
dilatation diagnosis
Dysplasia N/Oligo +/- +/- - +/- - 10%(AD) -
Obstruction N/Oligo +/- + - +/- - Sporadic
ARPKD N/Oligo - - - - - AR DNA
ADPKD N/Oligo + - - - - AD DNA
Beckwith-
Wiederman N/Poli - +/- + + - AD or Disomy Cyto/DNA
Perlman N/Oligo - +/- + + - AR -
Simpson-
Golabi-
Behmel ? ? ? + + +/- X-linked DNA
Trisomy 13 Oligo - +/- - + +/- Sporadic Cyto
Meckel
Gruber Oligo - - - + +/- AR DNA
Nephro- N - - - - - Sporadic -
calcinosis
 Ultrasound Diagnosis of Urinary Tract Anomalies 475
these conditions can be identified prenatally, usually hypoplasia, as well as renal failure. In these
on the basis of associated abnormalities, liquor circumstances, termination of pregnancy is a
volume and targeted invasive test. In many instances, reasonable option.
however, definitive diagnosis is dependent upon In the presence of normal amniotic fluid, serial
postnatal investigations. scanning should be undertaken to monitor the size
Sonographic detection of large, “bright” kidneys of the kidneys and renal function as indicated by
should stimulate a detailed examination of the rest liquor volume.
of the fetus paying particular attention to the rest of
the renal tract and other measurements. If the bladder Simple Renal Cysts
is enlarged, with or without dilated ureters, then the The incidence of simple renal cysts varies with
findings reflect an obstructive uropathy. If the kidneys gestational age. Scanning at 14-16 weeks´ gestation is
and all measurements lie above the 95th percentile 1/1100 132 and at 20 weeks is 1/2400.133
then an overgrowth syndrome (Beckwith-Wiedeman, The etiology is unclear, but there are two main
Perlman, Simpson-Golabi-Behmel syndrome, etc) theories134:
could be considered. (Figs 35.41 and 35.42). 1. They are retention cysts resulting from the
Karyotyping should be discussed, particularly when obstruction of renal tubules secondary to local
other malformations are detected. vascular damage or inflammation.
If the fetus has isolated hyperechogenic kidneys 2. The second to fourth generations of uriniferous
and a normal karyotype with no evidence of renal tubules fail to degenerate or unite with later
tract obstruction, then the etiology lies between renal generations of collecting tubules, persisting as
dysplasia, autosomal recessive polycystic kidney cystic collections.
dysplasia, autosomal recessive polycystic dysplasia, The cysts are usually solitary and unilocular with
nephrocalcinosis or a variant of normal. no communication with the renal pelvis. The rest of
Accurate prediction of the prognosis can be the kidney is normal.133
difficult, although liquor volume is a key indicator
since reduced or absent indicates that the outcome is Diagnosis: The cysts appear as a unilocular round or
likely to be poor and the pregnancy will frequently oval anechoic structure with well-defined borders,
end in a neonatal death subsequent to pulmonary usually near the periphery of the kidney. Cysts vary
in size (2-4mm).133

Fig. 35.41: Meckel-Gruber syndrome. Distended abdomen

due to the cystic renal dysplasia. Fig. 35.42: Large and bright kidneys with oligohidramnios
476 Textbook of Perinatal Medicine

The differential diagnosis is established between: Renal Tumors

1. Hydronephrosis of the upper pole moiety of a The congenital renal tumors are rare. The incidence
duplex kidney. is 1 per 125.000 newborns.139 The most frequent
2. Perinephric urinoma. tumor is the mesoblastic nephroma.It’s a benign
3. Cysts arising from structures close to the kidneys tumor that presents continuity with the normal
(duplication or mesenteric cysts). nephrons.. The Wilms’ tumor is rare in the fetus.
A s s o c i a t e d A n o m a l i e s: Most simple cysts are The etiology is unknown.
asymptomatic and rarely associated with structural Diagnosis
or other abnormalities. Occasionally they are
The diagnosis will generally be made before the
associated with:133, 136, 137 presence of a polyhydramnios and an abdominal
1. Pelviureteric junction obstruction. mass at level of renal fossa in third trimester.140 (Figs
2. Posterior uretharl valves. 35.43 and 35.44)
3. Turner sd. • The mesoblastic nephroma is unilateral and
4. Trisomy 13. ultrasonography seems a solid mass. Occasionally
5. Trisomy 18 it can be identified cysts, many of them are located
6. Trisomy 21(5% are associated with simple renal near the renal hilus, and almost all affect the renal
cysts). parenchyma. In occasions the tumor can be
Prognosis: The outcome is good for fetuses with simple adjacent to the kidney and compress it. The
cysts.133 mesoblastic nephromas is usually well defined.
When cysts do become symptomatic, simple • It can have polyhydramnios in 70% of the cases,
aspiration under ultrasound control is the treatment resulting from the polyuria secondary to the
of choice.138 hypercalcemia.141
• The hydrops is uncommon, and it bears a bad
Management: Simple cysts seen in the first half of prognosis142
pregnancy can be followed up with scans during the • The Wilms’ tumor presents some echoghaphic
third trimester. The majority resolves and those that characteristics very similar, should be made an
persist do not need any postnatal investigations. anatomopathological study for its diagnosis.143

Fig. 35.44: Neuroblastoma. Solid tumor and heterogeneous.

Fig. 35.43: Neuroblastoma. Solid tumor and heterogeneous. Color Doppler showed artery blood flow
 Ultrasound Diagnosis of Urinary Tract Anomalies 477
Differential Diagnosis 5. Bronshtein M, Amil A, Achiron R, Noy I, Blumenfeld Z.
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9. Mackenzie FM, Kingston GO, Oppenheimer L. The early
• The mesoblastic nephroma unusually associates to
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• The Wilms’ tumor associates to anomalies in 15% graphy. J Ultrasound Med 1994;13:49-51
of the cases: aniridia, genitourinary abnomalies 10. Sepulveda W. Stagiannis K.D., Flack N.J., Fisk N.M
Accuracy of prenatal diagnosis of renal agenesis with color
and hemihypertrophy144 flow imaging in severe second-trimester oligohydramnios..
Am J Obstet Gynecol 1995;173:1788 -1792 .
Genetic markers 11. Hoffman CK, Filly RA, Callen PW. The “lying down”
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Prognosis 14. Gembruch U, Hansmann M. Artificial instillation of
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20. Greenblatt AM, Beretsky I, Lankin DH et al. In utero
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 36
Fetal Echocardiography

Carlos Mortera and Jose M. Carrera

INTRODUCTION However the goal of prenatal Echocardiography

is to make a prediction of the pregnancy outcome,
Prenatal diagnosis of fetal cardiovascular malfor-
offering medical14 and surgical cardiac prognosis
mations is generally based on the use of ultrasound
about the short and long term surgical management.15
and echocardiography techniques during preg-
nancy.1,2
FETAL CARDIOVASCULAR ANATOMY
Anatomical cardiac anomalies,3,4 are identifiable
throughout the use of two dimensional echocardio- The fetal cardiovascular system is developed during
graphy, providing fetal anatomical cardiac the first nine weeks of gestation. Extraordinarily, the
structures2,4. Current use to 3D echocardiography heart is the only organ in the fetus capable of
provides images that may improve anatomical functioning while it is being developed. The “foramen
structural relationship.5,6 However Doppler echo- ovale” and “ductus arteriosus” become the only
cardiography studies allows for additional dynamic different features in a developed fetal heart16 when
information to the cardiologist 7 and interested compared to an adult heart. The right atrium is
obstetrician8,9 in prenatal diagnosis. Consequently, the presented as a slightly larger cavity than the left
application of such methods in normal and abnormal atrium. The superior and inferior vena cava are
fetal cardiac structures and function leads to an identifiable as they meet with the right atrium.
accurate congenital heart disease diagnosis inside the Pulmonary veins tend to be smaller in size due to the
uterus.10,11 reduced pulmonary blood flow, however they become
In order to successfully diagnose cardiac malfor- apparent in mature fetuses.
mations throughout the use of fetal echocardiography The tricuspid and mitral valves present similar
a number of integrated conceptual areas need to be features under echocardiographic analysis Fig. 36.1.
thoroughly understood to achieve a complete Two papillary muscles constitute the subvalvular
cardiovascular diagnosis. First it is required a apparatus of the mitral valve, when only one is
profound knowledge of cardiovascular fetal observed in the tricuspid valve. The tricuspid septal
physiology 12 and anatomy as well as fetal leaflet is distintibly apparent because it attaches to
cardiovascular pathology and cardiac rhythm the septum at a closer location than the mitral valve
disturbances and second to understand the causes and from the apex of the heart. This separation in valve
concepts of heart failure to identify the signs and positioning allows for effective visual recognition if
causes of fetal heart failure.13 the ventricles are pathologically inverted.
 Fetal Echocardiography 483
To ensure normal ventriculo-arterial connections to the fetus, resulting in two major circulations : “the
8,17 a “crossing” by the pulmonary and aortic Fetal Circulation “ and “the Feto-Placental circu-
outflows tracts and arteries must be identified when lation.16
examen with echo Fig 36.2. A parallel position of both Feto-Placenta venous circulation is characterized
great vessels at their origin from the heart would by the entry of the umbilical vein through the fetal
suppose a “transposition of the great arteries”.8 liver. Oxygenated blood travels from the placenta
In order to differentiate the “aortic arch from the entering the fetus through the “ductus venosus”
ductal arch”, Fig. 36.3 three supra-aortic vessels must which is an extension of intrahepatic umbilical vein.
be attached to the curve of the aortic arch before it It has been found that the flow dynamics of the
extends into the descending aorta. Positioned beneath circulatory system in this specific area are crucial for
the ductal arch is recognizable by its continuity from the fetal oxygenation process. The diameter of the
the pulmonary artery into the ductus arteriosus and ductus venosus is reduced as it meets with the inferior
the descending thoracic aorta . vena cava. This reduction in diameter accelerates the
oxygenated blood creating a directional jet towards
FETAL CARDIOVASCULAR PHYSIOLOGY the foramen ovale and left atrium. The entry of this
oxygenated blood stream is cyclically regulated by
The normal fetal heart structure and blood circulation the fetal heart rate. The change in volume in right
differ physiologically12 from that of the adult. The atrial cavity impose the cardiac filling pattern. This
placenta and the feto-placenta circulation become the allows the oxygenated blood to be propelled through
major source of oxygen in the uterus during fetal life the left atrium and left ventricle towards the coronary
as opposed to the adult lung autonomous respiratory arteries and fetal brain fetal brain. Less oxygenated
system. blood returning from the peripheral fetal body,
Two major fetal intracardiac shunts appear, one at coming from “superior vena cava and inferior vena
the foramen ovale level and other at the ductus cava”, enters the right atrium, right ventricle and the
arteriosus. These allow for a right to left direction of pulmonary artery . At this last point most of the blood
the almost total fetal cardiac output. Approximately is diverted through the “ductus arteriosus” towards
half of this circulatory blood volume will be sent to the descending aorta, leaving the pulmonary
the placenta to be oxygenated, returning subsequently circulation at minimum flow.

Fig. 36.1: Normal four chamber view . Systolic and diastolic color flow Doppler phases at the
A-V valves. Anatomic correlation with the heart specimen.
484 Textbook of Perinatal Medicine

Fig. 36.2: Normal Longitudinal Color flow Doppler cut at lateral dorsum.
Crossing of the outflow tracts and arteries and anatomic correlation.

Fig. 36.3: Normal aortic arch at posterior/ anterior dorsum. Normal Ductus arteriosus arch at posterior dorsum.
 Fetal Echocardiography 485
The lower part of the fetal body has low oxygen Color flow mapping increases the diagnostic
requirements. This area is supplied by part of less accuracy and understanding of fetal cardiovascular
oxygenated blood coming from the descending aorta. circulation. 8,9 Color flow displayed must be
The rest of the blood at this level is directed towards performed with the instrumentation settings at a high
the placenta through the umbilical arteries and pulse repetition frequency in order to avoid aliasing.
umbilical cord. The blood oxygenation process takes Intracardiac blood velocities are higher than in the
place at the placenta, which is then returned to the periphery, therefore color Doppler settings must be
fetus, closing the feto-placenta circulation . set up at high frame rates, reduced angle and high
Thus, two main circulatory systems are them filter to obtain good color resolution. However
developed during fetal life: fetal and feto-placenta diagnostic misinterpretation of color intracardiac
circulation. Both circulatory systems are maintained Doppler may occur in complex congenital heart
by the fetal heart. Consequently, high fetal cardiac disease if previous analysis of 2D cardiac malformed
output is required to keep both circulations anatomy has not been properly done.
functioning. This is translated in elevated heart rates 1. Two-dimensional echocardiography identifies
(130-160 beats per minute) rates which are also anatomical structures, spatial relation-ship,
partially imposed by the limited ventricular position of the heart, myocardial thickness and
compliance of the fetal heart. myocardial function . The superimposition of color
Doppler technique allows to perform selective
Another representative feature only present in the
cardiovascular flow dynamics in each heart
fetal circulatory system is the similar systolic pressure
structure.
levels between the right ventricle/ pulmonary artery
2. “Pulsed Doppler” is used for selective flow studies
and the left ventricle /aorta at a systemic level.
in each cavity or vessel and the instrument setting
Therefore right to left intracardiac shunts are
have to be adjusted according to the sampling site.
dependable on systemic vascular resistance as well
“Continuous Doppler” is necessary to identify
as changes in cardiac and vascular blood volume
high velocity blood signals as well as to quantify
adjustment.
intracardiac and Intravascular pressure gradients.
“Color Doppler” opacification of the blood flow
ASSESING THE FETAL HEART
in cardiac cavities and vessels allows to detects
Instrumentation and Technique abnormal turbulent accelerated flows produced by
valve regurgitation and stenosis or other cardiac
The study of the fetal heart requires the combination
defects.
of several dynamic ultrasounds techniques and
3. “M-mode color Doppler flow” is used to measure
sequential cardiac analysis18:
accurately the cavity size and vessels as well as to
The equipment to performed intracardiac fetal
evaluate cardiac rhythm disturbances and cardiac
Echocardiographic studies requires a range-gated 2D
function.
and pulsed Doppler to performed selective 4. Fetal position within the uterus must be
interrogation of blood flow, across the AV valves, understood to evaluate the spatial orientation of
ventricles and great arteries, Ductus arteriosus, the different heart structures in order to trace the
descending Aorta as well as the aortic arch. The best Doppler signal and map the color flow
scanning should also include the hepatic duct and Doppler displayed in anatomical position.
veins , the inferior vena cava, atrial flows, foramen “Anterior Dorsum” and “Posterior dorsum” are
ovale and when possible the pulmonary veins . The usually the best fetal position to study the color flow
equipment should also include CW Doppler to displayed in the aortic arch and the Aorta as well as
sample high velocity jets. the ductus arteriosus arch .
486 Textbook of Perinatal Medicine

“Posterior Dorsum” is the most favorable position 1. The normal position of the heart within the thorax
to obtain the four chamber view to evaluate the is of levocardia.(the heart is usually to the left,
ventricular filling pattern across de AV valves, opposite to the liver and superior to the stomach).
obtaining information about : atrial and ventricular In four chamber view, the thoracic aorta should
size and anatomy, integrity of the atrioventricular be in the left in close relationship with the left
septum and inlet septum, the AV valves and atrio- atrium. The fetal heart lies in a more horizontal
ventricular connections. position due to the large liver.
“Lateral Dorsum” identifies best the opacification 2. Septal integrity should be present although
of the right and left outflow tracts and outlet septum, weakening of inlet / outlet septum may give the
as well as ventriculo-arterial connections. impression of a ventricular septal defect in the
Transabdominal cardiac Doppler studies can be early stages of pregnancy; no posterior
performed with adequate level of cardiac definition confirmation have been possible, probably due to
from the 17 weeks of gestation onward, using a 3.5 a transitional echo view which cuts part of the left
MHz transducer. Cardiac scanning should include at outflow tract and the interventricular septum.
least 3 anatomical and functional cuts to demonstrate 3. The patent foramen ovale should be a visible atrial
structural and functional normal assessment. communication, of approximately the same size
as the ascending aorta but no larger than 6mm
along pregnancy and with detectable moving
Normal Anatomic and Functional Fetal
membrane.
Echocardiographic Features
4. Normal separation between the septal leaflet
A number of normal features should be identified in implantation of the mitral and tricuspid valves
the echocardiographic evaluation of the fetus: should identify right and left A-V valves. Fig. 36.4.

Fig. 36.4: Inflow of the heart with two normal A-V valves. Color Doppler also identifies the PFO.
Inflow of a heart specimen with one common A-V valve in atrioventricular septal defect. Echo / Anatomy correlation.
 Fetal Echocardiography 487
5. Myocardial contractility presents an out of systolic second peak (D) the diastolic phase, which is followed
phase, paradoxical septal movement; however by the atrial contraction inflection (A).
movement of the anterior and posterior heart walls
should be identified to evaluate ventricular Right / Left atrium and Foramen Ovale
myocardial movement and function . Doppler interrogation of the foramen ovale
6. A pericardial space translucency may be visualized demostrates a right-left shunting. Premature closure
in the absence a pericardial effusion . of the foramen ovale have been described.20 Doppler
7. The heart rate should be between 120 and 180 beats tracing in the pulmonary veins is also triphasic as in
per minute. the systemic veins; the lowest velocity deflection
8. Normal ventriculo-arterial connections should be occurs during atrial contraction. Timing of the phases
established when normal crossing of both in the venous flow of the pulmnary veins may be
ventricular outflow tracts and arteries are seen8 useful to diagnose “premature atrial contractions”.
(Fig. 36.2). Increase in right atrial or ventricular filling
9. Normal vessel relationship is seen by the pressure may lead to right heart failure. This increase
transverse three vessel view from left to right the in resistance to umbilical venous flow accentuates the
pulmonary artery, the Ao and the SCV are seen in atrial contraction and the corresponding Doppler
the same transverse plane.19 inflection wave at the “ ductus venosus,” creating a
10. The aortic arch should give origen to the three negative deflection wave that may exceed the zero
supraortic arteries. line at the venous return, this Doppler form should
11. The Ductus arteriosus arch should be identified be recognized as a sign of heart failure.
as a vascular structure in continuity with the The less oxygenated blood returning from the
descending aorta, in a right angle curvature when peripheral fetal body, coming from “superior vena
it meets the aorta. cava and inferior vena cava” as the blood enters the
12. Superior and Inferior vena cava should be right atrium, present a Doppler venous flow with
visualized in continuity entering the right atrium. triphasic wave form related to the same cardiac filling
13. The pulmonary veins should be seen entering the cycle; this wave forms exhibit more pronounce atrial
left atrium. inflection but less flow velocity that the waves
obtained in “ductus venosus”.
Normal Doppler Fetal Hemodynamics

Peripheral Venous Return Inflow Heart and Atrioventricular Valves

Umbilical vein and Ductus Venosus Doppler interrogation of the inlet heart examens the
Doppler sample at the umbilical vein level shows a diastolic filling function . Doppler wave forms
low velocity no pulsatile wave form slightly influence through the tricuspid and mitral valve are similar,
by diaphragmatic respiratory movements. The representing the ventricular filling pattern, the first
intrahepatic umbilical vein continuous with the peak E is followed by the A wave due to atrial
ductus venosus as it meets the inferior vena cava contraction an increase in ¨A¨ happens in early phases
(IVC). The diameter of the ductus venosus is reduced of pregnancy and may represent a transient restricted
as it meets with the inferior vena cava. This reduction compliance of the ventricles; normal velocity across
in diameter accelerates the blood flow converting the the AV valves increases along pregnancy. High heart
non pulsatile Doppler venous wave of the umbilical rate may produce single wave changes in
vein into a high velocity triphasic wave form directly morphology. AV valve stenosis or volume overload
influence by the cycling cardiac filling pattern. The alter the morphology and increases velocity across the
first peak (S) represents the systolic cardiac phase, the valves.
488 Textbook of Perinatal Medicine

Regurgitation of an AV valve is detected within tracts are identified. Subarterial and Infundibular
the atrial cavity. Although quantification of a VSD will be seen during this examination .
regurgitant flow by Doppler is difficult, detection of Semilunar valve systolic flow examination by
a significant regurgitant jet in fetal life represents a Doppler allows to measure time intervals to assess
considerable hemodynamic dysfunction.13 systolic function, but may also give also information
The integrity of the atrioventricular septum in about the presence of valve stenosis and or
continuity with the inlet septum should be seen as regurgitation. Blood velocity across a semilunar
color Doppler fills the ventricles. Weakening of the should no exceed 130 cm/sec therefore a increase
inlet septum may give the impression of a ventricular above this velocity could be due to valvular stenosis
septal defect in early stages of pregnancy; but no or increase blood volume. A turbulent high Doppler
posterior confirmation has been possible, being flow is usually produced by valve stenosis, the degree
probably due to a transitional echo cut .however an of obstruction is the key for measuring the severity
A-V septal defect has to excluded Fig 36.4. of this lesion. In fetal life, each semilunar valve allows
the passage of approximately half of the blood volume
Outflow Heart, Semilunar Valves and Arteries that will transverse the valve after birth; this reduced
Color Doppler has become an extremely effective tool blood volume will cause an underestimation of the
in identifying crossing flow patterns vs. parallel flows obstruction and of the valve pressure gradient,
at arterial level. The different color opacification of making the fetal assessment difficult. Valvular
each artery indicates opposing flow directions that regurgitation produces a backward flow into the left
represent normal crossing of the pulmonary and the or right ventricular outflow tract that in the fetus with
aortic outflow tracts and arteries 8 and normal normal heart rate (>130 beats/min.) represent
ventriculo-arterial connection Fig. 36.2. A single color structural valvular dysfunction.
representation in booth arteries identifies parallel
“Ductus Arteriosus” and Descending Aorta
relationship of the great arteries, being the most
frequent anatomical arterial relation ship seen in The pulmonary artery receives approximately have
transposition of the great arteries Figs 36.5A and B. of the total blood flow ejected by the right fetal heart.
However careful attention should be paid to fetal At this point most of the blood is diverted through
spatial orientation in the uterus in lateral dorsum to the “ductus arteriosus” towards the descending aorta,
evaluate arterial crossing relationship by color leaving the pulmonary circulation at minimum flow.
Doppler 24. The ductus arteriosus is a vascular structure in
Color Doppler also gives information about the continuity with the descending aorta, forming almost
integrity of the outlet septum when both outflow a right angle curvature when it meets the aorta; the

A B
Figs 36.5A and B: (A) Normal outflow right and left ventricular tracts and arteries. The opposite code opacification shows the
normal crossing relationship. (B) Heart specimen from a transposition of the great arteries. Color flow Doppler show parallel
opacification of both arteries.
 Fetal Echocardiography 489
ductus at this level may imposed a degree of flow 2. Comparative disproportion between atrial and
restriction however this is compensated with the ventricular cavities, as well as arterial size; may
active systolic contraction of the right ventricle; lead to demonstrate pathological dilatation or
Doppler wave form shows a slight increase systolic reduced diameter of these heart structures (Figs
velocity as the ductus meets the Aorta. However an 36.7 and 36.8).
abnormal increase in systolic and diastolic velocity 3. A single ventricular cavity.
above 130 cm/seg. is produced during ductal 4. A single atrium.
constriction with marked elevation of systolic and 5. A single atrio-ventricular valve. Fig. 36.4
diastolic velocity. Patients in indometacine treatment 6. Specific valvular anomalies. Ebstein´s anomaly
should be Doppler control to detect signs of ductal 7. Parallel ventricular outflow tracts and arteries. Fig.
constriction Fig. 36.6 and medication should be stop. 36.5
Sudden increase ductal constriction leads to increase 8. A single arterial trunk. (Truncus)
in afterload with tricuspid regurgitation.25,26 9. A septal defect.
Systolic arterial Doppler wave in the abdominal 10. Ventricular inversion.
aorta is followed by continuous diastolic flow as blood 11. Regurgitant valvular jets (by Doppler).
entering the intrabdominal umbilical arteries go in 12. Cardiomegaly.
the umbilical cord towards the placenta. 13. Signs of heart failure: pericardial effusion, ascitis,
hydrops
Abnormal Anatomical and Functional 14. Arteriovenous fístula
Echocardiographic Fetal Features 15. Arrhythmias; taquyarrhythmia, bradycardia
Abnormal features of echocardiography include:
Fetal Cardiovascular Pathology
1. Malposition of the heart is established when atrial
and visceral (liver/stomach) are seen in a wrong “Identification by two -Diamensional Echocardio-
position : The usual place for this structures is graphy and Color Doppler”.
termed as “Situs solitus”. “Situs inversus” involves Congenital heart disease (CHD) appear as a result
reversal of the normal atrial and ventricular of “structural malformations” developed during fetal
positions. “Situs ambiguous” describes an early phases of fetal life. 2,3 The severity of each
undefined medial visceral position. Dextrocardia, malformation marks the future prognosis of the
mesocardia, levocardia are terms which define the newborn with a perinatal death as high as 50%
location of cardiac apex. mortality 4, when congenital heart disease has been

A B C
Figs 36.6A to C: (A) Ductus arteriosus constriction under indometathin therapy. Color flow Doppler shows a turbulent ductal
flow. (B) Normal aortic arch. (C) Coarctation of the Ao. Color flow detects a turbulent flow at the descending aorta.
490 Textbook of Perinatal Medicine

Fig. 36.7: 4 chamber cut in left heart asymmetry due to Hypoplastic left heart

Fig. 36.8: Tricuspid atresia and Hypoplastic right heart. The Color Doppler helps to identify small right ventricular cavity

diagnosed in fetal life21. Chromosomal abnormalities atrium. Anomalous connections of the systemic veins
may be found as high as 42% of the fetal cases referred as well as pulmonary veins may be visually
because of CHD. 22 However “functional cardiac identified.23 The relative sizes of the right and left
anomalies” may occur as transitory disturbance atrium should be compared. Usually the right atrium
during fetal intrauterine growth and usually present is larger than the left atrium. Early closure or
a good prognostic outlook at term. reduction of the foramen ovale 20, (atrial septal
In an attempt to simplify congenital heart disease aneurysm) may be identified as well as a distended
complexity, cardiac malformations may occur at two foramen. The ventricles should be of similar size
basic levels following a segmental approach:7 although right ventricular dominance may be
i. “The inflow level”, including malformations at normally present.
systemic and pulmonary veins, atriums, Atrial Congenital cardiac malformations and conditions
septum, inlets valves, inlet /trabecular septum and at inflow level include:
ventricular cavities. 1. Anomalous venous connections of the systemic
ii. The outflow level which includes ventricles, outlet venous return or the pulmonary veins.
septum, outflow tracts, semilunar valves and 2. Atrial septal defects: Ostium Primun, Ostium
arteries. secundum , and sinus venosus defects and patent
foramen ovale with septal aneurismatic
Inflow Level membranous septum.
The veins are identified by using the four chamber 3. Atrioventricular valve anomalies: mitral/
view as they meet with the right atrium and left tricuspide atresia, mitral/tricuspid stenosis/
 Fetal Echocardiography 491
hypoplasia Fig. 36.8, Fig. 36.9. Atrioventricular the diagnosis is to demonstrate the origen of the
valve regurgitation. Single common valve, pulmonary artery arising from the left ventricle and
Ebstein‘s anomaly. the Aorta from the right ventricle.
4. Ventricular development: hypoplastic left heart, Single color code opacification in both arteries
hypoplastic right heart, single ventricle identifies parallel arterial relationship which
(univentricular heart), single inlet, double inlet, represents a discordance ventricular-arterial
atrioventricular canal complete and partial, and connection, so called transposition of the great arteries
ventricular inversion (atrioventricular discor- Fig. 36.5. Single opacification of one single arterial
dance) corrected transposition. trunk , truncus.
5. Ventricular septal Defect: inlet portion (perimemb- Congenital cardiac malformation and conditions
ranous), trabecular (muscular), and apical . at the outflow level include:
6. Pericardium (effusion) 1. Aortic valve / Pulmonary valve: atresia, stenosis
7. Myocardium: Ventricular anatomy. (right ventricle and regurgitation.
heavily trabeculated containing the tricuspid valve 2. Hypoplastic aortic arch / pulmonary trunk.
with a confluent papillary muscle/ left ventricle 3. Coarctation of the Aorta Fig. 36.6 / Aortic arch
smooth endocardial walls with the mitral valve interruption.
and two well defined papillary muscles. 4. Coronary arteries anomalies
Left ventricular myocardial contractility , function 5. Absent pulmonary valve syndrome.
and hypertrophy . 6. Single arterial trunk (truncus arteriosus).
8. Cardiomyopathies: hypertrophic (diabetes etc.), 7. Tetralogy of Fallot Fig. 36.10 / Pulmonary atresia
dilated (endocardial fibroelastosis etc.) + VSD
9. Cardiac tumors. 8. Double outlet right ventricle. Fig. 36.11
9. Double outlet right ventricle and transposition of
Outflow Level the great arteries. Fig. 36.11.
Color Doppler has become an extremely affective tool 10. Ventricular septal defect: infundibular,
in identifying “crossing flow patterns” versus perimembranous, subarterial, trabecular.
“parallel flows”. 8 The different color code 11. Aorto/pulmonary window
opacification of each artery indicates opposing blood 12. Anomalies of the Aortic Arch
flow directions that represent normal ventriculo- 13. Hypoplastic Aortic Arch and Coarctation of the
arterial connections24, Fig. 36.5. Although the key to Aorta Fig. 36.6 versus interrupted Aortic Arch.
The diagnosis of structural and functional heart

A B
Figs 36.9A and B: Hypoplastic left heart syndrome with mitral atresia and aortic atresia. (A) Single ventricular cavity corresponding
to the right ventricular. Tricuspid regurgitation is seen. (B) Eco/Angiogram to show the retrograde Aortic arch opacification as
no blood is ejected through the aortic valve.
492 Textbook of Perinatal Medicine

Fig. 36.10: Tetralogy of Fallot. The heart specimen shows reduced pulmonary artery compared to the ascending aorta. A double
aortic arch was present as well. Aortic-septal overriding can be seen by Eco demonstrates the Subarterial VSD.

A B
Figs 36.11A and B: Double outlet right ventricle (A) 2 parallel outflow tracts and arteries are seen coming of the right ventricle
with subpulmonary VSD. In double outlet right ventricle with TGA. (B) Double outlet right ventricle with normally related arteries
with subaortic VSD.

disease is possible during fetal life although not septal defects will be impossible to evaluate. Also in
always can be made with the amount of precision some cases of Fallot´s Tetralogy in which fetal
required. There are a number of congenital heart pulmonary blood obstruction is not jet well
malformations in which it is extremely difficult to established during prenatal period, it may be difficult
establish the before birth, as the fetal heart is not jet to identify the obstruction as the main functional/
fully adapted to the future adult circulation that will anatomical feature of this malformation. During fetal
take place after birth. life, malformations and vascular anomalies such as
In the newborn with congenital heart disease, as persistent ductus arteriosus, aorto-pulmonary
the pulmonary circulation and lung oxygenation window , Coarctation of the aorta and interruption
process begins, cardiac malformations will further of the aortic arch are extremely difficult to diagnose
developed. The intracardiac fetal shunts will close because no dysfunctional changes take place before
down as pulmonary artery pressure is reduced to one- birth although indirect cardiac signs as enlargement
quarter of the systemic pressure. of right heart cavities have been described.
During pregnancy some fetal heart defects such Coronary artery anomalies are also difficult to
as ostium secundum atrial defect, anomalous suspect. The diagnosis of atrioventricular or
pulmonary venous return and some small ventricular semilunar valve stenosis is similarly difficult; the
 Fetal Echocardiography 493
degree of obstruction to blood flow is the key to pulmonary atresia with intact septum o restrictive
measuring severity in these lesions. In fetal life each filling compliance lesions.
cardiac valve allows the passage of only half of the 4. Analysis of Doppler detection of valve leak at the
blood volume that will transverse the valve after birth heart.
because fetal intracardiac circulation pattern; this
reduced blood volume will cause an underestimate Fetal Cardiac Arrhythmias
the obstruction and valve pressure gradient making Fetal cardiac disrrythmias 27,28 are rhythm
the diagnosis by Doppler difficult. disturbances caused by irregular cardiac beats “
extrasystoles” or by regular accelerated Tachycardias
Diagnosis and Prognosis of Fetal Heart Failure
produced by ectopic heart beats superior to 180 beats
The Eco examination of the cardiovascular system per minute (bpm). On the contrary bradycardia are
provides much information about the well-being of slow regular heart rhythms, below 80 bpm.
the fetus. Heart failure is established when low cardiac Cardiac disrrythmias count for 1-2% of rhythm
output produces inadequate tissue perfusion. This alterations during pregnancy. Fetal arrythmias are
results in series of complex hormonal reflexes and also associated with a higher incidence of congenital
vascular adaptations to improve direct flow to vital heart disease. However irregular cardiac rhythms
organs. Peripheral vasoconstriction increases the fetal caused by extrasystoles count for 80-85% of benign
systemic resistances in response to cardiovascular rhythm disturbances in normal fetus with no need for
stress with excess production of catecholamines and specific treatment. Management of these disrrythmias
naturetic factor together with other complex humeral during pregnancy only require maternal rest and
agents to maintain arterial redistribution of fetal withdraw of stimulants.
cardiac output for the survival of the fetus . Taquy-Bradycardias 259 are frequent cause of heart
The diagnosis of fetal heart failure is established failure and hydrops. They usually require “in utero”
through the analysis of a number of cardiovascular treatment via maternal administration of anti
features. arrhythmic agents, premature delivery and cardiac
1. the cardio-thoracic size. Cardiomegaly is the pacing of the newborn as in the case of congenital
universal sign of heart failure. This is measured heart block.
using the C.T cardiac/chest circumference ratio.
Classification of Cardiac Arrhythmias
Normal =<0.5.
2. myocardial function .Assessment of cardiac “Irregular Heart Beats” Fig 36.13
function by global myocardium fibber shortening “Extrasystoles” Extrasystoles constitute the most
fraction is calculated by the ¨shortening fraction¨ frequent arrhythmia in the fetus and in the newborn,
using the difference between the diastolic and no treatment is required, only observation.
systolic dimensions divided by the diastolic It has been associated to high fetal catecholamines,
diameter. Normal >0.30. maternal hyperthyroidism and stimulants.
3. increased atrial reversal contraction at the venous “Sinus arrhythmia “ In this disorder, there is variability
Doppler triphasic pattern in the hepatic duct and between the sinus atrial contractions. It is recognized
IVC . This may be a sign of increased end diastolic by the variable space between Doppler pulsed waves
ventricular pressure. Increase A:S ratio peak atrial .
reversal divided by peak ventricular systole Fig “Premature Atrial contraction” Premature atrial
36.12. Normal values should be less than 7%. contraction is the most frequent ectopic arrhythmia
In the fetus with CHD the venous filling patterns often causing extrasystoles. It may be the origin of
should be normal with exception of tricuspid / supraventricular taquycardia.
494 Textbook of Perinatal Medicine

Fig. 36.12: A number of Doppler signs can predict fetal heart failure.
-Increase ¨a¨ in A-V flow.
-Deep diastolic phase at ductus venosus flow
-prominent and negative ¨a¨ wave at the IVC
-small pericardial effusion
-pulsatile deflection at the umbilical flow
 Fetal Echocardiography 495

Fig. 36.13: Supraventricular ectopic beats seen at:

-ductus venosus flow and IVC ( negative deflections)
-Run of Supraventricular tachycardia .

“Premature Ventricular contraction” Premature the Wolf-Parkinson-White syndrome, tachycardias

ventricular contractions are ventricular ectopic beats, are produced by a circular re-entry mechanism;
they are rare in the fetus. atrial activity is not visualized by echo therefore
no specific diagnosis of this syndrome can be
“ Regular fast heart rate” reliably made in utero.
“Sinus Tachycardia” This is a persistent cardiac rhythm Ventricular Tachycardia are rare in the fetus and
above 160 but below 200 beats/min., that may be newborn usually associated to myocardial
related to fetal response to catecholamines, anemia dysfunction or intramyocardial tumor. The
etc. ventricular heat rate is not as fast as in the
supraventricular tachycardia and is in the range of
Pathological Tachycardias 180 beats/min. This dysrrhythmia may present runs
They are regular fast heart rhythms above 200 beats of tachycardia with irregular heart beats and no
/minute, divided in two main groups: supraventri- relationship can be established between atrial and
cular and ventricular tachycardia. ventricular contractions.
Supraventricular tachycardia Fig 36.14 Start “Regular slow heart rate”
a. “Atrial tachycardia”, produced by an ectopic atrial Bradycardias: bradycardia is a slow cardiac rhythm
beat. with heart rates below 80 beats/min. The bradycardia
b. “Atrial flutter” a rapid atrial contraction of 300- include:
400 beats/minute. The atrial activity is blocked at a. “Transient sinus bradycardia” which can occur
the atrioventricular (A-V) node with ventricular during ultrasound examination. In this situation
response of 220 bpm .The p wave can be identified vagal stimulation over the head of the fetus may
at the movement of the atrial wall by m-mode produce transient bradycardia with spontaneous
echo. recovery. Persistent bradycardia may be the
c. “Intranodal Tachycardia” the most common fetal consequence of fetal hypoxia or congenital heart
and newborn tachycardia, it presents with a block with or without structural congenital heart
ventricular response between 220-280 bpm and a disease.
2/1 atrioventricular block. b. “Congenital heart block “ the result of a delay or
d. “Atrio-ventricular tachycardia with accessory a block in the transmission of atrial electrical
pathway” with conduction via the Kent or Mahian impulse along the atrioventricular conduction
intranodal and extranodal pathway conduction. In system. Three degrees may be present.
496 Textbook of Perinatal Medicine

Fig. 36.14: (A) Supraventricular Tachycardia using M-mode

Echo to establish a 2/1 atrioventricular rate comparing the atrial
wall movements and the aortic valve opening. (B) Ventricular
B bradycardia in a congenital complete A-V block

• “First degree block” is produced by a delay in A- ventricular rate of 50-60 beats/min Fig. 36.14.
V conduction system, it is not recognized by echo. Atrioventricular dissociation is the usual
• “Second degree heart block” occurs when an presentation of congenital heart block.
incomplete A-V conduction delay results in an c. Congenital heart block and persistent fetal
isolated atrial impulse which is not conducted bradycardia are either associated either with
through the A-V node, resulting in a missed congenital heart disease or with a structurally
ventricular contraction. normal heart. However, a normal fetal heart
• “Third degree heart block” produces an and congenital heart block can be related to
atrioventricular dissociation. The atrial contraction autoimmune maternal disease as lupus
is independent from the ventricles, it follows the erythematosus 30 , Sjogren´s syndrome and
sinus beats at atrial rate of 150 bpm. Atrio- rheumatoid arthritis, not always diagnosed before
ventricular conduction is blocked and ventricular pregnancy. Anti-Ro and anti-LA antibodies are
contraction is established at an autonomous most likely to be detectable in maternal blood.31
 Fetal Echocardiography 497
d. Congenital heart block with heart rates above 60 14. Small M, Copel JA.(2004) Indications for Fetal
Echocardiography. Pediatr Cardiol 25:250-222.
beats/min seems to have a reasonable outcome.
15. Mortera C. ( 2001 ). Fetal ultrasound in the preliminary
Pacemaker therapy in the newborn should be diagnosis of cardiac anomalies for management of the new
implanted when ventricular heart rate is below 70 born with Interventional Cardiac Catheterization. The
beats/min. Fetal hydrops and heart failure are perinatal Medicine of the New Millennum. 5th world
Congress of perinatal medicine 177-180
related to slow ventricular heart rate below 50 16. Rudolph, AM.(1974) Congetinal Heart disease .Year Book
beats/min. Fetal management should include Medical.(ed) Chicago.Chap 2 pp17-28.
maternal administration of terbutaline or 17. DeVore,GR. (1992) The aortic and the pulmonary outflow
sympathomimetics agents, as well as premature tract screening examination in the human fetus. J.
Ultrasound Med 11. 345-348.
delivery and pacemaker implantation in the 18. Allan (2004) Technique of Fetal Echocardiography .Pediatr
newborn.32 Cardiol. 25:223-233
19. Yoo SJ, Lee YH, Kim ES et al (1997). Three-vessel view of
REFERENCES the fetal upper mediastinum: an easy means od detecting
abnormalities of the ventricular outflow tracts and great
1. Allan ,LD . Tynan, MJ. Campbell,S. Wilkinson J. Anderson arteries during obstetric screening. Ultrasound Obstet.
RH.(1987) .Doppler Echocardiography and Anatomical Gynecol. 9: 173-182
correlates in the fetus . Br. Heart J. 57. 528-533. 20. Eyck,J. Stewart, PA. Wladimiroff, JW.(1991). Human fetal
2. Allan LD(2000) A practical approach to fetal heart scanning. foramen ovale flow velocity waveforms relative to fetal
Sem Perinatol 24:324-330. breathing movements in normal term pregnancies.
3. Cohen MS(2001) Fetal diagnosis and management of Ultrasound Obstet. Gynecol. 1. 5-7.
congenital Heart disease. Clin. Perinatol 28:11-29 21. Cohen MS.(2001) Fetal diagnosis and management of
4. Mortera,C. Salvador, JM. Torrens, M. Carrera, JM.(1992) congenital Heart disease. Clin Perinatol 28:11-29
Diagnostico prenatal de las Cardiopatias Congenitas 22. Allan LD, Sharland GK,Chita SK . et al.(1991) Chromosomal
mediante Ecocardiografia Doppler. Masson-Salvat. (ed) anomalies in fetal congenital heart disease. Ultrasound
Doppler en Obstetricia. Hemodinamica perinatal. Chap. 21. Obst. Gynecol. 8-11.
5. Chaoui R, Hoffmann J,Heling KS (2004) Three-dimensional 23. Wessels M.W, Frohn-Mulder IM, Cromme-Dijkhuis AH,
(3D) and (4D) color Doppler fetal echocardiography using Wladimiroff W.(1996). In utero-diagnosis of
spatio-temporal image correlation. Ultrasound Obstet infradiaphragmatic total anomalous pulmonary venous
Gynecol. 23(6):535-45. return.Ultrasound Obstet. Gynecol, 8. 206-209.
6. Maulik D, Nanada NC, Singh V, Dod H et al. (2003) Live 24. Mortera C, Maroto C, Maroto l.(1995) Echocardiografia
three-dimensional echocardiography of human fetus. Doppler de la circulacion fetal. In McGraw-Hill (ed).
Echocardiography 20(8):715-21. Principios y practica del Doppler Cardiaco.pp.365-389
7. Mortera C,. (1989) Diagnostico Prenatal de las Cardiopatias 25. Achiron R, Lipitz S, Kidrons D, Berant M, Hegesh J,
Congenitas: Valor de la Ecocardiografia. Tesis Doctoral. Rotstein Z. (1996) In utero congestive heart failure due to
Universidad de Barcelona. maternal indomethacin treatment for polyhydramnios and
8. Mortera C. Carrera JM. Torrents M. (1992) Doppler pulsado premature labour in a fetus with antenatal closure of the
codificado en color: Mapa Doppler color de la circulacion foramen ovale. Prenatal Diagnosis. 16. 652-656.
fetal. Masson-Salvat (ed) Doppler en Obstetricia. 26. Kim HS,Sohn S, Park MY, Choi JY.(2003) Coexistence of
Hemodinamica perinatal.Chap 20 . ductal constriction and closure of the foramen in utero.
9. Copel JA. Morotti R. Hobbins JC. Keinman CS. (1991) The Pedatr Cardiol 24(6): 588-590.
antenatal diagnosis of congenital heart disease using fetal 27. McCurdy CM,Reed KL. (1995) Fetal Arrhythmias. Raven
echocardiography: is color flow mapping necesary?. Obstet. Press Ltd NY (ed) .Doppler en Obstetrics and Gynecology.
Chap 26. 253-270.
Gynecol. 78(1) 1-8.
28. Kleiman CS, Copel JA. (1991) Electrophysiological
10. Chiba Y, Kanzaki T. Kobayashi H. et al.(1990) Evaluation
principles and fetal antiarrhythmic therapy. Ultrasound
of fetal structural heart disease using color flow mapping.
Obstet Gynecol 1:284-297.
Ultrasound Med. Biol. 16(2). 221-229.
29. Lynn Ls, Marx G.(1994) Diagnosis and treatment of
11. Kovalchin JP,Silverman NH(2004). The impact of Fetal
structural fetal cardiac abnormality and dysrhthmia.
Echocardiography. Pediatr. Cardiol 25: 299-306
Seminar in Perinatology Vol 18.3:215-227.
12. Rychick J. (2004) Fetal Cardiovascular Physiology. Pediatr.
30. Silverman E, Mamula M, hardin JA.et al( 1991). Inportance
Cardiol 25:201-209. of the inmune response to Ro/La particle in the
13. Huhta JC. (2004). Guidelines for the evaluation of Heart development of congenital herat block and neonatal lupus
Failure in the fetus with or without hydrops. 25:274-286. erythematosus. J Rheumatol 18:12-124.
498 Textbook of Perinatal Medicine

31. Schmidt KG,Ulmer HE, Silverman NH, et al (1991). 32. Comas C, Mortera C, Figueras J, Guerola M, et al (1997)
Perinatal outcome of fetal complete atrioventricular block. Bloqueo Auriculoventricular Completo Congénito
A multicenter experience.J.Am Coll Cardiol.91:1360-1366. Diagnóstico Prenatal y Manejo Perinatal.Rev Española de
Cardiol 50(7):498-506.
 37
Three-dimensional Ultrasound
in Prenatal Medicine
E Merz

INTRODUCTION TECHNICAL ASPECTS

During the past two decades three-dimensional All 3D/4D ultrasound examinations consist of four
ultrasound has evolved from a relatively tedious main steps 2,3 : 1. data acquisition, 2. 3D/4D
laboratory technique to a highly sophisticated visualization, 3. volume analysis/image processing,
technique for daily routine examinations, particularly and 4. storage of volumes, rendered images or image
in prenatal diagnosis. sequences (cine clips) (Table 37.1).
In 1989 the first commercially available ultrasound
scanner (Combison 330) with special 3D probes for 3D DATA ACQUISITION
transabdominal and transrectal scanning was For volume acquisition, the ultrasound beam has to
launched by Kretztechnik AG, Austria.1 This system be moved over the object of interest. This procedure
allowed fully automated volume acquisition and can be performed manually with external acquisition
multiplanar reconstruction of the 3D data set in three systems or automatically with internal acquisition
orthogonal planes. Due to rapid developments in systems.
computer and transducer technology, image quality
and processing speed improved tremendously in the External Acquisition Systems
following years. With the latest 4D technology of
These freehand systems do not require a specially
Voluson® 730 Expert (GE Medical Systems Kretz
designed transducer. The scans are performed using
Ultrasound), volume acquisition and volume display
a freehand technique with a conventional 2D probe,
can be accelerated in such a way that the fetus can be
whose position and movement in space are tracked
visualized three-dimensionally in real-time. This
by an add-on system.4 to 6 However, the freehand
gives the examiner a direct impression of the fetal
systems are not able to achieve 4D ultrasound.3
surface and movements.
Additional 3D/4D techniques have been
Internal Acquisition Systems
developed within the past 2-3 years: Glass body
rendering, Volume contrast imaging (VCI-A and VCI- These systems use specific probes with a fully
C) and Spatio-Temporal Image Correlation automated scanning technique.1,3,7 The automated
(DiagnoSTICTM). scanning movement can be achieved by using
500 Textbook of Perinatal Medicine

Table 37.1: Steps required in transvaginal and transabdominal 3D ultrasound [after Merz (3)]
Data acquisition
• Orientation in the 2D image
• Definition of the region of interest (ROI)
• Volume acquisition
3D visualization
• Multiplanar display
• Surface-rendered image (surface mode, light mode)
• Transparent image (maximum mode, X-ray mode)
• Vascular image (combination of surface or transparent rendering and color Doppler)
• Animated image (rendering of image sequences)
Volume/image processing
• Electronic scalpel
• Filtering
• Contrast and brightness control
• Color image
Storage of volumes, rendered images and image sequences

mechanical gears and/or electronic scanning Triplanar (= Multiplanar) mode

techniques such as steered phased arrays and/or
The triplanar mode allows re-slicing of acquired
curved/linear arrays in which different groups of
volumes in any direction3,8,9Thus any arbitrary plane
elements are excited.1 These probes can be used for
can be shown, even image planes that are not
3D and 4D ultrasound as well.
accessible with conventional 2D ultrasound. The
3D DISPLAY simultaneous display of all three perpendicular
In contrast to conventional 2D ultrasound which sectional planes, provides an ideal basis for a detailed
provides only one imaging mode to demonstrate the tomographic survey of the fetus and allows the
fetus, present 3D technology offers the ability to demonstration of a specific plane to be precisely
review the fetus in several different display modes: controlled (Figs 37.1 and 37.2).

Fig. 37.1: Fetus with physiologic umbilical hernia (ß) (9 weeks) Fig. 37.2: Multiplanar display of a fetus at 13 weeks of gestation.
in the multiplanar display. Upper left: midsagittal scan. Upper Upper left: coronal scan. Upper right: midsagittal scan. Lower
right: transverse scan. Lower left: coronal scan left: transverse scan of the head.
 Three-dimensional Ultrasound in Prenatal Medicine 501
Surface Mode A basic requirement for all three-dimensional
surface rendering is the presence of an adequate fluid
The surface mode can provide three-dimensional
pocket in front of the structure being imaged.
images of the outer and inner fetal surfaces (Figs 37.3
Overlying or adjacent structures such as the placenta,
to 37.5).2,3,10,11 For this purpose the region of interest
fetal limbs, and loops of the umbilical cord tend to
has to be framed with a volume box. For many years
obscure the structure of interest and must be removed
this volume box was only variable in size but
with the electronic scalpel.12
nowadays it is variable in size and shape. Various
rendering algorithms (surface mode, soft surface
Transparent Mode
mode, light mode, soft light mode) can be used in
surface rendering, either individually or in different The transparent mode provides a complete survey of
combinations.3 the fetal skeleton (Fig. 37.6). 13-14 Two different
rendering algorithms (maximum mode and X-ray
mode) can be used, either individually or in

Fig. 37.5: Surface view of a fetal

ear at 38 weeks of gestation.
Fig. 37.3: Surface view of a fetus at 12 weeks of gestation.

Fig. 37.4: Surface view of a fetal Fig. 37.6: Transparent view (maximum mode) of a normal
face at 32 weeks of gestation. fetal skeleton at 20 weeks of gestation.
502 Textbook of Perinatal Medicine

Fig. 37.7: Glass body rendering: The combination of transparent mode and power Doppler displays the vascular system of
the fetus. Left: Circle of Willis (35 weeks). Right: Fetal heart and aorta (30 weeks).

screen. The 3D cine mode can be used with the surface

mode, the transparent mode and the glass body
rendering.

4D DISPLAY

4D Ultrasound
With the acquisition of up to 25 volumes per second,
both the surface and movements of the fetus can be
demonstrated on the screen. This enables the parents
to observe the movements of the fetus and allows the
examiner to study the behavior of the fetus. The 4D
Fig. 37.8: Surface-rendered view of fetal yawing at 32 weeks. cine loop allows the examiner to scroll back through
The 4D cine loop allows scrolling back to the most interesting volumes to achieve the best surface demonstration of
movement.
the region of interest (Fig. 37.8). For 4D volume
rendering two rendering modes are always applied
combinations with the smooth surface mode or the simultaneously.
gradient light mode.
4D cine sequence
Glass Body Rendering
A 4D image cine sequence can be created with a
The combination of 3D Color Doppler or Power Dop- Voluson® 730 series machine in the real time 4D
pler and gray scale 3D images enables the physician mode. After storage as an AVI file, such a sequence
to analyze the fetal vascular system (Fig. 37.7). can be shown with a movie program in any personal
computer.
3D Cine Mode
DiagnoSTICTM (Spatio-Temporal
In order to obtain an overall 3D impression of the
Image Correlation)
object of interest a certain number of rendered views
are displayed in a fast sequence. In this way the DiagnoSTIC or STIC is a new technique for
observer can see the object of interest rotating on the assessment of the fetal heart, based on the automatic
 Three-dimensional Ultrasound in Prenatal Medicine 503
acquisition technology. It allows off-line multiplanar The development of this tool has facilitated a
analysis of the fetal heart. For DiagnoSTICTM, a slow marked improvement in tissue contrast resolution in
motion (7.5, 10 or 12.5 sec) volume scan of the fetal real-time and therefore enables inhomogeneous areas
heart is performed. The data is then rearranged and or subtle lesions to be detected. It provides additional
stuck together by correlation of its temporal and information simultaneously with conventional 2D
spatial domains. An EGC trigger is not necessary. The imaging, without the processing time of off-line 3D
result is a 4D real-time data set presenting one heart reconstruction. In VCI technology a mixture of surface
cycle in motion. This data set can also be rotated and mode and transparent maximum mode rendering is
analyzed in the triplanar view while the heart is employed.
beating at any stage of the cycle.
VCI-A
STIC-Color (Spatio–Temporal Image Correlation
Volume contrast imaging in the A-plane provides the
with Color Doppler)
examiner with an easy 4D approach. It reveals the
In this technique the STIC technique is combined with same anatomical region as in the 2D ultrasound
color Doppler information. This facilitates the image, but the tissue contrast is better with VCI-A
recognition and confirmation or exclusion of (Fig. 37.10).
congenital heart defects (septal defects, transposition
of the great vessels etc.) (Fig. 37.9).3,15-18 VCI-C
Volume contrast imaging in the C-plane allows an
Volume Contrast Imaging (VCI)
easy 4D real time approach in the coronal plane of
In VCI the probe is applied in the same way as in the region of interest (Fig. 37.11). VCI-C offers great
conventional 2D ultrasound and so is an easy potential in prenatal diagnosis because it scans planes
approach to 4D, even for the novice. This volume which are not accessible with conventional B-mode
rendering process is based on thick slice tissue data scanning. This is particularly important when the
3
and it is possible to select a slice thickness between fetus is in an unfavourable position.
3 and 20 mm. Displayed as a thick slice, the VCI
technique allows a 4D volumetric data acquisition.

Fig. 37.9: Fetal heart at 36 weeks. The STIC (spatio-temporal Fig. 37.10: VCI-A (volume contrast imaging in the A plane) of
image correlation) technique combined with color Doppler the fetal heart (29 weeks). This technique shows the same
displays blood flow in all three orthogonal planes at the same anatomical region as in the 2D ultrasound (upper left), but the
time. contrast is better in VCI-A (lower right).
504 Textbook of Perinatal Medicine

digitally. Today, various media are available for the

long-term storage of these volumes, such as
removable hard disks, magneto-optical disks (MOD)
and DVD.
When findings of interest are stored digitally on
non-degrading media, the examiner can retrieve the
volumes at any time and navigate through them in
the absence of the patient.7 This is of particular value
in the diagnosis of fetal anomalies, as it enables the
examiner to take the time to fully scrutinize equivocal
findings without upsetting the patient by lingering
at a particular site with the probe, which is often a
problem in conventional 2D examinations.3
Fig. 37.11: VCI-C (volume contrast imaging in the C plane).
This simple technique yields detailed morphologic information CLINICAL APPLICATIONS
of the plane perpendicular to the marked green line in the
For the examination in the first trimester the
conventional 2D plane. Here: 3D information of the fetal chest
in the coronal view (20 weeks). transvaginal 3D/4D probe is usually applied, and for
the second and third trimester examinations, the
abdominal 3D/4D probe is used. If the fetus is in a
VOLUME/IMAGE PROCESSING
cephalic presentation the transvaginal 3D/4D probe
In many cases the acquired data sets require post- can also be used in the second or third trimester to
processing. In order to obtain a high quality surface assess the fetal brain in a higher resolution.9,20
image, adjacent or overlapping structures which are The advantage of all the different 3D/4D
obscuring the fetus have to be removed with an rendering modes is that it is possible to visualize the
electronic scalpel. Low-level echoes in the amniotic normal embryonic and fetal development at all
fluid may be filtered out by increasing the threshold stages.21-23 The first view of the fetal face has an
value. In Color Doppler the angio threshold removes important psychological effect on the parents to
small motion artifacts and color noise. whom the detailed images are much better
Image brightness and contrast can be set to any recognizable than the 2D pictures. With the use of
desired value in all 3D/4D display modes just as in glass body rendering (3D and power Doppler) even
2D ultrasound. In glass body rendering, the color and the vascular system can be observed by the parents.
gray-scale areas can be adjusted independently of one For the sonographer, however, the detection of a
another. All changes are immediately visible on the fetal malformation is of more importance.24-33 Despite
monitor. These interactive control features make it the fact that with conventional 2D ultrasound
easy to display any object with optimal brightness and examinations most of the fetal abnormalities can be
contrast3,19 detected by the experienced examiner, 3D/4D
ultrasound provides additional information,
STORAGE OF VOLUMES, RENDERED IMAGES particularly for the experienced examiner. 7 3D
AND IMAGE SEQUENCES ultrasonography can depict many image planes that
are inaccessible with conventional 2D ultrasound. In
Long-Term Storage
the first trimester the tri-planar demonstration is
3D/4D ultrasound gives us the capability to store particularly helpful in the verification of a true mid-
volumes, rendered images, 3D and 4D cine sequences sagittal section which is necessary for an exact nuchal
 Three-dimensional Ultrasound in Prenatal Medicine 505
translucency (NT) measurement (Fig. 37.12).34-36 In NT In some cases it is also possible to find defects which
demonstration and measurement, the examination were not revealed with conventional 2D ultrasound
7
time can be dramatically reduced, especially in case In other cases the surface mode can also provide
of an unfavourable fetal position and the quality of impressive three-dimensional images of the inner fetal
the requested image can be improved.36 surfaces (Fig. 37.15).
In the second and third trimesters the photo- 4D ultrasound provides an excellent real-time 3D
realistic surface view of the fetus offers interesting view of the fetus. With the STIC technique even 4D
opportunities for the detection of abnormalities, fetal echocardiography has become reality. The
especially in subtle defects24-33 ( Figs 37.13 and 37.14). triplanar demonstration of the beating heart enables
a comprehensive assessment of the fetal heart

Fig. 37.12: Multiplanar demonstration of a fetus with increased

nuchal translucency thickness of 6.2 mm (à) (11+4 weeks).
Karyotype: Trisomy 18. Upper left: precise midsagittal scan. Fig. 37.13: Surface-rendered view of a small cleft lip at the
Upper right: transverse scan at neck level. Lower left: coronal right side (38 weeks).
scan. Lower right: surface view.

Fig. 37.15: Surface-rendered view of a fetus with left-sided

hydrothorax at 30 weeks of gestation. The fetal chest has been
Fig. 37.14: Surface-rendered view of the left hand with partly “removed” with the electronic scalpel, displaying the
postaxial hexadactyly (ß) (31 weeks). surface of the small left lung.
506 Textbook of Perinatal Medicine

3. Merz E. 3D Ultrasound in prenatal diagnosis. In: Merz E

(ed.). Ultrasound in Obstetrics. Thieme, Stuttgart - New
York 2004
4. Sakas G, Schreyer L, Grimm M. Preprocessing, segmenting
and volume rendering 3D ultrasonic data. In: IEEE
Computer Graphics and Applications. 1995;15:47-54
5. Guerra FA, Isla AI, Aguilar RC, Fritz EG. Use of free-hand
three-dimensional ultrasound software in the study of the
fetal heart. Ultrasound Obstet Gynecol 2000;16:329-334
6. Prager R, Gee A, Treece G, Berman L. Freehand 3D
ultrasound without voxels: volume measurement and
visualisation using the Stradx system. Ultrasonics 2002;
40(1-8):109-115
7. Merz, E., Bahlmann, F., Weber, G., Macchiella, D.: Three-
dimensional ultrasonography in prenatal diagnosis. J.
Perinatal Med 1995; 23:213-222
8. Kratochwil A. Importance and possibilities of multiplanar
examination in three-dimensional sonography. In: Merz E
Fig. 37.16: Glass body rendering (surface-rendered image) of
(ed.). 3-D ultrasound in Obstetrics and Gynecology.
an AV canal (23 weeks). The combination of transparent mode
Lippincott, Williams and Wilkins. Philadelphia – New York
and power Doppler displays the defect in the valvular plane.
– Baltimore 1998:105-108
9. Timor-Tritsch IE, Monteagudo A, Mayberry P. Three-
dimensional ultrasound evaluation of the fetal brain: the
three horn view. Ultrasound Obstet Gynecol. 2000;16:302-
morphology including the great vessels. Due to the
306
fact that the volume can be rotated and re-sliced in 10. Benoit B. Three-dimensional surface mode for
all three dimensions even complex anomalies of the demonstration of normal fetal anatomy in the second and
fetal heart can be demonstrated precisely. The third trimesters. In: Merz E (ed.). 3-D Ultrasound in
Obstetrics and Gynecology. Lippincott, Williams and
combination of STIC and Color Doppler allows an
Wilkins. Philadelphia – New York – Baltimore 1998:95-100
exact control of the cardiac blood flow while the heart 11. Pretorius DH, House M, Nelson TR. Fetal face visualization
in motion (Fig. 37.16). using three-dimensional ultrasonography. J Ultrasound
The interactive display in 3D/4D ultrasound is Med 1995;14:349-356
12. Merz E, Miric-Tesanic D, Welter C. Value of the electronic
particularly useful for the detection of specific scalpel (cut mode) in the evaluation of the fetal face.
abnormalities, making it possible to identify fetal Ultrasound Obstet Gynecol 2000;16:364-368
surface abnormalities and define the extent of a defect 13. Yanagihara T, Hata T. Three-dimensional sonographic
visualization of fetal skeleton in the second trimester of
in all dimensions. The same applies to the targeted
pregnancy. Gynecol Obstet Invest. 2000;49:12-16
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15. DeVore GR, Falkensammer P, Sklansky MS, Platt LD.
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16. Goncalves LF, Lee W, Chaiworapongsa T, Espinoza J,
Schoen ML, Falkensammer P, Treadwell M, Romero R.
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1995;5:222-227 34. Chung, BL, Kim HJ, Lee KH. The application of three-
25. Pretorius DH, House M, Nelson TR, Hollenbach KA. dimensional ultrasound to nuchal translucency
Evaluation of normal and abnormal lips in fetuses: measurement in early pregnancy (10-14 weeks): a
Comparison between three- and two-dimensional preliminary study. Ultrasound Obstet Gynecol 2000;15:122-
sonography. AJR 1995;165:1233-1237 125
26. Lee A, Deutinger J, Bernaschek G. Three-dimensional 35. Eppel W, Worda C, Frigo P, Lee A. Three- versus two-
ultrasound: abnormalities of the fetal face in surface and dimensional ultrasound for nuchal translucency thickness
volume rendering mode. Br J Obstet Gynaecol measurements: comparison of feasibility and levels of
1995;102:302-306 agreement. Prenat Diagn. 2001;21:596-601
27. Mueller G M , Weiner C P, Yankowitz J. Three-dimensional 36. Welter C, Merz E. Nuchal translucency-screening using 2D
ultrasound in the evaluation of fetal head and spine and 3D ultrasound. Ultrasound Obstet Gynecol 2003;22(
anomalies. Obstet Gynecol 1996;88:372-378 Suppl. 1):13
 38
Ultrasound-Guided Fetal Invasive
Procedures: Current Status
JM Troyano, MT Clavijo

INTRODUCTION 3. The characteristics of the surgical equipment or

Since the early eighties a varied amount of experiences the obtaining of the sample.
and trials of fetal puncture (fine needle aspiration) As the tendency is to obtain samples with the
have been carried out with diagnostic aims 1-5 . At the maximum diagnostic guarantee and a minimal risk
beginning, the only possible way to enter the foetal to the integrity of the pregnancy, it is of capital
evironment was with the support of a Fetoscope but importance, with few exceptions, to use sectio needles
the spectacular development of the already well no smaller than 18 g.
known Ultrasonography has permited the invasion It is clear that depending on the tissue sample we
of the intrauterine enviroment with tools that are more are aiming to obtain, it is not always possible to use
and more harmless in the use, especially in the innocuos tools. A clear example are the devices used
gradually tighter sections and the evolution of certain to date for skin biopsies to diagnose some types of
characteristics of the new needles that are now being Genodermatosis, which consist on clipper forceps
incorporated into the new biopsy techniques 3,6,7. Fetal measuring 2.5 mm.
puncture with diagnostic aims is technically possible, These methods in many cases require the use of
provided it is done by adequatelly trained hands, but an anesthetic, including in some, General Anesthesia,
the essential problem lies in establishing the correct previous to proceeding to the incision in the maternal
indications which are not yet quite defined 8. abdomen, with a scalpel, and the introduction of a
trocar sheath enquivalent in sectio to a Verre needle
TECHNIQUE GENERALIZATION that serves as a guide vehicle for the mentioned
Whatever the location of the foetal puncture may be, system or method.
a certain number of requirements are imperative. The complications derived from the use of 2.5mm
1. The operator must have sufficient working sectio needles and the transabdomen forceps method
experience in invasive echography. are closer to those of the fetoscope, added to the fact
2. The room should have surgical consideration or that the great flexibility in many cases of the method
rank, it is necessary to have an aseptic room for itself, having the availability of a great variety of
echographic intervention. A sterile wrap is needles of relatively small calibre (18g standard),
recommended for the ultrasound probe. We use a obteining very good biopsies, including in skin
surgical glove for an airtight seal. samples and visceral solid areas (Fig. 38.1) 2,7.
 Ultrasound-Guided Fetal Invasive Procedures: Current Status 509

Fig. 38.1: Different types of needles Fig. 38.2: Subtrochanteric muscle biopsy: echographic
and system for fetal biopsy monitoring. The arrow indicates the puncture position obliquely
to the fetal femur

Within the organs that are intrauterinally trocar syringe in all its circumference, acting as a
reachable. With worthy guarantees, the one that circular blade, and a conical sheath with vacuum
follows in difficulties after the skin sampling, is the suction embolous contriving through its interior
kidney, fundamentally due to its histological which allows to obtain cylinders of 2-5 mm in
parenchimal stratum constitution 9 . maximum length, with optimal safety conditions and
We can only consider satisfactory the samples or histological quality, similar to those of the Tru-Cut
cylinders that include corticomedular stratum. The method.
fetal availability in respect of its intrauterine position, Of all the viscus solid organs within reach, the one
the distance and the interposed tissue to the kidney that offers the least problem is the liver, its spongy
(skin, muscle) as well as perirenal fat and the very tissue constitution and its great size and volume in
capsule, are the elements that obstruct the obtaining the fetal abdomen allows optimal accessability and
of valid samples. consequently offers samples in practically 100 % of
The use in these cases of a catheter of 14-16g calibre all cases, using a conventional fine needle of 18-20 g.
with isometric aspiration techniques with constant The obtention of muscle tissue samples offers one
vacuum, allow to obtain valid samples, between 69- of the main difficulties due to the topographic and
80 %, while the use of 18-20g calibre catheter obtains anatomical characteristics of the skeleton, also the
the very best specimens between 25-30%. This means important motorous innervation. For this reason it is
that isometric (fine needle) puncture-aspiration necessary to correctly select the spot and the muscular
techniques do not always offer the results hoped for area least suspectible to provoke indelible functional
on solid organs, fundamentally the kidney, unless lessions.
wider catheters are used, that are far from the The most accessible topographic areas are the
“harmless philosophy” that should prevail in these external face of either thigh, but it is technically more
processes. attainable the vastus externus muscle (Fig. 38.2); it is
For these cases and others that are similar that a zone covered by the subtrochanteric fascia-lata in
could present themselves, depending on the tissue an oblicular direction descending towards the fetal
characteristics, the use of methods such as the femur, The use of the sure cut systems 18g with
Aspiration Biopsy Set that includes an 18g bisided incorporated vacuum aspiration allows a sucsesses
510 Textbook of Perinatal Medicine

rate over 75%. Conventional spinal needles with metre away from the surgical table, interplacing a
complementary aspiration by 50cc syringe vacuum serum of the same length between the needle and
allows to obtain sample with great difficulties. the syringe.
When the puncture area has liquid characteristics, 9. Except in exceptional circumstances such as
the echographic view is wide ranged, allowing a large pericardic and pleural overflow that need an
field of action. operating time of about 15-30 minutes, it is
4. In general, technically it is precise to choose the absolutely feasable to carry out without any
most direct route, avoiding any interpositing anaesthetic procedures.
obstacles, being also of interest to avoid the Aspiration in cystic disorders will fundamentally
placenta if at all possible. orientate the diagnosis. Aspiration on ovarian cysts
5. Once the crucial point to puncture has been is only indicated in complex cases derived from its
determined, the needle should be introduced dynamic volume or due to rare structural types with
within the field of view of the probe, frame by therapeutic aims more than to diagnostic ones.
frame until reaching the fetus. We collect suspicious chylous collections, where
6. It is recommended to approximate the puncture the presence of high lymphocyte concentrations
point without making direct contact with it in the practically give a sure diagnosis also the fact that it
first instance, until quite certain of the needles allows a genetic study in very few days, justifies this
angle to the chosen spot, being of capital type of procedures (Fig. 38.3).
importance to enter with only one sudden jab to The puncture of pericardic discharges has also the
avoid sudden fetal jolts or movements. same diagnostic aims as well as being therapeutic.
7. It is advisable in all free-hand fetal punctures Concerning brain punctures, the most
carried out, that the operator should take into representative, the ventriculocentesis, also allows us to
account the dynamic variations of fetal positions. accomplish serological marker studies in RCL,
8. For better manipulation, an assistant should be in independant to any derived therapeutic attitude,
charge of carrying out the isometric aspiration although in this last case the efficiency of the
process at a prudential distance, approximately a derivative proceedures in hydrocefalia is uncertain
(Fig. 38.4).

Fig. 38.3: Cystic lynphangioma: percutaneous puncture Fig. 38.4: Ventriculocentesis: obtaining cephaloraquideus liquid
deter mines qualitative and genetic characteristics determines the presence of viral bodies by polymerase chain
(lymphocytes) reaction
 Ultrasound-Guided Fetal Invasive Procedures: Current Status 511
Of all the structually cystic processes, the obtention one centimetre under strict echographic monitoring.
of fetal urine in dilated urological pathology Preferably the external third of the right lobe, should
represents the greatest and highest interest for be chosen, as it offers a minor principal
diagnosis value. The biochemical analysis of the foetal vascularization, if not, the suprahepatic vessels
urine allows us to detect irreversible tubular lessions should be avoided (Fig. 38.5).
from those which have a normal renal function. If the diagnosis being sought for is histological,
There is no doubt that the incorporation of the cylinder should be conserved in formaldehide if
biological molecular techniques and DNA studies on the contrary it is enzimatic, it should then be
allow to establish in many of the cases, the alterations airtight sealed in carbonic snow.
of any determined genetic locus 10-13 . The gestational age recommended should be
Ocassionally, we may find that we do not have around 20 weeks, provided that the hepatic
enough material due to the lack of family records of metabolism and main enzimatic processes are well,
desceased relations, in these cases the absence of this or practically established.
previous information constitutes a serious
inconvenience in order to establish a prenatal Indications
diagnosis, as this is based only on a small corionic- Prenatal diagnosis, fundamentally of enzimatic
villi, funicular or amniotic sample 11,14 . alterations and of lethal metabolic characteristics 15,16.
This situation is where sampling directly from the
fetal tissue is of special relevance for the diagnose of Ornitil Transcarbamylase Deficiencies (OTC)
one or the other, or in order to rule out any
This mithocondrial enzyme of the urea cycle is
pathological suspicion of family inheritance that are
synthesized in the liver or the intestines. Sex-linked
being submitted to any particular study.
disorders tied to the sex, are shown on the screening
“The taking of fetal samples by biopsy techniques
data of mothers who have urine excretion of orotic
is justified only in cases when the prenatal diagnosis
acid.
of any specific pathological illness is not possible, or
is frankly difficult, using any of the existing
Primary Hyperoxaliuria (PH)
conventional techniques.”
This is severe, charted renal insuffiency of rapid
LIVER BIOPSY evolution, that is characterized by the presence of

Technique
Fetal transabdominal aspiration-puncture using 18g
needles with conic catheter or spinal needles of the
same sectio with isometric vacuum aspiration using
a 50cc syringe and serum system. Once introduced
into the fetal kidney, soft brief inward outward
movements should be made in the same direction as
the puncture.
Firstly the aspiration system should be extracted
and last of all the needle, to avoid contaminating any
other tissue. The spot to be puntured should be
situated between the belly bottom and the border of Fig. 38.5: Liver biopsy: ecographic monitoring and histological
the rib. This fate is helped by the physiological samples of fetal liver (19 weeks). Extramedullar hematopoietic
hepatomegalia, introducing the needle aproximately foci can be detected
512 Textbook of Perinatal Medicine

Calcic oxalate deposits in the renal tubule, FETAL PUNCTURE IN THE

microlithiasis and interstitial fibrosis. The hepatic EVALUATION OF RENAL STATUS
level is accompanied by a total absence of alanine,
inactivity of the catalitic gliosilate aminotranferase The correction of a theoretic renal obstruction problem
and immunoreactive proteins. This is incompatible is possible, in spite of the difficulties and risks that it
with life. holds, even if in the majority of cases it is not
For diagnosis it is fundamental to have the necessary. We should start by stating that an
previous family clinical history available. ultrasound echography diagnosis of the obstructed
renal pathology does not necessarilly imply an
Carbamoyl Phosphate Synthetase Deficiency irrevesible function alteration. In this sense the
amniotic volume can be used as an indirect marker
This is an enzymatic defects of the urea cycle with of the actual renal function, but this does have the
recesive autosomic inheritance. Other autosomic inconvenience that it includes the possible measuring
recesive disorders may be detected by means of of the intrinsic clearance function.
hepatic biopsy, including: When taking into account the possibility of
• Non-ketotic hyperglycinemia practising an intrauterine derived therapy, this can
• Prenatal diagnosis of infantile neuronal ceroid- only be justificable in those fetus in whose kidneys
lipofuscinosis. there has been no irreversable damage. However, this
• Biliar atresia (type I cysts). makes it essential to establish a precise evaluation of
• Long-chain 3-hydroxyacyl-CoA dehydrogenase 17- the renal function, in order to adequately select those
20
fetus that will benefit from prenatal therapy.
The most conflictive situation is the renal dysplasia
Complications
. In the latter coexist tissular phenomena that are
The prenatal liver biopsy has few risks on a tissular characterized by fibrosis, dysplasia, cartilagenosis,
level, due to its own visceral characteristics. Those frequently associated to corticomedular cysts,
risks are derived from the main vascular tears which although not always so (Fig. 38.6).
will have great bleeding resulting in fetal death. In Aproximately 90% of all kidney dysplasias is
our experience (7 prenatal punctures), we have associated to dilated or obstructive disorders. In these
observed no complications (Table 38.1). cases it can be remarked that any derived therapeutic
action is unnecessary.
Table 38.1: Experience with seven prenatal punctures
for liver biopsy
The high resolution echography has turned into
the unquestionable kidney evaluation processes,
Reasons for biopsy Number of cases
however, it does have a few diagnostic limitations:
OTC diseases in the same family. 4 (Table 38.2).
Previous affected brother. 1
Mitocondrial respiratory deficit. 1 Table 38.2: Fetal Neuropathy. Echographic prediction
Non-ketosic hyperglycinemia. 1
Results Tissue Marker Sensibility Specificity
Prenatally confirmed diagnosis 2
Corticomedular Cysts 70% 100%
of OTC deficiency
Hyperecongenity 60% 90%
Prenatally non-confirmed diagnosis 1
Hydronefrosis 75% 70%
with neonatal exitus by hyperammonemia
Hydronefrosis + Cysts 90% 100%
Prenatally confirmed as non-affected fetuses. 4
 Ultrasound-Guided Fetal Invasive Procedures: Current Status 513

Fig. 38.6: Fibro-cortical dysplasia associated with corticomedullar cyst and renomegalia

In our experience the obstruction of a kidney practically in their totality by the proximal tube, if it
without objectible cysts or hyperechos does not, is present in fetal urine and in the amniotic fluid in
however, exclude dysplasia. This quite alarming fact large quantities (higher than 8 U/l), it is indicative of
occurs approximately in 25-30% of all cases 8-21 . tubular tissue destruction.
From this we can deduce that the echography on The detection of b -2 microglobuline would be
its own does not diagnose all renal dysplasias, and considered in the same manner. (Figs 38.7 and 38.8)
for this reason fetuses with pelvic dilation are Corresponden a los dos esquemas de la nefrona).We
subsidiary of derived drainage. found that the levels of biochemical markers are
A biochemical study of fetal urine is capital data sensibly low in the physiological urine in comparison
in the managing of these fetuses. The composition of with the cases affected with irreversible renal disorder.
the fetal urine stays constant, practically throghout The same outcome occurs with the tissular markers,
the pregnancy and with hypotonic characteristics. NAG and b2 microglobuline(Table 38.3).
This fact has automatically demonstrated an optimal
Table 38.3: Fetal Urinary Aspiration: Pathological
and reliable renal function and on the contrary and
Biochemical markers.
iso or hypertonic urine, a defficiency in renal function
Pathological Urine Values
with an infastous prediction.
Weeks
The biochemical markers that have close relation 18-20 20-30 >32
with a renal function are defined by the Na+, Cl- and +
Na (mEq/ml) 120.0 126.44±11.50 139.60
osmotic urine. Cl- (mEq/ml) 119.0 132.50±7.18 141.00
Another determining factor in the normal renal OsM (mOsm) 240 261.50±24.20 281.00
clearance function derived from the near high NAG (U/l) 18.0 25.83±0.85 25.73
b2mG (ml/l) 26.0 38.97±1.30 38.72
reabsorvative tubular activity, is the establishing of K+ (mEq/ml) 3.1 3.41±0.66 3.90
specific proximal tubular lession selective markers. Creatinine (ml/l) 1.2 2.54±0.83 3.70
These markers correspond to lisosomial proteins
exclusive of the proximate tubular structure and When we compare the relationship between the
become expressed by NAG (N-acetil D- ionic concentrations and the osmolarity (Na+ and Cl)
glucosaminidase). Low molecular weight proteins of the fetal urine, and those of the amniotic liquid,
filtered by the glomerular system and reabsorbed we do not find significant differences between fetuses
514 Textbook of Perinatal Medicine

Na +
Na
+
Na +
β2 mcG
NAG

Cl - N AG
NAG

Cl - β2 mcG
Cl -

Hypotonic β2 mcG
Urine
Urine and
Amniotic liquid
Fig. 38.7: Biochemical markers that have close relation with a
renal function are defined by the NA+, Cl- and osmotic urine
Fig. 38.8: Another determinating factors in the normal renal
derived from the near high reabsorbative tubular activity. Fetal
cleareance function correspond to lysosomial proteins
urine stays constant, practically through the pregnancy and
exclusive of the proximate tubular structure (NAG), if it is
with hypotonic characteristics.
presente in fetal urineand in the amniotic fluid in large
quantities, it is indicative of tubular tissue destruction,
with conserving and fetuses with patological Beta-2- microglobuline would be considered in the same
functionalities. But comparing the levels of NAG and manner.
b2-microglobuline, a significantly greater
concentrations of the two markers in the amniotic The increase in concentration of NAG and β2
liquid of the affected fetuses have been observed microglobuline increase possibly due to the
(Tables 38.4 and 38.5). cumulative effect of the amniotic clearance
Table 38.4
mechanism.
This opens the field of study of nephrouropathies
Physiological Values: Urine vs. Amniotic Liquid
Weeks
through the determination of these and other
Urine / Amn. Liquid 18-20 20-30 >32 parameters in the amniotic liquid, without the need
Na+ (mEq/ml) 42/137 42/140 47/140
for invasive study of the fetal urine 21 .
Cl- (mEq/ml) 23/109 47/109 41/108 The K+ and creatinine concentrations are different
OsM (mOsm) 98/267 102/273 102/271 in their predictive evaluation as there exists a great
NAG (U/l) 2.0/3.6 2.7/3.62 2.0/4.69 clearance effect in the placenta and great variability
b2mG (ml/l) 4.7/4.5 5.1/5.0 5.3/5.8
K+ (mEq/ml) 41/140 in its ionic charge, that makes the potasium filtration
Creatinine (ml/l) 1.9/.6 very disperse, in the other hand 90% of the K +
concentration are intracellular 8,21.
Table 38.5 Summarizing, we can adventure a prediction of
Pathological Values: Urine vs. Amniotic Liquid renal viability in relation to those parametres
Weeks expressed. In the Table 38.6 taking into account that
Urine /Amn. Liquid 18-20 20-30 >32 these values are applicable to any gestational age.
Na+ (mEq/ml) 120/132 126.4/140 139.6/140 The intrauterine determination of the
Cl- (mEq/ml) 119/107 132.5/149 141/158
characteristics of fetal urine offers absolute diagnostic
OsM (mOsm) 240/267 261.5/273 281/296
NAG (U/l) 18/16.9 25.83/20.34 25.73/20.8 possibilities about the normal renal clearance
b2mG (ml/l) 26/22.3 38.9/28.74 38.72/30.0 function.
K+ (mEq/ml) 3.1/138 3.4/140.6 3.9/148 Urine aspiration puncture with diagnostic aims is
Creatinine (ml/l) 1.2/0.7 2.54/0.82 3.7/0.9
technically feasable, using conventional spinal needles
 Ultrasound-Guided Fetal Invasive Procedures: Current Status 515
Table 38.6: Fetal Urine: Biochemical markers applicable of 18g having an aspiration system connected to a 20
to any gestational age and echographic image and cc syringe.
amniotic liquid volume to determine a renal function The way to aproach this depends on the fetal
status.
position available.
Prediction Bad Good If at the posterior back position we would not find
Echographic image hyperecog. + Cyst. Normal any great inconviniences in punctioning the bladder
Echography whilst for a lateral or anterior back where a
Amniotic Liquid Oligoamnios Normal.
nephrostomic aspiration is chosen (Fig. 38.9)
Fetal Urine In neither one nor the other, can any noticeable
+ complications be found, at least in our experience.8,21
Na >100 mEq/ml <100 mEq/ml
Cl- >90 mEq/ml <90 mEq/mll The nephrostomy aspiration allows us firstly to
Osmolarity >210 <210 re-evaluate the echostructural characteristics of the
NAG >8 U/l <8 U/l expanded kidney parenchyma, and secondly, as long
β -2 microglob. >4 mg/l <4 mg/l
as we use the 16g sure cut aspiration system, to carry
K+ Indifferent Indifferent
Creatinine Indifferent Indifferent out at the same time a renal biopsy without any
technical difficulties.

Fig. 38.9: Aspirative nephrostomy: echographic monitoring

516 Textbook of Perinatal Medicine

For this, once the nephrostomy urine aspiration and no smaller in surface area and that also include
has been done, without taking the needle out move it a thickness of the epithelial stratum, and comprising
towards the renal parenchyma and carry out the of conjunctive areas and basal membrane. Only by
aspiration with a s w i n g movement over the this can an acceptable reading be obtained 24 .
corticomedular area The second aspect to be taken into account is
The obtaining of samples of 2mm in length is the surgical biopsy material. We have already
enough for the detection of the histological exposed previously that the use of section 2.5 mm
characteristics that define a kidney dysplasia 8,9,21-23 . clipping tongs (forceps/clippers) introduced into
But the use of 16g catheters Aspiration Biopsy Set the amniotic eviroment by trocar, will allow the
(Fig. 38.3), once the technical problems of involving obtention of skin samples in 100% of all cases, and it
tissues have been solved, allowes to obtain samples is true that the residual skin lesions and any
in the 65% of the cases If conventional 18g catheters pregnancy complications there maybe, will not render
are used but inocuous, only 30% of the cases are any noticeable benefits in relation to the diagnostic
obtained. (J. Troyano, Ian Donald, School data.
Interuniversity of Medical Ultrasound, Dubrovnik The use of conventional needles and isometric
August 1996, unpublished observations). aspiration practising the slice technique, that consists
in inserting the needle sidelongly over the skin and
SKIN BIOPSY make scratching or scraping movements, as this will
As already stated in the generalization section about allow us to obtain skin strips of optimum quality with
fetal biopsies, the skin biopsy entails the most serious minimum damage to the integrity of the pregnancy
difficulties in the obtaining of adequate or sufficient (Fig. 38.10) 25-28 .
samples that would allow correct histopathological The third aspect to consider is the place selected
diagnosis or prediction. to proceed for the taking of the sample, as depending
The most important aspect is the obtention of valid on the disorder that we aim to diagnose prenatally,
samples, for this we need at least 1 mm strips of skin the biopsy area would be different. Not always the

Fig. 38.10: Left: skin biopsy in fetal abdomen, sidelongly scratching. Right: mature histologycal
cutaneous samples where keratohyalin and hemidesmosomes are detected
 Ultrasound-Guided Fetal Invasive Procedures: Current Status 517
same area of the fetal skin wrap will be valid, or will transmission as well as recesive types, the majority
suit the purpose of the biopsy. being lethal in short or medium terms.
These disorders can be classified as follows :
Technique • Bullous epidermolisis: Fetuses with large scale
blistered areas that once the blisters break, set off
Skin samples should, if possible, be taken from
intensive erosive zones with a fast loss of
different areas of the fetus.
electrolytes are affected 6,10,29,30.
The pregnancy stage recommended for this is
• Anhidrotic ectodermic dysplasias: Recessive
around 20 weeks, as after this time, the pilose folicles
disorder linked to the sex. The fetuses are born
and keratinization mechanisms begin to develop. The
without pilose follicles, without any hair or
study of the elements involved in the keratinization
sudoriparous glands. They develop hyperthermic
(keratohyalin and tonofibers), initially give suspicions
affectation by disregulation and general dryness
of the disorder.
syndromes 31 .
On the other hand, at this stage in the pregnancy
• Keratinization disorders: Also called Colodion baby
the dermoepidermical junction has definitively been syndrome, characterized by the appearance of reptile
established, and the gradual rise of intercellular skin due to epidermic membranes that are of quick
desmosomes, is a great help for the diagnosis of s h e d d i n g. Severe and lethal dehidrating
different forms of epidermolysis disorders.32,33
The sequence should follow the following steps: • Pigmentary atopies: Ocular syndromes with
• Echographic monitoring. severe intolerance to light and early or premature
• If it is possible, the placenta must be avoided development of skin cancers 31,34,35.
• Take into consideration the fetal position as on The diagnostic problems faced with these
some ocassions it will be necessary to obtain dermatosis are due to the development of the lesion
samples from different skin areas. has different topographic origins, so the need to select
• Rigorous sterilization. the punture spot has to be in accordance to the illness
• Optional local anaesthesia, depending on the that one is traying to detect.
surgical timing. The diagnostic possibilities of skin biopsies are
• Oblique needle incidence in the thickness and summarized as shown in Table 38.7.
surface of the skin, making a scraping or scratching Table 38.7: Diagnoses possible from fetal skin biopsies
movement without pulling back.
- Keratinization disorders:
• Try to obtain at least 1mm strips. The use of the Harlequin fetus.
vacum needles allow the collection of various Colodion baby.
fragments from the interior without the need of Sjögren-Larsson syndrome.
Congenital icthyosis.
withdrawing the needle. The puncture spot is in trunks and buttocks (Fig. 38.11)
• Immediately proceed to swim the samples in - Ampollous diseases:
saline serum for their histological staining and Herlitz ampollous junctional disease.
Hallopeau-Siemens ampollous dermolytic disease.
fixing process or for electronic microscopy Inverse dystrophic ampollous disease.
analysis. Cockayne-Touraine dystrophic ampollous disease.
The puncture spot is in waist, skin folds, abdomen and
buttocks (Fig. 38.12)
Indications - Pigmentary disorders:
They are most frequently based on the diagnosis of Negative tirosinase oculocutaneus albinism.
Chediak-Higashi disease.
some type of genodermatosis or congenital Anhidrotic ectodermic disease.
dermoepidermic disorders, of dominating autosomic The puncture spot in the skin-head (scalp) (Fig. 38.13)
518 Textbook of Perinatal Medicine

Fig. 38.12: Ampollous disease

Fig. 38.11: Keratinizationdisorder It is recommended to have kept previous samples

in order to be used as a study bank.

Complications
Now the tendency is to propose minimally invasive
techniques by the use of conventional needles 7 .38
The use of conventional needles does not withhold
more risks than the amniocentesis. On the other hand,
the trocar techniques and the 2.5 mm sectio biopsy
provoke around 5% of miscarriages due to iatrogenic
amniorexis, although similarly some indelible fetal
skin lesions have been described (Fig. 38.14). This does
not occur in cases where the scalp technique is carried
out with the use of conventional needles.

Fig. 38.13: Pigmentary disorder (scalp lesions) MUSCLE BIOPSY

This is carried out preferably for the prenatal
It is fundamental to have objective family history diagnosis of Duchenne’s muscular dystrophy (DMD),
in order to determine the biopsy spot 34,36,37. although it is also possible to detect other heredetary
miopathies as long as there is some clinical family
Complementary Requirements
history of these disorders 11,38,39 .
The study of the samples will be based on the For the diagnosis of Duchenne’s muscular
ultrastructural features stated beforehand. A great dystrophy, it is usual for the DNA analysis to be used.
deal of experience in fetal dermatology using When the recombinations within the DMD gene or
electronic microscopy is required to make the the DNA analysis are not sufficiently informative, or
diagnosis. if from the family history it is not clear if there are
It is fundamental to have objective family history possible carriers, so the direct examination of the
knowledge in order to determine the prenatal muscle and its analysis is the only way to give the
dermoepidermic structural markers. basis of an objective prenatal diagnosis.
 Ultrasound-Guided Fetal Invasive Procedures: Current Status 519

Fig. 38.15: Subtrochanteric muscle biopsy; the detection of

dystrophin by inmunofluorescence determines healthy muscle

• Connective infiltration.
• Nuclear and cellular morphological alterations
(Fig. 38.16).

Technique
Any muscular skeleton area is good, preferably of the
Fig. 38.14: Residual cutaneous lesion external face of any of the thighs or nuckle areas,
after biopsy with clipper system avoiding topographic places with inervation or vital
vascularization, in this manner indelible functional
The marker used is the dystrophine, its lessions will not be provoked. Preferably using 18g
determination by means of immunoflourescence conventional needles or even better, the sure cut
allows to differenciate the features of affected muscles method that have already been described 8,38,41-43 (Fig.
from those of the healthy ones. The absence of this 38.2).
protein from the skeleton muscles is practically Carrying out subtrochanteric punctures in a
pathognomonic of DMD 11,14,39,40 (Fig. 38.15). descending obliquest manner as possible, orientated
Some other times the prenatal diagnosis of DMD towards the fetal femur (Fig. 38.2).
may be impossible when there is only one previously The puncture success rate is of 75%.
affected male in the family, and there is no It is essential to determine muscle dystrophy by
identificable delection. immunoflourescense, being advisable but not
The absence of dystrophine in a skeleton muscle, determining the detection of phosfocreatinkinase and
is worth in itself the determination of the screening the study of the muscular structure at a morphological
of the DMD. Nevertheless this diagnosis can be muscular level, fat and connective infiltration.
reinforced by detecting a rise in fosfocreatinkinase of No complications are described.
more than 10 times its normal value in fetal blood. The fetus is susceptible to being studied by
Within the possibilities that can reinforce a prenatal invasive techniques. These techniques are only
DMD diagnosis or prediction we have: justified by the seriousness of a possible inherited
• Sex linked. illness, or by any other disorder detected during
• High values of fosfocreatinkinase. pregnancy; in the latter the need for biopsy diagnosis
• Absence of dystrophine. is exceptional, as the thoracocentesis, pericardio-
• Degenerated muscle. centesis and punctures of other thoracoabdominal,
• Fat infiltration. primary seek a therapeutic attitude, using the
520 Textbook of Perinatal Medicine

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Mahoney MJ. Invasive techniques for prenatal diagnosis:
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3. Golbus MS, Sagebield RW, Filly RA, et al. Prenatal diagnosis
of congenital icthyosiform erythroderma (epidermolytic
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4. KouseffBG, Matsouca LY, Stenn RS, et al. Prenatal diagnosis
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microscopy of fetal skin. J Invest Dermatol 1983;80:210-12
Fig. 38.16: Duchenne´s muscular dystrophy; degenerated 6. Dolan CR, Smith LT, Syber UP. Prenatal detection of
muscle as an associated sign: fat and connective infiltration, epidermolysis bullosa fetalis with pyloric atresia in a fetus
and morphological cellular alterations and leucocytes by abnormal ultrasound and elevated alphafetoprotein. A m
infiltration. J Genet 1993;47: 395-400
7. Rodeck CH. Fetoscopy guided by real time ultrasound for
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the fetus in utero. Br J Obstet Gynaecol 1980;87:449-56
extracted material for studying its analytical
8. Troyano JM, Padron E, Clavijo M. Fetal biopsy and
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Other punctures on fetal tumor formations Advanced Ultrasound II, Vol. 9. Ohrid, Macedonia: Dobri S.
(sacrococcygeal teratomas, solid cervical teratomas, Filipche, 1996:51-61
9. Campbell WA, Yamase HT, Salafia CA, Vintilizeos AM,
etc...), or liquid colections, such as pericariocentesis, Rodis JF. Fetal renal biopsy: technique development. Fetal
do not have an acceptable justification from a Diagn Ther 1993; 8:135- 43
therapeutic or diagnostic point of view, as the 10. Dunnill MG, Rodeck CH, Richards AJ et al. Use oftype VII
echographic evaluation and the present application collagen gene (COL7A1) markers in prenatal diagnosis of
recessive dystrophic epidermolysis bullosa. J Med Genet
of biophysical methods (Colour Doppler amongst 1995;32: 749-50
them) give an acceptable identification of their 11. Evans MI, Farrell SA, Greb A, Ray P, Johnson MP, Hoffman
vascularization and origin, including those of EP. In utero fetal muscle biopsy for the diagnosis of
Duchenne musçular dystrophy in a female fetus’ suddenly
suspicious neoplasm.44,45. (A. Kurjak, In: Ian Donald.,
at risk’. Am J Med Genet 1993;46:309-12
University School of Medical Ultrasound 16th Course, 12. Fox J, Hack AM, Fenton WA, etal. Prenatal diagnosis of
- Granada, Spain, June 14th-16th 1993, Unpublished) ornithine transcarbamylase deficiency with the use of DNA
In agreement with our conduct, we wolud like to polymorphisms. N Engl J Med 1986;315:1205
13. Matilla 1, Corral J, Miranda M, et al. Prenatal diagnosis of
express this thought: The fetus has been endowed by Werdnig-Woffmann disease: DNA analysis of a mummified
nature to surpass several inconvenientes provided by umbilical cord using closely linked microsatellite markers.
its forty weeks of developing. It is a “Real Titan” front Prenat Diagn 1994;14:219-22
any adversity and, its adaptability is exceptional. 14. Kuller JA, Hoffman EP, Fries MH, Golbus MS. Prenatal
diagnosis of Duchenne muscular dystrophy by fetal muscle
Don´t we disturb it! biopsy. Hum Genet 1992;90:34-40
Don´t we invade its privacy agressively! 15. Illum N, Lavard L, Danpure ZJ, AerenlundJensen H,
Let´s observe it minutelly and, only when it need Skovby F. Primary hyperoxaluria type 1: clinical
manifestation in infancy and prenatal diagnosis. Child
us, which generaly happens in few occations, it will
Nephrol Urol 1992;12:225-7
advise us, then, let´s help it. 16. Rodeck CH, Patrick AD, Pembrey ME, Tzannatos C,
J.M.Troyano-Luque (1993) Whitfield AE. Fetal liver biopsy for prenatal diagnosis of
 Ultrasound-Guided Fetal Invasive Procedures: Current Status 521
ornithine carbamyl transferase deficiency. Lancet 1982;1 31. Shimizu H, Ishko A, Kikushi A, Akiyarna M, Susumori K,
:297-9 Nishikawa 1. Prenatal diagnosis of tyrosinase negative
17. Goebel HH, Vesa J, Reiter B, et al. Prenatal diagnosis of oculocutaneous albinism by an electron microscopic dopa-
infantile neuronal ceroidlipofuscinosis: a combined reaction test of fetal skin. Prenat Diagn 1994;14:442-50
electron microscopic and molecular genetic approach. Brain 32. Akiyama M, Kim DK, Main DM, Otto CE, Holbrook KA.
Dey 1995;17:83-8 Characteristic morphologic abnormality of harlequin
18. Murotsuki J, Vehara 5, Okamura K, Yajima A, Oura 1, ichthyosis detected in amniotic fluid cells. J Invest Dermatol
Miyabayashi 5. Fetal liver biopsy for prenatal diagnosis of 1994; 102:210—13
carbamoyl phosphate synthetase deficiency. Am J Perinatol 33. Rizzo WB. Sjögren-Larsson syndrome. Semin Dermatol
1994;11: 160-2 1993;12:210—18
19. Tsushida Y, Kawarasaki H, Iwanaka T, Uchida H,
34. Akeo K, Shirai S, Okisaka S, et al. Histology of fetal ages
Nakanishi H, Uno K. Antenatal diagnosis of biliary atresia
with oculocutaneous albinism. Arch Ophthalmol 1996;1
(type 1 cyst) at 19 weeks gestation: differential diagnosis
14:613-16
and etiologic implications. J Pediatr Surg 1995;30:607-9
20. Von Dobeln V, Venizelos N, Westgren M, Hagenfeldt L. 35. Shimizu H, Niizeki H, Suzurnori K, et al. Prenatal diagnosis
Long chain 3-hydroxylacyl-CoA dehydrogenase in of oculocutaneous albinism by analysis of the fetal
chorionic villi, fetal liver, and fibroblasts and prenatal tyrosinase gene. J Invest Dermatol 1994;103:104-6
diagnosis of 3-hydroxylacyl-CoA dehydrogenase. J Inherit 36. Holbrook KA, Smith LI, Elias S. Prenatal diagnosis of
Metab Dis 1994;17:185-8 genetic skin disease using fetal skin biopsy samples. Arch
21. Troyano JM, de la Fuente P, eds. Prenatal features of fetal Dermatol 1993;129: 1437-54
kidney physiopathology and their intra and extrauterine 37. Normand J, Karasek MA. A method for the isolation and
treatment. A multidisciplinary problem. Santa Cruz de serial propagation of keratinocytes, endothelial cells and
Tenerife: University Hospital of the Canary Islands, fibroblasts from a single punch biopsy of human skin. Jn
1993:35-9 vitro Cell Dey Biol Anim 1995;31:447-55
22. Greco P, Loverro G, Carusso G, Clement R, Selvaggi L. 38. Evans MI, Krivchenia EL, Johnson MP, et al. In utero fetal
Diagnostic potential of fetal renal biopsy. Prenat Diagn muscle biopsy alters diagnosis and carrier risks in
1994;14:415 Duchenne and Becket muscular dystrophy. Fetal Diagn Ther
23. Gubler MC, Levy M. Prenatal diagnosis of Nail- Patella 1995;10:71-5
syndrorne by intrauterine kidney biopsy. Am J Med Genet 39. Fanin M, Pegoraro E, Angelini C. Absence of dystrophin
1993;47:122-4 and spectrin in regenerating muscle fibers from Becket
24. Elias S, Emerson DS, SimpsonJL, Shulrnan LP, Holbrook dystrophy patients. J Neurol Sci 1994;123:88-94
KA. Ultrasound-guided fetal skin sampling for prenatal 40 .Lindahl M, Backman E, Henriksson KG, Gorospe JR,
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41 dystrophinopathies. Neuromusc Disord 1995;5: 193-9
25. Bakharev VA, Aivazyan AA, Karetnikova NA, Mordovtsev 41. Benzie RJ, RayP, Thompson D, HunterAG, Ivey B, Salvador
VN, Yantousky Y. Fetal skin biopsy in prenatal diagnosis
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fetal muscle biopsy. Prenat Diagn 1994;14:235-8
26. Buckshee Li, Parveen 5, Mittal 5, Verma K, Singh M.
42. Evans MI, Hoffman EP, Cadrin C, Johnson MP, Quintero
Percutaneous ultrasound-guided fetal skin biopsy: a new
RA, Golbus MS. Fetal muscle biopsy: collaborative
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experience with varied indications. Obstet Gynecol
27. Holbrook KA, Wapner R, Jackson L, Zaeri N. Diagnosis
1994;84:913-17
and prenatal diagnosis of epidermolysis bullosa herpeti-
formis (Dowling-Meara). In a mother, two affected children 43. Evans MI, Quintero RA, King M, Kureshi F, Hoffman EP,
and an affected fetus. Prenat Diagn 1992;1 2:725-39 Johnson MP. Endoscopically assisted, ultrasound-guided
28. Suzumori K, Kanzak 1. Prenatal diagnosis of Harlequirn fetal muscle biopsy. Fetal Diagn Ther 1995;10:167-72.
Ichthyosis by fetal skin biopsy; report of two cases. Prenat 44. Troyano JM, Clavijo MT, Clemente I, Marco OY,
Diagn 1991 ;1 1:451-7 Rayward J, Mahtani VG. Kidney and urinary tract
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first successful trial in Asia. Dermatology 1994;188:46-9 1992; 79 (5); (Pt2):859
 39
The Role of Ultrasound Examination
of the Cervix in Pregnancy
Patrick Rozenberg, Y Ville

INTRODUCTION prematurely, as defined by a history of preterm

delivery, late miscarriage, conization, maternal
Preterm delivery is the main cause of perinatal
exposure to diethylstilbestrol (DES) during her fetal
mortality and morbidity1. Its prevalence has been
life, uterine malformation or a current multiple
stable for the last 20 years accounting for 5.9% and
pregnancy; iii) asymptomatic women without any
11% of all deliveries in France and in the USA
relevant history.
respectively2-4. This is mainly due to poor therapeutic
results and the inadequacy of the diagnostic criteria THREATENED PRETERM LABOR
for preterm labor. Risk scoring for preterm birth have The risk of preterm delivery is significantly associated with
both low sensitivity and positive predictive value 5-8. 2 ultrasound features : shortening of the cervical length
Only 15% of women with a previous history of and cervical wedging.
preterm delivery will do so in a subsequent Cervical length measured by transvaginal
pregnancy8. Routine digital cervical examinations ultrasonography < 20 mm, < 25 mm, or < 30 on
during pregnancy increases the risk for admission in admission had a positive and negative predictive
hospital without decreasing the incidence of value of 100% and 72%, 70% and 82%, and 65% and
prematurity9. In threatened preterm labor as defined 100%, on preterm delivery respectively. These patients
by painful contractions, cervical changes on digital delivered preterm despite tocolytic therapy during
examination and frequency of contractions both hospitalization.14 Thus, the risk of preterm delivery
remain poor predictors of preterm delivery 10-12,13. is especially high in women whose cervical length on
Different strategies have been developed to refine admission is < 20 mm, whereas a cervical length ³ 30
the risk of preterm delivery., including the use of mm is reassuring. Preterm delivery is also
transvaginal sonography (TVS) to measure and significantly associated with the presence of cervical
examine the length and shape of the cervix. TVS has wedging together with a short cervical length. This
been studied in 3 different populations : i) led to sensitivity, specificity, positive and negative
symptomatic women with threatened preterm labor predictive value of 100%, 74.5%, 59.4%, and 100%,
i.e. regular and painful contractions together with respectively.15
changes on digital examination of the cervix) ; ii) Ultrasound examination is more accurate than digital
asymptomatic women at high risk of delivering examination of the cervix in preterm labor.
 The Role of Ultrasound Examination of the Cervix in Pregnancy 523
In preterm labor with intact membranes, Gomez delivered after 28 days (p<0.001). Fibronectin testing
et al10 showed that despite cervical dilatation of < 3 could therefore be performed only in patients with a
cm, cervical length and cervical wedging (p < 0.005) short cervix to discriminate further those at true high
were highly predictive of preterm delivery, but digital risk of prematurity With specificity, positive and
examination of the cervix (dilatation and effacement) negative predictive values of 86%, 90%, 63%, 97%,
failed to do so. Survival analysis demonstrated a respectively in predicting delivery within 28 days.
shorter admission-to-delivery interval for patients
with an abnormal cervical length (p < 0.005). In ASYMPTOMATIC WOMEN AT
preterm labor following completion of a course of IV HIGH RISK OF PRETERM DELIVERY
tocolysis, cervical sonography performed better than There are 4 types of clinical studies addressing this
digital examination to predict delivery before 36 and issue: 1) observational studies examining the natural
even 34 weeks’, with a best cut-off of 30 mm on ROC course, 2) observational studies examining the course
curve analyses. 11,16 The positive and negative of those treated with cervical cerclage, 3) non-
predictive values were of 15% and 36%, and 97% and randomized interventional studies, and 4)
100% in singleton and twin pregnancies respectively randomized interventional trials.
when assessed at between 23 and 33 weeks’. When 1. Observational Studies of Ultrasound Features
analyzed for delivery before 37 weeks’ this held true Suggestive of Cervical Incompetence
for singletons but not for twins. Three ultrasound features are suggestive of
The comparison of cervical fetal fibronectin (fFN) assay and cervical incompetence:
TVS of the cervix to predict preterm delivery remains a Dilatation of the internal os (I.O.) (Fig. 39.1) was
controversial issue. the first ultrasound feature suggesting cervical
We found that prediction performances of vaginal incompetence and thus of at increased risk of preterm
fFN assay ³ 50 ng/ml and of a cervical length of £ 26 delivery. Dilatation of the I.O. > 5 mm before 30 weeks’
mm in threatened preterm labor between 24 and 34 gestation is associated with preterm delivery in 33.3%
weeks’ were similar with a high negative predictive vs 3.5% when the I.O. remained closed (p < 0.01).
value 86.6% and 89.1%, respectively. 17 The Digital cervical examination noted dilatation of the
combination of both tests performed better with a internal os in only 10 of the 26 (38.5%) patients in
NPV of 94.4% but the positive predictive value whom ultrasound showed cervical dilatation. 20
remained at around 50% although the odd ratio for Sacculation or prolapse of the membranes into a
delivering before 34 weeks’ was high (13.9, 95% CI : shortening cervix (Fig. 39.2) either spontaneously or
3.7 - 52.2). induced by transfundal pressure can be seen even
Rizzo et al.18 reported that cervical fFN ³ 60 ng/ when digital cervical examination shows a long and
ml performed better than the association of cervical closed cervix.21
length and the presence of funneling on ultrasound. Another study, in which ultrasound examinations
Furthermore, in patients with cervical fFN ³ 60 ng/ were performed at between 15 and 24 weeks,
ml a shorter admission-to-delivery interval was found compared three methods to detect cervical
in the presence of an abnormal cervical index. incompetence : transfundal pressure, coughing, and
More recently, multiple logistic regression analysis standing 22. The transfundal pressure was the most
found that only positive fibronectin testing (OR 11.25, predictive (sensitivity specificity, positive and
p=0.005) and functional cervical length £ 20 mm (OR negative predictive values of 83.3%; 97.2%; 88.2%; and
8.18, p=0.027) were independently associated with 95.8% respectively).
preterm delivery. 19 In the group with CL of 20-31 mm Shortening of the cervix in the absence of uterine
positive fetal fibronectin was found in 71.4% of contractions is also suggestive of cervical
patients delivered within 28 days and in 7.4% incompetence. A cervical length = 10th percentile (22
524 Textbook of Perinatal Medicine

Fig. 39.1: Dilatation of the internal os Fig. 39.2: Sacculation of the membranes into the cervix

mm) and funneling at the internal os (Fig. 39.3) at Prospective longitudinal evaluation of a large
between 16 and 30 weeks’ were associated with cohort of 469 high-risk pregnancies by TVS and
delivery within 2 and 4 weeks and before 35 weeks’ transfundal pressure on 1265 occasions at between 15
[33% vs 0 (p=0.01); 67% vs 0%, (p<0.001); and 100% and 24 weeks’ 24 compared various sonographic
vs 19%, p<0.001, respectively].23 Within this high risk cervical parameters to predict spontaneous preterm
group, women with medical or obstetrical birth. ROC curve analysis showed that cervical length
complications (including multiple gestation and £ 25 mm alone performed as well as a combination of
ruptured membranes), symptoms of preterm labor, risk factors, CL, funneling and transfundal pressure.
history of incompetent cervix that required cerclage The sensitivity for delivery at < 28, < 30, < 32 and <
were excluded. A short cervix or funneling beyond 34 weeks’ gestation was 94%, 91%, 83% and 76%,
20 weeks of gestation were also associated with an respectively, while the negative predictive value was
increased risk of preterm delivery before 35 weeks but 99%, 99%, 98% and 96%, respectively. Shortening of
not with an increased risk of delivering within 2 to 4 CL at weekly assessment helps differentiating cervical
weeks following TVS. competence from cervical incompetence in high-risk
women. (-0.3 mm/week v. -4.1 mm/week; p < 0.001).
25
Ultrasound diagnosis of cervical incompetence was
defined as progressive shortening of the endocervical
canal to 20 mm or less before 24 weeks’ gestation.
In this high risk group, CL < 25 mm by TVS of the
cervix performs better than CL<16 mm by digital
cervical examination in assessing the risk of delivery
before 35 weeks with relative risks of 4.8 and 2.0
respectively.26 In multiple pregnancies at between 24
and 28 weeks’, a cervical length = 25 mm by TVS was
the best predictor of preterm delivery before 32 weeks,
before 35 weeks, and before 37 weeks.27 There is a
Fig. 39.3: Funneling with shortening
continuous increase of 5% to 17% and 80% for this
of the functional cervical length risk with CL shortening down to 40 mm and 20 mm
 The Role of Ultrasound Examination of the Cervix in Pregnancy 525
and 8 mm respectively.28 Cervical length of £ 20 mm patients with cervical changes by ultrasound and
seems to perform as well as any combination of rescue procedure performed in symptomatic patients.
clinical and ultrasound features at predicting preterm This shows that the performance of US-indicated
birth 29 whereas CL >35 mm before 26 weeks’ seems cerclage in terms of preterm delivery rate and
to accurately identify a sub-group of twin pregnancies gestational age at delivery performed better than
at low-risk to deliver prematurely (3% to 4%). 30,31 emergency procedures. The benefit of cerclage in this
Although series are smaller, the predictive value group is however uncertain when compared to
of TVS of the cervix seems to hold true in triplets.32,33 elective cerclage on the basis of a relevant history.44,45
Cervical length of £ 25 mm between 21 and 24 weeks’ This therefore suggests that a new indication for
gestation was the best cut-off for the prediction of cerclage can be defined as cervical changes on serial
spontaneous preterm birth < 28 weeks’ gestation TVS in a high risk group.
(86%, 79%, 40%, 97% for sensitivity, specificity, 4. Randomized trials assessing ultrasound – based
positive predictive value, and negative predictive indications for cerclage in high risk women.
value, respectively).34 There are 2 such randomized trials published and
2. Follow- up studies in cervical incompetence their results are apparently contradictory. Althuisius
diagnosed by TVS and treated by cerclage have et al studied patients with a history of delivery before
established that cervical cerclage is followed by a 34 weeks with suspected cervical incompetence or
measurable increase in cervical length (Figs 39.4A preterm rupture of membranes at < 32 weeks without
and B). This applies to both rescue-cerclage 35,36 preceding contractions.46 In subsequent singleton
and elective procedures 35,37,38. However the pregnancies, they were randomized into two groups,
relation of this increase with outcome is with a ½ ratio, for either prophylactic cerclage (n=23)
controversial and the longer the pre-cerclage or a follow-up cervical TVS (n=44). In the follow-up
cervical length the more likely a delivery near term group, a cervical length < 25 mm before 27 weeks led
39
The value of CL shortening following cerclage to a second randomization for either therapeutic
(Fig. 39.4C) is also controversial. A decrease of at cerclage or expectant management. The obstetrical
least 10 mm is significant to predict delivery before characteristics of the prophylactic cerclage and
36 weeks’. 40,36,37 However, this may not be observational groups were similar. There was no
significant when 34 weeks’ is considered as a cut- significant difference in the rate of delivery before 34
off. 38 weeks (13.0% vs 13.6%) in these 2 groups. A cervical
3. The value of non-randomized interventional length < 25 mm before 27 weeks was found in 18 (41%)
studies based upon ultrasound diagnosis of patients in the observational group with a mean
cervical incompetence is controversial. TVS cervical length of 18.2 ± 5.9 mm at a mean gestation
together with transfundal pressure can be used in of 19.1 ± 2.9 weeks. The incidence of deliveries < 34
high risk women to define cervical incompetence weeks was significantly lower in the therapeutic
at between between 16 and 24 weeks’ whenever cerclage group when compared (1/10 vs 5/8) with
this causes dilatation of the internal os or the bed rest group (p=0.04).
membranes protrusion 41. There might therefore be a double benefit in
Serial TVS suggests that evidence fort cervical performing cerclage for ultrasound indication only
incompetence can be established by 24 weeks’.42 In a among asymptomatic patients at high risk:
retrospective analysis, Kurup 43 compared the • first, this would allow a significant reduction in
outcome in 3 categories of cerclage: elective cerclage the number of prophylactic cerclage. Indeed, in
indicated by the patient’s history, ultrasound- this study, cerclage was performed in only 40% of
indicated cerclage performed in asymptomatic the cases.
526 Textbook of Perinatal Medicine

• second, therapeutic cerclage before 27 weeks may Rust et al. hypothesized that these ultrasonographic
reduce the incidence of premature delivery before findings of the cervix during the second trimester
34 weeks among patients with a cervical length demonstrate a potential final common pathway of
<25 mm. multiple pathophysiological processes, such as
More recently, Althuisius et al.47 published the infection, immunologically mediated inflammatory
Final results of their trial on 35 women with definite stimuli, and subclinical abruptio placentae. This
risk factors of cervical incompetence and shortening hypothesis is supported by a 14.8% incidence of
of the cervix down to <25 mm at before 27 weeks, 19 abruptio placentae in their study. Abruptio placentae
were allocated randomly to the cerclage group and was not found in any of the women in Althuisius
16 to the bed rest group. Both groups were study. This difference in prevalence of abruptio
comparable for mean cervical length and mean placentae confirms that the study populations in both
gestational age at time of randomization. Preterm trials are basically different.
delivery before 34 weeks was significantly more
frequent in the bed rest group than in the cerclage TVS OF THE CERVIX IN CLINICAL
group (7 of 16 vs none, respectively; P = 0.002). The TRIALS IN THE GENERAL POPULATION
compound neonatal morbidity, defined as admission There is a relation between the risk of preterm delivery
to the neonatal intensive care unit or neonatal death, and the functional length of the cervix in the general
was significantly higher in the bed rest group than in population. In a prospective multicentre observational
the cerclage group (8 of 16 vs 1 of 19, respectively; P study, Iams et al.49 performed TVS of the cervix in
= 0.005). women with a singleton pregnancy at 24 weeks
The other randomized trial by Rust et al.48 led to (n=2915) and 28 weeks (n=2531) of gestation. Delivery
different conclusions but addressed a different before 35 weeks’ occurred in 126 (4.3%) of the 2915
population. Screening in the general population and patients examined at 24 weeks. Cervical length was
detecting cervical funneling > 25% or CL< 25 mm at normally distributed at 24 weeks (35.2 ± 8.3 mm) and
between 16-24 weeks for Rust et al were randomized at 28 weeks’ (33.7 ± 8.5 mm). The risk of preterm
into cerclage group or expectant management. Except delivery was inversely correlated with the length of
for the cerclage, all patients were treated identically the cervix.
before and after randomization. Cerclage did not Heath et al. 50 measured cervical length by
affect the perinatal outcome in any of the 2 trials. transvaginal sonography at 23 weeks’ in 2567
Several differences between these studies47,48 may singleton pregnancies in women attending routine
explain these contradictory results. Low-risk patients antenatal care. The risk for delivery at £ 32 weeks’
were screened for a short cervical length to be decreased from 78% at a cervical length of 5 mm to
included in Rust trial. In Althuisius’ , all but 1 patients 4% at 15 mm and 0.5% at 50 mm.
had risk factors for cervical incompetence. To et al.51 measured the cervical length in 6819
The main difference is therefore the initial selection singleton pregnancies at 22-24 weeks’ and looked for
of potential candidates. In Rust trial, measurement the presence of funneling to evaluate possible
of the cervical length was performed in patients who additional risk. Funneling of the internal os was
had risk factors for preterm birth. In Althuisius trial, present in about 4% of pregnancies and the prevalence
they were performed in patients who had risk factors decreased from 98% when the cervical length was £
for cervical incompetence. 15 mm to less than 1% at lengths of > 30 mm. The
All 3 trials included patients with short cervical rate of preterm delivery was 6.9% in those with
length, which implies high risk of preterm delivery funneling compared to 0.7% in those without
but not necessarily high risk of cervical incompetence. funneling (P < 0.0001). However, logistic regression
 The Role of Ultrasound Examination of the Cervix in Pregnancy 527
analysis demonstrated that funneling did not provide funneling and protrusion of the membranes through
a significant additional contribution to cervical length the cervix. Dynamic functional examination of the
in the prediction of spontaneous delivery before 33 cervix evaluates the changes in the internal os in
weeks’. response to uterine contractions or transfundal
Taipale et al. and Hassan et al 52, 53 confirmed the pressure. It has the advantage of screening for
relation between the risk of preterm delivery and the dilatation of the internal os even when the external
functional length of the cervix but showed the os is unchanged. Similarly it enables early detection
limitations of this screening method in the general of shortening of the supra-vaginal portion of the
population. Indeed routine TVS of the cervix cervix, which is not amenable to clinical examination.
performed between 18 and 22 weeks’ helped to We can hope that this early diagnosis will improve
identify patients at risk of preterm delivery; the efficacy of tocolytics.
nonetheless, the low prevalence of preterm births in TVS is a more discriminant approach than digital
these populations (2-3%) at low obstetrical risk is a examination of the cervix both in terms of positive
limitation to the development of such method of and negative predictive values. Among high risk
screening which would bring either a high false symptomatic patients (threatened preterm delivery),
positive rate if the cut-off is 29 mm (3.6%) or a low the data in the literature are sufficient to justify the
sensitivity if the cut-off is 15 mm (8.2%).52, 53 systematic use of TVS for a more accurate evaluation
Non-randomized interventional studies among patients of the risk of preterm delivery before any decision of
in whom ultrasound images are suggestive of a shortened hospital admission.
cervix reported encouraging results. 54 Cervical length Cervical ultrasound might also be useful at
was = 15 mm in 1.6% of the cases at 23 weeks’ in an selecting patients with complete or partial cervical
unselected population of singleton pregnancies. 54 The incompetence among asymptomatic women at high
attending physician decided upon performing a risk (history of preterm delivery, late miscarriage,
cerclage or expectant management. The two groups conization, maternal DES treatment, uterine
did not differ for ethnic or obstetrical characteristics. malformation or a current multiple pregnancy).
The median cervical length was 10 mm in both Among asymptomatic patients at high risk,
groups. In the cerclage group, the prevalence of progressive cervical incompetence may be a primary
preterm delivery before 32 weeks was 5%, whereas it uterine condition which could trigger premature
was 52% in the expectant management group. labor. Searching for funneling or protrusion of the
There is one randomized trials among patients with membranes into the cervix is therefore extremely
ultrasound images suggestive of cervical incompetence, that useful. In their absence, cervical incompetence should
was initiated following the results of Heath’ study. be sought by transfundal pressure. Compared with a
To et al 50 chose a cut-off CL of <15 mm at 23 weeks’ single cervical measurement at 16 to 18 weeks and 6
for To et al in the general population, with an overall days’ gestation, serial measurements up to 23 weeks
low incidence of preterm deliveries. In To et al cervical 6 days significantly improved the prediction of
length was measured indication. Randomisation into spontaneous preterm birth 21,25,66. A shortened cervix,
cerclage or expectant management did not lead to any although non-specific and rarely observed in the
difference in the mean maternal age nor in neonatal absence of uterine contractions, could also be the only
morbidity. warning of cervical incompetence. On the basis of
Guzman’s studies, ultrasound surveillance of such
CONCLUSION patients should begin by the fifteenth week.
TVS of the cervix is an objective evaluation. Cervical In the general population, TVS of the cervix should
biometry as well as anatomical survey looking for be a useful complement to ultrasound examination
528 Textbook of Perinatal Medicine

performed at 22-24 weeks of gestation and help 13. Iams JD, Newman RB, Thom EA, Goldenberg RL, Mueller-
Heubach E, Moawad A, Sibai BM, Caritis SN, Miodovnik
clinicians to better identify patients at low risk of
M, Paul RH, Dombrowski MP, Thurnau G, McNellis D; The
preterm delivery (NPV = 96.7% and PPV = 47.6%)53. National Institute of Child Health and Human
High risk patients as defined by short CL or the Development Network of Maternal-Fetal Medicine Units.
presence of cervical funneling could benefit from Frequency of uterine contractions and the risk of
spontaneous preterm delivery. N Engl J Med 2002; 346: 250-
weekly cervical ultrasound assessment in order to
5.
define further intervention including cerclage, 14. Murakawa H, Utumi T, Hasegawa I, Tanaka K, Fuzimori
tocolytics, steroids injection for lung maturation. R. Evaluation of threatened preterm delivery by
transvaginal ultrasonographic measurement of cervical
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preterm birth. In: Elder MG, Lamont RF, Romero R, editors. of the cervix by transvaginal ultrasonography predict active
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1-28. 16. Crane JM, Van den Hof M, Armson BA, Liston R.
2. Blondel B, Du Mauzaubrun C, Bréart G. Enquête nationale Transvaginal ultrasound in the prediction of preterm
périnatale 1995. Rapport de fin d’étude. Edition INSERM, delivery: singleton and twin gestations. Obstet Gynecol
Février 1996, Paris. 1997; 90: 357-63.
3. Ventura SJ, Martin JA, Curtin SC, Mathews MS. Final data 17. Rozenberg P, Goffinet F, Malagrida L, Giudicelli Y, Perdu
for 1997: national vital statistics reports (vol 47, No. 18). M, Houssin I, Safe-Femme, Nisand I. Evaluating the risk
Hyattsville (MD): National Center for Health Statistics; of preterm delivery: a comparison of fetal fibronectin and
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4. Ventura SJ, Martin JA, Curtin SC, Mathews MS. Report of length. Am J Obstet Gynecol 1997; 176: 196-9.
final natality statistics, 1996; monthly vital statistics report 18. Rizzo G, Capponi A, Arduini D, Lorido C, Romanini C.
(vol 46, No. 11; suppl). Hyattsville (MD): National Center The value of fetal fibronectin in cervical and vaginal
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5. McLean M, Walters WA, Smith R. Prediction and early
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Gynecol 1996; 175: 1146-51.
6. Keirse MJ. An evaluation of formal risk scoring for preterm
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birth. Am J Perinatol. 1989; 6: 226-33.
test: the combined use of fetal fibronectin and sonographic
7. Shiono PH, Klebanoff MA. A review of risk scoring for
examination of the uterine cervix for prediction of preterm
preterm birth. Clin Perinatol. 1993; 20: 107-25.
delivery in symptomatic patients. Acta Obstet Gynecol
8. Creasy RK, Merkatz IR. Prevention of preterm birth: clinical
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20. Okitsu O, Mimura T, Nakayama T, Aono T. Early prediction
9. Buekens P, Alexander S, Boutsen M, Blondel B, Kaminski
M, Reid M. Randomised controlled trial of routine cervical of preterm delivery by transvaginal ultrasonography.
examinations in pregnancy. European Community Ultrasond Obstet.Gynecol. 1992; 2: 402-409.
Collaborative Study Group on Prenatal Screening. Lancet 21. Guzman ER, Vintzileos AM, McLean DA, Martins ME,
1994; 344: 841-4. Benito CW, Hanley ML. The natural history of a positive
10. Gomez R, Galasso M, Romero R, Mazor M, Sorokin Y, response to transfundal pressure in women at risk for
Goncalves L, Treadwell M. Ultrasonographic examination cervical incompetence. Am J Obstet Gynecol 1997 ; 176 :
of the uterine cervix is better than cervical digital 634-8.
examination as a predictor of the likelihood of premature 22. Guzman ER, Pisatowski DM, Vintzileos AM, Benito CW,
delivery in patients with preterm labor and intact Hanley ML, Ananth CV. A comparison of
membranes. Am J Obstet Gynecol 1994; 171: 956-64. ultrasonographically detected cervical changes in response
11. Iams JD, Paraskos J, Landon MB, Teteris JN, Johnson FF. to transfudal pressure, coughing, and standing in
Cervical sonography in preterm labor. Obstet Gynecol 1994; predicting cervical incompetence. Am J Obstet Gynecol
84: 40-6. 1997; 177: 660-5.
12. Berghella V, Tolosa JE, Kuhlman K, Weiner S, Bolognese 23. Andrews WW, Copper R, Hauth JC, Goldenberg RL, Neely
RJ, Wapner RJ. Cervical ultrasonography compared with C, Dubard M. Second trimester cervical ultrasound :
manual examination as a predictor of preterm delivery. Am Association with increased risk for recurrent early
J Obstet Gynecol 1997;177:723-30. spontaneous delivery. Obstet Gynecol 2000 ; 95 : 222-6.
 The Role of Ultrasound Examination of the Cervix in Pregnancy 529
24. Guzman ER, Walters C, Ananth CV, O’Reilly-Green C, as assessed by transvaginal ultrasonography. Am J Obstet
Benito CW, Palermo A, Vintzileos AM. A comparison of Gynecol 1999 ;180 : 366-9.
sonographic cervical parameters in predicting spontaneous 38. El-Azeem SA, Samuels P, Fullana M, Walker H, Iams JD.
preterm birth in high-risk singleton gestations. Ultrasound Perioperative transvaginal sonography as an adjunct to
Obstet Gynecol 2001;18: 204-10. cervical cerclage. Am J Obstet Gynecol 2000 ; 182 (1) :
25. Guzman ER, Mellon C, Vintzileos AM, Ananth CV, Walter Abstract 117 (Society for Maternal-Fetal Medicine 2000 20th
C, Gibson K. Longitudinal assessment of endocervical canal Annual Meeting).
length between 15 and 24 weeks’ gestation in women at 39. Dijkstra K, Funai EF, O’Neill L, Rebarber A, Paidas MJ,
risk for pregnancy loss or preterm birth. transfudal Young BK. Change in Cervical Length After Cerclage as a
pressure, coughing, and standing in predicting cervical Predictor of Preterm Delivery. Obstet Gynecol 2000 ; 96: 346-
incompetence. Obstet Gynecol 1998; 92 : 31-7. 50.
26. Berghella V, Tolosa JE, Kuhlman K, Weiner S, Bolognese 40. Andersen HF, Karimi A, Sakala EP, Kalugdan R. Prediction
RJ, Wapner RJ. Cervical ultrasonography compared with of cervical cerclage outcome by endovaginal
manual examination as a predictor of preterm delivery. Am ultrasonography. Am J Obstet Gynecol 1994 ; 171 : 1102-6.
J Obstet Gynecol 1997; 177: 723-30. 41. Guzman ER, Rosenberg JC, Houlihan C, Ivan J, Waldron
27. Goldenberg RL, Iams JD, Miodovnik M, et al. The preterm R, Knuppel R. A New Method Using Vaginal Ultrasoud
prediction study: Risk factors in twin gestations. Am J and Transfundal Pressure to Evaluate the Asymptomatic
Obstet Gynecol 1996; 175: 1047-53. Incompetent Cervix. Obstet Gynecol 1994; 83: 248-52.
28. Skentou C, Souka AP, To MS, Liao AW, Nicolaides KH. 42. Macdonald R, Smith P, Vyas S. Cervical incompetence: the
Prediction of preterm delivery in twins by cervical use of transvaginal sonography to provide an objective
assessment at 23 weeks. Ultrasound Obstet Gynecol diagnosis. Ultrasound Obstet Gynecol 2001;18: 211-6.
2001;17: 7-10. 43. Kurup M, Goldkrand JW Cervical incompetence: Elective,
29. Guzman ER, Walters C, O’Reilly-Green C, Kinzler WL, emergent, or urgent cerclage. Am J Obstet Gynecol 1999
Waldron R, Nigam J, Vintzileos AM. Use of cervical ;181 : 240-6.
ultrasonography in prediction of spontaneous preterm 44. Guzman ER; Forster JK; Vintzileos AM; Ananth CV; Walters
birth in twin gestations. Am J Obstet Gynecol C; Gipson K. Pregnancy outcomes in women treated with
2000;183:1103-7. elective versus ultrasound-indicated cervical cerclage.
30. Imseis HM, Albert TA, Iams JD. Identifying twin gestations Ultrasound Obstet Gynecol 1998 Nov;12 : 323-7.
at low risk for preterm birth with a transvaginal ultrasonic 45. Berghella V, Daly SF, Tolosa JE, Divito MM, Chalmers R,
cervical measurement at 24 to 26 weeks’ gestation. Am J Garg N, Bhullar A, Wapner RJ. Prediction of preterm
Obstet Gynecol 1997; 177: 1149-55. delivery with transvaginal ultrasonography of the cervix
31. Yang JH; Kuhlman K; Daly S; Berghella V. Prediction of in patients with high-risk pregnancies: Does cerclage
preterm birth by second trimester cervical sonography in prevent prematurity ? Am J Obstet Gynecol 1999; 181 :
twin pregnancies. Ultrasound Obstet Gynecol 2000 ; 15 : 809.15.
288-91. 46. Althuisius SM, Dekker GA, van Geijn HP, Bekedam DJ,
32. Ramin KD, Ogburn PL, Mulholland TA, Breckle RJ, Ramsey Hummel P. Cervical Incompetence Prevention Randomized
PS. Ultrasonographic assessment of cervical length in Cerclage Trial (CIPRACT): Study design and preliminary
triplet pregnancies. Am J Obstet Gynecol 1999;180:1442-5. results. Am J Obstet Gynaecol 2000 ; 183 : 823-9.
33. To MS, Skentou C, Cicero S, Liao AW, Nicolaides KH. 47. Althuisius SM, Dekker GA, Hummel P, Bekedam DJ, van
Cervical length at 23 weeks in triplets: prediction of Geijn HP. Final results of the Cervical Figure
spontaneous preterm delivery. Ultrasound Obstet Gynecol 48. Rust OA, Atlas RO, Reed J, van Gaalen J, Balducci J.
2000;16 : 515-8. Revisiting the short cervix detected by transvaginal
34. Guzman ER, Walters C, O’Reilly-Green C, Meirowitz NB, ultrasound in the second trimester: Why cerclage therapy
Gipson K, Nigam J, Vintzileos AM. Use of cervical may not help. Am J Obstet Gynecol 2001;185:1098-1105.
ultrasonography in prediction of spontaneous preterm 49. Iams JD, Goldenberg RL, Meis PJ, Mercer BM, Moawad A,
birth in triplet gestations. Am J Obstet Gynecol Das A, Thom E, McNellis D, Copper RL, Johnson F, Roberts
2000;183:1108-13. JM and the National Institute of Child Health and Human
35. Funai EF, Paidas MJ, Rebarber A, O’Neill L, Rosen TJ, Young Development Maternal Fetal Medicine Unit Network. The
BK. Change in cervical length after prophylactic cerclage. length of the cervix and the risk of spontaneous premature
Obstet Gynecol 1999 ; 94 : 117-9. delivery. N Engl J Med 1996; 334: 567-72.
36. Guzman ER, Houlihan C, Vintzileos A, Ivan J, Benito C, 50. Heath VC, Southall TR, Souka AP, Elisseou A, Nicolaides
Kappy K. The significance of transvaginal ultrasonographic KH. Cervical length at 23 weeks of gestation: prediction of
evaluation of the cervix in women treated with emergency spontaneous preterm delivery. Ultrasound Obstet Gynecol
cerclage. Am J Obstet Gynecol 1996 ; 175 : 471-6. 1998; 12: 312-7.
37. Althuisius SM; Dekker GA; van Geijn HP; Hummel P. The 51. To MS, Skentou C, Liao AW, Cacho A, Nicolaides KH.
effect of therapeutic McDonald cerclage on cervical length Cervical length and funneling at 23 weeks of gestation in
530 Textbook of Perinatal Medicine

the prediction of spontaneous early preterm 50% risk of early spontaneous preterm delivery. Am J
delivery.Ultrasound Obstet Gynecol 2001;18 :200-3. Obstet Gynecol 2000 ; 182 : 1458-67.
52. Taipale P; Hiilesmaa V. Sonographic measurement of 54. Heath VCF, Souka AP, Erasmus I, Gibb DMF, Nicolaides
uterine cervix at 18-22 weeks’ gestation and the risk of KH. Cervical length at 23 weeks of gestation : the value of
preterm delivery. Obstet Gynecol 1998 ; 92 : 902-7. Shirodkar suture for the short cervix. Ultrasound Obstet
53. Hassan SS, Romero R, Berry SM, Dang K, Blackwell SC, Gynecol 1998 ; 12 : 318-22.
Treadwell MC,Wolfe HM. Patients with an 55. To MS, Skentou C, Liao AW, Cacho A, Nicolaides KH.
ultrasonographic cervical length = 15 mm have nearly a Lancet 2004.
 40
Labor and Puerperium

Ajlana Mulic-Lutvica

LABOR external version of a breech fetus, intrapartum twin

management, or manual or instrumental placental
There is no doubt that labour is a dangerous period
evacuation, as well as for confirmation of an empty
of our life and may result in birth-related disorders.
uterus after the completed procedure. Intrapartum
Preterm and post-date deliveries, multiple gestations,
ultrasound imaging is difficult due to discomfort in
preterm rupture of the membranes, intrauterine
women caused by pain, supine hypotension, and loss
growth disturbances, breech presentations and
of the “acoustic window” after rupture of the
intrapartum bleeding are associated with a
membranes, low station of the presenting part, and
considerable perinatal morbidity and mortality.
lack of appropriate ultrasound equipment in the labor
Healthy newborns with expected good quality of life
and delivery suite as well as inadequately trained
are the main goal of modern obstetrics. Numerous
examiners.1-3
different methods have been developed to achieve this
goal. One of the most widely used is without doubt
Ultrasound Admission Test
ultrasound. Although the value of ultrasound in
antenatal care is well established, it is surprising that Laboring women with inadequate or no prenatal care
the clinical knowledge of its advantages during the should be carefully examined with ultrasound when
intrapartum or postpartum period is sparse. arriving at the labor and delivery unit.
Nowadays, however, it is becoming increasingly
common for obstetricians to use bedside ultrasound Diagnosis of Fetal lLife or Death
and to have ultrasound equipment permanently Ultrasound diagnosis of fetal life or death is simple,
available in labor and delivery suites. By means of prompt and accurate. The fetal heart should be
an ultrasound admission test a selection of high-risk identified and the absence of fetal heart motion by
patients should be made. The uterus with its contents, real-time ultrasound and/or color Doppler implies
including the fetus, placenta, umbilical cord and fetal death. A completely quiescent fetus without body
amniotic fluid, as well as the cervix, can be assessed or breathing movements is an additional sign of fetal
in detail by ultrasound. Even the maternal pelvis has death. If the fetus has been dead for several days, the
become the subject of growing interest from ultrasound signs of fetal death are oligohydramnios,
sonographers. Ultrasound can also assist during the overlapping skull bones, hyperflexion of the spine and
performance of some obstetrical procedures including the presence of hydrops.
532 Textbook of Perinatal Medicine

Fetal Number for evaluation of amniotic fluid volume, such as the

largest vertical pocket and amniotic fluid index (AFI)
The presence of two separate heads, two spines and
have been published. A single largest vertical pocket
two heart motions is enough to identify a twin
of <2cm was labeled as oligohydramnios and a pocket
pregnancy. However, it is rare but not impossible to
of >8 as hydramnios. Phelan and co-workers 4
miss a multiple gestation even by ultrasound in a busy
described a four-quadrant method to measure the
labor and delivery room, and especially if one of the
amount of amniotic fluid. A value of AFI<5cm was
fetuses is dead. Moreover, as the number of fetuses
designated as oligohydramnios and a value of
increases, the accuracy of intrapartum ultrasound
AFI>24cm as polyhydramnios. The umbilical cord
diagnosis decreases. One of the possible explanations
and fetal limbs should be excluded from the
may be crowding and shadowing of one fetus by
measurement 4-6. Since its introduction in clinical
another, which creates a very confusing ultrasound
praxis AFI has been widely accepted as an accurate
image. Therefore, a thorough systematic approach
method to estimate amniotic fluid volume. In
should be adopted. All quadrants of the uterus must
antepartum surveillance, an AFI<5cm was considered
be explored in order to avoid missing a multiple
to be associated with an increased risk for adverse
gestation. Furthermore, ultrasound can be used to
pregnancy outcome and Cesarean section for fetal
estimate the amount of amniotic fluid, and to give
distress 7-9. Likewise an intrapartum AFI<5 was
information on fetal presentation, growth
considered to be associated with neonatal metabolic
discordance, signs of hydrops and fetal
acidosis 5,10. Premature rupture of membranes, growth
malformations. A correct intrapartum diagnosis and
deficiency, post-date pregnancy and fetal renal
painstaking management of delivery with the
anomalies are related to reduced amount of amniotic
assistance of ultrasound are essential for an optimal
fluid. A marked reduction in amniotic fluid increases
outcome in cases with multiple gestations.
the risk for cord compression and fetal death during
Fetal Presentation labor, especially in post-date pregnancies 6 .
Oligohydramnios in early labor should alert the
The presenting part of the fetus, be it head, breech, obstetrician, and it is recommended that careful
shoulder or compound presentation, can be simply intrapartum surveillance be used. However, in the
and accurately diagnosed by ultrasound. It should past several years AFI has been questioned as the
always be done before labour induction, Cesarean appropriate method of defining oligohydramnios.
sections, preterm deliveries, deliveries of multiple Results from randomised trials showed that the use
gestations and in cases of planned vaginal deliveries of AFI compared with the largest vertical pocket was
after previous Cesarean sections. associated with significantly higher rate of suspected
oligohydramnios11. The use of the test may increase
Placenta Location
interventions without improving neonatal outcome11,
12.
Intrapartum vaginal bleeding and transverse lie are A meta-analysis of 42 reports found only one study
diagnosis in which ultrasound can be of assistance to that correlated intrapartum AFI with the rate of
confirm or rule out placenta previa, or low-lying umbilical arterial pH < 7,00 13.
placenta. Prior to Cesarean delivery, ultrasound can Moreover Moses14 showed in a randomised study
be an aid to locate the placenta and help to decide of 499 pregnancies that neither the AFI nor the single
the type of uterine incision. pocket technique that was undertaken as a fetal
admission test intrapartum identified a pregnancy
Intrapartum Assessment of Amniotic Fluid that was at risk for an adverse outcome. As regard
Ultrasound has made it possible to assess the amount amnioinfusion for umbilical cord compression, in a
of amniotic fluid. Several semiquantitative methods systematic review of 12 studies it appears to reduce
 Labor and Puerperium 533
the occurrence of variable decelerations, lower the use tissue dystocia, and Cesarean section should be
of cesarean section for suspected fetal distress, and it advised. In addition, ultrasound detection of a severe
is associated with a reduction in puerperal infection15, fetal malformation in preterm labor can exclude the
16,17
. Amnioinfusion can also reduce the incidence of need for tocolytic therapy.
meconium aspiration17, 18. Hofmeyr18 performed a
systematic review of two studies of 285 women Estimation of Fetal Weight
related to prophylactic versus therapeutic Accurate knowledge of fetal weight in early labor is
amnioinfusion for oligohydramnios in labor. There is important. Many clinical situations in an acute care
no advantage of prophylactic amnioinfusion over setting require quick decision-making, often based on
therapeutic amnioinfusion carried out only when fetal estimated birth weight. Intrauterine growth
heart rate decelerations or thick meconium staining retardation, preterm labour, post-term gestations,
of the liquor occurred18. Likewise, in one study of 66 suspicion of macrosomia, and twin and breech
women serial amnioinfusion for preterm rupture of presentations are some of the clinical situations in
membranes did not detect significant differences which prediction of fetal weight may influence the
concerning caesarean section rate, low Apgar score management decision. Clinical estimation of fetal
or neonatal death rate. Author doesn’t recommend weight by abdominal palpation may be highly
the use of serial amnioinfusion for preterm rupture inaccurate, especially in the extremes of fetal size22,
of membranes19. 23.
Since the introduction of ultrasound in obstetrics,
a variety of equations using biparietal diameter (BPD),
Fetal Malformations
head circumference (HC), abdominal diameter (AD),
Preterm labour, breech presentations and multiple abdominal circumference (AC) and femur length (FL)
gestations imply an increased risk of fetal have been evaluated in order to find the most accurate
malformations. Ultrasound can be used to look for way to predict fetal weight. It is now generally
fetal malformations in these clinical situations. The accepted that ultrasound estimation of fetal weight
detection of an unsuspected fetal malformation may is more reliable than clinical estimation. Ultrasound
change the obstetrical management20. Anencephaly has contributed to an improvement in estimation of
or infantile polycystic kidneys have a dismal birth weight 22-26,29-31, although a few reports have
prognosis, and Cesarean section should be avoided questioned its accuracy 27-28 . The accuracy of
on fetal indications. The vaginal probe and a ultrasound estimation of fetal weight is +/_10-
diagnostic amnioinfusion may permit a definitive 15percentage. To avoid errors caused by a low station
diagnosis of bilateral renal agenesis or Potter of the fetal head and molding or dolichocephaly in
syndrome with severe oligohydramnios. That breech presentations, formulas based on FL and AC
diagnosis is not possible with the poorer resolution or adjusting BPD using cephalic index or HC should
of the transabdominal approach21. In addition, Color be used intrapartum24-25, 29-32. In spite of inherent
Doppler ultrasonography is useful to demonstrate the difficulties, the accuracy of intrapartum estimations
presence or absence of renal arteries. Diaphragmatic of fetal weights performed by the house staff in a busy
hernia as well as some structural or functional labor and delivery unit is comparable to that reported
abnormalities of the fetal heart may require prompt by more experienced examiners24, 25. Furthermore,
surgical or medical treatment after delivery, so an Pattersson 24 found that amniotic fluid volume,
accurate diagnosis before delivery is a prerequisite cervical dilatation or station of the fetal head did not
for appropriate neonatal management. Conjoined influence the accuracy of intrapartum estimation of
twins or sacrococcygeal teratoma may cause soft fetal weight.
534 Textbook of Perinatal Medicine

Fetal Well-being During Labor ultrasound component of BPP intrapartum

significantly increased the risk of cesarean delivery
The Biophysical Profile and admission to the neonatal intensive care unit
Several methods for assessing fetal well-being and for (NICU).
identifying a fetus at risk for intrauterine death or
injury have been evaluated. Manning 33, 34, originally Intrapartum Doppler
described the biophysical profile. The ability to see Antepartum Doppler studies have shown an
the fetus, its activities and environment yielded the association between Doppler velocimetry and fetal
concept of the “fetus as a patient”. The four well- being43, and the use of Doppler for antepartum
components included in the biophysical profile based surveillance in high-risk pregnancies can significantly
on ultrasound parameters are fetal breathing reduce perinatal mortality in these cases43-46. The first
movements, fetal body movements, fetal tone and intrapartum Doppler studies were performed with
amniotic fluid index. A reassuring biophysical profile continuous and pulsed wave Doppler. Later, color
score of >8 confers a high probability of perinatal Doppler and the transvaginal approach came into use.
survival, and it accurately predicts antepartum The most commonly examined vessels are the
umbilical venous pH34, 35. Fetal heart rate and fetal umbilical artery, uterine artery, fetal middle cerebral
body movements are the most sensitive indicators for artery and aorta. There are three semiquantitative
impending asphyxia antepartum. Oligohydramnios parameters that evaluate velocity waveform:
is associated with chronic fetal stress, and the absence pulsatility index (PI), resistance index (RI), and
of fetal body movements is predictive of impending systolic/diastolic ratio (S/D). Uterine contractions,
fetal demise34. As labor progresses, a decrease in the fetal breathing movements and frequent alterations
fetal motor activity is a normal finding36, 37. Fetal in maternal position during painful contractions, as
apnea is also a normal phenomenon during labor and well as engagement of the fetal head in the bony
has no adverse prognostic significance37. Sasson et al38 pelvis, may make it difficult to get intrapartum
did not find correlation between the intrapartum Doppler signals 47. Fairlie and colleagues 48 have,
biophysical profile and umbilical pH. Chua and co- however, shown that the reproducibility of umbilical
workers39 tried to select the best screening test to artery Doppler recordings during labor was
identify fetal compromise during labor. They comparable to the corresponding reproducibility from
concluded that women in early labor with an antepartum recordings. There is no significant change
equivocal admission test should be assessed by an in the umbilical artery resistance during normal
additional test like amniotic fluid index, umbilical labor47-50. Neither amniotomy nor oxytocin infusion
artery Doppler or vibroacustic stimulation, which change the umbilical artery resistence48. Likewise,
might be of some help to detect a fetus with an epidural block with enough replacement has no
increased risk of adverse outcome. Although negative effect on the S/D ratio51. Although Feinkind
observational studies33-35, 40 found that biophysical and coworkers52 found that intrapartum screening
profile score gives the best prediction of both acute with Doppler was sensitive enough to identify the
and chronic fetal compromise, a systematic review of fetus at risk for poor perinatal outcome, its use as a
RCTs (four studies of 2849 patients) do not support labor admission test is uncertain. At least two studies
the use of the biophysical profile as a test of fetal well- observed that intrapartum umbilical artery Doppler
being in high risk pregnancies41. However the power velocimetry is not good predictor of fetal distress
of these studies is not strong enough to prove that among unselected patients53, 54.
biophysical profile score is without value42. Kim SY Only in a high-risk population has a correlation
et al 40 has recently found that cessation of any been observed between the umbilical S/D ratio and
 Labor and Puerperium 535
umbilical cord pH48, 52. The intrapartum umbilical membranes with severe oligohydramnios is
artery S/D ratio might be of help in differentiating accompanied by variable decelerations due to cord
between variable decelerations caused by hypoxia or compression, an increased risk of metabolic acidosis,
by mechanical occlusion55. It can also distinguish chorioamnionitis, and a higher rate of Cesarean
between true- and false-positive intrapartum late section 9, 63,64,65 . It seems that FHR alone and
decelerations 56. In the uterine arteries and their biophysical profile are poor predictors of intrauterine
branches, a markedly reduced blood flow during infection. In a prospective study of 225 pregnancies
normal labor has been noticed by several complicated by PPROM with delivery between 24 and
investigators47, 49, 51. Apart from intrauterine growth 32 weeks gestation, AFI<5cm was the only significant
retardation and pre-eclampsia, preterm labor is also risk factor independently associated with early onset
associated with a significantly higher uterine artery neonatal sepsis and chorioamnionitis66. Nowak also
S/D ratio, probably due to decidual vascular concluded that oligohydramnios might be associated
abnormalities51. The few studies on fetal aortal blood with increased risk of chorioamnionitis 67. While
flow have shown decreased flow during labor if Vintzileos68 recommended frequent estimation of the
intrapartum analgesia with pethidine and with a biophysical profile as a simple test to predict the fetus
paracervical block were used47, 57. In cases with no at risk for developing sepsis, and questioned
analgesia or with epidural blocks, an increased amniocentesis as a method to detect the fetus at risk
intrapartum fetal aortic blood flow was noticed57. for infection, Yoon69 found amniotic fluid white blood
Doppler studies of fetal cerebral blood flow in labor cell count to be the best predictor of positive amniotic
may help to explain the patophysiology of fluid culture, histological and clinical
intrapartum asphyxia. Published data are, however, chorioamnionitis and neonatal morbidity. In a review
considerably controversial58-62. The aims of future of 12 studies Hofmeyr found that amnioinfusion to
investigations should be to elucidate the possible prevent infection in women with membranes
factors influencing the waveform pattern and possible ruptured for more than 6h was associated with a
reasons for discrepancy in current reports. reduction in puerperal infection17. Amnioinfusion for
umbilical cord compression in labor reduced FHR
Term and Preterm Premature Rupture of the decelerations, cesarean section for suspected fetal
Membranes (PROM, PPROM) distress, neonatal hospital stay>3days, and maternal
In cases of premature rupture of the membranes, hospital stay >3 days15. The assessment of fetal age,
ultrasound assessment may be of diagnostic help in weight and presentation is important when
the labor and delivery unit. The amniotic fluid volume determining optimal management. Tsoi et al70 studied
assessment, biophysical profile and cervix status are 101 women presented with preterm prelabor
ultrasound parameters of importance for evaluation amniorrhexis. He measured cervix length by
of fetal well-being as well as for estimation of the transvaginal ultrasound and concluded that
conditions for induction of labor. In order to look for prediction of delivery within 7 days is provided by
evidence of subclinical infection a diagnostic cervical length, gestation and presence of contractions
amniocentesis may be performed. In patients with at presentations.
premature rupture of the membranes, it has been
Threatened Preterm Labor
shown that the overall biophysical profile of the
healthy fetus is not altered63, 64. The most important More than 70% of women presenting with threatened
parameters to evaluate fetal well-being are the preterm labor do not progress to active
amount of amniotic fluid and fetal breathing labor and delivery. When confronted with a
movements. Thus, premature rupture of the potential of preterm labor, ultrasound evaluation can
536 Textbook of Perinatal Medicine

provide important information such as gestational of the amniotic sac through a dilated internal cervical
age, fetal weight, presentation, biophysical profile and os can also be observed and has been described as
the status of the cervix. Doppler velocimetry can the “hourglass membranes”.81
detect cases associated with uteroplacental Although ultrasound assessment of the cervix
impairment. Severe fetal malformations and placental seemed to be better than digital examination to predict
abruption should be excluded prior to institution of preterm delivery,78-83 qualitative analysis of nine
tocolytic therapy. Gestational age and birth weight are studies using a cervical length cut off 18-30 mm,
the most important predictors of neonatal survival. showed that transvaginal ultrasound assessment of
None of the various formulas for estimation of fetal cervical dilatation or length has poor predictive
weight seems to have superiority when applied to value.84 The sensitivity for predicting preterm birth
preterm labor71. In very-low-birth-weight fetuses, varied from 68% to 100% and the specificity ranged
ultrasound estimation of fetal weight is very accurate from 54% to 90%. The most recently published studies
and correlates with neonatal survival 72 . Fetal of women with threatened preterm labor, cervical
presentation can drastically change the delivery length cut off <15mm seemed to have higher
management. The value of the biophysical profile to probability to predict preterm delivery within 7
predict impending preterm delivery has been days.85, 86 Thus sonographic measurement of cervical
studied73. The individual biophysical parameters, length helps to distinguish between true and false
especially fetal tone rather than the total score, labor and to avoid overdiagnosis of preterm labor.85,86
demonstrate a strong relationship with the time
interval to delivery74. It has been shown that the Intrapartum Vaginal Bleeding
presence or absence of fetal breathing movements Two major clinical causes of vaginal intrapartum
might be helpful in differentiating between true and bleeding, which may require ultrasound expertise, are
false preterm labor73. Rising fetal prostaglandin levels placenta previa and placental abruption. The
during either term or preterm labor affect the fetal transabdominal approach may result in high false
respiratory center, and provide a possible explanation positive (2-7%) and false negative (2-8%) rates for
of the cessation of fetal breathing movements during placenta previa, depending on the time of
labor. 75, 76 Recently published systematic review scanning.87,88 An overdistended bladder, maternal
regarding the accuracy of absence of fetal breathing obesity, a posterior location of the placenta, the
movements in predicting preterm birth confirmed presence of fresh blood clots and an acoustic
that the absence of fetal breathing has the potential shadowing from the fetal head are factors that make
to be useful test in predicting preterm birth both the diagnosis of placenta previa difficult.
within 7 days and within 48 h of testing.77 Future Considerable improvement has been achieved by
researches are needed. transvaginal ultrasound where false-positive rate of
Cervical Sonography allows determination of 1% and a false-negative rate of 2% have been
cervical length, funneling, the cervical index (funnel observed.87 The focal zone of the vaginal probe is 2-
length +1/endocervical length) originally described 8cm, which provides optimal imaging of the internal
by Andersen and colleagues78, and dynamic changes os. It is enough to insert the probe to a distance of
in cervical anatomy.79 With the transvaginal approach, 2cm remote from the external os to avoid severe
errors due to a low presenting part, maternal obesity bleeding.
or an overdistended bladder can be avoided.80 The Tan et al 89 studied the role of transvaginal
transperineal or translabial approach is a good sonography in the diagnosis of placenta praevia and
alternative for departments where vaginal probes are performed transvaginal sonography in 70 women
not available in the labor and delivery suite. Prolapse diagnosed to have placenta praevia by
 Labor and Puerperium 537
transabdominal sonography. The diagnostic accuracy labor are responsible for a great number of all
of the TV approach was 92,8%, compared with 75,7% Cesarean sections.97 Cephalopelvic disproportion
for the TA route. They concluded that TV sonographic should be suspected in cases with an unengaged fetal
localisation of the placenta is superior to the TA head during labor, or in women with previous
approach for type 1 and 2 placenta praevia but no Cesarean section due to dystocia. Efforts have been
better for type 3 and 4. Transvaginal color Doppler made to establish ultrasound diagnostic criteria to
seems promising in the diagnosis of placenta previa estimate cephalopelvic disproportion during early
accreta90, 149. The ultrasound appearance of placental labor, based on results from ultrasound determination
abruption can vary. A high false-negative rate is a of the true conjugate and the transverse diameter of
problem. The normal anechoic retroplacental area the pelvic inlet before labor. 98, 99 This requires,
with signs of venous flow identified by pulsed however, special equipment and considerable
Doppler should not be interpreted as a placental expertise. Dystocia in late labor can be caused by
abruption91. Nyberg and colleagues92 reported results persistent occiput position. Clinical evaluation of the
of 57 cases of placental abruption, retrospectively position of the fetal head by digital palpation is
reviewed. The location of the hemorrhage was sometimes uncertain and inaccurate due to scalp
subchorionic in 81%, retroplacental in 16% and oedema, which causes difficulties in recognition of the
preplacental in 4% of the cases. The fetal mortality sutures and the fontanelles. Akmal et al100 studied the
rate was 20% with a placental abruption including accuracy of intrapartum routine digital examination
20% of the placenta. The ultrasound findings varied in defining the position of the fetal head and found
with the size and location of the haematoma, as well that digital examination during labor failed to identify
as with the time of the sonogram. Furthermore, the the correct fetal position in the majority of 496 cases.
risk of fetal demise was greater in retroplacental and Likewise he found among 64 women that digital
preplacental cases than in cases with subchorionic examination during instrumental delivery failed to
haematoma. In most of the cases with clinically identify the correct fetal head position in 26,6% of
suspected abruption, ultrasound findings are cases101. Ultrasound diagnosis of persistent occiput
negative93. It is likely that the free passage of blood posterior position is simple, by visualization of the
through the cervical os prevented the formation of a facial bones and orbits anteriorly and the spine
haematoma large enough to be visualized94. An acute posteriorly. By contrast, persistent occiput anterior
hemorrhage is usually hyperechoic to isoechoic, and position is confirmed when the facial bones and orbits
then gradually becomes anechoic during the are placed posteriorly and the spine anteriorly. The
following 1-2 weeks.94-95 Rivera and colleagues96 risk of cesarean section can be estimated during the
suggest that the use of ultrasound and nonstress early stage of active labor by the sonographically
testing in the expectant management of placental determined occiput position102. Rayburn and co-
abruption could result in a decrease in maternal and workers103 studied 86 patients with arrested labor and
perinatal mortality and morbidity. It must, however, showed that intrapartum ultrasound significantly
be remembered that a negative ultrasound finding improved the diagnosis of persistent occiput position,
should not postpone essential treatment when there and could be of help in the management of delivery.
is a clinical suspicion of placental abruption. Chou104 confirmed this recently. If midpelvic forceps
or vacuum extraction is to be performed, precise
Dystocia in Early and Late Labor
knowledge of the position of the fetal head is
Dystocia - “poor progress of labor” – is one of the mandatory; a more proper forceps application and
leading indications for operative delivery, and it has proper axis of traction may then be applied. Persistent
previously been shown that mechanical problems in occiput anterior position associated with labor
538 Textbook of Perinatal Medicine

dystocia is indicative of fetal macrosomia, and at delivery but caesarean section rate108. Ultrasound
shoulder dystocia can be expected103. A new method may be of help during an external version of a breech
to assess the descent of the fetal head in labor with fetus at term. Ferguson et al109 performed successful
transperineal ultrasound has been presented105. Head external version in 11 of 15 women at term who
deflection may cause either a brow or a face presented in active labour. In contrast review of three
presentation and then an abnormally broad diameter RCTs of 889 women shows that ECV is not useful in
makes the passage through the maternal pelvis preterm breech presentations.110 However if ECV fails
difficult. Such head deflection can be detected by and vaginal breech delivery is woman’s preference
ultrasound. Clinically, face presentation can be or if a breech presentation is diagnosed during early
mistaken for breech presentation, especially if there labor, a thorough and targeted ultrasound evaluation
is facial oedema. Ultrasound examination can should be performed. Valuable information that can
accurately exclude such an unpleasant surprise in the be obtained by ultrasound includes:
delivery unit. Knowledge of the position of the 1. Type of breech (frank, complete or footling;)
mentum anterior and occiput posterior are mandatory 2. Estimated birth weight;
for allowing vaginal delivery in cases with face 3. Amniotic fluid volume assessment;
presentation, and this can be confirmed by 4. Placental location (rule out placenta previa)
ultrasound. With a brow presentation, engagement 5. Rule out malformations (anencephaly, infantile
of the fetal head and delivery usually cannot take polycystic kidneys)
place if it persists. The brow presentation can, Additional information that substantially
however, be converted to either a vertex or face influences the decision-making can also be obtained
presentation to allow vaginal delivery106. With a by ultrasound, i.e.:
transverse lie during early labor, the position of the 1. Fetal head position (hyperextension);
head and back as well as the location of the placenta 2. Nuchal or extended arm;
should be identified before an external version or a 3. Nuchal cord;
Cesarean section is undertaken. When the back is 4. Cord presentation;
anterior, the risk of cord prolapse is greater. 5. Cephalopelvic disproportion.
Information obtained from ultrasound can facilitate The gold standard for evaluation of the maternal
the performance of the Cesarean section. pelvis has long been X-ray pelvimetry. This technique
can expose both fetus and mother to possible long-
Breech Presentation
term radiation hazards106. Rojansky and colleagues98
Recently published review of RCTs concerning proposed a simple ultrasound method for diagnosis
preferred method of delivery for breech at term, of hyperextension of the fetal head by measurement
showed that cesarean delivery occurred in of the cranio-spinal angle, and a method to measure
550|1227(45%) of those women allocated to a vaginal the obstetrical conjugate by transabdominal
delivery protocol 107 . Perinatal mortality and ultrasound. He studied 72 laboring women with
morbidity was greatly reduced in planned cesarean breech presentations and performed both traditional
section group (RR=0,31 95% CI 0,19 0,52). Reviewers X-ray and ultrasound evaluation of the head position,
concluded that planned cesarean section for breech type of breech and pelvic adequacy. A highly
at term should be preferred method of delivery. Result significant correlation between the two methods was
of this review has considerably influenced obstetrical demonstrated. He suggests that the ultrasound
praxis regarding delivery mode for breech at term. approach is reliable and may replace the X-ray
Nowadays there is enough evidence that external method in management of breech presentation in
cephalic version reduces not only breech presentation labor. Although similar suggestions had been
 Labor and Puerperium 539
proposed previously99, 111,112 sonographic pelvimetry presentation, gestational age or the presence of
has not yet become a routine praxis. discordant twins 119,120. There is a general aim for
Ultrasound indications for Caesarean sections, vaginal delivery unless presenting twin
according to Rojansky, are: a cranio-spinal angle of nonlongitudinal lie. A retrospective study comparing
150¤, an obstetrical conjugate of<10cm, and certain neonatal morbidity in term twins delivered by
non-frank breech presentations. Ballas et al113 suggest caesarean section with vaginal delivery found that
that hyperextension of the fetal head (angle >90) that neonatal respiratory disorders were significantly more
was present on radiographic assessment, should be a common in the first group121. In vertex/vertex twins,
contraindication to labor. Among twenty babies vaginal deliveries are most often planned. It has to
reported to have an angle >90, 8 of 11 delivered be remembered, however, that in about 20%, the
vaginally, sustained cervical cord lesions. The nine second twin will change position once the first is
babies delivered by caesarean section had no cervical delivered122. Therefore, ultrasound assessment should
damage. Sherer114 suggests an additional indication always be performed after delivery of the presenting
for abdominal delivery, namely “nuchal arm” twin, so that a transverse lie can be turned into a
(extension of an arm behind the fetal head). This longitudinal lie122-125. Moreover, ultrasound should be
condition can be diagnosed by ultrasound. He used to assess the fetal heart rate of the second twin,
pointed out that nuchal arm is a cause of severe birth and may be of help if a suddenly compromised second
trauma, and can result in persistent Erb’s palsy, twin needs a swift delivery by internal version and
torticollis and convulsions. Ultrasound can identify extraction. The same manoeuvre should be done if
a nuchal cord with single or multiple coils, although external version of the second twin to longitudinal
its clinical value is still controversial115. Lange and co- lie fails. If there is a vertex/non-vertex presentation,
workers116 defined cord presentation as the finding the ultrasonic estimated birth weight will be of vital
on ultrasound of loops of the umbilical cord below importance when deciding upon the route of delivery.
the fetal body and occupying the lower segment. Estimated birth weights between 2000 and 4000g can
Estimation of birth weight should be performed in be allowed for breech deliveries123, provided there is
patients with breech presentations who prefer vaginal a pelvic adequacy, no substantial growth discordance,
delivery; weights between 2000 and 4000g are no cord presentations, nuchal cord, extended arm or
reasonable limits within which a trial of labor can be head deflection. Retrospective study of 408 twin
permitted.117, 118 When fetal weight is estimated in deliveries showed that external cephalic version of
breech presentations, dolichocephaly should be the second twin and subsequent vaginal delivery in
identified by the cephalic index, and corrections made vertex non-vertex was successful in 75% of cases.
for this. For the purpose of avoiding errors due to Internal podalic version and assisted breech delivery
dolichocephaly, formulas based on femur length, was performed in 20 cases and the remaining two
abdominal diameter or abdominal circumference were delivered by caesarean section. Apgar scores
should be used.31, 32 were not significantly different among the various
groups and no complications arouse from external
Intrapartum Management of Multiple Gestations cephalic version performed on second non-vertex
Ultrasound is an indispensable diagnostic tool for twin.126
intrapartum management of multiple gestations.
Induction of Labor
Presentations and estimated weights are most
important when deciding on the mode and route of Pre-eclampsia, intrauterine growth retardation, post-
delivery. Estimation of fetal weight in twin gestations date pregnancies and diabetic pregnancies are
during labor seems to be reliable regardless of common causes of labor induction. In post-date
540 Textbook of Perinatal Medicine

pregnancies, the presence of severe oligohydramnios, being superior to the Bishop score131, 132. The same
fetal macrosomia and unfavorable cervix can be authors studied induction of labor for prolonged
revealed by ultrasound. Bishop127 originally described pregnancy and found cervical length and parity to
evaluation of the cervix before induction of labor by be significant independent prediction of the likelihood
digital vaginal examination. Results of numerous of Caesarean section, prediction of induction to
studies concerning the evaluation of the cervix by delivery interval and the likelihood of vaginal
ultrasound are contradicting128-135. An unfavorable delivery within 24h of induction133, 134. In post-date
cervix results in failed induction in 3-5%. A careful pregnancies or diabetic pregnancies, fetal macrosomia
evaluation of the cervix before induction of labor may should be ruled out since large-for-date infants have
help to avoid complications such as failed inductions an increased risk of traumatic birth injury135-137.
leading to Caesarean section. Since the introduction Formulas based on femur length and abdominal
of transvaginal ultrasound cervicometry, it has been circumference has the best correlation with actual
possible to assess the cervical status more objectively, birth weight in macrosomia138. Great efforts have been
and our ability to predict the course of labor seemed made to diminish the numbers of shoulder dystocia,
to be improved128. A sagittal section of the cervix can which is a nightmare for the obstetrician139-142. A cut-
be seen between the anterior anechogenic bladder and off value of 1,4 cm for the difference between the chest
echogenic rectum. Although the cervical length and diameter and biparietal diameter142 or 2,6cm for the
dilatation can be objectively measured by ultrasound, difference between abdominal diameter and
the consistency of the cervix can be assessed only by biparietal diameter143 can be helpful in estimating the
digital vaginal examination. Therefore, a combination risk of shoulder dystocia, and can thus be helpful in
of digital examination and vaginal ultrasound deciding the appropriate route of delivery. The fetal
assessment was recommended. The Bishop score subcutaneous tissue/femur length ratio is an
would seem to be the best and most cost-effective additional gestational age-independent parameter for
method to assess the cervix and predict the likelihood the intrapartum identification of a macrosomic
of success of labor induction and the duration of such fetus.144 Vaginal birth after Cesarean section has been
an induction. It seems that transvaginal ultrasound advocated as a safe method to reduce the increasing
does not predict successful labor induction in post Cesarean section rate.145 Prior to a trial of labor, the
term pregnancy as well as digital cervical myometrial thickness in the area of the prior
examination129. Reis et al130 obtained similar results Caesarean scar can be examined by ultrasound. It has
concerning induction at term. They found ultrasound been shown that defects in the lower uterine segment
measurement of the cervix and fibronectin test failed or abnormal uterine thickness can be visualized by
predicts accurately the outcome of induced labor. ultrasound.147
Digital examination and obstetric history were the
only variables independently associated with labor Third Stage of Labor
duration and predicted accurately vaginal delivery Herman and co-workers148 investigated the third
within 24 hours. Roman and colleagues136 showed stage of labor by dynamic ultrasound. They showed
that neither the Bishop score nor cervical length by that, immediately after delivery of the fetus, the
ultrasound was good predictor for the outcome of placenta-free uterine wall became thick and the
labor induction in an unfavourable cervix. In contrast uterine wall at the site of the placenta remained thin.
recently published studies as regard the value of As soon as the contraction phase began, the wall
ultrasound in the prediction of successful induction behind the placenta contracted gradually and only
of labor found sonographic parameters (cervical when it attained its final thickness did the placenta
length, occipital position posterior, cervical angle) detach. No hematoma was observed between the
 Labor and Puerperium 541
placenta and the uterine wall. Ultrasound during the the uterine cavity, can be evaluated by ultrasound153-
160
third stage of labor can help to clarify whether the . In the early puerperium, transabdominal
placenta has already detached or still is adherent to ultrasound examinations are to be recommended. The
the uterine wall. Directly after the delivery of the woman should have a moderately filled urinary
placenta, the uterine cavity is visualized as a thin bladder. Gentle compression with the probe should
bright central line. Krapp and colleagues149 has shown be used and measurements should be made between
that the disappearance of blood flow between the uterine contractions to avoid uterine distortion.
basal part of the placenta and the myometrium is the During the middle or late puerperal period, the
hallmark of normal placental separation: persistent transvaginal approach is preferable. Color Doppler161-
163
blood flow due to abnormal vascular connections is and transvaginal duplex Doppler164 with high
suggestive of placenta accreta. Although this method resolution have made it possible to study the vascular
can be helpful in making an early diagnosis and thus changes of the uterine involution non-invasively, and
preventing heavily postpartum hemorrhage by early these methods have improved our ability to recognize
manual removal of placenta, the clinical application puerperal abnormalities. The puerperal uterus should
is of limiting value due to lack of appropriate be assessed in sagittal, coronal and transverse sections
ultrasound equipment at delivery suites. (Fig. 40.1, Fig. 40.2). The coronal section is preferable
for investigation of uterine malformations. Some
Intrapartum Uterine Rupture ultrasound pictures are typical for the puerperium.165
The actual site of uterine rupture is usually difficult The involution of the uterus is a dynamic process that
to visualize by ultrasound.150 Indirect ultrasound has no parallel in normal adult life. The uterine
signs of uterine rupture are retroperitoneal hematoma dimensions and the uterine cavity diminish
and free peritoneal blood, most often localized in the progressively and substantially during the
cul-de-sac, the paracolic gutters, or the puerperium. There are two physiological lifesaving
subdiaphragmatic areas.151-152 Sometimes an extruded processes occurring soon after placenta delivery:
fetus or placenta can be seen. Although the clinical thrombotamponade (enhanced blood clotting
signs and symptoms of uterine rupture are most activity) and myotamponade (compression of the
important, the use of ultrasound may be of additional vessels by myometrial contraction). The appearance
aid in diagnosing this dangerous complication. of ultrasound finding during early puerperium
reflects these physiological changes. The normal
PUERPERIUM shape of the uterus in the sagittal plane during the
first postpartum days has been described as a “hockey
Normal Ultrasound Appearance stick”166, or a “crescent”156. This form of the uterus is
of the Postpartum Uterus typical only in the early puerperium and it is artificial.
The puerperium is defined as the period of 6-8 weeks An extremely great degree of uterine deformability
after birth during which the reproductive tract is caused by a heavy uterine corpus, a hypotonic
anatomically and physiologically returns to the lower uterine segment and supine position of the
nonpregnant state. When faced with puerperal examined woman. In the 2nd postpartum week, the
abnormalities, it is useful to know the normal shape changes and becomes more globular. The
ultrasound appearance, and the dynamic changes of position of the uterus also changes. In the early period
the uterus during the puerperium, in order to better the uterus arches over the sacral promontory in a
distinguish pathological from normal conditions. The retroverted position. Wachsberg and colleagues166
involution changes concerning the size, shape and pointed out the importance of this uterine angulation
position of the uterus, as well as the appearance of and its effect on the measurements of uterine length.
542 Textbook of Perinatal Medicine

Fig. 40.1: Three standard sections of the puerperal uterus:

a longitudinal (a), a coronal (b) and a transverse (c)

The uterus rotates along its internal cervical os and

in majority of women it achieves an anteverted
position in the beginning of the second postpartum
week. This position is then retained. In only a few
women does the uterus return to a retroverted
position at the end of puerperium165? Concomitantly
with the changes in dimension, shape and position
of the uterus, the uterine cavity goes through a
marked process of involution. During the first three
postpartum days lifesaving uterine contraction
approaches anterior and posterior uterine walls and Fig. 40.2: Transabdominal ultrasound scans of a normal
just virtual cavity appears. It is empty and decidua puerperal uterus on day 1; a longitudinal scan (a), a coronal
appears as a thin white line from the fundus to the scan (b), and a transverse scan (c) (New figure)
level of the internal cervical os. Sometimes this line
can be irregular and thicker which probably depends more irregular lines might represent cases with
on the amount of retained decidua. The separation of retention of more spongy decidual layer and perhaps
the placenta and membranes generally occurs in the fragments of membranes. It is unusual to find a
spongy layer, however the level varies. Already in the collection of fluid or any echogenic masses in the
1931 Williams wrote concerning the line of separation upper part of the cavity at that time. In the lower
of the placenta and membranes” “While separation uterine segment, however, a collection of fluid with
generally occurs in the spongy layer, the line is very mixed echo patterns is almost always present. It
irregular so that in places a thick layer of decidua is retained, comprises blood clots and probably small fragments
in others only a few layers of cells remain, while in still of retained membranes165, 166,168,169. This finding has
others the muscularis is practically bare” 167. The variation no clinical significance and the mass is usually
in sonographic appearance of the cavity could be seen expelled spontaneously. Small echogenic or
as a demonstration of these physiological variations echolucent dots in the cavity are harmless
in retained decidua. The thin white line seen on physiological findings 168. In contrast Sokol and
ultrasound might possibly represent cases in which colleagues170 found in 16 of 40 women echogenic
only the basal decidual layer is retained or if the material in the uterine cavity within 48 h after normal
muscularis is practically bare. Whereas the thicker and vaginal delivery. On the posterior wall of the uterus
 Labor and Puerperium 543
the prominent uterine vascular channels are regularly considered as a normal finding. Other investigators
seen160. From days 7-14, endometrial fluid can be seen have not been able to confirm this165, 168,169. Whether
in the whole cavity, not only in the lower segment or not a small amount of gas is seen in the uterine
(Figs 40.6B and C). Moreover, echogenic and non- cavity has, however, no clinical significance. Lavery
echogenic areas are seen in the whole uterine cavity, and Shaw160 described the prominent uterine vascular
probably comprising a mixture of blood, blood clots channels in the normal early postpartum period. With
and offcasts of necrotic decidua. The diameter of the color-Doppler a venous blood flow could be
cavity in the upper part of the uterus may then be demonstrated, which usually disappears during the
quite wide, which reflects a normal healing process 2nd and 3rd postpartum weeks. Besides conventional
of the placental site inside uterine cavity, necrotic ultrasound, Doppler technology is used to study
changes of retained decidua and an abundant hemodynamic events occurring during the
shedding of lochia. In contrast Edwards et al171 found puerperium161-164, 181-182. Normal pregnancy requires
an echogenic mass in a great proportion of normal the growth of many new vessels. Consequently
puerperal women. At 4 weeks postpartum, the uterus during puerperium dramatically regressive changes
is again empty and the uterine cavity is seen as a thin occur. The physiological destruction of the uterus
central line. Sometimes a small amount of fluid can involves not only muscle cells and decidua but also
be seen. By 8 weeks postpartum the involution the arteries. Tekay161 and Kirkiinen162 assessed the
process is complete, and the uterus has non-pregnant peripheral vascular resistance of the uterine arteries
dimensions. It lies in an anteverted position in 88% in the postpartum period and found that the
of cases165. In 12 % of cases the uterus has a retroverted pulsatility index value started to increase in the early
position corresponding well to normal prevalence of puerperium, remained unchanged during the next 6
retroversion of the uterus in general population. weeks and finally increased to reach the non-pregnant
Decidua and necrotic vessel ends are exfoliated, the values about 3 months after delivery. The prediastolic
placental site is recovered and a new endometrium is notch is also detected in the early puerperium and
regenerated from the basal layer of the decidua these hemodynamic changes can be partly explained
adjacent to the myometrium. In 1953 Sharman by the immediate contraction of the uterus 161, 162 Fluid
performed endometrium biopsies and identified fully collections in the fossa of Douglas are not a common
restored endometrium from the 16 th postpartum finding during the puerperium165, 169.
day172. Ultrasonically the cavity appears as a thin
Retained Placental Tissue
white line. This corresponds to an inactive
endometrium and reflects the hypoestrogenic state of Retained placental tissue in the uterine cavity
the puerperium (“the physiologic menopause”). It is postpartum is associated with a high risk of excessive
not common to find fluid or echogenic masses in the bleeding, either immediate or delayed. Immediate
uterine cavity at that time. There are conflicting data postpartum bleeding requires urgent management;
about the presence of gas in the uterine cavity during manual evacuation of the uterine cavity is warranted.
the normal puerperium. Previous studies have Ultrasound can be a valuable aid to confirm an empty
suggested a correlation between gas and endometritis uterine cavity after the evacuation by demonstrating
caused by E.coli or C. Perfringens 159.178 . These the easily visible bright echogenic linear echo in the
conditions are, however, nowadays very rare. middle part of the uterus. Delayed postpartum
Wachsberg and Kurtz173 detected gas in the uterine haemorrhage occurs in about 1- 2% of cases. It is most
cavity in 21% of the normal population, and often the result of abnormal involution of the placenta
suggested that gas in the uterine cavity did not site in the uterine cavity and endometritis, but it may
necessarily indicate endometritis but could be be caused by retention of placental tissue. In
544 Textbook of Perinatal Medicine

developed countries, half of postpartum women who of different kinds of intrauterine contents. Necrotic
are admitted to hospital with this condition undergo decidua, blood, blood clots and inflammatory necrotic
uterine surgical evacuation. In developing countries changes may essentially influence the ultrasound
it is a major contributor to maternal death174. Two image. Nevertheless the most common finding
etiological factors were identified as risk factors, associated with retained placental tissue is an
namely primary postpartum hemorrhage and a echogenic mass164, 168, 169, 177- 179. In contrast, Edwards
history of manual removal of a retained placenta. et al171 found in his study an echogenic mass on day
Uterus curettage was performed in 63% of cases. 7 in 51% of normal cases, in 21 % on day 14 and in 6%
Histological confirmation of residual placental tissue on day 21. He questioned ultrasound finding of an
was obtained in 37% following ultrasound diagnosis echogenic mass in uterine cavity as a sign of retained
and in 33% without previous ultrasound examination. placental tissue. The definition of an echogenic mass
The decision whether to perform uterine evacuation was not specified. Even Sokol et al 170 found
for retained placental tissue depends on both, clinical “echogenic material” in 40% of cases during 48 h after
finding and the ability to visualize retained placenta normal delivery. However, echogenic material was
by ultrasound. Although prompt curettage seems to localised in lower uterine segment in 14 of 16 women.
be necessary in many cases it usually doesn’t remove On the other side ultrasound appears as a valuable
identifiable placental tissue175. Moreover it is more tool to confirm an empty cavity. Lee and
likely to traumatize the implantation site and incite Mandrazzo178 found empty cavity in 20 of 27 patients
more bleeding. Consequently the complications rate with late puerperal bleeding. In only one case retained
is high. Hoveyda et al 176 reported in his review placental tissue was confirmed. The same authors
regarding secondary postpartum haemorrhage that reported that histological confirmation was obtained
the frequency of perforation of the uterus was 3% and
hysterectomy about 1%. Alexander and colleagues174
identified 45 papers about the management of women
with secondary postpartum haemorrhage and they
concluded that no information was available from
randomized trials to inform the management of
women with this condition. Since curettage in the
postpartum period can be dangerous, it is of great
value to have a tool that can diagnose retained
placental tissue. Many conflicting data exist about the
ultrasound appearance of retained placenta tissue.
The first studies were performed with old static
ultrasound equipment 154, 177,178 . They described
various ultrasound images of retained placental
tissue, and the rate of false-positive diagnosis was Fig. 40.3: Puerperal abnormalities as seen by the transvaginal
high. Despite the markedly improved imaging (a, b) or transabdominal(c, d) approach. (a) Retained placental
tissue is seen as an echogenic mass surrounded by a distinct
possibilities in the 1990s, confirmation or exclusion halo and easy detectable flow on the side of the mass; (b)
of retained placental tissue is still difficult 163, retained placental tissue which has persisted for a long time
164,168,169,176-180 postpartum and is seen as “a stippled pattern”; (c) after
. We cannot expect the same ultrasound
picture during early (Fig. 40.3) and late period of the cesarean section gas is observed in the uterine cavity with
clean and dirty shadowing well visualized; (d) a necrotic myoma
puerperium. The ultrasound appearance of retained which caused dysfunctional puerperal bleeding is seen in the
placental tissue may vary depending on the presence uterine cavity
 Labor and Puerperium 545
in eight of nine patients with ultrasound suspected detectable flow, always on the side of the circumscript
retained placenta tissue. If ultrasound finding shows echogenic mass, that was histological proven to be
an empty uterus with a thin white decidua/ retained placental tissue. It may be speculated that
endometrium, pure endometrial fluid or only small this highly vascularized area is responsible for the
echolucent or hyperechogenic dots, a clinically blood supply to retained placental tissue. Kelly and
significant amount of retained placental tissue is colleagues 198 described a rare cause of severe
unlikely 164, 165,168,169. Patients with persistent secondary postpartum haemorrhage - arteriovenous
dysfunctional postpartum bleeding are highly malformation of the uterus. By color Doppler
suspected of having retained placental tissue, and ultrasound, a localised area of increased vascularity
they often show a typical ultrasound image with a within the myometrium may be detected. Pulsed
“stippled pattern” of scattered hyperechogenic foci168. Doppler usually reveals a low resistance turbulent
Later on, retained placental tissue becomes flow. Thus uterine artery embolization may be
increasingly echogenic and the scattered appearance performed and unnecessary curettage should be
disappears168. A heterogeneous pattern may cause avoided. In contrast Van Schobroeck 182 found
confusion since retained placental tissue and necrotic enhanced myometrial vascularity (EMV) to be a
decidua with organized blood clots can give similar common transient ultrasound finding if
images during the 1st or 2nd postpartum week. Neil asymptomatic and it doesn’t require treatment. On
and colleagues180 compared ultrasound with clinical the other side, if in symptomatic patients residual
assessment for the diagnosis of retained placental placental tissue is suspected on ultrasound, EMV is
tissue related to secondary postpartum hemorrhage. an additional ultrasonic finding which can help
They concluded that both, clinical assessment and guiding the appropriate management. It has recently
ultrasound scan have limited diagnostic accuracy. been evaluated the accuracy of transvaginal
Transabdominal two-dimensional imaging alone is sonohysterography and compared it with
not specific enough. Transvaginal ultrasound has been transvaginal ultrasound163,183. It seems to be this new
advocated 164 with the use of a high frequency method more effective for evaluation of residual
(6,5MHz) transvaginal probe to better differentiate trophoblastic tissue. Power Doppler and three-
between retained placental tissue and blood clots dimensional ultrasound seems to be new unexplored
mixed with necrotic decidua. Transvaginal pulsed and modalities that could improve our abilities to
color Doppler is promising non-invasive methods to diagnose clinically significant retained placental
improve the diagnostic accuracy of ultrasound tissue. All of these new modalities need further
concerning retained placental tissue161,162,163. Achiron evaluation before their usefulness can be
and colleagues164 looked at the myometrial arterial recommended.
blood flow around intracavitary contents and found
Postpartum Endometritis
that patients with a resistance index below 0,35 had
residual tissue. These patients are suitable for invasive Whenever the obstetrician is faced with postpartum
treatment. A resistance index (RI) above 0,45 should bleeding accompanied by signs of endometritis, the
exclude diagnosis. Values between 0,35 and 0,45 were most important question is whether there is retained
designated as a “gray zone”. These patients could be placental tissue in the cavity or not. Previously, it has
treated conservatively with repeated ultrasound been considered that ultrasound finding of retained
examinations, and curettage should be performed placental tissue and endometritis overlap. Recent
only if conservative treatment failed. Alcazar and co- studies have, however, contradicted this view169. Only
workers181 found a RI value< 0,45 to be suggestive of if endometritis is the result of retained placental tissue
retained placental tissue. We observed easily can a similar ultrasound appearance be observed. An
546 Textbook of Perinatal Medicine

isolated endometritis without retained placental vein may sometimes be observed.193 Furthermore a
tissue has no pathognomonic ultrasound finding. complex or hypoechoic mass near the lower pole of
Confusion can sometimes arise in the presence of large the kidney particularly in clinical setting of an
retained and organized blood clots in the uterine “enigmatic puerperal fever” should suggest
cavity, that may mimic retained placental tissue. thrombophlebitis. An echogenic intracaval mass is
Clinical improvement following conservative considered diagnostic and anticoagulation treatment
treatment with antibiotics and uterotonic medications should be added.195
speaks against the presence of retained placental
Cesarean Section
tissue. Uterine involution could be delayed in cases
of endometritis, particularly if endomyometritis is Nowadays when Cesarean section rates are
present184. The detection of gas in the uterine cavity continuously rising, higher incidence of all puerperal
has been considered as a sign of endometritis. complications should be expected. The ultrasound
Madrazo159 found endometrial gas in 15% of patients appearance of the uterus after Cesarean section
with proven puerperal endometritis. Wachsberg and usually shows three distinctive patterns: 1) gas in the
Kurtz166, however, observed gas in 21% of women cavity 2) a small rounded area at the incision site that
postpartum; none of these women developed reflects tissue reaction due to localized oedema 185-187
endometritis. Whenever gas is present in the uterine and 3) some echogenic dots at the incision site, which
cavity a follow-up ultrasound should be performed is related to the type of closure and the suture material
to confirm its disappearance. It usually resolves used187. All these characteristics are normal findings
during the first two postpartum weeks. If ultrasound and no correlation with pathological conditions is
is performed after intrauterine manipulations or found. The ultrasound appearance of endometrial gas
Cesarean sections, it should kept in mind that highly is an intensively hyperechogenic focus equivalent in
echogenic foci caused by air are normal findings that echogenic to bowel gas with clean or dirty shadowing
must not be misinterpreted as retained placental or reverberation artifacts173, 188. Fat and calcium have
tissue or endometritis. Kirkiinen found that blood a similar ultrasound appearance. The gas usually
flow to the infected uterus could be different from disappears during the first 2 weeks after surgery. The
normal 162 . Deutchman and Hartman 184 have involution rate of the uterus following caesarean
described an uncommon result of endometritis - section is not different from the involution rate after
postpartum pyometra. A lucent area within the uterus vaginal delivery. Nakai et al197 studied uterine blood
with no echogenic components is suggestive of pus. flow resistance after Cesarean section and concluded
Ultrasound can assist in the proper diagnosis and be that the resistance index for the uterine artery didn’t
of help in guiding a drainage procedure. show any change during the early postpartum period.
Septic pelvic thrombophlebitis, well known as an The significant infectious morbidity is associated with
“enigmatic puerperal fever” is another uncommon caesarean section. Ultrasound may be useful in
complication of the puerperium. It most commonly postpartum women with clinical suspicion of a
presents in early postpartum period and antibiotic postoperative complication like phlegmona 186 ,
treatment is usually unsuccessful. Rudoff et al192 abscess, pyometra, haematometra, wound infection,
suggests ultrasound examination in case of clinical subfascial hematoma. If surgical drainage is chosen
suspicion of pelvic thrombophlebitis. Although as therapy, ultrasound guidance can be helpful.
ultrasound diagnosis of ovarian vein Ultrasound can also confirm the suspicion of an intra-
thrombophlebitis is well described193-195 the diagnosis abdominal postoperative hemorrhage by visuali-
is still difficult and an ultrasound expertise is needed. zation of free fluid in the abdomen. Baker et al185
Asymmetric dilatation of the ovarian or other pelvic described bladder flap haematoma after a low uterine
 Labor and Puerperium 547
transverse Caesarean section. A solid or complex mass few studies concerning the issue were published190,191.
between the posterior bladder wall and the anterior Szoke and Kiss190 examined in 1977 patients where
uterine wall may be observed by ultrasound. An manual examination revealed a uterus differing in
abscess appears as a cystic structure with internal shape from normal, the patient had a breech
debris surrounded by thicker irregular walls. An presentation in her previous or present pregnancy and
infected haematoma initially has similar ultrasound the involution of the uterus was slow. The ultrasound
appearance. During the resolution process, it may echo technique was applied and uterine anomalies
change and appears more solid. However the were found in five cases postpartum. In 1984 Land et
physician must be aware that ultrasound diagnosis al 191 performed ultrasonic hysterography in 104
is just a complement and clinical condition of the patients between the 2nd and 5th postpartum day. An
patient should guide the therapeutic approach. unexpectedly high number of women (16%) showed
an abnormal uterine configuration. The coronal
Uterine Myoma section seems to be the most appropriate section in
Myoma may obstruct the birth canal and thus be a order to reveal uterine cavity anatomy. It is difficult
cause for Cesarean section. Intracavitary myoma may to obtain the coronal section by abdominal
cause problems such as placental detachment with examination in non-pregnant patients. However the
subsequent postpartum bleeding. Ultrasound is the puerperium when the uterus is extremely large makes
best tool to make a correct diagnosis. A myoma is an exception. The ultrasound examination should
characterized by hypoechogenicity. Due to perform in the early puerperium because a large
degenerative processes, a myoma may appear as a uterus lies in near proximity to the ultrasound probe
bizarre heterogeneous pattern of solid and fluid areas, and highly echogenic decidua outlines well the shape
and thus be misinterpreted as retained placental of the cavity. Puerperal ultrasound can detect such
tissue. Pinpoint tenderness on palpation may direct an abnormality, providing an explanation for
the ultrasound examination and reveal the presence complications in labor and the puerperium.
of a necrotic myoma.
Postpartum Urinary Retention
Developmental Abnormalities of the Uterus Postpartum urinary retention is a relatively common
The prevalence of the congenital uterine condition and incidence ranges between 1-18
malformations in general population is unknown. percent.196 According to the International Continence
Failed fusion of the two Mullerian ducts to form the Society, 100 ml is considered as the upper limit of
genital organs may cause reproductive, fetal and residual urine. Ultrasound is the method of choice
maternal hazards. In addition to an increased risk of when assessing urinary bladder and residual urine
premature labor and abnormal fetal presentations, postpartum. Invasive catheterization with the
retained placental tissue with postpartum discomfort and the risk of infection can be avoided.
hemorrhage may be a consequence of this uterine Conventional bladder scanner is not to be
abnormality. It is well known that uterine anomalies recommended during the puerperium. Large uterus
may remain undiscovered except when they are may content fluid and thus a misinterpretation may
associated with reproductive or obstetric problems. be done. Many different techniques for bladder
Already in 1976 Bennett suggested puerperal volume measurement are used and the accuracy of
ultrasonic hysterography as a screening procedure the method varies widely.
prior to radiological examination in women whose We prefer a method where the longest distance of
reproductive performance suggests a diagnosis of the maternal bladder (d1) is measured in a
congenital malformation of the uterus189. Since that a longitudinal section, and then two perpendicular
548 Textbook of Perinatal Medicine

11. Chauhan SP, Doherty DA, Magann EF. Amniotic fluid

index versus single deepest pocket technique during
modified biophysical profile: A randomised clinical trial.
Am J Obstet Gynecol 2004.Aug; 19(2): 661-7
12. Alfirevic Z, Luckas M, Walkinshow SA, McFarlane M,
Curran R. A randomised comparison between amniotic
fluid index and maximum pool depth in the monitoring
of pos-term pregnancy. BJOG 1997; 104: 207-11
13. Chauhan SP, Sanderson M, Hendrix NW, Magann EF,
Devor LD. Perinatal outcome and amniotic fluid index
in the antepartum and intrapartum periods: a meta
analysis. Am J Obstet Gynecol 1999; 181: 1473-8
14. Moses J, Doherty DA, Magann EF, Chauhan SP, Morrison
JC. A randomised clinical trial of the intrapartum
Fig. 40.4: Residual urin volume measurement
assessment of amniotic fluid volume: amniotic fluid index
versus the single deepest pocket technique. Am J Obstet
diameters (d2, and d3) are measured in the transverse Gynecol 2004 Jun; 190(6): 1564-9
section (Fig. 40.4). The estimated amount of residual 15. Hofmeyr GJ. Amnioinfusion for umbilical cord
urine can be calculated using the formula for compression in labour. In: Cochrane Database of Syst Rev.
2001 (issue 3) Oxford: Update Software
approximation of the ellipsoid: 16. Moen MD, Besinger RE, Tomich PG, Fisher SG. Effect of
Volume (ml) = (d1 × d2 × d3) / 2 (Fig. 40.4). amnioinfusion on the incidence of postpartum
endometritis in patients undergoing Caesarean delivery.
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1994; 73: 607-10 159:531
99. Deutinger J, Bernaschek G. Vaginosonographical 116. Lange IR, Masning FA, Morrison I. Cord prolapse: is
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6 117. Gimovsky ML, Paul R. Singleton breech presentation in
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Intrapartum sonography to determine fetal head position. 143:733
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101. Akmal S, Tsoi E, Kametas N, Hargreaves C, Nicolaides presentation. Clin Perinatol 1996; 23:31-49
KH. Comparison of transvaginal digital examination with 119. Chauhan S, Washburne J, Martin J. Intrapartum
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assessment by house staff of birth weight among twins.
before instrumental delivery. Ultrasound Obstet Gynecol.
Obstet Gynecol 1993; 82:523
2003 May; 21(5): 437-40
120. Lukacs HA, MacLennan AH, Verco PW. Ultrasonic fetal
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agreement. Ultrasound Obstet Gynecol. 2004 Sep; 24(4):
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of twins and neonatal respiratory disorders. Am J Obstet
103. Rayburn WR, Siemers KH, Legino LJ. Dystoci in late
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labor: determining fetal position by clinical and ultrasonic
122. Houlihan C, Knuppel RA. Intrapartum management of
techniques. Am J Perinatol 1989; 6:161-89
multiple gestations. Clin Perinatol 1996; 23:91
104. Chou MR, Kreiser D, Taslimi MM, Druzin ML, El-Sayed
YY. Vaginal versus ultrasound examination of fetal 123. Chervenak F, Johnson R, Youcha S. Intrapartum
occiput position during the second stage of labor. Am J management of twin gestation. Obstet Gynecol 1985;
Obstet Gynecol 2004 Aug; 191(2): 521-4 65:119
105. Barbera A, Pombar X, Perugino G et al: A new method to 124. Chervenak F, Johnson RE, Berkowitz RL, Hobbins JC.
assess fetal head descent in labor with transperineal, Intrapartum external version of the second twin. Obstet
ultrasound. Ultrasound Obstet Gynecol 1996;8(Suppl 1): Gynecol 1983; 62:160
95 125. Hays PM, Smeltzer JS. Multiple gestations. Clin Obstet
106. Pritchard JA, MacDonald PC, Gant NF. Williams Gynecol 1986; 29:264
Obstetrics, 17th edn. Norwalk: Appleton-Century-Crofts, 126. Kaplan B, Peled Y, Rabinerson D.et al. Successful external
1985:660 version of B twin after the birth of A twin for vertex non
107. Hofmeyr GJ, Hannah ME. Planned caesarean section for vertex twins Eur J Obstet Gynecol Reprod Biol. 1995;
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reviews, 2001; issue 3. Oxford Update Software 127. Bishop EH. Pelvic scoring for elective induction. Obstet
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breech presentation at term. In Cochrane database of 128. Boozarjomehri F, Timor-Trisch I., Chao C. Transvaginal
systematic reviews, 2000; issue 4. Oxford Update sonography – an objective evaluation of the cervix in
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Vol 189, Issue 5, 1361- 7. during pregnancy. Obstet Gynecol 1988; 71:112
131. Rane SM, Guirgis RR, Higgins B, Nicolaides KH The value 148. Herman A, Weinraub Z, Bukovsky I, et al. Dynamic
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132. Yang SH, Roh CR, Kim JH. Transvaginal ultrasonography Gynecol 1993; 168:1496-9
for cervical assessment before induction of labor. J 149. Krapp M, Baschat AA, Hankeln M, Gembruch U. Gray
Ultrasound Med. 2004; Mar 23 (3) 375- 82. scale and color-Doppler sonography in the third stage of
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prolonged pregnancy the effect of parity in the prediction 150. Bedi DG, Salmon A, Wisett MZ et al. Ruptured uterus:
of the need for Caesarean section. Ultrasound Obstet sonographic diagnosis. J Clin Ultrasound 1986; 14:529-
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KH. Pre induction sonographic measurement of cervical case followed with sonography. Arch Gynecol Obstet
length in prolonged pregnancy the effect of parity in the 1991; 249:43-5
prediction of induction to delivery interval. 152. Suonio S, Saarikoski S, Kääriäinen J, Virtanen R.
135. Mastrogiannis DS, Knuppel RA. Critical management of Intrapartum rupture of uterus diagnosed by ultrasound:
the very low birth weight infant and macrosomic fetus. a case report. Int J Gynecol Obstet 1984; 22:411-13
153. Robinson HP. Sonar in the puerperium. Scott Med J 1972;
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154. Szoke B, Kiss D. The use of the ultrasonic echo technique
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in examining the normal and pathological involution in
examination when the cervix is unfavourable improve the
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prediction of failed labor induction? Ultrasound Obstet
155. Rodeck CH, Newton JR. Study of the uterine cavity by
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137. Wikström I, Bergström AR, Meirik O. Traumatic injury
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156. Defoort P, Benijts G, Martens G, Thiery M. Ultrasound
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assessment of puerperal uterine involution. Eur J Obstet
138. Hirata GI, Medearis AI, Horenstein J. Ultrasonographic
Gynecol Reprod Biol 1978; 8:95-7
estimation of fetal weight in the clinically macrosomic 157. Van Rees D, Bernstine R, Crawford W. Involution of the
fetus. Am J Obstet Gynecol 1990; 162:238 postpartum uterus: an ultrasonic study. J Clin Ultrasound
139. Wiznitzer A. Obstructed labor and shoulder delivery. Curr 1981; 9:55-7
Opin Obstet Gynecol 1995; 7:486-914 158. Seeds JW, Chescheir NC, Wade RV. Postpartum
140. Pearson JF. Shoulder dystocia. Curr Obstet Gynecol 1996; ultrasound. In Practical Sonography in Obstetrics and
6:30-4 Gynecology, 2nd edn. Philadelphia, New York: Lippincott-
141. Smith RB, Lane C, Pearson JF. Shoulder dystocia: what Raven, 1986:347-8
happens at the next delivery? Br J Obstet Gynaecol 1994; 159. Madrazo BL. Postpartum Sonography. In The principle
101:713-15 and Practice of Ultrasonography in Obstetrics and
142. Eliot JP, Garite TJ, Freeman RK, et al. Ultrasonic prediction Gynecology, 3rd edn. East Norwalk: Appleton-Century-
of fetal macrosomia in diabetic patients. Obstet Gynecol Crofts, 1985: 449-56
1982; 60:159-62 160. Lavery JP, Shaw LA. Sonography of the puerperal uterus.
143. Cohen B, Penning S, Major C, et al. Sonographic J Ultrasound Med 1989; 8:481-6
prediction of shoulder dystocia in infants of diabetic 161. Tekay A, Jouppila P. A longitudinal Doppler
mothers. Obstet Gynecol 1996; 88:10-13 ultrasonographic assessment of the alterations in
144 .Santolaya-Forgas TJ, Meyer WJ, Gauthier DW, Kahn D. peripheral vascular resistance of uterine arteries and
Intrapartum fetal subcutaneous tissue /femur length ultrasonographic findings of the involuting uterus during
ratio: an ultrasonographic clue to fetal macrosomia. IS J the puerperium. Am J Obstet Gynecol 1993; 168: 190-8
Obstet Gynecol 1994; 171:1072? 162. Kirkinen P, Dudenhausen J, Baumann H, et al. Postpartum
145. Martins ME. Vaginal birth after caesarean section. Clin blood flow velocity waveforms of the uterine arteries. J
Perinatol 1996; 23:141-53 Reprod Med 1988; 33: 745-74
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163. Zalel Y, Gamzu R, Lidor A, Goldenberg M, Achiron R. 180. Neill AMC, Nixon RM, Thornton S. A comparison of
Color Doppler Imaging in the Sonohysterographic clinical assessment with ultrasound in the management
Diagnosis of Residual Trophoblastic Tissue. Journal of of secondary postpartum haemorrhage. Eur J Obst &
Clinical Ultrasound 2002; Vol 30 No 4 May Gynecol and Reprod Biol 2002; 104:113-115
164. Achiron R, Goldenberg M, Lipitz S, Mashiach S. 181. Alcazar JL, Lopez-Garcia G, Zornoza A. A role of color
Transvaginal duplex Doppler ultrasonography in velocity imaging and pulsed Doppler sonography to
bleeding patients suspected of having residual detect retained trophoblastic tissue. Ultrasound Obstet
trophoblastic tissue. Obstet Gynecol 1993; 81:507-11 Gynecol 1996;8(Suppl 1): 41
165. Mulic-Lutvica A, Bekuretzion M, Axelsson O, et al. 182. Van Schoubroeck D, Van den Bosch T, Scharpe K, Lu C,
Ultrasonic evaluation of the uterus and uterine cavity Van Huffel S, Timmerman D. Prospective evaluation of
after normal, vaginal delivery. Ultrasound Obstet Gynecol blood flow in the myometrium and uterine arteries in the
2001; 18: 491-498 puerperium. Ultrasound Obstet Gynecol 2004; 23:378-381
166. Wachsberg RH, Kurtz AB, Levine CD, et al. Real-time 183. Wolman I, Hartoov J, Amster R, et al. Transvaginal
ultrasonographic analysis of the normal postpartum sonohysterography for the early detection of residual
uterus: technique, variability and measurements. J trophoblastic tissue. Ultrasound Obstet Gynecol 1996;
Ultrasound Med 1994; 13: 215-21 8(Suppl 1): 37
167. Williams JW. Regeneration of the uterine mucosa after 184. Deutchman ME, Hartmann KJ. Postpartum pyometra: a
delivery with special reference to the placental site. Am case report. J Fam Pract 1993; 36: 449-52
J Obstet Gynecol 1931; 22:664 185. Baker ME, Bowie JD, Killam AP. Sonography of post
168. Hertzberg BS, Bowie JD. Ultrasound of the postpartum cesarean- section bladder-flap haematoma. Am J
uterus, prediction of retained placental tissue. J Roentgenol 1984; 144:757-9
Ultrasound Med 1991; 10: 451-6 186. Lavery JP, Howell RS, Shaw L. Ultrasonic demonstration
169. Sakki A. Kirkiinen P. Ultrasonography of the uterus at of a phlegmona following Caesarean section – case report.
early puerperium. Eur J Ultrasound 1996; 4: 99-105 J Clin Ultrasound 1985; 13:134-6
170. Sokol ER, Casele H, Haney EI. Ultrasound examination 187. Burger NF, Dararas B, Boes EGM. An echogenic
of the postpartum uterus what is normal? J Maternal Fetal evaluation during the early puerperium of the uterine
Neonat Med. 2004; 15: 95-99 wound after caesarean section. J Ultrasound Med 1983;
171. Edwards A, Ellwood DA. Ultrasonographic evaluation 2:18
of the postpartum uterus. Ultrasound Obstet Gynecol 188. Carson PL. Clean and dirty shadowing at US a
2000; 16: 640-643 reappraisal. Radiology 1991; 181: 231-6
172. Sharman A. Reproductive Physiology of the Post-Partum 189. Bennett MJ. Puerperal ultrasonic hysterography in the
Period. Livingston: Edinburgh E. &S. 1966 diagnosis of congenital uterine malformations. Br J Obstet
173. Wachsberg RH, Kurtz AB. Gas within the endometrial Gynaecol 1976; 83(5): 389-92
cavity at postpartum US. A normal finding after 190. Szoke B, Kiss D. The use of ultrasonic echo technique in
spontaneous vaginal delivery. Radiology 1992; 183: 431- the diagnosis of developmental anomalies of the
3 uterus.1977
174. Alexander J, Thomas P, Sanhghera J. Treatments for 191. Land JA, Stoot JE, Evers JL. Puerperal ultrasonic
secondary postpartum haemorrhage. The Cochrane hysterography. Gynecol Obstet Invest 1984; 18(3): 165-8
Library, Issue 4: 2002 192. Rudoff JM, Astranskas LJ, Rudoff JC, et al.
175. Dewhurst C. Secondary postpartum hemorrhage. J Obstet Ultrasonographic Diagnosis of Septic Pelvic
Gynaecol Br Commonwealth 1966; 73: 53-58 Thrombophlebitis. J Ultrasound Med 1988; 7:287-291
176. Hoveyda F, MacKenzie IZ. Secondary postpartum 193. Warhit JM, Fagelman D, Goldman MA, et al. Ovarian vein
haemorrhage: incidence, morbidity and current thrombophlebitis: diagnosis by ultrasound and CT. J Clin
management. Br J Obstet Gynaecol 2001; 108: 927-930 Ultrasound 1984; 12: 301
177. Malvern J, Campbell S, May P. Ultrasonic scanning of the 194. Wilson PC, Lerner RM. Diagnosis of ovarian vein
puerperal uterus following secondary postpartum thrombophlebitis by ultrasonography. J Ultrasound Med
hemorrhage. J Obstet Gynaecol Br Commonw 1973; 1983; 2:187
80:320-4 195. Sherer DM, Fern S, Mester J, et al. Postpartum
178. Lee CY, Madrazo B, Drukker BH. Ultrasonic evaluation ultrasonographic diagnosis of inferior vena cava
of the postpartum uterus in the management of thrombus associated with ovarian vein thrombosis.Am J
postpartum bleeding. Obstet Gynaecol 1981; 58: 227-32 Obstet Gynecol 1997;177(2):474-5
179. Carlan SJ, Scott WT, Pollack R, et al. Appearance of the 196. Weissman A, Grisarn D, Shenhav M, et al. Postpartum
uterus by ultrasound immediately after placental delivery Surveillance of urinary retention by ultrasonography: the
with pathologic correlation. J Clin Ultrasound 1997; 25(6): effect of epidural analgesia. Ultrasound obstet Gynecol
301-8 1995;6:130-134
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197. Nakai Y, Imanaka M,Nishio J, et al. Uterine blood flow 198. Kelly SM, Belli AM, Campbell S. Arteriovenous
velocity waveforms during early postpartum course malformation of the uterus associated with secondary
following caesarean section. Eur J Obstet Gynecol Reprod postpartum hemorrhage. Ultrasound Obstet Gynecol
Biol 1997; 74(2): 121-4 2003;21:602-605.
 41
Safety of Diagnostic Ultrasound
in Obstetrics
B Breyer, A Kurjak, K Maeda

INTRODUCTION really of interest from a diagnostic point of view, but

when considering safety, such absorption within a
Diagnostic ultrasound has become an integral
short distance is exactly the type of phenomenon that
component of perinatal care. Even after widespread
may be of concern. All waves attenuate very strongly
use for almost four decades there has not been a single
in bone.
known instance of identifiable adverse effects caused
by the diagnostic intensity of ultrasound.
Describing Ultrasound Waves
Nevertheless, the need for continuing vigilance for
biosafety is well recognized. It has long been Ultrasound waves and pulses can be described using
recognized that, given certain circumstances, the following parameters:
ultrasound exposure can influence biological systems. 1. Propagation speed. The average speed for longi-
Diagnostic medical insonation, however, is generally tudinal waves in human soft tissue is 1540 m/s.
assumed to be safe. In calcified bones, the speed is about twice that in
This chapter addresses some complex issues about soft tissues. In gasses it is about 330 m/s. Shear
safety, and presents a review of available data from waves travel more slowly.
literature as well as from personal experience of the 2. Wavelength (?) is inversely proportional to
authors. frequen-cy. It greatly influences the resolution of
diagnostic machines. The higher the frequency, the
PHYSICAL BACKGROUND shorter the wavelength. For example, the
wavelength in the body at 3 MHz is approximately
Ultrasound Waves 0.5 mm.
Ultrasound waves convey mechanical energy through 3. The pulse length for Doppler measurements is
matter by passing energy from particle to particle. often longer than for B-mode imaging. These
Longitudinal waves induce pressure variations along pulses are transmitted at a repetition frequency
their way. In soft tissues, these waves are the most typically of the order of a few kilohertz (kHz).
common type. Other modes, like transverse or shear 4. The attenuation of ultrasound is proportional to
waves, can spread an appreciable distance, only in frequency. Absorption causes heating of tissues.
solids. When transmitted into bodily liquids, such 5 UItrasound pressure amplitude is the maximum
waves are absorbed within a very small distance. pressure induced by the compressional wave at a
Waves that spread only very short distances are not point in the tissue. If we operate with continuous
556 Textbook of Perinatal Medicine

wave (as in fetal cardiotocographic (CTG) of parameters are used. Intensity was the first such
monitoring) the wave is continuous. If, however, parameter. Later, it was recognized that this was not
we use pulses (such as in imaging), ultrasound is enough and therefore additional parameters were
transmitted in the form of short pulses and the introduced:
maximum positive (compressional), maximum 1. Acoustic power output is the total acoustic power
negative (rarefaction) and average pressure during that exits from a transmitting transducer. In
the pulse or during the total time must be taken commercial B-mode instruments the power ranges
into account. between 0.3 and 280 mW; in color Doppler
Energy is measured in Watt seconds or Joules; mapping between 15 and 400 mW; in pulsed
p o w e r is measured in Watts; intensity is measured in Doppler spectrometry between 10 and 450
Watts per square meter or centimeter. The attenuation mW.1–3
property is measured in db/cmMHz. 2. Spatial peak temporal average intensity (ISPTA) is the
In diagnostic applications, ultrasound waves are intensity averaged over time, but measured in the
mainly used in the form of beams and are usually position of the spatial peal (focus). When
transmitted in the form of pulses. In pulse considering the potential hazard of heating, we
applications, the energy flow exists in time only take this ISPTA into account. In commercial B-mode
during the pulse. Considering an example when the instruments this ranges between 0.3 and 990 mW/
pulse duration is one thousandth of the repetition cm2; in color Doppler mapping between 20 and
period, then the intensity during the pulse is about 2000 mW/cm2; and in pulsed Doppler spectro-
1000 times higher than the overall time average meters between 170 and 9000 mW/cm.2
intensity. 3. The intensity at the point of maximum pressure
Ultrasound beams can be focused in various ways, in a pulse is the pulse peak intensity. This is the
but the important feature from the safety standpoint temporal peal intensity.
is that focusing concentrates ultrasound energy and 4. When considering the potential hazard of
thus, potentially, increases the hazard. For safety cavitation spatial peak pulse average ISPPA is among
consideration, only transmission focusing is relevant. the significant parameters. In commercial pulsed
In scanning applications the beam moves, while in Doppler instruments this ranges between 1 and
Doppler spectrometry and M-mode imaging one 770 W/cm.2
tends to keep the beam in one position for a prolonged 5. Peak negative pressure is also among the parameters
time. for evaluation of the cavitation probability. It is
The ultrasound pulse consists of a few pressure easier to measure than the peak positive pressure,
oscillations around the static atmospheric pressure. which may be greatly distorted in shape. The peak
When considering safety, the positive peak pressure pressure varies in all types of modern equipment
pc and the negative peak pressure pr play a role. At between 0.4 and 5 MPa.1–3
high intensitites the positive peak pressure may The above parameters play a role in the body, but
become a few times higher than the negative peak are far easier to measure in water. In addition, it is
pressure. These effects are much more expressed in much easier to standardize them in water. Two
liquids in which there is little attenuation compared approaches are used: the measurement of all
to human tissues in which attenuation is much greater. parameters in water or the immediate calculation of
the in situ values taking into account conventional
Acoustic Parameters Used standard attenuation values, e.g. 0.3 dB/cm MHz. The
to Describe Ultrasound exposure bone is considered to be very attenuating so that
In order to concisely and exactly describe ultrasound nearly all the energy is absorbed within a short path.
waves in regard to their potential hazard a multitude Various organ or situation models have been
 Safety of Diagnostic Ultrasound in Obstetrics 557
conceived to represent specific situations, e.g. full the median in 35 mW/cm2; in M-mode the median is
bladder and uterus with an embryo. about 100 mW/cm2; in 2D velocity mapping (color
Doppler) the median is about 290 mW/cm2 and in
INSTRUMENT PROPERTIES pulsed Doppler the median is 1200 mW/cm.2 The
AND ACOUSTIC OUTPUT factor of increase of intensity between the various
In purely practical terms, it is necessary to know what modes is about three from mode to mode.1–3
properties of the scanners are important for their safe Another source of heat may be heating of the
use, both when acquiring a new machine and when transducer because of internal dissipation. When
using existing ones. Some properties are inherent to intracavitary probes are used this may be a factor for
the instrument while others depend on the application serious consideration. The extent of heating depends
and the way in which the instrument is used. on the probe design and materials used.
Heating of tissues is proportional to ISPTA in situ. Cavitation is less likely with short pulses. In B-
The general trend for an increase in the output of mode imaging the pulse length is usually less than
diagnostic ultrasound instruments.1 Since the 1980s, 0.5 µs, but in pulsed Doppler applications it can be
there have been instruments on the market with ISPTA up to 20 µs. It is possible to control this length by
above 1 W/cm 2 in pulsed Doppler operation varying the ‘sample volume’. Shorter ‘sample
regimens.2 The actual intensity greatly depends on volumes’ generally yield smaller ISPTA.
the mode of operation and settings (ALARA
ULTRASOUND THERAPY
principle4,5 should be obeyed). The lowest intensity
is used in fetal heart monitors (continu-ous wave In order to have a feeling of what these intensities
(CW) Doppler systems with the intensity below 100 may mean it is worth mentioning that the ultrasound
W/cm2), and then, in order of increasing intensities: machines used in physical therapy operate at
B-mode imaging scanners, 2D Doppler machines and intensities between 0.5 and 3 mW/cm.2 Therapy using
pulsed Doppler instruments. In many instruments it these machines is based on tissue heating, particularly
is possible to operate in various regimens. High-end heating of boundaries between soft and connective
scanners normally have the possibility of quasi tissue and bones. There exists an extensive body of
parallel operation in various regimens, e.g. gray scale, data1–3 on ultrasound machine outputs.
2D-flow mapping and Doppler spectrometry ‘at the There is the ever-developing ultrasound-treatment
same time’. In fact, the scanner switches quickly field that includes lithotripsy, physiotherapy and
between the various modes. ‘ultrasound knives’ of various types, particularly of
The actual acoustic power and pressures in the brain and liver surgery. Therefore, it is sensible to
pulses greatly depends on the mode of operation, consider how these applications, where the biological
Depth and length of examination also influence the effect is the essence of the application, compare to
exposure. The frequency influences the penetration diagnostic applications where, in ideal cases,
ability and thus may influence the acoustic power information is gathered without causing any
used. For example, the use of higher frequency biological effect.
intracavitary probes implies two opposite effects, i.e. Physiotherapy devices use continuous waves or
the scanning distance (range) is reduced, but the very long pulses of intensity between 0.5 and 3 W/
frequency is increased and, therefore, the attentuation cm.2 The mechanism used is heating. The therapist
per centimeter is reduced. Thus the acoustic energy must continuously move the probe in order not to
traversing the region of interest is about the same. overheat some structure in the patient.
In the current commercially available instrumen- Lithotripsy is done with short pulses that ‘bang’
tation, ISPTA varies with the mode: in B-mode imaging on the stones. Their average intensity is fairly low
558 Textbook of Perinatal Medicine

compared to the effects on the stones. However, their between the two extremes both in temperature and
acoustic pressures are very high, reaching nearly 10 duration is the present ‘gray zone’ of knowledge.
Mpa. The range of pressures overlaps with the Consensus is that exposure of adult proliferative
diagnostic equipment. tissue to heat at 42°C for up to 2 h11 can cause only
The important difference between these therapy reparable damage. The effects are proportional to ISPTA
applications and the diagnostic applications is the and the absorption coefficient. The absorption
frequency, normally 10–50 times lower in therapy. coefficient is proportional to frequency. Absorption
The application of ultrasound for treatment of also depends on the tissue type. In the case of
disease in the mother may inadvertently lead to longitudinal waves, absorption is at least an order of
damage to the fetus if serious precautions are not magnitude greater in bone than in soft tissues. Bodily
taken. fluids absorb very little so that they are unlikely to
heat up due to the traversing of ultrasound. Tissues
SAFETY OF DIAGNOSTIC with high connective tissue content absorb more.
ULTRASOUND IN OBSTETRICS However, they allow little attenuated ultrasound to
Obstetrics is a particularly sensitive field. A general reach structures positioned beyond them. On the
rule is that fast growing and developing tissues are other hand the absorption of shear waves is very high
more sensitive to outside influences. This applies to in soft tissues and, thus, if any shear wave is induced
embryonic and fetal tissues in particular. The potential in a bone it will be absorbed within a millimeter in
hazard varies in extent and nature during the the adjacent soft tissue. This may then significantly
intrauterine development. increase the temperature on such a boundary. Blood
Before implantation, physical stress can cause vessels and perfusion in the target area act as a cooling
abortion. After implantation, various tissues and system and take the heat away. If the perfusion is poor
organs become susceptible to damage at different the heat may accumulate. Fatty tissue and bones are
times. Between 5 and 10 weeks of gestation the neural structures with relatively poor perfusion and little
tube is prone to damage; the forebrain development consequent cooling. The heating may have multiple
is particularly important until the 20th week of maxima, i.e. near the transducer at the focus and at
gestation. The development of the right and left side specific media interfaces. The main problem may be
of the brain is not symmetrical in time, and nor is the the heating of nervous tissue caused by absorption
end result. Thus, it is important to be aware of possible within itself, by heating at the adjacent bone/soft
neurological effects and that such effects may show tissue boundaries (skull vertebrae). The same applies
as some sort of sidedness. to bone marrow. 12 While it is known that
hyperthermia can be teratogenic in animals, there is
Heating and its Effects no confirmed study in large mammals confirming that
diagnostic ultrasound-induced hyperthermia causes
The human body is a thermodynamic system.
such effects. It should be borne in mind that a higher
Chemical reactions depend on the temperature. The
body temperature, e.g. due to fever, may increase the
sensitivity of the reactions dictates the very narrow
damaging ultrasound energy.
temperature span in which the human body operates
well.
Non-thermal Effects
A very long temperature increase of 1.5°C above
37°C does not present a health hazard for humans6– Effects other than thermal are conceivable. In 1972 Hill
10
. It has been shown that exposure of mouse embryos considered the possibility of mechanical effects.13
for 5 min to a temperature increase of 4°C is hazardous Either cavitation, or other forces induced by altering
for their development. The temperature range com-pression, and rarefaction forces may damage the
 Safety of Diagnostic Ultrasound in Obstetrics 559
molecules of which the body is composed. Transient since the gas side presents very low resistance.
cavitation is known to have damaging potential, since Rarefaction pressures may present a potential hazard
collapsing bubbles generate shock waves that disrupt when using high-energy Doppler with the beam
nearby structures. The temperature at the point of hitting the lung.19 However, the fetal lung is not at
implosion is extremely high (a few thousand degrees). such risk since it is not filled with air. The reports of
In addition, relatively stable, oscillating bubbles change in neurological development such as speech
induce microstreaming of liquids around them, and handed-ness20–22 have not been confirmed by
possibly causing changes in metabolism or independent studies.
mechanical damage to cell membranes. If cavitation
is a possible cause of hazard then the mechanical Clinical Aspects
index 14,15 accepted by the Food and Drug The whole body of knowledge concerning the
Administration 16 might yield some means of biological effects of ultrasound is relevant only if it
comparing various scanners and modes of operation. helps in the estimation of whether diagnostic
In order to measure the pressure in situ it is
ultrasound as used today is hazardous for the patients
necessary to take into account the attenuation in the
and, if so, to what extent. It should be noted that even
intervening tissue. Using this convention, the
a significant change in rare conditions (for example
attenuation is taken to be 0.3 dB/cmMHz. It is a good
those that appear once in 10 000) may not be
idea to have this index displayed on the screen in
detectable because the statistics require too great a
order to choose the operation regimen that yields the
number of controlled cases. In such investigations we
required data while maintaining the mechanical index
must concentrate on the type of damage that is most
as low as possible.
likely to occur, based on the understanding of the
Streaming17,18 of absorbing and attenuating liquids
underlying mechanisms. Due to the bone/soft tissue
due to ultrasound passage is due to the variation of
interface the central nervous system is the most likely
energy concentration along the path (actually it is the
candidate for thermal damage. Damage of a small
change of the impulse). It depends on the attenuation
area in the brain may not yield easily detectable
coefficient of the liquid and its viscosity. Particles in
the liquid can contribute to streaming. A particular consequences unless it affects a sensory mechanism
type of streaming is microstreaming around an (vision, hearing, etc.). Other organs, once they consist
oscillating gas bubble. of a large number of cells, can repair partial
The basic biological effect that would cause mechanical damage. If the damage happens early,
concern in the case of collapsing bubbles is the destruction of a small number of cells may have very
generation of free radicals. This could lead to serious late consequences in the form of defective
alteration of chromo-somes. If the free radicals are development.
formed outside the membrane, the time needed for While there is no independently confirmed experi-
transport of such radi-cals to the nucleus is longer mental proof of such damage, the indications are that
than their halflife. However, there is no confirmed any effects are obtained only when the temperature
evidence of chromosomal effects, particularly in living rises by more than 2°C for a few minutes. Using
mammals. scanned beams and modern equipment it is very
Another possible non-thermal mechanism may be improbable that such a long time would be spent at
due to direct mechanical vibration of cell membranes. one spot.
This might cause changes in ion (calcium in particular) The application of echo/contrasts ought to be
permeability.4 restricted to adult scanning for the time being since
The soft-tissue to gas boundary may present a the existence of microbubbles may increase the
particularly favorable situation for mechanical effects probability of non-thermal effects.
560 Textbook of Perinatal Medicine

In vitro experiments yield a variety of of the possible temperature increase. The subvariants
demonstrated effects13,23,24. Such experiments can help of the thermal index are meant for specific situations,
indicate the direction of investigation in whole i.e. TIS for homogeneous soft tissue, TIC for
organisms, but they lack the important property of temperature increase of bone near the surface (e.g.
living tissues, namely that the individual cells are skull) and TIB for temperature increase at the bone
interconnected in a tissue unlike cells suspended in a boundary in the beam focus area. Using this labeling
culture. Under such conditions, the probability of non- standard, if the scanner is not capable of producing a
thermal mechanisms occurring is much higher than TI of more than 1, it does not have to be displayed.
in whole tissues. Other national and international bodies have
All the experimental indications of damage caused conceived other estimation means. The capability of
by diagnostic ultrasound, although independently an ultrasound system to cause heating may be
confirmed, indicate that the probability is low. This described by the ratio of acoustic power to the
means that in practice caution is advised, but no maximum temperature rise. The idea is to perform
absolute recommendation against the use of an actual worst-case calculation and to define the
diagnostic ultra-sound measurements is advised. conditions (and instrument settings) that yield the
maximum temperature increase so that all else is less
Standards and Labeling Recommendations hazardous. This is still in development as a consensus
There are no easy methods for measuring the about the tissue and beam properties has not been
temperature increase in a patient in vivo. Thus, it is achieved.11 Various sources give differing data9,25–28
necessary to resort to estimates based on experimental on ultrasound absorption in tissues and its action
work. Present solutions to this problem are certainly upon them. Nevertheless, the ultimate aim should be
approximate and partial, but the pressure of the reality a con-sensus in recommendations given by various
warrants such approaches. The National Council on bodies and organizations. This should be based on
Radiation Protection and Measurements (NCRP) and realistic esti-mates of the possibility of ultrasound-
The American Institute of Ultrasound in Medicine/ induced heating. This is, among other things, an
National Electrical Manufacturers Association important guideline for the industry to discontinue
(AIUM/NEMA)14 have developed models. The latter the increase in ultrasound energy outputs in new
body has devised an index for estimating the heating apparatus models.
likelihood that is not expected to be exceeded under This leads to guideline conclusions by expert
normal circumstances. This so-called thermal index groups, e.g. European Federation of Societies of
may be displayed on the screen to give the operator Ultrasound in Medicine and Biology (EFSUMB)
real-time relative guidance on the potential heating Watchdogs or the AIUM bioeffects committee that
of the tissues scanned. The value applies to the came to the consensus that when using the ISPTA of
situation in situ. There exists no internationally 720 mW/cm2, the maximum temperature rise in situ
accepted standard for any of the proposed indicators would not exceed 2°C, thus will be safe to use. The
of thermal hazard. The AIUM/NEMA thermal index present FDA regulation gives ISPTA values of 720, 430,
(TI) provides an estimate of temperature increase. By 94, 17 mW/cm2 for peripheral vessel, cardiac, fetal
convention, TI is the ratio of total acoustic power to and ophthalmic (i.e. eye lens) applications,
the acoustic power required to raise tissue respectively. The regulation is not limited to ISPTA but
temperature by 1°C. Although its basis is an includes a mechanical index. Measurements in
approximate calculation of the actual temperature humans would be difficult or unduly aggressive and
increase for a ‘standard’ tissue at a distance, it may thus are impossible. Experiments on excised tissue or
not be interpreted literally. It is a relative indication experimental animals can not be directly extrapolated
 Safety of Diagnostic Ultrasound in Obstetrics 561
to humans but give important guidelines as to where Industrial Standard regulated the output power of
to look for danger. The time-limited soft-tissue diagnostic ultrasound devices below 10 mW/cm2 in
experiments with ultrasound pulses equivalent to 1980, which was 1/100 of hazardous CW ultrasound
38-40
pulsed Doppler mode have shown heating below intensity at 1 w/cm2. However, ultrasound safety
2.5°C in various experiments. However, higher has been discussed again after the introduction of
temperature increases have been measured in animals Doppler flow velocity measurement, because pulsed
at skull bone/brain boundaries.11 Doppler method required definitely higher power
than B-mode ultrasound.
THE SAFETY OF DOPPLER ULTRASOUND Maximum intensity of commercial Doppler
In general, it is emphasized that ultrasonic ultrasound is 1 to 3 W/cm2. It is definitely higher than
examination should be performed only for medical that of B-mode imaging, and it is the level of
indications, and diagnostic ultrasound users should ultrasound physiotherapy for the tissue heating.
recognize the sensitivity of young biological tissues Ultrasound safety is warned even in the
of developing embryos and fetuses exposed to intense physiotherapy, e.g. therapeutic transducer should be
ultrasound.10 The users also should know ultrasonic always moved on the bone, young bone and pregnant
intensity of their devices, the mechanisms of woman is contraindicated to the physiotherapy. The
ultrasound bio-effect, and the prudent use of the difference between therapeutic ultrasound and pulsed
devices, because they are responsible for the Doppler is exposure duration i.e. it is short in Doppler
ultrasound safety. An important ultrasound bioeffect flow measurement and long in therapeutic
is thermal effect due to temperature rise induced by ultrasound. Therefore, thermal effect is big concern
ultrasound absorption, because malformations were in Doppler ultrasound bioeffect. Temperature rises not
reported in the exposure of animal embryos and only at the sample volume, but also in all tissues
fetuses to high temperature in biological experiments. passed by the ultrasound beam. The International
No hazardous thermal effect is expected when the Society of Ultrasound in Obstetrics and gynecology
temperature rise of exposed tissue is less than 1.5ºC, (ISUOG) also discussed the safe use of Doppler
and local temperature is lower than 38.5ºC.32 Five min’ ultrasound.37 Ultrasound intensity is less in color/
exposure to 41º C temperature can be hazardous to power Doppler flow mapping than pulsed Doppler
the tissue. Inertial cavitation and other mechanical due to the scanning procedure than stable irradiation
effects are concerned in the non-thermal bioeffects of of pulsed Doppler. Also temporal averaging intensity
ultrasound. of common color Doppler ultrasound is less than
720mW/cm2, which is lower than pulsed Doppler
The Intensity of Doppler Ultrasound devices, and lower than FDA regulation.16 Thermal
No hazardous thermal effect is expected in common effect is discussed in the first place, due to possible
B-mode imaging device because of minimum heat teratogenicity of heating. Exposure duration is
production due to low ultrasound intensity, i.e. World important for the safety of Doppler velocimetry.
Federation of Ultrasound in Medicine and Biology
The Effect of Heating on Mammal Fetuses
(WFUMB)32 concluded that the use of simple imaging
equipment is not contraindicated on thermal grounds. A terratogenic effect was reported by the biologists
The real-time B-mode, simple three dimensional (3D) after the exposure of animal embryos and fetuses to
and four dimensional (4D) imaging devices, high temperature, namely, malformations were found
ultrasonic fetal heart beat detector and fetal monitor in various species by experimental heating. The
are included in the category. Diagnostic ultrasound temperature was 39 to 50 ??Teratogenic effect on
safety was established in Japan, after the Japanese mammals are summarized in the report of National
562 Textbook of Perinatal Medicine

Council for Radiation Protection and Measurement Table 41.1. Non-hazardous exposure time (t min) to the
(NCRP).33 A discrimination line is found between the temperature rise above 37? and absolute temperature is
calculated by the equation 2 which is obtained from the
hazardous and no hazardous areas in the NCRP
results of experimental heating of animal fetus33
report. There is no malformation, if the fetus is heated
Temperature Absolute Non-hazardous Log t
in the area under the discrimination line which is
rise temperature exposure time; t
determined by connecting the points of high (o C) (o C) (min)
temperature/short exposure and low temperature/
1 38 1000.0 3.00
long exposure. Non-hazardous exposure is as short 2 39 251.8 2.40
as 1 minute in 43 ?, and infinite in physiological body 3 40 63,10 1.80
temperature. In case of ultrasound irradiation, TI 4 41 15.85 1.20
5 42 3.98 0.60
indicates the temperature rise, therefore, absolute 6 43 1.0 0
temperature is obtained by summing 37 ? and the
temperature rise derived from TI.
Non-
hazardous 100
0
Non-hazardous Exposure Time of exposure 80
0
the Fetus to the Heating time (min) 60
0
40
The guideline on the safety of mammals against the Temperature 0
20
0
heat can be found in the revised safety statement of rise 0
1? 2? 3? 4? 5? 6?
American Institute of Ultrasound in Medicine Temperature
38? 39? 40? 41? 42? 43?
(AIUM)35 published in 1998, which is based on the
NCRP report in 1992, where inverse relation was Fig. 41.1: Non-hazardous exposure time to the temperature
found between hazardous temperature level and rise between 1 and 6? above 37? (38 to 43? of absolute
exposure time. AIUM35 stated that the fetus tolerates temperature) in experimental heating of animal fetuses33
50 hours at 2? rise (absolute temperature is 39?), and (graphed by the equation 2).
1 min at 6? rise (43?). They also showed the relation
of the temperature rise (T) above 37? and non- Keeping the Safety of Doppler Sonography
hazardous exposure time (t min) by the equation 1,
and non-hazardous time (t min) is known with the General Safety of Diagnostic Ultrasound Device
equation 2 which is revised from equation 1 by the Electrical and mechanical safety is proved in
author; ultrasound devices by the manufacturer under
T (?) = 6 - { (log10 t) / 0.6 } - - - - - - - - - - - - - - (1) international and domestic guidelines. In a Doppler
t = 10 (3.6-0.6T) - - - - - - - - - - - - - - (2) scanner, TI, MI, transducer temperature and other
The relation of non-hazardous exposure time and related indices are displayed on the monitor screen34
the temperature rise as well as absolute temperature making the users to keep the safety of ultrasound
is known by the equation 2 (Table 41.1 and Fig. 41.1). diagnosis by themselves. Obstetric setting should be
The safety regarding the thermal effect of ultrasound confirmed before Doppler flow velocity
can be discussed by the relation of exposure time and measurements during pregnancy. Ultrasonic
the temperature, when the heat production of Doppler examinations should be done under medical
ultrasound is estimated from TI, which indicates the indications. Although ISUOG safety statement 37
temperature rise above 37? in the worst case of reported that there is no reason to withhold the use
temperature rise in ultrasound exposure to of scanners that have received current FDA clearance
standardized tissue model, i.e. maximum temperature in the absence of gas bodies, AIUM35 stated that for
rise is known by TI. the current FDA16 regulatory limit of 720 mW/cm2,
 Safety of Diagnostic Ultrasound in Obstetrics 563
the best available estimate of the maximum or less than 2 °C temperature rise above 37°C showed
temperature increase can exceed 2°C. Pulsed no adverse effects with exposure duration up to 50
ultrasound intensity threshold to suppress cultured hours, and that the upper limit of safe exposure
cell-growth curve was 240 mW/cm2 in our studies.40 duration was 16 min at 4 °C rise and 1 min at 6 °C
The FDA regulation may be still controversial from rise above normal, respectively. The AIUM opinion
the opinions and reports. on the effect of high temperature is similar to the
report of NCRP, 33 and the safety statement is
Thermal Effect of Doppler Scanner acceptable, if the temperature rise is accurately
The TI is a useful index of temperature rise induced determined by the thermal index (TI), because TI
by ultrasound exposure. Standard tissue models are indicates the worst tissue temperature elevation due
exposed to ultrasound and TI is determined in the to ultrasound exposure in clinical study.
worst case, i.e. the highest temperature rise is the base Although revised safety statement is useful in a
of TI.34 One TI stands for one degree C temperature retrospective safety confirmation after ultrasound
elevation, and in the same manner, temperature rises exposure of known exposure time and TI, fetal
for 3? above 37?, and absolute temperature is 40?, if exposure to the temperature rise for 4 to 6 °C may be
TI is 3. Local temperature rise is estimated only by TI controversial, where absolute temperature is 41 to
at present, therefore, TI is the index to estimate tissue 43°C. Non-hazardous exposure time at such
temperature in ultrasound examination, to study temperature higher than 40? is critically short in the
ultrasonic thermal effect, and to avoid possible NCRP report33 and AIUM statement,35 where safe
thermal hazard of intense ultrasound. TI is small and margin remains very narrow2, excess heating may not
temperature rise is low in the soft tissue exposure, be completely avoided, and it may be imperfect to
and TI is large and temperature rise is high in the bone precisely keep strict exposure time in the highest
exposure. Soft tissue TI (TIS) is, therefore, used in case temperature. The aim of this report is, therefore, to
of embryo which has no bone before 10 weeks of propose practically applicable safe exposure time in
pregnancy, and bone TI (TIB) is applied in the fetus the prospective situation before a Doppler ultrasound
with bone after 10 weeks. Cranial TI (TIC) is the index diagnosis.
for the intracranial flow examination.
Two Modes in the Exposure Time
No hazardous thermal effect is expected when the
to Diagnostic Ultrasound
temperature rise of exposed tissue is less than 1.5ºC,
and local temperature is lower than 38.5ºC, while 5 Two modes can be classified in the use of Doppler
min’ duration of 41? can be hazardous to the tissue. ultrasound. The TI lower than one (AIUM), or the
Its temperature rise is 4? above 37?, and TI can be 4. temperature rise below 1.5°C (WFUMB) after
Ultrasound examination is totally safe in the exposure temperature equilibrium can be adopted for the
with the TI less than one. In common daily practice, infinite exposure. Therefore, the mode is suitable for
therefore, TI should be less than one, particularly in research work, where exposure duration is hardly
long fetal examination, screening of pregnancy, or the expected before studying. TI may also be lower than
research study of no limit. The output power is one in the screening of fetus during pregnancy and
reduced, if the TI is higher than one on the monitor, in the fetal heart rate monitoring.
then TI decreases to the level lower than one.34 Clear A pulsed Doppler study is another situation,
flow velocity wave form is recorded even output where the user requires improved Doppler flow wave
power is reduced to 60% in the author’s experiment by using higher TI than one. In some ultrasound
on the small hand artery. lectures, speakers used to tell us higher TI than one
Revised safety statement of American Institute of in the Doppler sltudies, where they proved the safety
Ultrasound in Medicine (AIUM)35 stated that equal by shortened exposure. The technique is the same as
564 Textbook of Perinatal Medicine

the NCRP report33 which proved non-hazardous short time is obtained. The procedure was the same as the
exposure to high temperature. Therefore, the Doppler past regulation of simple ultrasound devices in Japan,
examination with the TI higher than one can be also where hazardous threshold intensity of CW
non-hazardous by the short exposure. ultrasound in our experimental study was divided
The relation among non-hazardous exposure to by the safety factor of 100 and output intensity was
high temperature, high temperature rise, and large regulated to be lower than 10 mW/cm2. There was
TI is achieved by the application of the author’s no problem in the safety of diagnostic ultrasound
equation 2 (Table 41.1 and Fig. 41.1). Exposure time before the introduction of Doppler flow studies.
is as long as 250 min, about 4 hrs, when TI is 2 and Although the factor is voluntarily changed by the user,
temperature is 39?, 1 hr if TI is 3 and temperature 40?, appropriate value will be discussed in this paper. As
and 15min even if TI is 4, where the temperature is ultrasound intensity may increase for about 3 times
41?according to the reports of NCRP33 and AIUM.35 in case of standing wave, 3 is the lowest safety factor.
These criteria is extremely useful in the retrospective The intensity increases due to the distortion of
confirmation of Doppler ultrasound safety of past ultrasound wave, and possible estimation error of TI11
examination. However, the prospective exposure time or others are further added the safety factor.
setting before examination should be further For example, non-hazardous exposure time is 252
discussed. min at 39°C (Table 41.1), where the temperature rises
for 2°C and corresponding TI is 2. If the safety factor
Prospective Exposure Time Setting is 50, 252 min is divided by 50, and the exposure time
before Doppler Examination is 5 min. By the same procedure, 1 min’ exposure time
is preset when TI is 3 (Table 41.2). The safety factor of
Exposure time is preset before the Doppler 100 may be too conservative, although the factor can
examination, where the TI is voluntarily increased to be selected by the user. Mildly longer exposure than
be higher than one with the intension to improve preset value may be included in the safety factor in
Doppler flow. NCRP report is the base of decision, most cases. Possibly 50 is appropriate safety factor in
where non-hazardous exposure time is determined the actual Doppler examination. The exposure time
by the temperature rise estimated by TI (Table 41.1 setting is coincidentally close to the safety statement
and 41.2, Fig. 41.1). It is unique in the present proposal of British Medical Ultrasound Society (BMUS) 41 ,
that obtained non-hazardous exposure time is divided where the exposure time is 4 min when the TI is 2
by the “safety factor” of 3 to 100, and actual exposure and 1min if TI is 2.5.

Table 41.2: Thermal index (TI), tissue temperature, non-hazardous exposure time in the NCRP report33, the safety factors
and exposure time to ultrasound are listed. Although the user can voluntarily set the safety factor and exposure time,
the author recommends to choose the safety factor at 50 and exposure time at 5 min when TI is 2.
TI Absolute Non-hazardous Exposure time (min) obtained by dividing
temperature exposure time non-hazardous exposure time of NCRP
(°C) of NCRP report33 report 33 by various safety factors
(min)
Safety Factor
3 10 50 100
6 43 1 0.3 0.1 .02 0.01 (no use)
4 41 16 5 0.2 .03 0.02 (no use)
3 40 64 21 6 1 0.6
2 39 256 85 25 5 2.5
 Safety of Diagnostic Ultrasound in Obstetrics 565
The users can voluntarily change the safety factor intracavitary scan user should also be careful on the
and prolong the exposure time, because they are transducer temperature.
responsible to the ultrasound safety. However, they
may also be responsible at the same time for the Mechanical Effects of Diagnostic Ultrasound
increased risk factor caused by the reduction of safety Mechanical index or MI is used for the estimation of
factor. mechanical bioeffect. It is rarefactional sound pressure
expressed in Mega-Pascal (MPa), divided by square
Other Thermal Issues
root of ultrasound frequency (MHz). The MI indicates
Ultrasound thermal effect has been discussed mainly non-thermal bioeffect of ultrasound particularly in the
in the relation to teratogenicity in the first trimester, collapse of gas bubbles in various liquids. Although
whereas animal fetal skull or the brain surface was gynecologic examination by contrast medium is still
heated and the temperature elevation was more than infrequent, its common use in adult circulation should
4°C by the exposure to intense ultrasound36. Thermal be carefully studied in the mechanical bioeffect.
damage of the brain can not be denied in the case. Although common B-mode imaging devices are low
Therefore, the use of maximum intensity level of in the thermal effect, its mechanical effect is similar
Doppler ultrasound is inadvisable in the flow study to the Doppler devices because instantaneous
even in late pregnancy. intensity of its ultrasound pulse is not much different
Caution should be paid regarding the temperature from Doppler machines, and therefore, even simple
of the tissue exposed to Doppler ultrasound in febrile imaging devices should be carefully handled in the
patients, where the basic temperature is higher relation to mechanical effect. It is rare to use contrast
than 37°C. For example, if TI is 2 in 38°C febrile medium in obstetrical tissue, free radicals formed in
patient, the temperature rise above physiologic the liquid due to inertial cavitation hardly reaches
condition is 3°C, the situation is the same as TI 3 in floating cells because of their short life, and no
non-febrile normal temperature case, and therefore, cavitation may occur within the cell due to the high
1 min of exposure time is allowed if the safety factor viscosity of cell plasma. However, biological effects
is 50. of acoustic streaming, capillary blood cell stasis by
Exposure duration should be recorded by the user the standing wave, or the direct ultrasonic pressure
in every study of voluntarily increased exposure time, require further basic studies. As hemorrhage is found
while TI which appeared on the monitor screen are in the lung of neonatal animals after the exposure to
recorded on the photograph or computer memory. intense ultrasound, lower MI than one is
The safety indices including TI and MI are recommended particularly in neonatal lung
recommended to be described in the “Methods” of examination. International Electrotechnical
the reports of Doppler ultrasound study on human Commission (IEC) is working on the classification of
subjects. diagnostic ultrasound devices by the MI.

Transducer Temperature in Transvaginal Scan CONCLUSION

Transvaginal scan user should be careful on the direct Diagnostic ultrasound safety has been mainly
heating of the attached tissue due to high surface discussed on the thermal effect. Simple real-time B-
temperature of the transducer, which directly attach mode, 3D and 4D imaging devices, fetal heart detector
vaginal wall, and the subjects are closer to the and fetal monitor, are not contraindicated due to
transducer than to abdominal ultrasound. The thermal effect, because of their very low ultrasound
transducer temperature, which is displayed on the intensity. Doppler flow machines are mainly
monitor screen, should be lower than 41°C. Every discussed with thermal effect, because of their
566 Textbook of Perinatal Medicine

definitely high ultrasound intensity. Safe fetal 7. Lyons EA, Dyke C, Toms M, Cheang M. In utero exposure
to diagnostic ultrasound: a 6 year follow-up. Radiology
exposure time to ultrasound determined by the NCRP
1988;166:687–90
criteria on the exposure to high temperature estimated 8. Smith CB. Birthweights of fetuses exposed to diagnostic
by TI is useful in the retrospective evaluation of past ultrasound. J Ultrasound Med 1984;3:395–6
ultrasound examination. In prospective estimation of 9. Saari Kemppainen A, Karjalainen O, Ylostalo P, Heinonen
OP. Ultrasound screening and perinatal mortality:
ultrasound safety in daily practice, the principle of controlled trial of systemic one-stage screening in
safe diagnostic ultrasound is the reduction of pregnancy. The Helsinki Ultrasound Trial. Lancet 1990;
ultrasonic intensity and exposure time when 336:387–91
displayed TI is above one. The research work and 10. Barnett SB, ter Haar G, Ziskin MC, Nyborg WL, Maeda K,
Bang J. Current status of research on biophysical effects of
pregnancy screening follow the principle. Moderately ultrasound. Ultrasound Med Biol 1994;20:205–18
higher TI is allowed in clinical study when the users 11. Barnett SB, Kossoff G, eds. Results of the WFUMB
require more improved Doppler flow wave by Symposium on Safety and Standardization in Medical
Ultrasound. Ultrasound Med Biol 1992;18 (Special issue)
increased intensity, where a limited short exposure
12. Barnett SB, Edwards MJ, Martin P. Pulsed ultrasound
time is prescribed and the users adhere the preset time induces temperature elevation and nuclear abnormalities
by their own responsibility. The author recommends in bone marrow cells of guinea pig femurs. Presented at
to use non-hazardous exposure time of NCRP report the 6th World Congress of Ultrasound in Medicine,
Copenhagen, Denmark, 1991: abstr 3405
after dividing it by the safety factor of 50, where 13. Hill CR. Ultrasonic exposure thresholds for changes in cells
exposure time is 5 min if TI is 2, and 1 min if TI is 3. and tissues. J Acoust Soc Am 1972;52:667–72
Higher TI or longer exposure may be applied by 14. American Institute of Ultrasound in Medicine. A I U M /
reducing safety factor under the users’ responsibility. NEMA Standard for Real-time Display of Thermal and
Mechanical Acousitc Output Indices on Diagnostic Ultrasound
Attention should be paid to the decreased safety in Equipment. AIUM Publications, 1992
febrile patient. Transvaginal transducer should be 15. Food and Drug Administration. Guide for Measuring and
used under 41°C. The mechanical effect may be Reporting Acoustic Output of Diagnostic Ultrasound.
Rockville, MD: Food and Drug Administration, Devices
similar in simple B-mode to Doppler devices. MI is
and Radiological Health, 1992
recommended to be less than one in ultrasound 16. Food and Drug Administration. Revised 510(k) diagnostic
examination, particularly in the studies on air ultrasound guidance for 1993. Rockville, MD: Food and
containing neonatal lung. Drug Administration, 1993
17. Nyborg WL. Acoustic streaming due to attenuated plan
waves. J Acoust Soc Am 1953;25:68–5
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1992 37. ISUOG Bioeffects and Safety Committee; Safety statement,
28. Dyson M. The susceptibility of tissues to ultrasound. In 2000 (reconfirmed 2002). Ultrasound Obstet Gynecol 2002;
Docker FM, Duck FA, eds. The Safe use of Diagnostic 19: 105.
Ultrasound. BIR, 1991;24 38. Ide, M; Japanese policy and status of standardisation.
29. Euopean Committee for Ultrasound Radiation Safety. Eur
Ultrasound in Med & Biol 1986; 12: 705-708.
J Ultrasound 1996;4:145
39. Maeda K, Ide M.; The limitation of the ultrasound intensity
30. ter Haar G. Commentary: safety of diagnostic ultrasound.
for diagnostic devices in the Japanese Industrial standards.
Br J Radiol 1996;69:1083–5
IEEE Trans Ultrasonics, Ferroelectrics and Frequency
31. EFSUMB. European Committee for Ultrasound Radiation
Control, 1986; UFFC-33: 241-244.
Safety – the Watchdogs, clinical safety statement. Eur J
40. Maeda K, Murao F, Yoshiga T, Yamauchi C, Tsuzaki T;
Ultrasound 1996;3:283
Experimental studies on the suppression of cultured cell
32. Barnett SB, Kossoff G; WFUMB symposium on safety and
standardisation in medical ultrasound: Issues and growth curves after irradiation with CW and pulsed
recommendations regarding thermal mechanisms for ultrasound. IEEE Trans Ultrasonics, Ferroelectrics and
biological effects of ultrasound. Hornbick, 1991, Ultrasound Frequency Control, 1986; UFFC-33: 186-193.
in Med & Biol 1992; 18:v-xix,731-814. 41. The Safety Group of the British Medical Ultrasound Society;
33. National Council on Radiation Protection and Guidelines for the safe use of diagnostic ultrasound
Measurements; Exposure Criteria for Medical Diagnostic equipment. BMUS Bulletin 2000; 3: 29-33.
 42
Behavioral Perinatology Assessed by
Four-Dimensional Sonography
A Kurjak, JM Carrera, W Andonotopo,
G Azumendi, M Medic A. Salihagic-kadic

INTRODUCTION conventional ultrasonic and non-ultrasonic methods.

The purpose of this article is to review and illustrate
Three-dimensional (3D) ultrasound has been available
presently available data on 4D ultrasound fetal
for more than 10 years. However, the 3D image freezes
behavior imaging in all three trimesters of pregnancy.
the object and therefore does not provide information
on movements or any information about the dynamic
NEUROPHYSIOLOGY OF FETAL BEHAVIOR
changes of the object of interest. A technique was
needed that would enable 3D imaging to be For centuries, maternal registration of fetal
performed in a real-time mode. This technique has movements and obstetrician auscultation of fetal
been recently introduced and has been called four- heartbeats were the only methods of the follow up of
dimensional (4D) sonography, because time becomes fetal well being in utero. However, during the past
a parameter within the 3D imaging sequence. This few decades, development of ultrasonic techniques
new diagnostic tool enables the continuous has enabled the direct visualization of fetus in utero,
monitoring of the fetal face and other surface features as well as the real time assessment of fetal activity.
of the fetus such as fetal extremities. This permits Ultrasonic studies have revealed the fascinating
exciting new possibilities for the study of fetal diversity of fetal intrauterine activities. It has been
behavior. shown that fetal activity occurs as early as the late
Four-dimensional (4D) ultrasound provides a new embryonic period, which is far earlier that a mother
tool for observation of the fetal face. Simultaneous can sense it. Furthermore, qualitative and quantitative
imaging of complex facial movements was not aspects of behavioral patterns expand rapidly as the
possible using real-time 2D ulrasound. 4D ultrasound pregnancy progresses, and the random movements
integrates the advantage of the spatial imaging of the of the fetal body, which are the earliest sign of fetal
fetal face with the addition of time. This new activity, change into the well-organized behavioral
technology therefore allows the appearance and patterns observed late in gestation. Analysis of the
duration of each facial movement and expression to dynamics of fetal behavior has led to the conclusion
be determined and measured. that fetal behavioral patterns directly reflect
In a relatively short period of time 4D sonography developmental and maturational processes of the fetal
has stimulated many multicentric studies on fetal central nervous system. Nevertheless, the ultrasound
behavior and even fetal awareness with more findings and their relevance in the assessment of the
convincing imaging and data than those obtained by development of the central nervous system can be
 Behavioral Perinatology Assessed by Four-Dimensional Sonography 569
interpreted only in comparison with the structural migration towards the pial surface and finally reach
developmental events in the particular period of their permanent position and form the permanent
gestation. Therefore, understanding the relation synapses. Early appearance of interneuronal
between fetal behavior and developmental processes connections, shown on Table 42.1, implicates a
in different periods of gestation may make possible possibility of an early functional development.
the distinction between normal and abnormal brain However, these first synapses exist only temporarily
development, as well as the early diagnosis of various and disappear due to the normal developmental
structural or functional abnormalities. processes. Namely, simultaneously with these
progressive processes, so called reorganization
Structural Development of processes occur. Some embryonic zones, types of
Human Central Nervous System neurons and glia and synapses that play the crucial
All the neurons and glial cell originate from role in certain periods of fetal brain development
embryonic ectoderm, precisely a structure called the eventually disappear, significantly changing structure
neural plate. During the fourth postconceptional and function of the brain. Reorganization processes
week, the neural plate bends into a neural tube, whose include apoptosis, disappearance of redundant
further growth reshaping and histological synapses, axonal retreat and transposition, and
characteristics directly reflect complicated transformation of the neurotransmitters’ phenotype.
histogenetic processes. The results of those processes The temporal overlapping of the major histogenetic
are specific transitional embryonic zones, which processes during the fetal brain development can be
cannot be observed in an adult brain. Three seen only in primates.
embryonic zones, ventricular, intermediary and Obviously, development of human brain is not
marginal zone (seen from ventricular to pial surface), completed at the time of delivery. In an infant born at
are present in all parts of neural tube, whereas term, characteristic cellular layers can be observed in
telencephalon contains additional two zones, motor, somatosensor, visual and auditory cortical
subventricular and subplate zone.1 areas. Although proliferation and migration are
Histogenetic processes are proliferation, migration completed in a term infant, synaptogenesis and
and differentiation of neurons and glial cells, as well neuronal differentiation continue very intensively.2
as the synaptogenesis and development of chemical Brain stem demonstrates high level of maturity,
specificity of neurons. The dynamics of the main whereas all histogenetic processes actively persist in
hystogenetic processes is shown in Table 42.1. cerebellum.3 Therefore, only subcortical formations
It is important to point out that proliferation of and the primary cortical areas are developed
neurons and glial cells occurs only in the ventricular completely in a newborn. Associative cortex, barely
zone and in the subventricular zone of telencephalon. visible in a newborn, is scantily developed in a 6
All the future neurons and glia originate from these months old infant. Postnatal formation of synapses
zones, form other transitional zones during their in associative cortical areas, which intensifies between

Table 42.1: Dynamics of the most important progressive processes in the development of the human brain.
Beginning The most intensive period Ending
Proliferation 3-4 weeks of gestation 8-12 weeks of gestation Approx. 20 weeks of gestation
Migration Simultaneously with
proliferation 18-24 weeks of gestation 38 weeks of gestation
Synaptogenesis 8 weeks of gestation 13-16 weeks of gestation, Puberty
after 24 weeks of gestation,
8th month – 2 year of postnatal life
570 Textbook of Perinatal Medicine

8th month and 2nd year of life, precedes the onset of observed, allowing the assumption of the existence
first cognitive functions, such as speech. Following of first afferent-efferent circuits (Table 42.2). The first
the 2nd year of age, many redundant synapses are reflex movements are massive and indicate a very
eliminated. The elimination of synapses begins very limited number of synapses in a cutaneous reflex
rapidly, and continues slowly until the puberty, when pathway.10 At that time, head tilting after perioral
the same number of synapses as seen in adults is stimulation was noted. During the 8 th week of
reached.3 gestation these massive reflex movements are
replaced with local movements, probably due to an
Functional Development increase in the number of axodendritic synapses.
of Fetal Nervous System Hands become sensitive at 10.5 weeks and lower
The functional development of human fetus cannot limbs begin to participate in these reflexes
be studied directly, but ultrasonic studies have made approximately at 14th week.10,11,12,13,14 From 10th week
possible the visualization of the fetal motor activity onwards, the number and frequency of movements
in utero. The ultrasonic studies of fetal spontaneous increase. By 14 – 19 weeks, fetuses are very active with
motor activity and the motor responses to stimulation, the longest period of inactivity lasting only 5 – 6
in comparison with the morphological studies and minutes. In the 15th week 15 different movements can
experiments on animal models have given us insight be observed. Besides the general body movements
into the complex dynamic of fetal development. The and isolated limb movements, retroflection,
overview of the functional development of fetal anteflection and rotation of the head can easily be
nervous system, which will be discussed further in seen. Moreover, face movements such as mouthing,
the text, is given in Table 42.2. yawning, hiccups, suckling, and swallowing, can be
added to a wide repertoire of fetal motor activity in
Fetal Motor Development this period (see Table 42.2).15 However, in such an
early gestation, dynamic pattern of neuronal
First synapses in the human nervous system appear production and migration, as well as the immature
approximately simultaneously with the formation of cerebral circuits are considered too immature for the
cortical plate, i.e. around 8th postconceptional week.4,5 cerebral involvement in the motor behavior (for
It is the period when earliest electrical activity and review see 16). Only at the end of this period a
transmission of information 6 occurs. First quantifiable number of synapses appear in the
spontaneous fetal movements were observed at 7,5th structures preceding cerebral cortex, probably
postconceptional week. These movements, consisting forming a substrate for the first cortical electric
of slow flexion and extension of fetal trunk activity, noted at the 19th week. 16 Studies of
accompanied by the passive displacement of arms anencephalic fetuses have also provided apparent
and legs7 and appearing in irregular sequences, were evidences that around 17th-20th gestational week
described as “vermicular”.8 In a little while, they are motor behavior becomes influenced by the
replaced by various general movements, that include supraspinal structures. Namely, in these fetuses
head, trunk and limb, such as “rippling” seen at 8th incidence of movements was normal or even
week, “twitching” and “strong twitching” at 9th and increased, but the complexity of movement patterns
9,5th week respectively, and “floating” “swimming” changed dramatically and movements were
and “jumping” at 10th week. 9 Isolated limb stereotyped and simplified.17,18
movements appear almost simultaneously with the Number of spontaneous movements tends to
generalized movements. increase until 32nd week of pregnancy, when their
Simultaneously with the onset of spontaneous frequency begins to decrease.19,20,21 By term, average
movements, earliest cutaneous reflex activity can be number of generalized movements per hour was
 Behavioral Perinatology Assessed by Four-Dimensional Sonography 571
Table 42.2: Chronology of the functional development of fetal nervous system.
Detailed description is given in the text.
Weeks of Motor system Sensor system Circadian rhythm
gestation
6 Earliest spontaneous movements, Development of taste buds
gross body movements Development of nociceptors
7 Generalized movements after
cutaneous stimulation
8 Movements of extremities, head trunk, Localized movements after
isolated limb movements cutaneous stimulation
9
10 Sporadic breathing movements Peripheral afferents from nociceptors
to spinal cord begin to form -
reflexive reactions to pain
Spontatnous movements observed Cutaneous reflexes seen in hands
over 15% of 24hour time
11
12
13 Spontaneous movements
and breathing movements
associated with heart rate
acceleration
14 Facial movements-swallowing, Legs sensitive to cuntaneous
yawning, grimacing, stimulation – reflexes
Very intensive motor activity, 15 different
types of body movements can be observed

15 Secretion of leptin and VIP-

possible regulators of appetite
16
17
18 Sporadic eye movements Alterations in cerebral blood
flow in response to painful stimuli
19
20 Nociceptors present all over the body
21
22
23 Elevation of cortisol and
beta endorphin levels in
response to painful stimuli
24 Breathing movements observed over
14% of 24 hours period Consolidation of eye
movements-alternation of
eye movement (EM) and
non-eye movement (NEM)
periods
25 Cochlear function established
(22-25 week) Response to
vibroacoustic stimulation
without lag time
26
27
28
29
Contd...
572 Textbook of Perinatal Medicine

Contd...

30 Number of breathing movements Fetus responds to purely

change in response to alteration in acoustic stimulation
CO2 concentration in maternal blood
31
32 The number of spontaneous
movements begins to decrease
33 Rapid eye movement (REM)
periods and slow eye
movement (SEM) periods
can be distinguished
34 Breathing movements sensitive to the
maternal plasmatic glucose concentration
35
36
37
38 Constant duration of eye-
movement and non –eye-
movement periods,
integration of eye
movements with other
parameters of fetal activity
(heart rate, movements)
39
40

found to be approximately 31 with the longest period could enrich our perspective of the intrauterine life.
between movements ranging from 50-75 minutes.22 It has been demonstrated that the fetal movement
This decrease is considered a result of cerebral patterns in the second half of pregnancy are almost
maturation processes, rather than a consequence of identical to those observed after birth,24,25 although
the decrease in the amniotic fluid volume. the repertoire of movements in newborns includes
Simultaneously with the decrease in the number of some patterns that cannot be observed in the fetus,
generalized movements, an increase in the facial such as the Moro reflex.26 The detailed description of
movements, including opening/closing of the jaw, fetal movement patterns at different gestational age,
swallowing and chewing can be observed. These studied by conventional as well as four dimensional
movements can be seen mostly in the periods of ultrasound will be given later in the text.
absence of generalized movements and that pattern Many factors, such as cigarette smoking 27or
is considered to be the reflection of the normal injection of corticosteroids for fetal lung maturation,28
neurological development of the fetus.19 However, not were proved to decrease the number of spontaneous
only the changes in the number of movements, but fetal movements. Furthermore, fetal activity is
also in their complexity are shown to be the result of increased in mothers suffering some kind of emotional
maturational processes. Our recent 4D ultrasound stress.29 The quality of fetal movement patterns is
study, which will be described later in the text, has altered in fetuses suffering intrauterine growth
shown even wider repertoire of fetal face and hand restriction. The movements become slower,
movements in third trimester of gestation, than it has monotonous, resembling cramps, and their variability
been previously described.23 Obviously, the story of in the strength and amplitude is reduced. These
fetal intrauterine activity is far from being completed changes could indicate the existence of brain lesions
and the development of new recording techniques in growth restricted and possibly hypoxic fetuses.
 Behavioral Perinatology Assessed by Four-Dimensional Sonography 573
Namely, despite the early assumptions, the alterations increases following an excess of carbon dioxide in
in the amplitude and complexity of movements in maternal blood.35, 36 This sensitivity to the alterations
these fetuses do not appear due to the in the plasmatic carbon dioxide level is connected to
oligohydramnios. In cases of premature rupture of the maturation of fetal respiratory neural centers,
fetal membranes and a subsequently reduced volume which is thought to occur during the last 10 weeks of
of amniotic fluid, movements occur less frequently, pregnancy (see Table 42.2). 37 The process of
but their complexity resembles that of movements maturation of fetal breathing movements is
performed in the normal volume of amniotic fluid (for accelerated in some conditions such as premature
review see 30). Obviously, the qualitative as well as rupture of membranes. For instance, decrease in fetal
quantitative analysis of fetal movements reveal the breathing has been observed following premature
integrity of fetal nervous system, and can be used for rupture of membranes38,39 and during the three days
the detection of various cerebral dysfunctions, and prior to the initiation of labor.37,40 Kisilevsky et al.
probably neuromuscular diseases.29,30 compared body movements and breathing patterns
in normal fetuses at 24 to 33 weeks of gestation and
Development of Specialized Movements fetuses threatening to deliver prematurely. High-risk
Studies on animals, especially various species of fetuses had a reduced level of body movements and
mammals, as well as their comparations with the an earlier onset of extended periods of breathing,
ultrasonic recordings of human fetuses, have revealed which occurred at 30 weeks in contrast to 33 weeks
that some specialized movement patterns, crucial for in the control group. 41 However, in this study
the survival of newborns, such as swallowing or accelerated maturation of breathing was not observed
rhythmic respiratory movements, develop and in the presence of ruptured membranes. Fetuses
mature during gestation. Although these patterns delivered prematurely had less breathing than those
somewhat differ from adult patterns, in the near term delivered at term. Maternal consumption of alcohol
fetuses they are developed sufficiently to enable the or methadone, and according to some authors, even
survival of the fetus. cigarette smoking, is known to decrease incidence of
In human fetus, breathing movements occur breathing movements. 42,43,44 On the other hand,
around 10th week of gestation.31 Early in gestation, aminophiline, used for the treatment of bronchial
they are present almost continually and are associated asthma, as well as conjugated estrogens and
with the activity in postural muscles of the neck and betamethasone increase the frequency of
limb. However, the frequency and complexity of the breathing.45,46 Increased number of fetal movements
breathing pattern changes as pregnancy progresses. following the elevation of the glucose concentration
Total breathing time in a 24 hour interval extends, as in maternal blood has been noted at 34th week of
well as the duration of individual breathing and non- gestation.47,48
breathing intervals.32,33 Changes in breathing patterns Another indispensable prerequisite for the
are considered to be a result of the maturation of fetal survival of the newborn is the ability to feed, i.e. to
lungs and respiratory and sleep centers in the fetal ingest food. In the human fetus, swallowing was
central nervous system. In 38th and 39th week of noted as early as 11 weeks of gestation,49 with daily
gestation, frequency of movement decreases to a 41 swallowing rates near term of 200 – 500 ml. 50,51
respiration per minute and the movements become Swallowing of amniotic fluid proteins and growth
as regular as in the postnatal period.34 Approximately factors contributes to the growth and maturation of
at the 30th week of gestation, the regulation of fetal fetal gastrointestinal tract, and possibly to the fetal
breathing movements by the plasmatic level of carbon somatic growth.52 Namely, amniotic fluid provides 10-
dioxide is established and number of respirations 14% of the nitrogen requirements in the normal fetus,
574 Textbook of Perinatal Medicine

and esophageal atresia is often associated with lower Fetal Vestibular and Auditory System
birth weight.53 Many authors agree that swallowing It is generally accepted that reflexes of the brain stem,
patterns develop in utero in all species in which there which includes vestibulary, olfactory and auditory
is significant fetal fluid excretion (urine and lung reflexes, develop early in gestation. 56 Vestibular
liquid) into the amniotic cavity. Thus, fetal swallowing ganglionic cells mature earlier than the neurons of
contributes to the regulation of amniotic fluid lateral and inferior vestibule nuclei, which are
volume.52 In some, although not all cases with fetal functional from the 9 gestational weeks onward.57
esophageal atresia, the volume of amniotic fluid is Vestibule stimulation is thought to contribute to the
increased. The normal volume of amniotic fluid in development of fetal movements. Namely, gravity-
some of these cases could be explained by the free environment in uterus appears to promote the
coexistence of tracheoesophageal fistula which could development of vestibulary reflexes.58 According to
allow the intake of liquid during respiratory electrophysiological examinations of the evoked
movements (for review see 54). Furthermore, potentials in prematurely delivered healthy infants,
polyhydramnios sometimes, though not always, cochlear function develops between 22 and 25 weeks
develops in anencephalic fetuses. However, some of of gestation, whereas its maturation continues during
these fetuses have an intact swallowing reflex, the first 6 months upon delivery. 59-61 Maternal
whereas the cases with normal amniotic fluid volume heartbeats and motility of the gastrointestinal tract
and decreased fetal swallowing have been described during digestion appear to generate 90 decibels
(for review see 54). Spontaneous fetal swallowing is, noise62 in utero. However, fluid in the fetal ear, as well
like most motor patterns, correlated with as the immaturity of cochlea, complicate the sound
neurobehavior. The development of dypsogenic transmission, so that only strong acoustic stimuli can
mechanisms and their influence on fetal swallowing produce fetal reflex movements, such as startle motion
will be described later in the text. Here we have to of the trunk and/or flexion of the extremities,
emphasize that fetal swallowing patterns differ accompanied by changes in the heart rate. These are
significantly from those seen in the adult and that the seen during or soon after vibroacoustic stimulation.61
fetus daily swallows 5 to 10 times more fluid per body Applying acoustic stimulation with wide spectrum
mass unit.55 of frequencies directly on the maternal abdomen,
Shahidullah at al have registered reflex movements
Development of Fetal Sensor System with a short lag time in 20 week old fetuses, and
The combination of ultrasonic studies, patho- movements without the lag time in 25 week old
anatomical examinations and the studies of premature fetuses.63 However, these movements were explained
infants have provided a wide spectrum of evidence as a reflex response to vibroacoustic stimulation or
that the ability to register vibrations, acoustic stimuli, proprioceptor stimulation. Kisilevsky et al. reported
and even light is acquired during intrauterine life. It an increased number of fetal movements and heart
is well known that fetus can sense pain and respond rate during acoustic stimulation performed with the
to the painful stimulus with a variety of responses, sound transmitter placed 10 cm above the maternal
such as movements, circulatory and hormonal abdomen, in 30 week old fetuses.64
responses, although the question of the emotional
response to pain or memorization of the unpleasant Fetal Vision
events in utero still remains unresolved. Fetus can also Intrauterine environment is not completely deprived
sense the taste of amniotic fluid and even functions of light. Moreover, some experimental results indicate
such as appetite, satiety and thirst seem to be that the development of visual and auditory organs
developed during intrauterine life (see Table 42.2). could not be possible without any light or acoustic
 Behavioral Perinatology Assessed by Four-Dimensional Sonography 575
stimulation.62 Although structural development of the spinal cord. Higher perception or processing of
sensor pathways is a prerequisite for functional painful sensation does not exist at this stage. 10
development, final organization of brain circuitries However, some investigators indicate that facial
relies predominantly on guidance from external reflexes in response to somatic stimulation, which
output.16 In cortical area 17 synaptogenesis perisits could indicate the emotional reaction to pain, develop
between 24 weeks and 8 months after delivery,65 rather early in gestation.13 These reflexes are thought
whereas myelinization of the optical tract begins at to be coordinated by subcortical systems and probably
32 weeks of gestation 66 and cones of the central reflect development of these lower brain circuitries.74
foveola reach the adult proportions late in As for the autonomic responses to pain, an elevation
childhood.196 of cortisol and beta-endorphin levels in plasma in
response to needle pricking of the innervated hepatic
Fetal Pain vein was registered in a 23 week old fetus, whereas
the stimulation of the uninnervated umbilical cord
During the past decade, fetal perception of pain has had no effect .75,76 Alterations in cerebral blood flow,
been not only an object of interest for scientists, but i.e. blood flow redistribution during invasive
also an important issue in public debates, in relation procedures, were noted in an 18 week old fetus.77
to late abortion and an increasing number of These results indicate that painful stimuli trigger wide
intrauterine operations. The pain consists of two spectra of reactions in the central nervous system,
components; perception of stimulus and an emotional such as activation of the hypothalamic pituitary axis
reaction or unpleasant feeling of the noxious stimulus. or autonomic reflexes, even without reaching the
These occur in two anatomically and physiologically cortex. Furthermore, we have to emphasize that these
distinct systems in the brain. The response to painful hormonal, autonomic and metabolic responses can be
stimulation can be regarded at three different levels; neutralized by analgesics such as fentanyl.77,78 The
somatosensory response, pain-induced autonomic reduction of fetal responses to pain is extremely
and endocrinological reflexes, and pain related important because many studies have shown the
behavior (for review see 68). In the human fetus, the influence of the early pain experiences on the later
first nociceptors appear at the seventh week of behavioral variables or on the later developmental
gestation and by the 20th week these are present all outcomes.79 One of the most important effects of
over the body. Peripheral afferents begin to make painful experience is a prolonged stress response.80 It
synapses to the spinal cord, approximately during includes fluctuations in blood pressure and cerebral
weeks 10-30,69 The myelination of these pathways70 blood flow, and hypoxemia, which may predispose
and the development of functional spinal reflex to intracranial hemorrhage.77 Experiments on animals
circuitry develop almost simultaneously.70,71 Higher have revealed that elevated cortisol levels, equivalent
parts of pain pathways include the spinothalamic to those secreted during the stress response in
tract, established at the 20th week and myelinized by humans, were associated with degenerative changes
29 weeks of gestation 72 and thalamo-cortical in fetal hypothalamus.81 Finally, long term-follow up
connections which begin to grow into the cortex at studies of fetuses treated in the intensive care units
24-26 weeks. 66 Finally, at the 29th week, evoked (ICU) and exposed to pain and/or stress have
potentials can be registered from the cortex, indicating demonstrated the correlations between the stay in ICU
that the functional connection between periphery and and altered pain thresholds and abnormal pain-
cortex operates from that time onwards.71,73 related behavior later in life.80,82 All these findings
Earliest reactions to painful stimuli are motor underline the importance of stress-free environment
reflexes, resembling withdrawal reflexes. These for normal physiological and psychological
reactions are completely reflexive and are guided by development.
576 Textbook of Perinatal Medicine

Fetal Taste, Appetite and Satiety when compared to the adult, despite the intact
dipsogenic nuclei. Reduced swallowing during
It is generally believed that appetite and satiety
systemic hypotension despite the elevated renin
functions develop during the intrauterine period in
plasma levels, together with the increased amount of
all precocial species. In the human fetus, taste buds
liquid swallowed under normal conditions, indicates
are developed from the 7th week of gestation
that fetal dipsogenic response might differ from the
onwards. 83 Sucrose increases swallowing in the
adult.99
human fetus, whereas the incidence of swallowing
movements decreases following the injection of
Lipiodol, a bitter extract of poppy seeds, into the Cyclic Behavior and Development
amniotic fluid.83 The main endocrine regulators of of Circadian Rhythms
appetite, leptin and neuropeptide Y (NPY) are Fetal life in utero is organized in cyclical patterns.
secreted as early as 15 and 18 weeks, respectively, in Periods of activity alternate with periods of rest. The
the human fetus, but the ontogeny and functions of observation of human infants resulted in the
their regulatory pathways have not been delineated hypothesis that the alternations of activity and
in the human fetal brain.84,85,86 However, experiments inactivity periods reflect the elementary ultradian
on animals have shown the increase of swallowing rhythm of the fetal central nervous system,
upon ingestion of NPY.87 Swallowing was increased uninfluenced by external input.
following the injection of leptin, which is in For instance, eye movements, which become
contradiction with leptin function in adults. 88 observable at 16 - 18 weeks of gestation, begin to
Therefore, some authors postulated that the presence consolidate at 24-26 weeks of gestation, and the
of NPY pathways and the immaturity of leptin periods of eye movements begin to alternate with
pathways may potentiate feeding and facilitate non-eye movement periods. During the last 10 weeks
weight gain in newborns, despite high body fat of gestation, both switching and maintaining
levels.52 mechanisms responsible for this ultradian rhythms
mature, and constant mean values of duration of eye
Development of Dypsogenic Mechanisms
movement (EM) and non-eye movement (NEM)
Experiments on animal models, especially fetal lambs, periods are achieved by 37-38 weeks. At that time,
have shown that dipsogenic mechanisms begin to EM and NEM last 27-29 and 23-24 minutes
modulate fetal swallowing during intrauterine life. respectively, which is similar to the values in
For instance, in fetal lambs swallowing and arginine neonate.100 In the adult human, rapid eye movements
vasopressin secretion increase following the central (REM) are present during the active sleep, alternate
administration of hypertonic saline and angiotensin with the slow eye movements, or deep sleep (SEM)
II.89,90 Ross et al. have identifed the hypertonicity- and are accompanied by changes in electrocortical
activated neurons in dipsogenic hypothalami nuclei, activity.101 In fetus, REM and SEM movements can be
such as the parvocellular and magnocellular division registered at 33 weeks of gestation. At 36-38 weeks of
of periventricular nucleus and supraoptic nucleus in gestation, they become integrated with other
near-term ovine fetus. 91,92,93 These authors also parameters of fetal activity, such as heart rate and fetal
suggested that exaggerated fetal swallowing under movements, into organized and coherent behavioral
physiologic conditions (5-10 times more liquid in states.102
proportion to the adult) might be the result of tonic In fetal animals, simultaneous measurements of
activation of angiotensin II receptors and production fetal electrocortical activity, eye and body movements
of nitric oxide.94,95 Nevertheless, the fetus appears to have shown that deep sleep, characterized by high
have reduced sensitivity to osmotic stimuli.96,97,98 voltage waves and decreased fetal activity, occurred
 Behavioral Perinatology Assessed by Four-Dimensional Sonography 577
during 54% of the total time each day. The total length melatonin. This hormone is present in humans, as well
of REM sleep period, characterized by low voltage as in other mammals, and its plasma concentrations
waves and rapid eye movements lasted 40% of the exhibit daily variations, with the peak during the
total time each day. Wakeful state (6% of a day) is night. Therefore, its role in sleep induction has been
characterized by low voltage waves.103 In human suggested (for review see 105). Seasonal alterations
premature newborns, born 4 weeks prior to the term, in melatonin concentrations have also been reported.
60-65 % of sleeping total period is REM sleeping, Daily oscillations of melatonin concentrations in
whereas in a term newborn, REM sleeping period plasma are present throughout gestation, 105 and
includes 50% of total 16 hours of sleep.104 Intensive various human tissues including the central nervous
activity of neuronal circuits during the REM sleep is system express some types of melatonin
thought to contribute to the development of central receptors.106,107 However, its role in the orchestration
nervous system.104 of fetal circadian rhythms remains to be confirmed.
Circadian system is a kind of biological clock that
receives information from the environment and sends BASIC TECHNOLOGY OF 4D SONOGRAPHY
efferent outputs that orchestrate circadian rhythms The rapid development of digital ultrasound systems
(105). In mammals, the major role in orchestration of allows 3D image reconstructions and lately 4D real
these rhythms is played by the suprachiasmatic time inspection of anatomical regions and
nucleus (SCN) of the hypothalamus that oscillates pathological changes. However, three-dimensional
with a period of close to 24 hours. Biological images are static and do not provide information of
oscillations of SCN are entrained by the life/darkness movements and dynamic changes of the object of
cycle, which is registered by retinal receptors and interest .23 Moreover, fetal movements are the source
transmitted by the retino-hypothalamical tract. of significant artifacts and volume scanning should
Efferent pathways from SCN include projections into be performed during the fetal inactive phase, i.e.
the various nuclei of the hypothalamus, and possibly, whenever fetus is active, qualitative 3D image is
endocrine SCN secretion. In human fetus, as well as unobtainable. This fact limits the usage of classic 3D
other mammal species, SCN is developed by mid- ultrasound. Four-dimensional overcomes above this
gestation, but its maturation continues after birth, as disadvantage, making it possible to obtain qualitative
shown by an increase in the number of neurons 3D image regardless of fetal movements. The only
containing adrenalin vasoperssine (AVP) and limiting factor for 4D sonography is the quantity of
vasoactive intestinal polipeptide (VIP) during the first adjacent amniotic fluid.
year of postnatal life (for review see 105). Circadian The acquisition of volume datasets is performed
rhythms in behavior, cardiovascular function and by 2D scans with special transducers (linear, convex,
hormones are present in human fetuses, as well as in transvaginal) designed for 2D scans, 3D and real time
fetal sheep and monkey, and are entrained to the 4D volumes.108 The real time 4D mode is obtained
light/darkness cycle. However, the question whether from simultaneous volume acquisition and
that rhythm is generated by the fetus itself or computing of 3D images which is in fact multi-
influenced by maternal rhythms, remains to be dimensional ultrasound.109 The movement of the
resolved, although some animal experiments indicate ultrasound beam over the region of interest (ROI) is
the importance of the maternal SCN. In this case, the automatic. Such design enables simplified 3D and 4D
transmission of the signal to the fetus would acquisition. Ultrasound probes include a scanning
necessarily require an endocrine mediator, but no such mechanism moved by built in electromotor. The
a molecule has been identified yet. Latest results processing speed allows continuous acquisition and
suggest the role of maternal pineal hormone processing of 4D volumes.
578 Textbook of Perinatal Medicine

The volume acquisition begins with a 2D image depends on the following important points: region
and superimposed volume box. The initial 2D image of interest (ROI) size and volume box size, ROI
is the central 2D image of the volume. According to position or direction of view and accessibility to the
the dimensions of the volume box, the volume scan object. The render box determines the contents that
sweeps between the margins of the volume box. The will be rendered. Structures that are not selected by
volume box is set to frame region of interest (ROI). volume box will be cut from 3D reconstruction.
The following steps are important for producing Region of interest can be sized, moved and rotated
reliable 4D images: in all directions arbitrary by operator. Volume data
1. Orientation in real time 2D mode can be acquired from different 2D modes: grayscale
2. Selection of region of interest (ROI) imaging, CFI and Power Doppler imaging. There are
3. Starting the volume scan. Volume data is shown different rendering modes available: Surface, Trans-
in a multiplane display on the monitor (transverse, parent (maximum, minimum, X-ray) and Light, some
sagittal and coronal) of them can be active simultaneously in real time.
During the 3D and 4D acquisition, sweep time Volume rendering is a process of visualization of
depends on the volume box size, scan quality and 3D structures on an animated 2D screen and render
adjusted scan parameters such as depth, number of modes determine how the 3D image will be presented
focuses and other parameters which affect B-mode on screen.
image frame rate.
Surface Rendering or Gray Scale Rendering
4D Rendering
In the surface rendering mode, only signals from the
The pixel is the smallest element of 2D images while surface of region of interest (ROI) are extracted and
the voxel is the smallest information unit in 3D and displayed in the plastic appearance. Surface rendering
4D imaging. Volume rendering provides visualization examination of the fetus focuses the sonographer‘s
of animated voxel-based images on a two- attention exclusively on fetal external anatomy (Fig.
dimensional screen. Because of instant computer 42.1).
technology development and fast data transmition, This mode is capable of clear visualization of fetal
volume acquisition and data processing are normal surface anatomy or surface anomalies such
accelerated to enable 3D rendering in real time (4D). as myelomeningocoele, omphalocele, cleft lip/palate,
Fast volume data processing enables calculation of 5- macroglossia and limb defects (Figs 42.2 to 42.6).
30 volumes per second depending on the system Furthermore, visualization of the spatial relationship
hardware and size of the render box. As 4D imaging between surface structures enables accurate diagnosis
is almost a real time, there is always some delay as a of subtle malformations and anomalies such as
result of time needed to reconstruct 3D image from micrognathia, overlapping fingers, hexadactilia and
2D scans. It is always desirable to achieve as many auricular malposition or malformation.
volumes per second (volume rate) as possible. The surface image can be displayed in “textural”
Number of volumes per second is some kind of trade mode. The gray values can be colored by different
of between image quality and frame rate. 3D and 4D color maps, but the most successful map for 4D image
image quality mostly depends on 2D image quality. is “body heat” map. The texture mode can also be
Prior to volume acquisition it is important to achieve “smoothed”, showing smooth surfaces on 4D
the best 2D image quality, adjusting: depth, focus reconstructions. Texture and smooth surface displays
position and number of focuses, frequency and gain. are suitable for use in applications such as fetal face,
All 2D image artifacts will be also present on 3D and abdominal wall, genitals, umbilical cord (Fig. 42.7),
4D image reconstruction. Good 4D image acquisition and the surfaces of urinary bladder.110-112
 Behavioral Perinatology Assessed by Four-Dimensional Sonography 579

Fig. 42.1: 3D surface rendering of the normal hand movement. Note the alteration of the palm position

Fig. 42.2: 3D surface rendering of omphalocele Fig. 42.3: 3D surface rendering of macroglossia

Fig. 42.4: 3D Surface rendering of myelomeningocoele Fig. 42.5: 3D surface rendering of bilateral cleft lips
580 Textbook of Perinatal Medicine

Fig. 42.6: 3D surface rendering of arthrogryposis of the fingers

showing rigid and fixed postureSurface rendering gives the best
result when ROI structures are surrounded by fluid or Fig. 42.7: 3D surface rendering of
hypoechoic tissue. Selecting the threshold level, voxels with umbilical cord around the arm
gray values below the threshold value selected are not shown
on the reconstructed image. Selecting threshold parameter
influences the quality of surface rendered image. Maximum Mode
Maximum gray values are displayed. It is suitable for
The surface can be displayed in “light” mode.
visualization of fetal bone structures and is the
Closer structures are brighter while distant structures
method of choice for imaging of the spatial
are displayed darker. Variation of the light mode is
relationships between bones. 115 Moreover, this
“gradient light mode” showing virtual illumination
modality offers an option of complete visualization
from spot light source.113
of curved bones such as ribs or clavicle on single
Transparent Mode image.
Evaluation of the complete skeleton, particularly
In the transparent mode, contrary to surface mode, the thoracic skeleton in the developing fetuses often
only the signals from the inner layers of ROI are is difficult with 2D US because of curvature of the
extracted providing spatial reconstruction of internal bones. Ribs can be completely observed using the 3D
structure of ROI. According to the echogenicity of US transparency mode. This modality reduces the
extracted signals there are two sub-modalities: echogenicity of soft tissues, leaving behind echogenic
maximum and minimum mode. In the maximum structures namely the bones. The curvature and
mode there are only the signals of highest relationship of the rib ends to the vertebral bodies
echogenicity, whereas in the minimum mode only the and the anterior chest wall can be demonstrated as
signals of lowest echogenicity are extracted from the well as the entire length.
entire volume. In the transparent mode only The vertebral column is originally curved
maximum gray values are displayed. This mode is anteroposteriorly. If it is pathologically curved
suitable for visualization of fetal bones, endometrium laterally, it is impossible to display the whole vertebral
and breast. column in a single sectional image by 2D US. The
advantage of 3D ultrasound (Fig. 42.8) is the ability
Minimum Mode
to visualize both curvatures at the same time.
Minimum gray values are displayed for visualization Anomalies such as scoliosis, kyphosis, lordosis and
of vessels, cystic structures and parenchyma of spina bifida may be overlooked by 2D ultrasound,
different organs.114 but are easy to recognize by using the three-
 Behavioral Perinatology Assessed by Four-Dimensional Sonography 581
The reconstructed volume scan offers a user friendly
technique to acquire data from the fetal heart and its
visualization in a 4D sequence. The volume
acquisition occurs in two ways: First, data is
performed by a single, automatic volume sweep. In
the second step, the system examines the data in
proportion to their spatial and temporal domain and
processes a 4D sequence. This sequence presents the
heart beating in real-time in a multi-planar display.
After the volume acquisition, the heart can be
assessed off-line, without being dependent on the
patient..116-117

Removing Overlaying Structures

This option is called Magic-Cut or The Electronic
Fig. 42.8: 3D Maximum mode showing the vertebral column scalpel. During 3D and 4D scanning in most cases
there are structures that are interfering or are
dimensional maximum mode. Congenital malfor- superimposed to the reconstructed image. Magic-Cut
mations of the fetal spine can be identified easier using tool enables successful removal of overlaying
3D surface and transparent mode reconstruction structures using 3D imaging. Unwanted structures
together. Specific vertebral body levels may be can be cut off from the image in all three directions
accurately identified by simultaneous evaluating of along the x, y, and z axes. There is also a possibility of
axial planes of the spine within the volume rendered using this tool to remove some structures from real
image. It is difficult to acquire the entire spine in a time 4D volumes. The cutting tool enables the
single volume and thus multiple volumes are often operator to have improved visibility to the object from
necessary to evaluate the spine completely. all directions.118

Volume Contrast Imaging (VCI) Data Review and Networking

Using 4D it is possible to make high contrast 2D Volume data sequences can be stored on the hard disk
images. The rendered algorithm is a combination of of the ultrasound unit or at different media (CD-R,
surface texture mode and minimum transparency 4D MO-Disc) in various formats: 2D image, 2D cine
mode. It is possible to display a couple of millimeters (selected sequence of 2D images), 3D volume
thin volume slice showing very good contrast (sequence of 3D rotating images) and 4D volume.
between different tissues. The user can define the Since the complete volume data set is saved, it is
thickness of the slice that is scanned using 4D image possible to review saved examinations without any
rendering. The reconstructed image shows improved loss of image quality. Stored data can be interactively
tissue contrast. VCI is used for better visualization of processed with additional 3D reconstruction
nodular or diffuse lesions in parenchyma of organs possibility.
such as liver and spleen. 3D and 4D imaging provides additional
dimensions to conventional 2D sonography. The main
Spatio-Temporal Image Correlation (STIC) in advantage of ultrasound in general is dynamic
Fetal Echocardiography imaging of human body. 4D imaging is following this
Spatio-Temporal Image Correlation (STIC) is a new tradition permitting visualization of dynamic changes
method for clinical investigation of the fetal heart. inside body and organs. Using 4D ultrasound in
582 Textbook of Perinatal Medicine

obstetrics it is possible for the first time to monitor Classification of Movement Patterns
quality and quantity of fetal movements on 3D real
1. Just discernible movements (between 7 and 8.5
time reconstructed images.
weeks)
2. Startle
ASSESSMENT OF FETAL BEHAVIOR
3. General movements (Fig. 42.9).
Prenatal motility is considered to reflect the 4. Hiccup
developing nervous system but also involves 5. Breathing
functional and maturational properties of fetal 6. Isolated arm or leg movement
hemodynamics and the muscular system. Despite 7. Isolated retroflexion of the head
medical reports from 100 years ago and 25 years of 8. Isolated rotation of the head
systematic research initiated by Prechtl and associates, 9. Isolated anteflexion of the head
the study of prenatal behavior is in its infancy. 10. Jaw movements
Fetal behavior can be defined as fetal activities 11. Hand-face-contact: In this pattern of movement,
observed or recorded with ultrasonographic the hand slowly touches the face, the fingers
equipment. As it is not yet possible to assess functional frequently extend and flex (Figs 42.12 to 42.15).
development of the CNS directly, investigators started 12. Stretch
to analyze fetal behavior as a measure of neurological 13. Rotation of the fetus.128
maturation.119
A turning point in the assessment of fetal behavior
was the introduction of real-time ultrasound. This
technique allowed the investigation of spontaneous
fetal motor activity in utero.118,120 For the first time,
studies of spontaneous prenatal movements and
behavior in utero were performed and published.
Since fetal body movements give important
information about the condition of the fetus, their
quantitative as well as qualitative aspects were
analyzed. De Vries and colleagues described the
developmental pathway of fetal movements in a
longitudinal study of 12 healthy nulliparous women.15
They reported not only how to describe a particular
movement, but also how these movements were
performed in terms of speed and amplitude.15

Assessment of Fetal Movements

Using ultrasound imaging, de Vries and colleagues Fig. 42.9: Four-dimensional ultrasound sequence of the fetus
focused on the first half of pregnancy while at 12 weeks of gestation showing general movements. The
Roodenburg and co-workers investigated the second complex movements of the limb, trunk and head are cleary
visible and cause a shift in fetal position. In the first sequence,
half of pregnancy.24,121 In the classic paper de Vries the right limb is bent in elbow joint. In the next sequence, the
and her team classified at least to 13 different fetus has dropped the hand and has begun to deflect the elbow
movement patterns24: joint. In the last sequence, further elevation of hand is seen
 Behavioral Perinatology Assessed by Four-Dimensional Sonography 583
However, the lack of definition specificity and embryonic feature is the head, which is strongly
long-term follow-up and the reliability of descriptions flexed anteriorly. Upper and lower limb buds are
have limited the usefulness of some of these studies. visible on the lateral aspects of the embryo. However,
In only two studies, fetal motor behavior has been embryonic movements are not frequent and consist
described. 130,131 The descriptor of ‘general mainly of moving of the head towards the rest of the
movements’ has been applied to the movement of body. At 8-9 weeks, the head is less flexed and the
preterm newborns.132 changes of the position of the head towards the body
Relying on the observations of apparently typical are clearly visible.
spontaneous human fetal movements, de Vries and General movements are the first complex fetal
co-workers recorded variations in ‘general move- movement patterns observable by two-dimensional
ments’ that they believed suggested abnormalities of ultrasound.15 They can be recognized from 8-9 weeks
the CNS.122 Following their lead, other researchers of pregnancy and continue to be present until 16-20
have selected, as a dependent variable, general weeks after birth.127 According to Prechtl these are
movements or ‘gross movements’ involving the whole gross movements, involving the whole body. 128
body. 123 Fetal motor behavior has been des- Movements of the limbs, trunk and head are of
cribed.124,125 The descriptor of ‘general movements’ variable speed, but smooth in appearance. They wax
has been applied to the movement of preterm and wane in intensity, force and speed, and they have
newborns.126 Unfortunately, the lack of definition a gradual beginning and end. 128 The qualitative
specificity, long-term follow-ups and the reliability of characteristics of general movements can be altered
descriptions have limited the usefulness of some of some pathological conditions, such as in fetuses of
these studies. Nevertheless, careful observation and women with type 1 diabetes mellitus or fetuses with
analysis of fetal movements could be useful in the anencephaly (17,129). The range of the movements
assessment of the integrity of fetal central nervous varies from forceful and jerky in character and of large
system, as will be described later in the text. amplitude in anencephalic fetuses (Fig. 42.10), to the
The Zagreb group has evaluated the advantages monotonous and rigid or chaotic in diabetic
of four-dimensional over two-dimensional real-time pregnancies. Qualitative alterations of general
sonography in the assessment of early fetal movements (Fig. 42.11) seem to be useful in the
behavior. 118 With four-dimensional transvaginal assessment of the severity of associated neurological
sonography these authors found body movements at disability. The complex sequences of extension and
7 weeks of pregnancy (Table 42.3).118 The observed flexion of the legs and arms (Fig. 42.9), may be better
body movements consisted of the changing position assessed with 4D ultrasound. Furthermore, 4D
of the head towards the body. Therefore, this sonography seems to be the method of choice for
technology enables the visualization of the moving detecting subtle changes such as superimposed
phenomenon 1 week earlier than two-dimensional rotations and changes in direction of the movements.
ultrasound. At 7 weeks of gestation, the dominant The application of this new technique could improve

Table 42.3: The incidence of spontaneous embryonic/fetal movement according to gestational age
Gestational age CRL (mm) No movements Gross body movements Limb movements Complex limb
(weeks) movements
7-8 0 – 15 31 12 0 0
9-10 16 – 30 26 11 7 0
11-12 31 – 50 19 16 12 8
CRL crown-rump length
Adapted from reference 118
584 Textbook of Perinatal Medicine

Fig. 42.10: 4D sequence of anencephalic fetus at 19 weeks of pregnancy, only hand to head movement in one direction of the
left arm could be seen, their onset was abrupt and jerky. Body movements in anencephalic fetus showed lack of positional
changes showing a waxing and waning in intensity. Using this technique, the function of lower level CNS responsible for these
forceful, monotonous changes are evaluated.

Fig. 42.11: 4D sequence of normal fetus at the same age as Fig. 42.10, hand movement could be observed in any direction.
We can see head movement (retroflexion and rotation) followed by palm opening position simultaneously. Qualitative alteration
of movements can be used as a marker of the severity of associated neurological disability.

the analysis of fetal movements and could allow the ultrasound. The organization of the movement
definition of the precise criteria for the assessment of pattern occurs as their frequency increases.130 It seems
the integrity of fetal nervous system. that fetal arms explore the surrounding environment
In the literature, there is a range between 8 and 12 and cross the midline, while the palmar surface is
weeks concerning the first appearance of limb oriented towards the uterine wall. The fetal legs are
movements .15,129 De Vries found isolated arm and leg extended to the uterine wall. This phenomenon can
movements at 8 weeks of pregnancy. 15 With 4D be seen two weeks earlier using 4D ultrasound.118
ultrasound, the limb movements were detected at 8- Despite its presence, these movement patterns are less
9 weeks of gestation (Table 42.3).118 In this interval, organized in comparison with those observed at 14
limbs are elongated and their segments are weeks by two-dimensional ultrasound. Complex limb
discernible. Isolated arm and leg movements were movement consists of changes in position of the limb
clearly visible and consisted of changes in position of segments towards each other, seen by 4D ultrasound.
the extremities towards the body without observable More limb joints are active and move simultaneously,
flexion or extension in joints. for example as extension or flexion in arm and elbow
Limb movements become more complex with or hip and knee. The elevation of the hand, extension
advancing gestational age. Specific movements can of the elbow joint, with a slight change in direction
be recognized at 14 weeks by two-dimensional and rotation, can be seen simultaneously.
 Behavioral Perinatology Assessed by Four-Dimensional Sonography 585
Sparling and Wilhelm also described spontaneous weeks, 0 and 6 with a median value of 2 at 15 weeks,
movements in fetuses from 12 to 35 weeks of gestation 18 and 28 with a median value of 25 at 16 weeks. The
(Table 42.4) and recorded the characteristics of hand highest range was registered at 13 weeks of gestation.
movement. 130 Many movements appeared to be Data from Table 42.5B demonstrate the incidence of
directed to a body part or the uterine wall. The hands hand to head movements (Fig. 42.15). There is notable
of the fetuses moved with a variety of frequencies and decrease in their incidence, followed by a plateau at
apparent force. Joint ranges of motion changed 14 weeks of gestation. The incidence varied from 4 to
throughout movements rather than remaining the 29 at 13 weeks and from 0 to 7 at 16 weeks of gestation.
same, as in floating. These movements suggested Table 42.5C shows the incidence of hand at mouth
primary and secondary circular reactions in which a movements (Fig. 42.13). The incidence varied between
movement is repeated, presumably because it has 0 and 4 with a median value of 2 at 13 weeks, and
functional importance to the organism.131,132 During between 0 and 2 with a median value of 2 at 16 weeks.
later gestational periods, the fetuses’ hands were
directed to and manipulated body parts and features
of the environment, such as the umbilical cord.

Table 42.4: Developmental Motor Characteristics

of Low-Risk Fetuses
Gestational Age (weeks) Description
8 Trunk flexion and extension
12 Isolated random-appearing movement of extremities
14 All movement patterns present; an increased frequency
of movement that is more “organized” in appearance
compared with movement at 12 weeks; arms appear to
“explore” while legs extend against uterine wall; arm
crosses midline, extending palmar surface to opposite
uterine wall
16 Decreased frequency of movements from 14 weeks, with
pincer graps, thumb in mouth Fig. 42.12: This picture shows the hand to face contact.
20 More bilateral movement (eg, legs extend together
against uterine wall, arms flex, and hands are often held
together near the face)
26-32 Independent movement of extremities to all parts of the
uterus and specific body parts; no cephalocaudal
development; but apparent distal-proximal develop-
ment in extremities
37-38 Decreased frequency of movements; hand often molded
to occiput, or dorsum of hand rests against uterine wall
Adapted from reference 126

Our recent study, performed by 4D sonography,

has shown that the amount of isolated arm
movements decreases gradually from 13 through 16
weeks (Table 42.5A). All recordings have been made
during 15-minutes intervals. The incidence varied
between 50 and 120 with a median value of 60 at 13 Fig. 42.13: The hand movement in
weeks, 17 and 27 with a median value of 23 at 14 the direct contact to the mouth
586 Textbook of Perinatal Medicine

The highest range was found at 15 weeks of gestation. onwards, the hand near face movement pattern was
At 13 weeks, a plateau was observed and was present visible in all 15 fetuses with an incidence of 2 to 9 and
until 16 weeks. Although this plateau was evident, a median value of 8. At 16 weeks, the range was from
mild fluctuations occurred. In contrast to most other 1 to 7 with a median value of 3. Although the plateau
movement patterns, hand near mouth movements was observed, mild fluctuation was evident,
(Table 42.5D) decreased gradually from 13 weeks especially at 15 weeks. From Table 42.5F, we can
onwards with a single fluctuation in 14th week (it recognize that the incidence of hand near face
varied between 0 and 3 with a median value of 1). movement is stable between 13 and 16 weeks of
The incidence of hand to face movement (Figs 42.12 gestation with slight increase at 14 and 15 weeks. At
and 42.15) is characterized by a decrease at 14 weeks 13 weeks, the range was the widest (from 0 to 12),
followed by a plateau (Table 42.5E). From 13 weeks with the median value of 3. The incidence of hand to
ear movements decreased between 13 and 16 weeks
(Table 42.5G). It varied between 4 and 12 with a
median value of 8 at 13 weeks, and 0 and 3 with a
median value of 0 at 16 weeks. The incidence of the
hand to eye movement (Fig. 42.15) pattern showed
the same developmental trend as hand to head and
hand to face movement patterns (Table 42.5H). At 13
weeks, the incidence was between 4 and 12
occurrences per 15 minutes observation time with a
median value of 8. At 16 weeks, the range was from
0 to 3 with a median value of 1.23
Other developmental tendencies in hand
movement have been noted.133 Movements such as
thumb in mouth and bilateral leg extension against
the uterine wall were considered as functionally
important. The frequently observed leg extension
against the uterine wall was believed by the authors
to be a possible precursor to later participation in the
Fig. 42.14: 3D image showing the direction of hand
movement to the nose birthing process. Early movements of the arms

Fig. 42.15: Several 3D images of hand direction to the face (a), to the head (b), to the eye (c)
 Behavioral Perinatology Assessed by Four-Dimensional Sonography 587
Table 42.5: The incidence of several characteristics of hand movements from 13 to 16 gestational weeks showed by
4D sonography. (a) Isolated hand movement (b) Hand to head movements (c) Hand to mouth movements (d) Hand near
mouth movements (e) Hand to face movements (f) Hand near face movements (g) Hand to ear movements (h) Hand
to eye movemets.
Adapted from reference 23
588 Textbook of Perinatal Medicine

appeared to assist the fetus in identifying components facial expressions such as smiling ranged between 2
of its environment. Attributing function to any of and 7 with a median of 2 and scowling between 2 and
these early movements, however, does not imply that 4 with a median of 2. It is evident that eyelid and
the assigned function is preliminary to or necessary mouthing movements dominate at this gestational
for the appearance of a spontaneous behavior.133,25 age. The continuity between fetal and neonatal
behavior has also been suggested.133 These findings
Assessment Of Fetal Facial may stimulate multicentric studies of the fetal
Expressions by 4D Ultrasound behavior and responsiveness as a sign of neurological
Recent srudies have demonstrated that during the maturation. In the long term, fetal behavioral studies
second and third trimester it is possible to study total may become a means of assessing fetal well-being.23
fetal facial activities. In addition to yawning, sucking The Zagreb group has attempted to evaluate four-
and swallowing described by 2D real-time imaging, dimensional sonography in the assessment of fetal
it is now possible to study a full range of facial facial expression. They have classified 8 different facial
expressions including smiling, crying, and eye-lid expressions:
movements.23, 134
Classification of Facial Movement Patterns
The fetal behavioral patterns have been evaluated
in 10 gravidas in the third trimester between 30-33 1. Yawning: This movement is similar to the yawn
weeks of gestation. 23 The incidence of eyelid observed after birth: An involuntary wide opening
movements ranged between 4 and 20 with a median of the mouth, with maximal widening of the jaws
value of 17, mouthing movements ranged between 2 followed by quick closure often with retroflexion
and 19 with a median value of 12, mouth and eyelid of the head and sometimes elevation of the arms.
movements ranged between 0 and 13 with a median This movement pattern is non-repetitive. (Fig.
value of 5. The incidence of pure mouth movements 42.16).
such as the mouth opening ranged between 4 and 13 2. Swallowing: Indicating that the fetus is drinking
with a median of 5, tongue expulsion ranged between amniotic fluid. Swallowing consists of
0 and 2 with a median of 2, yawning ranged between displacements of tongue and/or larynx.
0 and 2 with a median of 1 and pouting ranged Swallowing activity develops earlier than sucking
between 0 and 9 with a median of 3. The incidence of in the course of fetal development.

Fig. 42.16: Yawning expression of the fetus. An involuntary wide opening of the mouth, with maximal widening of the jaw,
followed by quick closure often with retroflexion of the head and sometimes elevation of the arms
 Behavioral Perinatology Assessed by Four-Dimensional Sonography 589
3. Sucking: Rhythmical bursts of regular jaw The early results, presented above, indicate that
opening, and closing at a rate of about one per fetal facial grimaces, resembling the emotional
second. Placing the finger or thumb on the roof of expressions in humans, are present during the third
the mouth behind the teeth and sucking with lips trimester of gestation. However, the precise criteria
closed. Thumb sucking is a very frequent fetal for of distinction of theses expressions in fetus remain
behavioral pattern (Fig. 42.17). to be established. A possibility to study fetal facial
4. Smiling: A facial expression characterized by expressions allows dealing with new research
turning up the corners of the mouth (Fig. 42.21). questions and indicates a great potential for 4D
5. Tongue expulsion: A facial expression sonographic studies in the psychological and fetal
characterized by expulsion of the tongue (Fig. behavioral sciences. Facial expressions are an
42.18). important channel of nonverbal communication. The
6. Grimacing: The wrinkling of the brows or face in characteristics of facial expressions can provide
frowning to express of displeasure (Fig. 42.22). different mode to the expert for understanding the
7. Mouthing: A facial expression characterized by hidden side of the fetus in utero, a side that may not
mouth manipulation to investigate an object. be accessible in the form of any verbalizations.
Mouthing is most common in fetus and it may However, the clear evidences that fetal emotional
develop into a persistent, stereotyped behavior processing exists in the third trimester of gestation or
pattern (Fig. 42.19). that it is related to facial expressions are still lacking
8. Isolated eye blinking: a reflex that closes and opens and extensive multicentric studies should be
the eyes rapidly. Brief closing of the eyelids by conducted in order to clarify this area. We believe that
involuntary normal periodic closing, as a the fetal facial expressions and fetal behaviors related
protective measure, or by voluntary action (Figs to emotions could reveal a part of the emotional aspect
42.20 and 42.21). of the intrauterine life. If this assumption becomes
They have also tried to identify emotional confirmed, it is possible to imagine that we could
expressions as the combinations of several facial construct a system, which relates the discrete
expressions mentioned above (Fig. 42.20 to 42.22). emotions, like happiness, anger, sadness etc. and
various intensities of the fetal facial expressions in
utero to the external events. A system might be able

Fig. 42.17: This picture shows sucking expression. The fetus

is placing the thumb into the mouth, probably on the roof of
the mouth and sucking with lips closed. Fig. 42.18: Facial expression charaterized by tongue expulsion.
590 Textbook of Perinatal Medicine

to be constructed where componential and general

internal states like pleasure control the each parameter
unit and establish a pleasure score of the fetus that
can be used to drive facial expressions?

CONCLUSIONS
Behavioral perinatology assessed by 4D sonography
should be an interdisciplinary area of research
involving concepts and conducting studies of the
dynamic interplay between behavioral processes in
fetal, neonatal, and infant life.135-137 Understanding
the technical aspects of 4D ultrasound is important
for utilizing its full potential. Furthermore, image
post-processing should be considered as a part of
examination. Sometimes, additional information
about the range of interest can be provided with post-
Fig. 42.19: On this image sequence, mouthing could be processing.
observed as a facial expression pattern. We can se a series of The study of fetal behavior has provided us with
rhytmic movement involving the mandible and tongue, an important contribution to understanding the
characterized by constant frequency and duration until
hidden function of the developmental pathways of
dissapearance.

Fig. 42.20: The picture shows fear expressions of the fetus. We can se the hand to the mouth movement together with eyelid
opening. We assumed that this complex expression could be related to the imminent possibility of fetal danger, a nearby threat,
a displeasure position, or of bodily harm.

Fig. 42.21: Several facial expressions characterized by turning up the corners of the mouth shows the smiling fetus.
 Behavioral Perinatology Assessed by Four-Dimensional Sonography 591

Fig. 42.22: In this picture the fetus shows wrinkling of the brows or face in frowning, maybe to express of displeasure or anger.
The frontalis muscle can also be responsible for the appearance of grimacing. However, the main agent responsible for the
appearance of scowling is the corrugator muscle.

the fetal CNS and the potential to investigate 12. Fitzgerald M. An update on ccurrent scientific knowledge.
London: Department of health 1995.
neurologic deficits in utero.
13. Humphrey T. Some correlations between the appearance
of human fetal reflexes and the development of the
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 43
Fetal Central Nervous System

Ritsuko K Pooh, KyongHon Pooh

INTRODUCTION existence of gray zone between normality and

abnormality.
Recent advances of prenatal imaging technologies
such as transvaginal ultrasound, three-dimensional
CNS DEVELOPMENT
ultrasound, magnetic resonance imaging have been
remarkable and contributed prenatal evaluation of The brain is a three-dimensional structure and should
fetal abnormalities in utero. Owing to those be comprehended in the three orthogonal views of
technologies, fetal malformations have been reliably sagittal, coronal and axial section. During fetal period,
diagnosed with increasing accuracy and at earlier the embryonal premature CNS structure develops to
gestation. As for fetal central nervous system mature structure (Fig. 43.1). Within this rapid change
assessment, a new field of ‘neurosonography’1 has been of development, various developmental disorders
established. Many of congenital CNS anomalies, and/or insults result in various phenotypes of fetal
which were disclosed in the late pregnancy or after CNS abnormalities. For understanding fetal CNS
birth, have been recently demonstrated by use of high diseases, basic knowledge of the development of the
frequency transvaginal sonography before viability. nervous system is essential. The developmental stages
More advances of technological development will and their major disorders are described as Table 43.1.
clarify unknown neuropathological facts during fetal
period
Diagnostics of the fetal CNS is one of the most
difficult fields in Perinatology. There are several
reasons why the prenatal CNS evaluation is difficult;
lack of essential knowledge of CNS anatomy and pathology,
rapid changes of normal CNS development during
pregnancy, inexperience of CNS neuroimaging techniques.
When the beginners start prenatal CNS imaging,
those three may be the most frequent reasons of Fig. 43.1: Developing brain and spinal cord during pregnancy.
toughness in prenatal assessment. However, after Fetal central nervous system changes in size and appearance
from early premature structure into late mature structure with
overcoming those problems, there still exist difficulties
gyral formation. CH; cerebral hemisphere, C; cerebellum, D;
in assessment of fetal CNS diseases, because of diencephalon, M; medulla, SC; spinal cord, f; forebrain, mb;
difficulty in prediction of neurological prognosis and midbrain, IV; fourth ventricle
 Fetal Central Nervous System 597
Table 43.1: Developmental stages and major disorders

Developmental stage Disorders

Primary neurulation (3-4 weeks’ gestation) Spina bifida aperta, Cranium bifidum
Caudal neural tube formation
(secondary neurulation, from 4 weeks’ gestation) Occult dysraphic states
Procencephalic development (2-3 months’ gestation) Holoprosencephaly
Agenesis of the corpus callosum,
Agenesis of the septum pellucidum,
Septo-optic dysplasia
Neuronal proliferation (3-4 months’ gestation) Micrencephaly, Macrencephaly
Neuronal migration (3-5 months’ gestation) Schizencephaly
Lissencephaly, Pachygyria
Polymicrogyria
Organization (5 months’ gestation – years postnatal) Idiopathic mental retardation
Myelination (Birth – years postnatal ) Cerebral white matter hypoplasia

It is believed that the brain anatomy must be of major fetal anomalies 3. In the middle and late
complicated and there must be lots of terms to pregnancy, fetal CNS is generally evaluated through
remember. In this chapter, essential anatomical maternal abdominal wall. The brain, however, is
structures are selected for neuroimaging and three-dimensional structure, and should be assessed
comprehension of fetal CNS diseases. Figure 43.2 and in basic three planes of sagittal, coronal and axial
43.3 show the basic anatomy in the axial, sagittal and sections. Sonographic assessment of the fetal brain in
anterior coronal sections of the brain. For the sagittal and coronal sections, requires an approach
understanding hydrocephalus, ventriculomegaly from fetal parietal direction (Fig. 43.6). Transvaginal
and/or other intracranial lesions, the ventricular sonography of the fetal brain opened a new field in
system (Fig. 43.4) and CSF circulation (Fig. 43.5) medicine, “neurosonography” 1. Transvaginal
should be understood. approach to the normal fetal brain during the second
and third trimester was introduced in the beginning
TECHNOLOGY of 1990s. It was the first practical application of three-
Transabdominal sonographic technique, by which it dimensional central nervous system assessment by
is possible to observe the fetal internal organs through two-dimensional (2D) ultrasound4. Transvaginal
maternal abdominal wall and uterine wall, has been observation of the fetal brain offers sagittal and
most widely used for fetal imaging diagnosis. By coronal views of the brain from fetal parietal
transabdominal approach, fetal brain structure mostly direction5-8 through the fontanelles and/or the sagittal
in the axial section and fetal back structure including suture as ultrasound windows. Serial oblique
the vertebrae and spinal cord in the sagittal section sections3 via the same ultrasound window reveal the
can be well demonstrated. However, in trans- intracranial morphology in detail. This method has
abdominal approach to the fetal central nervous contributed to the prenatal assessment of congenital
system, there are several obstacles such as maternal CNS anomalies and acquired brain damage in utero.
abdominal wall, placenta and fetal cranial bones. Three-dimensional (3D) ultrasound is one of the
Introduction of high-frequency transvaginal trans- most attractive modality in a field of fetal ultrasound
ducer has contributed to establishing “sonoembryo- imaging. There are two scanning methods of free-
logy”2 and recent general use of transvaginal sono- hand scan and automatic scan. Automatic scan by
graphy in early pregnancy enabled early diagnoses dedicated 3D transducer produces motor driven
598 Textbook of Perinatal Medicine

3rd ventricle
4th ventricle
Atrium cerebellum
Anterior horn of
Cisterna
Lateral ventricle
Choroid plexus magna

A P A P

AW
(atrial width)

Cavum septum
pellucidum

Axial section of the fetal brain Oblique axial section

Fig.43.2: Basic anatomical knowledge

CC (body) superior sagittal sinus

cingulate sulcus/gyrus fornix dura matter
cingulate sulcus falx
CC (splenium) anterior horn of
CC (genu) corpus callosum
lateral ventricle

Parieto- choroid
occipital plexus
sulcus
septum p ellucidum cerebral
Sylvian
third ventricle aqueduct
fissure
pituitary grand cereb ellum
pons
lenticulostriate middle cerebral artery
fourth v entricle
medulla arteries internal carotid artery
Fig. 43.3: Basic anatomical knowledge of sagittal (left) and anterior coronal cutting sections of the brain. CC; corpus callosum

anterior horns atrium

posterior horn

foramen of choroid plexus

Monro

third ventricle cerebral aqueduct

fourth vent ricle

inferior horns Magendie

Luschka

Fig. 43.4: Basic anatomical knowledge of ventricular system and

cerebrospinal fluid (CSF) flow.
 Fetal Central Nervous System 599
superior sagittal sinus arachnoid
subarachnoid space granulation

cerebrum

ventricl e choroid plexus

f. of Monro
third ventricle
aqueduct
cerebellum
fourth ventricle cerebellum
Foramen of Magendie
and Luschka

Inside view of the brain Outside view of the brain

Fig. 43.5: Cerebrospinal fluid (CSF) circulation. Inside and outside views of the brain. CSF is produced from
choroid plexus of ventricles. CSF runs through the third ventricle, aqueduct and fourth ventricle, goes to surface
of the brain and spinal cord, and then absorbed by arachnoid granulation. From “Handbook on hydrocephalus
for patients”, Research Committee of “Intractable Hydrocephalus”, Japanese Ministry of Health and Welfare,
©1993, with permission. (Schema by courtesy of chairman of the Committee, Prof. Mori K)

AF

PF

Fig. 43.6: Schema of transvaginal sonography (upper left) Lateral view of vertex presenting
fetus and transvaginal transducer. (upper right) Frontal view of transvaginal approach. Clear
imaging is possible by rotating and angle-changing of the transducer. (lower left) Scheme of
transfontanelle/transsutural approach of the fetal brain. (lower right) Cranial bony structure
from parietal direction. AF; anterior fontanelle, S; sagittal suture, PF; posterior fontanelle.
Those spaces are used as ultrasound windows
600 Textbook of Perinatal Medicine

automatic sweeping and is called as a fan scan. With Easy storage/extraction of raw volume data set
this method, a shift and/or angle-change of the enables off-line analysis and consultation to
transducer is not required during scanning and scan neurologists and neurosurgeons16,17.
duration needs only several seconds. After acquisition Recent fast magnetic resonance (MR) imaging is
of the target organ, multiplanar imaging analysis is being used increasingly as a correlative imaging
possible. Combination of both transvaginal modality because it uses no ionizing radiation,
sonography and 3D ultrasound9-12 may be a great provides excellent soft tissue contrast, has multiple
diagnostic tool for evaluation of three-dimensional planes for reconstruction, and a large field of view18.
structure of fetal CNS. There are several useful Recent advances in fast MR imaging technology, such
functions in 3D ultrasound as bellows; as half-Fourier and the 0.5-signal-acquired single-shot
• Surface imaging of the fetal head fast spin-echo (SE), half-Fourier rapid acquisition with
• Bony structural imaging of the calvaria and relaxation enhancement (RARE) sequences, has
vatebrae remarkably improved the T2-weighted image
• Multiplanar imaging of the intracranial structure resolution despite a short acquisition time, and
• Three-dimensional sono-angiography of the brain minimized fetal and/or maternal respiratory motion
circulation artifacts without needs of fetal sedation 19 . MR
• Volume calculation of target organs such as imaging has a great potential especially in the
intracranial cavity, ventricle, choroid plexus and evaluation of CNS and several reports have published
intracranial lesions on normal and abnormal CNS anatomy by using fast
• Simultaneous volume contrast imaging by four- MR imaging techniques20-23.
dimensional ultrasound. NORMAL FETAL CENTRAL
In multiplanar imaging of the brain structure, it is NERVOUS SYSTEM IMAGING
possible to demonstrate not only the sagittal and
The calvaria and its major sutures develop between
coronal sections but also the axial section of the brain,
12 and 18 weeks of fetal life, with dura as guiding
which cannot be demonstrated from parietal direction
tissue in the morphogenesis of the skull24. The cranial
by a conventional 2D transvaginal sonography.
bones are detectable by sonography from 10 weeks
Parallel slicing provides a tomographic visualization
of gestation on. At 12 weeks, premature cranial bones
of internal morphology similar to MR imaging.
and sutures in between are detectable (Fig. 43.7). The
Volume extracted image and volume calculation of
sagittal suture, lambdoid sutures and posterior
the fetal brain in early pregnancy was reported in fontanelle are recognizable from 13 weeks. As the fetal
1990s 13,14 . We used VOLUSON 730 Expert (GE parietal portion has the anterior/posterior fontanelles
Medical Systems, Milwaukee, USA) with transvaginal and sagittal suture which is the widest suture among
3D transducer and 3D View version 3.2 software the fetal cranial sutures25, transvaginal approach to
(Kretztechnik AG, Zipf, Austria) for volume extraction the fetal brain using those spaces as ultrasound
and volume estimation of the brain structure. windows, demonstrates the detailed brain structure
Furthermore, with application of four-dimensional without obstacles of the cranial bone, and is the most
(4D) ultrasound, real-time images with increased reasonable way for brain assessment. Recent
contrast resolution can be obtained in not only the advanced 3D ultrasound has been able to depict
same plane as 2D cutting section but also vertical vertebral body, intervertebral disk space and vertebral
plane to 2D image 15. Fetal neuroimaging with lamina (Figs 43.8 and 43.9).
advanced 3D/4D technology is easy, non-invasive, From eight weeks of gestation, premature
and reproducible methods. It produces not only sonolucent ventricular system is detectable (Fig.
comprehensible images but also objective imaging 43.10). Before 16 weeks of gestation, lateral ventricles
data which can be graphed in volume calculation. are occupied by the choroid plexus (Fig. 43.11). Basic
 Fetal Central Nervous System 601

S
AF P
S P
F C P P AF
vertebral lamina
vertebral body
F F
O
M L
PF
12 w 13 w 15 w

intervertebral
d isk space
AF C
AF
F F
© Ritsuko K. Pooh, 2003

Fig. 43.9: Fetal vertebral structure by 3D US at

21 weeks of gestation
ALF
12 w 17 w
mesencephalon
Fig. 43.7: Fetal cranial structure in early gestation (3D US
images) (upper left) 12 weeks, from the oblique front. (upper fourth ventricle
middle) 13 weeks, from the back. (upper right) 15 weeks, from
the top of head. (lower left) 12 weeks, from the front. (lower diencephalon
right) 17 weeks. Oblique position. Premature shape of cranial
bones, sutures, and fontanelles at 12 to 13 weeks change its
appearance to the neonatal shape. AF; anterior fontanelle, PF;
posterior fontanelle, ALF; anterolateral fontanelle, F; frontal
bone, P; parietal bone, O; occipital bone, C; coronal suture, M;
metopic suture, S; sagittal suture, L; lambdoid suture.

© Ritsuko K. Pooh, 2003

Fig. 43.10: Normal intracranial structure at 8 weeks of gestation
in parallel cutting slices of three orthogonal views. Sagittal,
coronal, axial sections from above. Premature sonolucent
ventricular system is visible

Fig. 43.8: Three orthogonal views and 3D reconstructed image

of normal fetus at 16 weeks of gestation. Movement of region
of interest (arrow) provides 3D reconstruction image of the Fig. 43.11: Normal intracranial structure at 14 weeks of gestation.
surface level (lower left), neural arch level (lower middle) and Axial view (left) and parasagittal view (right). Choroid plexus
vertebral body level (lower right). (arrows) occupies most of the lateral ventricle
602 Textbook of Perinatal Medicine

knowledge of images in several cutting sections

obtained by transvaginal scanning, is shown in Figure
43.12. Three orthogonal views by 3D ultrasound is
useful for obtaining easy orientation. Multiplanar
image analysis is possible (Fig. 43.13). By 3D
ultrasound, the brain structure can be observed in
parallel cutting slices of any sections (Fig. 43.14). 3D
transvaginal power Doppler demonstrates clear
anatomical vascular formation (Fig. 43.15). Vertebrae
and spine should be observed carefully for detection
of back abnormalities such as spina bifida or scoliosis.
Fetal sagittal sectional screening is preferable (Fig.
43.16).
Volume analysis by 3D ultrasound provides
exceedingly informative imaging data 15. Volume
Fig. 43.13: 3D multiplanar image analysis (normal brain at 23
weeks of gestation). Three orthogonal view is useful to obtain
CC orientation of the brain structure. Coronal (left upper), sagittal
CP (right upper) and axial (left lower) images can be visualized on
a single screen. Any rotation of the brain image around any
(x,y,z) axis is possible

CSP analysis of the structure of interest provides an

C
IV PH intelligible evaluation of the brain structure in total,
CC AH and longitudinal and objective assessment of enlarged
ventricles and intracranial occupying lesions. Any
intracranial organ can be chosen as a target for
volumetry no matter how distorted its shape and
appearance may be (Fig. 43.17).

C HYDROCEPHALUS AND VENTRICULOMEGALY

CSP Syl F IN UTERO
Both “hydrocephalus” and “ventriculomegaly” are
CP the terms, used to describe dilatation of the lateral
ventricles. However, those two should be
distinguished from each other. Hydrocephalus
signifies dilataed lateral ventricles resulted from
32w increased amount of cerebrospinal fluid and
Fig. 43.12: Normal views of fetal brain at 26 weeks of intracranial pressure, while ventriculomegaly is a
gestation. Sagittal (upper), coronal (middle) and axial dilatation of lateral ventricles without increased
(lower) sections. CC; corpus callosum, CSP; cavum intracranial pressure due to hypoplastic cerebrum or
septum pellucidum, C;cerebellum, IV; 4th ventricle, AH;
other intracerebral abnormalities such as agenesis of
anterior horn of the lateral ventricle, PH; posterior horn
of the lateral ventricle, CP; choroid plexus, Syl F; sylvian corpus callosum. Of course, ventriculomegaly can
fissure sometimes change into hydrocephalic state. In
 Fetal Central Nervous System 603

Fig. 43.14: Normal intracranial structure at 19 weeks of gestation in parallel cutting

slices of three orthogonal view. Sagittal, coronal, axial sections from above

MCA branches
PcA
MCA ACA

ICA

Fig. 43.15: 3D power Doppler image of fetal brain circulation. (left) View from the front. Bilateral
internal carotid arteries (ICA) and middle cerebral arteries (MCA) and branches of MCA are
demonstrated. (right) Oblique view. Anterior cerebral artery (ACA) and pericallosal artery (PcA)
are demonstrated
604 Textbook of Perinatal Medicine

sonographic imaging, those two intracranial

conditions can be differentiated by visualization of
subarachnoid space and appearance of choroids
plexus. In normal condition, subarachnoid space,
visualized around the both cerebral hemispheres is
preserved during pregnancy (Fig. 43.18). Choroid
plexus, which secretes cerebrospinal fluid (CSF)
within the ventricles, is a soft tissure and easily
affected by pressure. Obliterated subarachnoid space
Medulla and spinal cord
and dangling choroid plexus in the case of
hydrocephalus (Figs 43.19 and 43.20). In contrast, the
subarachnoid space and choroid plexus are well
preserved in cases of ventriculomegaly(Fig. 43.21). It
is difficult to evaluate obliterated subarachnoid space
in the transabdominal axial section and this method
may not differentiate accurately hydrocephalus with
increased intracranial pressure from ventriculo-
megaly without pressure. Therefore, it is suggested
that the evaluation of fetuses with enlarged ventricles
Fig. 43.16: Normal vertebral structure in the sagittal section
at 19 weeks of gestation. Lower figure shows the medulla and should be evaluated in the parasagittal and coronal
spinal cord in the craniospinal region views by transvaginal way or 3D multidimensional
analysis. In some cases with hydrocephalus, the
septum pellucidum is destroyed and both ventricles
Lateral Ventricle 5(ml) are fused each other (Fig. 43.19). This condition should
Ventricle

4
be differentiated from lober type of
3
2 holoprosencephaly. Furthermore, intracranial venous
P< 0.001,r2 =0.793
1 blood flow may be related to increased intracranial
0
10 14 18 22 26 30 34 38 (wks)
Gestational Age
pressure. In normal fetuses, blood flow waveforms
of dural sinuses, such as superior sagittal sinus, vein
(ml)
of Galen and straight sinus have pulsatile pattern26
Choroid Plexus

Choroid Plexus
(Fig. 43.22). However, in cases with progressive
P< 0.001,r2 =0.373
2

hydrocephalus, normal pulsation disappears and

1
blood flow waveforms become flat pattern26 (Fig.
0
10 14 18 22 26 30 34 38 (wks) 43.23). In cases with progressive hydrocephalus, there
Gestational Age
may be seven stages of progression (Fig. 43.24); (1)
increased fluid collection of lateral ventricles, (2)
Fig. 43.17: 3D volume extraction and volumetric analysis of
lateral ventricle and choroid plexus. On three orthogonal incresed intracranial pressure, (3) dangling choroids
sections, the target organ can be traced automatically or plexus, (4) disappearance of subarachnoid space, (5)
manually with rotation of volume imaging data. After tracing, excessive extension of the dura and superior sagittal
volume extracted image (right) is demonstrated and volume
sinus, (6) disappearance of venous pulsation, and
calculation data is shown. Middle graphs show normograms of
ventricular size (upper) and choroid plexus size (lower) during finally, (7) enlarged skull. In general, both
pregnancy. hydrocephalus and ventriculomegaly are still
 Fetal Central Nervous System 605
Normal
SAS
Cerebrum

ventricle
Choroid plexus
Ventriculomegaly SAS

C
V
V

Hydrocephaly Choroid plexus

C

V V
Fig. 43.19: US images of hydrocephalus at 34 weeks of
gestation. (upper) Coronal Images. Septum pellucidum was
destroyed maybe due to enlargement of bilateral ventricles and
both ventricles were fused. Dangling choroid plexus is seen.
(lower) Parasagittal and sagittal images. Dangling choroid
Fig. 43.18: Schema of ventriculomegaly and hydrocephaly. In
plexus and obliterated subarachnoid space are seen.
cases of ventriculomegaly without increased intracranial
pressure, subarachnoid space (SAS) and choroid plexus
appearance are well preserved, while in cases of hydrocephaly
with increased intracranial pressure, dangling choroid plexus
and gradual disappearance of SAS are seen.

IIIrd v.

Fig. 43.20: Hydrocephalus due to aqueductal obstruction at 19 weeks of gestation.

Left figure: Three orghogonal views with anterior coronal (upper left) and median sagittal (upper right) and axial (lower left) slices.
Bilateral ventriculomegaly and third ventriculomegaly (IIIrd v.) are seen. No enlargement of forth ventricle indicates obstruction of
the aqueduct. Right figure: Three orghogonal views with parasagittal (upper left) and posterior coronal (upper right) and axial
(lower left) slices. Subarachnoid space is already obliterated and dangling choroid plexus (arrowheads) is seen. Lower right pink
figure shows extracted 3D ventricular image by VOCAL mode. Ventricle in this case was tenfold size of normal 19-week-ventricle.
606 Textbook of Perinatal Medicine

SSS
SSS SSS

ICV
ICV SS
SS

Galen

SS

Fig. 43.22: Normal cerebral venous circulation. (left) Sagittal

image of color Doppler. SSS; superior sagittal sinus. ICV;
internal cerebral vein. G; vein of Galen. SS; straight sinus. (right)
Normal blood flow waveforms of dural sinuses. In normal
fetuses, venous flow always have pulsations
Fig. 43.21: US image of ventriculomegaly at 29 weeks of
gestation. Enlarged ventricle exists but subarachnoid space
is well preserved and no dangling choroid plexus is seen.
From those findings, non-increased intercranial pressure (ICP)
is estimated. This condition should be differentiated from
hydrocephalus with increased ICP
Increased fluid collection of lateral ventricles

Incresed ICP

Dangling CP

Disappearance of SAS

Excessive extension of the dura and SSS

Disappearance of venous pulsation

Fig. 43.23: Disappearance of venous pulsation in cases with

hydrocephalus. Normal dural sinuses have pulsatile patterns Enlarged skull
of flow waveform. (Fig. 43.22). In cases with progressive
hydrocephalus, venous pulsation disappeared (right figures) Fig. 43.24: Progressive stages of hydrocephalus. ICP;
maybe because of excessive extension of the dura and dural intracranial pressure, CP; choroid plexus, SAS; subarachnoid
sinuses space
 Fetal Central Nervous System 607
evaluated by the measurement of biparietal diameter 15 mm. The majority of with prenatally detected
(BPD) and atrial width (AW) in transabdominal axial isolated mild ventriculomegaly are developmentally
section. As a screening examination, the measurement normal32. Pilu and his colleagues33 reviewed 234 cases
of AW is useful with a cut-off value of 10 mm27,28 . As of borderline ventriculomegaly including an
described above, however, hydrocephalus and abnormal outcome in 22.8% and concluded that
ventriculomegaly should be differentiated from each borderline ventriculomegaly carries an increased risk
other and hydrocephalic state should be assessed by of cerebral maldevelopment, delayed neurological
changing appearance of intracranial structure. To development and, possibly, chromosomal aberrations.
evaluate enlarged ventricles, examiners should The treatment of hydrocephalus includes a
carefully observe the structure below and specify miniature reserver 34,35 , shunt procedure and
causes of hydrocephalus: neuroendoscopy. Ventriculoperitoneal shunt is the
• Choroids plexus, dangling or not most popular procedure. Effectiveness of shunt
• Subarachnoid space, obliterated or not procedure for congenital hydrocephalus has been
• Ventricles, symmetry or asymmetry proven from earlier. However, it has been known that
• Visibility of third ventricle there are various complications of shunting, such as
• Pulsation of dural sinuses shunt infection•Cobstruction of the shunt tube, over
• Ventricular size (3D volume calculation if possible) drainage, under drainage, and slit ventricle
• Other abnormalities syndrome. To reduce those complications, various
Genetic hydrocephalus is rare but important in types of shunt devices, such as antisiphon device or
counseling couples on subsequent pregnancy. X- pressure programmable valve shunt device have been
linked hydrocephalus (HSAS, hydrocephalus due to developed. Third ventriculostomy by neuroendos-
stenosis of the aqueduct of Sylvius), MASA (mental copy has recently become performed in children with
retardation-aphasia-shuffling gait-adducted thumbs) obstructive hydrocephalus, and the number of shunt-
syndrome, X-linked complicated spastic paraparesis independent cases has been increased. It has been
(SP1) and X-linked corpus callosum agenesis (ACC) controversial, however, whether infants less than the
are all due to mutations in the L1 gene29. The gene age of one have a higher risk of treatment failure after
encoding L1 is located near the telomere of the long neuroendoscopic procedures than older children.
arm of the X chromosome in Xq28. Therefore, it was Some concludes that neuroendoscopy presents an
suggested to refer this clinical syndrome with the effective alternative for the treatment of
acronym CRASH, for Corpus callosum hypoplasia, hydrocephalus in cases under the age of one 36 .
Retardation, Adducted thumbs, Spastic paraplegia However, third ventriculostomy still does not seem
and Hydrocephalus 29 . It has been reported that to be effective in neonates because of their prematurity
mutations which produce truncations in the of absorption ability in neonates and small infants.
extracellular domain of the L1 protein are more likely
to produce severe hydrocephalus, grave mental CONGENITAL CNS ANOMALIES
retardation or early death than point mutations in the Cranium bifidum
extracellular domain or mutations affecting only the
Prevalence: anencephaly; 0.29/1,000 births37, overall
cytoplasmic domain of the protein30. For the families,
neural tube defect (NTD);0.58-1.17/1000 births38-40,
prenatal CNS diagnosis of male infants is important.
Many reported remarkable reduction of prevalence
Morphology-based approach becomes feasible
of NTDs after using folic acid supplementation and
between postmenstrual weeks 15 and 20. Prior to this
fortification37-40, although some reported no decline
gestational age, the diagnosis should rely on
of anencephaly rate41.
molecular biology tests31.
Borderline ventriculomegaly is defined as a width Definition: As in spina bifida, cranium bifidum is
of the atrium of the lateral cerebral ventricles of 10- classified into four types of encephaloschisis
608 Textbook of Perinatal Medicine

(including anencephaly and exencephaly),

meningocele, encephalomeningocele, encephalo-
cystocele, and cranium bifidum occulutum.
Encephalocele occurs in the occipital region in 70-80%.
Acrania, exencephaly and anencephaly are not
independent anomalies. It is considered that
dysraphia (absent cranial vault, acrania) occurs in
very early stage and disintegration of the exposed
brain (exencephaly) during the fetal period results in
anencephaly42.
Etiology: multifactorial inheritance, single mutant
genes, specific teratogens (valproic acid), maternal
diabetes, environmental factors, predominant in
Fig. 43.25: A crania at 10 weeks of gestation. (left) US coronal
females
image at 10 weeks. Note the normal appearance of amniotic
Pathogenesis: Failure of anterior neural tube closure membrane, which indicates this condition is not amniotic band
syndrome. (right) 3D US image of the same fetus as left image
or a restricted disorder of neurulation.
Associated anomalies: open spina bifida (iniencephaly),
Chiari type III malformation, bilateral renal cystic
dysplasia and postaxial polydactyly with occipital
cephalocele (Meckel-Gruber syndrome), hydro-
cephalus, polyhydramnios,
Prenatal diagnosis: Acrania in Figure 43.25, anence-
phaly in Figure 43.26 and early detection of inience-
phaly in Figure 43.27.
Differential diagnosis: Amniotic band syndrome (ABS).
In cases of ABS, cranial destruction occurs secondarily
to an amniotic band, similar appearance is observed.
However, ABS has completely different pathogenesis
from acrania/excencephaly.
Prognosis: Anencephaly is a uniformly lethal anomaly.
Other types of cranium bifidum, various neurological
deficits may occur, depending on types and degrees.
Fig. 43.26: Anencephaly in middle gestation. (same case as
Recurrence risk: used to be high recurrence risk of 5- Fig. 43.25). (upper left) US sagittal image at 23 weeks of
13%, however, recently declined by use of folic acid gestation. (upper right) US coronal image. (lower left) 3D US
image. (lower right) External appearances of stillborn fetus at
supplementation and fortification.
25 weeks of gestation. It is clear that excencephalic brain tissue
Obstetrical management: Termination of pregnancy can scattered in the amniotic space compared with this case at 10
weeks
be offered in cases with anencephaly.
Neurosurgical management: For other cranium bifidum, tissue into the intracranial cavity. Ventriculoperitoneal
surgical operation aims at transposition of cerebral shunt for hydrocephalus.
 Fetal Central Nervous System 609
Etiology: Multifactorial inheritance, single mutant
genes, autosomal recessive, chromosomal abnor-
malities (trisomy 18, 13), specific teratogens (valproic
acid), maternal diabetes, environmental factors,
predominant in females
Pathogenesis: Spina bifida aperta; An impairment of
neural tube closure
Spina bifida occuluta: Caudal neural tube mal-
formation by the processes of canalization and
retrogressive differentiation.
Associated anomalies: Chiari type II malformation,
hydrocephalus, scoliosis (above L2), polyhydramnios,
additional non-CNS anomalies,
Prenatal diagnosis: Figure 43.28 to 43.31.

Fig. 43.27: 3D detection of a fetus with iniencephaly and acrania Differential diagnosis: Sacrococcygeal teratoma
at 10 weeks of gestation. (Upper left) Three orthogonal views
of the fetus. Spina bifida (arrow) was desmonstrated in the Prognosis: Disturbance of moter, sensory and sphincter
coronal section. (Lower left) 3D images show the fetal lateral function. Depends on lesion levels. Below S1; enable
and dorsal views. (Right) External appearance of aborted fetus to walk unaided, above L2; wheelchair dependant,
at the end of 11 weeks of gestation. The brain and a part of
spinal cord was detached at delivery
variable at intermediate level.
Recurrence risk: Decreased, almost no recurrence rate43
by use of folic acid supplementation and fortification.
Spina Bifida
Obstetrical management: In case with spina bifida
Prevalence: 0.22/1000 births37, overall neural tube
defect (NTD);0.58-1.17/1000 births 38-40 , Many aperta, especially with defect of skin, cesarean section
reported remarkable reduction of prevalence of NTDs is preferable to protect the spinal cord and nerves and
after using folic acid supplementation and prevent infection.
fortification37-41 Neurosurgical management:
Definition: Spina bifida aperta, manifest form of spina 1. Spina bifida aperta; In cases with defect of normal
bifida is classified into 4 types; meningocele, skin tissue, immediate closure of spina bifida
myelomeningocele, myelocystocele, myeloschisis after birth reduces spinal infection. Spinal cord
Spina bifida occuluta is a generic term of spinal reconstruction is the most important role of
diseases covered with normal skin tissue, and does operation. Miniature Ommaya reservoir
not indicate spinal diseases which cannot be placement and subsequent ventriculoperitoneal
diagnosed by external appearance., cutaneous shunt are required for hydrocephalus (see
abnormalities near the spinal lesion are found; skin Chapter 5). For symptomatic Chiari malfor-
bulge (subcutaneous lipoma), dimple, hair tuft, mation, posterior fossa decompressive craniec-
pigmentation, skin appendage and hemangioma. In tomy and/or tonsillectomy is performed.
case with thickened film terminale, dermal sinus, or 2. Spina bifida occuluta; The aim of surgical
diastematomyelia (split cord malformation), treatment for is decompression of the spinal cord
abnormal tethering and fixation of the spinal cord and cutting off tethering to the spinal cord (Figs
occur. 43.22 to 43.23).
610 Textbook of Perinatal Medicine

Fig. 43.28: Prenatal US image of myelomeningocele, spina

bifida at 20 weeks of gestation. (left) 3D bony demonstration of
lumber spina bifida. 3D ultrasound shows the exact level of
spina bifida. (middle) 3D surface reconstruction of large
myelomeningocele (white arrows). (right) External appearance
of aborted fetus at 21 weeks of gestation. Note the central canal
of the spinal cord (black arrow) in large myelomeningocele
Fig. 43.30: 3D US image of myelomeningocele with kyphosis
at 16 weeks of gestation. Three orthogonal views and surface
reconstruction image. (upper left) Sagittal US image. Spinal
cord completely protrude into the sac surface from spinal canal
and severe kyphosis are seen (upper right) Axial US view .
(lower left) Coronal US view of myelomeningocele. Lower right
figure demonstrates the sagittal vertebral bony structure by
3D thick slice.

Fig. 43.29: Myelomeningocele in early pregnancy. 2D sagittal

view at 9 weeks of gestation (upper left) shows the cystic lesion
(arrow). Three dimensional dorsal views at 9 weeks (lower left)
clearly demonstrate a neural tube defect at the lower lumber
and sacral level (arrowheads). Right figure shows the same Fig. 43.31: 2D sagittal section of myelomeningocele at 19
fetus at 12 weeks of gestation. Arrows indicate the lumbosacral weeks of gestation. The spinal cord (arrow) protrudes from
myelomeningocele spinal canal toward the sac surface of myelomeningocele

Chiari Malformation Definition: Chiari classified anomalies with cerebellar

Prevalence: Depends on prevalence of spina bifida herniation in the spinal canal into three types by
(Chiari type II malformation). According to recent contents of herniated tissue; contents of type I is a lip
remarkable reduction of prevalence of NTDs after of cerebellum, type II part of cerebellum, fourth
using folic acid supplementation and fortification, ventricle and medulla oblongata, pons, and type III
prevalence has declined. Other types are rare. large herniation of the posterior fossa. Thereafter, type
 Fetal Central Nervous System 611
IV with just cerebellar hypogenesis was added. cerebellum through the foramen magnum into the
However, this classification occasinnally leads to upper cervical region, and (4) a variety of bony defects
confusion in neuroimaging diagnosis. Therefore, at of the foramen magnum, occiput, and upper cervical
present, the classification as below is advocated. vertebrae44.
i. Type I: Herniation of only cerebellar tonsil, not
Associated anomalies: Hydrocephalus caused by obs-
associated by myelomeningocele
truction of fourth ventricular outflow or associated
ii. Type II: (Figs 43.6 to 43.61 and 43.62) Herniation aqueductal stenosis. Myelomeningocele or
of cerebellar tonsil and brain stem. Medullary myeloschisis (type II), cephalocele or craniocervical
kink, tentorial dysplasia, associated with meningocele (type III), cerebellar hypogenesis (type
myelomeningocele IV), and syringomyelia (type I).
iii. Type III: Associated with cephalocele or
craniocervical meningocele, in which cerebellum Prenatal diagnosis: Prenatal US diagnosis by features ;
and brainstem herniated. lemon sign which indicates deformity of the frontal
iv. Type IV: Associated with marked cerebellar bone, banana sign which indicates abnormal shape
hypogenesis and posterior fossa shrinking of cerebellum without cisterna magna space (Fig.
43.34), medullary kink (Fig. 43.35), small clivus-
Synonyms: Arnold-Chiari malformation. supraocciput angle45.
Etiology: Depends on the types Differential diagnosis: craniosynostosis,
Pathogenesis: Schematic picture and macroscopic Prognosis: Nearly every case of Myelomeningocele is
findings, MRI images are in Figures 43.32 and 43.33. accompanied morphological Chiari II malformation.
Chiari malformation occurs according to; (1) Inferior Many cases with Chiari II are asymptomatic.
displacement of the medulla and the fourth ventricle However, clinical features due to Chiari malfor-
into the upper cervical canal, (2) elongation and mation, such as feeding disturbances, laryngeal
thinning of the upper medulla and lower pons and stridor or apneic episode, are found in approximately
persistence of the embryonic flexure of these 9-30% of cases. In cases with these clinical features,
structures, (3) inferior displacement of the lower vital prognosis is often poor.

Fig 43.32: Schema and macroscopic finding of Chiari type II malformation. Chiari type II malformation is characterized by
inferior displacement of the lower cerebellum through the foramen magnum with obliteration of the cisterna magna, inferior
displacement of the medulla into the spinal canal, and elongation of the fourth ventricle and aqueduct. Right picture shows the
macroscopic view of the elongated aqueduct, IVth ventricle and cerebellum from the specimen of an aborted fetus at 21 weeks
of gestation
612 Textbook of Perinatal Medicine

Recurrence risk: Depends on types of Chiari malfor-

mation. Decreased according to decline of NTD
recurrence rate by use of folic acid supplementation
and fortification.
Neurosurgical management: Neurosurgical Decom-
pression of foramen magnum (FMD) for any types of
Chiari malformation. Syringo-subarachnoid shunt for
Chiari type I.

Holoprosencephaly
Incidence: 1 in 15,000-20,000 live births, however, initial
incidence may be more than sixtyfold greater in
aborted human embryos45,46.
© Ritsuko K. Pooh, 2003
Classification44 : Holoprosencephalies are classified
Fig. 43.33: MR images of aborted fetuses at 20-21 weeks of
gestation. (left) 20 weeks of gestation. Sacral myelomeningo- into three varieties;
cele (arrowhead) and Chiari type II malformation are demons- i. Alobar type; A single-sphered cerebral structure
trated. (right) 21 weeks of gestation. Lumbosacral myelo- with a single common ventricle, posterior large
meningocele with Chiari type II malformation is seen. This case, cyst of third ventricle (dorsal sac) , absence of
Myelomeningocele is complicated with holoprosencephaly.
olfactory bulbs and tracts and a single optic
Normal karyotype. Severe medullary kink (arrow) is seen
nerve.
ii. Semilobar type; with formation of a posterior
portion of the interhemispheric fissure
iii. Lobar type; with formation of the interhemi-
spheric fissure anteriorly and posterorly but not
in the midhemispheric region. The fusion of the
fornices is seen47.
Etiology: 75% of holoprosencephaly has normal
Fig. 43.34: Chiari type II malformation at 16 weeks of gestation. karyotype, but chromosomes 2, 3, 7, 13, 18 and 21 have
Chiari type II malformation is observed in most cases with been implicated in holoprosencephaly44. Particularly,
myelomeningocele and myeloschisis. (left) Typical lemon sign
(arrows). (middle) Typical banana sign (arrows). (right) 3D trisomy 13 has most commonly been observed.
reconstruction internal image of Chiari type II malformation Autosomal dominant transmission is rare.
(arrows)
Pathogenesis: Failure of cleavage of the prosencephalon
and diencephalon during early first trimester (5-6
Normal
weeks) results in holoprosencephaly.
Associated anomalies: Facial abnormalities such as
cyclopia, ethmocephaly, cebocephaly, flat nose, cleft
lip and palate are invariably associated with
horoprosencephaly. Extraceerebral abnormalities are
also invariably associated, such as renal cysts/
© Ritsuko K. Pooh, 1999
dysplasia, omphalocele, cardiac disease and or
Fig. 43.35: Medullary kink in a case of Chiari II malformation at
19 weeks of gestation. (left) Medullary kink (arrowhead)
myelomeningocele
associated obliterated cisterna magna is demonstrated. (right) Prenatal diagnosis: Alober type in Figure 43.36 and
Comparative normal image in the same cutting section at the
same gestation. The cisterna magna, cerebellum and semilober type in Figures 43.37. Figure 43.38 shows
medullospinal portion are clearly demonstrated facial appearance in cases of holoprosencephaly.
 Fetal Central Nervous System 613

© Ritsuko K. Pooh, 2003

Fig. 43.36: Alober holoprosencephaly at 15 weeks of gestation.
Three orthogonal images of intracranial structure show a Fig. 43.37: Semilober holoprosencephaly at 33 weeks of
complete single ventricle within a single-sphered cerebral gestation. Upper left shows dorsal sac (arrows) in the median
structure section. Upper right demonstrates the fused ventricle . Lower
figures are fetal MR images. Sagittal (left), coronal(middle) and
axial (right) sections A blind end of nasal cavity and
hypotelorism are seen in the sagittal and axial MR images
respectively

Normal 31w

© Ritsuko K. Pooh, 2004

Fig. 43.38: Facial abnormality in cases of holoprosencephaly. Normal 29w

Upper figures are prenatal 3D facial images and lower figures
show postpartum face appearance of each baby. Left; alober Fig. 43.39: Complete agenesis (upper) and hypogenesis (lower)
holoprosencephaly at 20 weeks, Middle and right; semilober of the corpus callosum. All images are transvaginal median
type in late pregnancy. Hypotelorism, exophthalmos are (mid-sagittal) images. Right images are normal images of the
common. Left and middle cases had cleft lip and palate and corpus callosum at the same gestational age as each left image.
obstruction of the nasal cavity. Right case had a single and
obstructed nasal cavity
614 Textbook of Perinatal Medicine

Differential diagnosis: Hydrocephalus, hydranence-

phaly,
Prognosis: Extremely poor in alobar holoprosence-
phaly. Uncertain in lobar type. Various but poor in
semilober type.
Recurrence risk: 6%48, but much lower in sporadic or
trisomy cases, much higher in genetic cases.
Management: Chromosomal evaluation is offered.
Fig. 43.40: Fetal MR images of complete agenesis of the corpus
Agenesis of the Corpus Callosum callosum at 33 weeks of gestation. Anterior coronal section
(left) and median section (right). No communicated bridge is
Prevalence: Uncertain, but 3-7:1,000 in the general seen. Note the bull’s horn like appearance of the anterior horns
population is estimated. of lateral ventricle in the coronal image

Definition: Absence of the corpus callosum, which may

be devided into (complete) agenesis, partial agenesis
or hypogenesis of the corpus callosum.
Complete agenesis: complete absence of the corpus
callosum
Partial agenesis (hypogenesis): absence of splenium or
posterior portion in various degrees.
Etiology: Chromosomal abberation in 20% of affected
cases, such as trisomy 18, 8 and 13. Autosomal
dominant, autosomal recessive, X-linked recessive,
part of mendelian syndromed such as Walker-
Warburg syndrome, and X-linked dominant such as
Aicardi syndrome.
Pathogenesis: Uncertain, but callosal formation may be ACA
associated with migration disorder.
Fig. 43.41: Agenesis of the corpus callosum with abnormal
Associated anomalies: Colpocephaly (ventriculomegaly gyration at 36 weeks of gestation. Upper figure shows the three
with disproportionate enlargement of trigones, orthogonal view of the brain with agenesis of the corpus
callosum with an abnormal gyrus (arrow). Lower left figure is a
occiital horns and temporal horns, not hydrocephaly),
thick slice of the sagittal section. Abnormal gyration (arrow) is
superior elongation of the third ventricle, more clearly demonstrated. Lower right shows the intracranial
interhemnispheric cyst, lipoma of the corpus angiostructure by 3D power Doppler. Normal pericallosal artery
callosum. does not exist and radial formation of the branches of anterior
cerebral arteries (ACA) is seen
Prenatal diagnosis: median sonographic images in
Prognosis: Various. Depends on associated anomalies.
Figures 43.39, 43.41 and fetal MRI in Figure 43.40.
Most cases with isolated agenesis of the corpus
Colpocephaly is shown in Fig. 43.42.
callosum without other abnormalities are asympto-
Diagnosis: As the corpus callosum is depicted after 17 matic and prognosis is good. Complete agenesis has
or 18 weeks of gestation by ultrasound, it is a worse prognosis than partial agenesis50. Epilepsy,
impossible to diagnose agenesis of the corpus intellectual impairment or psychiatric disorder51 may
callosum prior to this age49. occur later on.
 Fetal Central Nervous System 615
Synonyms: de Morsier syndrome (septo-optic
dysplasia)
Etiology: maternal drug (multidrug, valproic acid53,
cocaine 54 ), autosomal recessive, HESX1
55
homeodomain gene mutation
Pathogenesis: May occur as a vascular disruption
sequence, with other prosencephalic or neuronal
migration disorders.
Associated anomalies: Schizencephaly, gyral
abnormalities, heterotopias, hypotelorism,
ventriculomegaly, communicating lateral ventricles,
bilateral cleft lip and palate, hypopituitarism.
Differential diagnosis: dysgenesis of the corpus
© Ritsuko K. Pooh, 2004
callosum, lobar holoprosencephaly
Fig. 43.42: Fetal US and MR images of characteristic ventricular
shape in a case with agenesis of the corpus callosum. Upper Prognosis: Depends on associated anomalies. Variable
left; US axial image, upper right; US parasagittal image. Lower degree of mental deficit, multiple endocrine
left; MR axial image, lower right; MR parasagittal image. Note dysfunction. In cases with isolated absent of septum
the tear-drop appearance of the lateral ventricles in the axial
section. Ventricular appearance in the parasagittal section is pellucidum, prognosis may be good.
called as “colpocephaly” Recurrence risk: unknown
Management: Confirmation of diagnosis after birth is
Recurrence risk: Depends on etiology. Chromo- important for genetic counseling. Endocrine
somal;1%, autosomal recessive;25%, X-linked dysfunction should be searched and corrected. Shunt
recessive male; 50%. procedure in cases with progressive ventriculomegaly.
Management: Standard obstetrical care. Chromosomal
evaluation is offered. In cases with interhemispheric Lissencephaly
cyst, postnatal fenestration or shunt procedure may Incidence: Unknown, rare
be performed.
Definition: Characterized by a lack of gyral
Absent Septum Pellucidum, Septo-optic development and divided into two types :
Lissencephaly type I: a smooth surface of the brain.
Dysplasia
Cerebral wall is similar to that of an approximately
Incidence: Unknown, rare 12-week-old fetus56.
Definition isolated lissencephaly
i. Absent septum pellucidum: Absence of the septum Miller-Dieker syndrome with additional
pellucidum with or without associated craniofacial abnormalities, cardiac anomalies,
anomalies. The septum pellucidum can be genital anomalies, sacral dimple, creases, and/or
destroyed by concomitant hydrocephalus or by clinodactyly.
contiguous ischemic lesions such as Lissencephaly type II: Cobblestone appearance.
porencephaly. . An isolated absent septum Walker-Warburg syndrome with macrocephaly,
pellucidum52 exists but rare. congenital muscular dystrophy, cerebellar
ii. Septo-optic dysplasia: Absence of the septum malformation, retinal malformation
pellucidum and unilateral or bilateral hypoplasia Fukuyama congenital muscular dystrophy with
of the optic nerve. microcephaly and congenital muscular dystrophy
616 Textbook of Perinatal Medicine

Synonyms: Agyria, Pachygyria, Walker-Warburg Etiology: Uncertain. In certain familial case, a point
syndrome was known as HARD±E syndrome mutation in the homeobox gene, EMX2 was found61,62.
(hydrocephalus, agyria, retinal dysplasia, with or Cytomegalovirus infection was also related in some
without encephalocele). cases63.
Etiology: Isolated lissencephaly is link to chromosome Pathogenesis: Neuronal migration disorder.
17p13.3 and chromosome Xq24-q24. Miller-Dieker Associated anomalies: Ventriculomegaly, microcephaly,
syndrome is also link to chromosome 17p13.3. Walker- polymicrogyria, gray matter heterotopias, dysgenesis
Warburg syndrome is autosomal recessive of the corpus callosum, absence of the septum
inheritance. Fukuyama congenital muscular pellucidum, and optic nerve hypoplasia.
dystrophy is link to chromosome 9q31, fukutin57. Differential diagnosis: Porencephaly, arachnoid cyst or
Pathogenesis: Defective neuronal migration with four, other intracranial cystic cystic masses. MR imaging
rather than six, layers in the cortex. is useful in diagnosis of schizencephaly64.
Associated anomalies: Polyhydramnios, less fetal Prognosis: Variable. Generally suffer from mental
movement, colpocephaly, agenesis of the corpus retardation, seizures, developmental delay and motor
callosum, Dandy-Walker malformation, In Miller- disturbances.
Dieker syndrome, micrognathia, flat nose, high Recurrence risk: unknown.
forehead, low-set ears, cardiac anomalies, genital
Management: Ventriculoperitoneal shunt for
anomalies in male are often observed. In Walker-
progressive hydrocephalus.
Warburg syndrome
Prenatal diagnosis: Prenatal diagnosis 58-60 of Dandy-Walker Malformation, Dandy-Walker
lissencephaly without previous history of an affected Variant, Megacisterna Magna
child probably cannot be reliably made until 26 to 28 Incidence: Dandy-Walker malformation has an
weeks’ gestation42. estimated prevalence of about 1:30,000 births, and is
found in 4-12% of all cases of infantile hydro-
Prognosis: Type I; Hypotonia, paucity of movements,
cephalus65. Incidence of Dandy-Walker variant and
feeding disturbance, seizures, The prognosis is poor,
megacisterna magna is unknown.
and death occurs. Type II; Severe seizures, mental
Definition: At present, the term Dandy-Walker
disorders, severe muscle disease with hypotonia.
complex66 is used to indicate a spectrum of anomalies
Death in the first year is common.
of the posterior fossa that are classified by axial CT
Recurrence risk: Depends on etiology. scans as it follows. Dandy-Walker malformation,
Management: Karyotyping is recommended to detect Dandy-Walker variant, and mega-cisterna magna
the chromosomal defect. Standard obstetrical care. seem to represent a continuum of developmental
anomalies of the posterior fossa66.Figure 43.43 shows
Schizencephaly the differential diagnosis of hypoechoic lesion of the
posterior fossa.
Incidence: Rare
i. (classic) Dandy-Walker malformation: cystic dilata-
Definition: A disorder characterized by congenital tion of fourth ventricle, enlarged posterior fossa,
clefts in the cerebral mantle, lined by pia-ependyma, elevated tentorium and complete or partial
with communication between the subarachnoid space agenesis of the cerebellar vermis.
laterally and the ventricular system medially (Figs ii. Dandy-Walker variant: variable hypoplasia of the
43.6 to 43.52). 63% is unilateral and 37% bilateral. cerebellar vermis with or without enlargement
Frontal region in 44% and frontoparietal 30%56. of the posterior fossa
 Fetal Central Nervous System 617

Fig. 43.43: Differential diagnosis of “ hypoechoic lesion” of the

posterior fossa

iii. Megacisterna magna: enlarged cisterna magna

with integrity of both cerebellar vermis and
fourth ventricle
Etiology: Mendelian disorders such as Warburg,
chromosomal aberration such as 45,X, partial
monosomy/trisomy, viral infections and diabetes
Pathogenesis: During development of the fourth
ventricular roof, a delay or total failure of the foramen
of Magendie to open occurs, allowing a buildup of
CSF and development of the cystic dilation of the
fourth ventricle. Despite the subsequent opening of
the foramina of Luschka (usually patent in Dandy-
Walker malformation), cystic dilatation of the fourth
ventricle persists and CSF flow is impaired.
Associated anomalies of Dandy-Walker malformation: Fig. 43.44: Early stage of Dandy Walker malformation at 11
Hydrocephalus. Other midline anomalies, such as weeks of gestation. Abnormal dilatation of the posterior fossa
agenesis of the corpus callosum and holopros- (arrowheads). Upper right figure is a sagittal image at the same
gestational age in a normal case. Amniocentesis revealed
encephaly and occipital encephalocele. Extracranial trisomy 9 mosaicism and the fetus died in utero at 19 weeks
abnormalities such as congenital heart disease , neural
tube defects and cleft lip/palate. A frequency of is preferable. To observe the elevated tentorium,
additional anomalies ranging between 50 and 70%. sagittal section is preferable.
Prenatal diagnosis: DW malformation in Figure 43.44 Differential diagnosis: infratentorial arachnoid cyst,
and 43.46, DW variant in Figure 43.45. To observe the other intracranial cystic tumor, hydrocephalus,
agenesis of the cerebellar vermis, axial cutting section cerebellar dysplasia (Fig. 43.47).
618 Textbook of Perinatal Medicine

©RKPOOH1997
Cerebellar dysplasia

Normal
© Ritsuko K. Pooh, 2002 cerebellum

© Ritsuko K. Pooh, 2003

Fig. 43.47: Cerebellar dysplasia in a case of trisomy 18. (upper
left) Transvaginal median image. Small cerebellum within a
Fig. 43.45: Dandy Walker variant at 20 weeks of gestation. normal size of posterior fossa. (upper middle) Transabdominal
Upper figures show the 2D axial, 2D posterior coronal, 3D thick axial image. (lower left) Fetal MR sagittal image. (lower middle)
slices of oblique coronal and axial sections from the left. MR axial image. (upper right) Macroscopic photograph of
Hypoplasia of the vermis (arrows) is demonstrated and no cerebellar dysplasia in another case of trisomy 18. Compared
marked ventriculomegaly was seen. Lower left figure shows with normal cerebellum shown in a right lower figure, hypo-
the median section. Partial agenesis of the corpus callosum plastic cerebellum is easily identified
(arrowhead), floated celebellum (triangle arrowhead) and cystic
formation of the posterior fossa are seen. Lower right figure
shows the median cutting section of the specimen of an aborted Prognosis: Progressive hydrocephalus, not observed
fetus at 21 weeks of gestation. This case had other complicated in neonates but often progressive during the first one
anomalies and the karyotype was partial trisomy of
month. Cases diagnosed in utero or neonatal period,
chromosome 10
outcome is generally unfavorable. Nearly 40% die,
and 75% of survivors exhibit cognitive deficits.
Prognosis of Dandy-Walker variant is good. Clinical
significance of megacisterna magna is uncertain.
Recurrence risk: Depends on etiology. Generally 1-5%
(Dandy-Walker malformation)
Management: Cystperitoneal shunt, cyst-ventriculo-
peritoneal shunt

Arachnoid Cyst
Prevalence: 1% of intracranial masses in newborns
Definition: Congenital or acquired cyst, lined by
arachnoid membranes, and filled with fluid collection
Fig. 43.46: Dandy walker malformation at 28 weeks of gestation.
Left figure shows the median section of the brain. Corpus
which is the same character as the cerebrospinal fluid.
callosum (CC) is normally demonstrated and Dandy Walker The number of cysts is mostly single, but two or more
cyst (DWC, arrows) is seen in the posterior fossa. Right upper cysts can be occasionally observed. Location of
figure is a 3D view in the posterior coronal section. Hypoplastic arachnoid cyst is various; approximately 50% of cysts
vermis of the cerebellum (arrowhead) is seen. Right lower
figures, three orghogonal views and an extracted ventricular
occurs from the Sylvian fissure (middle fossa), 20%
appearance, demonstrate moderate ventriculomegaly in this from the posterior fossa, and 10-20% each from the
case convexity, suprasellar, interhemisphere, and
 Fetal Central Nervous System 619
quadrigeminal cistern. Interhemisperic cysts are often
associated with agenesis or hypogenesis of the corpus
callosum.
Etiology: Unknown.
Pathogenesis: Congenital arachnoid cyst is formed by
maldevelopment of the arachnoid membrane. CSF
accumulation in the subarachnoid space or
intra-arachnoid layers from a choroid plexus-like
tissue within the cyst wall, leads to a progressive
distension of the lesion.
Associated anomalies: Unilateral or bilateral
© Ritsuko K. Pooh, 2003
hydrocephalus, macrocrania
Fig. 43.48: Fetal arachnoid cyst at 31 weeks of gestation.
Prenatal diagnosis: Figure 43.48 to 43.50. Detection in
(upper) Transvaginal US image. Sagittal (left) and coronal
the first trimester was reported67. (middle, right) sections. (lower left) Fetal MR sagittal image.
The cyst occupies supra- to infratentorial space. Not only
Differential diagnosis: Porencephaly, schizencephaly,
cerebrum but also cerebellum are compressed by the cyst.
third ventriculomegaly, intracranial cystic type tumor, (lower right) Fetal MR coronal image. Midline is conspicuously
vein of Galen aneurysm, Dandy-Walker arcuated. Unilateral scalp and skull bone are extended due to
malformation, large cisterna magna, external the existence of the huge cyst. Note the difference between
right and left head size
hydrocephalus.
Prognosis: Generally good. Postnatally, many are
asymptomatic and remain quiescent for years,
although others expand and cause neurological symp-
toms by compressing adjacent brain, ventriculo-
megaly, and/or expanding the overlying skull.
Recurrence risk: Unknown.
Obstetrical management: Arachnoid cysts may increase
or decrease its size. Therefore, expectant management
of antenatally diagnosed cases is suggested68. In cases
with accompanied hydrocephalus, mode and timing
of delivery may be modified.
Fig. 43.49: Transvaginal US images of middle fossa arachnoid
Postnatal management: In cases with those symptoms cyst at 29 weeks of gestation. (upper) serial coronal sections.
or with prospects of neurological symptoms, (lower) serial sagittal sections. Compressed adjacent cerebrum
treatment should be considered. Operation methods is demonstrated
includes;
• Cyst fenestration by craniotomy Craniosynostosis
• Cyst fenestration by neuroendoscopy
Incidence: unknown
• Cyst-peritoneal shunt
Craniotomy, shunting or neuroendoscopic method Definition: Premature closure of cranial suture, which
has been still controversial69,70. may affect one or more cranial sutures. Simple sagittal
620 Textbook of Perinatal Medicine

Apert syndrome: Brachycephaly, irregular synos-

tosis, especially coronal suture. With midfacial
hypoplasia, syndactyly, broad distal phalanx of
thumb and big toe
Pfeiffer syndrome: Brachycephaly, synostosis of
coronal and/or sagittal sutures. With hyper-
telorism, broad thumbs and toes, partial syn-
dactyly
Antley-Bixler syndrome: Brachycephaly, multiple
synostosis, especially of coronal suture.
With maxillary hypoplasia, radiohymeral synos-
tosis, choanal atresia, arthrogryposis.
Etiology: Crouzon (AD, variable), Apert (AD, usually
new mutation), Pfeiffer (AD), Antley-Bixler (AR). In
five autosomal dominant craniosynostosis syndromes
(Apert, Crouzon, Pfeiffer, Jackson-Weiss and Crouzon
Fig. 43.50: US and MR images of interhemispheric cyst at 24
syndrome with acanthosis nigricans) result from
weeks of gestation. Upper left; US median section, upper right;
US anterior coronal section, lower left; MR median section, lower mutations in FGFR genes71.
right;MR anterior coronal secrion. Cystic lesion exists between
hemispheres. Intracystic cyst is visible on US images Pathogenesis72: (1) cranial vault bones with decreased
growth potential, (2) asymmetrical bone deposition
at perimeter sutures, (3) sutures adjacent to the
synostosis is most common. Various cranial shapes
prematurely fused suture compensate in growth more
depend on affected suture(s).
than those sutures not contiguous with the closed
suture; (4) enhanced symmetrical bone deposition
Sagittal suture Scaphocephaly or occurs along both sides of a non-perimeter suture
dolichocephaly. continuing prematurely closed suture.
Bilateral coronal suture Brachycephaly Associated anomalies: hypertelorism, syndactyly,
Unilateral coronal suture Anterior polydactyly, exophthalmos
plagiocephaly Prenatal diagnosis: Figure 43.51 shows prenatal appea-
Metopic suture Trigonocephaly rance in Apert syndrome and postnatal findings are
Lambdoid suture Acrocephaly shown in Figure 43.52. Abnormal craniofacial appea-
rance can be detected by 2D/3D ultrasound73,74 .
Unilateral lambdoid suture Posterior
plagiocephaly Prognosis: Various. In some of trigonocephaly and
Coronal/lambdoid/metopic syndromic types, prognosis is poor.
or squamous/sagittal suture Cloverleaf skull Recurrence risk: Depends on etiology.
Total cranial sutures Oxycephaly Management: Operative aim of cranioplasty is
improvement of intracranial pressure and cosmetic
Syndromes change.
Crouzon syndrome: acrocephaly, synostosis of
Vein of Galen Aneurysm
coronal, sagittal and lambdoid sutures with ocular
proptosis, maxillary hypoplasia Incidence: rare.
 Fetal Central Nervous System 621
22 w 27w 34w
Pathogenesis: Venous sac most probably represents
persistence of the embryonic median prosencephalic
vein of Markowski, not the vein of Galen, per se75.
Associated anomalies: Cardiomegaly, high cardiac
output, secondary hydrocephalus, macrocrania,
cerebral ischemia (intracranial steal phenomenon),
subarachnoid/cerebral/intraventricular hemorr-
hages.
Prenatal diagnosis: 2D and 3D color/power Doppler
© Ritsuko K. Pooh, 1999 detection is possible.
Fig. 43.51: Prenatal craniofacial appearance of Apert Differential diagnosis: arachnoid cyst, porencephalic
syndrome. (upper) Longitudinal changing appearance of frontal
bossing and low nasal bridge at 22, 27 and 34 weeks of
cyst, intracranial teratoma. Color/power Doppler is
gestation in a case of Apert syndrome. (lower left)Irregular helpful for differential diagnosis.
cranial shape at 20 weeks. (lower middle)Cranial shape at 34
weeks. Note the bilateral indentation. (lower right) Intracranial Prognosis: According to earlier review, outcome did
sagittal US image at 34 weeks. Mild ventriculomegaly is seen not differ between treated and non-treated group and
over 80% of cases died76. However, Recent advances
in treatment have improved outcome, such that 60-
100% survive and over 60% have a good neurological
outcome77,78.
Recurrence risk: Unknown.
Management: Evaluation of the fetal high-output
cardiac state for the proper obstetrical management.
Percutaneous embolization by microcoils is recent
main postnatal treatment and remarkably improved
outcome.

Choroid Plexus Cysts

Fig. 43.52: 3D reconstruction CT and MR images of Apert Incidence: 0.95-2.8% of all fetuses scanned79-81.
syndrome. (The same case as Fig. 43.51). (upper) 3D recons-
Definition: Cysts with fluid collection within the
truction CT. Fusion of bilateral coronal suture and squamous
suture, defect of frontoparietal cranial structure and craniofacial choroids plexus, which may exist unilaterally or
bony dysplasia are recognizable. (lower) Postnatal MR images. bilaterally. They are depicted in the second trimester
Marked shortening of anterior cranial fossa is seen. Mild and usually resolve by the 24th week.
ventriculomegaly and absent septum pellucidum are seen
Etiology: Normal variant, chromosomal aberration
such as trisomy 18 and others.
Definition: Direct arteriovenous fistulas between
choroidal and/or quadrigeminal arteries and an Pathogenesis: Choroid plexus is located within the
overlying single median venous sac. ventricular system and produces cerebrospinal fluid.
Within the choroidal villi, choroid plexus cysts exists,
Synonyms: vein of Galen malformation.
surrounded by the loose stroma of the choroid
Etiology: unknown. plexus82.
622 Textbook of Perinatal Medicine

Prenatal diagnosis: Figure 43.53. Macroscopic photo is

shown in Figure 43.54. It is impossible to distinguish
normal from abnormal karyotypes only by location
and appearance of choroid plexus cyst. Detection of
additional anomalies is important for differential
diagnosis.
Differential diagnosis: intraventricular hemorrhage,
Prognosis: Choroid plexus cysts, per se, are usually
asymptomatic and benign, but rarely, symptomatic
and disturbs CSF flow83,84.Isolated choroids plexus
cysts may be normal variation.
Recurrence risk: Unknown.
Management: Fetal karyotyping examination should
Fig. 43.53: Choroid plexus cysts (CPC) in cases of trisomy 18 be offered if additional abnormalities are found.
(left) and normal karyotype (right). Left figures; three orthogonal
views and inside 3D view of CPC in a case of trisomy 18 at 17
ACQUIRED BRAIN ABNORMALITIES IN UTERO
weeks of gestation. Various additional anomalies were detected.
Right figures; three orthogonal views and inside 3D view of In terms of encephalopathy or cerebral palsy, ‘timing
CPC in a case with normal karyotype at 16 weeks. No additional
of brain insult, antepartum, intrapartum or
abnormalities. Normal postnatal course. Impossible to
distinguish normal from abnormal karyotypes only by location postpartum?’ is one of the serious controversial issues
and appearance of choroid plexus cyst. Detection of additional including medico-socio-legal-ethical problems 85 .
anomalies is important for differential diagnosis. Although brain insults may relate to antepartum
events in a substantial number of term infants with
hypoxic-ischemic encephalopathy, the timing of insult
cannot always be clarified. It is a hard task to give
antepartum evidences of brain injury predictive of
cerebral palsy. Fetal heart rate monitoring cannot
reveal the presence of encephalopathy, and
neuroimaging by ultrasound and MR imaging is the
most reliable modality for disclosure of silent
encephalopathy. In many cases with cerebral palsy
with acquired brain insults, especially, term-delivered
infants with reactive fetal heart rate tracing and good
Apgar score at delivery, are not suspected having
encephalopathy and often overlooked for months or
years. Recent imaging technology has revealed brain
Fig. 43.54: Macroscopic appearance of choroid plexus cyst.
insult in utero.
Arrows indicate the choroid plexus cyst. The specimen was
from an aborted fetus of trisomy 18 at 20 weeks of gestation Brain Tumors
Incidence: Extremely rare
Associated anomalies: In cases of trisomy 18, associated
Definition: Tumors located in the intracranial cavity.
anomalies include growth retardation, congenital
heart diseases such as ventricular septum defect and Histological types: Brain tumors are devided into
double outlet right ventricle, overlapping finger, facial teratoma, most commonly reported and nontera-
anomaly, cerebellar dysplasia and others. tomatous tumor. Nonteratomatous tumors includes
 Fetal Central Nervous System 623
Diagnosis: Intracranial masses with solid, cystic or
mixture pattern with or without visualization of
hypervascularity by ultrasound and fetal MRI.
Brain tumor should be considered in cases with
nexplained intracranial hemorrhage.
Prenatal diagnosis: Prenatal diagnosis of intracranial
tumor and its vascularization by 3D power Doppler
is shown in Figure 43.55.
Differential diagnosis: arachnoid cyst, vein of Galen
aneurysm, porencephaly, schizencephaly,
periventricular leukomalacia, subdural hemorrhage
Prognosis: Fetal demise, stillborn may occur.
Prognosis in neonates is generally poor, but
Fig. 43.55: Ultrasound images and tumoral vascular visualization depends on timing of diagnosis and the histological
by 3D power Doppler in a fetus of intracranial tumor with type of tumor. Choroid plexus papilloma has minimal
interventricular hemorrhage (35 weeks and 5 days of gestation).
(upper) Sagittal, coronal and axial US images. Huge tumor mortality rate and high likelifood of neonatal
(arrowheads) with hemorrhage within the tumor in the fronto- outcome. Mortality rate of teratomas is over 90%,
parietal lobe.complicated with unilateral hydrocephalus with medulloblastoma over 80%. Other tumors have
intraventricular hemorrhage (arrow). (left lower) Oblique sagittal various prognosis.
view from fetal left side. (right lower) Oblique coronal view from
fetal frontal side. Tumor is fed by numerous feeding arteries from Recurrence risk: Unknown.
anterior cerebral artery. Feeder arteries have low resistant flow
waveform. One large vein which drains blood from tumor is visible. Management: Cesarean section may be considered.
The draining vein has pulsatile flow Neurosurgical tumor resection including subtotal
hemispherectomy by craniotomy and chemotherapy
neuroepithelial tumor, such as medulloblastoma, are possible treatments for neonatal tumors. Radiation
astrocytoma, choroids plexus papilloma, choroids therapy is usually not indicated in neonates.
plexus carcinoma, ependymoma, ependymoblastoma,
and mesenchymal tumor such as craniopharyngioma, Subependymal Pseudocysts
sarcoma, fibroma, hemangioblastoma, hemangioma Prevalence: 2.6-5% of all neonates, 1% of premature
and miningoma, and others of lipoma of the corpus newborns, unknown in fetuses
callosum, subependymal giant-cell astrocytoma
Definition: Cystic formation, which is located in the
associated with tuberous sclerosis (often accompanied
caudothalamic groove or in the caudate nucleus,
by cardiac rhabdomyoma).86,87
lateral to the wall of the anterior horns of lateral
Location of tumor: Supratentorial predominance in ventricles.
neonatal tumor. Infratentorial predominance in
Synonyms: Periventricular pseudocysts89,90
medulloblastoma. Choroid plexus papilloma is
located within the lateral ventricles. Etiology: Infection (cytomegalovirus, rubella),
subependymal hemorrhage, metabolic diseases,
Associated abnormalities: Macrocrania or local skull
chromosomal delations (del q6, delp4) cocaine
swelling, epignathus, secondary hydrocephalus,
exposure and others
intracranial hemorrhage, intraventricular
hemorrhage, polyhydroamnios, heart failure by high- Pathogenesis: Cystic cavity is lined by a pseudocapsule,
cardiac output88, hydrops. consisting of aggregates of germinal cells and glial
624 Textbook of Perinatal Medicine

tissue, but no epithelium can be found. Origin of

pseudocysts is uncertain. Maybe cystic matrix
regression or germinolysis.
Associated anomalies: congenital infection such as
cytomegalo virus, congenital heart diseases,
associated CNS abnormalities
Prenatal diagnosis: Figure 43.56.
Differential diagnosis: Periventricular leukomalacia
Prognosis: Good in cases with isolated subependymal
pseudocysts. In cases with accompanied
abnormalities, such as cardiac disease,
cytomegalovirus infection, other intracranial
abnormalities, or cases with atypical pseudocysts,
prognosis may be poor.89-91
Recurrence risk: unknown.
Fig. 43.56: Subependymal cysts (Fetal US images and neonatal
Management: In many cases, cysts regress in several MR images). (upper) Coronal and sagittal images. (middle left)
axial image. (middle right) Anterior coronal section. Note
months afterbirth. Normal obstetrical/neonatal care. bilateral beads-like cystic formation. (lower) MR sagittal, coronal
and axial images at 3 days afterbirth. No neurological symptoms
Porencephaly at the age of one.

Incidence: unknown
Definition: Fluidfilled spaces replacing normal brain
parenchyma and may or may not communicate with
the lateral ventricles or subarachnoid space.
Synonyms: Porencephalic cyst
Etiology: Ischemic episode, trauma92 demise of one
twin, intercerebral hemorrhage, infection,
Pathogenesis: Easy to occur when immature cerebrum
has some factors with propensity of dissolution and
© Ritsuko K. Pooh, 2003
cavitation, (high content of water, myelinated fiber
Fig. 43.57: Fetal US and MR images of porencephaly at 25
bundles, deficient astroglial response). Timing of
weeks of gestation. (upper left) Transvaginal US coronal image.
ischemic injury (maybe as early as second trimester) Defect of parietolateral part of the unilateral cerebrum. This
is strongly related to porencephaly, hydran- case has also absent septum pellucidum. (upper middle)
encephaly93 Parasagittal US image. Porencephalic part is fused with the
unilateral ventricle. Echogenesity of inside ventricular wall
Associated anomalies: intercerebral hemorrhage, indicates intraventricular hemorrhage. (upper right)
interventricular hemorrhage, hydrocephalus Transabdominal US axial image. (lower) Fetal MR images at
the same day. Coronal, parasagittal and axial sections from
Prenatal diagnosis: Figure 43.57. Some cases in utero the left side.
have been reported94,95.
Differential diagnosis: schizencephaly, arachnoid cyst, cyst never causes a mass effect, which is observed in
intracranial cystic tumor, other cysts. Porencephalic cases with arachnoid cyst or other cystic mass lesions.
 Fetal Central Nervous System 625
This condition is acquired brain insult and differen-
tiated from schizencephaly of migration disorder.
Prognosis: Various, depends on timing and size of
lesion. Seizures, neurological deficits, cerebral palsy
often occur96
Recurrence risk: Unknown.
Management: Ventriculoperitoneal shunt if hydro-
cephalus progresses.

Hydranencephaly
Incidence: 1-2.5:10,000 births
© KyongHon Pooh, 2002
Definition: Absence of the cerebral hemispheres and a Fig.43.58: Hydranencephaly. Hydranencephaly is charac-
sac-like structure containing cerebral spinal fluid terized by absence of the cerebral hemispheres with an
surrounding the brainstem and basal ganglia. incomplete or absent falx and a sac-like structure containing
cerebral spinal fluid surrounding the brainstem and basal
Etiology: Ischemic episode, trauma, demise of one ganglia. In this case, tentorium and falx cerebri are recognized.
twin, intercerebral hemorrhage, infection. There are Cerebral cortex is depicted in only a little part of occipital lobe.
several theories but bilateral occlusion of the Brain stem and cerebellum are preserved to be normal. Cause
of hydranencephaly may be obstruction of the bilateral internal
supraclinoid segment of the internal carotid arteries97 carotid arteries. Note the remarkable increase of head
or of the middle cerebral arteries is one of the cause circumference
of subtotal defects of cerebral hemisphere.
Pathogenesis: Easy to occur when immature cerebrum Definition: Hemorrhage, bleeding inside of the
has some factors with propensity of dissolution and cranium. Intracranial hemorrhage includes subdural
cavitation, (high content of water, myelinated fiber hemorrhage, primary subarachnoid hemorrhage,
bundles, deficient astroglial response). Timing of intracerebellar hemorrhage, intraventricular
ischemic injury (maybe as early as second trimester) hemorrhage and intraparenchymal hemorrhage other
is strongly related to porencephaly and hydran- than cerebellar99.
encephaly. Etiology: trauma, alloimmune and idiopathic
Prenatal diagnosis: Recently hydranencephaly from 11 thrombocytopenia, von Willebrand’s disease, specific
weeks of gestation has been reported98. medications (warfarin) or illicit drug (cocaine) abuse,
seizure, fetal conditions including congenital factor-
Associated anomalies: Large head (Fig. 43.58) X and factor-V deficiencies, intracranial tumor, twin-
Differential diagnosis: Massive hydrocephalus, alober twin transfusion, demise of a co-twin, vascular
holoprosencephaly, porencephaly diseases, or fetomaternal hemorrhage, extracorporeal
membrane oxygenation (ECMO)100.
Prognosis: Extremely poor.
Associated anomalies: hydrocephalus, hydran-
Recurrence risk: unknown
encephaly, porencephaly, or microcephaly.
Management: No active treatment. Shunt procedure for
Prenatal diagnosis: Figure 43.59.
progressive increase of infant’s head.
Differential diagnosis: Intracranial tumor
Intracranial Hemorrhage
Prognosis: Poor in premature infants. Apnea, seizures,
Incidence: unknown, rare in utero and other neurological symptoms.
626 Textbook of Perinatal Medicine

low birthweight, associated immature cerebro-

vascular development and lack of appropriate
autoregulation of cerebral blood flow in response to
hypoxic-ischemic insults101.
Pathogenesis: Distinctive and consist primarily of both
focal periventricular necrosis and more diffuse
cerebral white matter injury. Two most common sites
are at the level of the cerebral white matter near the
trigone of the lateral ventricles and around the
foramen of Monro. Volpe93 describes three factors,
such as 1)periventricular vascular anatomical and
physiological factors, 2)cerebral ischemia, 3)intrinsic
vulnerability of cerebral white matter of premature
newborn, are strongly related to PVL.
Fig 43.59: US and MR images in a fetus with cerebral hemorr-
hage and mild ventriculomegaly at 35 weeks of gestation. Prenatal diagnosis: Figure 43.60.
Ultrasound parasagittal (upper left) and anterior coronal (upper
right) images of the brain. Arrows indicate intracerebral
Differential diagnosis: Subarachnoid (periventricular)
hemorrhage. Arrowhead shows a porencephalic part fused with pseudocysts, porencephaly, other intracranial cystic
the lateral ventricle. Lower figures are MR images showing the formation,
same cutting sections as upper US images
Prognosis: Neurological features of PVL in neonatal
period is probable lower limb weakness and as
Recurrence risk: Depends on etiology.
features of long-term sequelae, spastic diplegia,
Management: Ventriculoperitoneal shunt if interectual deficits and visual deficits are observed93.
hydrocephalus progresses.
Recurrence risk: Unknown.
FETAL PERIVENTRICULAR Management: Early rehabilitation.
LEUKOMALACIA (PVL)
Incidence: 25-75% of premature infants at autopsy are
complicated with periventricular white matter injury.
However, clinically, incidence may be much lower. 5
to 10% of infants less than 1500g birth weight. In at
term infants, PVL is very rare.
Definition: Multifocal areas of necrosis found deep in
the cortical white matter, which are often symmetrical
and occur adjacent to the lateral ventricles. PVL
represents a major precursor for neurological and
intellectual impairment, and cerebral palsy in later
life. Fig. 43.60: Fetal PVL (periventricular leukomalacia) at 29 weeks
of gestation. Bilateral wide-spread type PVL(arrows) was seen.
Etiology: birth trauma, asphyxia and respiratory No particular maternal episode existed before and during
failure, cardiopulmonary defects, premature birth/ pregnancy
 Fetal Central Nervous System 627
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implication. Ultrasound Obstet Gynecol. 2002;20:400-2. fetal choroid plexus: morphology and histogenesis. Am
68. Elbers SE, Furness ME. Resolution of presumed J Med Genet 1987 ;27:977-82.
arachnoid cyst in utero. Ultrasound Obstet Gynecol 83. Lam AH, Villanueva AC. Symptomatic third ventricular
1999;14:353-5. choroid plexus cysts. Pediatr Radiol 1992;22:413-6.
69. Ciricillo SF, Cogen PH, Harsh GR, et al: Intracranial 84. Parizek J, Jakubec J, Hobza V, Nemeckova J, Cernoch Z,
arachnoid cysts in children. A comparison of the effects Sercl M, Zizka J, Spacek J, Nemecek S, Suba P. Choroid
of fenestration and shunting. J Neurosurg, 1991;74: 230- plexus cyst of the left lateral ventricle with intermittent
235. blockage of the foramen of Monro, and initial
70. Nakamura Y, Mizukawa K, Yamamoto K, Nagashima T. invagination into the III ventricle in a child.Childs Nerv
Endoscopic treatment for a huge neonatal prepontine- Syst. 1998 ;14:700-8.
suprasellar arachnoid cyst: a case report. Pediatr 85. Pooh RK, Maeda K, Pooh KH. An Atlas of Fetal Central
Neurosurg 2001;35):220-4. Nervous System Disease. Diagnosis and Management.
71. Hollway GE, Suthers GK, Haan EA, Thompson E, David Parthenon CRC Press, London, New York, 2003.
DJ, Gecz J, Mulley JC. Mutation detection in FGFR2 86. Wakai S, Arai T, Nagai M. Congenital brain tumors. Surg
craniosynostosis syndromes. Hum Genet. 1997;99:251- Neurol 21:597-609, 1984.
5. 87. Volpe JJ. Brain tumors and vein of Galen malformation.
72. Delashaw JB, Persing JA, Broaddus WC, Jane JA. Cranial Neurology of the Neuborn (4 th ed) Philadelphia; WB
vault growth in craniosynostosis. J Neurosurg Saunders.2001, pp841-856.
1989;70:159-65. 88. Sherer, D.M., Abramowicz, J.S., Eggers, P.C., Metlay, L.A.,
73. Benacerraf BR, Spiro R, Mitchell AG. Using three- Sinkin, R.A., Woods, J.R. Jr. Prenatal ultrasonographic
dimensional ultrasound to detect craniosynostosis in a diagnosis of intracranial teratoma and massive
fetus with Pfeiffer syndrome. Ultrasound Obstet craniomegaly with associated high-output cardiac
Gynecol. 2000;16:391-4. failure. Am J Obstet Gynecol 1993; 168:97-9.
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89. Lu JH, Emons D, Kowalewski S. Connatal periventricular resonance imaging (MRI) of ischemic brain injury.Prenat
pseudocysts in the neonate. Pediatr Radiol 1992;22(1):55- Diagn. 2001;21:729-36.
8. 96. Scher MS, Belfar H, Martin J, Painter MJ. Destructive
90. Malinger G, Lev D, Ben Sira L, Kidron D, Tamarkin M, brain lesions of presumed fetal onset: antepartum causes
Lerman-Sagie T. Congenital periventricular pseudocysts: of cerebral palsy. Pediatrics. 1991 ;88:898-906.
prenatal sonographic appearance and clinical 97. Stevenson DA, Hart BL, Clericuzio CL. Hydran-
implications. Ultrasound Obstet Gynecol. 2002 encephaly in an infant with vascular malformations. Am
Nov;20(5):447-51. J Med Genet 2001 15;104:295-8.
91. Bats AS, Molho M, Senat MV, Paupe A, Bernard JP, Ville 98. Lam YH, Tang MH. Serial sonographic features of a fetus
Y. Subependymal pseudocysts in the fetal brain: prenatal with hydranencephaly from 11 weeks to term.
diagnosis of two cases and review of the literature.
Ultrasound Obstet Gynecol 2000 ;16:77-9.
Ultrasound Obstet Gynecol. 2002 Nov;20(5):502-5.
99. Sherer DM, Anyaegbunam A, Onyeije C. Antepartum
92. Eller KM, Kuller JA. Porencephaly secondary to fetal
fetal intracranial hemorrhage, predisposing factors and
trauma during amniocentesis. Obstet Gynecol.
1995;85:865-7. prenatal sonography: a review. Am J Perinatol
93. Volpe JJ. Hypoxic-Ischemic Encephalopathy: Neuro- 1998;15:431-41.
pathology and pathogenesis. Neurology of the Neuborn 100. Hardart GE, Fackler JC. Predictors of intracranial
(4th ed) Philadelphia; WB Saunders.2001, pp296-330. hemorrhage during neonatal extracorporeal membrane
94. Meizner I, Elchalal U. Prenatal sonographic diagnosis oxygenation. J Pediatr 1999;134:156-9.
of anterior fossa porencephaly. J Clin Ultrasound. 101. Rezaie P, Dean A. Periventricular leukomalacia,
1996;24:96-9. inflammation and white matter lesions within the
95. de Laveaucoupet J, Audibert F, Guis F, Rambaud C, developing nervous system. Neuropathology
Suarez B, Boithias-Guerot C, Musset D. Fetal magnetic 2002;22:106-32.
 44
Ultrasound of the Fetal Thorax

Ashok Khurana

INTRODUCTION social and legal need for informed parental counseling

Technological advances in transducer and software have placed a new responsibility on the shoulders of
technology have in recent years remarkably the practicing ultrasonologist.
improved visualization of structures in the fetal There is now a pressing demand for an accurate
thorax (Figs 44.1 to 44.4) way beyond the minimum diagnosis, the formulation of a prognosis and the
requirement recommended by the American Institute institution of appropriate management whether it be
of Ultrasound in Medicine1 over the last few decades. expectant observation, in-utero therapy or a referral
Additionally, novel methods of in-utero treatment, to a tertiary care centre.
the evolution of neonatal surgical techniques and This presentation reviews current concepts in the
anesthesia, the newer understanding of the natural evaluation of the fetal thorax (excluding cardiac
course of several malformations and the pressing conditions).

Fig. 44.1 Fig. 44.2

632 Textbook of Perinatal Medicine

Fig. 44.3 Fig. 44.4

EMBRYOLOGY surfactant. From late fetalhood and upto childhood,

squamous epithelium forms and alveoli continue to
A knowledge of the embryology of the thoracic
form after birth.3
viscera is imperative to understand the outcome of
congenital thoracic malformations and their direct
SONOANATOMY OF THE FETAL THORAX
bearing on fetal lung developments and ultimate fetal
and neonatal outcomes. The fetal thorax extends from the clavicles to the
Development of the lung begins at 5 weeks.2 The fetal diaphragm. The diaphragm is continuous, thin
epithelium of the respiratory system develops from and hypoechoic (Fig. 44.5) and moves with
endoderm. The connective tissue, cartilage and respiratory movements in the third trimester of
muscle develop from splanchnic mesoderm and pregnancy. The thorax is bounded by the sternum
neural crest cells. anteriorly, the spine posteriorly and the ribs
At 26 days the foregut evaginates to form a
laryngotracheal diverticulum. This then gets
separated from the foregut by longitudinal folds
which progress to form the tracheoesophageal
septum. The lungs develop in four stages. From 5-
17 weeks all elements are developed except those
involved in gas exchange. This is also called the
pseudoglandular period. From 16-25 weeks
(canalicular period) the lumen of bronchi and
bronchioles become larger, and, respiratory
bronchioles and alveolar ducts develop. Some
terminal sacs develop and the tissue becomes more
vascular. From 25 weeks to birth, many more terminal
sacs develop, the epithelium becomes very thick,
capillaries bunch into alveoli, Type I alveolar cells
develop, and, Type II alveolar cells begin producing Fig. 44.5
 Ultrasound of the Fetal Thorax 633

Fig. 44.7

reduced number of alveoli.9 PH is rarely primary

and rarely unilateral.10, 11 It is usually secondary and
consequent to any prolonged severe oligoamnios,12,
13, 14, 15
in skeletal dysplasias with a small bony thorax,
in sizable intrathoracic masses,16, 17 consequent to
neuromuscular dysfunction as in the Pena-Shokeir
Fig. 44.6 Syndrome, 18 in Trisomy 12, 18 and 21 and in
conditions with decreased pulmonary artery
circumferentially. The heart is the most prominent
perfusion.19
structure in the thorax. The lungs are seen to surround
Thoracic perimeter (TP) measurements20, 21, 22, 23
it. The left lung is limited in its extent by the heart
(Fig. 44.8) are made at the level of the four-chamber
(Fig. 44.6). The lungs are homogeneously echogenic
view and should exclude the soft tissue areas beyond
and largely isoechoic with other mediastinal
the ribs. The thoracic perimeter/ abdominal perimeter
structures. The heart occupies one third to one half
ratio 24, 25, 26 is steady through the late second
of the thorax and its location and axis are important
trimester and in the third trimester: >0.80. Lung
to identify and evaluate non-cardiac conditions as
lengths 27 although well studied (Fig. 44.9) are not
well. Cardiac and mediastinal shifts have a
easily reproducible. Fetal lung volumes by 3D
tremendous bearing on the prognosis of a chest lesion.
No fluid is seen in normal pleural spaces. The pleural
and pericardial space should be evaluated to assess
for hydrops, which again, is a prognostic factor in
the assessment of a chest mass. With some effort and
resort to color flow mapping (Fig. 44.7) and power
Doppler studies, the aortic arch, pulmonary artery,
ductus arteriosus, pulmonary veins, the trachea,
esophagus and the thymus can be adequately
evaluated. 4, 5, 6

PULMONARY HYPOPLASIA (PH)

Adequate lung development is central to fetal
viability. 7, 8 Hypoplastic lungs show a low lung to
body weight ratio and histologically demonstrate a Fig. 44.8
634 Textbook of Perinatal Medicine

Fig. 44.9

Fig. 44.10
reconstruction techniques (Fig. 44.10) are reliable and
reproducible.28, 29
The pathogenesis of pulmonary hypoplasia myxoma and fibroma,38, 39, 40 esophageal duplication
commences with either inadequate thoracic space for cysts,41 enteric cysts41 and neurenteric cysts,42, 43, 44
growth, inadequate breathing movements of and thoracic neuroblastoma. Mediastinal lesions are
whatever cause, inadequate fluid within the lung and rare but important in the perspective of a differential
suboptimal quantities of amniotic fluid. 30 Lung diagnosis of a mass adjacent to the mediastinum but
echogenicity does not correlate with lung maturity. arising from the adjacent lung or from the abdomen.

GENERAL FEATURES OF CHEST MASSES CONGENITAL DIAPHRAGMATIC HERNIA (CDH)

Not all lung masses can be delineated in the 18-20 CDH has an incidence of 1-4.5/10,000 live births.45
weeks anomalies scan although embryologically they The incidence is higher in the fetus and a fair number
do exist.31, 32 Depending on their size and growth are lost in utero or in the neonatal period prior to
they result in unilateral or bilateral hypoplasia of the clinical identification. CDH is more common on the
lungs. Prognosis depends on the size of the lesion, left side but not infrequently right sided or bilateral.
heart and mediastinal displacements, presence of The diaphragm forms between the 6th to 14th week
hydrops, associated structural anomalies, underlying of pregnancy by fusion of the septum transversum,
chromosomal abnormalities and the bearing of pleuroperitoneal membranes, mesentery of the
associated polyhydramnios on preterm premature esophagus and the body wall. Failure of fusion
rupture of membranes and prematurity.33, 34, 35 especially of the pleuroperitoneal membranes results
Common chest masses include congenital in a herniation of abdominal contents into the thorax
diaphragmatic hernia (CDH) and congenital cystic when the gut returns to the abdomen. The disorder
adenomatoid malformations (CCAM). Other lung is progressive and the organs that herniate include
masses include bronchogenic cysts, neurenteric cysts, the stomach, liver, spleen, small bowel and colon.
congenital lobar emphysema (CLE), bronchial atresia, Left sided CDH usually involves the stomach. Right
pulmonary gigantism, bronchopulmonary sided CDH usually involves herniation of the liver.
sequestration (BPS) and mediastinal masses. The The herniation may be small, isoechoic and
mediastinal lesions include teratomas,36 thymomas,37 intermittent46 and therefore go unrecognised except
goiter, cardiac lesions such as rhabdomyoma, when the problem is specifically looked for. Over
 Ultrasound of the Fetal Thorax 635

Fig. 44.11

four of five fetuses die in the neonatal period usually

Fig. 44.12
because of pulmonary hypoplasia and pulmonary
hypertension. Pulmonary hypertension is consequent
to poorly understood but well documented medial
wall muscular hypertrophy of the small pulmonary
arteries extending upto the preacinar vessels.
Newborns have a high incidence of feeding problems,
gastroesophageal reflux, chronic lung disease and
neurodevelopmental delays.45, 47 Sonographic signs48
include a low abdominal perimeter, failure to
visualize the fetal stomach in the fetal abdomen (Fig.
44.11), visualisation of the herniated viscera in the
thorax (Fig. 44.12 and Fig. 44.13), cardiomediastinal
shift, pleural effusions and hydrops. There may also
be failure to delineate the diaphragm in its entire
extent. Right sided hernias are difficult to identify Fig. 44.13
because of isoechoic lung and these should be
evaluated by color Doppler to confirm the portal vein
location in the thorax (Fig. 44.14 and Fig. 44.15).
Although identification of the liver is not critical for
a diagnosis of CDH, it has a major bearing on the
prognosis.49, 50 This is so because after surgical repair
the ductus venosus and umbilical vein often get
kinked or compromised thereby contributing to
morbidity and often mortality. When bowel segments
are not fluid-filled as is common in the second
trimester, they may appear as a non-specific chest
mass (Fig. 44.16). Careful real time scanning would
reveal peristalsis in the third trimester. Occasionally
a gall bladder may be seen in the CDH. Bilateral
hernias may be difficult to detect because of no Fig. 44.14
636 Textbook of Perinatal Medicine

Fig. 44.17

Fig. 44.15

Fig. 44.16 Fig. 44.18

Fetal therapy has found a reasonable place in the

cardiomediastinal shift. Ascites within an herniation treatment of CDH.57 The aim of surgery is to prevent
may be mistaken for a pleural effusion. lung hypoplasia. Although fetal therapy initially
Not all fetuses with a CDH have a poor involved reduction of the hernia by open repair in
prognosis.51, 52, 53, 54 Prognosis depends on gestational utero, current practice involves clipping of the
age at diagnosis, particularly if 24 weeks or earlier, trachea. Currently, videofetoscopic techniques are
large size, dilated stomach, presence of the liver, even under evaluation. Tracheal occlusion results in
its left lobe in left sided lesions, small contralateral increased lung volume and accelerated lung maturity
lung, bilateral herniation (Fig. 44.17) and the presence similar to the pathophysiology seen in laryngeal and
of associated anomalies (Fig. 44.18). Because of the tracheal atresia. 58
higher incidence of CDH in certain syndromes, a
CONGENITAL CYSTIC ADENOMATOID
facial and cardiac survey merit special attention.
MALFORMATIONS (CCAM)
These syndromes include Trisomy 18, Fryn’s, Lethal
pterygium, Beckwith-Wiedemann, Cornelia De CCAMs occur consequent to failure of induction of
Lange, Apert’s, and Goldenhahr.55, 56 mesenchyme by bronchiolar epithelium. Lack of
 Ultrasound of the Fetal Thorax 637
normal cellular development is considered to be (Fig. 44.22) Prognosis depends on associated
consequent to focal bronchial atresia. The lesion is pulmonary hypoplasia, pulmonary hypertension,
hamartomatous and characterised by focal abnormal hydrops, associated anomalies, polyhydramnios and
proliferation of bronchiolar like air spaces and absence prematurity. Microcystic lesions are more likely to
of alveoli.59 It is usually unilateral. Some may be cause pulmonary hypoplasia and hydrops. The
associated with sequestration in the same lung. arterial supply is via a pulmonary artery and drainage
Diagnosis depends on the demonstration of a mass into a pulmonary vein. Treatment of the lesion
in the thorax.60 This may be macrocystic (cysts 02-10 consists of expectant management, monitoring for
mm) (Fig. 44.19), microcystic (cysts 0.3-0.5 mm) (Fig. hydrops or premature/ term delivery followed by
44.20) or mixed.31, 32 (Fig. 44.21) These may cause a lobectomy if necessary.33 Referral to a tertiary care
cardiomediastinal shift, ipsilateral and contralateral centre is important because emergency thoracic
lung compression, pulmonary hypoplasia and surgery is often needed. Recurrence is rare in later
hydrops. The lesion may regress spontaneously.61 pregnancies. Since Klinefelter’s syndrome and

Fig. 44.19 Fig. 44.20

Fig. 44.21 Fig. 44.22

638 Textbook of Perinatal Medicine

Trisomy 18 are known for an association with

CCAMs, it is appropriate to obtain a karyotype when
the condition is diagnosed.
In utero aspiration of a larger cyst, thoraco-
amniotic shunting of a larger cyst and in utero
resections have been attempted and are methods of
gaining time to achieve viability. In utero resection
has been tried only in fetuses with the poorest
prognosis since the procedure itself carries a high
morbidity and mortality.

Bronchopulmonary Sequestration (BPS)

Also known as pulmonary sequestration and
accessory lung, BPS is a congenital malformation
consisting of lung parenchyma which is separated
from normal lung. It receives arterial supply of
systemic origin and does not communicate with the
normal tracheobronchial tree. Sequestrations arise
Fig. 44.23
from a supernumerary anomalous outpouching of the
foregut. If these arise prior to closure of the pleura
they have no separate pleural envelope and are called
intralobar sequestrations. If these originate after
closure of the pleura they are called extralobar
sequestrations and have their own pleura. Intralobar
sequestrations drain into pulmonary veins and
extralobar sequestrations usually drain into a
systemic vein, usually the azygos, hemiazygos or Fig. 44.24
inferior vena cava. Extralobar sequestrations may be
thoracic or extrathoracic and may even communicate sequestrations are likely to resolve. Persistent
with the esophagus. 62 They are occasionally sequestrations may stabilise or may need surgical
associated with other thoracic and foregut anomalies resection (postnatal).
such a CDH, CCAMs, bronchogenic cysts and
Bronchogenic Cysts
neurenteric cysts. A wide variety of extrapulmonary
anomalies including congenital heart disease, renal These arise as a consequence of abnormal foregut
anomalies and hydrocephalus have been reported budding and show variable echogenicity and variable
to coexist with sequestrations. Many sequestrations progress. They may be mediastinal or peripheral and
show extensive subpleural lymphatics which account often show associated foregut malformations and
for ipsilateral pleural effusions. Typical sonographic hemivertebrae. The usual manifestation is an
appearances63 include a lobar or triangular echogenic echogenic lesion representing fluid filled lung
lesion in the lung base, usually left basal (Fig. 44.23). beyond the stenosis. The left upper lobe is the most
Color Doppler studies reveal a systemic arterial frequent site. Occasionally these are multiple. These
supply64 (Fig. 44.24). There is a variable mediastinal are usually innocuous and do not require specific
shift and hydrops. Several sequestrations regress obstetric management. Their importance lies in being
spontaneously.65 No specific features indicate which one of the differential diagnoses of a fetal lung mass.60
 Ultrasound of the Fetal Thorax 639
Laryngeal and Tracheal Atresia
These are rare congenital anomalies which are
associated with demise soon after birth, unless
treated antenatally. These arise consequent to either
subglottic laryngeal atresia, tracheal stenosis or
atresia, or, tracheal webs or cysts and are also known
as Congenital High Airways Obstruction (CHAOS).
Embryologically, persistent fusion of the sixth
branchial arches is apparently involved. Patho-
logically, failure of efflux of fluid from the fetal lung
results in exaggerated lung development. Ultra-
sound features66, 67 include symmetric enlargement
of both lungs (Fig. 44.25) with anterior displacement
of the heart. The lungs are homogeneously echogenic, Fig. 44.25
often similar to autosomal recessive infantile
polycystic kidneys, since the underlying lesion
consists of numerous fluid-filled spaces. The
diaphragm is flat or inverted and cutaneous edema
is common as is hydrops. Polyhydramnios is seen
consequent to esophageal compression. The distal
trachea and bronchii may be identified as tubular
bulging fluid laden structures in the mediastinum.
Over half the fetuses with this abnormality have renal
agenesis, facial anomalies and central nervous system
malformations. To salvage a fetus with this anomaly
it is necessary to establish a functional airway before
the fetus is removed from placental support.68
Fig. 44.26

Congenital Lobar Emphysema (CLE)

Although this condition has clinical manifestations
in the pediatric age group, it can be seen in the fetus
as a solid lung mass akin to a microcystic CCAM or
an ELS. It is usually located in the upper lobe unlike
ELS. There is one case report of a spontaneous
regression after indomethacin treatment.69

Pleural Effusion
Unlike a small amount of pericardial fluid which may
be physiological, a fetal pleural fluid collection is
always abnormal.
Fig. 44.27
Primary pleural effusions are accumulations of
pleural fluid which may be idiopathic (Fig. 44.26 and malformations70. They are unilateral, or, if bilateral
Fig. 44.27) or consequent to thoracic duct then markedly asymmetric. Mediastinal shifts are
640 Textbook of Perinatal Medicine

Stage of Lung Development Time period/ airway epithelium Characteristic Changes Anomalies or connective
tissue development

Embryonic 3-6 weeks • Ventral outpouching of • Tracheoesophageal fistula

4 weeks: primitive laryngotracheal diverticulum • Sequestration
epithelial cells from foregut • Laryngeal atresia
• Asymmetric dichotomous • Neurenteric cyst
branching to form main stem • Esophageal duplication
bronchii • Bronchogenic cyst
• 6-7 weeks: vascular connection • Lung agenesis
with atria

Pseudoglandular 5-17 weeks • Continued airways branching • Laryngeal/tracheal/

8 weeks: neurosecretory upto terminal bronchioles bronchial atresia
cells appear • Appearance of mucus • Congenital cystic adeno-
10-12 weeks: presecretory glands and cartilage matoid malformation
and preciliated • Smooth muscle and epithelial • Diaphragmatic hernia
14 weeks: ciliated cells, cell differentiation • Sequestration
neuroepithelial bodies • Closure of pleural and
peritoneal cavities

Canalicular 16-25 weeks • Respiratory bronchioles • Lung hypoplasia

20-22 weeks: pre-clara cells • Capillary bed comes in
24 weeks: Type I and Type II close apposition with
24-26 weeks: clara cells airway tubules
• General thinning of both
mesenchyme and epithelium
• Surfactant protein begins
to be expressed at the end of
this stage

Saccular 26-36 weeks

True alveolar surfactant • Secondary crests subdivide • Lung hypoplasia
saccules
• First true alveoli at about
36 weeks
• Maturation of epithelium—
Type II cells
• Flattening of Type I cells

Alveolar 36 weeks – 3 years • Septation of alveoli and

increasing size
• Growth of capillary network
matching alveoli formation
• 85% of alveoli form postnatally
 Ultrasound of the Fetal Thorax 641
prevention of pulmonary hypoplasia, the possibility
of spontaneous regression and referral to a tertiary
care centre. Ultrasound guided interventions in such
a fetus would include amniocentesis or cordocentesis
for a complete diagnosis, and, from a therapeutic
viewpoint, cyst aspiration, thoracentesis or a thoraco-
amniotic shunt.

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echocardiography: VI. Assessment of cardiothoracic J Ultrasound Med 10:287, 1991.
disproportion – A new technique for the diagnosis of 37. de Miguel Campos E, Casanova A, Urbano J, et al:
thoracic hypoplasia. Am J Obstet Gynecol 155:1066, 1986. Congenital thymic cyst: Prenatal sonographic and
22. Songster GS, Gray DL, Crane JP: Prenatal prediction of postnatal magnetic resonance findings. J Ultrasound
lethal pulmonary hypoplasia using ultrasonic fetal chest Med 16:365, 1997.
circumference. Obstet Gynecol 73:261, 1989. 38. Gushiken BJ, Callen PW, Silverman NH: Prenatal
23. Chitkara U, Rosenberg J, Chervenak FA, et al: Prenatal diagnosis of tuberous sclerosis in monozygotic twins
sonographic assessment of the fetal thorax: Normal with cardiac masses. J Ultrasound Med 18:165, 1999.
values. Am J Obstet Gynecol 156:1069, 1987. 39. Green KW, Bors-Koefoed R, Pollack P, et al:
24. Vintzileos AM, Campbell WA, Rodis JF, et al: Antepartum diagnosis and management of multiple fetal
Comparison of six different ultrasonographic methods cardiac tumors. J Ultrasound Med 10:697, 1991.
for predicting lethal fetal pulmonary hypoplasia. Am J 40. Schmaltz AA, Apitz J: Primary heart tumors in infancy
Obstet Gynecol 161:606, 1989. and childhood. Report of four cases and review of
25. D’Alton M, Mercer B, Riddick E, et al: Serial thoracic literature. Cardiology 67:12, 1981.
versus abdominal circumference ratios for the prediction 41. Reed JC, Sobonya RE: Morphologic analysis of foregut
of pulmonary hypoplasia in premature rupture of the cysts in the thorax. AJR Am J Roentgenol 120:851, 1974.
membranes remote from term. Am J Obstet Gynecol 42. Fernandes ET, Custer MD, Burton EM, et al: Neurenteric
166:658, 1992. cyst: Surgery and diagnostic imaging. J Pediatr Surg
26. Yoshimura S, Masuzaki H, Gotoh H, et al: 26:108, 1991.
Ultrasonographic prediction of lethal pulmonary 43. Macualay KE, Winter TC III, Shields LE: Neurenteric cyst
hypoplasia: Comparison of eight different shown by prenatal sonography. AJR Am J Roentgenol
ultrasonographic parameters. Am J Obstet Gynecol 169:563, 1997.
175:477, 1996. 44. Wilkinson CC, Albanese CT, Jennings RW, et al: Fetal
27. Roberts AB, Mitchell JM: Direct ultrasonographic neurenteric cyst causing hydrops: Case report and
measurement of fetal lung length in normal pregnancies review of the literature. Prenat Diagn 19:118, 1999.
and pregnancies complicated by prolonged rupture of 45. Katz Al, Wiswell TE Baumgart S: Contemporaries
membranes. Am J Obstet Gynecol 163:1560, 1990. controversies in the management of congenital
28. D’Arcy TJ, Hughes SW, Chiu WS, et al: Estimation of diaphragmatic hernia. Clin Perinatol 25:219, 1998.
fetal lung volume using enhanced 3-dimensional 46. Lewis DA, Reickert C, Bowerman R, et al: Prenatal
ultrasound: A new method and first result. Br J Obstet ultrasonography frequently fails to diagnose congenital
Gynecol 103:1015, 1996. diaphragmatic hernia. J Pediatr Surg 32: 352, 1997.
 Ultrasound of the Fetal Thorax 643
47. Bernbaum J, Schwartz IP, Gerdes M, et al: Survivors of 60. Mayden KL, Tortora M, Chervenak FA, et al. The
extracorporeal membrane oxygenation at 1 year of age. antenatal sonographic detection of lung masses. Am J
The relationship of primary diagnosis with health and Obstet Gynecol 148:349, 1984.
neurodevelopmental sequelae. Pediatrics 96:907, 1995. 61. Budorick NE, Pretorius DH, Leopold GR, et al:
48. Guibaud L, Filiatrault D, Garel L, et al: Fetal congenital Spontaneous improvement of intrathoracic masses
diaphragmatic hernia: Accuracy of sonography in the diagnosed in utero. J Ultrasound Med 11:653, 1992.
diagnosis and prediction of the outcome after birth. AJR. 62. Gerle RD, Jaretzki AD, Ashley CA, et al: Congenital
Am J Roentgenol 166:1195, 1996. bronchopulmonary-foregut malformation. Pulmonary
49. Albanese CT, Lopoo J, Goldstein RB, et al: Fetal liver sequestration communicating with the gastrointestinal
position and perinatal outcome for congenital tract. N Engl J Med 278: 1413, 1968.
diaphragmatic hernia. Prenat Diagn 18:1138, 1998. 63. Lopoo JB, Albanese CT, Goldstein RB, et al: Fetal
50. Bootstaylor BS, Filly RA, Harrison MR, et al: Prenatal pulmonary sequestration: A favorable cystic lung lesion.
sonographic predictors of liver herniation in congenital Obstet Gynecol 94:567, 1999.
diaphragmatic hernia. J Ultrasound Med 14:515, 1995. 64. Hernanz-Schulman M, Stein SM, Neblett WW, et al:
51. Dommergues M, Louis-Sylvestre C, Mandelbrot L, et Pulmonary sequestration: Diagnosis with color Doppler
al: Congenital diaphragmatic hernia: Can prenatal sonography and a new theory of associated
ultrasonography predict outcome? Am J Obstet Gynecol hydrothorax. Radiology 180:817, 1991.
174:1377, 1996. 65. Langer B, Donato L, Riethmuller C, et al: Spontaneous
52. Geary MP, Chitty LS, Morrison JJ, et al: Prenatal regression of fetal pulmonary sequestration. Ultrasound
outcome and prognostic factors in prenatally diagnosed Obstet Gynecol 6:33, 1995.
congenital diaphragmatic hernia. Ultrasound Obstet 66. Scott JN, Trevenen CL, Wiseman DA, et al: Tracheal
Gynecol 12:107, 1998. atresia: Ultrasonographic and pathologic correlation. J
53. Sharland GK, Lockhart SM, Heward AJ, et al: Prognosis Ultrasound Med 18:375, 1999.
in fetal diaphragmatic hernia. Am J Obstet Gynecol 166:9, 67. Choong KKL, Trudinger B, Chow C, et al: Fetal
1992. laryngeal obstruction: Sonographic detection.
54. Losty PD, Vanamo K, Rintala RJ, et al: Congenital Ultrasound Obstet Gynecol 2:357, 1992.
diaphragmatic hernia – Does the size of the defect 68. DeCou JM, Jones DC, Jacobs HD, et al: Successful ex
influence the incidence of associated malformations? J utero intrapartum treatment (EXIT) procedure for
Pediatr Surg 33:507, 1998. congenital high airway obstruction syndrome (CHAOS)
55. Sheffield JS, Twickler DM, Timmons C, et al: Fryns owing to laryngeal atresia. J Pediatric Surg 33:1563, 1998.
syndrome: Prenatal diagnosis and pathologic 69. Richards DS, Langham MR Jr, Mahaffey SM: The
correlation. J Ultrasound Med 17:585, 1998. prenatal ultrasonograhic diagnosis of cloacal exstrophy.
56. Harrison MR, Adzick NS, Estes JM, et al: A prospective J Ultrasound Med 11:507, 1992.
study of the outcome for fetuses with diaphragmatic 70. Longaker MT, Laberge JM, Dansereau J, et al: Primary
hernia. JAMA 271:382, 1994. fetal hydrothorax: Natural history and management. J
57. Geary M: Management of congenital diaphragmatic Pediatr Surg 24:573, 1989.
hernia diagnosed prenatally: An update. Prenat Diagn 71. Benaceraff BR, Frigoletto FD Jr: Mid-trimester fetal
18:1155, 1998. thoracentesis. J Clin Ultrasound 13:202, 1985.
58. Silver MM, Thurston WA, Patrick JE: Perinatal 72. Wilkins Haug LE, Doubilet P: Successful thoracoamniotic
pulmonary hyperplasia due to laryngeal atresia. Hum shunting and review of the literature in unilateral pleural
Pathol 19:110, 1988. effusion with hydrops. J Ultrasound Med 16:153, 1997.
59. Moerman P, Fryns JP, Vandenbergthe K, et al: 73. Weber AM, Philipson EH: Fetal pleural effusion: A
Pathogenesis of congenital cystic adenomatoid review and meta-analysis for prognostic indicators.
malformation of the lung. Histopathology 21:315, 1992. Obstet Gynecol 79:281, 1992.
644 Textbook of Perinatal Medicine

45 Three-Dimensional Ultrasound of
Blood Flow in the
Fetal Cardiovascular System
R Chaoui

INTRODUCTION possibilities of 3D ultrasound of the cardiovascular

system in normal and abnormal pregnancies, looking
In the recent five years three-dimensional ultrasound
for possible future applications of this method in
moved from a toy of advertisement with the
prenatal diagnosis.
highlight of baby facing to a new powerful diagnostic
tool in prenatal medicine. This was mainly achieved
TECHNICAL BACKGROUND
by the development of fast processors enabling rapid
3D-image acquisition and the advent of new software The main aspects that have to be considered when
allowing new 3D image display. evaluating a three-dimensional imaging system are
The use of color and power Doppler ultrasound a) the volume data acquisition, b) the image rendering
in the nineties improved the prenatal diagnosis of display.
malformations involving the cardiac and vascular
system. 1-3 Malformations of the cardiovascular Volume Data Acquisition
system are often complex and difficult to understand The acquisition of a volume with information of the
when only gray-scale imaging is used. Two- fetal heart or the fetal vessels can be achieved either
dimensional color or power Doppler ultrasound can in 3D static mode, that means a volume consisting of
help in a better assessment of fetal abnormalities, a series of still images or in 4D mode, which reflects
but they generally enable the visualization of only the beating character of the heart. The latter can be
those vessels with a straight course or lying in a two- acquired either in live real-time 3D or as off-line 4D,
dimensional plane.4-6 In most cases the examiner is which was possible recently by the advent of the
reconstructing mentally a spatial image of the new software of spatial and temporal image
examined vessels.5 correlation (STIC).12,13 In these acquisitions heart and
In the recent years few cases reports and studies vessels can be visualized either on gray scale mode,
demonstrated that the 3D power Doppler ultrasound or in combination with color Doppler 14 , power
(3D-PDU) helps in the reconstruction of the vessels Doppler or B-flow. The acquisition of a volume with
of interest and thus improves the understanding of gray scale information is reduced to the demons-
the spatial appearance of the vascular tree.4,7,8 Images tration of the lumen of the heart or the vessels,
produced were very similar to results known from whereas in Doppler or B-Flow techniques blood flow
radiology acquired either by X-ray 9-11 or MR- is visualized. To acquire a volume with a potentially
angiography. This chapter aims to present the actual good 3D/4D image the examiner should spend time
Three-dimensional Ultrasound of Blood Flow in the Fetal Cardiovascular System 645
in optimising the presetting of the color and power the transparent minimum mode and the transparent
Doppler or B-flow or to increase the contrast on the inversion mode.
gray scale. Most experience shared in this chapter was
acquired with a Voluson 730 Expert system (GE
Image Rendering Kretztechnik, Zipf, Austria) using mechanical
Image rendering: is the process of creating a 3D visual transducers for acquisition and the 4D view software
representation of the parameters of interest. for 3D/4D volume reconstruction. The 4D of the fetal
Generally the principle used is the “planar geometric heart was achieved either with live 3D or by using
projection” of the 3D-image, i.e. a 2D-image the integrated STIC software as described elsewhere.
representing the 3-D data. For the 4D image it will Only the latter permitted a 4D of color or power
be a 2D projection with cine-loop. The impression of Doppler information of the heart. It is expected that
the third dimension is generally given by the on-line in near future other companies will provide new
rotation of the image on the screen and by different software with new possibilities of 3D/4D acquisition
shadowing of anterior and posterior structures. and rendering, but the fields of interest will probably
Color maps can be used as well as different remain unchanged.
postprocessing means of increasing the brightness
CLINICAL APPLICATION
and transparency of color. The examiner can decide
whether to visualize only the vessels of interest or The clinical application of 3D/4D in prenatal
in combination with grey scale information in the so visualization of the fetal cardiovascular system is
called “glass body” rendering (Fig. 45.1). closely related to the regions of interest known from
Interestingly the system allows also a gradual the application of color and power Doppler
increase of the transparency allowing at the beginning ultrasound. We refer to reviews on the benefit of
the visualization of the surface in grey scale but with using color Doppler in fetal diseases.2,3 Some years
progression of transparency the visualization of the ago4 we examined in a study the application of 3D-
vessels inside the structure of interest (Fig. 45.1). 7 Power Doppler Ultrasound in prenatal diagnosis on
For information using no Doppler assistance but only 45 normal and 87 abnormal pregnancies including
the grey scale information, there are two volume mainly vascular abnormalities. In this study we used
rendering features permitting a 3D/4D appearance: a prototype system and satisfactory image

Fig. 45.1: A longitudinal view of the abdomen seen from the right side in glass body mode. From left to right
the transparency is gradually increased allowing a progressive visualization of power Doppler information.
646 Textbook of Perinatal Medicine

information was collected in only 56 out of the 87

abnormal cases examined (64%). Following eight
regions were found to be of interest: vessels of the
placenta, umbilical cord, abdomen, kidneys, lung,
brain and fetal tumors as well as the heart and great
vessels. In following some findings of the main
regions of interest with the possible anomalies
involving the vascular system demonstrable on 3D
ultrasound. The fetal heart will be separately
discussed in the second part of this section. Fig. 45.3: 3D power Doppler Ultrasound showing a central insertion
of the umbilical cord (left) and a velamentous insertion (right)

Peripheral Vascular System in 3D

Intraabdominal Vessels
Umbilical Cord and Placenta
The vessels of interest are the umbilical vein, the
From our experience it seems to be the structure most ductus venosus, the portal vein system, the hepatic
easily accessible to 3D throughout pregnancy. veins, splenic vessels, inferior vena cava and
Intraplacental vessel network architecture can be abdominal aorta (Fig. 45.6). The visualization of the
visualized with this method.15 The umbilical cord can lower abdomen gives a good orientation in
be rendered at different places from its insertion on visualizing the umbilical arteries around the urinary
the placental side (Fig. 45.2 and 45.3) to its attachment bladder in normal conditions. Since the application
on the fetal abdominal wall.4 Abnormalities like of color Doppler and the intensive study of the ductus
placenta praevia, vasa praevia 16 or velamentous venosus, abnormalities of intrahepatic venous system
insertion (Fig. 45.3) can be demonstrated as well as were detected to be more common as expected.
single umbilical artery or less important conditions Conditions to study by 3D power Doppler could
as the connecting vessels in twin pregnancies, nuchal involve the abnormal cord insertion on the abdomen
cord or true and false knot (Fig. 45.4) or the free (omphalocele, gastroschisis) (Fig.45.7), abnormal
course of the umbilical cord (Fig. 45.5). umbilical vein size (varix or ectasia) but the main
field of interest seems to be the absence of ductus
venosus (Fig. 45.8) with the different possibilities of
connection of umbilical vein. In these conditions 3D
power Doppler demonstrates the spatial course of
the aberrant vessel. Another interesting condition is
the abnormal course of vessels in isomerism i.e.

Fig. 45.2: 3D color Doppler ultrasound showing a posterior placenta Fig. 45.4: Fetus seen from behind with the umbilical cord around
with central insertion of the umbilical cord. There is a single umbilical the neck (Left). False knot of the umbilical cord
artery
Three-dimensional Ultrasound of Blood Flow in the Fetal Cardiovascular System 647

Fig. 45.7: Longitudinal view from the right side in a fetus with
gastroschisis, showing in comparison to fig. the distortion in the course
of the umbilical vein (UV), and the descending aorta (AO). The superior
mesenteric artery is streched and arises in direction of the abdominal
wall.

Fig. 45.5: Fetus holding the umbilical cord with the

hand in front of its face

Fig. 45.6: Longitudinal view of the abdomen view from the right side Fig. 45.8: Longitudinal view of the intraabdominal vascular tree in a
showing the descending aorta (Ao), the inferior vena cava (IVC), the 22 week fetus with agenesis of ductus venosus and connection of the
umbilical vein (UV) with ductus venosus (DV) as well as hepatic umbilical vein into the hepatic vein system
veins.
648 Textbook of Perinatal Medicine

interruption of inferior vena cava with azygous

continuity (Fig. 45.9).
Renal vessels: The visualization of renal vessels is
known to increase the accuracy of diagnosis of
kidneys malformations in the fetus. The renal
vascular tree is well visualized in a coronal plane
with the descending aorta showing a horizontal
course. Conditions with possible benefit of 3D-PDU
application are agenesis of one or both kidneys,
arteries in duplex kidney, horseshoe or pelvic kidney
(Fig. 45.10), but the 3D rendering adds only few
information to 2D color and was probably
overestimated in our fewer investigations.
Intracerebral vessels: The anatomy of intracranial vessel
architecture became more important in the recent
years and is closely related to the structural anatomy
of the brain. A transversal insonation allows easily
the reconstruction of the circulus of Willis (Fig. 45.11),
whereas a more sagittal approach enables the
visualization of the pericallosal artery with its Fig. 45.10: Pelvic kidney showing the abnormal renal artery
ramifications.17 Choosing a lower velocity scale flow
arising in the region of the bifurcation of the iliac arteries

in the cerebral veins and sagittal sinus can be imaged

as well. Main fields of interest are the abnormal

Fig. 45.9: Fetus with left isomerism (polysplenia): with an interruption Fig. 45.11: Circulus of Willis as demonstrated with 3D PDU, with
of the inferior vena cava (*), which is absent on 3D-PDU. Venous the anterior (ACA), middle (MCA) and posterior (PCA) cerebral
blood from the inferior part of the body returns via the azygos vein, arteries
which is dilated and seen side by side near the aorta. Compare with
the normal finding Fig.
Three-dimensional Ultrasound of Blood Flow in the Fetal Cardiovascular System 649

Fig. 45.12: 3D PDU of a vein of Galen aneurysm at 22 weeks gestation Fig. 45.14: Pulmonary veins and arteries are
with the dilated vessel between the hemispheres and in the posterior demonstrated with 3D color Doppler ultrasound
fossa

anterior cerebral artery in agenesis of corpus The role of color or power Doppler in predicting
callosum, the aneurysm of the vein of Galen (Fig. pulmonary hypoplasia failed and it is not expected
45.12) and disturbed vascular anatomy in cerebral that the 3D demonstration of the vessels could be in
malformations (holoprosencephaly (Fig. 45.13), this field of great interest in the near future.
hydrocephaly, encephalocele, etc..). Improved image
Fetal tumors or aberrant vessels: Aberrant vessels can
information can be reached by using tranvaginal
be visualized in the presence of several malfor-
ultrasound of the fetal brain in fetuses with vertex
mations like lung sequestration, choriangioma,
position (Fig. 45.13).
lymphangioma or in (sacrococcygeal) teratoma,
Lung vessels: Proximal and peripheral lung arteries acardiac twin etc. Fetal tumors can be of interest to
and veins can be seen from their origin into peripheral be visualized not only for their risk of cardiac failure
pulmonary segments (Fig. 45.14). Fields of interest
are the analysis of the 3D vessel architecture in cystic
lung malformation, congenital diaphragmatic hernia
and in bronchopulmonary sequestration (Fig. 45.15).

Fig. 45.13: Fetus with trisomy 13 and lobar holoprosencephaly as Fig. 45.15. In this fetus with an echogenic lung segment the diagnosis
seen by transvaginal ultrasound (Left). 3D Power Doppler shows the of bronchopulmonary sequestration is supported by the demonstration
aberrant bizarre course of the anterior cerebral artery of an aberrant vessel araising from the descending aorta (arrow).
650 Textbook of Perinatal Medicine

due to the presence of arterio-venous fistulae, but

also to assess compression of shifting of neighboring
organs (Fig. 45.16A and B). Some fields of interest
are chorangioma, teratoma, lung sequestration,
acrania (TRAP), hemangioma, renal tumors, and
cardiac rhabdomyomas etc..

The Fetal Heart in 3D and 4D

An extended fetal echocardiographic examination is
achieved by acquiring and documenting different
cross-sectional planes.1,18 An examiner acquiring these
cardiac cross sectional planes during different cycles
is automatically reconstructing mentally the heart in
the third and fourth dimension (3D+time). In the last
Fig. 45.16b: The 3D rendering gives the complete aspect
decade three and four-dimensional fetal echocardio- of the tumor and the surrounding vessels
graphy was investigated intensively in laboratories
using external work stations, static volume sweep, part will not be covered in this chapter mainly
matrix transducers and recently a new ultrasound focusing on the 3D appearance of blood flow. First
equipment with integrated software (STIC ™) was steps were acquired by combining power Doppler
introduced allowing a reliable 3D and 4D fetal mode with 3D to get the image of the four-cavities
echocardiography.12,14 (Fig. 45.17)4 or the spatial arrangement of the great
Surface rendering can be applied to the fetal heart vessels.11 These views could help in the demons-
by using the interface between the cavities and the tration of interventricular communications as a
cardiac walls. The views are however either the ventricular septal defect (Fig. 45.18). Their main
known views from 2D ultrasound (four-chamber and potential could be the demonstration of the crossing
five chambers) or could be new views as well, which of the great vessels and the aortic arch under normal
still to be defined. 19 Such views could focus on conditions (Fig. 45.19) versus a transposition of the
demonstrating the AV-valves or the interventricular great arteries4 (Fig. 45.20). The application of STIC
or interatrial septum. The future will show which with color Doppler and “glass body mode” allows
views are appropriate for clinical application. This a more precise and dynamic appearance of the

Fig. 45.16a: In this fetus at 27 weeks with sacrococcygeal teratoma Fig. 45.17: 3D-PDU of a normal four-chamber-view (left) with right
there was an intraabdominal masses as well (arrows). In different and left atria (RA,LA), right and left ventricles (RV,LV) in 3D power
planes one recognizes the descending aorta, one renal artery and mode (left) and glass body mode
the bifurcation of iliac arteries with the arising of umbilical arteries
(A.umb).
Three-dimensional Ultrasound of Blood Flow in the Fetal Cardiovascular System 651

Fig. 45.18: A muscular ventricular septal defect (VSD) connecting Fig. 45.20: Parallel course of the great vessels in
both right and left ventricles, whereas the vessels show a regular transposition of the great vessels. Compare with Fig.
crossing

relationship of the vessels to one each other (Fig. structures in a projection. Especially in a longitudinal
45.21). 14 view the aortic and ductus arch can be seen properly.
An interesting rendering mode is the “transparent The use of the new software of “inversion mode”
minimal mode” rendering (Fig. 45.22 and 45.23 left), permits the demonstration of a negative image of
in which blood vessels can be seen as hypoechoic the projection in minimum mode, but the image gets
more plasticity and appears more three-dimensional
than the minimal mode (Fig. 45.23 right and 45.24).

Fig. 45.21: 3D and 4D volume rendering with transparent gray scale

and surface color Doppler of two fetuses: On the left a normal finding
with the regular crossing of the great vessels). On the right a fetus
Fig. 45.19: Aortic arch with the origin of the cephalic vessels. with transposition of the great arteries with parallel course of both
Behind the brachiocephalic artery the superior vena cava is seen vessels.
652 Textbook of Perinatal Medicine

Fig. 45.22: Longitudinal view of the heart, the aortic arch Fig. 45.24: Crossing of the great vessels as
and the hepatic vessels in transparent minimum mode demonstrated with the inversion mode

The breakthrough two years ago was achieved Potential of 3D is that it facilitates not only the
by the software allowing the acquisition of a STIC understanding of the spatial arrangement of the
volume combined with color Doppler or power chambers showing their size and shape, but the
Doppler information. We presented extensively this course of the great vessels can be better understood.
technique elsewhere. 14 Using this technique the Crossing of vessels vs. parallel course, abnormal
examiner is able to assess the haemodynamic spatial
course as seen in double aortic arch, right arch with
changes throughout the cardiac cycle. The 3D/4D
a sling20, or simply tortuous hypoplastic aorta or
volume rendering of color or power Doppler STIC
pulmonary artery in different anomalies may be fields
provides images similar to an angiography, when
for future research.21
the feature glass body is chosen.

Fig.23: A longitudinal view of a fetal abdomen in minimum mode (left) and inversion mode (right). Not blood flow is visualized
but hypoechoic structures as gallbladder and urinary bladder in addition to the usual vessels.
Three-dimensional Ultrasound of Blood Flow in the Fetal Cardiovascular System 653
REFERENCE 11. Chaoui R, Kalache KD. Three-dimensional power
Doppler ultrasound of the fetal great vessels. Ultrasound
1. Chaoui R, McEwing R. Three cross-sectional planes for Obstet Gynecol 2001; 17(5):455-456.
fetal color Doppler echocardiography. Ultrasound 12. DeVore GR, Falkensammer P, Sklansky MS, Platt LD.
Obstet Gynecol 2003; 21(1):81-93. Spatio-temporal image correlation (STIC): new
2. Chaoui R. Color Doppler Sonography in the assessment technology for evaluation of the fetal heart. Ultrasound
of the fetal heart. In: Nicolaides KH, Rizzo G, Hecher Obstet Gynecol 2003; 22(4):380-387.
K, editors. Placental and fetal Doppler. London: 13. Vinals F, Poblete P, Giuliano A. Spatio-temporal image
Parthenon Publishing, 2003: 171-186. correlation (STIC): a new tool for the prenatal screening
3. Chaoui R. Color Doppler Sonography in the diagnosis of congenital heart defects. Ultrasound Obstet Gynecol
of fetal abnormalitites. In: Nicolaides KH, Rizzo G, 2003; 22(4):388-394.
Hecher K, editors. Placental and fetal Doppler. London: 14. Chaoui R, Hoffmann J, Heling KS. Three-dimensional
Parthenon Publishing, 2000: 187-203. (3D) and 4D color Doppler fetal echocardiography using
4. Chaoui R, Kalache KD, Hartung J. Application of three- spatio-temporal image correlation (STIC). Ultrasound
dimensional power Doppler ultrasound in prenatal Obstet Gynecol 2004; 23(6):535-545.
diagnosis. Ultrasound Obstet Gynecol 2001; 17(1):22-29. 15. Pretorius DH, Nelson TR, Baergen RN, Pai E, Cantrell
5. Chaoui R, Kalache KD. Three-Dimensional Color Power C. Imaging of placental vasculature using three-
Imaging: Principles and First Experience in Prenatal dimensional ultrasound and color power Doppler: a
Diagnosis. In: Merz E, editor. 3D Ultrasonography in preliminary study. Ultrasound Obstet Gynecol 1998;
Obstetrics and Gynecology. Philadelphia : Lippincot 12(1):45-49.
Williams and Wilkins, 1998: 135-142. 16. Lee W, Kirk JS, Comstock CH, Romero R. Vasa previa:
6. Chaoui R, Kalache KD, Bollmann R. Three-Dimensional prenatal detection by three-dimensional ultrasono-
Color Power Doppler in the assessment of fetal vascular graphy. Ultrasound Obstet Gynecol 2000; 16(4):384-387.
anatomy under normal and abnormal conditions . In: 17. Pooh RK, Pooh KH. The assessment of fetal brain
morphology and circulation by transvaginal 3D
Kurjak A, editor. Three-Dimensional Power Doppler in
sonography and power Doppler. J Perinat Med 2002;
Obstetrics and Gynecology. New York-London :
30(1):48-56.
Parthenon Publishing Group, 2000: 113-119.
18. Chaoui R. The examination of the normal fetal heart
7. Lee W, Kalache KD, Chaiworapongsa T, Londono J,
using two-dimensional echocardiography. In: Yagel S,
Treadwell MC, Johnson A et al. Three-dimensional
Silvermann N, Gembruch U, editors. London New York:
power Doppler ultrasonography during pregnancy. J Martin Dunitz, 2003: 141-149.
Ultrasound Med 2003; 22(1):91-97. 19. Chaoui R, Hoffmann J, Heling KS. Basal Cardiac View
8. Hartung J, Kalache KD, Chaoui R. [Three-dimensional on 3D/4D fetael echocardiographiy for the assessment
power Doppler ultrasonography (3D-PDU) in fetal of AV-Valves and great vessels arrangement.
diagnosis]. Ultraschall Med 2004; 25(3):200-205. Ultrasound Obstet Gynecol 2004; 22:228-Abstract.
9. Heling KS, Chaoui R, Bollmann R. Prenatal diagnosis 20. Chaoui R, Schneider MBE, Kalache KD. Right aortic arch
of an aneurysm of the vein of Galen with three- with vascular ring and aberrant left subclavian artery:
dimensional color power angiography. Ultrasound prenatal diagnosis assisted by three-dimensional power
Obstet Gynecol 2000; 15(4):333-336. Doppler ultrasound. Ultrasound in Obstetrics and
10. Gagel K, Heling KS, Kalache KD, Chaoui R. Prenatal Gynecology 2003; 22(6):661-663.
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Med 2003; 22(12):1399-1403. Gynecol 2003; 22:Abstract.
 46
Specific Aspects of Ultrasound
Examination in Twin Pregnancies
E Quarello, Y Ville

INTRODUCTION DETERMINATION OF CHORIONICITY AND

AMNIONICITY (Fig. 65.1)
Although twins account for only 2% of all pregnancies
they are responsible for 20% of perinatal morbidity Gestational sacs count should not be performed before
and the incidence of twining has increased by 50% 6 weeks’. Indeed before that, one sac could be left
over the last 20 years. Embryologically, 2/3 of twins unnoticed. Embryos can be counted from 7 weeks’
are dizygotic, resulting from fertilization of two onwards and yolk sacs can be identified between 8
ovocytes by two spermatozoids. 1/3 of twins are and 12 weeks’ . Amnionicity should not be confirmed
therefore monozygotic resulting from the splitting of before 9 weeks’. Prior to 9 weeks of gestation,
one fertilized egg. Depending of the time of splitting amnionicity cannot be assessed reliably, even with the
after fecondation, 1/3 of monochorionic twins will be use of high frequency vaginal ultrasound probes.1
dichorionic when this occurs within the first 4 days. Determination of chorionicity is the main determinant
The majority however will therefore be of both specific and non-specific complications in twin
monochorionic. It is only when splitting occurs after pregnancies. This is therefore the main aim of
8 days in 5% of these that the twins are mono- ultrasound examination in twins. Eighty percent of
amniotic. When splitting occurs after 12 days, the twin pregnancies are dichorionic. Diagnosis of
siamese twins will share some organs. Among twin chorionicity should be made in the first trimester of
pregnancies, the incidence of perinatal mortality and pregnancy, ideally between 9 and 12 weeks’, however
morbidity is 2 to 6 times higher in monochorionic this is still reliable until 14 weeks’ but it becomes
pregnancies. Both specific and non-specific uncertain thereafter when the twins are of the same
complications justify closer surveillance by sex.
ultrasound. Indeed, ultrasound examination in twins Chorionicity can be established based on :
is subjected to technical difficulties related to the • Gestational sacs count
presence of two fetuses in the uterine cavity and this • Presence of the lambda sign before 14 weeks’, as
impact both on biometry and morphological and opposed to the T-sign in monochorionic pregnancies
functional assessment. Specific features should also • Presence of the Twin Peak thereafter
be surveyed during ultrasound examination of all • Identification of 2 distinct placental masses
twin pregnancies. • Determination of different fetal genders
 Specific Aspects of Ultrasound Examination in Twin Pregnancies 655
A
B

D E F

Fig. 46.1: Assessment of chorionicity and amnionicity. A. Dichorionic pregnancy (DCP) before 9 weeks’
showing two gestational sacs. B. DCP showing the lambda sign of the fused chorions. C . interamniotic
membrane in a DCP at 22 weeks’ counting more than 2 layers. D Monochorionic pregnancy (MCP)
before 9 weeks showing one gestational sac and 2 yolk sacs. E. MCP at 12 weeks’ showing the T sign
at the membrane attachment on the placenta without chorion interposition. F interamniotic membrane
in a MCP at 22 weeks’ counting only 2 layers. G. Monoamniotic twins at 12 weeks’. H. Cord entanglement
in a monoamniotic twin pregnancy at 17 weeks’.

• Examination of the inter-twin fetal membranes echoic triangular base of the intertwin membranes on
The « Lambda » sign 2 and the « Twin a single placental mass. These feature the triangular
Peak »3specific features of dichorionic pregnancies but projection of villous tissue at the union of two fused
have been described at two different gestational chorionic plates. In monochorionic placentae, a single
periods. They both appear as a thick hyper or iso- chorionic layer cannot therefore project on the
656 Textbook of Perinatal Medicine

placenta; this features an abrupt junction on the • Visualisation of the yolk sacs and extra-amniotic
placenta described as the T sign. A lambda sign is the spaces. The number of yolk sacs and extra-
guarantee for a dichorionic pregnancy with a amniotic spaces matches the number of amniotic
sensitivity close to 100%.4 It can be found throughout sacs. Two yolk sacs are seen in monochorionic
pregnancy but the significance of its absence is reliable diamniotic pregnancies and only one in
only before 14 weeks’. Non visualisation of the monoamniotic pregnancies.5 They can be seen as
lambda sign with the presence of the T sign has a non contiguous in dichorionic pregnancies
positive predictive value for monochorionicity close • Cords entanglement in monoamniotic twins can
to 100%. be best visualised using colour Doppler. Doppler
The presence of two placental masses is predictive flow within the cord mass should also show a bi-
of a dichorionic pregnancy, however this may feature phasic arterial flow.
a placenta bipartita in up to 15% of these cases. • Conjoined twins can only be seen in mono-
Monochorionicity cannot be confirmed by the amniotic pregnancies and can be suspected when
presence of a single placental mass since two separate visualising close proximity of both twins which
placentae are frequently fused after 15 weeks’. The also show concomitant movements.
presence of vascular anastomoses on the chorionic
plate joining the two funicular circulations is a specific EXAMINATION BEFORE 15 WEEKS
feature of monochorionicity but is time consuming Examination before 15 weeks’ is critical and a well
and its reproducibility remains to be established. documented picture should be kept in the notes in
Different fetal genders is specific of dichorionicity order to confirm chorionicity whenever clinically
since it would confirm a dizygotic pregnancy. The relevant later on in pregnancy.
reverse is not true.
Inter-twin membrane is the result of the fusion of NUCHAL TRANSLUCENCY MEASUREMENT IN
two amniotic and two chorionic layers in dichorionic TWIN PREGNANCIES
pregnancies. This is made of only two amniotic layers
Nuchal translucency measurement can be used in
in monochorionic-diamniotic pregnancies. In the late
twins to reliably screen for fetal aneuploidy. The false
second and third trimester, ultrasound examination
positive rate for each dichorionic twin is 5% and is
can assess the thickness of the inter-twin membranes
therefore similar to that in singletons. However in
using cut-off measurements of 1.5 or 2 mm or better
monochorionic twins, nuchal translucency is
counting 2 or 4 layers in monochorionic and in
measured above the 95th centile for CRL in either twin
dichorionic pregnancies respectively. Technically, this
inasmuch as 8.5% of the cases. Sebire et al reported
requires to use magnification and the lowest gain
an 88% detection rate for a false positive rate per
possible and an angle of insonation to the membranes
pregancy of around 10% and 15% in dichorionic and
close to 45°. A right angle, although theoretically more
in monochorionic pregnancies respectively. 6
suitable is subjected to more artefactual images.
Discordance of NT measurements between
Amnionicity can be determined upon :
monochorionic twins is also predictive of the
• Visualisation of the inter-amniotic membrane .
development of twin-to-twin transfusion syndrome
However non visualisation of the membrane in a
(TTTS) with a sensitivity of 33% and a positive
diamniotic pregnancy can arise due to technical
predictive value of 28%. The likelihood ratio of
difficulties, mainly before 8 weeks’ of pregnancy
developing TTTS at 10 to 14 weeks of gestation is 4.2
or in obese patients
(IC 95%, 3.0-6.0).6
 Specific Aspects of Ultrasound Examination in Twin Pregnancies 657
SPECIFIC COMPLICATIONS OF The diagnosis of TTTS requires that the pregnancy
MONOCHORIONIC TWINS is monochorionic and relies on the association of
polyuria-related polyhydramnios in one the
A/ Twin-to-Twin Transfusion Recipient-twin together with oliguria-related
Syndrome (Fig. 65.2) oligohydramnios in the Donor-twin. Polyhydramnios
In all monochorionic pregnancies, a single placental is defined by a vertical deepest pool of amniotic fluid
mass implies that the two fetuses share some placental of at least 8 cm before 20 weeks’ and 10 cm thereafter
units with a shared vascularisation of these and oligohydramnios is present when the deepest
cotyledons. An imbalance in placental sharing will fluid is at most 2 cm. Up to 28% of all monochorionic
arise in around 15 % of monochorionic pregnancies.6 twins seen at 12 weeks’ on ultrasound will develop
Indeed the natural history of monochorionic twins as some discrepancy in the volume of amniotic fluid
observed by serial ultrasound examination suggest and/or a discrepancy in size 6 by 16-18 weeks’. This
that up to 28% of all monochorionic twins scanned at does not meet the criteria for TTTS and has led to a
12 weeks’ will show some discrepancy either in long standing misunderstanding on the diagnosis and
abdominal circumference or in amniotic fluid volume, the prognosis of TTTS. It is only half of these, therefore
with membrane folding at 16-18 weeks’ but only up 14% of the starting number which will develop the
to half of these (14% of the starting number) will poly-oligo-hydramnios sequence. The fetal size,
develop twin-to-twin transfusion syndrome in the although the Recipient is usually appropriately grown
second or early third trimester; 6,7 Twin-to-twin and the Donor is usually smaller is not an important
transfusion syndrome results from an acute criteria for the diagnosis of TTTS.
hemodynamic imbalance through the vascular When oligohydramnios confines to anhydramnios,
placental anastomoses. The Donor twin becomes the inter-twin membranes are difficult to visualise and
hypovolemic, oliguric and around 2/3 of these will the Donor-twin is “stuck” on the placenta or the
also show some degree of growth restriction. uterine wall. This can lead to a false diagnosis of
Oligohydramnios develops in this sac. There is monoamniotic pregnancy or the suspicion of various
hypervolemia in the Recipient twin which is therefore malformations in the compressed Donor twin.
polyuric leading to polyhydramnios in its sac and is Pushing the abdominal wall in regard to the Donor
exposed to high output cardiac failure. Although a twin will demonstrate that this twin cannot move due
net transfer of blood is likely to initiate it, this is not to anhydramnios. Hypervolemia in the recipient often
the only mechanism involved in the syndrome. In shows a cardiothoracic index of more than 0.55 with
order to maintain volemia, the fetal rennin- a thick myocardium and the presence of tricuspid
angiotensin system is activated in the donor twin and regurgitation, which has no prognostic value when
suppressed in the recipient with preferential maternal- the recipient is not hydropic. The best first line
fetal transfer of fluid to the recipient.8 A paradoxical treatment consists of fetoscopic surgery to coagulate
effect of a transfer of renin towards the recipient twin the anastomotic chorionic plate vessels.9
through the placental anastomoses, could also Arterial and venous fetal Doppler can be normal
contribute to the development of hypertension and or show absent or reverse end diastolic flow in the
cardiomyopathy in this fetus. A velamentous umbilical arteries. Absent or reverse flow in the a-
insertion of the cord of either twin on the placenta is wave of the ductus venosus usually corresponds to
found in up to 30 to 50 % of all monochorionic severe hypoxemia or cardiac overload in the Donor
pregnancies and this is likely to play a significant role or the recipient twin respectively. Pic-systolic
in creating hemodynamic imbalance between the two velocities in the middle cerebral artery is sensitive to
feto-placental circulations. anemia and to polycythemia showing values above
658 Textbook of Perinatal Medicine

A B C

D E F

G
Figs 46.2A to G: A. Folding of the membranes (Arrow) in a monochorionic twin pregnancy at 17 weeks’. B. Cross
section through the fetal abdomen of 2 monochorionic twins discordant for growth at 20 weeks’. C. Cross section
through the fetal abdomen of the stuck donor-twin in anhydramnios against the uterine wall (d) and the recipient
twin in polyhydramnios (R) in twin-to-twin transfusion syndrome. D. Cross section through the fetal pelvis of the
stuck Donor and of the Recipient showing absent and distended bladder respectively. E. The Donor in anhydramnios
is wrapped in its membranes as shown in a sagittal plane (F) and in a cross section through the pelvis showing an
empty bladder. This « sling sign « could lead to the false impression that the amniotic fluid volume is normal on
both sides of a floating inter-twin membrane. G. Examination of the Recipient’s 4-chamber view of the heart with
color Doppler showing tricuspid regurgitation.
 Specific Aspects of Ultrasound Examination in Twin Pregnancies 659
1.5 MoM or below 0.7 MoM respectively.10 However single umbilical artery in the cord of the acardiac twin
a difference in hemoglobin is unusual in utero in most and this sets the basis for an increased cardiac
cases of TTTS.11 workload in the normal twin also named the pump-
Quintero12 has proposed a classification of TTTS twin. The acardiac mass can grow and develop to
in 4 stages which has the advantage of homogenising various degrees, increasing the mass of tissue which
the diagnostic criteria. Stage 1 corresponds to the the normal twin heart has to bear. (Fig. 65.3) This can
association of polyhydramnios in the recipient and therefore lead to the development of high-cardiac
oligohydramnios in the donor which bladder is output hydrops in up to 50% of pump-twins. The
visible. Stage 2 is similar but the bladder cannot be bigger the acardiac mass, the higher the likelihood
visualised in the donor. In Stage 3, Doppler exami- for hemodynamic decompensation of the pump
nation shows marked abnormalities with absent or twin.13 The acardiac twin usually bears several major
reversed end diastolic flow or absent or reversed a malformations allowing for embryological
wave in the umbilical arteries or in the ductus venosus classification,13 the most frequent being the acardiac
respectively. Stage 4 is characterized by the presence acephalus , however rudimentary organs, especially
of hydrops in either twin. Stage 5 is when one or both limbs and spine are often present. Early in the
twins have died in utero. pregnancy, this is often mistaken for either an early
TTTS can also develop in monoamniotic embryonic demise or for a placental tumour. The key
pregnancies. Polyuric polyhydramnios is then seen to the diagnosis is the use of colour Doppler showing
together with a small or unseen bladder in its co-twin. retrograde perfusion of the acardiac mass, and
eventually demonstrating the placental anastomoses.
B/Acardiac Twin
C/ Monoamniotic pregnancies
The acardiac twin is defined by the presence of one
monochorionic twins without a clearly anatomically The fetuses will be seen in close proximity and both
defined heart; the co-twin is usually normal. crossing of their limbs and cord entanglement as seen
Vascularisation of the monochorionic placenta almost by colour Doppler will establish the diagnosis.
invariably shows the presence of two superficial
anastomoses between the two cord insertions: one D/Conjoined Twins
artery-to-artery and one vein-to-vein anatomoses These are 4-5 % of all monochorionic monoamniotic
flowing in opposite directions. There is usually a twins. The embryological classification refers to the

Figs 46.3A to C: A. Monochorionic twin pregnacy showing an acardiac twin at 13 weeks’ showing rudimentary head, spine and
lower extremities. B. Acardiac mass showing retrograde flow on power Doppler at 14 weeks. C. Edematous acardiac mass at
25 weeks’.
660 Textbook of Perinatal Medicine

part of their body through which they are attached, Monochorionic twins however are the only one to see
the most frequent type being thoracopagus.14 Organ acute polyhydramnios developing polyhydramnios
sharing can be symmetrical or asymmetrical. The due to TTTS.
extreme form of the latter constitutes the fetus-in-fetu
where a rudimentary fetal mass can be found as a CERVICAL CHANGES IN TWIN PREGNANCIES
hyper-echogenic tumoral mass into an otherwise Although twin pregnancies are 1% of all pregnancies
usually normal fetus, child or even adult. and 2% of all deliveries, twins account for 15% of all
There is a clear benefit for an early diagnosis of a maternal morbidity and mortality. This is mainly due
unique embryonic mass often characterised by the to preterm delivery with 12% of all preterm neonates
presence of two beating hearts. Embryonic / fetal being twins.
movements are always simultaneous and a single The advantage of cervical ultrasound over digital
umbilical cord with more than 3 vessels can be examination has also clearly been shown in twins.
identified. Relative risk of preterm delivery within a week of
cervical ultrasound examinationhave been reviewed
AMNIOTIC FLUID VOLUME by Ong et col.17 à 4.1 (1.10 – 15.47, IC 95 %) et 11.7
IN TWIN PREGNANCIES (4.23 – 32.17, IC 95 %) respectivement pour des valeurs
inférieures aux seuils de 25 et 20 mm.
A/Oligohydrammnios, Anahydramnnios and
the« Stuck twin Phenomenon »
GROWTH DISCORDANCE IN TWINS
All causes of oligohydramnios in singleton can affect
This is the second most frequent complication in twins
one or both twins and should be investigated in the
and the second contributor to neonatal mortality and
same way. The stuck-twin phenomenon can therefore
morbidity. Conflict of interest may arise between
affect both monochorionic and dichorionic
twins as to define optimal timing for delivery. In the
pregnancies to the same extent. However when
second and 3rd trimesters of pregnancy, the cut-off
oligohydramnios affects only one twin, the twin with
value for EBW estimate is of at least 20%.
a normal amount of fluid is often unduly credited for
having polyhydramnios and a wrong diagnosis of MALFORMATIONS IN TWINS
twin-to-twin-transfusion syndrome is often
The presence of two embryos / fetuses increases the
suspected. It is therefore critical to use an objective
risk as compared to singletons. A recent series 18has
measurement of the amniotic volume, mainly using
gathered data on 260,000 twin pregnancies among 12
the deepest pool measurement15 Another important
millions births. 5,500 twin pregnancies carry at least
pitfall is to consider that 2 layers of membranes tightly
one malformed twin outside specific risks associated
wrapped around the stuck-twin, featuring the “sling-
with monochorionicity representing 2.14 % vs 1.72 %
sign “16 could be mistaken as free-floating membranes
for singletons. 101 malformations malformative
separating two cavities with a normal amount of fluid
sequences have been reported, 37 of which are more
in each sac. Aetiologies that are more prone to affect
prevalent in twins. The rprevalence of fetal
twins include: low urinary tract obstruction, severe
malformations in twins is therefore of around 25 %
intrauterine growth retardation and preterm prelabor
with relative risks of 8 % to 60 %. Dizygotic twins
rupture of the membranes.
only carry non-specific malformations.
Monochorionic twins will bear malformations both
B/Polyhydramnios in Twins non-specific and specific to monochorionicity. Specific
All malformations seen in singletons such as malformations include those arising from a delay in
anencephaly, bowel atresia are more frequent in twins. zygotic splitting or midline abnormalities as well as
 Specific Aspects of Ultrasound Examination in Twin Pregnancies 661
those resulting from a sequence of events following frequency transvaginal ultrasonography. Am J Obstet
Gynecol 1994 ;170 :824-9
severe hemodynamic imbalance through placental
2. Bessis R and Papiernick E. Echographic imagery of
anastomoses. Furthermore, only 5 to 20% of amniotic membranes in twin pregnancies. Twin Research
monozygotic pregnancies are concordant for fetal 3 :Twin biology and multiple pregnancy pp 183-7
malformations.19 These differences can also arise from 3. Finberg HJ. The ‘twin peak’ sign : a reliable evidence of
dichorionic twinning. J Ultrasound Med 1992 ;11 :571-7
post-zygotic genetic abnormalities, different 4. Sepulveda W, Sebire NJ, Hughes K, Odibo A and Nicolaides
susceptibility to their exposure to environmental KH. The lambda sign at 10-14 weeks of gestation as a
factors. de predictor of chorionicity in twin pregnancies. Ultrasound
Obstet Gynecol 1996 ;7 :421-423
5. Bromley B, Benacerraf B. Using the number of yolk sac to
INTRAUTERINE FETAL DEATH OF ONE TWIN
determine amnionicity in early first trimester
Perinatal mortality in twins is up to 7-fold higher than monochorionic twins. J Ultrasound Med 1995 ;14 :415-419
6. Sebire NJ, Souka A, Skentou H, Geerts L, Nicolaides KH.
in singletons.20 Intyrauterine death of one twin can Early prediction of severe twin-to-twin transfusion
result from non-specific fetal complications such as syndrome. Human Reprod 2000 ;15 :2008-10
these seen in singletons, including cord compression 7. Sebire NJ, d’Ercole C, Carvelho M, Sepulveda W, Nicolaides
and severe growth restriction as well as from specific KH. Inter-twin membrane folding in monochorionic
pregancies. Ultrasound Obset Gynecol 1998;11:324-327.
complications related to hemodynamic imbalance, 8. Mahieu-Caputo D, Dommergues M, Delezoide AL, Lacoste
including TTTS and collapse. In monochrorionic M, Cai Y, Narcy F, Jolly D, Gonzales M, Dumez Y and
twins, the death of one fetus will threaten its co-twin Gubler MC. Twin-twin transfusion syndrome. Role of the
fetal renin-angiotensin system. Am J Pathol 2000 ;156 :629-
by causing an abrupt and profound drop in systemic
636
blood pressure subsequent to the exsanguinations of 9. Senat MV, Deprest J, Boulvain M, Paupe A, Winer N, Ville
the survivor in its dead co-twin and its placenta Y. Endoscopic laser surgery versus serial amnioreduction
through the inter-twin anastomoses. Peak-systolic for severe twin-to-twin transfusion syndrome.N Engl J
Med. 2004 Jul 8;351(2):136-44
velocities in the midcerebral arteries of the survivor 10. Senat MV, Loizeau S, Couderc S, Bernard JP and Ville Y.
measured above 1.5 MoM within 24 hours of the co- The value of middle cerebral artery peak systolic velocity
twin’s death will predict anemia/hypovolemia in this in the diagnosis of fetal anemia after intrauterine death of
twin. (sensitivity 90% for a 10% false positive rate).10 one monochorionic twin. Am J Obstet Gynecol
2003;189:1320-4
Exsanguination will lead to fetal death or severe 11. Denbow M, Fogliani R, Kyle P, Letsky E, Nicolini U, Fisk
ischemic sequelae in the survivor in 25% and 25% of NM. Haematological indices at fetal blood sampling in
the cases respectively. Ischemia-related malformations monochorionic pregnancies complicated by feto-fetal
transfusion syndrome. Prenat Diagn 1998;18:941-946.
include cerebral lesions such as periventricular
12. Quintero R, Morales WJ, Allen MH. Staging of twin-to-twin
leukomalacia, porencephaly, hydrocephalus and transfusion syndrome. J Perinat 1999;19:550-555.
migrational anomalies; renal ischemia and mesenteric 13. Moore TR, Gale S , Benirschke K. Perinatal outcome of 49
ischemia leading to bowel atresia. These lesions will pregnancies complicated by acardiac twining. Am J Obstet
Gynecol 1990;163:907-12.
only be amenable to prenatal diagnosis from 2-3 14. Spencer R. Parasitic conjoined twins: external, internal,
weeks following the acute event. detached. Clin Anat 2001;14:428-444
In dichorionic pregnancies, the co-twin will only 15. Hill LM, Krohn M, Lazebnik N, Tush B, Boyles D, Ursiny
be exposed to a persistant cause of death and to JJ. The amniotic fluid index in normal twin pregnancies.
Am J Obstet Gynecol 2000;182:950-4.
prematurity. 21,22 16. al-Kouatly HB, Skupski DW. Intrauterine sling : a
complication of the stuck twin syndrome. Ultrasound
REFERENCES Obstet Gynecol 1999 ;14 :419-21
17. Ong S, Smith A, Smith N, Campbell D and Wilson A.
1. Monteagudo A, Timor-Tritsch IE and Sharma S. early and Cervical length assessment in twin pregnancies using
simple detrmination of chorionic and amniotic type in transvaginal ultrasound. Acta Obstet Gynecol Scand
multifetal gestations in the first fourteen weeks by high- 2000 ;79 :851-853
662 Textbook of Perinatal Medicine

18. Mastroiacovo P, Castilla EE, Arpino C, Botting B, Cocchi 21. Bajoria R, Wee LY, Anwar S and Ward S. Outcome of twin
G, Goujard J, Marinacci C, Merlob P, Métneki J, Mutchinick pregnancies complicated by single intrauterine death in
O, Ritvanen A and Rosano A. Congenital malformations relation to vascular anatomy of the monochorionic
in twins : an international study. Am J Med Gen placenta. Human Reprod 1999 ;14 :2124-2130
1999 ;83 :117-124 22. Fusi L and Gordon H. Twin pregnancy complicated by
19. Schinzel AAGL, Smith DW, Miller JR. Monozygotic single intrauterine death. Problems and outcome with
twinning and structural defects. J Pediatr 1979 ;95 :921-930 conservative management. BJOG 1990 ;97 :511 – 516
20. Benirschke K and Kim CK. Multiple pregnancy. N Engl J
Med 1973; june 14 :1276-1283
 Echocardiography in Early
47 Pregnancy: A New Challenge in
Prenatal Diagnosis

Carmina Comas, Josep M Martínez, Alberto Galindo,

Olga Gómez, Carlos Millán, Guillermo Azumendi

ABSTRACT reduction in detection rates and an increase in false

Within the last decade, two significant events have positive and negative rates. The cardiac anomalies
contributed to the increasing interest in early fetal detected at this early stage of pregnancy are mainly
echocardiography. First, the introduction of high- defects involving the four-chamber view, indicating that
frequency vaginal ultrasound probes allows detailed defects solely affecting the outflow tracts are difficult
visualization of cardiac structures at early stage of to diagnose in the first trimester of pregnancy. Heart
gestation, making early detection of fetal malformations defects diagnosed early in pregnancy tend to be more
possible. Second, the close relationship observed complex than those detected later, with a higher
between some first trimester sonographic and Doppler incidence of associated structural malformations,
markers and congenital heart defects allows an early chromosomal abnormalities and spontaneous abortions.
identification of a high-risk group at 11-14 weeks of The neonate follow-up or postmortem examination in
gestation. In this context, from the early 1990s, many case of termination of pregnancy are essential to assess
authors have examined the potential role of the the actual role of early fetal ecocardiography. At present,
transvaginal approach to obtain earlier diagnosis of fetal early fetal echocardiography is a promising technique,
cardiac malformations. Further studies have appeared wich can be of considerable value for patients at high-
in the literature showing that early transvaginal risk. This technique is, however, currently limited to a
echocardiography in experienced hands is a fairly few specialized centers.
sensitive investigative tool. Although some The aim of this review is to explore the possibilities
malformations are detected as early as 11 weeks’ of examining the fetal heart at this early stage of
gestation, the optimal gestational age to perform the pregnancy. This article also present our experience in
early scan is at least 13 weeks’ gestation. Transvaginal the first multicenter trial in early fetal echocardiography
ultrasound is the preferred approach, although most of performed in Spain. In accordance with other studies,
the authors agree that results can be improved if this experience stresses the usefulness of early
transabdominal ultrasound is also incorporated. The echocardiography when performed by expert operators
further application of colour Doppler enhances on fetus specifically at risk for cardiac defects. Our
visualization. The sensitivity and specificity of early review of these additional 48 cases contributes to the
fetal echocardiography for the detection of heart expanding literature on the ability of transvaginal
anomalies is acceptable compared to the ones obtained ultrasonography to detect fetal heart defects in early
by mid-gestational echocardiography, showing a slight pregnancy.
664 Textbook of Perinatal Medicine

INTRODUCTION of nuchal translucency8 regardless the fetal karyotype.

Since earlier diagnosis of congenital malformations
Prenatal detection of fetal congenital heart defects
is increasingly demanded, the option of an early fetal
(CHD) remains the most problematic issue of prenatal
echocardiography must be taken into account12-14. The
diagnosis1. Major CHD are the most common severe
use of high-frequency vaginal ultrasound probes
congenital malformations, with an incidence of about
along with substantial improvements in magnification
5 in a thousand live births, whenever complete
and processing of the imaging, together with the
ascertainment is done and minor lesions are
introduction of color Doppler, have extensively
excluded 1,2 . Congenital heart anomalies have a
contributed to the development of the technique,
significant effect on affected children’s life with up to
allowing better visualization of cardiac structures
25-35% mortality rate during pregnancy and the
earlier in pregnancy 12,15,16. Although most of the
postnatal period, and it is during the first year of life,
groups perform early fetal echocardiography between
when the 60% of this mortality occurs. Moreover,
13 and 16 weeks’ gestation, we can name it as so when
major CHD are responsible for nearly 50% of all
performed before the 18th week of gestation. Despite
neonatal and infant deaths due to congenital
several studies that stated that fetal heart examination
anomalies, and it is likely to be significantly higher if
could be incorporated in first or early second trimester
spontaneous abortions are considered. Although CHD
examinations, its use is currently still limited to a few
use to appear isolated, they are frequently associated
specialized centers.
with other defects, chromosomal anomalies and
genetic syndromes. Their incidence is 6 times greater
TECHNICAL ISSUES
than chromosomal abnormalities and 4 times greater
than neural tube defects1-3. Regarding early fetal echocardiography, some
Most major CHD can be diagnosed prenatally by institutions use predominantly the transvaginal (TV)
detailed transabdominal second trimester approach 14,17-22 while others prefer the trans-
echocardiography at 20-22 weeks’ gestation1,3-6. The abdominal one 23-26. Most of the authors reporting
identification of pregnancies at high-risk for CHD early fetal echocardiography prefer the TV approach
needing referral to specialist centres is of paramount due to its increased resolution associated with higher
importance in order to reduce the rate of overlooked frequency transducers and also because given that
defects6,7. However, the main problem in prenatal equivalent tranducers frequencies, the TV probes
diagnosis of CHD is that the majority of cases take provide better quality images 27 . However, most
place in pregnancies with no identifiable risk factors. importantly, authors with background training as
Therefore, there is wide agreement that cardiac pediatric cardiologists are more likely to use the
ultrasound screening should be introduced as an transabdominal approach in contrast with most of
integral part of the routine scan at 20-22 week. When obstetricians, who are well used to the TV route.The
applied to low-risk population, scrutiny of the four superiority of transvaginal sonography is usually well
chamber view allows only the detection of 40% of the accepted before the 14th week. Between the 15th and
anomalies while additional visualization of the 18th week both transabdominal and transvaginal
outflow tracts and the great arteries increase the rate routes seem to offer similar advantages and
up to 60-70%3-5. disadvantages, and beyond the 18th week the
Recently, the finding of an increased nuchal transabdominal echocardiography seems to achieve
translucency8,9 or an altered ductus venosus blood better results1,5,16,27,28.
flow 10,11 at 10-14 weeks’ gestation have been The combination of two-dimensional echocardio-
associated with a high-risk for CHD and their graphy with color Doppler flow imaging proved
prevalence increase exponentially with the thickness generally helpful, in particular by visualization of
 Echocardiography in Early Pregnancy: A New Challenge in Prenatal Diagnosis 665
blood flow on both great arteries and of two divided chamber view through a transverse section of the fetal
ventricular inflows. The addition of color Doppler chest: normal situs solitus; normal size and axis of
flow studies provides substantial improvement in the the heart in relation to the chest; both atria equal in
diagnostic accuracy of early echocardiography, as was size, with the foramen ovale flapping within the left
also shown by DeVore for transabdominal atrium; both ventricles equal in size and contractility;
sonography in the second half of pregnancy 29. atrial and ventricular septa are of normal appearance;
When performing early fetal echocardiography, we tricuspid and mitral valves are normally inserted,
firstly recommend to scan by the TV route, following opening and closing together. Color and pulsed
the examination by the transabdominal probe when Doppler are particulary useful to confirm normal
a complete study is not possible. The highest inflow to the ventricles and to detect turbulent flow
frequency must always be used, whatever the route or jets suggesting valve regurgitation. It is useful to
is chosen. Obviously, a high-resolution real-time assess the four-chambers in different views: apical,
ultrasound has to be used. For color Doppler basal and long axis with the interventricular septum
evaluation, the energy output levels have to be lower perpendicular to the ultrasound beam in order to
than 50mW/cm2 spatial peak-temporal average. Since visualize better the integrity of the septum. Then, the
color Doppler is dissipated over a wide area of origin and double crossing of the great arteries must
interest, thermal effects resulting from Doppler be correctly identified: the left ventricle outflow tract,
insonation should not be a matter of concern, unlike
with the continuity between the interventricular
pulsed Doppler in which the whole energy of the
septum and the anterior wall of the ascending aorta;
beam is focused at a specific location. Besides, the
the right ventricle outflow tract, more superior,
embryonic developmental of the heart has been
anterior, almost perpendicular to the axis of the
completed by the time the scan is performed.
ascending aorta and connecting to the descending
ULTRASOUND ANATOMY OF aorta in the three vessels view. Color Doppler is also
THE NORMAL HEART of help to better visualize the outflow tracts confirm
anterograde flow through the semilunar valves and
Embryonic heart beat can be detected as early as the
great arteries, and makes easier the examination of
fifth week of gestation, and normal development of
both aortic and ductal archs and their confluence.
its function shows an increasing heart rate from 80-
Pulsed Doppler may be used to assess blood flow
90 beats per minute at 5 weeks’ gestation to 170-180
through the aortic and pulmonic valves in order to
beats per minute at the end of the 9-10th week. As
confirm normal anterograde flow and to detect very
pregnancy progresses, the control of the heart rate
high velocities suggesting valve stenosis. Finally, color
matures with increasing vagal dominance, and the
baseline rate declines to 145-155 beats per minute with and pulsed Doppler are also very useful to identify
the appearance of beat to beat variation, most likely normal systemic and pulmonary venous return. Figs
resulting from the functional adaptation to the 47.1 to 47.10 illustrates images obtained at early fetal
development of the heart and autonomic nervous scan by 2D echocardiography and Color Doppler in
system maturation, and remains more or less constant a structurally normal heart. In our experience, the
during the rest of intrauterine life 30,31. average duration of the complete fetal cardiac scan is
The structural development of the heart begins on over 15 minutes. It essentialy depends on the
day 16 and it is finished by the 10th week. Early fetal gestational age at the examination, and can be even
echocardiography has the same goals that the shorter if there is a favourable fetal lie. In our setting,
standard one, and we advocate to perform it in a a subsequent transabdominal echocardiography is
segmental approach. The first objective of the scheduled for all our patients at 20-22 weeks’
examination is to assess the normality of the four gestation.
666 Textbook of Perinatal Medicine

Left cardiac axis

RV
LV RV
RA
LV
LA

FO
DAo
RV right ventricle
RV right vent ricle LV: left ventricle
LV: left vent ricle
RA : right atr ium
LA: left atr ium
FO: foramen ovale
Fig. 47.3: Early fetal echocardiography by 2D in a structurally
DA o: descending aort a
normal heart. The short axis view, showing an anterior right
ventricule and a posterior left ventricle.
Fig. 47.1: Early fetal echocardiography by 2D in a structurally RV right ventricle; LV: left ventricle
normal heart. The 4 chamber-view: normal situs solitus; normal
size and axis of the heart in relation to the chest; both atria
equal in size, with the foramen ovale flapping within the left
atrium; both ventricles equal in size and contractility; atrial and
A o PA
ventricular septa are of normal appearance; tricuspid and mitral SVC
valves are normally inserted.
RV right ventricle; LV: left ventricle; RA: right atrium; LA: left
atrium; FO: foramen ovale; DAo: descending aorta

AAo
PA : pulmona r ar t ery
A o: aor ta

RV S VC : super ior v ena cav a

RA LV Fig. 47.4: Early fetal echocardiography by 2D in a structurally

IVS
normal heart. The 3 vessel-view: Cross-sections of the
LA pulmonary artery, ascending aorta and superior vena cava in
a transverse view of upper mediastinum. In normal conditions,
DAo the structures in the 3 vessel-view are in descending order of
size from left to the right.
PA: pulmonar artery; Ao: aorta; SVC: superior vena cava

between the 13 and 16 weeks of gestation, since a

Fig. 47.2: Early fetal echocardiography by 2D in a structurally complete cardiac examination is rarely achieved
normal heart. The 5 chamber-view: left ventricle outflow tract
in the long axis view showing the continuity between the before the 13th week of gestation14,17,18,20-22,26 . Articles
interventricular septum and the anterior wall of the ascending on early fetal echocardiography demonstrate an
aorta. increase in visualization rates of the four-chamber
RV right ventricle; LV: left ventricle; RA: right atrium; LA: left
view and the outflow tracts in the last decade, with
atrium; AAo: ascending aorta; DAo: descending aorta; IVS:
interventricular septum visualization rates greater than 90% at 13 weeks’
gestation 28. To maximize the reduction of
uninterpretable examinations, early fetal
Most of the authors agree that the best window of echocardiography should be preferably performed at
time to perform the early echocardiography is 13 completed weeks’ gestation. Using current
 Echocardiography in Early Pregnancy: A New Challenge in Prenatal Diagnosis 667

RV
PA

DA DAo RV
LV

AAo
LV
RV: righ ventricle
LV: left v entricle
PA: pulmonar art ery
DAo RV: righ ventricle
D A: ductus art erios us LV: left ventricle
D Ao: descending aor ta
A Ao: ascending aor ta

Fig. 47.7: Early fetal echocardiography by 2D and Color Doppler

Fig. 47.5: Early fetal echocardiography by 2D in a structurally in a structurally normal heart. Color Doppler in the 4chamber-
normal hear t. The left sagital view of ductal and aor tic archs view is particulary useful to confirm normal inflow to the
RV: righ ventricle; LV: left ventricle; PA: pulmonar artery; DA: ventricles and to detect turbulent flow or jets suggesting valve
ductus arteriosus; DAo: descending aorta; AAo: ascending regurgitation.
aorta RV: righ ventricle; LV: left ventricle

SVC
IVC
Ao
PA

SV C: sup erior vena cava

I VC: infer ior vena cava Ao : aor ta
PA: pulmonar ar tery

Fig. 47.6: Early fetal echocardiography by 2D in a structurally Fig. 47.8: Early fetal echocardiography by 2D and Color Doppler
normal heart. Systemic venous return to the right atrium throw in a structurally normal heart. Color Doppler is particulary useful
the superior and inferior vena cava. to demonstrate the crossing of the great arteries.
SVC: superior vena cava; IVC: inferior vena cava Ao: aorta; PA: pulmonar artery

technology, the four-chamber view and the outflow complete atrioventricular canal defect, with complete
tracts are often demonstrated by two-dimensional heart block and atrioventricular valve regurgitation
echocardiography only, but color Doppler imaging was diagnosed at 11 weeks + 4 days’ gestation using
enhances and makes the identification of the a 5-MHz transvaginal probe. The same year,
structures faster, increasing the succes rate of the Bronshtein et al 33 reported the diagnosis of a
examination, and allows even earlier identification of ventricular septal defect with overriding aorta and a
the structures. further case of an isolated ventricular septal defect
with pericardial effusion, both cases at 14 weeks’
DIAGNOSIS OF CONGENITAL HEART DEFECTS gestation. Since then, an increasing number of case
The first diagnosis of a CHD by early echocardio- reports and series on the early diagnosis of CHD have
graphy was reported by Gembruch et al32 in 1990. A been reported, both in high-risk and low-risk
668 Textbook of Perinatal Medicine

V supraaortic
branches

trachea Aortic arch

DAo

D A o: des cending aort a

Fig. 47.9: Early fetal echocardiography by 2D and Color Doppler Fig. 47.10: Early fetal echocardiography by 2D and Color
in a structurally normal heart. Color Doppler is particulary useful Doppler in a structurally normal heart. Color Doppler is
to demonstrate the normal V confluence of the ductal and aortic particulary useful to demonstrate the aortic arch.
archs (V sign). Note that normally the trachea is located behind DAo: descending aorta
the aortic arch

population. Tables 47.1 and 47.2 summarizes some the diagnosis of 173 cases of CHD over 36323 fetuses
of the largest and most significant studies on the evaluated by transvaginal ultrasound at 11-17 weeks’
detection of CHD using early fetal echocardiography gestation over a 14-year period of time, with 99% of
in high-risk and low-risk pregnancies 14,17-22,24-26,34-39 . scans performed at 14-16 weeks’ gestation and 86%
Obviously, studies in unselected population report of them in low-risk population. Recently, two
less encouraging results, with lower visualization institutions went further and reported their
rates and detection rates. The largest series so far is experience performing the echocardiography as early
the one published by Bronshtein et al20. They report as between 10 and 13 weeks’ gestation22,26.

Table 47. 1: Results of early fetal echocardiograpy to diagnose cardiac defects in high-risk
population (only series with at least 10 cardiac defects diagnosed)

Author, year Route GA Success Risk N Cases 11-16 ws 20-22 ws

Gembruch, 9314 TV 11-16 90.3% high 114 13 92% 100%

24
Zosmer, 99 TA 13-17 high 323 27 89% 96.3%
25
Simpson, 00 TA 12-15 98.7% high 229 17 76% 94%
Huggon, 0226 TA 10-14 86.8% high 478 68 94%
Haak, 0222 TV 10-13 95.5% high 45 13 54%
20
Bronshtein, 02 TV 11-17 > 99% high 6175 46 >90%
21
Comas, 02 TV 12-17 94.6% high 337 48 79% 96%
Lopes, 0339 TV 12-16 94,9% high 275 37 89%

Route: main approach. TV: transvaginal, TA: transabdominal

GA: range of gestational age at scan, in weeks
Success: visualization succes rate for the complete early fetal echocardiograpy
N: total number of pregnancies scanned
Cases: total number of cardiac defects (pre- and postnatally)
11-16 ws: percentage of the cardiac defects identified at early echocardiograpy
20-22 ws: percentage of the cardiac defects identified at mid-trimester echocardiograpy
 Echocardiography in Early Pregnancy: A New Challenge in Prenatal Diagnosis 669
Table 47. 2. Detection rate of cardiac defects at early ultrasound to screen for
congenital malformations in low-risk population

Author, year GA Success Risk Normal Cases 11-16 ws 20-22 ws

Achiron, 94 18 13-15 98% low 660 6 50% 50%

34
Hernadi, 97 12 low 3991 3 33% 100%
D’Ottavio, 9735 13-15 low 3490 8 25% 80%
17
Yagel, 97 13-16 99% low 6924 66 64% 81%
36
Economides, 98 12-13 low 1632 3 0% 33%
37
Whitlow, 99 11-14 low 6443 10 40% 60%
Guariglia, 0038 10-16 low 3592 11 18% 56%
19
Rustico, 00 13-15 <50% low 4785 41 10% 32%
20
Bronshtein, 02 11-17 99% low 30148 127 97% 99%

GA: range of gestational age at scan, in weeks

Success: visualization succes rate for the extended cardiac examination (4 chambers + outflow tracts)
Normal: total number of pregnancies screened
Cases: total number of cardiac defects (pre- and postnatally)
11-16 ws: percentage of the cardiac defects identified at early scan
20-22 ws: percentage of the cardiac defects identified at mid-trimester scan

The most frequent fetal heart anomalies diagnosed trimester of pregnancy. Heart defects diagnosed early
at early echocardiography are summarized in Table in pregnancy tend to be more complex than those
47. 3 (true positive cases) 14,18-21,24-26,34,35,37,39. Note that detected later, with a higher incidence of associated
only the main anomaly for each fetus is presented in structural malformations, chromosomal abnormalities
the table, even though some fetuses had several and spontaneous abortions. It is widely accepted that
cardiac anomalies. It should be noted that defects such the spectrum of CHD diagnosed during prenatal life
a small isolated ventricular septal defect or valvular is different from that observed in postnatal series, with
stenosis are not reported in these studies. Table 47. 4 a higher incidence of associated extracardiac lesions
summarizes the published cases of cardiac anomaly and a significant relationship with chromosomal
not detected in early pregnancy (false negative cases) abnormalities in comparison with postnatal life3-5,17.
14,19-21,24-26,34-37,39
. Furthermore, when the cardiac defects are detected
The results of these studies support the use of early during the early pregnancy, they use to be even more
fetal echocardiography to detect the majority of major complex, probably corresponding to the most severe
CHD in both low-risk and high-risk populations, spectrum of the disease21,25,26 and use to cause more
during the first and early second trimester of severe hemodynamic compromise in the developing
pregnancy. The cardiac anomalies detected at this fetus. A common finding is the presence of an
early stage of pregnancy are mainly defects involving hygroma or hydrops associated with CHD, whereas
the four-chamber view, such as large ventricular this is not so when the diagnosis is done later in
septal defects, atrioventricular septal defects and pregnancy1,5,21. As a result, many of these fetuses are
malformations resulting in asymmetry of the not going to survive long into the second trimester,
ventricles, indicating that defects solely affecting the but this does not argue against early diagnosis.
outflow tracts are difficult to diagnose in the first Indeed, when the intrauterine demise of the fetus
670 Textbook of Perinatal Medicine

Table 47. 3: Fetal heart anomalies diagnosed at early echocardiography

(true positive cases at early fetal echocardiography)

True + A B C D E F G H I J K L M N O P Q R Overall

Gembruch, 9314 6 1 1 2 2 12
24
Zosmer, 99 3 3 2 1 4 2 3 1 4 1 24
19
Rustico, 00 2 1 1 1 5
25
Simpson, 00 3 2 3 2 2 1 13
26
Huggon, 02 5 29 12 9 1 1 1 1 1 60
20 *
Bronshtein,02 4 1 4 13 2 9 25 31 22 5 18 17 3 2 13 169
21
Comas, 02 4 8 10 4 1 3 2 2 1 3 38
18
Achiron, 94 2 2 1 1 1 1 8
34
Hernadi, 97 1 1
35
D’Ottavio, 97 2 2 4
37
Whitlow, 99 1 1 1 3
19
Rustico, 00 1 2 1 4
39
Lopes, 03 2 6 11 5 1 1 1 1 3 2 33

OVERALL 4 2 21 71 5 46 54 9 43 24 12 5 29 2 19 9 6 13 374

A abnormal veno-atrial connections; B atrial septal defects; C tricuspid atresia or dysplasia; D atrioventricular septal defect
E single ventricle; F ventricular septal defects; G aortic atresia, aortic stenosis, hypoplastic left heart
H pulmonary atresia or stenosis; I tetralogy of Fallot; J transposition of great arteries; K truncus
L double outlet right ventricle; M aortic arch anomalies; N isomerism;O miocardiopathy; P ectopia cordis
Q complex cardiac defect, others; R vascular ring

* This series include cases with tetralogy of Fallot and double outlet right ventricle

Table 47. 4: Fetal heart anomalies not detected at early echocardiography

(false negative cases at early fetal echocardiography)

False- A B C D E F G H I J Overall

Gembruch, 9314 1 1
Hernadi, 9734 1 1 2
D’Ottavio 9735 1 3 2 1 7
Economides, 9836 1 1 1 3
Whitlow, 9937 2 1 2 1 1 7
Zosmer, 9924 1 1 1 3
Rustico, 0019 1 4 1 2 1 9
Simpson, 0025 3 1 4
Comas, 0221 4 1 3 1 1 10
Huggon, 0226 2 2 1 2 7
Bronshtein, 0220 1 1 1 1 4
Lopes, 0339 3 1 4
OVERALL 18 2 2 1 13 10 5 3 6 1 61

A ventricular septal defects; B atrial septal defects; C abnormal veno-atrial connections; D tricuspid atresia or dysplasia
E atrioventricular septal defect; F aortic atresia, aortic stenosis, hypoplastic left heart; G tetralogy of Fallot
H transposition of great arteries; I aortic arch anomalies; J miocardiopathy
 Echocardiography in Early Pregnancy: A New Challenge in Prenatal Diagnosis 671
occurs days or weeks before the delivery, the twin pregnancies. The women were attending the
pathological examination is certainly more difficult prenatal diagnosis units of either Institut Universitari
to perform. All these considerations should be taken Dexeus in Barcelona (Group I), Hospital 12 de Octubre
into account when counselling the parents complex in Madrid (Group II) or Institut Clínic d’ Obstetrícia,
CHD. Ginecologia i Neonatologia del Hospital Clínic in
This review presents our experience in the first Barcelona (Group III) for ultrasound examination
multicenter trial in early fetal echocardiography because of an increased a priori risk for heart
performed in Spain 21 . In accordance with other anomalies. These are referral centers for prenatal
studies, this experience stresses the usefulness of early diagnosis of CHD. Fetal echocardiography was
echocardiography when performed by expert performed combining transvaginal and
operators on fetus specifically at risk for cardiac transabdominal probes between 12 and 17 weeks’
defects. Our review of these additional 48 cases gestation. When possible, we selected the 14th week
contributes to the expanding literature on the ability of gestation as the optimal time for TV scan because
of TV ultrasonography to detect fetal heart defects in the visualization of heart structures is better at this
early pregnancy. time. This is a prospective design study, performed
from September 1999 to May 2001, where the overall
OUR EXPERIENCE IN EARLY PRENATAL group was reviewed focusing in the feasibility of
DIAGNOSIS OF CONGENITAL HEART diagnosing fetal CHD by early echocardiography. An
ANOMALIES informed consent was obtained from each patient and
the study was approved by our ethics committees.
Methods
Epidemiological data are summarized in Table 47.
A multicenter study was made of 334 fetuses from 5, for the overall group and according to the reference
330 selected high-risk pregnant women, including 4 unit. Maternal age ranged from 17 to 46 years (mean

Table 47.5: Our experience21: Epidemiological DATA

GROUP I GROUP II GROUP III OVERALL

(GROUP I+II+III)

n (pregnancies) 68 (4 twins) 130 132 330 (334 fetuses)

Study period 9/99 to 5/01

GA (mean, range) 14.9 (12-17) 13.7 (12-16) 14.3 (13-16) 14.2 (12-17)

MA (mean, range) 33 (26-46) 33 (17-45) 32 (19-42) 33(17-46)

30% > 34 years 37% > 34 years 38% > 34 years 36% > 34 years

Ultrasound system Toshiba SSH-140 Acuson 128 XP Acuson 128 XP –

5.0-7.5 MHz TV 5.0-7.0 MHz TV Aspen
3.0-6.5MHz TA 3.5-5.0 MHz TA 5.0-7.0 MHz TV
3.5-5.0 MHz TA

Optimal visualization 65/72 (90.3%) 119/130 (91.5%) 132/132 (100%) 316/334 (94.6%)

Overall follow-up 44/72 (61.1%) 108/130 (83.1%) 129/132 (97.8%) 281/334 (84.1%)

GA gestational age (weeks); MA maternal age (years); TV transvaginal; TA transabdominal

672 Textbook of Perinatal Medicine

33 years with 36% of women over 34 years). The visualization, only when an anomaly was suspected
median gestational age at scan was 14.2 weeks (range a second scan was arranged two weeks later.
12-17 weeks). The distribution of gestational ages was Ultrasound examinations were performed using a
as follows: 23 cases at 12 weeks, 76 cases at 13 weeks, multifrequency real-time vaginal probe (5.0-7.5MHz)
101 cases at 14 weeks, 72 cases at 15 weeks, 54 cases and convex abdominal probe (3.0-6.5MHz) on a
at 16 weeks and 8 cases at 17 weeks. Toshiba ultrasound system (Toshiba SSH-140A,
Fetal echocardiography was performed in a Toshiba Co., Tokyo, Japan), Acuson 128 XP or Aspen
population with an increased a priori high- risk for (Acuson Inc., Mountain View, CA), and General
congenital heart defects. Criteria for inclusion were Electric Logic 400 or Logic 500 (GE Medical Systems,
family history of CHD (n=37), ultrasound markers for Milwaukee, Wisconsin). The ultrasound examination
chromosomal abnormalities (n=186), as increased was mainly performed transvaginally, completed
nuchal translucency (NT) (NT>99th centile) or nearly always by the transabdominal route. For color
abnormal ductus venosus (DV) flow (pulsatility index Doppler evaluation, the energy output levels were
for veins in the DV >95th centile), suspected cardiac lower than 50mW/cm 2 spatial peak-temporal
or extracardiac anomalies at early second-trimester average. The duration of complete heart examination
scan (n=43), maternal pregestational diabetes (n=33), was less than 30 minutes. All the examinations were
pregnancy affected by a chromosomal abnormality made by three experienced operators (CC, JMM and
(n=8), exposition to teratogens (n=3), genetic AG).
sonography (n=22) and as a screening test (n=2). These When indicated, fetal karyotyping by chorionic
last two cases refer to two twin pregnancies in which villus sampling or amniocentesis was offered.
the main indication for the echocardiography was an According to the policy of our institutions, invasive
ultrasound marker for chromosomal abnormality in testing was recommended as a result of advanced
one fetus, but the echocardiographic examination was maternal age (>35 years), family history of
performed to both fetuses for practical reasons. For aneuploidy, biochemical screening for Down’s
NT and DV assessment, measurements were made syndrome higher than 1/270 or ultrasound anomalies
between 10 and 16 weeks’ gestation. Nuchal (including malformations or NT>95th centile).
translucency was systematically assessed in all cases, Fluorescence in situ hibridation (FISH) studies to test
while DV blood flow was only measured in Group I for 22q11 deletion was also offered when a heart
and II. We have used our own published nomograms malformation affecting the great arteries was
to define increased NT or abnormal DV 40. Genetic suspected. When possible, in those who continue their
sonography was offered to high-risk population pregnancies, a follow-up detailed ultrasound scan
refusing invasive karyotyping test. was carried out at 20-22 weeks’ gestation. When
For each fetus, visualization of the 4-chamber view karyotyping was not performed, chromosomal
(with both atria, atrioventricular valves and abnormalities were excluded at neonatal examination.
ventricles), the origin and double-crossing of the great Reliability was assessed by conventional
arteries, aortic and ductal archs and systemic venous transabdominal echocardiography at 20-22 weeks, by
return was attempted in a segmental approach. Two- post-natal follow-up in the first 3 months of life, and/
dimensional mode and color/pulsed Doppler flow or by autopsy in cases of termination of pregnancy
imaging were used in all cases, while M-mode was (TOP). Minor cardiac anomalies described in the
occasionally performed. The operators kept a record literature as difficult or impossible to diagnose early
of optimal visualization (complete visualization of (atrial septal defects or patent ductus arteriosus) were
heart structures) or partial visualization (incomplete not considered when calculating the validity of the
visualization of heart structures). In cases of partial early echocardiography.
 Echocardiography in Early Pregnancy: A New Challenge in Prenatal Diagnosis 673
Results normal heart in a Down’syndrome affected by a
patent ductus arteriosus who had neonatal surgery,
The rate of optimal visualization of the fetal heart was
Karyotyping was performed in 290 cases of our
94.6% (316/334). In 48 out of 334 (14.4%) fetuses the
series (86.8%), including all cases with cardiac
final diagnosis was abnormal, including 48 cases of
abnormalities. Among the whole series, 51 cases had
structural heart abnormalities (Table 47. 6). In 38 out
an abnormal karyotype. These chromosomal
of 48 cases with heart defects the diagnosis was
abnormalities included trisomy 21 (n=28), 45XO (n=7),
suspected at early echocardiography. These true
trisomy 18 (n=6), trisomy 13 (n=2), 22q11
positive cases were as follows: 13 cases of abnormal
microdeletion (n=1), triploidy (n=1), trisomy 7 (n=1),
outflow tracts, 8 cases of atrioventricular defect, 4
partial trisomy 15 (n=1), rearrangement (n=1) and
cases of hypoplastic left heart (HLH), 5 cases of
others (n=3). Among the heart defects, 27 cases (56.3%)
tricuspid atresia or dyspasia, 3 cases of isolated
had an abnormal karyotype (13 trisomy 21, 5 trisomy
ventricular septal defect (VSD), 3 cases of ectopia
18, 3 Turner’ syndrome, 2 trisomy 13, 1 trisomy 7, 1
cordis, 1 case of aortic coartation and 1 severe complex
partial trisomy 15, 1 rearrengement and 1 case with a
heart defect. True positive diagnoses are summarized
22q11 microdeletion detected by FISH) and 31 cases
in Table 47. 7. Figs 47.11 to 47.15 illustrate some
(64.6%) showed additional sonographic extracardiac
examples of detected CHD early in pregnancy.
anomalies, including mainly cystic hygroma,
There were ten false negative cases (2 cases of
congenital diaphragmatic hernia, abnormal situs
HLH, 3 cases of atrioventricular defect, 4 cases of VSD
visceralis, single umbilical artery, bilateral dysplastic
and 1 case of Tetralogy of Fallot) (Table 47. 8). There
kidneys, hydrops, limb-body wall complex,
were no false positive diagnoses. When considering
omphalocele, exencephaly, holoprosencephaly,
the validity of the early echocardiography, we have
pyelectasis, choroid plexus cysts, hemivertebra and
excluded one case of isolated pericardial effusion, two
pleural effusion.
cases of significant tricuspid regurgitation within a
In CHD group, increased NT at 10-16 weeks’
structurally normal heart, a child affected by an
gestation was noted in 21 fetuses (43.8%), while
ostium secundum atrial septal defect, a structural
abnormal DV blood flow was found in 18 out of 37
fetuses with DV assessment (48.6%).
Table 47.6: Our experience21: congenital heart defects
The outcome of fetuses with a CHD was poor. In
OVERALL 37 cases a TOP was performed at parents request
(GROUP I+II+III) before 20 weeks’ gestation and in 1 case a selective
Prevalence 48/334 (14.4%)
feticide was offered in a twin pregnancy discordant
True positive 38/48 (79.2%) for a CHD. The outcome of the surviving fetuses was
False negative 10 poor, with 2 cases of neonatal death (1 ventricular
False positive 0 septal defect, 1 hypoplastic left heart) and 8 surviving
Chromosomal abnormalities 27/48 (56.3%)
Extracardiac abnormalities 31/48 (64.6%) children (1 ventricular septal defect, 3 atrioventricular
Increased NT 21/48 (43.8%) defects, 1 pulmonary stenosis, 1 ventricular septal
Abnormal DV 18/37 (48.6%) defect diagnosed of Noonan‘s syndrome, 1 case of
Outcome 37 TOP
Tetralogy of Fallot, and 1 single ventricle with
1 selective feticide
2 postnatal death transposition of great arteries who died 3 months after
8 surviving paliative surgery). Pathological examination was
Follow-up 33/48 (68.8%) performed in 25 cases. In 16 cases the autopsy was
Autopsy available 25/41 (61.0%)
not available, either because of the selective feticide
NT nuchal translucency; DV ductus venosus; TOP in a twin pregnancy, or because the termination was
termination of pregnancy
performed in other hospital without fetal necropsy,
674 Textbook of Perinatal Medicine

Table 47. 7: Our experience21: Fetal heart anomalies diagnosed at early echocardiography (true positive cases at early
fetal echocardiography) Fetal data of true positives cases (congenital heart defects, gestational age at diagnosis, associated
findings, karyotyping studies and follow-up)

Case CHD GA Associated findings Karyotype Follow-up

1 AVSD 17 Increased NT Trisomy 21 TOP, no autopsy

2* Hypoplastic RV 16 Single UA Normal TA-echo confirmative
Tricuspid atresia Selective feticide
Abnormal great arteries
3 AVSD 14 Increased NT Trisomy 21 TOP, no autopsy
4 AVSD 13 Cystic hygroma Trisomy 21 TOP, no autopsy
5 VSD 17 Cystic hygroma Normal Surviving
Follow-up confirmative
Noonan syndrome
6 VSD 15 Abnormal situs 22q11 deletion TOP, autopsy: abnormal situs
Abnormal great arteries Single UA visceralis, VSD, hypoplastic RV,
truncus
7 AVSD 12 Increased NT Trisomy 21 TOP, no autopsy
8 Abnormal great arteries 14 Cystic hygroma Normal Surviving, postnatal echo: tetralogy of
Fallot
9 HLH, DORV, 16 Bilateral renal dysplasia Normal TOP, autopsy confirmative
Pulmonary atresia
10 VSD, DORV 16 Increased NT Partial trisomy 15 TOP, autopsy confirmative
11 Truncus 15 Polimalformative fetus Trisomy 13 TOP, autopsy confirmative
12 VSD, DORV, Pulmonary atresia 12 Exencephaly Normal TOP, no autopsy
13 VSD, DORV 16 Ventriculomegaly, single UA Normal TOP, no autopsy
14 Tetralogy of Fallot 16 Increased NT, bilateral renal Normal TOP, no autopsy
dysplasia, omphalocele
15 Tetralogy of Fallot 13 Increased NT, bilateral renal Trisomy 7 TOP, no autopsy
dysplasia
16 AVSD 16 – Normal Surviving; Follow-up confirmative
17 AVSD 13 Increased NT Trisomy 21 TOP, autopsy confirmative
Hydrops
18 AVSD 13 Increased NT Trisomy 21 TOP, autopsy confirmative
Omphalocele
19 VSD 16 Holoprosencephaly Trisomy 13 TOP, autopsy confirmative
20 VSD 13 Increased NT Trisomy 21 TOP, autopsy confirmative
21 HLH 13 Exencephaly Normal TOP, no autopsy
22 HLH 12 Increased NT 45XO TOP, no autopsy
23 HLH 12 Increased NT, hydrops 45XO TOP, autopsy confirmative
24 Aortic coartation 16 Cystic hygroma, hydrops 45XO TOP, no autopsy
25 Trisuspid atresia 16 Increased NT Normal TOP, autopsy confirmative
26 Tricuspid atresia 16 Increased NT Normal TOP, autopsy confirmative
27 Ectopia cordis 12 Limb-body wall complex Normal TOP, no autopsy
28 Ectopia cordis 14 Limb-body wall complex Normal TOP, autopsy confirmative
29 Ectopia cordis, 14 Increased NT Trisomy 18 TOP, autopsy confirmative
Tricuspid atresia Limb-body wall complex
30 Tricuspid dysplasia 13 Increased NT Trisomy 21 TOP, no autopsy
31 VSD, overriding aorta 13 Increased NT Trisomy 18 TOP, no autopsy
Omphalocele
32 DORV+ mitral atresia 13 Increased NT Trisomy 18 TOP, no autopsy
33 VSD, tricuspid atresia 14 Increased NT Normal TOP, autopsy confirmative
34 Pulmonary stenosis 15 – Normal Surviving
Follow-up confirmative
35 Single ventricle, TGA 15 – Normal Surviving
Follow-up confirmative a
36 VSD, pulmonary atresia 16 Increased NT Rearrengement TOP, autopsy confirmative
37 AVSD 16 Increased NT Trisomy 21 TOP, autopsy confirmative
Abnormal situs
38 HLH+ abnormal situs 16 Increased NT Normal TOP, autopsy confirmative

CHD: congenital heart defect; GA: gestational age (weeks); TOP: termination of pregnancy; TA-echo: transabdominal conventional second-trimester
echocardiography; *twin pregnancy; AVSD: atrioventricular septal defect; VSD: ventricular septal defect; LV: left ventricle; RV: right ventricle; ASD:
atrial septal defect; DO: double outlet; HLH: hypoplastic left heart; TGA: transposition of great arteries; UA: umbilical artery; CDH: congenital diaphragmatic
hernia; NT: nuchal translucency
a
death at 3 months of life after paliative surgery
Echocardiography in Early Pregnancy: A New Challenge in Prenatal Diagnosis 675

13 weeks’ gestation
cystic hygroma
abnormal ductus venosus flow
trisomy 21
Fig. 47.11: Atrioventricular septal defect detected at 13 weeks’ gestation in a fetus affected by cystic
hygroma and trisomy 21. Note the abnormal reveresed A wave in the ductus venosus

cystic hygroma 46,XX

abnormal outflow tracts left cardiac axis deviation
intrauterine death at 36weeks’ gestation necropsy: tetralogy of Fallot
Fig. 47.12: Tetralogy of Fallot detected at 16 weeks’ gestation in a fetus affected by cystic hygroma and normal
karyotype. Note the left cardiac deviation and the dominance of the aorta compared with the small pulmonary artery
at the 3 vessel view in the upper mediastinum
676 Textbook of Perinatal Medicine

15 w eeks’ gestation
abnormal ductus venosus flow
trisomy 18
termination of pregnancy (TOP)
necropsy confirmative

Fig. 47.13: Atrioventricular septal defect with unbalanced right ventricle dominance and double
outlet right ventricle at 15 weeks’ gestation. Note the abnormal reveresed A wave in the ductus venosus

15 weeks’ gestation increased NT

abnormal ductus venosus flow absent nasal bone single umbilical artery
trisomy 18, TOP, necropsy confirmative
Fig. 47.14: Hypoplastic left heart and double outlet right ventricle at 15 weeks’ gestation in a trisomy 18. Note
the identification of multiples markers of chromosomal abbormality (increased nuchal translucency, abnormal
ductus venosus flow, absent nasal bone, single umbilical artery)
 Echocardiography in Early Pregnancy: A New Challenge in Prenatal Diagnosis 677

17 weeks’ gestation
left cardiac axis deviation 45 X0
TOP
necropsy: confirmative

Fig. 47.15: Hypoplastic left heart and aortic stenosis at 17 weeks’ gestation in a Turner syndrome. Note the left
cardiac axis deviation, the opposite color flow in the V sign at the upper mediastinum level and the severe
reduction of the aortic outflow tract compared to the main pulmonary ar tery

Table 47.8: Our experience21: Fetal heart anomalies not detected at early echocardiography (false negative cases at
early fetal echocardiography) Fetal data of false negatives cases (congenital heart defects, gestational age at diagnosis,
associated findings, karyotyping studies and outcome)

Case CHD GA1 GA2 Method Associated Karyotype Outcome

diagnosis findings

1* HLH 14 20 TA-echo Congenital

Diaphragmatic hernia Normal Neonatal death
after surgery
2 Ostium primum, 14 20 Autopsy Hydrops Normal TOP
ASD, HLH Cystic higroma
3 AVSD 14 20 TA-echo Single umbilical artery Trisomy 21 TOP
Short femur
4 AVSD 16 33 TA-echo - Normal Surviving
5 AVSD 15 23 TA-echo Echogenic foci Trisomy 21 Surviving
Pleural effusion
6 VSD 12 14 Autopsy Pyelectasis Trisomy 21 TOP
7 VSD 15 28 TA-echo Choroid plexus cysts Trisomy 18 Neonatal death
Hemivertebra
8 VSD 13 15 Autopsy NTD 48,XXY+18 TOP
9 Tetralogy of Fallot 13 20 TA-echo Pyelectasis Trisomy 21 TOP
10 VSD 13 21 TA-echo - Normal Surviving

* twin pregnancy; CHD congenital heart defect, GA1 gestational age of the echocardiographic examination in early pregnancy
(weeks); GA2 gestational age at diagnosis (weeks); TOP termination of pregnancy; HLH hypoplastic left heart; TA-echo
transabdominal echocardiography; ASD atrial septal defect; AVSD atrioventricular septal defect; VSD ventricular septal defect;
NTD neural tube defects
678 Textbook of Perinatal Medicine

or due to the unavailability of an adequate material finding of an increased NT seems to vary between 4-
for pathological exam (fragmentation), or because the 9%24,54. Recently, Galindo et al. have examined the
parents declined the examination. prevalence, distribution and spectrum of cardiac
In our series of early echocardiography, a complete defects in 353 chromosomally normal fetuses with
follow-up was possible in 281 cases (84.1%), 61.1% in increased NT, with a complete follow-up in 97% of
Group I, 83.1% in Group II and 97.8% in Group III . the cases55. This multicenter Spanish study present
When a heart defect was detected, a complete follow- an overall prevalence of heart defects of 9,1%,
up was possible in 33 out of 48 cases (68.8%). increasing significantly from 5,3% in those with NT
>95th centile to 24% when thickness >6mm.
Fetal Heart Rate Interestingly, most of the cardiac defects can be
prenatally detected. A wide range of cardiac
The diagnosis of fetal arrhytmia early in pregnancy
anomalies were observed in this series, with the most
may rise the suspicion of a fetal chromosomal
common being atrioventricular septal defects and
abnormality 34-36 , an increased risk for a later
tricuspid atresia. Hyett et al reported that about 55%
miscarriage35,37,38,41 or the presence of a CHD42. The
of major CHD were associated with a fetal NT
factors that control fetal heart rate in the first trimester
thickness above 95th centile at 10-14 weeks of
are uncertain, so the underlying cause of the abnormal
gestation 8. However, others have failed to
pattern in chromosomally abnormal fetuses remains
demonstrate such a strong association49,50,53,54,56-58 ,
obscure. A delay in maturation of sympathetic and
raising the matter that the routine assessment of the
parasympathetic systems as well as an abnormally
four chambers and great vessels at mid-second
developed and responsive myocardium have been
trimester remains as the most important screening
proposed30,43. An alternative explanation could be that
tool for the detection of major CHD56,59. Theoretically,
fetal arrhythmias are a reflection of an underlying
both types of screening used in combination should
structural heart disease, which are a common feature
improve the overall sensitivity of prenatal diagnosis
in trisomic fetuses35,42,44,45. Baschat et al46 reported
of major cardiac defects.
four cases of severe CHD associated with bradycardia
The physiopathogenic mechanism of this
(likely to be atrioventricular block) during early relationship is not easy to explain11,44,45,53,59,60-63 .
echocardiography at 11-14 weeks’ gestation. All cases Pathological examination of fetuses with increased NT
had either increased NT or generalized edema and thickness at 10-14 weeks have demonstrated a high
complex CHD. Most authors find a high correlation prevalence of cardiac defects and abnormalities of the
between abnormal heart rate and increased NT in great arteries and of subtle defects, such as widening
chromosomally abnormal fetuses, thus supporting the of the aortic valve and ascending aorta, narrowing of
hypothesis that cardiac defects may be involved in the aortic isthmus and persistence of the left superior
the physiologic basis of nuchal translucency35,36,47. vena cava. Another proposed mechanism to explain
the increased NT is an early cardiac function
Nuchal Translucency and Ductus Venosus
impairment suggested by an abnormal DV flow
Nuchal translucency measurement at 10-14 weeks’ pattern. However, Matias et al10 reported that most
gestation is a widely accepted method to screen for of chromosomally normal fetuses with increased NT
chromosomal abnormalities. Recent studies have but normal DV flow did not have a CHD. This finding
suggested the potential role of an increased NT might contradict a cardiac involvement in the
thickness 8,9,11,48-51 or an abnormal DV flow pattern pathogenesis of the increased NT in most of the
10,11,52,53
at early pregnancy as a screening tool for fetuses, and suggest that only fetuses with abnormal
CHD, in addition to its role in screening for DV blood flow are those at high-risk of CHD. On the
chromosomal defects. The risk of CHD after the other hand, in cases with CHD and both enlarged NT
 Echocardiography in Early Pregnancy: A New Challenge in Prenatal Diagnosis 679
and abnormal DV, because the type of cardiac defects the second trimester26,69,70. The chromosome defect
cannot always explain the hemodynamic changes most frequently found to be associated with tricuspid
found in these fetuses, some other mechanisms seem regurgitation was trisomy 21, but all types of
to be envolved53. karyotype anomalies were seen in association69. In
Based on ultrasonographic and post-mortem view of these results, the authors propose to assess
morphological studies, the findings in increased NT the four-chambers view and the outflow tracts for
fetuses can be classified in three categories64. First, an disproportion and to use color Doppler to rule out
association between increased NT and cardiac tricuspid regurgitation in each first or early second
anomalies, combined with an abnormal ductus trimester ultrasound to screen for chromosomal
venosus flow pattern, has been described in some anomalies26,27 . Since these unexpectedly good results
cases, leading to the theory that cardiac failure causes were obtained in particularly high-risk fetuses, they
NT enlargement. Second, various types of remain to be confirmed in unselected population.
abnormalities have been found in the extracellular
matrix of the nuchal skin of fetuses with increased ADVANTAGES AND LIMITATIONS
NT. Third, abnormal lymphatic development has been The first benefit of performing early fetal
demonstrated in fetuses with increased NT. Many echocardiography would be an early reassurance of
hypotheses on NT enlargement are based on normality in order to relieve anxiety and reduce
associations and speculations.Therefore, wihin this emotional trauma to the parents at high-risk for CHD.
context, it is not clear whether all these cardiovascular Early prenatal diagnosis of CHD will allow us to
anomalies are the cause of the increased nuchal optimize the genetic counselling to the parents by
translucency or both events are the result of another permitting further testing such as fetal karyotyping
pathophysiologic mechanism. and in those cases with severe defects it may provide
the parents with the option of an earlier and safer
Chromosomal Abnormalities
termination of pregnancy13,14,17 . In selected cases,
The detection of a CHD may be the first clue to the there is the possibility of pharmacologic therapy.
diagnosis of a chromosomal abnormality or a genetic Furthermore, the correct timing and place for delivery
syndrome. The incidence of chromosomal defects in may be planned and arranged well in advance.
CHD diagnosed prenatally may be as high as 30-40%, However, there are certain disadvantages of the
and 15% when the CHD is presented isolated. These early scanning which reduce its diagnostic accuracy
figures increase up to 40-60% when the CDH is compared with the conventional examination at 20-
diagnosed during the first trimester20-22,26. This is 22 weeks’ gestation 1,5,13,14,17 . The transvaginal
much higher than the incidence in liveborns. Also, the technique requires a substantial amount of operator
high rate of spontaneous abortion loss in early experience, yet it can not be learned from the second
pregnancy suggest a higher rate of chromosomal trimester examination as the early transabdominal
abnormalities in first trimester fetuses with CHD. scan. Unfavourable fetal position or limited angles of
Therefore, whenever a CHD is diagnosed, karyotype insonation due to the less mobile capacity of the
evaluation is mandatory, including FISH test to rule transvaginal probe may not be overcome. Also, spatial
out 22q11 deletion65-68. orientation can be challenging by the transvaginal
Recently, the early finding of isolated tricuspid scan. In such cases, we recommend a transabdominal
regurgitation or disproportion of the cardiac scan that will help us to quickly asses the situs and
chambers and/or outflow tracts, has been regarded obatin a good spatial orientation. The small size of
to be highly associated with fetal chromosomal the fetal heart is an important limiting factor to obtain
abnormalities, even in the absence of structural heart an optimal sonographic visualization, and also to
disease, as it had been previously described during obtain a successful pathological examination,
680 Textbook of Perinatal Medicine

particularly before the 13th week of gestation. At 13- of early fetal echocardiography as a diagnostic
14 weeks of gestation the transverse diameter of the technique. Therefore, we advocate that a precise
heart at the four-chambers view ranges between 5 to pathological report have to be compulsory for an
8 mm, and the great artery diameter at the level of adequate assessment of the reliability of early fetal
the semilunar valves ranges between 0.8-1.8 mm5. echocardiography. This is still a major drawback in
Moreover, this exploration is more time-consuming most of the studies1,5,21,26.
and requires a high level of training of the examiner. Termination of pregnancy is an option only before
Finally, the biggest disadvantage of first-trimester 22 weeks of gestation in our country. Whenever a
echocardiography is the later manifestation of termination takes place, it is of vital importance to
structural and functional changes in some CHD. Some obtain permission for autopsy in order to confirm the
cardiac lesions are progressive in nature, such as mild diagnosis and to search for any other associated
pulmonary and aortic stenosis or coarctation and even malformations. Ideally this should be performed by
hypoplastic left heart syndrome. Some obstructive a pathologist who is familiar with the small size of
lesions, as a result of a reduced blood flow, may the specimen and with special examination techniques
increase the severity of the lesions, resulting in a such as dissection microscopy 5,21,22,45. Current
restricted growth in chambers or arteries. This may methods of terminating early pregnancies others than
be the biggest disadvantage of performing the early using prostaglandins are less recommended because
scan. Progression usually is towards a more severe do not usually allow the retrieval of suitable
form of lesion that may be sometimes only discernible specimens for appropriate examination to correlate
in the second or even in the third trimester, although ultrasound and pathological findings45. This method
in some rare cases a regression to a less severe form allows a more gentle extraction of the embryo or fetus
may be observed. In this sense, the false negative cases so that a pathological examination for verification of
published in literature are particularly instructive the prenatally diagnosed malformation can be
demonstrating these limitations (Table 47. 4). Another performed. A pathological investigation after TOP
disadvantage of early fetal echocardiography is the following the diagnosis of a CHD should be always
possible detection of defects that could resolve recommended, preferably in referral laboratories,
spontaneously in later pregnancy, such as muscular being of paramount importance to validate early
venticular septal defects, resulting in unnecessary echocardiography. In particular semilunar valve and
anxiety in the parents. aortic arch defects are usually underdiagnosed. We
Therefore, a normal early examination does not are aware of some cases in which Doppler findings,
preclude a subsequent abnormal heart development such turbulent flow and very high velocities, are more
at the second trimester ultrasound, or even in the third reliable to diagnose valve stenosis than pathological
trimester or the postnatal period. After a normal early examination, even during the second trimester.
fetal echocardiography, a conventional Indeed, this is a problem and a major challenge not
transabdominal echocardiography at 20-22 weeks of only for ultrasonographers but also for pathologists.
gestation is strongly recommended.
INDICATIONS OF EARLY FETAL
PATHOLOGICAL CONFIRMATION ECHOCARDIOGRAPHY
Pathological confirmation in the case of an early Since most CHD are detected in low-risk pregnancies,
termination of pregnancy or perinatal death is and knowing the high prevalence of heart defects in
particularly important in those areas where a non selected population (incidence of CHD in low
ultrasound diagnosis is most challenging. Only a risk population 1\238),20 some authors suggest that
complete diagnosis will make an individual genetic an early detailed cardiac examination should be
counselling possible and will validate the accuracy performed in all pregnant women17,20 . Indeed, very
 Echocardiography in Early Pregnancy: A New Challenge in Prenatal Diagnosis 681
few cardiac defects have been identified in the unclear, this examination should be generally
pregnancies in which a family history was the main reserved for patients at high-risk for CHD. However,
indication for the early fetal echocardiography, which only the accumulation of results from carefully
is consistent with the recurrence rate of 2-3% for collaborative studies as the present series will clear
siblings. The main value of the early scan in such define the role of early transvaginal echocardiography.
family-risk cases lies in the reassurance that it gives
to the parents. As we have previously stated, in most CONCLUSION
of the studies the early echocardiography is somewhat Fetal echocardiography performed by expert
less reliable and may result in a higher false-negative
operators is reliable for an early reassurement of
and false-positive results in comparison with the 20-
normal cardiac anatomy.
22 weeks transabdominal echocardiography. Besides,
1. Transvaginal sonography enables good
early echocardiography is most time-consuming and
visualization of fetal heart earlier in gestation. The
requires a high level of expertise of the examiner.
four-chambers view and the extended
Therefore, it is difficult to offer this scan as a screening
examination to the great vessels can be imaged
test to the general population. In this context, the
in almost 100% at 13-14 weeks of gestation. Less
identification of a high-risk collective is of paramount
than 5% of patients will need a repeated scan
importance.
because of inadequate visualization.
Currently, the importance of the aforementioned
2. The combination of transvaginal and transabdominal
limitations of early fetal cardiac examination justifies
routes and the application of colour Doppler
restriction of its use to fetuses at high risk of having
enhances visualization.
cardiac anomalies 5,10,14,18,21,22,26 . The indications
3. Most CHD are detected in low-risk population. As
proposed for early fetal echocardiography are:
we can not perform a tarjeted fetal
• increased nuchal translucency (>95th or 99th
echocardiography as a screening test, we need
centile) is the main indication of referral in all
to improve the identification of high-risk group
recently reported studies
pregnancies. Increased nuchal translucency at 10-
• abnormal ductus venosus blood flow, regardless
the measurement of the nuchal translucency 14 weeks’ scan and, maybe, ductus venosus
• fetuses affected by other structural malformations: blood flow assesment seem to be the newest and
hygroma, hydrops, omphalocele, situs inversus, most promising risk factors for fetal CHD, and
arrythmia may be particularly useful during the first
• suspected cardiac anomalies at screening trimester.
ultrasound 4. Currently, early fetal echocardiography should be
• pregestational diabetes of the mother offered to high-risk pregnancies. Some authors
• high-risk family, with a previously affected child, advocate routine early extended cardiac
a first-degree relative affected by a congenital heart examination in low-risk pregnancies. At present,
disease or a genetic disease in which CHD are as long as the sensitivity, specificity and
common predictive value of early echocardiography is still
• women at high risk of chromosomal abnormality unclear, this examination should be generally
declining invasive test for karyotyping reserved for patients at high-risk for CHD.
• pregnancies affected by a chromosomal 5. Whenever a normal heart is diagnosed in the
abnormality early scan, it has to be supplemented with the
Currently, as long as the sensitivity, specificity and conventional transabdominal examination at 20-22
predictive value of early echocardiography is still weeks’ gestation.
682 Textbook of Perinatal Medicine

Fetal echocardiography performed by expert Belgian Multicentric study 1984-92. Ultrasound Obstet.
Gynecol 1995;5:366-371.
operators is reliable to diagnose most major
8. Hyett J, Perdu M, Sharland G, Snijders R, Nicolaides KH.
structural heart defects in the first and early second Using nuchal translucency to screen for major cardiac
trimester of pregnancy. defects at 10-14 weeks of gestation: population based
1. Cardiac defects diagnosed early in pregnancy tend cohort study. Br Med J 1999;318:81-5.
9. Devine PC, Simpson LL. Nuchal translucency and its
to be more complex than those detected later on and relationship to congenital heart disease. Semin Perinatol
use to cause more severe hemodynamic 2000;24:343-51.
compromise in the developing fetus. 10. Matias A, Huggon I, Areias JC, Montenegro N,
Nicolaides KH. Cardiac defects in chromosomally
2. Many CHD can be detected at the beginning of the
normal fetuses with abnormal ductus venosus blood
second trimester. flow at 10-14 weeks. Ultrasound Obstet Gynecol
3. The incidence of associated structural malformations, 1999;14:307-10.
chromosomal abnormalities and spontaneous abortions 11. Bilardo CM, Müller MA, Zikulnig L, Schipper M, Hecher
K. Ductus venosus studies in fetuses at high risk for
is significantly high. chromosomal or heart abnormalities: relationship with
4. A complete work-up including pathological and nuchal translucency measurement and fetal outcome.
karyotype evaluation should be warranted in Ultrasound Obstet Gynecol 2001;17:288-94.
12. Johnson P, Sharland G, Maxwell D, Allan L. The role of
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if spontaneous loss of the pregnancy occurs. 1992;2:248-51.
5. The small size of specimens at this time of gestation 13. Bronshtein M, Zimmer EZ, Gerlis LM, Lorber A, Drugen
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renders pathological examination difficult and in high-risk and low-risk pregnancies. Obstet Gynecol
requires high expertise and careful inspection, 1993;82:225-9.
irrespective of the technique used for 14. Gembruch U, Knopfle G, Bald R, Hansmann M. Early
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6. Clinical follow-up in the neonate and postmortem Gynecol 1993;3:310-17.
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Hansmannn M. First-trimester diagnosis of fetal
47. Yagel S, Anteby E, Ron M, Hochner-Celnikier D. The role
congenital heart disease by transvaginal two-
of abnormal fetal heart rate in scheduling chorionic villus
dimensional and Doppler echocardiography. Obstet
sampling. Br J Obstet Gynaecol 1992;99:739-40.
Gynecol 1990;75:496-8. 48. Hyett JA, Moscoso G, Papapanagiotou G, Perdu M,
33. Bronshtein M, Siegler E, Yoffe N, Zimmer EZ. Prenatal Nicolaides KH. Abnormalities of the heart and grat
diagnosis of ventricular septal defect and overriding arteries in chromosomally normal fetuses with increased
aorta at 14 weeks’ gestation using transvaginal nuchal translucency thickness at 11-13 weeks of
sonography. Prenat Diagn 1990;10:697-705. gestation. Ultrasound Obstet Gynecol 1996;7:245-50.
34. Hernadi L, Torocsik M. Screening for fetal anomalies in 49. Moscoso G. Fetal nuchal translucency: A need to
the 12th week of pregnancy by transvaginal sonography understand the physiological basis. Ultrasound Obstet
in an unselected population. Prenat Diagn 1997;17:753- Gynecol 1995;5:6-8.
9. 50. Mavrides E, Cobian-Sanchez F, Tekay A, Moscoso G,
35. D’Ottavio G, Meir YJ, Rustico MA, Pecile V, Fischer- Campbell S, Thilaganathan B, et al. Limitations of using
Tamaro L, Conoscenti G, Natale R, Mandruzzato first-trimester nuchal translucency measurement in
GP.Screening for fetal anomalies by ultrasound at 14 and routine screening for major congenital heart defects.
21 weeks. Ultrasound Obstet Gynecol 1997;10:375-80. Ultrasound Obstet Gynecol 2001;17:106-110.
684 Textbook of Perinatal Medicine

51. Hyett JA, Perdu M, Sharland GK et al. 1997. Increased nuchal translucency at 10-14 weeks’ gestation. J Med
nuchal translucency at 10-14 weeks of gestation as a Genet 1998;35:222-4.
marker for major cardiac defects. Ultrasound Obstet 61. Schwärzler P, Carvalho JS, Senat MV, Masroor T,
Gynecol 10:242-6 Campbell S, Ville Y. Screening for fetal aneuploidies and
52. Huisman TWA, Bilardo CM. Transient increase in nuchal fetal cardiac abnormalities by nuchal translucency
translucency thickness and reversed end-diastolic ductus thickness measurement at 10-14 weeks of gestation as
venosus flow in a fetus with trisomy 18. Ultrasound part of routine antenatal care in an unselected
Obstet Gynecol 1997:10:397-9. population. Br J Obstet Gynaecol 1999;106:1029-1034.
53. Haak MC, Twisk JW, Bartelings MM, Gittenberger-de 62. Michailidis GD, Economides DL. Nuchal translucency
Groot AC, van Vugt JM. Ductus venosus flow velocities measurement and pregnancy outcome in karyotypically
in relation to the cardiac defects in first-trimester fetuses normal fetuses. Ultrasound Obstet Gynecol 2001;17:102-
with enlarged nuchal translucency. Am J Obstet Gynecol 105.
2003;188:727-33 63. Hyett J, Moscoso G, Nicolaides K. Abnormalities of the
54. Martinez JM, Echevarría M, Borrell A, Puerto B, Ojuel J, heart and great arteries in first trimester chromosomally
A Fortuny. Fetal heart rate and nuchal translucency in abnormal fetuses. Am J Med Genet 1997;69:207-16.
detecting chromosomal abnormalities other than Down 64. Haak MC, van Vugt JM. Pathophysiology of increased
syndrome. Obstetrics and Gynecology 1998; 92: 68-71. nuchal translucency: a review of the literature. Hum
55. Galindo A, Comas C, Martínez JM, Gutierrez-Larraya F, Reprod Update 2003;9:175-84
Carrera JM, Puerto B, Borrell A, Mortera C, de la Fuente 65. Berg KA, Clark EB, Astemborski JA et al. 1998. Prenatal
P. Cardiac defects in chromosomally normal fetuses with detection of cardiovascular malformations by
increased nuchal translucency at 10-14 weeks of echocardiography: an indication for cytogenetic
gestation. J Matern Fetal Neonatal Med 2003;13:163-70 evaluation. Am J Obstet Gynecol 69:494-7
56. Bilardo CM, Pajkrt E, De Graaf IM et al. Outcome of 66. Schwanitz G, Zerres K, Gembruch U et al. 1990. Prenatal
fetuses with enlarged nuchal translucency and normal detection of heart defects as an indication for
karyotype. Ultrasound Obstet Gynecol 1998;11:401-6. chromosome analysis. Ann Genet 33:79-83
57. Maymon R, Jauniaux E, Cohen O et al. Pregnancy 67. Gembruch U, Baschat AA, Knopfle G et al. 1997. Results
outcome and infant follow-up of fetuses with abnormally of chromosomal analysis in fetuses with cardiac
increased first trimester nuchal translucency. Hum anomalies as diagnosed by first- and early second-
Reprod 2000;15:2023-7. trimester echocardiography. Ultrasound Obstet Gynecol
58. Carvalho JS. Nuchal translucency, ductus venosus and 10:391-6
congenital heart disease: an important association-a 68. Lazanakis MS, Rodgers K, Economides DL. 1998.
cautious analysis. Ultrasound Obstet Gynecol Increased nuchal translucency and CATCH 22. Prenat
1999;14:302-6. Diagn 18:507-10
59. Snijders RJM, Noble P, Sebire N, Souka A, Nicolaides KH. 69. Huggon IC, DeFigueiredo DB, Allan LD. Tricuspid
UK multicentre project on assessment of risk of trisomy regurgitation in the diagnosis of chromosomal anomalies
21 by maternal age and fetal nuchal transludcency in the fetus at 11-14 weeks of gestation. Heart
thickness al 10-14 weeks of gestation. Lancet 2003;89:1071-3
1998;351:343-6. 70. Simpson JM, Sharland GK. Nuchal translucency and
60. Brady AF, Pandya PP, Yuksel B et al. Outcome of congenital heart defects: heart failure or not?. Ultrasound
chromosomally normal livebirths with increased fetal Obstet Gynecol 2000;16:30-6.
 48
Prenatal Diagnosis of Fetal
Cytomegalovirus Infection
Y Ville, O Picone, G Makridemas, M Leruez-ville

INTRODUCTION et al., 2002). Preconceptional maternal immunity [RR

0.31; 95% IC 0.17-0.58] and maternal age of 25 years
Congenital cytomegalovirus (CMV) infection is likely
or older [RR 0.19;95% CI 0.07-0.49] are highly
to have become the most prevalent infection-related
protective against congenital infection (Fowler et al.,
cause of congenital neurological handicap since
2003).
rubella vaccination has become universal in
The possibilities for prenatal diagnosis have
developped countries (Stagno et al., 1986). However,
emerged more rapidly than those for establishing the
prenatal diagnosis and screening policies have been
prognosis of an infected fetus (Ville et al., 1998) and
rather incoherent for the last 25 years and obstetricians
the possibilities of treatment are still experimental. In
have showed great reluctance to tackle that issue (Ville
this review, we will address the possibilities and limits
et al., 1998). Indeed, although the infection is frequent
of prenatal imaging and biology in assessing both the
with 1-2% of all neonates excreting CMV in their
diagnosis and the prognosis of fetal CMV infection.
urine, 90% of these will remain asymptomatic (Fowler
et al., 1992). However, among symptomatic neonates,
PRENATAL ULTRASOUND EXAMINATION.
half will be severely so and one third of these will
die, while 60% will develop significant neurological Overall, less than half of fetal infections are diagnosed
and developmental sequelae. Among the moderately by ultrasound (Hagay et al., 1996; Lipitz et al., 1997;
symptomatic neonates, 65-75% will develop normally Enders et al, 2001; Liesnard et al., 2000; Azam et al.,
whereas 25-35% will have some degree of handicap 2001; Lazzarotto et al., 2000; Drose et al., 1991, Revello
at long-term follow-up. Furthermore, between 5% and et al., 1999, Guerra et al., 2000) and multiple organ
15% of the asymptomatic cases will also develop long- system involvement is present in more than 50% of
term developmental abnormalities, mainly the cases (Crino et al., 1999) at the time of prenatal
sensorineuro-hearing loss which can be bilateral in diagnosis, ranging from 15% to 100% (Table 48.1) and
up to 50% of the cases (Stagno et al., 1986; Fowler et is very likely subjected to reporting bias.
al., 1992; Peckham et al.,1987). Epidemiological risk Indeed, the review of the paediatric literature
factors have been extensively reviewed elsewhere suggests that most symptomatic congenitally infected
(Gaytant et al., 2002). Maternal age below 25, low neonates obviously escaped ultrasound screening and
socio economic status and presence of children age 1- one should be aware that ultrasound alone is not a
3 in the home are the more constently quoted (Gaytant sensitive test for fetal infection or affection.
 686
Table 48.1: Fetal abnormalities diagnosed in utero in cases of congenital cytomegalovirus infection, except cerebral abnormalities (Table 2).
IUGR: In utero growth restriction, US: Ultrasound, *Isolated abnormality

Series Congenital CMV (n) Fetuses with US findings (n) IUGR Hydrops Ascites Pericardial effusion Pleural Effusion Skin oedema
Hyper- echogenic bowel Hepato-megaly Spleno-megaly Liver calcifi-cations Cardio-megaly Placento-megaly Oligo-hydr-amnios Poly-hydr-amnios

Enders
et al., 2001 189 41 12 4 15 3 - 2 2 3 1 - 2 2 4 1
Liesnard
et al., 2000 68 4 - - - - - - 2 - - - - - - -
Lipitz
et al., 1997 51 11 6 2 1 - 1* - 2 (1*) - - - - - - -
Azam
et al., 2001 26 5 - - 1* - - - 1 1 - - - 1* - -
Lazzarotto
et al., 2000 25 3 1 - - - - - - 2 1 - - - - -
Drose
et al., 1991 19 18 4 (1*) - 4 1 3 1 - - - 3 (1*) 3 (1*) 5 6 7
Revello
et al.,1999 19 4 1* - 2 (1*) - - - - - - - - - - -
Textbook of Perinatal Medicine

Preece
et al., 1983 9 - - - - - - - - - - - - - - -
Hohlfeld
et al., 1991 8 2 - 1* 1* - - - - - - - - - - -
Malinger
et al., 2003 8 8 - - - - - - - - - 2 - - - -
Lamy
et al., 1992 7 2 - - - - - - - - - - - - - -
Steinlin
et al., 1996 7 - - - - - - - - - - - - - - -
Lynch
et al., 1991 6 6 2 (1*) 1 1 - - - 1 - - - - - 3 -
Schneeberger
et al., 1994 4 1 1* - - - - - - - - - - - - -
Grose
et al., 1992 3 2 1 - - 1 - - - - - - - - 1 -
Hogge
et al., 1993 3 2 - - 1* - - - - - - - - - - -
Tassin
et al., 1990 3 3 2 - 1 1 - - - 1 - - - 1 2 -
Agius
et al., 1985 2 - - - - - - - - - - - - - - -
Ahlfors
et al., 1988 2 - - - - - - - - - - - - - - -
Duvekot
et al., 1990 2 1 1* - - - - - - - - - - - - -
Contd...
Contd...
Forouzan
et al.,1992 2 2 - - - - - - 2 - - - - - - -
Gabrielli
et al.,2003 2 - - - - - - - - - - - - - - -
Inoue
et al.,2001 2 - - - 2 - - 2 - - - - - - 2 -
Morris
et al.,1994 2 - - - - - - - - - - - - - - -
Nigro
et al.,1993 2 - - - - - - - - - - - - - - -
Saigal
et al.,1982 2 - - - - - - - - - - - - - - -
Filloux 1 1 - 1 with 1 - 1 - - - - - - - - -
et al., 1985 tachycardia
Price
et al., 1978 1 1 - - 1 - - - - - - - - 1 - 1
Achiron
et al.,1994 1 1 - - - - - - - - - - - - - -
Chaoui
et al.,2002 1 1 1 - - - - - - - 1 - - - - -
Heinrich
et al.,2002 1 1 - - 1 1 - - - - - - - - - -
Nigro
et al.,1999 1 1 1 - - - - - - - - - - 1 - -
Nigro
et al.,1999 1 1 1 - - - - 1 - - - - - - - -
Nigro
et al.,1999 1 1 - - 1 - - - - - - 1 - - - -
Nigro
et al.,2002 1 1 - - - - - - 1 - - - - - 1 -
Peters
et al.,1995 1 1 1 - 1 - - - - - - 1 1 1 1 -
Pletcher
et al.,1991 1 1 - - - - - - 1 - - - - - - -
Rousseau
et al.,2000 1 1 1 - - - - - 1 - - - - - 1 -
Seguin
et al.,1988 1 1 1 - - - - - - - - - - - - -
Soussotte
et al.,2000 1 - 1 - - - - - - - - - - - - -
Vogler
et al.,1986 1 - - - - - - - - - - - - - - -
Yamashita
et al., 1989 1 1 - - 1 - - - - - - 1 - - - -
Prenatal Diagnosis of Fetal Cytomegalovirus Infection

Watt-Morse
et al.,1995 1 1 - - 1 - - - - - - - 1 - - -
TOTAL 490 130 37 (4*) 9 (1*) 32 (4*) 7 5 (1*) 6 13 (2*) 7 3 7 (1*) 5 (1*) 9 (1*) 17 8
687
688 Textbook of Perinatal Medicine

Longitudinal observational surveys of intrauterine herpes virus with a prolonged latency within
infection cases are lacking since the other half of maternal monocytes which will eventually reach the
prenatally diagnosed cases were recognized as a result fetus via the umbical circulation.
of maternal screening. The majority of these cases The placenta, where the virus replicates, will act
reported to date were terminated on the basis of both as a barrier against CMV but also as a reservoir
proven fetal infection without ultrasound findings or which may release the virus into the fetal circulation
before they could eventually develop (Liesnard et al., at any stage of the pregnancy, irrespective of the time
2000; Lazzarotto et al., 2000). However, three small of seroconversion (Goff et al., 1987; Kumazaki et al.,
prospective series reported a 15-25% sensitivity for 2002). Within 4 to 8 weeks following maternal viremia,
antenatal ultrasound (Guerra et al., 2000; Revello et an early but inconstant sign of vertical infection is
al., 1999; Lazzarotto et al., 2000). therefore likely to be placentitis as defined by a
The predictive value of ultrasound, like that of any thickness of 4 cm or more and a heterogeneous
other diagnostic test, increases with the prevalence appearance typically with calcifications co-existing
of the disease and therefore works better in a with hypoechoic areas (Drose et al., 1991) (Fig. 48.2).
population pre-selected by screening for maternal Once the virus reaches the fetal circulation, the
seroconversion. However, even in such a high-risk fetal kidney is hit early and preferentially which may
population, at least 90% of infected fetuses are cause transient oligohydramnios and less often renal
expected to be asymptomatic (Crino et al., 1999). The hyperechogenicity. This appears to be more frequent
ultrasound features of this progressive disease will than polyhydramnios (Drose et al., 1991). Viral
also vary significantly with time and serial ultrasound enterocolitis often shows with transient or persistant
follow-up is likely to perform better than routine appearance of at least grade-2 hyper-echogenic bowel
cross-sectional examination at any fixed gestation as an early ultrasound finding which may be
(Ville et al., 1998). accompanied by high hCG and AFP levels in maternal
The pathophysiology of fetal CMV infection blood (Pletcher et al., 1991; Forouzan et al., 1992;
allows to expect progressive and sometimes only MacGregor et al., 1995; Peters et al., 1995). This usually
subtle or transient findings on ultrasound in cases of represents meconial ileus or bowel perforation and
fetal infection. (Fig. 48.1) Indeed, irrespective of the meconial peritonitis (Dechelotte et al., 1992; Huang
mode of transmission to the mother, CMV is a viremic et al., 1997). Several weeks can elapse until other

Figs 48.1A and B: Placentitis showing a thick and heterogeneous placenta (A) . Hyperechogenic bowel and hepatomegaly
(B) are not specific features of systemic fetal infection.
 Prenatal Diagnosis of Fetal Cytomegalovirus Infection 689

A B

C D

E F
Figs 48.2A to F: Cerebral features include ventriculomegaly (A) often preceding microencephaly (B) which in turn can
precede microcephaly as illustrated by a sloping forehead on the profile view of the face (C). More subtle features include
parenchymal punctiform calcifications (D), subependymal cyst (E) and hyperechogenicity of the germinal matrix (F)
690 Textbook of Perinatal Medicine

features of fetal infection, if any, show-up on antenatal infectious origin (Holzgreve et al., 1993). It can be of
ultrasound, and some of the formers may have 2 types. Destructive ventriculomegaly is often
disappeared by then. moderate and will often precede microcephaly,
Overt systemic disease will appear as hepato- showing even subtle enlargement of pericerebral
splenomegaly and possibly ascites in the fetus as a spaces as an early sign of micro-encephaly.
result of cholestatic hepatitis and liver insufficiency Obstructive ventriculomegaly can occur as a result
(Chaoui et al., 2001). Less often, generalized oedema of obstruction of the foramen of Monroe and / or of
and ascites will suggest anaemia-related hydrops due Magendie and Lushka by ventriculitis-related oedema
to the combined effect of liver failure and marrow or intra-ventricular haemorrhage (Nigro et al., 2002).
infection. This spectacular presentation has also The same mechanisms can lead to less common
proven to eventually be transient with both presentations such as mega-cisterna magna, cerebellar
ultrasound and biological normalisation at follow-up hypoplasia or haemorrhage, pseudo-Dandy Walker
(Watt-Morse et al 1995). Cardiomyopathy, expressed malformations and schizencephaly (Twickler et al.,
as cardiomegaly with a thick myocardium which may 1993; Malinger et al., 2003).
contain punctuate calcifications is a rare finding which More subtle anomalies can be identified as
could also participate to the development of fetal associated findings with any of the features described
hydrops, eventually associated with tachy-arythmia above or as isolated findings, making the diagnosis
(Drose et al 1991, Chaoui et al 2001) Calcifications of more difficult. Non-specific vasculitis in the fetal
the fetal liver, spleen, and even lungs could appear thalami and basal ganglia (Estroff et al., 1992)
and remain as a result of a systemic disease. (Stein et described as candle-stick images, punctuate
al 1995) echogenicity within the brain parenchyma or
Intrauterine growth restriction (IUGR) may underlying the rim of the lateral ventricles together
develop as a result of either fetal infection or placental with strands across the lateral ventricles (Fakhry et
infection or both. It can therefore be advised to screen al., 1991; Achiron et al., 1994). Germinolysis-related
for CMV as part of the assessment of any IUGR fetus sub-ependymal cysts can also be overlooked by
below the 5 th centile. Indeed, this could be a routine fetal ultrasound examination when fetal
completely isolated finding irrespective of placental infection is not known (Fig. 48.2E and 2F) (Malinger
or fetal Doppler values (Boppana et al., 1997; Conboy et al., 2003; Butt et al., 1982; Achiron et al., 1994). Rare
et al., 1987). cases of corpus callosum abnormalities have also been
Affection of the fetal brain shows mainly late and described in utero and postnatally (Malinger et al.,
multiple suggestive and heterogenous ultrasound 2003; Mehta et al., 2001).
features of fetal infection and of fetal affection Abnormal myelinisation and gyration of the fetal
(Malinger et al., 2003) (Table 48.2). These can be brain is another pitfall for fetal brain ultrasound
present when the previously described features have examination and the development of fetal MRI is a
resumed, therefore weeks or months after the onset recent and definite asset in the complete assessment
of maternal and even that of fetal infection. of high-risk fetuses (Barkovich et al., 1994; Soussotte
Microcephaly is a major form of the disease, et al., 2000; Malinger et al., 2003). Lisencephaly could
however this may prove to be a very difficult reflect injury before 16 or 18 weeks’ whereas
diagnosis to establish, especially in a growth retarded polymicrogyria could reflect injury at 18 to 24 weeks.
fetus (Noyola et al., 2000; Ahlfors et al., 1986). Cases with normal gyral patterns have probably been
Ventriculomegaly, unilateral or bilateral, is a injured during the third trimester showing diffuse
common entry to the diagnosis since around 5% of heterogenity in the white matter (Barkovich et al.,
all ventriculomegaly diagnosed in utero are of 1994). Both T1 and T2 sequences are therefore useful.
 Table 48.2: Fetal brain abnomalies diagnosed in utero in cases of congenital cytomegalovirus infection
Series
Congenital CMV (n) Ventriculo-megaly Hydro-cephaly Micro-cephaly Brain and periven-tricular calcifica-tions Agenesis or
abnormal corpus callosum Reduced Gyration Choroid Plexus Cyst Cystic structure in cerebellumLissen-cephaly Hypoplastic or small Cerebellum
Sub ependymal cysts

Enders et al., 2001 189 7 7 12 3 2 - - 2 2 2 -

Guerra et al., 2000 68 4 (2*) - - - - - - - - - -
Boppana** et al., 1997 56 4 - - 3- - 3 - - - - -
Liesnard et al., 2000 55 1 2(1*) 2 - - 1 - - - - -
Lipitz et al., 1997 51 3 - - 1 - - 1 - - - -
Azam et al.,2001 26 1 - 2 (1*) - - - - - - - -
Lazzarotto et al.,2000 25 2 (1*) - - 1 1 - - - - - -
Drose et al.,1991 19 - 6 (1*) 2(1*) 3 - - - - - - -
Barkovich** et al.,1994 11 9 - 6 7 1 2 - 1 - 7 6
Malinger et al.,2003 8 5 - - 6 1 4 - - - 2 (1*) 3
Lamy et al.,1992 7 - - - 2* - - - - - - -
Lynch et al.,1991 6 3 - - 1 - - - - - - -
Butt** et al.,1984 4 4 - - 4 - - - - - - 2
Revello et al.,1999 4 2 - - - - - - - - - -
Hogge et al.,1993 3 - - 1 1 - - - - - - -
Tassin et al.,1990 3 1 2 1 2 - - - - - - -
Inoue et al.,2001 2 2 - - - - - - - - - -
Nigro et al.,1999 2 - - 1 - - - - - - - -
Ries** et al.,1990 2 2 - - 2 - - - - - - -
Seguin et al.,1988 2 - - 1 - - - - - - - -
Twickler et al.,1993 2 2 - 2 - - - - - - - -
Achiron et al.,1994 1 1 - - 1 - - - - - - 1
Chaoui et al.,2002 1 1 - - - - 1 - - - - -
Estroff et al.,1992 1 1 - - 1 - - - - - - -
Graham et al., 1982 1 1 - - 1 - - - - - - -
Mehta** et al.,2001 1 1 - - 1 1 (with Lipoma) - - - - - -
Mittelman-Handwerker et al.,1986 1 1 - - - - - - 1 - 1 1
Nigro et al.,1999 1 - - - - - - 1 - - - -
Nigro et al.,2002 1 1 - - - - - - - - - -
Peters et al.,1995 1 1 - 1 1 - - - - - - -
Pletcher et al.,1991 1 1 - - - - - - - - - -
Rousseau et al.,2000 1 - - 1 - - - - - - - -
Soussotte et al.,2000 1 - - 1 1 - 1 - - - - 1
Toma** et al.,1989 1 - - 1 1 - - - - - - -
Watt-Morse et al.,1995 1 1 - - - - - - - - - -
TOTAL 304 32 (3*) 13 (2*) 21 (2*) 21 (2*) 6 12 2 2 - 4 (1*) 14
Prenatal Diagnosis of Fetal Cytomegalovirus Infection
691
692 Textbook of Perinatal Medicine

It is noteworthy that although the relationship by PCR amplification. Sensitivity varies between 45
between the ultrasound features described above and and 100% for both PCR and culture, the lowest figures
fetal CMV infection is well established, CMV is rarely beeing obtained when amniocentesis was performed
reported in series of cases bearing these anomalies. before 21 weeks, and less than 6-8 weeks from
This further emphasizes the poor performance of maternal seroconversion. (Hohlfeld et al., 1991;
ultrasound to diagnose fetal CMV infection in the Baldanti et al., 1995; Lipitz et al., 1997; Lamy et al.,
general population. 1992; Donner et al., 1993; Nigro et al., 1999; Antsaklis
et al., 2000). However the free interval can be even
MATERNAL AND FETAL BIOLOGY. longer depending on the placental ability to contain
When the diagnosis of CMV infection is suspected on infection (Goff et al., 1987) The overall false negative
the basis of any of the ultrasound findings described rate of amniocentesis is around 12% (52/365) [0-25%]
above this can be excluded only if maternal serology (Lynch et al., 1992, Donner et al., 1993, Ruellan et al.,
shows negative IgG and negative IgM. Indeed, IgM 1996; Bodéus et al., 1999; Antsaklis et al., 2000;
which can be present both in primary and non Lazarotto et al., 2000; Liesnard et al., 2000; Enders et
primary infections are often negative at the time of a al., 2001; Gouarin et al., 2001; Lipitz et al., 2002;
positive fetal ultrasound examination several weeks Revello et al., 1999; Revello et al., 2002; Nigro et al.,
or months following maternal infection. At that time, 1999) and has been reported to be much lower and
both maternal viruria and viremia are also likely to even down to 0% when the conditions of sampling
be negative although they have been found positive were ideal (Revello et al., 1999; Hohlfeld et al., 1991).
for 3 to 12 months following maternal infection The variation in sensitivity may also account for
(Revello et al., 1998). the differences in PCR methods used. Each PCR
The diagnosis of fetal infection is made by recovery method reported in the literature has its own protocol
of the virus or by amplification of its genome in the (e.g; single-round PCR, nested PCR, or commercial
amniotic fluid (AF) retrieved by amniocentesis tests) and tested different volumes of fetal specimen,
(Revello et al., 2002; Gaytant et al., 2002). Indeed, the leading to variable sensitivities. Moreover, the CMV
amniotic fluid is colonized once the virus has infected genome sequences amplified in these PCR tests varied
the fetal kidneys and replicates in the tubular with various fragments of the immediate early protein
epithelium to be passed in the urine. Viral DNA is gene or of the glycoprotein B gene being most
therefore accumulating in the amniotic fluid as it does frequently used. Genetic diversity in those two genes
in the urine of infected individuals postnatally. This is well recognised (Chou et al., 1992), but the design
provides with clear guidelines for performing of primers and probes did not always account for this.
amniocentesis in CMV infection in pregnancy. False PCR positive results have also been reported
Following seroconversion or re-activation, the process when the neonate was not infected in 9/179 (5%) [0-
leading to CMV excretion in the fetal urine will take 30%] questioning the quality of the technique (Azam
an average of 6-8 weeks and this interval should be et al., 2001; Donner et al., 1993; Nigro et al., 1999;
recognised in order to avoid false negative prenatal Revello et al., 1999; Lazarotto et al., 2000; Enders et
diagnosis (Revello et al., 2002). This should also be al., 2001; Gouarin et al., 2001; Bodeus et al., 1999). False
performed when fetal urination is well established positive diagnosis may be explained by
and therefore not before 22 weeks. contamination of the AF with the maternal blood
Detection of infectious CMV in amniotic fluid may during amniocentesis if the mother had a positive
be performed by the use of rapid virus isolation in CMV DNAemia at the time of sampling. Indeed,
cell cultures (“shell vial culture”) (Revello et al., 2002; Revello et al showed that CMV DNA may be
Gleaves et al., 1984) as well as CMV DNA detection recovered in the blood of nearly 50% of
 Prenatal Diagnosis of Fetal Cytomegalovirus Infection 693
immunocompetent patients up to three months after To date, CMV detection in fetal blood is therefore
CMV primary infection (Revello et al., 1998). Another generally considered to be unsuitable for prenatal
explanation could be laboratory contamination diagnosis. However, the value of viral quantification
occurring during PCR testing. Indeed, in some of (DNA and IgM) in fetal blood to identify fetuses at
these studies a nested CMV PCR was used, which is risk of developing severe congenital infection is
known to be a very sensitive technique but at high emerging and this issue will be developped in the
risk of contamination. Generalisation of semi- second part of this review (Enders et al., 2001; Revello
automated real time PCR might help to overcome the et al 1999; Revello et al 2002).
risk of contamination and achieve absolute specificity
for prenatal diagnosis of CMV infection. These results CONCLUSION
however establish PCR as a reliable technique in CMV infection in pregnancy is not only when
reference laboratories. The question of performing a suggestive ultrasound features are diagnosed but also
second amniocentesis when the result of the first often questioned as a result of an individual or
examination is negative remains unanswered. population-based screening result. Interpretation of
However, to date, informations available on 13 cases maternal serology and indication for invasive and non
with a false negative result (Lynch et al., 1992; Enders invasive testing requires some knowledge of the
et al., 2000) did not show any symptom at the age of natural history of CMV transplacental infection.
up to 36 months although one neonate was growth- Amniocentesis remains the gold standard invasive
restricted. test to diagnose fetal infection and in the absence of
Another question without an answer today is that ultrasound features this should be performed after
of the risk of fetal iatrogenic infection when maternal 22 weeks’ and at least 6 weeks following maternal
viremia is positive at the time of amniocentesis. seroconversion.
However the commonly understood pathophysiology
of vertical transmisssion of CMV to the fetus makes REFERENCES
this possibility unlikely.
1. Achiron R, Pinhas-Hamiel O, Lipitz S, Heiman Z, Reichman
B, Maschiach S. 1994. Prenatal ultrasonographic diagnosis
PRENATAL DIAGNOSIS IN FETAL BLOOD of fetal cerebral ventriculitis associated with asymptomatic
maternal cytomegalovirus infection. Prenat Diagn 14:523-
There are few data available on the prenatal diagnosis 6.
of CMV infection in fetal blood. 2. Agius G, Baillargeau E, Ranger S, Castets M. 1985. Infection
congénitale à Cytomégalovirus chez des jumeaux
The sensitivity of IgM detection in fetal blood is
dizygotes. Arch Fr Pediatr 42:63-64.
around 50% (Revello et al., 2002, Liesnard et al., 2000). 3. Ahlfors K, Ivarsson SA, Bjerre I. 1986. Microcephaly and
The sensitivity of CMV rapid or classic culture is even congenital cytomegalovirus infection : a combined
lower ranging from 0 to 40% (Donner et al., 2000; prospective and retrospective study of a swedish infant
population. Pediatrics 78:1058-1063.
Azam et al., 2001; Liesnard et al., 2000; Revello et al., 4. Ahlfors K, Ivarsson SA, Nilsson H. 1988. On the
2002). This is probably due to the small volume unpredictable development of congenital cytomegalovirus
retrieved by cordocentesis and PCR methods should infection. A study in twins. Early Human Development
be preferred. However the sensitivity achieved by 18:125-135.
5. Antsaklis A, Daskalakis G, Mesogitis S, Koutra P, Michalas
PCR in fetal blood varied greatly in three studies S. 2000. Prenatal diagnosis of fetal primary
published, ranging from 40 to 92% (Liesnard et al., cytomegalovirus infection. Br J Obstet Gynaecol 107:84-88.
2000; Revello et al., 2002; Enders et al., 2001). Enders 6. Azam AZ, Vial Y, Fawer CL, Zufferey J, Hohlfeld P. 2001.
Prenatal diagnosis of congenital cytomegalovirus infection.
et al (Enders et al., 2001) reported a 100% sensitivity
Obstet Gynecol 97: 443-448.
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and in fetal blood. Polymerase chain reaction for prenatal diagnosis of
694 Textbook of Perinatal Medicine

congenital cytomegalovirus infection. J Med Virol 47:462- 22. Fakhry J, Khoury A. 1991. Fetal intracranial calcifications;
466. the importance of periventricular hyperechoic foci without
8. Barkovich AJ, Lindan CE. Congenital cytomegalovirus shadowing. J Ultrasound Med 10:51-54.
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considerations. 1994. Am J Neuroradiol 15:703-715. Hydrops fetalis with supraventricular tachycardia and
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10. Boppana SB, Fowler KB, Vaid Y, Hedlund G, Stagno S, Britt 1992. The outcome of congenital cytomegalovirus infection
WJ, Pass RF. 1997. Neuroradiographic findings in the in relation to maternal antibody status. N Engl J Med
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414. and prevention of congenital cytomegalovirus infection. J
11. Butt W, Mackay RJ, De Crespigny L, Murton LJ, Roy RND. Am Med Ass 26:1008-11
1984. Intracranial lesions of congenital cytomegalovirus 27. Gabrielli L, Lazzarotto T, Foschini MP, Lanari M, Guerra
infection detected by ultrasound scanning. Pediatrics 73:611- B, Eusebi V, Landini MP. 2003. Horizontal in utero
614. acquisition of cytomegalovirus infection in a twin
12. Chaoui R, Zodan Marin T, Wisser J. 2002. Marked pregnancy. J Clin Microbiol 41:1329-1331.
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Ultrasound Obstet Gynecol 20:299-302. review of the epidemiology and outcome. Obst Gynecol Surv
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in gp116 and gp55 components of glycoprotein B of human 29. Gleaves CA, Smith TF, Shucter EA, Pearson GR. 1984. Rapid
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14. Conboy TJ, Pass RF, Stagno S, Alford C, Myers GJ, Britt with urine specimens by using low-speed centrifugation
WJ, Mc Collister FP, Summers MN, Mc Farland CE, Boll and monoclonal antibody to an early antigen. J Clin
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cytomegalovirus infection. J Pediatr 111:343-348. cytomegalovirus infection in the placenta and maternal
15. Crino JP. 1999. Ultrasound and fetal diagnosis of perinatal tissues during late gestation. Am J Obstet Gynecol 156:1265-
infection. Clin Obstet Gynecol 42:71-80. 1270.
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Rodesch F. 1993. Prenatal diagnosis of 52 pregnancies at 32. Grose C, Meehan T, Weiner CP. 1992. Prenatal diagnosis of
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82: 481- 486. after amniocentesis. Pediatr Infect Dis 11: 605-607.
18. Drose JA, Dennis MA, Thickman D. 1991. Infection in utero: 33. Graham D, Guidi SM, Sanders RC. 1982. Sonographic
US findings in 19 cases. Radiology 178:369-374. features of in utero periventricular calcification due to
19. Duvekot JJ, Theewes BA, Wesdrop JM, Roumen FJ, cytomegalovirus infection. J Ultrasound Med 1:171-172.
Bouckaert PX. 1990. Congenital cytomegalovirus infection 34. Guerra B, Lazzarotto T, Quarta S, Lanari M, Bovicini L,
in a twin pregnancy: a case report. Eur J Pediatr 149:261- Nicolosi A, Landini MP. 2000. Prenatal diagnosis of
262. symptomatic congenital cytomegalovirus infection. Obstet
20. Enders G, Bader U, Lindermann L, Schalsta G, Daiminger Gynecol 183: 476-482.
A. 2001. Prenatal diagnosis of congenital cytomegalovirus 35. Hagay ZJ, Biran GB, Ornoy A, Reece EA. 1996. Congenital
infection in 189 pregnancies with known outcome. Prenat cytomegalovirus infection: a long-standing problem still
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21. Estroff JA, Richard BP, Teele RL, Benacerraf BR. 1992. 36. Henrich W, Meckies J, Dudenhausen JW, Vogel M, Enders
Echogenic vessels in the fetal thalami and basal ganglia G. 2002. Recurrent CMV infection during pregnancy:
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11:686-688. Gynecol 19: 608-611.
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37. Hogge WA, Buffone GJ, Hogge JS. 1993. Prenatal diagnosis brain atrophy in a woman with intrauterine
of cytomegalovirus (CMV) infection: a preliminary report. cytomegalovirus infection. 1986. J Reprod Med 31; 1061-1064.
Prenat Diagn 13:131-136. 55. Morris DJ, Sims D, Chiswick M, Das VK, Newton VE. 1994.
38. Hohlfeld P, Vial Y, Maillard-Brignon C, Vaudaux B, Fawer Symptomatic congenital CMV infection after maternal
CL. 1991. Cytomegalovirus fetal infection: prenatal recurrent infection. Pediatr Inf Dis 13:61-64.
diagnosis. Obstet Gynecol 78:615-618. 56. Nicolini U, Kustermann A, Tassis B, Fogliani R, Galimberti
39. Holzgreve W, Feil R, Louwen F, Miny P. 1993. Prenatal A, Percivalle E, Revello M, Gerna G. 1994. Prenatal
diagnosis and management of fetal hydrocephaly and diagnosis of congenital cytomegalovirus infection. Prenat
lissencephaly. Child’s Nerv Syst 9:51-54. Diagn 14:903-906.
40. Huang YC, Lin TY, Huang CS, Hseun C. 1997. Ileal 57. Nigro G, Clerico A, Mondaini C. 1993. Symptomatic
perforation caused by congenital or perinatal congenital cytomegalovirus infection in two consecutive
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41. Inoue T, Matsumura N, Fukuoka M, Sagawa N, Fujii S. 58. Nigro G, La Torre R, Sali E, Auteri M, Mazzocco M,
2001. Severe congenital infection with fetal hydrops in a Maranghi L, Cosmi E. 2002. Intraventricular hemorrhage
cytomegalovirus seropositive healthy women. Eur J Obstet in a fetus with cerebral cytomegalovirus infection. Prenat
Gynecol 95:184-186. Diagn 22:558-561.
42. Kiriazopoulou V, Bondis J, Frantzidou F, Athanasiadis A, 59. Nigro G, La Torre R, Anceschi MM, Mazzocco M, Cosmi E.
Diza E, Simitsopoulou M, Souliou E. 1996. Prenatal 1999. Hyperimmunoglobulin therapy for a twin fetus with
diagnosis of fetal cytomegalovirus infection in seropositive Cytomegalovirus infection and growth restriction. Am J
pregnant women. Eur J Obstet Gynecol. 69:91-95. Obstet Gynecol 180:1222-1226.
43. Kumazaki K, Ozono K, Yahara T, Wada Y, Suehara N, 60. Nigro G, La Torre R, Mazzocco M, Coacci F, Riosa B,
Takeuchi M, Nakayama M. 2002. Detection of cytome- D’Emilio C, Cosmi EV. 1999. Multi system cytomegalovirus
galovirus DNA in human placenta. J Med Virol 68:363-369. fetopathy by recurrent infection in a pregnant women with
44. Lamy H, Mulongo K, Gadissieux JF, Lyon G, Gaudy V, Van hepatitis B. Prenat Diagn 19:1070-1072.
Lierde M. Prenatal diagnosis of fetal cytomegalovirus 61. Nigro G, Mazzocco M, Anceschi M, La Torre R, Antonelli
infection. 1992. Am J Obstet Gynecol 166:91-94. G, Cosmi E. 1999. prenatal diagnosis of fetal
45. Lazzarotto T, Guerra B, Spezzacatena P, Varani S, Gabrielli cytomegalovirus infection after primary or recurrent
L, Pradelli P, Rumpianesi F, Banzi C, Bovicelli L, Landini maternal infection. Obstet Gynecol 94:909-914.
MP. 1998. Prenatal diagnosis of congenital cytomegalovirus 62. Noyola DE, Demmler GJ, Williamson WD, Griesser C,
infection. J Clin Microbiol 36:3540-3544. Sherry S, Llorente A, Littman T, Williams S, Jarrett L, Yow
46. Lazzarotto T, Varani S, Guerra B, Nicolosi A, Lanari M, MD, and the congenital CMV longitudinal study group.
Landini MP. 2000. Prenatal indicators of congenital 2000. Cytomegalovirus urinary excretion and long term
cytomegalovirus infection. J Pediatrics 137: 90-95. outcome in children with congenital cytomegalovirus
47. Liesnard C, Donner C, Brancart F, Gosselin F, Delforge ML, excretion. Pediatr Infect Dis 19:505-510.
Rodesch F. 2000. Prenatal diagnosis of cytomegalovirus 63. Peckham C, Stark O, Dudgeon JA, Martin JAM, Hawkins
infection: prospective study of 237 pregnancies at risk. G. 1987. Congenital cytomegalovirus infection: a cause of
Obstet Gynecol 95:881-888. sensorineural hearing loss. Arch Dis Child 62:1233-1237.
48. Lipitz S, Yagel S, Shalev E, Achiron R, Mashiach S, Schiff 64. Peters MT, Lowe TW, Carpenter A, Kole S. 1995. Prenatal
E. 1997. Prenatal diagnosis of fetal primary diagnosis of congenital cytomegalovirus infection with
cytomegalovirus infection. Obstet Gynecol 89:763-767. abnormal triple-screen results and hyperechoic fetal bowel.
50. Lynch L, Daffos F, Emanuel D, Giovangrandi Y, Meisel R, Am J Obstet Gynecol 173:953-954.
Forestier F, Cathomas G, Berkowitz RL. 1991. Prenatal 65. Pletcher BA, Williams MK, Mulivor RA, Barth D, Linder
diagnosis of fetal cytomegalovirus infection. Obstet Gynecol C, Rawlinson K. 1991. Intrauterine cytomegalovirus
165:714-718. infection presenting as fetal meconium peritonitis. Obstet
51. McGregor SN, Tamura R, Sabbagha R, Brenhofer JK, Gynecol 78: 903-905.
Kambich MP, Pergament E. 1995. Isolated hyperechoic fetal 66. Preece PM, Blount JM, Glover J, Fletcher GM, Peckham CS,
bowel: significance and implications for management. A m Griffiths PD. 1983. The consequence of primary
J Obstet Gynecol 173:1254-1258. cytomegalovirus infection in pregnancy. Arch Dis Child
52. Malinger G, Lev D, Zahalka N, Ben Aroia Z, Watemberg 58:970-975.
N, Kidron D, Ben Sira L, Lerman-Sagie T. 2003. Fetal 67. Price JM, Fisch AE, Jacobson J. 1978. Ultrasonic findings in
cytomegalovirus infection of the brain: the spectrum of fetal cytomegalovirus infection. Journ Clin Ultras 6:215-294.
sonographic findings. Am J Neuroradiol 24:28-32. 68. Revello MG, Gerna G. 2002. Diagnosis and management
53. Mehta N, Hartnoll G. 2001. Congenital CMV with callosal of human cytomegalovirus infection in the mother, fetus
lipoma and agenesis. Pediatr Neurol 24:222-224. and new born infant. Clin Microbiol Rev15: 680- 713.
54. Mittelman-Handwerker S, Pardes JG, Post RC, Sumala M, 69. Revello MG, Zavattoni M, Furione M, Baldanti F, Gerna G.
Rosenberg JC, Chervenak FA. Fetal ventriculomegaly and 1999. Quantification of human cytomegalovirus DNA in
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amniotic fluid of mothers of congenitally infected fetuses. 78. Soussotte C, Maugey-Laulom B, Carles D. 2000.
J Clin Microbiol 37:3350-3352. Contribution of transvaginal ultrasonography and fetal
70. Revello MG, Zavattoni M, Sarasini A, Baldanti F, De Julio cerebral MRI in a case of congenital cytomegalovirus
C, De-Giuli L, Nicolini U, Gerna G. 1999. Prenatal infection. Fetal diagn Ther 15:219-233.
diagnostic and prognostic value of human cytomegalovirus 79. Stagno S, Pass RF, Gretchen Cloud MS, Britt WJ, Henderson
load and IgM antibody response in blood of congenitally RE, Walton PD, Veren DA, Page F, Alford CA. 1986. Primary
infected fetuses. J Infect Dis 180:1320-1323. cytomegalovirus infection in pregnancy. J Am Med Assoc
71. Revello MG, Zavattoni M, Sarasini A, Percivalle E, 256:1904-1908.
Simoncini L, Gerna G. 1998. Human cytomegalovirus in 80. Stein B, Bromley B, Michlewitz H, Miller WA, Benacerraf
blood of immunocompetent persons during primary BR. 1995. Fetal liver calcifications: sonographic appearance
infection : prognostic implications for pregnancy. J Infect and post-natal outcome. Radiology 197:489-492.
Dis 177: 1170-1175. 81. Steinlin MI, Nadal D, Eich GF, Martin E, Boltshauser EJ.
1996. Late intrauterine cytomegalovirus infection: clinical
72. Ries M, Deeg KH, Heininger U. 1990. Demonstration of
and neuroimaging findings. Pediatr Neurol 15:249-253.
perivascular echogenicities in congenital cytomegalovirus
82. Tassin GB, Maklad NF, Stewart RR, Bell ME. 1991.
infection by colour Doppler imaging. Eur J Pediatr 150:34-
Cytomegalic inclusion disease: intrauterine sonographic
36.
diagnosis using findings involving the brain. A m J
73. Rousseau T, Douvier S, Reynaud I, Laurent N, Bour JB,
Neuroradiol 12:117-122.
Durand C, Spagnolo G, Sagot P. 2000. Severe fetal 83. Toma P, Magnano GM, Mezzano, P, Lazzini F, Bonacci W,
cytomegalic inclusion disease after documented maternal Serra G. 1989. Cerebral ultrasound images in prenatal
reactivation of CMV during pregnancy. Prenat Diagn 20:333- cytomegalovirus infection. Neuroradiology 31:278-289.
336. 84. Twickler DM, Perlman J, Maberry MC. 1993. Congenital
74. Ruellan-Eugene G, Barjot P, Campet M, Vabret A, cytomegalovirus infection presenting as cerebral ventri-
Herlicoviez M, Muller G, Levy L, Guillois B, Freymuth F. culomegaly on antenatal sonography. Am J Perinatol 10:404-
1996. Evaluation of virological procedures to detect fetal 406.
human cytomegalovirus infection: avidity of IgG 85. Vogler C, Kohl S, Rosenberg HS. 1986. Cytomegalovirus
antibodies, virus detection in amniotic fluid and maternal infection and fetal death in a twin. J. Reprod Med 31: 207-
serum. J Med Virol 50:9-15. 210.
75. Saigal S, Lunyk O, Larke B, Chernesky MA. 1982. The 86. Ville Y. 1998. The Megalovirus. Ultrasound Obstet Gynecol;
outcome of children with congenital cytomegalovirus 12:151-153.
infection. Am J Dis Child 136:986-901. 87. Watt-Morse ML, Laifer SA Hill LM. 1995. The natural
76. Schneeberger PM, Groendaal F, de Vries LS, van Loon AM, history of fetal cytomegalovirus infection as assessed by
Vroom TM. 1994. Variable outcome of a congenital serial ultrasound and fetal blood sampling: a case report.
cytomegalovirus infection in a quadruplet pregnancy after Prenat Diagn 15:567-570.
primary infection of the mother during pregnancy. Act 88. Yamashita Y, Iwanaga R, Goto A, Kaneko S, Yamashita F,
Paediatr 83:986-989. Waseda N, Ishimatsu J, Hamada T. 1989. Congenital
77. Seguin J, Cho CT. 1988. Congenital Cytomegalovirus cytomegalovirus infection associated with fetal ascites and
Infection in one monozygotic twin. J Am Med Ass 260:22. intrahepatic calcifications. Acta Paediatr Scand 78:965-967.
 49
Fetal Hydrops

Tamas Marton, Phillip M Cox

FETAL HYDROPS ANAEMIA-RELATED HYDROPS

Fetal hydrops is a combination of generalised soft It is well known that fetal anaemia can be readily
tissue oedema and fluid (effusion) in one or more detected with the help of ultrasound/Doppler,
body cavity. measuring the Middle Cerebral Artery velocity. For
Hydrops still has a high mortality causing fetal details see the relevant chapter of this book. The
demise in more than 50% of the detected cases and causes of fetal anaemia should be subdivided, as they
post natal mortality following live birth is also around affect the prognosis for the pregnancy and fetus.
50%.1 There may be many causes. According to the
traditional classification, the hydrops can be divided Immune Hydrops
into immune and non immune types. A more Historically, immune hydrops (due to maternal anti-
clinically (fetal medicine) oriented approach could be D iso-immunisation) was the commonest cause of
to divide cases into those due to fetal anaemia and fetal anaemia and hydrops. Fortunately, these severe
non-anaemia related hydrops. The practical reason for cases of anti-D isoimmunisation are now very rarely
this categorisation is that fetal anaemia is still the most seen, as a result of anti-D immunoglobulin
common cause of hydrops and in most cases fetal prophylaxis for Rhesus negative mothers. In the
anaemia is easily detectable in utero. It can often be absence of prophylaxis, the disease still occurs.
treated with intrauterine transfusion and thus Immune hydrops is the result of a maternal IgG-
anaemia related hydrops has a better prognosis than mediated haemolytic disease of the fetus, the severest
other forms. form of which is erythroblastosis fetalis.
In different parts of the world there are different There are further antigens that can cause immune-
causes of hydrops. For example, in underdeveloped mediated fetal haemolytic disease including: Rhesus
countries, Rhesus isoimmunisation still remains a anti- C,c,E,e, anti-Kell, anti-MNS, anti-Duffy and anti-
major cause; whereas in Southern China, fetal á- A or anti-B.
Thalassaemia is a main causative factor. In contrast, Isoimmunisation due to the non-Rh groups such
in the developed world structural and chromosomal as Kell, MNS, and Kidd have assumed increasing
anomalies and Parvovirus B19 infection are the most importance as the incidence of Rh-D sensitisation has
frequent causes of hydrops. decreased.
This chapter aims to be a comprehensive library Anti-Kell disease has a particularly poor
of the various fetal conditions that play role in fetal prognosis, probably because the anaemia is partly
hydrops and presents a few characteristic features. haemolytic and partly the result of suppressed
698 Textbook of Perinatal Medicine

erythropoiesis.2 A significantly higher incidence of Other inherited forms of dyserythropoiesis are

polyhydramnios was found among fetuses with Kell listed in Box 49.2. These represent rarities.
isoimmunisation and the maternal serum titre is much
lower than in the RhD group.3 Fetal Anaemia as a Consequence
of Fetal Blood Loss
Genetically Determined
Internal fetal haemorrhage may lead to severe
Haemolytic Disease of the Fetus
anaemia due to blood loss. The commonest site of
There are a number of genetically determined haemorrhage is the brain, but intrathoracic and
haemolytic diseases of the fetus, which can rarely lead intraabdominal haemorrhages may also occur.
to fetal hydrops. (see Box 49.1) Spontaneous fetal haemorrhage should always
Box 49.1: Genetically determined haemolytic anaemias prompt a search for maternal antiplatelet antibodies
causing fetal hydrops. to exclude alloimmune thrombocytopenia.11,12
• Glucose phosphate isomerase deficiency (AD in adult Placental subchorial/intervillous haemorrhage
cases, Neonatal and fetal form most likely AR)4causes can also originate from the fetus.
haemolytic crisis, very rarely fetal anaemia and hydrops. Fetomaternal haemorrhage (i.e. haemorrhage from
• Glucose – 6 – phosphate dehydrogenase (G6PD)
the fetal into the maternal circulation) is common.
deficiency (X linked dominant) Haemolytic episodes.
• Pyruvate kinase deficiency of erythrocyte (AR)5 Tiny haemorrhages are probably universal. Massive
haemorrhage may be acutely fatal but smaller or
Noninfectious Disorders recurrent bleeds may lead to an anaemic, hydropic
of Erythrocyte Production fetus. A maternal Kleihauer-Betke test is an essential
Alpha Thalassaemia (AD) is a common cause of fetal part of the investigation of hydrops.13
hydrops in Chinese population.6 Thalassaemias are a Haemorrhage can also occur into a necrotic congenital
group of inherited abnormalities of the haemoglobin tumor.
synthesis. Haemoglobin has an alpha and a beta chain.
Homozygous alpha thalassaemia (deletion of both á- Human Parvovirus B19 infection
chain alleles of the corresponding region of Parvovirus one of the most important factors causing
chromosome 16) is responsible for the fetal hydrops anaemia and hydrops.
(Bart syndrome). Clinical classification, such as In pregnant women it can cause miscarriage
thalassaemia major, intermedia and minor refer only (6.5%),14 hydrops and intrauterine death, although
to the clinical severity of the disease. It is also apparent most infected women give birth to healthy neonates
that, at least in some cases, compound heterozysity without any intervention.15 In a metaanalysis of 165
is responsible for the hydropic change of the fetus. reported cases of antenatal HPVB19 cases, there was
Anaemia in thalassaemia is the result of short a 10.2% excess risk of fetal death. Transplacental
turnover time of erythrocytes with a reduced transmission was confirmed in 69 (24.1%) of 286
haemoglobin content. reported maternal infections. According to a separate
Box 49.2. Inherited dyserythropoietic conditions metaanalysis HPVB19 infection was present in 57 out
associated with fetal hydrops. of 299 (19.1%) non-malformed cases of non-immune
• Congenital dyserythropoietic anaemia (AD) 7 is hydrops fetalis.16 Parvovirus affects not only the
characterised by ineffective erythropoiesis and erythroid cell lines, inhibiting erythrocyte production,
multinuclear erythroblasts.
• Congenital erythropoietic porphyria (AR)8
but also infects the cardiac myocytes. In most cases
• Diamond-Blackfan syndrome (AD)9 causes congenital the hydrops is a consequence of severe anaemia,
hypoplastic anaemia. though at least in some chronic cases it appears that
• Leukaemia (associated with Down syndrome)10 a direct effect on the heart cannot be excluded.
 Fetal Hydrops 699
2.6 Infections, in which anaemia plays a role in the of the systemic venous return. The lesions that
hydrops see below. belong in this group are seen in Box 49.3. Fetal lung
lesions associated with hydrops are almost always
NON ANAEMIA-RELATED HYDROPS lethal.24
Occlusions of the superior or inferior vena cava
Infection-Induced Fetal Hydrops17
and ductus venosus are also reported to result in
The most common infections causing fetal hydrops hydrops.
are: b. Cardiac disease, including developmental
Parvovirus B19 (see 2.5), Cytomegalovirus, 18 abnormalities, tachyarrhythmia and bradycardia
Herpes simplex virus, Toxoplasma gondii, Treponema may all cause fetal hydrops. A list of these
pallidum, Coxsackievirus type B, Adenovirus. conditions are in Box 49.4.
Congenital Chagas’ disease is also reported to be c. Vascular shunts result in high-output cardiac
associated with hydrops.19 failure and subsequent hydrops.
The mechanism, by which the different infections This occurs in fetal sacrococcygeal teratoma 36-38 and
cause hydrops varies. For example, Herpes simplex in arteriovenosus malformations at various locations
virus causes liver damage, whilst Coxsackie- and in the body. In the head – vein of Galen aneurysm,
Adeno-viruses lead to myocarditis and fetal intracranial arteriovenosus malformation and
tachyarrhytmia.20,21 intracranial teratoma have been described.39 Cervical,
Congenital syphilis results in generalised chronic abdominal, 40 or cutaneous haemangiomas, AV
infection,22 with anaemia, thrombocytopenia and later malformations of the liver and lung, large placental
ascites. In congenital syphilis, the mother can be chorangioma and angiomatosis of the fetus are also
seronegative with an infected fetus,23 and this may rare causes of hydrops.
also be true for Parvovirus (personal observation). Hydrops can occur as a complication of
monochorionic twinning, often because of high
Structural Anomalies output cardiac failure of one twin.41 In twin to twin
a. Tumors or tumorlike/hamartomatous lesions transfusion syndrome, volume overload in the
within the body cavities may cause hydrops with recipient leads to failure and hydrops, whilst in TRAP
compression or obstruction of the major vessels sequence reversed perfusion of a large acardiac co-
twin by the pump twin is the cause. There are also
reported cases with myocardial infarct of the recipient
Box 49.3. Obstruction of systemic venous return.
in twin to twin transfusion syndrome 42 and transient
Thorax: hydrops of the donor after amniocentesis.43
• Congenital Cystic Adenomatoid Malformation of the
lung,25,26
Box 49.4. Congenital heart conditions in fetal hydrops.
• Pulmonary extralobar sequestration,27
• Large diaphragmatic hernia, • Congenital heart disease24,30
• Intrathoracic teratoma, • Atresia of the aortic or pulmonary trunk,
• Intrathoracic lymphangioma,28 • Various malformations of the great arteries,
• Cardiac or pericardial tumor,29 • Atrioventricular septal defect,
• Laryngeal atresia {Kalache, Chaoui, et al. 1997 174 /id}. • Right or left ventricular hypoplasia, divided right
Abdominal tumor or tumorlike lesion: ventricle,31
• Abdominal teratoma, • Cardiomyopathy.32
• Cystic kidneys, • Fetal bradycardia: congenital heart block,33 maternal SLE,
• Obstructive uropathy, Lupus anticoagulant.
• Hepatoblastoma, • Fetal tachycardia with myocarditis –e.g. Adenovirus,
• Ovarian cyst, Coxsackievirus, Parvovirus, Chagas’ disease or WPW
• Other tumor. syndrome34;35
700 Textbook of Perinatal Medicine

d. Other circulatory problems: It has been suggested Further Genetic Causes

that long, and / or overcoiled umbilical cord with
Box 49.6 contains the most frequent genetic
increased vascular resistance, may in some
syndromes that cause hydrops. Osteochondro-
instances cause circulatory failure and consequent
dysplasias are important because of the inheritance
hydrops.44
and the number of recognised syndromes is
Chromosome Abnormality growing.
(including Turner syndrome)
Box 49.6. Osteochondrodysplasias and other genetic
X monosomy (45,X0- Turner syndrome) is the most syndromes causing hydrops
common chromosome aneuploidy related to hydrops. Osteochondrodysplasias
It appears that failure of the lymph vessel • Blomstrand type chondrodysplasia [(AR) short limbs,
development causes the hydropic change.45 It is also polyhydramnios, hydrops fetalis, facial anomalies,
apparent that in 90% of the hydropic Turner syndrome increased bone density, and a remarkable advanced
skeletal maturation]
fetuses the heart weight is under the 2.5th centile and • Greenberg dysplasia [(AR) Radiological features: “moth-
it has been suggested that this is a major cause of fetal eaten” appearance of the markedly short long bones,
demise in Turner syndrome fetuses.46 bizarre ectopic ossification centres, and marked
Trisomy 21: hydrops or nuchal swelling was platyspondyly with unusual ossification centres]58
• Conradi-Hunermann, chondrodysplasia punctata [(X
diagnosed in approximately 40% [cystic hygroma and linked - D) Disorganisation of the spine, premature
increased nuchal fold thickness (30.5 per cent), echogenity of femoral epipheses, and frontal bossing with
hydrops (9.6 per cent)] according to a large series.47 depressed nasal bridge, polyhydramnios]59
Other karyotypic abnormalities associated with • Osteogenesis imperfecta congenita (AD)
• Achondrogenesis type IA [(AR) polyhydramnios,
hydrops include: Trisomy 18, Trisomy 13, Trisomy 15, subgaleal edema, microcephaly, a narrow thorax,
and Trisomy 10 mosaicism. pericardial effusion, and a severe short-limbed dwarfism
with unossified tubular bones and vertebral bodies]60
Metabolic and Storage Disease • Achondrogenesis type IB [(AR) sulphate transporter gene
mutation, severe rhisomelia, narrow chest, flat face,
Metabolic and storage disease represents less than 1% polyhydramnios, possible umbilical hernia]
of all hydrops cases. These are individually rare, but • Achondrogenesis type II [(AD) Marked micromelic
important because of autosomal recessive inheritance dwarfism, barrel shaped, small chest, polyhydramnios]
and thus 25% recurrence risk. The relevant enzyme • Short rib polydactyly syndrome Type II [(AR) short ribs,
polydactyly (prae or postaxial), possible polycystic
defects are listed in Box 49.5. kidneys, median cleft lip]61
• Short rib polydactyly syndrome Type IV (AR) markedly
Box 49.5. Lysosomal and glycogen storage diseases narrow ribs, micromelia, shortened limbs with postaxial
that cause hydrops heptasyndactyly polycystic renal dysplasia
Lysosomal storage disease:48 • Fibrochondrogenesis (AR)
• Mucopolysaccharidosis type VII49 • Kniest like dysplasia (AR)
• Mucolipidoses I (Sialidosis III)50 • Campomelic dysplasia (AR)
• Mucolipidosis II (I-cell disease) Other genetic syndromes associated with hydrops:
• Gaucher disease51 • Arthrogryposis multiplex,
• Farber disease52 • Lethal multiple pterygium syndrome,
• GM1-gangliosidosis53 • Fetal akinesia
• Niemann-Pick disease54 • Beckwith-Wiedemann syndrome
• Moroquio disease55 • Simpson-Golabi-Behmel syndrome62
Glycogen storage disease • Smith-Lemli-Opitz syndrome
• Type IIb (glycogen storage disease limited to the heart)56 • Tuberous sclerosis
• Type IV57 • Congenital arteral calcification
 Fetal Hydrops 701
MISCELLANEOUS proportion of the cases enough to make a diagnosis.
Fortunately CMV, Parvovirus and Adenovirus
According to recent studies Fetal haemochromatosis
antibodies are available to prove infection in paraffin
appears to be the result of fetal liver disease and in
embedded blocks of the fetal tissues. According to
the late second trimester of pregnancy results in
published figures a meticulous examination,
severe panhypoproteinemia with non-immune
including clinical studies, such as Kleihauer-Betke test
hydrops.63,64
and maternal auto-antibodies, leaves approximately
Maternal indomethacin therapy mainly in the
10-20% of cases unexplained.68,69
third trimester has been reported causing early closure
The proverb that a good clinical history is half the
of ductus arteriosus and consequent fetal hydrops.65
diagnosis is very true with regard to the pathologist’s
One case of iatrogenic intrauterine hypothyroidism
work while undertaking an autopsy of a hydropic
and subsequent fetal hydrops has also been
fetus. Nowadays fetal hydrops is generally
published, which was caused by maternal
investigated prenatally. Clinical data can draw
propylthiouracil medication for maternal Grave’s
attention to subtle signs (which would otherwise be
disease.66 In another case report fetal hyperthyreosis
missed, especially in autolytic fetuses) and makes the
and hydrops, was caused by a hyperthyroid mother
pathologist widen the investigation in the relevant
with Grave’s disease by antithyroid antibodies 67
direction. Samples are taken that cannot be taken later,
Mother also had a history of three prior perinatal
such as frozen tissue for metabolic studies or DNA,
deaths between 26 and 28 weeks’ gestation, all
frozen sections for immunohistochemistry, specially
associated with fetal hydrops. After maternal therapy
fixed tissue for electronmicroscopy, instruction to the
with propylthiouracil, resolution of non-immune
cytogenetic or histochemistry laboratory to save cells
hydrops was documented and a healthy neonate
for biochemical studies etc.
subsequently delivered to term.
It is essential to seek for and document any
INVESTIGATIONS IN HYDROPS68,69 prenatal finding, as it is an important feedback to the
clinician and provides the parents with information.
Pathologic examination of fetuses with non-immune In summary: because of the wide spectrum of
hydrops requires a multidisciplinary approach. The causes of hydrops, a multidisciplinary approach to
first and most important is the macroscopic diagnosis is recommended based on proper
description and identification of structural communication and exchange of information between
abnormalities. Developmental abnormalities may the clinician and pathologist.
draw attention to the possibility of a chromosome
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polysaccharidosis type VII as a cause of recurrent non- 278.
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 SECTION 6
Doppler Ultrasound
S Weiner, K Ertan
 50
3D/4D Color and
Power Doppler in Obstetrics

George Bega, Stuart Weiner

INTRODUCTION demonstrate any arbitrary plane and most

importantly, even planes that are otherwise
Two-dimensional ultrasound (2DUS) derived color
impossible to be obtained by the conventional 2D
and power Doppler imaging is commonly used in
ultrasound. In the multiplanar display, three
fetal imaging. The information derived from 2DUS
perpendicular planes are displayed simultaneously.
color and power Doppler images is displayed in a
cross-sectional image plane. It is from these cross Correlation between these three planes is used to
sectional ultrasound planes that we develop a three- confirm a given desired plane, such as the mid-sagittal
dimensional perception of the vascular anatomy. or mid-coronal plane. This process generally involves
Nevertheless, the ability to visualize, fully understand placing the planar center point at the point of interest
and differentiate between normal and abnormal in one of the planes and observing the location of the
vascular anatomy with 2D ultrasound is often limited. corresponding center points in the other two planes. 1,2
These limitations become especially important in In this manuscript we intend to review the current
complex anatomical abnormalities. Recent and potential future applications of three and four
developments in digital signal processing and dimensional (4DUS) color and power Doppler
transducer design have made possible the acquisition ultrasound in Obstetrics. In the Technical
of volume ultrasound data with color and power Considerations section, the reader will be introduced
Doppler that can also be interactively manipulated to the basics of 3DUS volume acquisition, display,
through the volume. In three dimensional ultrasound analysis, volume calculation and perfusion studies.
(3DUS) or volume ultrasound, a volume (rather than The main clinical applications will be presented with
a slice) of ultrasonographic data is acquired and a special section on techniques of 3D color and power
stored. The stored data can be analyzed and displayed Doppler in fetal echocardiography. The somewhat
in numerous ways and new and more sophisticated limited literature as related to 3D color and power
tools are being introduced at a very fast rate. Although ultrasound will be reviewed as well. Last but not least,
these new and relatively complex applications are not networking capabilities will be discussed.
widely known or understood in the field of
TECHNICAL ASPECTS OF ACQUISITION AND
ultrasound, there seems to be little doubt that these
tools will become a routine part of our diagnostic DISPLAY
imaging toolset. One of the most significant Three-dimensional ultrasound acquires two-
advantages of acquiring a volume ultrasound data is dimensional planar ultrasound data in a volume and
the ability to navigate through the saved volume and as such represents an extension of the conventional
708 Textbook of Perinatal Medicine

2D ultrasound imaging. Considering this, 3DUS does multiple 2DUS images as the probe is manually swept
not necessarily replace 2DUS but rather extends its’ through the region of interest. This method typically
capabilities in time and space. Being a 2D ultrasound acquires one 3DUS volume and in principle cannot
based technique makes 3DUS vulnerable to all acquire 4D data, as that would require the operator
drawbacks and limitations of 2D ultrasound. As such, to continuously move his/her hand at fast acquisition
problems related to image resolution, penetration, speeds, which is impossible in reality. The second one
depth, artifacts and body habitus are also present in is the acquisition of volumes with a dedicated three-
3DUS and are even made worse and compounded dimensional ultrasound transducer (Fig. 50.1). A
across a volume of data. Consequently, image and mechanical device moves the transducer elements at
color and power Doppler setting optimization plays a pre-selected speed and a pre-selected angle
a huge role in acquiring adequate information that automatically in a fan shape through the region of
could be used clinically. Using 3DUS color and power interest.3,4 While color and power Doppler ultrasound
Doppler techniques generally requires an additional volumes can be reliably obtained with mechanically
investment of time which in experienced hands, swept dedicated transducers, their acquisition time
typically goes anywhere from 5-20 minutes and at is typically slow as there simply is more information
times, depending on the complexity of the case and to acquire and process. There is a special fetal heart
the experience of the examiner, significantly more. package that displays heart volumes with either color
This additional time is not so much related only to or power Doppler data in 4D, called Spatio-Temporal
scanning and acquiring the data, which is only a Image Correlation (STIC). This technique, which will
portion of the learning curve, but to exploring the be discussed in more detail at the fetal echo-
saved volume data afterwards in a meaningful way. cardiography section, is an exception to the otherwise
Given the fact that this information can be digitally fact that currently mechanically swept transducers
saved, either temporarily in the hard disk of the cannot display 4D color and power data. The third
equipment or permanently in a removable disk such
as CD-ROMs or DVD-ROMs, makes the exploration
of the saved volume data after the patient is
discharged a real possibility.
Important to understand is the concept of volume
data and how they are acquired. The acquisition of
one single volume of ultrasound data is called a 3D
ultrasound acquisition and the volume is commonly
called a 3D volume. The introduction of dedicated
transducers in the mid nineties made possible the
continuous acquisition of 3D volumes and on the fly
display of either multiplanar or rendered views. This
continuous acquisition displaying motion views of
moving targets such as the fetus or the fetal heart was
Fig. 50. 1: This image illustrates the principle of image
called the fourth dimension and the imaging registration and the effect of a dedicated 3D volume transducer
technique 4D. There are basically three methods of with a built in position sensing device in it. The images in the
acquiring volumes of ultrasound data for three- right are represent a volume acquired with a free hand
transducer and the images in the left represent a volume
dimensional ultrasound (3DUS) imaging. The first
acquired with a dedicated volume transducer and appear well
and the oldest one is the free-hand method which registered. The controlled acquisition and reliable registration
utilizes a normal 2D ultrasound transducer with a are prerequisites for obtaining clinically useful ultrasound
position sensing device mounted that can acquire volumes with color or power Doppler
 3D/4D Color and Power Doppler in Obstetrics 709
method is the volume acquisition through matrix b. Adjust the gain to avoid “bleeding” in the vessel
array transducers. These newly introduced dedicated wall by decreasing the gain at the minimally
volume transducers have a very high number of acceptable level, typically no more than 50-70%.
transducer elements (typically as of this writing from c. Adjust the wall filter, usually the medium
3000-4000 elements) and produce a thick ultrasound settings work better.
beam in all directions. All elements of the matrix array d. Set the dynamic motion differentiation to avoid
transducer transmit and receive. Interestingly, the first background noise signals.
imaging and data processing take place in the e. Sensitivity works better in medium scale.
transducer itself as it contains a built in data processor. f. Priority set on high generally brings better signal.
These transducers are electronically steered and have g. Pulse repetition frequency (PRF) should be
no need for mechanical sweeping. As such, they can adjusted according to the particular vessel size
produce very high acquisition speeds even with color and blood flow, typically a higher PRF is needed
or power Doppler.5,6 These transducers are the future for higher velocity vessels (i.e. intracardiac flow)
in volume imaging and will make a revolution in our and lower PRF is needed for small and/or
capabilities of investigating fetal and/or placental branching vessels (i.e. brain) especially placental
vasculature with 3D/4D color and power Doppler. or retro-placental (venous) vessels.
For the time being matrix array technologies are h. Start in 2D gray scale image with the highest
mainly being investigated in adult echocardiography frame rate as possible. That translates into a
but slowly studies are being conducted in obstetrics volume with the highest quality, as there will be
as well.7 All of these methods rely on specialized more frames in a volume. Factors that affect the
three-dimensional software, which allows processing frame rate are the angle opening in the 2D beam
of the acquired volumes either on-line through a built- (use the narrowest angle you can), the number
in computer or off-line on a workstation. of focal zones, and the amount of depth (the less
In this manuscript we will present work with the the better). Harmonic imaging helps significantly
dedicated mechanical volume transducers (the second in imaging in the near field but not much in the
method) as for the moment this is the best and most far field but important to know is that it does
commonly used technique of acquiring clinically slow down the frame rate.
useful data in obstetrics. The 2D power and color Doppler ultrasound
principles above should be incorporated to adequate
IMAGE OPTIMIZATION 3D volume acquisition principles such as:
One of the most common problems practitioners a. Start with the slowest acquisition speed that is
encounter in their learning curve of acquiring 3D color practically possible in order to leave time to the
and power Doppler is optimization of the settings. transducer to acquire the maximum amount of
While there is no fixed recipe for every occasion there information. Typically the slower the speed of
is a set of principles and techniques that if understood acquisition the higher the quality of the obtained
well should be helpful in obtaining adequate volume.
information. First we start with the 2D color or power b. Ask the mother to hold still for the expected time
Doppler information. Normal 2DUS principles of frame that the acquisition takes place. That is
visualizing vessels with color and power Doppler anywhere between 5- 15 seconds depending on
should be followed (and the following work better in the size of the volume box and the angle of
a 3D volume acquisition as well) such as: acquisition.
a. Being as parallel to the vessel or vessels of interest c. Try to acquire volumes at quiet fetal states to
as possible. avoid motion artifacts.
710 Textbook of Perinatal Medicine

Analyze the volume right after acquisition for possible improve) as software updates or better probes emerge
acquisition related artifacts due to fetal breathing, that improve color or power Doppler sensitivity.
respiration, or movement. Explore the B or the C Published nomograms for vascularity cannot be used
window as those are the computer-generated views for imaging with other types of machines or with
where the hidden artifacts can be depicted. Window different generations of the same probe because of
A is the acquisition plane and as such may or may variable color sensitivity. Nevertheless, the
not show artifacts. information obtained can provide important
qualitative assessment of vascularization and blood
FLOW VOLUME AND PERFUSION STUDIES flow changes in different normal and abnormal
For the first time 3D ultrasound allows very accurate physiologic states. While a few studies have been
volume measurements. Multiple studies have shown conducted in gynecology, no studies have been
that volume measurements are feasible and reported in obstetrics yet.
nomograms of several different organ systems in the
CLINICAL APPLICATIONS
fetus have been generated.8-12 A very interesting
aspect of obtaining power and color Doppler volumes Color and power Doppler information in a volume
is that this information can give an overall estimation have shown to be very useful in visualizing the fetal
of the blood supply of a given anatomical area. Many anatomy (Figs 50. 2 to 50.10). Several authors have
efforts have been made by the industry to further post reported their positive experiences with the use of 3D
process this information with the purpose of Doppler.13,14 Studies have shown that 3D color and
quantifying the amount of blood supply. One of the power Doppler, as used with a free hand 3D
most useful programs is the so-called 3D-Shell
imaging method. In this method a 3D volume is
acquired with power Doppler; then a volume of
interest (VOI) inside the initial acquired volume can
be traced. Inside the volume of interest the gray scale
and color histograms can be evaluated together or
separately and expressed as a mean value. The
expected clinical value of these power and color
Doppler volume quantification methods is better
estimation of blood flow within the area of interest
(i.e. tumor). For this purpose four indices have been
proposed:
1. Average gray value of non-color voxels (MG).
2. Vascularization index (VI): ratio of number of
color voxels to total number of voxels inside VOI.
3. Flow index (FI): ratio of sum of color intensities
to number of color-voxels inside VOI.
4. Ratio of sum of color intensities to total number
of voxels outside VOI (VFI).
Importantly, while these measurements provide a
useful method in quantifying blood flow and
Fig. 50. 2: This is a 3D power Doppler (without the gray scale)
vascularity in the acquired volumes, their information
display of the Circulus of Willis at 26 weeks gestation. Note the
is based on digitized color voxel information. The anterior, middle and posterior cerebral arteries as well as the
accuracy of this information may change (i.e. basilar artery
 3D/4D Color and Power Doppler in Obstetrics 711

Fig. 50. 3: The same case as Fig. 50. 2. A volume rendered in Fig. 50. 5: Power Doppler rendered volume of a fetus at 20
transparent mode in Gray scale and 3D power Doppler weeks gestation with Noonan syndrome. Note the absence of
information in the same display. This display is generally used ductus venosus and the umbilical vein draining directly to the
to display the brain vasculature in power Doppler as well as right atrium. Note the distorted angio-architecture as compared
the brain gray scale infor mation simultaneously for better to the normal fetus in Fig. 50. 4
orientation and correlation. Typically the color Doppler rendering
can be combined with the gray scale at different percentages
to the liking of the operator

Fig. 50. 4: This is a 3D power Doppler rendered volume of the Fig. 50. 6: The same patient as in Fig. 50. 5 but the volume has
fetal cardiovascular system of a normal 23 weeks gestation been rendered in a 3D color Doppler again without the gray
fetus. This volume has been rendered only with the 3D power scale information. The information provided from 3D Color
Doppler without the presence of any gray scale information. Doppler is similar to the one provided by 3D power Doppler but
As this is volume data, it can be rotated to depict different views in color Doppler we have additional information regarding the
of the anatomy. Note the detailed visualization of descending direction of flow. RA- right atrium, DA- ductus venosus, UV-
aorta, inferior vena cava (IVC), right atrium, umbilical vein, right umbilical vein, UA-umbilical arteries
hepatic and left veins, left portal vein and ductus venosus.
712 Textbook of Perinatal Medicine

Fig. 50. 9: A composite image of several different volumes of a

frontal view through the fetal body of a fetus at 22 weeks
gestation with congenital diaphragmatic hernia. In surface
anterior view the volume has been rendered with surface
rendering settings at a very anterior level right behind the
sternum to show the fetal liver, the diaphragm and the heart
displaced in the right. In surface posterior view the volume has
been rendered again with surface rendering settings but at a
posterior level to show the fetal stomach up in the chest, the
Fig. 50. 7: Multiplanar display and a rendered display of a fetus disappearance of the diaphragm posteriorly and to the left, as
at 25 weeks gestation with persistent right umbilical vein. A- well as the left lobe of the liver going up in the chest. In minimum
transverse plane through the fetal abdomen at the level obtained intensity view the volume has been rendered with minimum
to measure the abdominal circumference. S-stomach, G- intensity settings (good for fluid filled structures) at a posterior
gallbladder, RPUV-right persistent umbilical vein. The right level to better display the fetal stomach up in the chest as well
umbilical vein passes lateral and to the right side of the as left lobe of the liver vessels up in the chest. In 3D power
gallbladder connecting with the left portal vein. This is the view the volume has been rendered with both surface and 3D
intrahepatic form of the right umbilical vein. B- a perpendicular power Doppler to better visualize the fetal heart and liver vessels
view to plane A. C- a coronal view to plane A. D- the rendered in relationship to the chest wall and the diaphragm. Note the
3D power Doppler view with the arrow pointing at the persistent distorted angio-architecture as compared to the normal fetus
right umbilical vein. Note that all these 4 windows are interactive in Fig. 50. 8
with each other. Window A and D can be correlated to identify
the right umbilical vein both in cross-sectional and rendered
view

Fig. 50. 8: A composite image of a frontal view through the

fetal body of a normal fetus at 20 weeks gestation. The volume Fig. 50. 10: A 3D volume of the fetal heart and vessels of a
was acquired with and without power Doppler. The volumes normal fetus at 22 weeks rendered with minimum intensity
are displayed in 3D surface rendering to visualize tissue projection. This is a unique and very helpful view that visualizes
interfaces of heart, lung, liver and bowel (first to the right), the vessels in gray scale without any color or power Doppler
minimum intensity projection to visualize fluid filled structures information. This rendering parameter can be employed in all
such as heart and stomach, and in surface and 3D power acquisition modes (3D, 4D and STIC) and can be a useful
Doppler to visualize the relationships between vascular addition to the information provided by the 3D color or power
orientation and the fetal body Doppler
 3D/4D Color and Power Doppler in Obstetrics 713
ultrasound system was useful in imaging tumors
(chorioangioma, teratoma, hygroma, lung sequestra-
tion), the fetal brain (vein of Galen aneurism, corpus
callosus agenesis, vascular malformations), kidneys
(agenesis of the kidneys, renal arteries), fetal
abdominal vessels, umbilical cord anomalies, and
placental disorders.14 Lee et al demonstrated that 3D
color and power Doppler, as acquired with an
automated 3D probe could visualize placental
angiogenesis as early as 7.1 weeks gestation, cerebral
and neck vessels as early as 12.9 weeks gestation,
brain vessels, cord insertion, placenta and vasa
previa.15 In an interesting study, Kalache described
the use of 3D power Doppler ultrasound to identify
vascular congenital anomalies of fetal portosystemic
Fig. 50. 11: Multiplanar and rendered display of a placental
and umbilical venous system. He found 8 out of 310 volume acquired with 3D color Doppler at 20 weeks gestation.
fetuses with portosystemic venous malformations. In A we see the acquisition plane, in this case along the long
When an umbilical vein or ductus venosus anomaly axis of the placenta, in B we see the short axis and C the
is suspected, the operator has to construct the 3D coronal view. In D wee the 3D color Doppler and gray scale
rendered view of the placenta. Note that the rendered view
orientation of the vessels from cross-sectional 2D represents a rather thin slice through the placenta and not the
images. Power Doppler in 3D allows visualization of whole placental volume. That thickness of this particular volume
low velocity flow, blood flow is displayed can be judged and appreciated at window B where you can
independent of its velocity and the vessels a see the green interrupted lines
visualized throughout the volume ensuring spatial
orientation (Figs 50.11 and 50.12).16 demonstrate how
3D color and power Doppler can have an important
role in visualizing complex anatomical arrangements
otherwise quite difficult with 2D ultrasound.
Hull et al reported their experience in using 3D
color and power Doppler in imaging the placenta.17
They found that 3D ultrasound with color Doppler
imaging allowed a more accurate diagnosis of
placenta percreta. They had seen several patients in
whom the use of 3D ultrasound with color flow and
power Doppler imaging allowed refinement of the
diagnosis of placental invasion, correctly predicting
placenta percreta with bladder invasion. They feel that
the multiplanar capability is they key to 3D ultra- Fig. 50. 12: A composite image of 4 different image displays of
sound utility. Other useful applications of 3D color the placenta. In 2D power Doppler view in the upper right we
and power Doppler reported by this group are placen- see scattered power Doppler signal in a thin 2D ultrasound
slice. In 3D gray scale we see a rendered view through the
tal cord insertion and vasa previa visualization.17 placenta in gray scale. In 3D power Doppler and gray scale we
see the great depth perception and detail of placental
Fetal Echocardiography vasculature provided by 3D power Doppler in a 3D volume. In
3D Power Doppler Only we can see more clearly the vascular
Three dimensional volume acquisition speed has been anatomy of the placenta without the gray scale superimposed
improved significantly over the last 5 years. In the in it
714 Textbook of Perinatal Medicine

past it was generally believed that increases in ultrasound. 20-24 Recently Chaoui published a
acquisition speeds will have a great impact in 3D fetal comprehensive prospective study in which he
echocardiography. While the Voluson 730 Expert (GE examined the potential of color Doppler STIC in the
MEDICAL, Milwaukee, USA) can achieve speeds of evaluation of normal and abnormal fetal hearts. He
acquisition up to 32 frames per second, in acquiring included 35 normal fetuses and 27 fetuses with
fetal heart volumes these high speeds do not congenital heart defects (CHD) examined between 18
necessarily translate into higher quality volumes. and 35 weeks of gestation. Volume acquisition was
Indeed, the opposite is true. Slower volumes yield achieved by initiating the image capture sequence
higher quality information as there are more 2D from the transverse four-chamber view. Volumes were
frames incorporated in the volume. To overcome this stored for later offline evaluation using a personal
obstacle, a new volume acquisition technology was computer-based workstation in a multiplanar mode
introduced. This technology is called Spatio-Temporal and as spatial volume rendering. Successful
Image Correlation (STIC). With STIC an extra slow acquisition was possible in all 62 cases. Spatial volume
(by 3D ultrasound standards) acquisition from 7.5-15 rendering was attempted in 18 fetuses with CHD. In
seconds is performed over a preselected area of the the four normal fetuses had inadequate visualization
fetal heart, typically at the level of the 4-chamber view. using color Doppler STIC, as the region of interest was
The acquisition angle varies from 15 degrees to 40 perpendicular to the ultrasound beam. In two fetuses
degrees and again is user selectable. The same image with CHD inadequate visualization was related to an
optimization criteria apply just as the ones mentioned
above. After the acquisition, post processing of spatial
and temporal data is performed so the 2D acquired
images are correlated in time and space. This
information is displayed in a classic multiplanar view
and/or in a cine sequence depicting heart motion with
total control on interactive re-slicing and/or rendering
the same as you would in a static 3D volume.
Typically, in gray scale, this acquisition has a very high
b-mode frame rate (approximately 150 frames/sec)
due to the relatively small region of interest.
STIC technique was initially introduced only in
gray scale but latter the acquisition of fetal heart
volumes with STIC could be achieved with color and/
or power Doppler information. This development
opened up a whole new area in evaluating the fetal
Fig. 50. 13: A composite image of a multiplanar view of the
heart with 3D ultrasound. STIC represents the first fetal heart acquired with 3D STIC color Doppler at the 4
significant development in 3D fetal heart scanning chamber view level. In the lower left there is a diagram illustrating
that has the potential to perform a full fetal echo exam the acquisition of a fetal heart volume with a dedicated volume
out of a single fetal heart volume at the level of the 4 transducer where the transducer is kept stationary and the
mechanically steered transducer elements sweep through the
chamber view. Studies done prior and post the volume of the heart at a predetermined angle and speed. After
introduction of STIC were able to demonstrate that a the acquisition of the volume, the cross-planar center point is
volume of the fetal heart can provide all the standard placed at the descending aorta in plane A and oriented at 6
imaging views for a fetal echo (Figs 50.13 to 50.15).4,18 o’clock position. This rotation will ensure that we can obtain
the ductal arch at B and the descending aorta in C. A STIC
Several reports have been demonstrating the value volume with color Doppler depicts in red the atrioventricular
of STIC to the evaluation of the fetal heart with 3D flow (see A) and in blue the outflow tracts (see B)
 3D/4D Color and Power Doppler in Obstetrics 715

Fig. 50. 15: This image is a multiplanar and rendered view of a

fetal heart volume obtained with STIC and color Doppler at the
level of the 4-chamber view in a patient with transposition of
the great arteries. In A the heart is seen at the level of the 4
chamber view and the atrio-ventricular flow is seen in red. In B
we see a plane through the fetal heart that is perpendicular to
A that shows a cross section of the outflow tracts in blue. In C
Fig. 50. 14: This image shows the 4-chamber view image with we see a cross-sectional view of the heart tight under the atrio-
color Doppler extracted from a STIC 3D color Doppler volume. ventricular valves. In D there is a rendered view of the outflow
The green lines represent the scan planes where the additional tracts (in blue color). Note the fact that the outflow tracts do not
views of the heart, such as inferior vena cava/superior vena crisscross as normally expected do but they exit the ventricle
cava (IVC/SVC) or aortic arch can be obtained. The vertical in a parallel fashion indicative of a d-transposition of the great
axis of the display can be aligned with these scan planes by vessels
rotating the image plane and simultaneously maintaining the
descending aorta as the pivot point by placing the cross planar
point in it. Typically the ductus arteriosus plane is the plane
that goes through the descending aorta (placed at 6 o’clock) While the potential of this technique is clear, there are
upward intersecting the left atrium, right ventricle and the a number of potential pitfalls that are worth
sternum. The IVC/SVC plane is a plane parallel to the plane of mentioning. The acquisition is still relatively slow,
ductus arteriosus and to the right of it close to the level of right
atrium. Aortic arch is a plane that can be found by rotating the from 7.5-15 seconds and as such fetal breathing and
4-chamber view plane around 35-40 degrees from the ductus gross body movement do commonly occur. Careful
arteriosus plane and maintaining the descending aorta as the evaluation of the windows B and C in the multiplanar
pivot point by keeping the cross planar point there
display after the acquisition is crucial to ensure that
no artifacts are present. Adjusting the volume box
enlarged heart in late gestation, in which the entire tightly around the region of interest helps as it
cardiac volume could not be acquired. The third case generally increases the frame rate. The best frame
was an 18-week fetus with complex CHD and rates recommended are the ones above 15 Hz,
transposed great vessels in which artifacts were typically with higher rates in smaller hearts and
related to confluent color signals as a result of low slower rates in bigger hearts. Important adjustment
resolution in the reconstructed plane. He concluded is the acquisition angle, as the default settings tend
that STIC in combination with color Doppler to be very narrow. Optimal angles vary from 15 to 30
ultrasound is a promising new tool for multiplanar degrees and are related to the gestational age. The
rendering of the fetal heart.24 earlier the gestational age the narrower the angle.
716 Textbook of Perinatal Medicine

NETWORKING during acquisition. Typically the coronal

reconstructed plane, which is unique to 3DUS, has the
A potential benefit of 3DUS lies in ultrasound
lowest resolution of the three planes in the
documentation, storage and networking. Digitally
multiplanar display. There definitely is a learning
saved volumes of patient data can be readily
curve associated with the adequate use of this
transferred to a remote site for interpretation or
technology. Professionals contemplating the
second opinion consultation. Further research is
introduction of this modality into their practices
needed to define the indications, the potential
should consider dedicating time and effort for
advantages and limitations of volume data transfer
additional training in its principles. As this technology
across networks, but it is clear that this is a better
improves and becomes more widely available, clinical
method for sharing ultrasound information as you do
indications for its use will continue to emerge. There
not rely only on still 2D images or videotapes but have
is a great need for comprehensive and rigorous
the whole anatomy that can be manipulated at any
research studies that would hopefully standardize
plane. Using this technology one would expect that
optimal acquisition and analysis of 3D color and
in the future primary clinical sites in remote areas
power Doppler studies for specific fetal indications.
would have access to expert consultation and off-line
interpretation, enabling high quality and cost effective
medical care. The digitally stored patient volumes can REFERENCES
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sonographers in training facilitating training in Dimensional Ultrasound. Lippincott Williams and
Willkins 1999.
ultrasound. As this information is digital, it can be 2. Riccabona M. Pretorius DH. Nelson TR. Johnson D.
encrypted for patient data safety considerations, and Budorick NE. Three-dimensional ultrasound: display
efficiently compressed with loss-less algorithms to be modalities in obstetrics. J Clin Ultrasound. 1997.
shared across hospital networks. 25(4):157-67.
3. Kavic MS. Three-dimensional ultrasound. Surg
Endoscopy. 1996. 10(1):74-6.
CONCLUSION 4. Bega G, Kuhlman K, Lev-Toaff A, Kurtz A, Wapner R.
Application of three-dimensional ultrasonography in the
It is important to emphasize that 3DUS color and evaluation of the fetal heart. J Ultrasound Med 2001;
power Doppler information is based on acquisition 20:307–313
and reformatting of conventional 2DUS data. 5. Ota T, Kisslo J, Von Ramm OT, Yoshikawa J. Real-Time,
Therefore, it is not surprising that 3DUS is prone to Volumetric Echocardiography: Usefulness of Volumetric
Scanning for the Assessment of Cardiac Volume and
the same problems that affect 2DUS, such as Function. J Cardiol 2001; 37 Suppl 1:93-101.
unfavorable body habitus, motion and shadowing 6. Kisslo J, Firek B, Ota T et al. Real-Time Volumetric
artifacts and poor scanning technique. Although Echocardiography: The Technology and the Possibilities.
Echocardiography 2000; 17:773-779.
3DUS with color and power Doppler may improve
7. Sklansky MS, DeVore GR, Wong PC. Real-time 3-
overall comprehension of the vascular anatomy, it dimensional fetal echocardiography with an
does not make up for poor scanning technique. Poor instantaneous volume-rendered display: early
resolution in 2DUS will very likely result in sub description and pictorial essay. J Ultrasound Med. 2004
Feb;23(2):283-9.
optimal image quality in the volume data as well. 8. Liang RI, Chang FM, Yao BL, Chang CH, Yu Ch, Ko HC.
Imaging the vessels in perpendicular planes with the Predicting birth weight by upper-arm volume with use
beam will also result in poor imaging as the best of three-dimensional ultrasonography. Obstet Gynecol
results are achieved with parallel vessel orientation 1997. 177. 3. 632-638.
9. Lee W. Comstock CH, Kirk J. Smith R. Monck J.
to the ultrasound beam. The resolution of the three Deenadayalu R. Bendick P. Birthweight prediction by
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varies according to their deviation from the plane thigh and abdomen. J Ultrasound Med 1997. 16:799-805.
 3D/4D Color and Power Doppler in Obstetrics 717
10. Pohls UG. Rempen A. Fetal lung volumetry by three- 18. DeVore GR, Polanco B, Sklansky MS, Platt LD. The “spin”
dimensional ultrasound. Ultrasound Obstet Gynecol. technique: a new method for examination of the fetal
1998. 11(1):6-12. outflow tracts using three-dimensional ultrasound.
11. Laudy J. Janssen M. Struyk P. Stijnen T. Wladimirof J. Ultrasound Obstet Gynecol. 2004 Jul;24(1):72-82.
Three dimensional ultrasonography of normal fetal lung 19. Devore GR, Falkensammer P, Sklansky MS, Platt LD.
volume: a preliminary study. Ultrasound Obstet Gynecol Spatiotemporal image correlation (STIC): new
1998;11:13-16. technology for evaluation of the fetal heart. Ultrasound
12. Lee A. Kratochwil A. Stumpflen I. Deutinger J. Obstet Gynecol 2003;22:380–387.
Bernaschek G. Fetal lung determination by three
20. Vinals F, Poblete P, Giuliano A. Spatio-temporal image
dimensional ultrasonography. Am.J.Obstet.Gynecol.
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13. Matijevic R. Kurjak A. Three dimensional color and
power imaging: experience in prenatal diagnosis. In 2003;22:388–394.
Kurjak A ed. Clinical Application of 3D Sonography. 21. Goncalves LF, Lee W, Espinoza J, Huang R,
Parthenon Publishing, New York. 2000:155-160. Chaiworapongsa T, Schoen ML, DeVore G, Romero R.
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15. Lee W, McNie B, Chaiworapongsa T, Conoscenti G, fetal echocardiography using new acquisition and
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 Non-invasive Detection of
51 Fetal Anemia by
Doppler Ultrasonography

Leonardo Pereira

INTRODUCTION ∆OD 450 assessment is a reliable predictor of fetal

anemia in most cases of alloimmunization. However,
Cases of hemolytic disease of the newborn have been
because amniocentesis ∆OD450 assessment is limited
described as early as 1609 in France,1 however it was
to hemolytic causes of fetal anemia and because it has
not until 1932, over 300 years later, that the association
the potential to cause fetal-maternal hemorrhage and
of erythroblastosis with fetal hydrops, jaundice and
worsen sensitization, active research for nearly 30
hemolytic anemia was characterized by Diamond,
years has focused on attempts to detect fetal anemia
Blackfan, and Baty.2 Shortly thereafter, the discovery
non-invasively.
of the Rhesus blood group by Landsteiner and Weiner
in 1940, and their demonstration of agglutination
ULTRASONOGRAPHIC EVALUATION OF
when rhesus monkey red blood cell antiserum was
FETAL ANEMIA
mixed with Rh-positive, but not Rh-negative blood,
stands as one of the most important hematologic Serial ultrasound evaluations for fetal hydrops in
discoveries of the 20th century.3 From this landmark cases of suspected anemia have become a routine
achievement, treatment of hemolytic disease of the component of perinatal medicine. The observation of
newborn with transfusion therapy and ultimately hydrops on ultrasound is highly specific for severe
prevention of Rh sensitization with anti-D immune anemia, with most hydropic fetuses having
globulin became possible. However, despite the hemoglobin levels which are less than 5 g × dl–1. The
availability of postnatal transfusion therapy, the finding of fetal hydrops in cases of suspected anemia
medical practice of this era was limited by an inability should lead directly to therapeutic interventions
to screen for hemolytic disease antenatally. aimed at restoring blood volume. However, basing
The discovery that Rh sensitization could be treatment on the presence of hydrops alone may miss
quantified by assessing the spectral absorption curve over 50% of fetuses with hemoglobin concentrations
of amniotic fluid 450 nm (∆OD450) was first described below 6.0 g × dl–1.7
by Bevis and Walker and then further characterized Partially because of this shortcoming, many
by Liley in 1961.4-6 From this important observation, investigators have attempted to detect fetal anemia
successful antenatal management strategies were prior to the onset of hydrops. Rightmire et al.
developed for Rh alloimmunized patients and for published one of the first successful endeavors at non-
those alloimmunized with non-Rh antigens as well. invasive diagnosis of fetal anemia in non-hydropic
Years of experience have taught us that amniocentesis fetuses in 1986. The authors developed a model of
 Non-invasive Detection of Fetal Anemia by Doppler Ultrasonography 719
combined Doppler measurements of the fetal aorta, multiples of the median (MoM). In this study, 83
inferior vena cava, and umbilical vein which was able women were RhD alloimmunized, 18 were Kell
to predict fetal anemia with a mean error of only 3.8 sensitized and another 9 were alloimmunized to non-
hematocrit units in a retrospective study. 8 Nicolaides RhD antigens. The authors also published reference
et al. prospectively measured six different tables for fetal hemoglobin levels and middle cerebral
ultrasonographic parameters, including umbilical artery peak systolic velocities, which have served as
vein diameter and placental thickness, but concluded the basis for further research studies and are useful
that in the absence of hydrops, none of these reference guides for current clinical management (see
successfully distinguished mild from severe fetal Figs 51.1 and 51.2).
anemia.9 This observation was confirmed by Whitecar Teixeira et al. in 2000 published results from a
et al. who reported on a variety of parameters prospective cohort study of 26 fetuses (24 cases of RhD
including amniotic fluid volume, intrahepatic and and 2 cases of RhC alloimmunization), and using a
extrahepatic umbilical vein diameters, hepatic length, peak systolic velocity above 1 standard deviation (SD)
and splenic perimeter. 10 Most of these parameters reported a sensitivity of 73% and specificity of 93%
have proven unreliable clinically. Attempts to for fetal hematocrit values below 3 SD.14 A large
accurately predict fetal anemia by measurement of the prospective, intent to treat trial of 125 cases of red cell
mean blood velocity in the fetal aorta have likewise alloimmunization was published by Zimmermann et
not been clinically applicable.11 al. in 2002 and confirmed the findings of previous
Measurement of peak systolic velocity as opposed authors.17 This trial reported that for the detection of
to mean blood velocity seems to have improved the
clinical utility of Doppler velocimetry. One author has
reported on the utility of measuring peak systolic Weeks MCA-PSV (Multiples of the Median)
Gestation 1.00 1.29 1.50 1.55
velocity in the splenic artery for the detection of fetal cm×sec-1 cm×sec-1 cm×sec-1 cm×sec-1
anemia in cases of Rhesus factor alloimmunization12
18 23.2 29.9 34.8 36.6
and no fewer than 7 prospective studies have reported
on the reliability of peak systolic velocity 20 25.5 32.8 38.2 39.5
measurements in the middle cerebral artery for 22 27.9 36.0 41.9 43.3
detection of fetal anemia in pregnancies complicated
24 30.7 39.5 46.0 47.5
by red cell alloimmunization (including Kell
sensitization) and parvovirus B19 infection. 13-19 26 33.6 43.3 50.4 52.1

28 36.9 47.6 55.4 57.2

Evidence Supporting Middle Cerebral Artery
30 40.5 52.2 60.7 62.8
Peak Systolic Velocity Measurements for
Fetal Anemia 32 44.4 57.3 66.6 68.9

34 48.7 62.9 73.1 75.6

In 1995, Mari et al. reported that middle cerebral
artery peak systolic velocity Doppler measurements 36 53.5 69.0 80.2 82.9
could accurately predict fetal anemia in a prospective 38 58.7 75.7 88.0 91.0
series of 16 pregnancies complicated by maternal red
40 64.4 83.0 96.6 99.8
cell alloimmunization.13 This report was followed in
2000 by a larger multi-centered study in which 111 Legend: MCA-PSV: middle cerebral artery peak systolic
velocity; cm: centimeters; sec: seconds
fetuses at risk for anemia were followed
From: G. Mari et al. N Engl J Med 2000; 342:9-14
prospectively.15 In this cohort, 23 fetuses had moderate
to severe anemia without hydrops and in all 23 middle Fig 51.1: Middle Cerebral Artery Peak Systolic Velocity as a
cerebral artery peak systolic velocities were above 1.5 Function of Gestational Age
720 Textbook of Perinatal Medicine

Weeks Fetal Hgb (Multiples of the Median) calvarium, as if one were measuring the biparietal
Gestation 1.16 1.00 0.84 0.65 0.55 diameter. Center and magnify the image until the fetal
g×dl-1 g×dl-1 g×dl-1 g×dl-1 g×dl-1 calvarium fills the image window. Following
18 12.3 10.6 8.9 6.9 5.8 identification of midbrain structures, including the
thalami and cavum septum pellucidum, move the
20 12.9 11.1 9.3 7.2 6.1
transducer in a slight caudal direction and identify
22 13.4 11.6 9.7 7.5 6.4 the circle of Willis using color Doppler. The bilateral
24 13.9 12.0 10.1 7.8 6.6 middle cerebral arteries should then be visualized
26 14.3 12.3 10.3 8.0 6.8 flowing anteriorly and outward just behind the orbits.
The sample volume line should be parallel to the walls
28 14.6 12.6 10.6 8.2 6.9
of the vessel, as close to a 0-degree angle of insonation
30 14.8 12.8 10.8 8.3 7.1 as possible (see Fig. 51.3). Either the ipsilateral or
32 15.2 13.1 10.9 8.5 7.2 contralateral middle cerebral artery can be measured,
but angle correction should not be used. The peak
34 15.4 13.3 11.2 8.6 7.3
systolic velocity should be measured in the proximal
36 15.6 13.5 11.3 8.7 7.4 middle cerebral artery, 2 mm after its origin from the
38 15.8 13.6 11.4 8.9 7.5 internal carotid artery. Placement of the sample
40 16.0 13.8 11.6 9.0 7.6
volume line in the proximal MCA is crucial since
systolic velocity decreases with distance from the
Legend: Hgb: hemoglobin; g: grams; dl: deciliter
point of origin of the MCA.15, 21
From: G. Mari et al. N Engl J Med 2000; 342:9-14
The sample volume should be made relatively
Fig. 51.2: Fetal hemoglobin as a function of gestational age small so that the Doppler signal does not incorporate
the internal carotid artery. The peak systolic velocity
should be measured at the highest point of the
moderate to severe fetal anemia, middle cerebral Doppler waveform. The measurement should be
artery peak systolic velocities over 1.5 MoM had a repeated multiple times during periods of fetal apnea,
sensitivity of 88% and specificity of 87%. while the fetus is relatively stationary. The highest
Further studies have provided evidence that Doppler measurement obtained should be recorded.
middle cerebral artery peak systolic velocity Doppler When performed in this fashion, multiple sources
can be used to estimate actual hemoglobin have previously reported low intraobserver and
concentrations18 and to predict the timing of a second interobserver variability rates between 2.3% and
in-utero blood transfusion.20 4.0%.13, 21-22
In addition to cases of red cell alloimmunization,
2 studies have found that, in a total of 42 cases of Management with Middle Cerebral Artery Peak
parvovirus B19 infection, middle cerebral artery peak Systolic Velocity Compared to Conventional
systolic velocity assessment could detect fetal anemia Management with Amniocentesis ∆OD450
with sensitivity between 94% to 100% and specificity Based on the results of the previously mentioned
between 93% and 100%.16, 19 studies,13-19 clinical reliance upon serial middle
cerebral artery peak systolic velocity Dopplers is
Technique for Measuring the Middle Cerebral becoming more common. However, few studies have
Artery Peak Systolic Velocity compared Doppler velocimetry to conventional
Measurement of peak systolic velocity in the middle management with amniocentesis. At time of
cerebral artery should be technically straightforward publication of this chapter, only two published trials
in most cases. Obtain an axial view of the fetal had compared the 2 management strategies.
 Non-invasive Detection of Fetal Anemia by Doppler Ultrasonography 721

Fig. 51.3: Doppler assessment of the fetal middle cerebral artery; A arrow (correct position of Doppler cursor over anterior MCA);
B arrow (correct position of Doppler cursor over posterior MCA); C arrow (correct measurement of the PSV); MCA: middle
cerebral artery; PSV: peak systolic velocity; R: right; L: left; cm: centimeters; sec: seconds

The first study, published by Nishie et al. followed cerebral artery peak systolic velocity Doppler may
28 non-hydropic fetuses and found that conventional have a better predictive value for moderate to severe
management and middle cerebral artery peak systolic anemia in red cell alloimmunization, eliminate the
velocity Doppler were both accurate predictors of fetal need for amniocentesis, and reduce the number of
anemia in cases of red cell alloimmunization.23 The percutaneous umbilical cord blood samplings (PUBS)
authors suggested in their conclusion that performed on non-anemic fetuses.
management with middle cerebral artery peak The main benefit to management with middle
systolic velocity Doppler could decrease the number cerebral artery peak systolic velocity Doppler is a
of invasive procedures performed in their population. reduction in invasive procedures and avoidance of
A second study, by Pereira et al., also reported potential complications. Transplacental fetal
outcomes on 28 cases of red cell alloimmunization hemorrhage, which may worsen sensitization, occurs
followed with both middle cerebral artery peak following 2-11% of amniocenteses.25-27 Another 1-2%
systolic velocity Doppler and conventional of amniocenteses are complicated by rupture of
management with amniocentesis. 24 In this study, amniotic membranes, premature labor, vaginal
management by middle cerebral artery peak systolic bleeding, or infection, while fetal loss occurs in
velocity Doppler compared favorably to conventional approximately 0.5% of cases. 28 Complications
management, with a sensitivity of 91% and a associated with PUBS are even more common, with
specificity of 100% for moderate to severe fetal at least 50% of procedures complicated by umbilical
anemia. The authors concluded that compared to cord vessel bleeding and a procedure-related loss rate
conventional management, management by middle of 2-3%.29
722 Textbook of Perinatal Medicine

In the U.S there are approximately 14,000 cases of heart syndrome that compromise left ventricular
alloimmunization annually. cardiac output may result in decreased middle
Extrapolating from published trends, management cerebral artery peak systolic velocities. Amniocentesis
with middle cerebral artery peak systolic velocity ∆OD450 measurements should not be affected by the
Doppler could avoid 24,500 amniocenteses and over presence of congenital heart disease and may be
1500 PUBS per year in the U.S population.24 With a superior to Doppler in this setting.
complication rate of 0.5% for amniocentesis and a Another limitation of middle cerebral artery peak
conservative estimate of 2% for PUBS, one pregnancy systolic velocity Doppler occurs in the setting of fetal
loss or preterm delivery per 100 patients (over 140 hydrops. The middle cerebral artery peak systolic
annually) could be avoided by using middle cerebral velocity in hydropic fetuses may be diminished by
artery peak systolic velocity Doppler over conven- compromised cardiac output. In these cases, the fetus
tional management - and these would likely occur in may not be able to maintain adequate cardiac output
a mildly anemic or non-anemic fetuses. Furthermore, resulting in a lower middle cerebral artery peak
an additional benefit would occur from avoiding systolic velocity than would be expected for the
procedure related bleeding complications which degree of anemia. False negative middle cerebral
increase sensitization and worsen disease. artery Dopplers have been previously reported in
hydropic fetuses with severe anemia. 17, 32
Limitations of Middle Cerebral Artery Peak
Systolic Velocity
Potential Pitfalls in Measuring Middle Cerebral
Management of suspected fetal anemia by middle Artery Peak Systolic Velocity
cerebral artery peak systolic velocity Doppler has
Serial middle cerebral artery peak systolic velocity
limitations. The accuracy of middle cerebral artery
Doppler measurements must be conducted in strict
peak systolic velocity Doppler appears to diminish
adherence with proper technique as previously
after 35 weeks’ gestation, leading to higher false
discussed to maintain diagnostic accuracy. Measure-
positive rates for prediction of anemia. 17,30
ments taken in the distal middle cerebral artery or
Furthermore, multiple intrauterine transfusions
with an angle of insonation above 20 degrees may
increase fetal blood viscosity, which may alter the
underestimate the peak systolic velocity and decrease
predictive accuracy of middle cerebral artery peak
sensitivity.
systolic velocity Doppler. 20, 31 The reliability of middle
Intermittent vascular constriction of the middle
cerebral artery peak systolic velocity Doppler to
cerebral artery can occur and may explain several
predict fetal anemia in fetuses after 3 or more
transfusions has not been tested prospectively, and reported cases where an elevated middle cerebral
false negative cases have been reported. 17,20 At artery peak systolic velocity measurement has not
present, serial amniocenteses for ∆OD450 assessment been reproducible.17, 19
should be considered in fetuses greater than 35 weeks Multiple factors influence fetal cerebral hemo-
gestation and in those who have received 3 or more dynamics and can influence middle cerebral artery
in-utero transfusions. This will also allow for fetal Doppler studies. Variations in fetal heart rate, both
lung maturity, which will assist in planning perinatal bradycardia33-34 and tachycardia 35 alter flow through
management. the middle cerebral artery. Fetal behavioral state and
The predictive accuracy of middle cerebral artery activity level also result in dynamic changes in middle
peak systolic velocity Doppler in fetuses with cerebral artery perfusion. 36 For these reasons, the
compromised left- sided cardiac output from middle cerebral artery peak systolic velocity should
structural heart disease has not yet been established. be measured during periods of fetal apnea and when
Anomalies such as mitral stenosis or hypoplastic left fetal activity is minimal.
 Non-invasive Detection of Fetal Anemia by Doppler Ultrasonography 723
Alterations in middle cerebral artery Doppler Algorithm for Fetal Surveillance using Middle
waveforms should be anticipated during active labor Cerebral Artery Peak Systolic Velocity
and in fetuses with severe intrauterine growth
For clinical purposes, a sample algorithm for
restriction. The reliability of middle cerebral artery
management of suspected fetal anemia using middle
peak systolic velocity to detect anemia during active
cerebral artery Doppler velocimetry is shown in (Fig.
labor has not been established, and Yagel et al.
reported a 40% reduction in middle cerebral artery 51.4) and can be summarized as follows:
blood flow impedence during labor.37 Fetuses with Identify pregnancies at risk for fetal anemia such
severe intrauterine growth restriction display similar as: patients with prior affected pregnancies, antibody
reductions in cerebral blood flow impedence titers which have reached a critical threshold level,
independent of hematocrit.38-39 This is likely due to anti-Kell antibodies, congenital parvovirus, suspected
“brain-sparing,” which has been characterized by a feto-maternal hemorrhage (e.g., strongly positive
decrease in the middle cerebral artery pulsatility index Kleihauer-Betke test or unexplained elevated
as a cephalization of blood flow in response to fetal maternal serum alpha-fetoprotein level). Beginning
hypoxemia.39-41 at 18-20 weeks gestation, perform weekly sonograms

Identify at risk pregnancies:

prior affected pregnancy
critical maternal serum titer
Kell sensitized,
other suspected etiology for fetal anemia

Weekly U/S assessment for hydrops and measurement of the MCA-PSV

from 18-20 weeks gestation until 35 weeks gestation

MCA-PSV < 1.5 MoM MCA-PSV between MCA-PSV > 1.5 MoM then Fetal Hydrops on U/S
repeat every 7 days 1.29 and 1.5 MoM, or repeat within 24 hours and prepare for
(If MoM stable x 3 weeks MoM value increasing, prepare for cordocentesis cordocentesis and
and < 1.29 MoM, then then repeat in 2-7 days and possible transfusion at possible transfusion
repeat every 10-14 days) that time within 24 hours

After transfusion # 1 After transfusion # 2 After transfusion # 3

Repeat U/S and MCA- Repeat U/S and MCA- revert to conventional
PSV every 2-7 days PSV every 2-7 days management by U/S and
After 35 weeks gestation amniocentesis ? OD450
revert to conventional
management by U/S and
amniocentesis ? OD450

Fig. 51.4: Antenatal surveillance for fetal anemia using MCA-PSV; Legend: MCA: middle cerebral artery;
PSV: peak systolic velocity; U/S: ultrasound; MoM: multiples of the median
724 Textbook of Perinatal Medicine

to measure the middle cerebral artery peak systolic systolic velocity will prove a valuable modality for
velocity and evaluate for evidence of fetal hydrops. avoiding an unnecessary cordocentesis.
If the middle cerebral artery peak systolic velocity is The possibility of measuring middle cerebral
less than 1.5 MoM then repeat it weekly for the next artery peak systolic velocity Dopplers in fetuses with
3 weeks. If over that time, the middle cerebral artery platelet or neutrophil disorders, such as neonatal
peak systolic velocity remains stable and is under 1.29 alloimmune thrombocytopenia, should be explored
MoM then it is probably safe to follow the middle remembering that the basis for elevated middle
cerebral artery peak systolic velocities every 10-14 cerebral artery peak systolic velocities is not actual
days. hematocrit but decreased blood viscosity.
If serial middle cerebral artery peak systolic
velocities remain between 1.29 and 1.5 MoM or are Suspected Fetal Hemorrhage
increasing in MoM values, then repeat the middle Acute or chronic fetomaternal hemorrhage may lead
cerebral artery peak systolic velocity measurement in to anemia, hydrops, and intrauterine death. In
7 days or less. If at any time the middle cerebral artery suspected cases, the diagnosis of fetomaternal
peak systolic velocity is > 1.5 MoM, then plan to repeat hemorrhage is typically made by demonstration of
the measurement in 12-18 hours and plan for a fetal erythrocytes in maternal circulation by
cordocentesis with preparations for a possible in-utero Kleihauer-Betke acid-elution stain. Measurement of
transfusion at that time. the maternal serum alpha-fetoprotein level may also
If there is sonographic evidence of fetal hydrops be useful in cases of suspected fetomaternal
then plan for a cordocentesis and transfusion even if hemorrhage.
the middle cerebral artery peak systolic velocity is < As in cases of red blood cell alloimmunization, the
1.5 MoM. appearance of hydrops in the setting of fetomaternal
Continue to follow at risk fetuses as outlined above hemorrhage remote from term should generally be
until the fetus reaches 35 weeks gestation or has treated with intrauterine transfusion as these fetuses
received > 3 in-utero transfusions, then revert back are at risk for in utero demise.44-6 Based on limited
to conventional management by amniocentesis data, it appears that middle cerebral artery peak
∆OD450 measurements. systolic velocities may be useful for detection of fetal
anemia in these cases. Baschat et al., in 1998, reported
Areas for Future Research with Middle Cerebral a case of acute fetomaternal hemorrhage in which the
Artery Peak Systolic Velocity middle cerebral peak systolic velocity was elevated
Areas for future research include studies to determine at presentation (hematocrit < 11%) and then
how well middle cerebral artery Dopplers predict normalized after in utero transfusion (hematocrit
anemia in fetuses with genetic syndromes 27%).47
(thrombocytopenia-absent radius, Fanconi Some authors have reported that intraplacental
Syndrome), hemoglobinopathies (alpha-thalassemia), Dopplers may be useful in predicting adverse
or viral infections which can cause a myocarditis as pregnancy outcomes (IUGR, preeclampsia) in cases
well as anemia. There have been case reports of fetuses of fetomaternal hemorrhage. In 1996, Jaffe and Woods
with hydrops due to parvovirus B19 that were not reported results from 32 patients followed due to
anemic at time of umbilical cord sampling and abnormal first trimester Doppler studies. In these
recovered without transfusion. 42-43 In these cases, patients, an abnormal ratio of intraplacental resistive
hydrops may be due to the myocarditis caused by the index (RI) to umbilical artery RI (defined as > 1)
tropism of parvovirus B19 for myocardial cells. between 22 and 25 weeks gestation was associated
Perhaps in these cases, middle cerebral artery peak with adverse pregnancy outcomes in 17/21 women
 Non-invasive Detection of Fetal Anemia by Doppler Ultrasonography 725
compared to 2/11 controls.48 A second study in 1997 the field of Doppler velocimetry is ongoing, and in
by Haberman and Friedman compared intraplacental the near future further advances in our ability to
pulsatility index (PI) to umbilical artery PI and detect fetal anemia non-invasively are certain to
reported a higher rate of IUGR and preeclampsia emerge.
when the intraplacental PI to umbilical artery PI ratio
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MB, Cusack TJ, Miller TC, Shah JJ. Diagnosis of subdural
and treated by intravascular transfusion. Am J Perin
hemorrhage in utero. J Neurosurg 1985;63:977-9.
1992;9:22-4.
51. Daffos F, Forestier F, Muller JY, Reznikoff-Etievant M,
46. Montgomery LD, Belfort MA, Karolina A. Massive
Habibi B, Capella-Pavlovsky M, Maigret P, Kaplan C.
fetomaternal hemorrhage treated with combined
intravascular and intraperitoneal fetal transfusions. Am Prenatal treatment of alloimmune thrombocytopenia.
J Obstet Gynecol 1995;173:234-4. Lancet 1984;2(8403):632.
 52
Doppler Ultrasound Studies in the
Fetal Pulmonary Circulation

Dennis C Wood, Jr and Juha P Räsänen

INTRODUCTION forms of congenital heart disease, pulmonary

obstructions and anomalous venous connections will
The fetal lungs may be quickly evaluated for size and
typically be missed at anatomic fetal ultrasound. In
function by observation using real time ultrasound:
there should be adequate amniotic fluid but there the second half of pregnancy, diaphragmatic fetal
should be no thoracic fluid spaces, cysts or echo dense breathing movements may reassure the observer of
areas. The size of the lungs should occupy about 2/ normal physiologic growth of the lungs, but this does
3 the area of the thoracic cavity in a transverse plane not rule out lethal pulmonary hypoplasia. However,
at the level of the four-chamber view of the heart. The changes in lung size and heart position may be signs
heart should have a normal 45° axis from the sternal/ of potential neonatal pulmonary hypoplasia and
spine axis in the levocardia position and occupy the hypertension problems (Fig. 52.1).
other third of the chest cavity. The pulmonary outflow The fetal pulmonary circulation consists of the
tract should emerge from the heart aiming toward the pulmonary arteries, ductus arteriosus and pulmonary
left shoulder and cross anteriorly over the aortic veins, all of which may be identified with ultrasound
outflow tract that aims toward the right shoulder. by 16 weeks gestation. However, subtle differences
While these observations of normality in the first half in the circulation of the fetal lungs and the vascular
of the second trimester will typically rule out most connections to the heart require interrogations of the

Fig. 52.1: 4 chamber heart in the transverse thorax view with normal size lungs and diaphragmatic hernia with small lungs
 Doppler Ultrasound Studies in the Fetal Pulmonary Circulation 729
venous and arterial Doppler color and spectral flow the dorsal surface of the sinoatrial part of the heart,
patterns. These investigations may be both difficult which divides and connects with the pulmonary
and time consuming because of fetal lie and plexus. As the atria expand, this single pulmonary
movement, maternal habitus and the presence of fetal vein is carried into the right atrium but eventually
breathing and may require an advanced ultrasound becomes absorbed into the left atrium as four separate
system. It is important to remember that normal ostia. Therefore, the pulmonary veins actually drain
appearing fetal lungs and normal cardiac situs can into the systemic venous system until about day 30,
be seen with any major structural cardiac abnormality when they become the proximal pulmonary veins of
including pulmonary atresia and totally anomalous the left atrium. In anomalous migratory patterns, the
pulmonary venous connection. pulmonary veins can continue with their connection
as a common venous sack, draining to the ascending
PULMONARY ANGIOGENESIS vein of Marshall to the innominate vein to the superior
The cardiovascular system is the first organ developed vena cava, to a connection below the diaphragm to
in the embryonic period: primitive blood vessels are the hepatic veins, or continue in part or completely
in place to accommodate the output of the heart which attached to the right atrium or the vena caval
begins to beat in the human fetus as early as 19 connections to the right atrium.
gestational days. Endothelial cells are the earliest Pulmonary development in the post embryonic
specialized cells. They form endothelial tubes and fetus has been studied extensively in various animal
recruit precursors to smooth muscle cells that form models and has generally divided into three
the arteries, arterioles, veins and venules. overlapping morphological stages: the pseudo-
Proliferation, migration, matrix production and glandular lung, the canalicular lung and the sacular
contractile protein expression characterize early stage of the viable lung.3 Development of the human
circulatory development.1 Vasculogenesis within the pulmonary vasculature is closely timed to cardiac
primitive lungs may be considered to be of constant development. In the human embryo at 5 weeks, it has
capillary production, fusion and regression. During been shown that the upper poles of the right and left
the embryonic period, the lung appears as a ventral lungs are supplied by primitive pulmonary arteries,
diverticulum of the foregut that becomes separated which arise from the sixth aortic arch between the
in a caudocranial direction from the future esophagus pulmonary trunk and the dorsal aorta. The lower
by the laryngyotracheal grooves. By day 26, that poles are supplied from the dorsal aorta via
developing bud divides and grows into the intersegmental arteries that penetrate through the
surrounding mesenchyme into right and left lungs.2 diaphragm. Anomalous growth at this connection
Blood is pumped from the heart into the common leads to pulmonary sequestration. As the branching
truncus arteriosus which divides into paired right and bronchi develop, so do the aligned pulmonary veins
left branches which connect to the dorsal aorta via and arteries.
various arches, most of which will regress and During the early pseudoglandular period (5 to 17
disappear. The sixth or most proximal arch connection weeks), the bronchial system has formed such that at
to the distal aorta is maintained throughout fetal life, each airway generation, there is an accompanying
typically on the left side, as the ductus arteriosus. The artery, in addition to supernumerary bronchial
sixth arch vessel gives rise to the main branches of arteries which supply the major airways and
the pulmonary arteries, and, with the helical division pulmonary arteries. 4 The lung therefore possesses
of the truncus and muscular division of the two vascular systems: a low pressure pulmonary
conotruncus, becomes the main pulmonary artery, the system and a high pressure bronchial system. By the
anterior vessel originating from the right ventricular end of the pseudoglandular period, Kitaoka counted
outflow tract. At the same time, a bud develops from twenty generations of airways with their
730 Textbook of Perinatal Medicine

accompanying arteries; the adult human lung

averages 24 generations.5 During this period, the
growth in veins and arteries is enormous, not in total
length or volume, but in the number of generations.
The canalicular stage (16 to 26 weeks) represents
the development of the gas exchange tissues. During
this period, pulmonary capillary expansion
corresponds to epithelial cell differentiation that
permits the formation of thin air-blood barriers and
surfactant production. The tremendous growth of the
capillary system into the lung parenchyma gives rise
to the concept of “canals” and gives the lungs a
spongy appearance. Arteries and veins develop both
in length and diameter as they follow the growth of
the preacinar airways.
The saccular stage of lung development (24 weeks
to birth) is demarcated by the expansion of the Fig. 52.2: Color Doppler image of pulmonary vascularity
alveolar spaces. The interstitium between the
airspaces contain the capillary system and the decrease further. In a-cross sectional study of 100
development of a network of elastic fibers where the uncomplicated singleton pregnancies we evaluated
postnatal interalveolar wall will be located. The human fetal pulmonary blood flow by Doppler
arterial pathways increase in length and diameter. It techniques to analyze the relationships between
has been shown that the diameter of the artery is a proximal and distal pulmonary arterial blood velocity
function of the distance from the previous branching waveforms and to determine normal pulmonary
such that the diameters are constant at a given arterial vascular impedance and physiologic
distance from the end of the alveolar tree.6 Arterial parameters in proximal and distal branch pulmonary
growth is faster centrally than in the periphery. arteries. We found that high resistance, high pressure
Distally, the number of additional branches grows and low blood flow characterize the fetal pulmonary
exponentially. The intrapulmonary veins begin to circulation throughout pregnancy.7
grow the circular muscular layer of mature vessels Using color Doppler to identify and align the
during the saccular period. The function of the lung vessel in a position parallel to the pulsed Doppler
tissue changes dramatically with birth but the beam, a narrow sample volume was placed into the
structure is not radically altered (Fig. 52.2). proximal part of the branch pulmonary artery
immediately after the bifurcation of the main
PULMONARY VASCULAR RESISTANCE
pulmonary artery. Using color Doppler guidance in a
(IMPEDANCE)
high resolution magnification imaging mode, distal
Fetal pulmonary arterial vascular impedance pulmonary arteries beyond the first bifurcation of the
decreases significantly during the second half of branch pulmonary artery were identified and
pregnancy. The linear decrease in the vascular waveforms were obtained during fetal apnea and in
impedance during the second trimester and in the the absence of fetal body movements (Fig. 52.3).
beginning of the third trimester may be related to the Waveforms were also measured at the aortic and
growth of the lung and to the increase in the number pulmonary valve levels and at the ductus arteriosus.
of resistance vessels. During the latter part of the third Proximal left and right pulmonary artery diameters
trimester pulmonary vascular impedance does not were measured from captured real-time images. In
 Doppler Ultrasound Studies in the Fetal Pulmonary Circulation 731

Fig. 52.3: Site of pulmonary Doppler imaging

each fetus, a sagittal section right lung length was valve were significantly longer than at the pulmonary
measured from the tip of the apex to the base of the valve. In this study population, the fetal heart rate
lung on the dome of the diaphragm during fetal did not change significantly during the second half
apnea, as described by Roberts and Mitchell. 8 of pregnancy. There were no significant differences
Proximal right pulmonary artery Doppler in PI-values, peak systolic velocities, TTP-intervals or
measurements were obtained successfully in 98% of pulmonary artery diameters between right and left
cases and proximal left pulmonary artery Doppler proximal and distal pulmonary arteries. Both
measurements in 96% of cases, respectively. In the proximal right and left pulmonary arterial diameters,
distal pulmonary artery, success rate on the right side as well as the right lung length, increased significantly
was 88% and on the left side 94%. during the second half of pregnancy, demonstrating
During the second half of pregnancy the pulsatility a 2.5-fold increase in their respective measurements.
index (PI) values in both proximal and distal left and In the proximal pulmonary arteries the PI-values
right pulmonary arteries decreased and the systolic and peak systolic velocities were significantly higher
peak velocities and time to peak velocity (TTP) and TTP-intervals were significantly longer when
intervals increased significantly. In the proximal compared with the distal pulmonary arteries. The
branch pulmonary arteries, a near linear decrease in ratio between the peak systolic velocities in proximal
the PI values was detected until 34-35 weeks of and distal pulmonary arteries decreased significantly
gestation, while in the distal pulmonary arteries, after with advancing gestational age. However, the ratio
31 weeks of gestation there was no significant between the proximal and distal branch pulmonary
decrease in the PI-value. Respectively, peak systolic artery PI-values did not vary significantly during the
velocities in the proximal branch pulmonary arteries study period. This study demonstrated that
increased in a linear fashion until 30 weeks of ultrasound techniques may be used to evaluate
gestation and remained unchanged until term. human fetal pulmonary circulation as early as 18
Proximal and distal pulmonary arterial TTP-intervals weeks of gestation.
were significantly shorter at 18 - 22 weeks of gestation The shape of the proximal branch pulmonary
and at term (36-40 weeks) than at the pulmonary arterial Doppler velocity waveform profile is unique
valve. The TTP-interval at the ductus arteriosus was in the fetal circulation (Fig. 52.4). It is characterized
shown to be significantly longer than at the by rapid initial flow acceleration followed by a very
pulmonary or aortic valves. TTP-intervals at the aortic early and rapid deceleration phase, producing a
732 Textbook of Perinatal Medicine

least the third generation vessels, and in these

segments, the linearly decreasing vascular impedance
during the latter part of the second trimester
represents the increase in the number of resistance
vessels. The vascular impedance does not decrease
markedly during the third trimester of pregnancy.
It is assumed that the phenomenon of wave
reflection in a vascular bed is closely related to
impedance. From the heart to the periphery, the
pulsatility of pressure waves progressively increases
Fig. 52.4: Distal pulmonary artery waveforms while the flow velocity waves decline. This explains
the difference between the proximal and distal branch
needle-like systolic peak followed by a short, but pulmonary artery PI-values. The forward propagating
relatively stable systolic flow segment culminating in waves of pressure and flow demonstrate the same
a gradual decay in systolic flow. At the beginning of configuration, but after wave reflection, the retrograde
diastole, proximal branch pulmonary artery blood flow waves are inverted, while the retrograde pressure
flow patterns demonstrate a short reverse flow waves are not. Wave reflections occur mainly in
interval following either no or a small amount of arterial system at the level of arterial-arteriolar
diastolic flow. The fetal branch pulmonary artery junctions.11
Doppler tracing is similar to that obtained by direct Vasodilatation decreases the wave reflection and
invasive blood flow recordings in fetal lambs.9 Fetal impedance while increasing flow.12 The changes in
growth during the second half of pregnancy is the branch pulmonary arterial vascular impedance are
characterized by a 2.5-fold increase in the lung length, similar to changes in the fetoplacental vascular
as well as in the diameters of proximal pulmonary impedance during the same pregnancy period. The
arteries. The significant decrease in the PI-values in continuing angiogenesis in both the fetoplacental unit
both proximal and distal pulmonary arteries during and fetal lung causes diminished wave reflections
the study period suggests a significant decrease in the associated with progressively declining vascular
pulmonary vascular impedance. There is no difference impedance. If the angiogenesis or angiomorphology
in changes in the pulmonary vascular impedance is abnormal in the fetoplacental unit this vascular
between the right or left lungs during the second half pathology results in increased vascular impedance
of pregnancy. associated with enhanced wave reflections (increased
The PI patterns in the distal and proximal systolic to diastolic ratio).13 We speculate that the
pulmonary arteries during the second half of failure of angiogenesis in fetal lungs could cause
pregnancy are different. In the distal pulmonary similar changes in vascular impedance, increasing the
arteries the decrease in the PI-values reaches the pulsatility of the Doppler waveform. The plateau
plateau stage around 31 weeks of gestation, while in stage, especially in the distal pulmonary artery
the proximal pulmonary arteries the PI-values vascular impedance during the third trimester, could
decrease in a linear fashion until 34-35 weeks of be explained by acquired vasoconstriction in the
gestation. In fetal lambs, a 40-fold increase in the total pulmonary circulation, even though the number of
number of the fifth and sixth generation vessels and resistance vessels is increasing in a linear fashion
a 4-fold increase in the lung weight characterizes the during this period according to animal studies.14
latter part of gestation.10 The medial width of these However, other factors affect the regulation of the
vessels remains unchanged throughout the gestation. pulmonary circulation. For example, prostaglandin I2
In our study, distal pulmonary arteries represent at production is increased after lung distention,
 Doppler Ultrasound Studies in the Fetal Pulmonary Circulation 733
distortion or spontaneous ventilation of fetal lungs a structural obstruction in the ductus arteriosus that
without changes in O 2 environment producing accelerates outflow into the descending aorta and
pulmonary vasodilatation.15 increase the PI above that of the main pulmonary
The changes in the peak systolic velocities support artery.21 We speculate that during the latter part of
the concept that during the last trimester, the decrease the second trimester and in the beginning of the third
in pulmonary vascular impedance reaches the plateau trimester, the decrease in the vascular impedance may
stage. Fetal lamb studies have revealed that an be related to the growth of the lung and especially to
increase in the pulmonary vascular resistance due to the increase in the number of resistance vessels.
hypoxia reduces the magnitude and duration of the During the latter part of the third trimester, the
forward flow in pulmonary arteries, while pulmonary vascular impedance does not decrease
acetylcholine, which is a potent pulmonary further.
vasodilator, produces a marked increase in the
magnitude and duration of systolic flow and reduces Pulmonary Blood Flow Effects on Fetal
or eliminates backflow. 16 However, peak systolic Combined Cardiac Output
velocities are not only affected by changes in afterload The human fetal pulmonary circulation has an
or vascular impedance, but also by fetal cardiac important role in the distribution of the cardiac
contractility, compliance, size of the vessels, and the output. 22 The latter part of the second and the
distance between the point of measurement and the beginning of the third trimester is characterized by a
fetal heart will affect peak systolic velocities. decrease in the pulmonary vascular resistance and an
TTP-intervals increased significantly from 18-22 increase in the proportion of pulmonary blood flow
weeks of gestation to term in all the vessels examined, of the fetal combined cardiac output. This proportion
while the fetal heart rate was unchanged. At the is higher in human fetuses than suggested by previous
pulmonary valve level the TTP-interval was animal studies. The proportion of blood flow across
significantly longer than in the proximal and distal the foramen ovale decreases. Later during the last
pulmonary arteries and significantly shorter than in trimester, the pulmonary vascular resistance increases
the aortic valve level and ductus arteriosus. These again. The proportion of pulmonary blood flow of the
findings are partially in agreement with Machado et fetal combined cardiac output remains about 20%
al, concerning difference between aortic and during this period, and is proportionate to that of the
pulmonary TTP-intervals17 and with Choi et al and foramen ovale blood flow. Right ventricular
Hata et al demonstrating significant increases in dominance persists and even increases towards the
aortic, pulmonary and ductal TTP-intervals with end of pregnancy (Fig. 52.5).
increasing gestation.18 ,19 Invasive animal studies have We studied 63 normal singleton fetuses in
shown significant increase in both mean systemic and uncomplicated pregnancies referred for fetal
pulmonary arterial pressures with advancing echocardiography in a cross-sectional manner
gestation. Mean pulmonary arterial pressure is higher between 19 and 39 weeks of gestation (median 28
than mean systemic pressure throughout gestation.20 weeks) to establish the relative outputs of the left and
These findings parallel significant increases in cardiac right ventricles. The normal distribution of human
output, peak systolic velocities, vessel size and by fetal combined cardiac output from the left and right
significant decrease in the placental vascular ventricles was determined and the weight-indexed
impedance. The difference in the mean arterial pulmonary (R Pi ) and systemic (R Si ) vascular
pressures and TTP-intervals may therefore be resistances and the changes during the second half of
explained by the differences in end organ impedance: pregnancy were established.
the placenta for the systemic circulation and the lung Volumetric blood flow was calculated by using the
parenchyma for the pulmonary circulation. There is formula: Q = Fetal Heart Rate × Valve Area × Time
734 Textbook of Perinatal Medicine

Fig. 52.5: Distribution of fetal cardiac output

Velocity Integral. Left ventricular cardiac output proportions of QP and QFO remained unchanged. At
(LVCO) equals the blood flow through aortic valve. 38 weeks of gestation, the proportion of RVCO (60%)
Right ventricular cardiac output (RVCO) equals the was higher than that of LVCO (40%). The proportion
blood flow through the pulmonary valve. Combined of flow across the ductus arteriosus (QDA ) did not
cardiac output (CCO) is the sum of LVCO and RVCO. change significantly. The correlation between RVCO
Total pulmonary artery blood flow (Q P ) was calculated from blood flow across the pulmonary
calculated by combining right and left pulmonary valve to the combined QDA and QP was excellent. RPi
artery blood flows. We calculated blood flows across decreased from 20 to 30 weeks of gestation but
the aortic and pulmonary valve annuli, right and left increased from 30 to 38 weeks of gestation. However,
pulmonary arteries and ductus arteriosus. Foramen RSi continuously increased from 20 to 38 weeks of
ovale blood flow was estimated by the formula QFO gestation. Thus, the RPi /RSi decreased from 20 to 30
= LVCO - QP. weeks of gestation and later remained unchanged.
Biometric weight-indexed pulmonary and The area and TVI of aortic and pulmonary valves,
systemic vascular resistances were calculated by using ductus arteriosus and branch pulmonary arteries
the formula: Ri = P / Qi , where P is blood pressure increased significantly with advancing gestational age
(mm Hg) and Qi is weight indexed volume blood flow as did right and left ventricular stroke volumes.
(ml/min/kg). These indexes were analyzed at 20, 30 RVSV/LVSV-ratio was greater at term of pregnancy
and 38 weeks of gestation. Systemic blood flow (QSi) than at 20 weeks of gestation. Fetal CCO, RVCO and
was calculated by pulmonary volume blood flow LVCO increased more than 10-fold from 20 weeks to
from CCO. The mean transpulmonary pressure term, and Q DA, Q FO and Q P increased also
gradient was assumed to be equal to mean systemic significantly with advancing gestation. The PV area,
blood pressure. At 20 weeks of gestation human fetal RVSV and RVCO were greater than AV area, LVSV
blood pressure is about 30 to 35 mm Hg.23 At 30 and and LVCO. The ratio between diameters of the
38 weeks of gestation fetal blood pressure values were pulmonary valve and the ductus arteriosus increased
assumed from values in newborns at the same significantly from 20 weeks of gestation towards the
gestational age.24 term of pregnancy. The DA area was always greater
From 20 to 30 weeks of gestation the proportion than LPA or RPA area, but the ratio of LPA or RPA to
of pulmonary blood flow (QP) of the combined cardiac DA area increased significantly with advancing
output doubled (13 to 25%), while the proportion of gestation. There were no significant differences in the
flow across the foramen ovale (QFO) decreased by half area, TVI or volume blood flow between right and
(34 to 18%). After 30 weeks of gestation the left pulmonary arteries. The proportions of QP and QFO
 Doppler Ultrasound Studies in the Fetal Pulmonary Circulation 735
of the CCO remained unchanged from 30 to 38 weeks Effects of Indomethacin Treatment on
of gestation. Pulmonary Circulation
During the third trimester, the proportion of QP of Maternally administered indomethacin used as
the LVCO is about 50% suggesting that the Q P tocolysis is transferred across the placenta to the
contribution to the LVCO increases with advancing fetus. 31 Maternal and fetal serum levels of
gestation. These measurements concur with indomethacin are identical after few hours of maternal
previously published estimates.25 Our results show oral administration of indomethacin.32 Indomethacin
that the proportion of Q P of the human fetal CCO is is known to reduce fetal urine output leading to
clearly higher than suggested in previously published decreased amniotic fluid volume. 33 Another well-
animal studies, where the proportion of QP of the CCO known effect of indomethacin on the fetus is the
was estimated at less than 10%.26,27 constriction or even occlusion of the ductus
Volume blood flow across the FO is very difficult arteriosus. 34 It is evident that the prevalence of
to assess directly. The cross-sectional area of the FO indomethacin-induced fetal ductal constriction
is difficult to calculate accurately because of the shape increases with advancing gestational age.35,36 These
and relative size and position of the flap tissue of the fetal side effects of indomethacin are usually
septum primum and the fact that the blood velocity reversible after either reducing the indomethacin dose
waveform is multiphasic during the cardiac cycle.28 or stopping the indomethacin therapy. 37 Maternal
However, our measurements correlated with indomethacin therapy affects human fetal pulmonary
published diameters of the foramen ovale and arterial vascular impedance.38
showed linear increase with advancing gestation.29 In a cross-sectional study, we compared Doppler
In our study, the Q FO increased 4-fold, but its echocardiographic findings in three groups of fetuses
proportion of the CCO decreased by half from 20 between 24 and 34 weeks of gestation. 52 normal
fetuses were without maternal medication, while 33
weeks to term. At 20 weeks of gestation it represents
fetuses without constriction of the ductus arteriosus,
about 73% of the LVCO, but after 30 weeks of
15 fetuses with mild to moderate and 8 fetuses with
gestation its proportion has decreased to about 50%
severe ductal constriction occlusion during maternal
of the LVCO. In the human fetus the QFO has an
indomethacin therapy. The indication for maternal
important role, because highly oxygenated blood
indomethacin therapy was preterm labor; the daily
returning from the placenta is directed via the ductus
indomethacin dose varied between 50 and 200 mg.
venosus across the FO to the left atrium.30 Thus the
Blood velocity waveforms across the ductus, aortic
most oxygenated blood from the placenta is supplied
and pulmonary valves, and proximal right or left
to the fetal coronary and cerebral circulations. Our pulmonary artery were obtained. The constriction of
findings suggest that during the third trimester, the the ductus arteriosus was defined as mild to moderate
FO becomes relatively restrictive and therefore unable when the pulsatility index of the ductus arteriosus
to increase its proportion of the CCO. This supports varied between 1.0 and 1.9. The ductal constriction
proportional right ventricular dominance in the was defined as severe if the PI value was less than
human fetus during the last trimester of pregnancy. 1.0. During the second half of pregnancy normal
After 20 weeks of gestation, the right ventricular values for the PI of the ductus arteriosus are between
output becomes dominant. At 38 weeks of gestation 1.9 and 3.0.39 Occlusion of the fetal ductus arteriosus
RVCO (60%) significantly exceeds LVCO (40%) as a was diagnosed when no blood flow across the ductus
proportion of the CCO, which may explain the arteriosus could be identified by color, continuous or
appearance of relative RV>LV disproportion seen in pulsed Doppler techniques but tricuspid regurgitation
late third trimester fetuses. was identified (Fig. 52.6).
736 Textbook of Perinatal Medicine

Fig. 52.6: Ductal constriction with high velocity and increased diastolic flow

Pulsatility indices were measured in the peripheral have been shown to be fetal pulmonary vasodilators
pulmonary arteries and left and right ventricular in near term animal models.40 Indomethacin, which
outflows. Combined cardiac outputs were calculated. is a prostaglandin synthetase inhibitor, may affect fetal
The pulsatility of the peripheral pulmonary arteries pulmonary function by decreasing lung liquid
was constantly greater in the indomethacin fetuses production and altering pulmonary hemodynamics.
than in the control group. After 26 weeks gestation During rhythmic distention of the lungs in the fetal
the values in the mild to moderate group were lambs, prostaglandin synthetase inhibitors have been
significantly higher than in the control group. In the demonstrated to abolish the 4-fold decrease in
study groups I and II, LVCO, RVCO and CCO were pulmonary vascular resistance seen without
similar to the control group. In the study group III, prostaglandin inhibitors.41,42 However, indomethacin
RVCO and CCO were lower than in the control group. has not been shown to change the pulmonary vascular
Only LVCO did not differ from the control group. response to increased oxygen tension in fetal lambs. 43
Human fetal pulmonary arterial vascular impedance In the presence of indomethacin induced ductal
is increased by maternal indomethacin therapy even constriction in fetal lambs the smooth muscle has been
without ductal constriction. In the presence of mild found to be significantly increased and the external
to moderate DC the magnitude of the increase in the diameter decreased in the fifth generation resistance
vascular impedance is related to the gestational age. vessels in the lung tissue compared to control
In the group with severe ductal constriction or fetuses.44 Also, in fetal lambs the acute mechanically
occlusion of DA pulmonary vascular impedance is induced occlusion of the ductus arteriosus decreases
similar to the control group. In this group, decreased the total fetal cardiac output by about 34%.45 We have
RVCO and CCO without significantly increased earlier demonstrated that pulmonary vascular
LVCO show that these fetuses were unable to impedance decreases significantly during the second
redistribute the cardiac output from the right to the half of pregnancy until 34-35 weeks of gestation and
left ventricle. Interestingly, the newborns with ductal thereafter it remains unchanged. Likewise, weight-
occlusion in utero did not show any signs of indexed pulmonary vascular resistance decreases
pulmonary hypertension during the neonatal period. significantly from 20 to 30 weeks of gestation and
Prostaglandins are potent vasoactive substances, increases again from 30 to 38 weeks of gestation.46
which have a role in the pulmonary vascular changes Maternal indomethacin therapy without
occurring after birth. Prostaglandins D 2, E1, and I2 constriction of the fetal ductus arteriosus is associated
 Doppler Ultrasound Studies in the Fetal Pulmonary Circulation 737
with higher pulsatility index values in the branch by using the formula: EFo = (1.055 × CSA × TVIac) ×
pulmonary arteries than in the control fetuses. This (PSV/TTP). In adults, a close correlation has been
finding suggests that prostaglandins have a role in found between the mean left ventricular ejection force
the regulation of the human fetal pulmonary and ejection fraction suggesting that Doppler
circulation. In fetuses with mild to moderate ductal echocardiography can be used for the noninvasive
constriction, the pulsatility index values were higher assessment of right and left ventricular performance.
and the average weekly change in the pulsatility index The mean left ventricular ejection force has been
values was significantly different from the control shown to be more sensitive for the diagnosis of mild
group. This suggests that after 27-28 weeks of to moderate left ventricular systolic dysfunction than
gestation the human fetus is able to regulate branch the peak aortic blood velocity or mean acceleration.48
pulmonary arterial vascular tone in response to Human fetal right and left ventricular ejection
increased pulmonary arterial pressure. In the group forces both increase 10-fold during the second half of
with severe constriction or occlusion of the ductus gestation. 49,50 There is no significant difference
arteriosus the pulsatility index values of the branch between the right and left ventricular ejection forces
pulmonary arteries were not different from the control in utero. Right ventricular performance is modified
group showing that further increase in the pulmonary by abnormal loading conditions: it is increased by a
arterial pressure overcomes the regulatory capacity chronic volume overload and decreased by an acute
of the pulmonary circulation. In these fetuses right pressure overload. These findings demonstrate that
ventricular and combined cardiac outputs were less the human fetal right ventricle is able to adapt its
than in the control group, while the left ventricular systolic function when it is facing chronically
cardiac output remained similar to the control group increased volume load. Pressure overload against the
demonstrating that these fetuses were not able to right ventricle must be dramatically increased as in
redistribute the cardiac output from the right to the severe ductal constriction or occlusion before the right
left ventricle. ventricular ejection force (RVEF) decreases
demonstrating the capability of the right ventricle to
The Effects of Right Ventricular Loading maintain its systolic performance. 51 In growth-
Conditions on Pulmonary Circulation retarded fetuses both ventricular ejection forces are
The equation for ventricular ejection force estimates reduced compared to normal fetuses as related to the
the energy transferred from the ventricular severity of fetal compromise. Animal studies have
myocardial shortening to work done by accelerating suggested that early systolic flow is less affected by
blood into the circulation. This information can be changes in afterload and preload than flow during
used for the assessment of the ventricular systolic late systole.52,53
function. Ventricular ejection force does not require To determine whether abnormal loading
estimation of ventricular volumes and is independent conditions can modify human fetal right ventricular
of ventricular configuration. Newton’s second law of ejection force, we studied 73 normal fetuses, 27 fetuses
motion defines force as the product of mass and with hypoplastic left heart syndrome, 14 fetuses with
acceleration: Force = Mass x Acceleration. The mass mild to moderate constriction of the ductus arteriosus
of blood accelerated across the aortic and pulmonary and 7 fetuses with severe constriction or occlusion of
valves over a time interval is calculated by the ductus arteriosus. In the normal and ductal
multiplying the density of blood, which is 1.055, with constriction/occlusion groups, blood velocity
the cross sectional area and the TVI at the valve. The waveforms were recorded at the level of the aortic
acceleration component is calculated by dividing peak and pulmonary valves, and in the group with
systolic velocity by the time to peak velocity hypoplastic left heart syndrome at the level of the
interval.47 Ventricular ejection force (EFo) is calculated pulmonary valve. The ventricular ejection forces were
738 Textbook of Perinatal Medicine

calculated. In the HLHS group, 7 patients terminated group. However, right ventricular ejection force was
the pregnancy after diagnosis and there was one similar in fetuses with holosystolic tricuspid
stillborn fetus. Except for one newborn, who had a regurgitation to those without tricuspid regurgitation.
heart transplant operation, others underwent three- Rizzo showed that in fetal intrauterine growth
stage palliative cardiac surgery. All the fetuses in the restriction secondary to uteroplacental insufficiency,
HLHS group had a normal karyotype. In the ductal both ventricular ejection forces were symmetrically
occlusion or constriction groups there were no decreased. A direct relationship was present between
perinatal or neonatal deaths. ejection force and umbilical vein pH values,
In the normal group, right and left ventricular suggesting that decreased ejection force was primarily
ejection forces increased and were equal during the caused by myocardial dysfunction. In ductal
second half of gestation. The average weekly increases constriction or occlusion groups, there were no signs
were greater in the hypoplastic left heart syndrome of placental insufficiency and the growth of the fetuses
group than in the normal group. In the group with was appropriate for gestational age in all cases. Also
mild to moderate ductal constriction, both ventricular during fetal ductal constriction the umbilical artery
ejection forces were similar to those of the normal PI is similar to or even significantly less than without
group. The average weekly increase was lower in the constriction suggesting that fetal ductal constriction
group with severe ductal constriction or occlusion and indomethacin therapy itself are not detrimentally
than in the normal group, but the LVEF did not differ affecting placental impedance.56 It seems that the
from that of the normal group. This study showed human fetus with normal placental function is able
that that chronic volume overload increases and to maintain right ventricular ejection force
relatively acute pressure overload decreases human development until there is a dramatic increase in the
fetal RVEF. right ventricular afterload. This demonstrates the
Increased chronic volume load (HLHS group) was capability of the right ventricle to maintain its systolic
associated with increased ejection force developed by function, which seems to be disturbed only after the
the right ventricle. This demonstrates the capacity of pulmonary artery diastolic pressure is significantly
the right ventricle to adapt its systolic performance increased. We believe that in cases of severe ductal
and to maintain adequate cardiac output. This also constriction or occlusion, which develops in a short
shows that chronic volume overload the right time interval, the right ventricular systolic pressure
ventricular ejection force rises with other parameters is increased without myocardial hypertrophy leading
of ventricular size, i.e. mass, end-diastolic volume and to increased systolic wall tension and myocardial
stroke volume. In fetuses with anemia due to red cell oxygen consumption. During that period, the foramen
alloimmunization, intravascular transfusion, which ovale becomes relatively restrictive because its fixed
represents acute volume overload transiently, dimension and ability to increase blood flow is
decreases fetal cardiac output with a recovery to limited, which results in a decreased combined
baseline levels by the day following the correction of cardiac output.
the anemia.54 ,55 It has been proposed that relative
hyperviscosity secondary to the acute correction of Effects of Maternally Administered Oxygen on
anemia during the transfusion increases afterload. The Fetal Pulmonary Circulation
transient decrease in the cardiac output could also Maternal hyperoxygenation decreases human fetal
represent the time period needed for the adaptation pulmonary arterial vascular impedance and increases
of the ventricles to the acute volume overload. pulmonary blood flow between 31 and 36 weeks of
Severe ductal constriction or occlusion signi- gestation. Earlier in pregnancy, between 20 and 26
ficantly decreased right ventricular ejection force, weeks of gestation, maternal hyperoxygenation does
possibly because of tricuspid regurgitation in this not alter human fetal pulmonary circulation. These
 Doppler Ultrasound Studies in the Fetal Pulmonary Circulation 739
findings shows that the reactivity of the human fetal values. One fetus at 36 weeks of gestation developed
pulmonary circulation to oxygen develops between a reversal of diastolic blood flow in the DA during
these two study periods and oxygen tension in the maternal hyperoxygenation (from the aorta to the
fetus has a role in the regulation of the fetal pulmonary artery). The estimated QFO remained
pulmonary circulation. Fetal oxygen tension has a role stable in groups 1, 2 and 4 during the study period
in the regulation of the pulmonary circulation and in whereas maternal hyperoxygenation after 30 weeks
the distribution of fetal cardiac output during the gestation decreased foramen ovale blood flow
latter part of the third trimester when the human fetal significantly. The foramen ovale blood flow decreases
pulmonary arterial bed is under acquired because the pulmonary volume blood flow increases
vasoconstriction, directing right ventricular cardiac significantly without any change in the LVCO. In fetal
output from the pulmonary circulation to the systemic lambs, the foramen ovale blood flow decreases by an
circulation. Maternal hyperoxygenation, at least after average of 50% during maternal hyperbaric
31 to 36 weeks of gestation, mimics the changes in oxygenation at near term gestation.58 Both distal and
the fetal central hemodynamics, which occur after proximal pulmonary arteries showed a similar
birth.57 decrease in the PI values during maternal
To determine the role of oxygen tension on the hyperoxygenation suggesting that both sampling sites
human fetal pulmonary arterial circulation during the gave the same information about the pulmonary
second half of gestation we studied 20 women vascular reactivity.
between 20 and 26 weeks of gestation and 20 women This study supports the concept that in the human
between 31 and 36 weeks of gestation with normal fetus the reactivity of the pulmonary arterial bed to
singleton pregnancies. They were randomized to changes in the fetal oxygen tension develops after 21-
receive either 60% humidified oxygen or medical 26 weeks of gestation and is detectable by noninvasive
compressed air (room air) by face mask. Fetal aortic Doppler ultrasound techniques between 31 and 36
and pulmonary valve, ductus arteriosus, and right, weeks of gestation. This suggest that human fetal
left and distal pulmonary artery blood velocity pulmonary circulation is under acquired vaso-
waveforms were obtained by Doppler ultrasound constriction at least after 31 to 36 weeks of gestation
before, during and after maternal administration of with blood flow directed from the pulmonary
either 60% oxygen or room air. Left and right circulation to the systemic circulation. The reactivity
ventricular cardiac outputs, and DA (QDA), RPA and of the pulmonary arterial circulation to oxygen with
LPA (Q P ) volume blood flows were calculated. advancing gestation has been explained by an
Foramen ovale blood flow was estimated. Pulsatility increasing amount of smooth muscle in small
index values of DA, RPA, LPA and DPA were pulmonary arteries.59 The decrease in the pulmonary
calculated. Maternal hyperoxygenation did not vascular resistance is mainly caused by the release of
change any of the measured fetal parameters between endothelium derived nitric oxide, which leads to
20 and 26 weeks, while between 31 and 36 weeks the vasodilatation of the pulmonary arterial bed.60,61
PI values of RPA, LPA and DPA decreased and the PI The decrease in the pulmonary vascular
of DA increased. QP increased, and QDA and Q FO impedance and the increase in the pulmonary blood
decreased. LVCO and RVCO were unchanged. All flow by maternal hyperoxygenation between 31 and
changes returned to baseline after maternal hyper- 36 weeks of gestation were accompanied by opposite
oxygenation was discontinued. Reactivity of the changes in the fetal ductus arteriosus. The decrease
human fetal pulmonary circulation to maternal hyper- in the DA PI has been associated with the constriction
oxygenation increases with advancing gestation. of the DA and the increase in the DA PI has been found
The mean increase in the Q P was 24.5% and the in the cases with increased right ventricular cardiac
mean decrease in the QDA was 17.1% from the baseline output.62 This study shows that the changes in the
740 Textbook of Perinatal Medicine

DA PI may also reflect fetal pulmonary vascular hypoplastic. Pulmonary hypoplasia is defined as
impedance. The decrease in the pulmonary vascular incomplete or underdevelopment of lung tissue
impedance directs blood flow from the systemic present at autopsy as determined by the wet lung to
circulation to the pulmonary circulation. Mainly this body weight ratio, reduced alveoli count or by
affects the diastolic flow component in the DA by reduced lung DNA content. 68 Fetal detection of
decreasing it or even reversing the direction of the pulmonary hypoplasia is based on ultrasound
blood flow during diastole. This leads to increased imaging techniques based on a reduced chest size for
PI in the DA, because the end-diastolic velocity and gestational age. The thoracic to abdominal ratio of 0.89
the mean velocity during the cardiac cycle decrease. is relatively constant throughout gestation and a ratio
In normal circumstances, the direction of the blood of less than 0.77 is consistent with pulmonary
flow in the human fetal DA during the diastole is from hypoplasia.69
the pulmonary artery to the aorta. This study supports The association between pulmonary hypoplasia
previous animal data that the increase in the and reduced amniotic fluid volume was first observed
pulmonary blood flow and the decrease in the in infants with bilateral renal agenesis. 70
pulmonary vascular impedance during maternal Abnormalities that result in olighydramnios include
hyperoxygenation are not caused by the constriction renal agenesis, renal dysplasia and those that restrict
of the ductus arteriosus.63,64,65 In the presence of the urinary flow into the amniotic sac. Urethral atresia or
ductal constriction peak systolic, end-diastolic and stenosis, urethral valve and bladder outlet
mean velocities across the ductus arteriosus are obstructions also restrict urinary flow. In pregnancies
increased in the human fetus leading to decreased PI with prolonged leakage of amniotic fluid or
value. These findings agree with those of Burchell et premature rupture of the membranes may also be
al where children and adults with patent ductus subject to pulmonary hypoplasia. With these
arteriosus and pulmonary hypertension when conditions, it has been proposed that compression or
breathing of a low oxygen mixture either initiated or forced flexion of the fetal trunk secondary to restricted
increased the blood flow from the pulmonary artery movement. 71 It has been shown that fetal lung
to the aorta whereas the breathing of 100% oxygen expansion becomes restricted within 48 hours of
caused opposite changes.66 diminution of amniotic fluid but that that process may
be reversed by amnioinfusion.72 A reduction in fetal
PULMONARY HYPOPLASIA breathing patterns in patients with reduced amniotic
Pulmonary hypoplasia is a term that describes lungs fluid may also contribute to pulmonary hypoplasia,
that are sufficiently small enough to impede the although there are conflicting reports.73,74,75
exchange of respiratory gases leading to severe Fluid in the fetal thorax either as primary
neonatal pulmonary disease or death.67 It occurs hydrothorax or from hydrops fetalis is one of the most
secondarily to other fetal anomalies that restrict common causes of pulmonary hypoplasia with
volumetric lung expansion. It can be associated with overall mortality reported at over 50%.76 If fluid is
mediastinal shift or cardiac malposition. However, drained from the chest in fetal hydrothorax by
pulmonary hypoplasia is different from pulmonary catheter or needle aspiration, lung growth may be
agenesis where there is complete absence of a lung restored.77 Other “space occupying lesions” of the
and from pulmonary aplasia where there is absence fetal thorax include cardiomegaly (mitral valve
of a broncus or bronchiolar pathway as survival is insufficiency associated with giant left atrium and
likely with either of those two malformations. As gas aortic stenosis, Ebstein’s anomaly of the tricuspid
exchange does not occur in the fetal lung, it is difficult valve and tricuspid valve dysplasia), pericardial
to prove that fetal lungs may be functionally effusion and neuroblastoma.
 Doppler Ultrasound Studies in the Fetal Pulmonary Circulation 741
The incidence of congenital diaphragmatic hernia the thoracic circumference to the abdominal
is estimated at 1 in 3000 to 5000 births. As a result of circumference were the most clinically useful. 88
incomplete closure of the pleuroperitaneal Recently, estimates of lung volumes from three-
membranes, the abdominal contents may enter the dimensional ultrasound have been used in an attempt
thorax and result in a mediastinal shift. This may to estimate lung maturity and predict hypo-
effect the growth of the effected side and the plasia.89,90,91,92 We and others believe that a method
contralateral lung, and may cause esophageal that evaluates function as well as relative size may
obstruction resulting in polyhydramnios. Postnatal prove to be a more reliable predictor of post natal
survival is approximately 50% depending upon the pulmonary dysfunction from pulmonary hypoplasia.
degree of pulmonary hypoplasia.78 In the absence of Pulmonary blood flow parameters may be measured
a congenital closure defect, the diaphragm may be by the methods previously mentioned. We have seen
affected by abnormal development of function as in in the fetus later found to have lethal pulmonary
phrenic nerve agenesis and Pena Shokeir syndrome hypoplasia that the proximal and distal pulmonary
leading to an elevation or eventration of the dome of artery flow patterns are reduced in peak velocity
the diaphragm.79 Central neural defects that as while pulsatility indices are increased. Those patients
associated with absent fetal breathing movements with space occupying lesions such as diaphragmatic
may also lead to pulmonary hypoplasia including hernias may have a blunted or no response to a
anencephaly, microcephaly and encephalocele.80 maternal hyperoxia test after 32 weeks gestation.93
Congenital cystic adenomatoid malformation One of the more easily obtained waveform patterns
(CCAM) of the lung is a failure of maturation of recorded during these studies has been the proximal
certain bronchial structures during the pulmonary venous flow, which normally increases
pseudoglandular stage of development. The lesion is significantly with maternal hyperoxia. Mitchell et. al.
typically unilobar and consists of cystic areas that may showed a high resistance pattern quite different from
be identified on ultrasound. Type I lesions have a that of normal fetuses in the peripheral pulmonary
single or multiple large cysts and represent 50% of arteries in ten fetuses with bilateral multicystic
CCAMs. Type II has multiple smaller cysts and may dysplastic kidney disease all of whom died from
be associated with gastrointestinal or renal anomalies. associated pulmonary hypoplasia.94 Yoshimura et. al.
Type III lesions are large with cysts often too small to made similar observations in the proximal pulmonary
measure and carry a poor prognosis. When associated artery flow patterns with lethal pulmonary
with developing hydrops fetalis, preterm surgical hyperplasia in hydrops fetalis, thanatophoric dwarfs
intervention has been offered. 81 and Potter syndrome. 95 Roth et. al. has found an
Pulmonary hypoplasia is also associated with association with lethal pulmonary hypoplasia with
skeletal dysplasias because of a narrowed or the lack of pulmonary artery flow patterns with
constricted fetal thorax.82,83 These anomalies may power color Doppler techniques.96 Chaoui et. al. has
include Jeunes Syndrome (asphyxiating thoracic shown that abnormal pulmonary artery flow patterns
dystrophy), achondrogenesis, achondroplasia, may be seen as early as 19 to 23 weeks gestation in
osteogenesis imperfecta, thanatophoric dwarfism and fetuses with lung hypoplasia.97
hypophosphasia. Ultrasound measurements of fetal
lung or chest size as a ratio to normal gestational A Test for the Prediction of
biometric measurements have been advanced as Lethal Pulmonary Hypoplasia
predictors of pulmonary hypoplasia. 84,85,86,87 To determine the predictive accuracy of our test for
Yoshimura et al analyzed several methods of neonatal death from pulmonary hypoplasia we
prediction for fetal lung hypoplasia, concluding that measured the Doppler changes in fetal pulmonary
the lung area against gestational age and the ratio of artery blood flow in room air and during maternal
742 Textbook of Perinatal Medicine

hyperoxygenation. Women carrying fetuses with pulmonary blood flow in the normal fetus. The
those congenital anomalies as illustrated above or reactivity of the pulmonary arterial circulation to
with prolonged olighydramnios often associated with oxygen with advancing gestation has been explained
pulmonary hypoplasia were offered participation in by an increasing amount of smooth muscle in small
the study as part of a comprehensive fetal pulmonary arteries.99 The decrease in the pulmonary
echocardiogram. Each fetus at > 30 weeks gestation vascular resistance is mainly caused by the release of
had the Doppler blood flow pattern in the first branch endothelium-derived nitric oxide, which leads to
of either the right or the left pulmonary artery vasodilatation of the pulmonary arterial bed.100,101
measured before and again during at least 10 minutes The method to accurately predict those fetuses
exposure to maternal breathing of 60% oxygen by who will die from pulmonary hypoplasia is important
mask. An increase in the relative fetal pulmonary for parental counseling and subsequent decision-
blood flow with oxygen (a decrease of at least 25% of making regarding obstetric and neonatal
the pulsatility index) was considered a reactive test. management. As the oxygen challenge is an extension
A change of less than 20% in the flow pattern during of our comprehensive fetal echocardiogram, we also
maternal hyperoxygenation was a non-reactive test measure the cardiac circumference to thoracic
and suggested pulmonary hypoplasia. The primary circumference ratio (CC/TC) and the thoracic circum-
outcome for this study was neonatal outcome of death ference to the biometric abdominal circumference
from pulmonary hypoplasia. In the 29 pregnancies ratio (TC/AC) as well as M-mode measurements of
the ventricles in systole and diastole. These
that met criteria for our study, 14 fetuses who had a
measurements typically show normal size heart for
non-reactive hyperoxygenation test, 11 (79%) died of
gestational age, but the CC/TC and TC/AC are
pulmonary hypoplasia. Of the 15 that had a reactive
widely divergent relative to the cause of the small
hyperoxygenation test, only 1 (7%) died in the
lungs. For example, oligohydramnios may show a
neonatal period. Sensitivity, specificity, positive, and
relative cardiomegaly whereas a diaphragmatic
negative predictive values were 92%, 82%, 79%, and
hernia will have a relatively small heart to thoracic
93%, respectively, with an odds ratio of 51 (95% CI
size. Likewise, we have seen exaggerated fetal
4.6-560).98 We have now performed over one hundred
breathing movements in fetuses who have lethal
of these oxygen challenge tests with excellent results
pulmonary hypoplasia and an absence of such
in sensitivity and specificity.
movements in fetuses with long standing oligo-
The oxygen challenge method evaluates fetal
hydramnios who have a normal physiologic response
pulmonary function and therefore may prove to be a to maternal oxygen and go on to a normal neonatal
more reliable predictor of postnatal pulmonary course. Difficulty in performing the examination
dysfunction from pulmonary hypoplasia as compared occurs, especially in the fetuses with diaphragmatic
to those that evaluate relative anatomic size. Maternal hernia, who has hard to image lungs and who
hyperoxygenation increases fetal pulmonary blood typically increases both its gross body movements
flow by decreasing pulmonary arterial vascular and breathing movements when exposed to an
impedance. The changes we have observed between increased oxygen environment.
31 and 36 weeks of gestation mimics the changes in Intrauterine growth restricted (IUGR) fetuses with
the fetal hemodynamics after birth. 15 During oligohydramnios can have a negative response to
normoxia, when the human fetal pulmonary arterial maternal hyperoxygenation. Those fetuses may
bed is under acquired vasoconstriction, right present in extremis with abnormal Doppler
ventricular cardiac output is directed away from the measurements in the MCA, FLUA and DV, suggesting
lungs and into the systemic circulation via the ductus redistribution of cardiac output by cephalization,
arteriosus. Increased blood oxygen content decreases placental insufficiency and congestive heart failure
pulmonary vascular resistance and thus increases with increased central venous pressure. The blunted
 Doppler Ultrasound Studies in the Fetal Pulmonary Circulation 743
or absent response to oxygen appears to be an PULMONARY SEQUESTRATION
extension of redistribution of cardiac output as these
Pulmonary sequestration is a rare anomaly identified
fetuses, who were delivered within hours of their
in-utero by a difference in echo density of a particular
oxygen tests, did reasonably well in the newborn
period and were eventually discharged home (Figs lobe of the lung. It is seen as either above or below
52.7 and 52.8). the diaphragm and is defined as either intra-
pulmonary or extrapulmonary depending on its
CYSTIC ADENOMATOID MALFORMATION position relative to the visceral pleura. It may present
Probably the most common lung lesion detected in- with mediastinal shift or cardiac malposition and
utero by ultrasound is cystic adenomatoid occasionally with hydrops from impingement or
malformation. This appears as an echo bright portion torsion of the inferior vena cava. The sequestered lobe
within a lobe of the lung and maybe associated with receives its blood supply from the aorta rather than
large, small mixed or micro cysts, appearing as a solid the pulmonary artery with venous return usually to
mass. It is characterized by dysplastic or hamarto- the right atrium via the inferior vena cava. The
matous tissue often mixed with normal tissue and majority of sequestrations are extrapulmonary and
typically confined to a single lobe. Regression is occupy the lower portion of either hemi-thorax. Color
common, but when large and/or associated with directed pulsed Doppler may be used to identify the
hydrops it may be lethal because of pulmonary arterial origin from the descending aorta and thereby
hypoplasia. As it is likely to be the result of early differentiate sequestration from cystic adenomatoid
maldevelopment of terminal brochiolar structures,
malformation. Most subdiaphragmatic sequestationas
color or power Doppler in the area of the lesion may
identified in-utero regress and may not require
show pulmonary arterial flow around but not into the
neonatal surgical resection (Fig. 52.10).
lesion (Fig. 52.9).

Fig. 52.7: Positive change in Doppler flow patterns of pulmonary vascular reactivity with oxygen

Fig. 52.8: Negative change in Doppler flow patterns of pulmonary vascular reactivity with oxygen
744 Textbook of Perinatal Medicine

of the pulmonary veins are easily identified from the

4 chamber image just as the LVOT comes into view.
Anomalous connection of the pulmonary veins
should be ruled out when major structural congenital
heart defects are identified. By combining high
resolution ultrasound magnification with the color
flow and narrow sample size pulsed Doppler
techniques we have described, blood flow connection
abnormalities of the veins and arteries including
sequestered lobes of the fetal lung may be identified.
However, hydrothorax, cystic masses and
diaphragmatic hernias may impede pulmonary blood
flow to the extent that the flow may be difficult or
Fig. 52.9: Cystic adenomatoid malformation
impossible to observe or measure in one or both of
the fetal lungs. Congenital malformations of
pulmonary circulation should be considered in the
presence of other forms of congenital heart disease.
Direction of the fetal ductus arteriosus should be
evaluated with both color and pulsed Doppler when
arterial connection or obstruction is suggested in
order to identify a ductal dependent lesion (Fig. 52.11).
Major pulmonary venous abnormalities can
generally be ruled out by imaging the right and left
venous ostia as they connect into the left atrium on
either side of the descending aorta when seen in the
four-chamber view of the heart in a transverse image
of the thorax (Fig. 52.12). Exceptions to expect are
when there is visceral heterotaxy when the stomach
and heart may be on opposite sides of the fetus and/

Fig. 52.10: Color Doppler of sequestration flow pattern

CONGENITAL PULMONARY BLOOD FLOW

ABNORMALITIES
Observable abnormalities of fetal pulmonary
circulation may be related to structural congenital
heart disease or to thoracic space occupying lesions.
The pulmonary artery should be superior and anterior
to and slightly larger than the aorta in the 4 chamber
view of the fetal heart. The pulmonary artery blood Fig. 52.11: Color Doppler of nor mal pulmonary ar tery
flow is directed toward the fetal left shoulder and bifurcation with pulmonary valve Atresia and reversed ductus
ductus arteriosus. Likewise, the normal connections arteriosus flow pattern
 Doppler Ultrasound Studies in the Fetal Pulmonary Circulation 745
they may enter the right atrium, coronary sinus, the
right or left superior vena cava, the inferior vena cava
or into the azygous venous system as single
attachments with otherwise normally connecting
pulmonary veins. In cases of hypoplastic left heart
syndrome, the pulmonary veins may appear dilated
for gestational age, but may be anomalously
connected and associated with pulmonary venous
stenoses. Stenosis of pulmonary veins may be difficult
to identify in fetal life from ultrasound because of the
Fig. 52.12: Color Doppler of normal pulmonary venous
connections
relative paucity of pulmonary blood flow. Pulmonary
venous dimensions can usually be measured
successfully after 22w gestation. Pulmonary venous
or when there is a common atrium or large atrial blood flow is best measured with color directed
septal defect. Ipsilateral venous connections may be pulsed Doppler techniques in a lateral approach to
seen in these diagnoses but may be difficult to identify the 4 chamber view.
by fetal echocardiography. Both partially anomalous We believe that all fetal ultrasound anatomic
and totally anomalous pulmonary venous connection survey examinations should include identification
are typically associated with a disproportion of right and relative quantification of the outflow tracts of the
sided chambers larger than the left sided structures. heart. The pulmonary artery should arise above the
More obvious is total anomalous pulmonary venous anterior right ventricle aiming toward the left
connection (TAPVC) to the coronary sinus where a shoulder at the ductus arteriosus, while the aorta
dilated coronary sinus can be identified as an eccentric arises centrally from the left ventricle aiming toward
line parallel to the mitral valve annulus in the four- the right shoulder in a 90° crossing fashion relative
chamber view. However, a dilated coronary sinus may to the main pulmonary artery. The ascending aorta
also be seen with normally connected pulmonary and the main pulmonary artery should be about the
veins when the left superior vena cava drains into the same size. Pulmonary outflow obstructions may not
coronary sinus behind the lower left corner of the left become obvious on fetal ultrasound until the third
atrium. The extra line in the left atrium may also trimester. A form of hypoplastic right heart where
signify the membrane in cortriatriatum (triatrial heart) there is pulmonary atresia with intact ventricular
where the common pulmonary venous sack is septum may have a normal four-chamber view in the
attached to the posterior left atrial wall but may drain second trimester and normal sized pulmonary arteries
anomalously into the right atrium or via restricted at birth. In these cases, the pulmonary valve may
fenestrations into the left atrium. The most common acquire more severe obstruction with fetal growth
type of TAPVC is when the common pulmonary resulting in a reversal of flow through the ductus
venous sac is not attached to the left atrium but to a arteriosus. We have seen this in the recipient twin in
vein that ascends to join the innominate vein which twin to twin transfusion syndrome as well as in
then flows into the right superior vena cava and right singleton pregnancies. In these situations, the left
atrium. The form of TAPVC most likely to become ventricle begins to become disproportionately larger
obstructed in the early newborn period is when the than the right ventricle during the second trimester
common pulmonary venous sack is attached to a vein as blood flow patterns change. Color Doppler is useful
that descends below the diaphragm and connects to in proving a normal pulsed Doppler flow pattern into
a hepatic venous structure. Partially anomalous the main pulmonary artery. Normally, the forward
pulmonary venous veins are difficult to identify as flow pattern from the right ventricle into the
746 Textbook of Perinatal Medicine

pulmonary artery is a hollow envelope rarely density of airway endtips. Anatomical Record,
1996;244:207-213.
exceeding 0.7 meters per second. Pulmonary stenosis
6. Hislop A, Reed l, “Growth and development of the
can be recognized by a course spectral flow pattern respiratory system-anatomic development”, in Scientific
measuring greater than 1.0 meter per minute and Foundations of Pediatrics, Davis JA and Dobbing J, Eds.,
often associated with tricuspid valve regurgitation. Heinemann, London, 1972.
7. Rasanan J, Huhta JC, Weiner S, Wood, DC, Ludomirski
Pulmonary outflow obstruction should be considered A, Fetal branch pulmonary artery vascular impedance
with presumptive fetal diagnoses of Ebstein’s during the second half of pregnancy, Am J of Obstet
malformation of the tricuspid valve, double outlet Gynecol, 1996;174:1441-1449.
8. Roberts AB, Mitchell JM. Direct ultrasonographic
right ventricle (DORV), transposition of the great
measurement of fetal lung length in normal pregnancies
arteries (d or l-TGA), ventricular septal defect, and pregnancies complicated by prolonged rupture of
tetralogy of Fallot and in cases of early diagnosis of membranes. Am J Obstet Gynecol 1990;163:1560-66.
transient cystic hygroma associated with Noonan’s 9. Lewis AB, Heymann MA, Rudolph AM. Gestational
changes in pulmonary vascular responses in fetal lambs
syndrome. In those cases with the physiology of in utero. CIRC RES 1976;39:536-41.
tetralogy of Fallot with pulmonary atresia, color 10. Tessler FN, Kimme-Smith C, Sutherland ML, Schiller VL,
Doppler is useful in identifying collateral arterial Perrella RR, Grant EG. Inter- and intra-observer
variability of Doppler peak velocity measurements: An
vessels feeding the lungs form the aorta. It is
in-vitro study. Ultrasound Med Biol 1990;16:653-7.
important to differentiate this disease from truncus 11. O’Rourke MF. Vascular impedance in studies of arterial
arteriosus. Collateral vessels can also be seen using and cardiac function. Physiol Rev 1982;62:571-621.
color Doppler in cases of pulmonary sequestration. 12. Downing GJ, Maulik D, Phillips C, Kadado TR. In vivo
correlation of Doppler waveform analysis with arterial
We use a team approach of prenatal counseling by input impedance parameters. Ultrasound Med Biol
the perinatologist, neonatologist, pediatric 1993;19:549-59.
cardiologist and cardiothoracic surgeon for the family 13. Giles WB, Trudinger BJ, Paird PJ. Fetal umbilical artery
flow velocity waveforms and placental resistance:
of any fetus with congenital heart disease that may
pathological correlation. BR J Obstet Gynaecol
require prenatal or early neonatal intervention. Any 1985;92:31-8.
suggestion of a fetal anomaly of venous or arterial 14. Levin DL, Rudolph AM, Heymann MA, Phibbs RH.
connection or obstruction must be confirmed after Morphological development of the pulmonary vascular
bed in fetal lambs. Circulation 1976;53:144-51.
deliver by newborn echocardiography or at cardiac 15. Heymann MA. Regulation of the pulmonary circulation
catheterization. in the perinatal period and in children. Intensive Care
Med 1989;15:S9-S12.
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Tooley WH. Aortic blood pressure during the first 12 ductus arteriosus constriction versus increased right
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Allan L. Assessment of changes in blood flow through newborn. Semin Perinatol 1980;4:101-7.
the lungs and foramen ovale in the normal human fetus 41. Wlodek ME, Harding R, Thorburn GD. Effects of
with gestational age: a prospective Doppler inhibition of prostaglandin synthesis on flow and
echocardiographic study. Br Heart J 1994;71:232-237. composition of fetal urine, lung liquid, and swallowed
26. Rudolph AM, Heymann MA. Circulatory changes fluid in sheep. Am J Obstet Gynecol 1994;170:186-95.
during growth in the fetal lamb. Circ Res. 1970;26:289- 42. Velvis H, Moore P, Heymann MA. Prostaglandin
299. inhibition prevents the fall in pulmonary vascular
27. Morin FC III, Egan EA, Ferguson W, Lundgren CEG. resistance as a result of rhythmic distension of the lungs
Development of pulmonary vascular response to oxygen. in fetal lambs. Pediatr Res 1991;30:62-8.
43. Morin FC, Egan EA, Norfleet WT. Indomethacin does
Am J Physiol 1988;254:H542-H546.
not diminish the pulmonary vascular response of the
28. Soyeur D, Schaaps JP, Kulbertus H. Pulsed Doppler
fetus to increased oxygen tension. Pediatr Res
assessment of fetal blood flow across the foramen ovale
1988;24:696-700.
and pulmonary vascular bed. Eur Heart J. 1990;11:90.
44. Levin DL, Mills LJ, Weinberg AG. Hemodynamic,
29. Phillipos EZ, Robertson MA, Still KD. The
pulmonary vascular, and myocardial abnormalities
echocardiographic assessment of the human fetal
secondary to pharmacologic constriction of the fetal
foramen ovale. J Am Soc Echocardiogr 1994;7:257-263.
ductus arteriosus. A possible mechanism for persistent
30. Kiserud T, Eik-Nes SH, Blaas HG, Hellevik LR. Foramen
pulmonary hypertension and transient tricuspid
ovale: an ultrasonographic study of its relation to the
insufficiency in the newborn infant. Circulation
inferior vena cava, ductus venosus and hepatic veins.
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Ultrasound Obstet Gynecol 1992;2:389-396. 45. Tulzer G, Gudmundsson S, Rotondo KM, Wood DC, Yoon
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of indomethacin in pregnant and parturient women and J Obstet Gynecol 1991;165:775-8.
their newborn infants. Zentralbl Gynaekol 1973;95:635- 46. Rasanen J, Wood DC, Weiner S, Ludomirski A, Huhta
41. JC. Role of the pulmonary circulation in the stribution
32. Moise KJ, Ou CN, Kirshon B, Cano LE, Rognerud C, of human fetal cardiac output during the second half of
Carpenter RJ. Placental transfer of indomethacin in the pregnancy. Circulation 1996;94:1068-73.
human pregnancy. Am J Obstet Gynecol 1990;162:549- 47. Kenny, J. F., Plappert, T., Doubilet, P., Saltzman, D. H.,
54. Cartier, M., Zollars, L., Leatherman, G. F. and St. John
33. Kirshon B, Moise KJ, Wasserstrum N, Ou CN, Huhta JC. Sutton, M. G. (1986). Changes in intracardiac blood flow
Influence of short-term indomethacin therapy on fetal velocities and right and left ventricular stroke volumes
urine output. Obstet Gynecol 1988;72:51-3. with gestational age in the normal human fetus: a
34. Moise KJ, Huhta JC, Sharif DS, Ou CN, Kirshon B, prospective Doppler echocardiographic study.
Wasserstrum N, Cano L. Indomethacin in the treatment Circulation., 74, 1208-16.
of premature labor. Effects on the fetal ductus arteriosus. 48. Isaaz, K., Ethevenot G, Admant, P., Brembilla, B. and
N Engl J Med 1988;319:327-31. Pernot, C. (1989). A new Doppler method of assessing
35. Tulzer G, Gudmundsson S, Tews G, Wood DC, Huhta left ventricular ejection force in chronic congestive heart
JC. Incidence of indomethacin-induced human fetal failure. Am. J. Cardiol., 64, 81-7.
ductal constriction. J Matern Fetal Invest 1992;1:267-9. 49. St. John Sutton, M., Gill, T., Plappert, T., Saltzman, D. H.
36. Moise KJ. Effect of advancing gestational age on the and Doubilet, P. (1991). Assessment of right and left
frequency of fetal ductal constriction in association with ventricular function in terms of force development with
maternal indomethacin use. Am J Obstet Gynecol gestational age in the normal human fetus. Br. Heart J,
1993;168:1350-3. 61:285-89.
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50. Rizzo, G., Capponi, A., Rinaldo, D., Arduini, D. and ductus arteriosus constriction versus increased right
Romanini, C. (1995). Ventricular ejection force in growth- ventricular output. J Am Coll Cardiol. 1991;18:532-536.
retarded fetuses. Ultrasound Obstet Gynecol, 5, 247-55. 63. Morin FC III, Egan EA, Ferguson W, Lundgren CEG.
51. Rasanen J, Debbs RH, Wood DC. Weiner S, Weil SR, Development of pulmonary vascular response to oxygen.
Huhta JC, Human fetal right ventricular ejection force Am J Physiol. 1988;254:H542-H546.
under abnormal loading conditions during the second 64. Rasanen J, Huhta JC, Weiner S, Wood DC, Ludomirski
half of pregnancy, Ultrasound in Obstetrics and A. Fetal branch pulmonary arterial vascular impedance
Gynecology. 10(5):325-32, 1997. during the second half of pregnancy. Am J Obstet
52. Noble, M. I. M., Trenchard, D. and Guz, A. (1966). Left Gynecol. 1996;174:1441-1449.
ventricular ejection in conscious dogs: II. Determinants 65. Heymann MA, Rudolph AM, Nies AS, Melmon KL.
of stroke volume. Circ. Res., 19, 148-52. Bradykinin production associated with oxygenation of
53. Noble, M. I. M. (1968). The contribution of blood the fetal lamb. Circ Res. 1969;25:521-534.
momentum to left ventricular ejection in the dog. Circ. 66. Burchell HB, Swan HJC, Wood EH. Demonstration of
Res., 23, 663-70. differential effects on pulmonary and systemic arterial
54.. Copel, J. A., Grannum, P. A., Green, J. J., Belanger, K., pressure by variation in oxygen content of inspired air
Hanna, N., Jaffe, C. C., Hobbins, J. C. and Kleinman, C. in patients with patent ductus arteriosus and pulmonary
S. (1989). Fetal cardiac output in the isoimmunized hypertension. Circulation. 1953;8:681-694.
pregnancy: A pulsed Doppler-echocardiographic study 67. Harding R, Hooper SB, Regulation of lung expansion and
of patients undergoing intravascular intrauterine lung growth before birth, Journal of Applied Physiology,
transfusion. Am. J. Obstet. Gynecol., 161, 361-5. 81:209-224, 1996.
55. Moise, K. J., Mari, G., Fisher, D. J., Huhta, J. C., Cano, L. 68. Askenazi SS, Perlman, Pulmonary hypoplasia: lung
E. and Carpenter, R. J. (1990). Acute fetal hemodynamic weight and radial alveolar count as critical diagnosis,
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Levine R, Fagerstrom RM, Walker B, Berkowitz RL,
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normal values, American Journal of Obstetrics and
on fetal intracardiac Doppler velocity waveforms. Am.
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70. Potter EL, Bilateral renal agenesis, J Pediatrics, 29:68-76,
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1946.
W. and Cano, L. (1990). The effect of indomethacin on
71. Rotschild A. Ling EW. Puterman ML. Farquharson D.
the pulsatility index of the umbilical artery in human
Neonatal outcome after prolonged preterm rupture of
fetuses. Am. J. Obstet. Gynecol., 162, 199-202.
the membranes. American Journal of Obstetrics and
56. Khowsathit, P., Tian, Z. Y., Wood, D. C., Cohen, A. W.
Gynecology. 162(1):46-52, 1990 Jan.
and Huhta, J. C. (1995). Indomethacin-induced placental
vasodilation: Association with fetal ductal constriction. 72. Savich RD. Guerra FA. Lee CC. Padbury JF. Kitterman
J. Matern. Fetal Invest., 5, 30-2. JA. Effects of acute oligohydramnios on respiratory
57. Rasanen J, Wood DC, Debbs R, Cohen J, Weiner S, Huhta system of fetal sheep. Journal of Applied Physiology.
JC, Reactivity of the human fetal circulation to maternal 73(2):610-7, 1992 Aug.
hyperoxygenation increases in the second half of 73. Roberts AB. Mitchell J. Pulmonary hypoplasia and fetal
pregnancy, a randomized study, Circulation, 97:257-262, breathing in preterm premature rupture of membranes.
1998. Early Human Development. 41(1):27-37, 1995 Mar 17.
58. Assali NS, Kirschbaum TH, Dilts PV. Effects of hyperbaric 74. Fisk NM. Talbert DG. Nicolini U. Vaughan J. Rodeck CH.
oxygen on uteroplacental and fetal circulation. Circ Res. Fetal breathing movements in oligohydramnios are not
1968;22:573-588. increased by aminoinfusion. British Journal of Obstetrics
59. Levin DL, Rudolph AM, Heymann MA, Phibbs RH. and Gynaecology. 99(6):464-8, 1992 Jun.
Morphological development of the pulmonary vascular 75. Ohlsson A. Fong K. Hannah M. Heyman Z. Gonen R.
bed in fetal lambs. Circulation. 1976;53:144-151. Rose T. Baboolal R. Prediction of lethal pulmonary
60. Mital S, Konduri GG. Vascular K+ATP channels mediate hypoplasia and chorioamnionitis by assessment of fetal
O 2 induced pulmonary vasodilation in fetal lambs. breathing. British Journal of Obstetrics and Gynaecology.
Pediatrics. 1996;98:527. Abstract. 98(7):692-7, 1991 Jul.
61. Mital S, Konduri GG. Oxygen causes pulmonary 76. Longaker MT. Laberge JM. Dansereau J. Langer JC.
vasodilation by stimulating synthesis and release of ATP Crombleholme TM. Callen PW. Golbus MS. Harrison
in fetal lambs. Pediatrics. 1996;98:533. Abstract. MR. Primary fetal hydrothorax: natural history and
62. Tulzer G, Gudmundsson S, Sharkey AM, Wood DC, management. Journal of Pediatric Surgery. 24(6):573-6,
Cohen AW, Huhta JC. Doppler echocardiography of fetal 1989 Jun.
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77. Blott M. Nicolaides KH. Greenough A. Pleuroamniotic 90. Pohls UG. Rempen A. Fetal lung volumetry by three-
shunting for decompression of fetal pleural effusions. dimensional ultrasound. Ultrasound in Obstetrics and
Obstetrics and Gynecology 1988;71(5):798-800. Gynecology 1998;11(1):6-12.
78. Harrison MR. Adzick NS. Estes JM. Howell LJ. A 91. D’Arcy TJ. Hughes SW. Chiu WS. Clark T. Milner AD.
prospective study of the outcome for fetuses with Saunders J. Maxwell D. Estimation of fetal lung volume
diaphragmatic hernia [see comments]. JAMA using enhanced 3-dimensional ultrasound: a new
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79. Persutte WH. Lenke RR. Kurczynski TW. Brinker RA. Gynaecology 1996;103(10):1015-20.
Antenatal diagnosis of Pena-Shokeir syndrome (type I) 92. Lee A, Kratochwil A, Stumpflen I. Deutinger J.
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movements and lung maturation in the congenitally 93. Rasanen J, Wood DC, Debbs RH, Tolosa J, Huhta JC,
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Physiology 1984;6(4):367-75. human fetuses, Abstract, Society of Perinatal
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Howell LJ. Fetal lung lesions: management and outcome. 94. Mitchell JM, Roberts AB, Lee A. Doppler waveforms from
American Journal of Obstetrics and Gynecology the pulmonary arterial system in normal fetuses and
1998;179(4):884-9. those with pulmonary hypoplasia. Ultrasound in
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Hallermann C. Prenatal sonographic chest and lung 95. Yoshimura S, Masuzaki H, Miura K, Muta K, Gotoh H,
measurements for predicting severe pulmonary Ishimaru T. Diagnosis of fetal pulmonary hypoplasia by
hypoplasia. Prenatal Diagnosis 1999;19(7):614-9. measurement of blood flow velocity waveforms of
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Z. Gonen R. Prenatal ultrasonic prediction of autopsy- 96. Roth P, Agnani G, Arbez-Gindre F, Pauchard JY, Burguet
proven pulmonary hypoplasia. American Journal of A, Schaal JP, Maillet R. Use of energy color Doppler in
Perinatology 1992;9(5-6):334-7. visualizing fetal pulmonary vascularization to predict
85. Nimrod C, Davies D, Iwanicki S, Harder J, Persaud D, the absence of severe pulmonary hypoplasia.
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8. 97. Chaoui R, Kalache K, Tennstedt C, Lenz F, Vogel M.
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thoracic versus abdominal circumference ratios for the lung hypoplasia. European Journal of Obstetrics,
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1989;73(2):261-6. 99. Levin DL, Rudolph AM, Heymann MA, Phibbs RH.
88. Yoshimura S. Masuzaki H. Gotoh H. Fukuda H. Ishimaru Morphological development of the pulmonary vascular
T. Ultrasonographic prediction of lethal pulmonary bed in fetal lambs. Circulation 1976;53:144-151.
hypoplasia: comparison of eight different 100. Mital S, Konduri GG. Vascular, K+ ATP channels mediate
ultrasonographic parameters. American Journal of O 2 induced pulmonary vasodilation in fetal lambs.
Obstetrics and Gynecology 1996;175(2):477-83. Pediatrics 1996;98:527 Abstract.
89. Laudy JA. Janssen MM. Struyk PC. Stijnen T. Wladimiroff 101. Mital S, Konduri GG. Oxygen causes pulmonary
JW. Three-dimensional ultrasonography of normal fetal vasodilation by stimulating synthesis and release of ATP
lung volume: a preliminary study. Ultrasound in in fetal lambs. Pediatrics 1996;98:533 Abstract.
Obstetrics and Gynecology 1998;11(1):13-6.
 Uteroplacental and
53 Umbilical Circulation:
Physiologic changes in Pregnancy

A Kubilay Ertan, H Alper, Werner

INTRODUCTION INDICES
Doppler sonography in obstetrics is a widely accepted Although measurement of volume flow changes in
functional method of examining the uteroplacental an organ would be ideal, in vivo the current methods
and fetal unit. It is a noninvasive means and became for determining true flow are too inaccurate to derive
almost a standard technique in antenatal care. This meaningful conclusions which can be of clinical value.
method became an important tool for qualifying high Consequently we rely on indices of resistance and
risk pregnancies. Color Doppler ultrasound velocity derived from the Flow velocity waveforms
represents blood flow changes as a color image, (FVW) of a vessel.
superimposed on the real-time ultrasound image Blood flow velocity in the fetal circulating system
being examined. In this way different vessels of the depends on the type of vessel: The arteries always
uteroplacental circulation can be accurately identified. have a pulsatile pattern (Fig. 53.1), whereas veins have
Also, by identifying the vessel at a fixed point, e.g. either a pulsatile or continuous pattern (Fig. 53.2).
where the uterine artery crosses the external iliac Analysis of Doppler sonographic FVWs quanti-
artery, it is possible to examine the same point in the tatively, is more difficult than analyzing qualitatively.
circulation. Endovaginal color Doppler transducers Qualitative analysis also overcomes erroneous
allow easy and quick visualization of even the measurements in small vessels. There are plenty of
smallest vessels in the uteroplacental and fetal indices for qualitative analysis. Following are the most
circulation. This, in turn, has enabled us to build a frequently used indices:
picture of the physiological changes in uteroplacental • Systolic/Diastolic ratio (S/D ratio, Stuart 1980)
and fetal blood flow before and during the early • Resistance index (RI, Pourcelot 1974)
stages of pregnancy. 1 • Pulsatility index (PI, Gosling and King 1977)
One of the first steps towards realizing the In analyzing sonographic results and calculating
potential of Doppler ultrasound is to gain a clear indices, following characters are used:
understanding of the physiological changes that occur S= Temporal peak of maximum frequency
in the uteroplacental circulation during normal D= End-diastolic maximum frequency
pregnancy. With this knowledge, we can obtain a C= Temporal average of maximum frequency, Fmean
clearer understanding of the pathophysiological I= Instantaneous spatial average frequency
changes that occur in the presence of disease. E= Temporal average of spatial average frequency
 Uteroplacental and Umbilical Circulation: Physiologic changes in Pregnancy 751

Fig. 53.1: Doppler sonography of fetal aorta wit a pulsatile pattern

Fig. 53.2: Umbilical artery with a pulsatile (upper line) and umbilical vein with a continuous pattern (lower line)

Calculations of formulas are as follows (Fig. 53.3): independent and are therefore easily applied in
S/D ratio = S/D clinical practice.
RI = (S-D)/S In practice, none of the indices is superior to the
PI = (S-D)/C other2-4 and any index may be used. Although S/D
The above presented indices overcome also a very ratio is easily calculated, RI is the easiest to interpret.
serious problem involved with the angle between the RI values approach to zero if the resistance decreases
ultrasound beam and the direction of blood flow and approach to one if resistance increases. If end-
(insonation angle). These indices are relatively angle diastolic flow is absent, PI is the only index making
752 Textbook of Perinatal Medicine

Fig. 53.3: Scheme of the Doppler curve (I.). S= systolic, D= diastolic, C= Temporal average of maximum frequency.
Calculation of formulas of the main Doppler sonographic indices (II.)

evaluation of blood flow possible, because in this Changes in Uterine Artery Circulation in Early
situation S/D will equal to infinite and RI to one. The Pregnancy
PI is more complex because it requires the calculation
The uterine artery FVW was characterized by an early
of the mean velocity, but modern Doppler
diastolic notch and a gradually increasing flow
sonographic devices provide those values in real time.
velocity during early pregnancy. The peak systolic
PHYSIOLOGIC COLOR DOPPLER velocities (PSV) increase, whereas the S/D and RI
SONOGRAPHIC CHANGES OF THE decrease progressively during early pregnancy. The
EMBRYONIC AND UTEROPLACENTAL enddiastolic velocity increases progressively. In all of
VESSELS IN EARLY PREGNANCY the cases during early gestational development, an
early diastolic notching was determined, but there
Results of a recent study performed by Ertan et al,5
was a gradually flattening in the depth of the notch
evaluating the uteroplacental and fetal circulation
(Fig. 53.4). At the third trimester of pregnancy this
during early pregnancy in non-complicated
“notch” disappeared. The RI of the uterine arteries
pregnancies showed that vascular impedance to blood
decreased gradually, which means that the resistance
flow in all examined vessels decreased significantly
of the arteries lessens during pregnancy progression.
throughout the first gestational trimester. Resistance
to flow was highest in the main uterine artery and
Changes in Umbilical Circulation in Early
decreased towards the spiral artery. When the flow
Pregnancy
velocity waveform patterns of the arteries under
investigation were analyzed, specific changes were The color signal of the umbilical artery was recorded
observed. In all of the cases during early gestational for the first time at 7 weeks’ gestation.
development, an early diastolic notching was From week 10 onward it was able to show the
determined in the uterine arteries. The flow velocity enddiastolic velocity and from week 16 onward
waveforms of the fetal aorta and umbilical arteries diastolic signals were present in all cases (Fig. 53.5
were similar: until week 10 the arteries were typically and 53.6). The PSV between week 7 and 9 remained
without a diastolic flow. From week 16 onward, constant and from week 9 onward it increased, while
diastolic velocities were present in all signals at the S/D and RI decreased progressively during the first
fetal aorta and umbilical arteries. 16 weeks of gestation.
 Uteroplacental and Umbilical Circulation: Physiologic changes in Pregnancy 753
Changes in Fetal Aorta Circulation in Early
Pregnancy
The color signal of the fetal aorta was possible to be
recorded for the first time at 7 weeks’ gestation. The
main problem in achieving Doppler signals of the
aorta were fetal body movements and to make
measurements with a correct angle, less than 60°.
The FVW was similar to the umbilical artery. Until
week 10 of gestation the FVW was typically without
a diastolic flow (Enddiastolic zero flow). From week
16 onward, diastolic velocities were present in all
aortic signals (Fig. 53.7). The PSV increases and the
S/D and RI decreases progressively during the first
Fig. 53.4: Dopplersonography of uterine artery in first 16 weeks of gestation.
trimester of pregnancy (7+6 wks.) with early notch
UTEROPLACENTAL AND FETAL CIRCULATION
AFTER MIDPREGNANCY

The Maternal Side: Uterine Circulation

The uterine artery is a branch of the internal iliac
artery. It courses along the lateral wall of the pelvis
before crossing the external iliac artery and reaching
the uterus at the level of the cervix. After giving off a
cervical branch, it ascends along the lateral wall of
the body of the uterus in a tortuous manner, before
Fig. 53.5: Doppler velocity waveforms of umbilical artery
anastomosing with the Fallopian branch of the
(enddiastolic zero flow) and continuously venous blood flow of ovarian artery. As it passes along the body of the
umbilical vein in 11+4 wks. of pregnancy uterus it gives off the arcuate arteries, which

Fig. 53.6: Doppler velocity waveforms of umbilical artery with Fig. 53.7: Doppler velocity waveforms of fetal aorta with an
an enddiastolic flow (lower line) in 13+4 wks. of pregnancy enddiastolic flow in 15+4 wks. of pregnancy
754 Textbook of Perinatal Medicine

encompass the uterine body. These in turn give off not significantly change from when it enters the cervix
radial arteries that penetrate into the inner third of up to the point that it reaches the body of the uterus.
the myometrium, where they become the basal It is important to measure at this level, before the
arteries. The spiral arteries, a continuation of the basal uterine artery enters the uterus and branches into the
arteries, supply the endometrium, their coiled form arcuate arteries. An arcuate artery can exhibit a
allowing contraction during menstruation (Fig. 53.8).1 relatively low resistance pattern even when the
Using transvaginal Color Doppler sonography, it uterine artery has high resistance with persistent
is possible to identify the uterine artery in early notching present (Fig. 53.10). It is therefore necessary
pregnancy at the level of the cervical os, as it enters to ensure that the uterine artery is examined as it
the uterus, and as it ascends into the uterine body (Fig. reaches the uterus at the level of cervix, if the changes
53.9). It is possible to examine the uterine artery by in the uterine circulation are to be interpreted as a
the transabdominal approach after 12 weeks’ whole. Similarly, if the sample site is too low on the
gestation, when the uterus becomes an abdominal cervix, the cervical branch of the uterine artery will
organ. The FVWs obtained from the uterine artery do be examined; this can show high resistance when the
main uterine artery waveform is normal.1
Blood flow velocities in the uterine artery depends
on the localization of placenta and gestational age.6
If the placenta is laterally located, blood flow
velocities in the ipsilateral uterine artery are more
important than the flow velocities of the contralateral
vessel. Differences between flow velocities of the right
and left uterine artery are evident at early stages of
pregnancy. But in the third trimester, the difference
between the S/D ratio of the vessels decrease up to
0.3-0.4.2 If an abnormal flow pattern is observed in
the uterine arteries in midpregnancy, this most
probably indicates the defective perfusion of
Fig. 53.8: Power Doppler of arcuate and
fetoplacental unit, which predicts a high probability
intraplacental arteries
for developing preeclampsia and/or intrauterine
growth restriction.7

Fig. 53.10: Flow in different parts of the uteroplacental

circulation can be measured with Color Doppler technology,
Fig. 53.9: Color Doppler sonographiv view of the main here the relatively low resistance pattern of the uteroplacental
uterine ar tery crossing the iliac artery arteries
 Uteroplacental and Umbilical Circulation: Physiologic changes in Pregnancy 755
At early stages of pregnancy enddiastolic flow The Fetal Side: Umbilical Arteries, Fetal Aorta
velocities in placental arteries are low, but systolic and Middle Cerebral Artery
flow is evident.2 With trophoblastic invasion and
maturation of the uteroplacental vessels, beyond the Umbilical Arteries
second trimester the high pressure system is Blood flow velocity in the umbilical arteries increases
converted to a low pressure system, and vascular with the progressing gestational age (Fig. 53.13). As a
resistance declines.8 The biologic variability after the result, S/D ratio continuously decreases due to
middle of the second trimester becomes almost stable. increasing arterial blood flow. With progressing
Before 24 weeks’ gestation early diastolic notching, gestational age enddiastolic flow becomes evident
due to the immature uteroplacental vascular system, during the whole heart cycle, matching with previous
is normally observed. Beyond this gestational age, longitudinal studies of Fogarty et al2 and Hünecke et
persistent early diastolic notching is associated with al,12 as with many cross-sectional studies. 13-16
preeclampsia (Fig. 53.11 and 53.12).9-11
Trudinger et al 17 put forth the following
mechanisms to explain this development:
• Continuous maturation in placental villi
• Continuous widening of placental vessels cause a
continuous decrease in vascular resistance
• Continuous increase in fetal cardiac output
• Continuous changes in the vessel compliance
• Continuous increase in fetal blood pressure.
Especially in the third trimester of pregnancy,
depending on the above factors normal values
become scattered on nomograms. This scattering is
more prominent in the S/D ratio than the PI.
Resistance index is not affected by above factors after
Fig. 53.11: Normal Doppler flow velocity waveform of the 28 weeks’ gestation.
uterine artery in the third trimester

Fig. 53.12: Pathological waveforms of uterine artery in 29+3 Fig. 53.13: Blood velocity waveform in umbilical artery in the
wks. of pregnancy with IUGR and preeclampsia late pregnancy
756 Textbook of Perinatal Medicine

Descending Fetal Aorta gestational age should be taken into account as well.
In general, the accepted time for starting Doppler
Beside the umbilical arteries, routine Doppler
sonographic examinations is the beginning of the
sonographic measurements on the descending fetal
second trimester. This is the right time that allows for
aorta are possible. As the gestational age increases S/
modifications in antenatal care in a high risk
D ratio of fetal aorta decreases insignificantly,
pregnancy. For specific conditions, earlier timing of
paralleling to the results of Hecher et al.18 The FVW
measurements may be considered.21
of the fetal aorta shows a continuous forward stream
The main objective in using fetomaternal Doppler
during the whole heart cycle, but when compared to
sonographic nomograms is to improve perinatal
the FVW of the umbilical arteries, the enddiastolic
outcome in high risk pregnancies. Curves presented
flow is less than the systolic component. Due to this
below depict normal fetal and maternal Doppler
reason the S/D ratio in the fetal aorta is greater than
sonographic values standardized according to
the S/D ratio in the umbilical arteries. As pregnancy
gestational age, and can be used in routine practice
progresses, the diameter of the vessel gets wider and
(Fig. 53.14 to 53.25).
as a result peripheral resistance decreases, and
Doppler sonographic nomograms are used for
diastolic flow increases. Nevertheless, this does not
differentiation of normal and abnormal blood FVWs,
cause a significant S/D ratio decrease in the fetal
which helps to determine high risk pregnancies. By
aorta. Resistance and Pulsatility indices are not
taking threshold values of pathologic pregnancies into
affected significantly, and show a similar course as in
consideration, nomograms are capable of differen-
the umbilical arteries.
tiating between normal and abnormal.22 While using
these nomograms, it must always kept in mind that
Middle Cerebral Artery (MCA)
the values on these nomograms should not be taken
The most favorably positioned vessel for Doppler as mathematical equations, and that limitations of
sonographic examination of the fetal brain perfusion sensitivity and specificity exist.
is the middle cerebral artery. Biologic variability of
vessels perfusing the fetal brain is excessive due to Using Nomograms in Practice
the fetal activity status. As pregnancy progresses the
Just like the defense mechanism of peripheral
vascular resistance decreases 19. During the early vasoconstriction in an adult in the face of hemorrhagic
stages of pregnancy, enddiastolic flow velocities in shock, the “brain sparing” mechanism (Brain sparing
cerebral vessels are weak, but velocities increase effect) becomes active in a fetus with hypoxia or
towards the end of gestation. Hyperactivity of fetus, chronic placental insufficiency. As a result of the brain
increase of intrauterine pressure (e.g. poly- sparing effect, resistance either in the umbilical artery
hydramnios), and external pressure to the fetal head (UA) and fetal descending aorta (FDA) increases. As
(e.g. by the probe) might erroneously increase a consequence Doppler indices related to these vessels
enddiastolic flow velocities.20 Different investigators increase. The end-diastolic blood flow increases in
have undertaken studies utilizing data obtained from middle cerebral arteries (MCA) by the same effect.
umbilical arteries and MCA to develop indices for Doppler indices for this vessel decreases consequently.
evaluation of intrauterine risk. Some points should be considered while using
Doppler sonographic nomograms:
DEPENDENCY OF DOPPLER FLOW VELOCITY
1. Among the measurements performed on the UA
WAVEFORMS ON GESTATIONAL AGE
and FDA, values between 90-95th percentiles
The amount of perfusion in trophoblastic tissue is should be considered as borderline and repeat
related to gestational age. For this reason, in follow-ups should be planned. Values exceeding
interpreting the Doppler sonographic findings, the 95th percentile are considered abnormal.
Uteroplacental and Umbilical Circulation: Physiologic changes in Pregnancy 757
Umbilical artery
Systolic/Diastolic (S/D) ratio nomogram
6

S/D 3

0
26 28 30 32 34 36 38 40 42
Gestational w eek

Fig. 53.14: Umbilical artery Systolic/Diastolic (S/D) ratio nomogram

Umbilical artery
Resistance index (RI) nomogram
1

0.9

0.8

0.7

0.6
RI 0.5

0.4

0.3

0.2

0.1

0
26 28 30 32 34 36 38 40 42
Gestational w eek

Fig. 53.15: Umbilical artery Resistance index (RI) nomogram

758 Textbook of Perinatal Medicine

Umbilical artery
Pulsatility index (PI) nomogram
1.8

1.6

1.4

1.2

1
PI
0.8

0.6

0.4

0.2

0
26 28 30 32 34 36 38 40 42
Gestational w eek

Fig. 53.16: Umbilical artery Pulsatility index (PI) nomogram

Descending fetal aorta

S/D ratio nomogram
12

10

S/D 6

0
26 28 30 32 34 36 38 40 42
Gestational w eek

Fig. 53.17: Descending fetal aorta S/D ratio nomogram

Uteroplacental and Umbilical Circulation: Physiologic changes in Pregnancy 759
Descending fetal aorta
RI nomogram
1

0.9

0.8

0.7

0.6

RI 0.5

0.4

0.3

0.2

0.1

0
26 28 30 32 34 36 38 40 42
Gestational w eek
Fig. 53.18: Descending fetal aorta RI nomogram

Descending fetal aorta

PI nomogram
3

2.5

PI 1.5

0.5

0
26 28 30 32 34 36 38 40 42
Gestational w eek
Fig. 53.19: Descending fetal aorta PI nomogram
760 Textbook of Perinatal Medicine

Middle cerebral artery (MCA)

S/D ratio nomogram
14

12

10

8
S/D
6

0
26 28 30 32 34 36 38 40 42
Ge stational w ee k
Fig. 53.20: Middle cerebral artery S/D ratio nomogram

Middle cerebral artery (MCA)

RI nomogram
1

0.9

0.8

0.7

0.6

RI 0.5

0.4

0.3

0.2

0.1

0
26 28 30 32 34 36 38 40 42
Ge stational w ee k

Fig. 53.21: Middle cerebral artery RI nomogram

Uteroplacental and Umbilical Circulation: Physiologic changes in Pregnancy 761
Middle cerebral artery (MCA)
PI nomogram
3.5

2.5

PI
1.5

0.5

0
26 28 30 32 34 36 38 40 42

Ge stational w ee k

Fig. 53.22: Middle cerebral ar tery PI nomogram

Uterine artery
S/D ratio nomogram
3.5

2.5

2
S/D
1.5

0.5

0
26 28 30 32 34 36 38 40 42
Gestational w eek
Fig. 53.23: Uterine ar tery S/D ratio nomogram
762 Textbook of Perinatal Medicine

Uterine artery
RI nomogram
1

0.9

0.8

0.7

0.6

RI 0.5

0.4

0.3

0.2

0.1

0
26 28 30 32 34 36 38 40 42
Gestational w eek
Fig. 53.24: Uterine artery RI nomogram

Uterine artery
PI nomogram
1.4

1.2

0.8
PI
0.6

0.4

0.2

0
26 28 30 32 34 36 38 40 42
Gestational w eek
Fig. 53.25: Uterine artery PI nomogram
 Uteroplacental and Umbilical Circulation: Physiologic changes in Pregnancy 763
2. Doppler values between 5-10th percentiles in MCA gestation. Resistance continues to fall throughout
should be considered as borderline and repeat the remainder of the pregnancy.
follow-ups should be planned. Values below the 3. In normal pregnancy there is a gradual fall in
5th percentile are considered abnormal. resistance, an increase in diastolic flow and a
3. Measurements taken after 24 weeks’ gestation disappearance of the diastolic notch in the uterine
from uterine arteries are more valuable. The early artery FVW.
diastolic notching, and values exceeding the 95th 4. Pre-eclampsia, intrauterine growth retardation and
percentile are considered as abnormal. One point placental abruption are associated with inadequate
to remember is that notching by itself predicts an placentation/function, and a relationship exists
elevated risk of preeclampsia. between these complications and a failure of
physiological change in the uteroplacental
CONCLUSION
circulation.
In normal pregnancies, uteroplacental flow velocities
become almost stable after the middle second ACKNOWLEDGEMENT
trimester, meanwhile fetal blood flow velocities also
The authors acknowledge Mr. Aykut BARUT, MD
alter. With advancing gestational age, S/D ratio in the
(Zonguldak/Turkey), Hakan SADE, MD (Zonguldak/
umbilical artery and MCA decreases. Although the
Turkey), and Mehmet Vural, MD (Zonguldak/Turkey)
S/D ratio in the descending aorta is almost stable
for their technical and editorial assistance in the
during pregnancy, advancing gestational age narrows
preparation of this manuscript.
the biologic variability of the flow spectrum.
Accordingly , it is recommended to use gestational
age matched nomograms to define threshold values, REFERENCE
and to differentiate and predict pathologic 1. Harrington K, Thompson O, Aquilina J. Uteroplacental
pregnancies. and umbilical circulation: physiological changes in
pregnancy. In: Kurjak A, editor. Textbook of Perinatal
The key points relating to physiological changes
Medicine. New York: Parthenon Publishing; 1998. p. 422-
in the uteroplacental and fetal circulation can be 26.
summarized as follows: 2. Fogarty P, Beattie B, Harper A, Dornan J. Continuous
1. The technique of Doppler ultrasound is a non- wave Doppler flow velocity waveforms from the
umbilical artery in normal pregnancy. J Perinat Med
invasive method of examining the uteroplacental
1990;18:51-57.
and fetal circulation. Color Doppler sonography 3. Deutinger J. Physiology of Doppler blood flow in
allows the uteroplacental and fetal circulation to maternal blood vessels in pregnancy. Gynakologe
be investigated throughout pregnancy. 1992;25:284-91.
2. The main changes in FVW in the fetal and 4. Fendel H, Fendel M, Pauen A, Liedtke B, Schonlau H,
Warnking R. Doppler studies of arterial blood flow in
uteroplacental vessels happen in the first trimester the uterus during labor. Z Geburtshilfe Perinatol
of pregnancy and go on slowly in the remaining 1984;188:64-67.
periods. Fetal and uteroplacental velocities 5. Ertan AK, Wagner A, Tanriverdi HA, Schmidt W.
increase gradually during early pregnancy and Physiologic color Doppler sonographic changes of the
embryonic and uteroplacental vessels in early pregnancy
velocimetric indices show a progressive decrease . Ultrasound Review Obstet Gynecol 2003;3:219-22.
of the uteroplacental resistances. In early 6. Schneider KT. Standards in der Perinatalmedizin -
pregnancy the umbilical artery and fetal aorta Dopplersonographie in der Schwangerschaft. Frauenarzt
FVW’s are initially of high resistance, with absent 1997;38:452-58.
7. Bower S, Schuchter K, Campbell S. Doppler ultrasound
end-diastolic flow. Resistance falls rapidly towards screening as part of routine antenatal scanning:
the end of the first trimester; and end-diastolic prediction of pre-eclampsia and intrauterine growth
flow is usually present by the 16th week of retardation. Br J Obstet Gynaecol 1993;100:989-94.
764 Textbook of Perinatal Medicine

8. Brosens I, Dixon HG, Robertson W. Fetal growth 15. Schulman H, Fleischer A, Stern W, Farmakides G, Jagani
retardation and the arteries of the placental bed. Br J N, Blattner P. Umbilical velocity wave ratios in human
Obstet Gynaecol. 1977;84:656-64. pregnancy. Am J Obstet Gynecol 1984;148:985-90.
9. Campbell S, Pearce JM, Hackett G, Cohen-Overbeek T, 16. Thompson RS, Trudinger BJ, Cook CM. Doppler
Hernandez C. Qualitative assessment of uteroplacental ultrasound waveform indices: A/B ratio, pulsatility
blood flow: early screening test for high-risk pregnancies. index and Pourcelot ratio. Br J Obstet Gynaecol.
Obstet Gynecol 1986;68:649-53. 1988;95:581-88.
10. Hoffmann H, Chaoui R, Bollmann R, Bayer H. Potential 17. Trudinger BJ, Ishikawa K. Use of Doppler ultrasound in
clinical application of Doppler ultrasound in obstetrics. the high-risk pregnancy. Clin Diagn.Ultrasound
Zentralbl Gynakol. 1989;111:1277-84. 1990;26:119-37.
11. Trudinger BJ, Giles WB, Cook CM. Uteroplacental blood 18. Hecher K, Spernol R, Szalay S, Stettner H, Ertl U.
flow velocity-time waveforms in normal and Reference values for the pulsatility index and the
complicated pregnancy. Br J Obstet Gynaecol. 1985;92:39- resistance index of blood flow curves of the umbilical
45. artery and fetal aorta in the 3d trimester. Ultraschall Med
12. Huneke B, Holst A, Schroder HJ, Carstensen MH. 1989;10:226-29.
Normal values for relative Doppler indices. A/B ratio, 19. Vetter K. The significance of Doppler blood flow
resistance index and pulsatility index of the uterine measurement in recognizing placental insufficiency. Arch
artery and umbilical artery in normal pregnancy. A Gynecol Obstet 1988;244 Suppl:S12-S18.
longitudinal study. Geburtshilfe Frauenheilkd. 20. Vyas S, Nicolaides KH, Bower S, Campbell S. Middle
1995;55:616-22. cerebral artery flow velocity waveforms in fetal
13. Arabin B, Bergmann PL, Saling E. Simultaneous hypoxaemia. Br J Obstet Gynaecol. 1990;97:797-803.
assessment of blood flow velocity waveforms in 21. Mires GJ, Christie AD, Leslie J, Lowe E, Patel NB, Howie
uteroplacental vessels, the umbilical artery, the fetal PW. Are ‘notched’ uterine arterial waveforms of
aortaand the fetal common carotid artery. Fetal Ther. prognostic value for hypertensive and growth disorders
1987;2:17-26. of pregnancy? Fetal Diagn.Ther. 1995;10:111-18.
14. Arduini D, Rizzo G. Normal values of Pulsatility Index 22. Ertan AK, Hendrik HJ, Tanriverdi HA, Bechtold M,
from fetal vessels: a cross-sectional study on 1556 healthy Schmidt W. Fetomaternal Doppler sonography
fetuses. J Perinat Med 1990;18:165-72. nomograms. Clin Exp Obstet Gynecol 2003;30:211-16.
 54
Doppler Sonography in
High Risk Pregnancy

A Kubilay Ertan, H Alper, Werner

INTRODUCTION THE SAFETY OF DOPPLER ULTRASOUND IN

OBSTETRICS
One of the main aims of routine antenatal care is to
identify the ‘at risk’ fetus in order to apply clinical The safety of Doppler ultrasound in Obstetrics
interventions which could result in reduced perinatal remains a concern. The data available to date suggests
morbidity and mortality. 1 Doppler sonography in that diagnostic ultrasound has no adverse effects on
obstetrics is a widely accepted functional method of embryogenesis or fetal growth. In addition,
examining the utero-fetoplacental unit. ultrasonographic scanning has no long term effects
Doppler ultrasound is a non-invasive technique on cognitive function or noted changes of visual or
whereby the movement of blood (usually in a vessel) hearing functions. However, although B and M mode
is studied by detecting the change in frequency of scans are safe during pregnancy, color, power and
reflected sound. Doppler ultrasound has been used pulsed Doppler procedures should be performed with
in obstetrics since 1977 to study the feto-placental
caution due to possible thermal effects. Lastly, a new
(umbilical) circulation,2 and since the 1980’s to study
method, the three dimensional technique, was
the utero-placental (uterine) circulation3 and fetal
introduced. While there are no studies regarding the
circulation. 4 Recently, this method became an
safety of this new technique, the short acquisition time
important tool for qualifying high risk pregnancies.
and the post-processing analysis may decrease
Information obtained with Doppler sonography
exposure and thus reduce the risk of possible effects
helps obstetricians managing patients in situations
like pregnancies complicated by intrauterine growth of the ultrasound waves on fetal development.14
restriction (IUGR), Rhesus alloimmunization, In particular the use of pulsed Doppler involves
multiple pregnancies, and anamnestic risk factors. the use of higher intensities compared to diagnostic
Examination of the uteroplacental and fetomaternal ultrasound, and hence may cause significant tissue
circulation by Doppler sonography in the early second heating and thermal effects. However these thermal
trimester helps predicting pregnancy complications effects depend on the presence of a tissue/air interface
like preeclampsia, IUGR and perinatal death. 5-13 and may therefore not be clinically significant in
This chapter aims to introduce Doppler obstetric ultrasound examinations.15 Clearly, while
sonographic examinations in high risk pregnancies. there is continuing concern regarding the safety of
Doppler blood flow velocity waveforms (FVWs) of Doppler ultrasound, it should only be used in cases
the fetal side (umbilical artery, descending aorta, and of proven value or controlled investigational
middle cerebral artery) are discussed. circumstances.
766 Textbook of Perinatal Medicine

INDICATIONS OF DOPPLER SONOGRAPHY IN Umbilical Artery (UA)

OBSTETRICS
It has been shown in a longitudinal, observational
Prospective randomized studies of fetal vessels and study that Doppler ultrasound of the UA is more
their collective evaluation have shown no benefit of helpful than other tests of fetal wellbeing (e.g. heart
Doppler Sonography in screening the nonselected rate variability and biophysical profile score) in
population.16 In high risk pregnancies, however, there distinguishing between the normal small fetus and
is definitive evidence that the use of Doppler studies the ‘sick’ small fetus.18 However its exact role in
can significantly reduce the number of antenatal optimizing management, particularly timing of
examinations and the number of necessary inductions delivery, remains unclear, and is currently being
of labor and cesarean deliveries for fetal distress. investigated by many study groups. The optimal
Doppler Sonography reduces the perinatal mortality, timing of delivery in pregnancies complicated by
the number of elective deliveries, the incidence of highly pathological Doppler flow findings is still an
intrapartum distress, and the occurrence of hypoxic issue to be resolved. The established approach to
encephalopathy. 17 A definite benefit has been resolve this question and to improve the perinatal
established for Doppler Sonography in selected cases morbidity and mortality by the use of Doppler
(Table 54.1). examination is being investigated in multicenter
clinical trials,19 e.g. the trial of umbilical and fetal Flow
CHANGES IN DOPPLER SONOGRAPHIC in Europe Group (TRUFFLE-Protocol, unpublished
RESULTS DURING THE COURSE OF data).
PREGNANCY AND COMPLICATED Blood flow velocity in the UA increases with the
PREGNANCIES advancing gestation. As a result impedance to blood
flow continuously decreases due to increasing arterial
During the course of pregnancy and in some specific blood flow in the systole and diastole. End-diastolic
pregnancy complications, Doppler sonographic velocity is often absent in the first trimester 2;20 and
results of fetomaternal vessels display changing the diastolic component increases with advancing
values. Chronic placental insufficiency is a major gestation (Fig. 54.1).21 With advancing gestational age
research application for Doppler sonography in high end-diastolic flow becomes evident during the whole
risk pregnancies. Various fetal vessels are examined
to determine/diagnose perinatal problems.

Table 54.1: Indications for Doppler Sonography in

Obstetrics
• Suspicion of intrauterine growth restriction (IUGR)
• Pregnancy induced hypertension (PIH)/preeclampsia/
eclampsia
• Suspicion for a fetal malformation or disease
• Multiple pregnancy with discordant growth
• Investigation of fetal cardiac anomaly or heart disease
• Fetal heat rate abnormalities/arrhythmia
• Preexisting maternal diseases with vascular relevance
• Prior history of IUGR or intrauterine fetal death Fig. 54.1: Normal flow velocity waveforms of the umbilical
• Prior history of (PIH)/preeclampsia/eclampsia artery in the third trimester
 Doppler Sonography in High Risk Pregnancy 767
heart cycle (Fig. 54.1), proven with previous healthy. Doppler sonography has become the most
longitudinal studies of Fogarty et al22 and Hünecke important investigation method to differentiate
et al,23 as with many cross-sectional studies.21;24 between these fetuses.
Trudinger et al25 explained this phenomenon with It should be noted that Doppler sonography is not
the following mechanisms: suitable for the primary diagnosis of fetal growth
• Continuous maturation in placental villi restriction, but it provides an excellent adjunctive
• Continuous widening of placental vessels cause a method for risk differentiation in suspicious cases.
continuous decrease in vascular resistance
Pathophysiology of abnormal FVWs in placental
• Continuous increase in fetal cardiac output
insufficiency 27 : In the presence of placental
• Continuous changes in the vessel compliance
insufficiency, there is greater placental resistance,
• Continuous increase in fetal blood pressure.
which is reflected in a decreased end-diastolic
Especially in the third trimester of pregnancy,
component of the UA FVWs.28-32 An abnormal UA
depending on the above factors normal values
FVW has a S/D ratio above the normal range. As their
become scattered on nomograms. This scattering is
placental insufficiency worsens, the end-diastolic
more prominent in the S/D ratio than the PI.
velocity decreases (Fig. 54.2), then become absent (Fig.
Resistance index is not affected by above factors after
54.3), and finally it is reversed (Fig. 54.4). Some fetuses
28 weeks’ gestation.
have decreased end-diastolic velocity that remains
Flow velocity waveforms of the UA are slightly
constant with advancing gestation and never become
different at the abdominal wall and the placental site,
absent or reversed, which may be due to a milder
with indices higher at the fetal abdominal wall than
form of placental insufficiency (Fig. 54.2). Pitfalls can
the placental insertion 26. The difference, however, is
be caused due to e.g. fetal breathing (Fig. 54.5).
minimal, and therefore in clinical practice it is not
Abnormal UA Doppler studies, but not normal
important to obtain the FVWs always at the same
results were found to be associated with lower arterial
level. FVWs must always be obtained during fetal
and venous pH values, an increased likelihood of
apnea periods because fetal breathing affects the
intrapartum fetal distress, more admissions to the
waveforms.
In case of an abnormal test, clinical experience and neonatal intensive care unit (NICU), and a higher
randomized controlled trials showed significant incidence of respiratory distress in IUGR fetuses.33
association with an adverse perinatal outcome.

Intrauterine Growth Restriction

The IUGR fetus is a fetus that does not reach its
potential growth. Environmental factors responsible
may be due to maternal, uteroplacental and fetal
factors. Many authors have reported on the
association between an abnormal UA Doppler FVW
and IUGR.
Differentiating the fetus with pathologic growth
restriction that is at risk for perinatal complications
from the constitutionally small but healthy fetus has
been an ongoing challenge in obstetrics. Not all infants
whose birth weight is below the 10th percentile have
been exposed to a pathologic process in utero; in fact, Fig. 54.2: Abnormal flow velocity waveforms of the umbilical
most small newborns are constitutionally small and artery in the third trimester (high resistance index)
768 Textbook of Perinatal Medicine

Therefore, intensive antenatal surveillance in fetuses

with suspected IUGR if the UA Doppler FVWs are
normal was not recommended by the authors.
Conflicting data were presented by McCowan et al
34
; They confirmed that abnormal UA Doppler studies
are associated with a poor perinatal outcome in IUGR
fetuses but also concluded that the perinatal outcome
in small for gestational age fetuses with normal UA
Doppler studies is not always benign (i.e. low
ponderal index, postnatal hypoglycemia, admission
Fig. 54.5: Pitfalls in umbilical artery
to the NICU). Recently, Ertan et al35 suggested that
Doppler velocimetry (fetal breathing)
reversed flow should be seen as a particular clinical
entity with higher incidences of perinatal and overall In our clinical experience, when an IUGR fetus is
mortality, and severe intrauterine growth restriction suspected, the UA, FDA and MCA are the first fetal
compared to absent enddiastolic flow (Figs 54.3 to vessels to be assessed. The ductus venosus (DV),
54.4). umbilical vein, inferior vena cava Doppler
examinations are secondary vessels to be examined,
only when an abnormal FVW is detected on the
arterial vessels. Adding serial Doppler evaluation of
the UA, MCA and DV to IUGR surveillance will
enhance the performance of the biophysical score in
the detection of fetal compromise and therefore
optimizing the timing of intervention.36

Comparison of Perinatal Outcome in Fetuses with

Reverse or Absent Enddiastolic Flow in the
Umbilical Artery/Fetal Descending Aorta35
An abnormal flow velocity waveform is a good
predictor for poor perinatal outcome in high risk
pregnancies.37-41 The absence or reversal of end-
Fig. 54.3: Absent end-diastolic flow (AEDF) of the umbilical diastolic flow in the umbilical artery (UA) and fetal
artery in the third trimester
aorta is widely accepted as an ominous sign of fetal
compromise, with a very high perinatal mortality
(35% to 100%) and morbidity.27,39,42,43
The incidence of absent enddiastolic flow is low,
and of reversed flow it is even lower (reverse flow/
absent enddiastolic flow ratio = 1:10).27,42,43 Studies
so far analyzed the fetal outcome in reversed and
absent enddiastolic flow cases together as one
clinical entity. The difference between the prognosis
of fetuses with reversed flow and absent
enddiastolic flow is still unknown.
We undertook a study, in which the highly
Fig. 54.4: Reverse flow (RF) of the umbilical artery pathologic flow profiles, consisting of absent
 Doppler Sonography in High Risk Pregnancy 769
enddiastolic flow and reverse flow at the umbilical values of umbilical arterial PO2, PCO2 and HCO3
artery and fetal aorta were compared for perinatal were not different among the groups.
outcome. The aim of this study was to clarify All the fetuses with absent and reversed
whether reverse flow at the umbilical artery and enddiastolic flow were admitted to the NICU, and
fetal aorta worsens perinatal outcome more than there was no difference in the duration of NICU
absent enddiastolic flow at the same vessels and treatment required. The rates (83% versus 86%,
to assess the possibility of making predictions respectively for group I and II) and duration of
about the further course of pregnancy. mechanical ventilation were not different among
the groups.
MATERIALS AND METHODS: During a ten-year
period 30 cases with reverse flow in the umbilical Neonatal cerebral hemorrhage occurred more
artery and/or fetal aorta (Group I) were detected. often in group I, but without statistical significance
We selected matched pairs of 30 cases with absent (27.8% versus 17.2%). Neonatal morbidity (Table
enddiastolic velocities (Group II). The selection 54.3) included infections, hyaline membrane
criterion into the groups was an absent or reverse syndrome, icterus, and anemia and shock lung,
flow at the time of delivery. Fetal malformations without statistical difference between the groups.
and chromosomal anomalies were excluded from Only hypocalcaemia was found more often in
both groups. For matching of the absent group I (p<0.05).
enddiastolic flow group fetuses to the reversed flow There was a significantly higher overall and
group same gestational ages, estimated fetal perinatal mortality in the reversed enddiastolic
weights and gestational ages at delivery were flow group (53% and 27%) as compared to the
stipulated. absent enddiastolic flow group (10% and 7%)
(p<0.05).
RESULTS: Maternal complications were similar in
both groups. Intrauterine growth retardation and DISCUSSION: Reverse flow in umbilical
oligohydramnios incidences were significantly velocimetry is associated with dismal perinatal
more common (p<0.05, Table 54.2) in the reverse outcome. Perinatal mortality ranges from 35% to
flow group (83% and 70% versus 73% and 43%). 100%, and postnatal morbidity is significant.37;43,
45
The median time interval between the The above presented study 35 confirmed the
registration of reverse flow and death of fetuses was adverse fetal outcome in fetuses with reversed
2.5 days. After diagnosis of reverse flow, 11 fetuses enddiastolic flow in the umbilical artery and/or
(91.7%) died within a week (three on the same day, fetal aorta with a high overall mortality (53.3%) and
two on the next day, three on the second day, and perinatal mortality (26.8%).
the remaining 4 cases on day 3-8). Because of the low incidences of reverse flow
The mean gestational age at live birth was 31 cases, most authors have studied the effect of both
weeks in both groups. Of the 18 survivors in group reverse flow and absent enddiastolic flow velocity,
I, 17 (94.4%) were delivered by cesarean section. often referred to an “ARED-Flow”, on the fetal
This was not significantly different from group II. outcome together as one entity.46 Reverse flow was
The main indication for the cesarean section was considered to be the last phenomenon preceding
fetal distress. The mean birth weight (1071(112g fetal death.37,47,48
versus 1214(82g) was not statistically different Absent or reversed enddiastolic flow in the
between the groups. umbilical artery or fetal aorta, is closely associated
The mean values and the frequency of with intrauterine growth retardation due to
pathological Apgar scores (7) at 1, 5 and 10 minutes, uteroplacental insufficiency and higher rates of
the arterial cord blood pH values, and the mean preeclampsia.39,40,43 On the other hand, fetuses with
770 Textbook of Perinatal Medicine

intrauterine growth retardation have a high risk of becomes absent or reversed, the fetus is in a state
developing absent or reversed enddiastolic flow.44 of hypoxia and acidosis, and fetal death is
These fetuses with reverse flow had a very high impending”.49 Our results showed almost the same
incidence of oligohydramnios, intrauterine growth frequency of neonatal acidosis in 33% (pH<7.2) in
retardation and maternal pregnancy induced the reverse flow group, compared to 31% in cases
hypertension. Therefore, pregnant women with with absent enddiastolic flow velocities. As
these complications should be evaluated with significant reduction in the proportion of villous
Doppler sonography to detect the compromised tissue occupied by the peripheral villi in
fetuses. pregnancies with absent or reversed enddiastolic
Several authors found an increasing association flow was well documented previously,54,55 in our
between reversed flow of the umbilical artery and presented cases the higher intrauterine death rates
the rate of fetal malformations, especially in the reverse flow group denotes an extreme
congenital heart anomalies, ranging from 12% to placental insufficiency.
The incidence of infection, hyaline membrane
50%. 43;49 These malformations of fetuses were
syndrome and icterus was not influenced by
associated with a low growth potential, not only
reverse or absent enddiastolic flow. The incidence
for the fetus (intrauterine growth retardation) but
of anemia and shock lung was especially high, and
also for the placenta, regardless of whether the
hypocalcaemia occurred statistically more frequent
placenta/neonatal weight was normal or below
in the neonates with reversed enddiastolic flow.
normal. 39 For a better understanding of this
There was no difference in NICU-admission and
correlation, an additional study of subgroups with
mechanical ventilation rates and duration of NICU
fetal malformations including more cases would
stay. The overall neonatal morbidity was not
be required.49
significantly different between the groups. This
A close association between the reversed flow suggests that both highly pathological Doppler
and neonatal cerebral hemorrhage has been findings are affecting the surviving neonates
reported.44 The inappropriate autoregulation of the adversely. However, the higher rates of intrauterine
cerebral blood flow which is induced by extreme and neonatal deaths in the reversed flow cases
prematurity is the major risk factor for intracerebral should be noticed.
hemorrhage.50 The highly pathological Doppler findings (absent
Normal fetal blood velocity values are considered and reverse enddiastolic flow) of the umbilical
reassuring and are generally believed to artery and fetal aorta, which are attributable to
characterize a normal fetal oxygenation.51 Absent severe impairment of placental circulation, and are
or reversed enddiastolic flow velocity in the representing compromised fetal condition with
umbilical artery is associated with fetal high incidence of perinatal and neonatal mortality.
hypoxia.47,52,53 Although normal results of blood- In our opinion, the finding of a reverse flow
gas analysis from umbilical vessels were observed spectrum of the umbilical arteries or fetal aorta
in some cases with reversed or absent enddiastolic should be accepted as a more abnormal Doppler
flow velocities, infants with this severe Doppler finding, compared to absent enddiastolic flow. If
flow pathologies are at a high risk for neonatal absent or reversed enddiastolic flow is detected, a
asphyxia.51 It was further suggested that fetuses very close antenatal follow up is advised and
with reverse flow should immediately be delivered delivery should be considered if biophysical
after diagnosis.48 “Once the diastolic component parameters and venous Doppler indices become
of umbilical artery flow velocity waveforms abnormal.
 Doppler Sonography in High Risk Pregnancy 771
Table 54.2: Antenatal complications of the reversed Impact on Perinatal Consequences
(n=30) and absent enddiastolic flow cases (n=30)
Abnormal UA FVWs are associated in IUGR fetuses
Type of complication Reverse Absent
with one of the following outcomes: early delivery,
flow n (%) flow n (%)
reduced birth weight, oligohydramnios, NICU
Pregnancy induced 19 (63.3) 19 (63.3)
admission, and prolonged hospital stay. 27,57 In a meta-
hypertension
HELLP syndrome 1 (3.3) 6 (20) analysis it was shown that the use of UA Doppler
Gestational diabetes 1 (3.3) 2 (6.7) sonography in pregnancies complicated by IUGR
Fetal Infection 1 (3.3) 0 reduces perinatal mortality up to 38% and improves
Abruptio placenta 0 4 (13.3)
Birth weight in g (M± SD) 1071±112 1214±82
perinatal outcome.17 A review consisting of 7000 high
Intrauterine growth 25 (83.3) 19 (63.3) risk pregnancies58 found that Doppler ultrasound was
retardation* (< 5. Percentile) associated with a trend toward reduction in perinatal
Oligohydramnios* 21 (70) 13 (43.3) death especially in pregnancies complicated with
HELLP= Hemolysis, elevated liver enzymes, low platelets preeclampsia or IUGR. The Doppler ultrasound use
(*= p<0.05) was also associated with fewer inductions of labor and
fewer hospital admissions, without reports of adverse
perinatal effects. The reviewers concluded that the use
Table 54.3: Perinatal and neonatal parameters of the
reverse (n=18) and absent enddiastolic (n=29) flow cases of Doppler ultrasound in high risk pregnancies is
(live-born) likely to reduce perinatal mortality.
Reverse Absent enddiastolic
flow n (%) flow n (%) Neonatal Intraventricular Hemorrhage
5’ Apgar < 7 7 (39) 13 (45) Fetal status as well as neonatal complications of
pH < 7.2 6 (33) 9 (31) prematurity in IUGR both contribute to adverse
Cerebral hemorrhage 5 (27.8) 5 (17.2)
Infections 8 (44.4) 8 (27.6)
perinatal outcome and increase the risk for the
Anemia 8 (44.4) 9 (31.0) development of intraventricular hemorrhage (IVH).
Hypocalcemia* 3 (16.7) 0 Data suggest that absent and reversed end-diastolic
Hyaline membrane 12 (67) 19 (66) flow in the UA early in gestation carries a high risk of
syndrome
Icterus 8 (44.4) 12 (41.4) subsequent neonatal IVH 59 . However, this
Shock lung 3 (16.7) 2 (6.9) observation is not independent of other perinatal
Lung emphysema 2 (11.1) 0 variables: prematurity and difficult births remain the
Retinopathy 1 (5.6) 3 (10.4)
most important determinants of this complication.
Muscle hypotony 1 (5.6) 3 (10.4)

(*= p<0.05) Neuromotor Outcome

Valcomonico et al57 evaluated the association of UA
Chromosomal Abnormalities
Doppler velocimetry with long term neuromotor
It was shown that absent end-diastolic flow in the UA outcome in IUGR fetuses with normal (n=17), reduced
is associated with chromosomal abnormalities like (n=23) and absent or reversed (n=31) UA end-diastolic
trisomies, triploidies or chromosomal deletions.56 flow. The infants who survived the neonatal period
Setting out from the point that structural anomalies were observed for a mean of 18 months. Their
are more frequent in fetuses with chromosomal postural, sensorial and cognitive functions were
aberrations, the authors recommended a rapid evaluated at 3, 6, 9, 12 and 18 months of age. Although,
acquisition of a karyotype in fetuses with congenital due to small number of cases the results did not reach
anomalies and an absent end-diastolic flow in the statistical significance, the incidence of permanent
UA.35 neurological sequelae increased as the UA end-
772 Textbook of Perinatal Medicine

diastolic flow decreased (35% with absent or reversed Multiple Gestation

flow, 12% with reduced flow, and 0% with normal
The S/D ratio of twins at the UA are in agreement
flow). Recently, in another study 60 twenty three IUGR
with singleton pregnancies in the third trimester.66
fetuses with absent or reversed UA end-diastolic flow
Twins with an abnormal UA FVW tend to be born
were matched with fetuses with appropriate growth.
earlier, have a higher perinatal mortality and
All children were followed for 6 years, and intellectual
morbidity, and have more frequent structural
development, neuromotoric development was
anomalies than fetuses without abnormal Doppler
significantly diminished in fetuses with abnormal
results.67
FVWs. Only social development was not impaired in
In cases of twin-twin transfusion syndrome, a poor
fetuses with abnormal UA FVWs. Similar results were
placental implantation site, or chromosomal
previously published by our working group, too.38,61
anomalies discordant growth between the twins may
Intrapartum Studies occur. This is a very high risk situation, with a high
perinatal mortality and morbidity. The diagnosis is
A review of intrapartum UA Doppler velocimetry for made mainly by ultrasound biometry. The best
adverse perinatal outcome gave disappointing predictor for diagnosis of discordant twins appears
results.62 Out of 2700 pregnancies, which were to be the presence either a difference in the UA S/D
evaluated for the intrapartum use of Doppler ratio greater than 15% or a different estimated fetal
velocimetry, the technique proved to be a poor weight greater than 15%.68 Recently it has been
predictor for outcome measures like low Apgar scores, reported that abnormal UA velocimetry can be
intrapartum fetal heart rate abnormalities, umbilical observed in small twins more often in monochorionic
arterial acidosis, and cesarean section for fetal distress. than dichorionic twins. 69 Doppler ultrasound
Umbilical Artery Doppler Ultrasound in Unselected abnormalities of the UA in either twin are associated
Patients with poor perinatal outcome in twin-twin transfusion
syndrome.
Theoretically, the use of routine UA Doppler
ultrasound in unselected or low risk pregnancies The Biophysical Profile and Multivessel Doppler
would be to detect those pregnancies in which there Ultrasound in IUGR
has been failure to establish or maintain the normal
low-resistance umbilical and uterine circulations, (a Biophysical profile scoring (BPS) and Doppler
pathological process leading to placental dysfunction surveillance are the primary methods for fetal
and associated with intrauterine growth retardation assessment in IUGR. As placental insufficiency
and preeclampsia), before there is clinical evidence worsens, the fetus adapts by progressive
of fetal compromise. In practice, observational and compensation. Previously it has been suggested that
longitudinal studies of Doppler ultrasound in the sequential changes in arterial and venous flow
unselected or low risk pregnancies have raised doubts occur before some biophysical parameters (fetal tonus,
about its application as a routine screening test, and movement, breathing, amniotic fluid volume and
authors have cautioned against its introduction into non-stress test) decline.70,71 Baschat et al36 evaluated
obstetric practice without supportive evidence from whether multivessel Doppler parameters (UA, UV,
randomized trials.63-65 The relatively low incidence of MCA, DV, and inferior vena cava) precede biophysical
significant, poor perinatal outcomes in low risk and fetal parameters in fetuses with severe IUGR. They
unselected populations presents a challenge in found that combining multivessel Doppler and
evaluating the clinical effectiveness of routine UA composite BPS will provide significant early warning
Doppler ultrasound, as large numbers are required and a definitive indication for action in the
to test the hypothesis. management of severe IUGR, and suggested that
 Doppler Sonography in High Risk Pregnancy 773
delivery timing may be based on this new gold Increased placental impedance combined with
standard. redistribution of blood flow from nonvital to vital
organs may result in changes in the aortic FVWs. An
Fetal Descending Aorta (FDA) elevated S/D-Ratio, RI and PI (Fig. 54.7) is associated
Beside the UA, routine Doppler sonographic with both IUGR and adverse perinatal outcomes, such
examination at the descending fetal aorta is possible. as severe growth restriction, necrotizing enterocolitis,
FVWs of the FDA are usually recorded at the level of fetal distress, and perinatal mortality.74-81 Absent end-
the diaphragm. In fact, FVWs at the level of the diastolic flow at the FDA is also a predictor of fetal
diaphragm and distally to the origin of the renal heart rate abnormalities (Fig. 54.8). It was shown that
arteries are different.72 Normal blood FVWs in the absent flow in the FDA were detected 8 days prior to
FDA is highly pulsatile, with a minimal diastolic the onset of decelerations at fetal heart rate
component (Fig. 54.6). The descending part of the
aorta provides perfusion to the fetal abdominal
organs, umbilical-placental circulation, and lower
extremities. The flow velocity waveform of the FDA
shows a continuous forward stream during the whole
heart cycle, but when compared to the FVW of the
UA, the end-diastolic flow is less than the systolic
component. Due to this reason the S/D ratio in the
fetal aorta goes far than the S/D ratio in the UA. As
pregnancy advances, the fetal aortic diameter gets
wider, which decreases peripheral resistance and
increases diastolic flow component. Nevertheless, this
does not cause a significant S/D ratio decrease in the
FDA.73 Resistance and Pulsatility indices in the last
trimester are also not affected significantly, and show Fig. 54.7: Abnormal flow velocity waveforms of the fetal
a similar course as in the UA. descending aorta in the third trimester (high resistance index)

Fig. 54.6: Normal flow velocity waveforms of the fetal Fig. 54.8: Absent end-diastolic flow (AEDF) of the fetal
descending aorta in the third trimester descending aorta (FDA) in the third trimester
774 Textbook of Perinatal Medicine

monitoring.78 The sensitivity and specificity of absent

end-diastolic flow in the FDA for prediction of IUGR
with fetal heart rate abnormalities are 85% and 80%,
respectively. 80,81
Abnormal FVWs of the FDA were also evaluated
for intellectual function, and minor neurological
dysfunction.38,61,82,83 At 7 years of age, verbal and
global performances as well as neurological
examination were significantly better in the fetuses
with normal aortic FVWs.
Albeit, most of the studies showed Doppler
Fig. 54.10: Circle of Willis and middle cerebral artery
velocimetry abnormalities of the FDA is a predictive visualized with color Doppler
test for the onset of decompensation due to placental
insufficiency in the IUGR fetuses (Figs 54.8 to 54.9), it
can not be recommended as a screening or diagnostic important to know which artery is being examined
test for IUGR in an unselected obstetric population.84 during clinical practice.86
The most favorably positioned vessel for Doppler
Middle Cerebral Artery (MCA) sonographic examination of fetal brain perfusion is
The circle of Willis is composed anteriorly of the the MCA. As the pregnancy advances, the vascular
anterior cerebral arteries (branches of the internal resistance in the MCA decreases (Fig. 54.11),87 and the
carotid artery that are interconnected by the anterior Doppler indices change. During the early stages of
communicating artery) and posteriorly of the two pregnancy, end-diastolic flow velocities in cerebral
posterior cerebral arteries (Branches of the basilar vessels are small or absent, but velocities increase
artery that are interconnected on either side with towards the end of gestation. In the normal
internal carotid artery by the posterior communi- developing fetus, the brain is an area of low vascular
cating artery). 85 These two trunks and the MCA, impedance and receives continuous forward flow
another branch of the internal carotid artery, supply throughout the cardiac cycle. IUGR due to placental
the hemispheres on each side (Fig. 54.10). All of the insufficiency is likely to be caused by redistribution
defined arteries have different FVWs, therefore, it is

Fig. 54.9: Reverse flow (RF) in the fetal descending aorta Fig. 54.11: Normal flow velocity waveforms of the middle
cerebral artery in the third trimester
 Doppler Sonography in High Risk Pregnancy 775
of fetal blood flow in favor of the fetal brain and standard deviations below normal for gestation.
“stress organs”, at the expense of less essential organs When the oxygen deficit becomes greater, there is a
such as subcutaneous tissue, kidneys, and liver. tendency for the MCA PI to rise; this presumably
Finally, the already low resistance to blood flow in reflects the prefinal stage due to development of brain
the brain drops further to enhance brain circulation edema (Fig. 54.13).
(Fig. 54.12). This results with increased end-diastolic Hyperactivity of fetus, increase of intrauterine
velocities, and a decrease in the S/D ratio of the MCA pressure (e.g. polyhydramnios), and external pressure
(“Brain sparing effect”).88 to the fetal head (e.g. by the probe) might erroneously
Abnormalities of the UA flow correlated with fetal increase end-diastolic flow velocities in the MCA.91
compromise better than intracerebral artery blood Different investigators have undertaken studies -
flow impairment. This suggests that high placental utilizing data obtained from the UA and MCA- to
impedance precedes the onset of the “brain sparing develop indices for evaluation of intrauterine risk.85
effect”. In a study, in which 576 high risk pregnancies
were evaluated for the UA and MCA velocimetry, Prediction of Fetal Hemoglobin in Red Cell
neither test was able to predict adverse perinatal Alloimmunization
outcome in the normal growing fetus. 89 Results
showed that simultaneous assessment of UA and Fetal anemia caused by red cell alloimmunization can
MCA velocimetry in IUGR fetuses did not improve be detected noninvasively by Doppler ultrasound on
the perinatal outcome. When the UA velocimetry was the basis of an increase in the peak systolic velocity
normal, the MCA velocimetry did not improve the in the MCA. 92,93 Although there is not a strong
prediction of IUGR or adverse perinatal outcome. correlation between these two parameters when the
However, when both arteries velocimetric values were fetus is nonanemic, the correlation becomes stronger
abnormal, the risk of being growth restricted and as the hemoglobin levels decrease. 93 Prospective
having an adverse perinatal outcome was doubled. evaluation of the MCA peak systolic velocity to detect
It has been reported that the MCA PI is below the fetuses at risk for anemia in red cell alloimmunization
normal range when pO2 is reduced.90 Maximum showed that 90 of the 125 anticipated invasive
reduction in PI is reached when the fetal pO2 is 2-4 procedures could be avoided.94

Fig. 54.12: Abnormal flow velocity waveforms of the middle Fig. 54.13: Low end-diastolic flow (“normal PI”) after the brain
cerebral artery in the third trimester (“ brain sparing effect”) sparing effect (“de-centralisation) this presumably reflects the
preterminal stage due to development of brain edema
776 Textbook of Perinatal Medicine

In anemic fetuses, change in hematocrit leads to a Table 54.4: Indications for fetal venous
corresponding alteration in blood viscosity and to an Doppler Sonography
impaired release of oxygen to the tissues. Increased • Fetal arrhythmias
cardiac output and vasodilatation are the main • Suspected twin-twin transfusion syndrome
mechanisms by which the fetus attempts to maintain
• Nonimmune hydrops fetalis (NIHF)
the oxygen and metabolic equilibrium in various
organs. It is likely that when the fetus is nonanemic • Suspected stenosis in the cardiac outflow tract
or mildly anemic, there are only minor or insignificant • Congenital heart disease
hemodynamic changes. Therefore, the blood velocity • Severe centralization of the fetal circulation (brain
does not change. When the fetus becomes more sparing)
anemic, various mechanisms compensate to maintain • Suspicious fetal heart rate tracings
the oxygen and metabolic equilibrium in the various
organs. The MCA peak systolic velocity changes
high-risk pregnancies, a subject that is dealt with later
proportionally to the hemoglobin deficiency.
in this section.
Doppler measurements appear to be valuable for
estimating hemoglobin concentration in fetuses at risk
CONCLUSION
for anemia. Doppler sonography of the MCA has the
potential to decrease the need for invasive testing Doppler ultrasound is a noninvasive technique that
(amniocentesis, cordocentesis) and its potential is commonly used in high risk pregnancies.
risks.95 Examination of fetomaternal vessels using Doppler
sonography has been subject of intensive investigation
Fetal Venous Circulation in recent years. However, to date, randomized
controlled trials were able to establish only limited
In recent years research on the fetomaternal
clinical value of Doppler velocimetry to improve
circulation has focused more on the venous side of
perinatal outcome in high risk situations. Umbilical
the fetal circulation. Physiologically, blood flow
artery, fetal descending aorta and middle cerebral
velocities in the umbilical vein (UV) and the portal
artery Doppler velocimetric studies are acceptable
circulation are steady and non-pulsatile. However, it
tools in the diagnosis and management of intrauterine
has been shown that both fetal body and breathing
growth restricted fetuses, and in the reduction of
movements can interrupt the FVWs. In a recent
perinatal mortality in high risk pregnancies. The
review, it was concluded that several pathologic
majority of severely compromised fetuses also show
conditions such as non-immune hydrops, severe
pathological venous velocimetry, which might give
IUGR, and cardiac arrhythmias also result in an
valuable clinical information for surveillance in high
abnormal, pulsatile venous blood flow.96 However,
risk pregnancies and their optimal perinatal
the relationship between fetal venous blood flow
management. In addition, Doppler sonography might
patterns and imminent fetal asphyxia or fetal death
have a role in predicting long term neuromotor
is still unknown. Recently, studies on venous
outcome. Large scale randomized controlled trials are
circulation in the fetal brain97 and pulmonary venous
needed to establish the clinical utility of Doppler
circulation in the diagnosis of pulmonary hypoplasia
ultrasound in obstetrics.
were performed. 98 Venous Doppler has also
applications in several other disorders (Table 54.4).
ACKNOWLEDGEMENT
An understanding of the fetal venous circulation
provides a platform for the clinical management of The authors acknowledge Mr. Aykut BARUT, MD
perinatal problems, especially timing of delivery in (Zonguldak/Turkey), Hakan SADE, MD (Zonguldak/
 Doppler Sonography in High Risk Pregnancy 777
Turkey), and Mehmet Vural, MD (Zonguldak/Turkey) complicated pregnancy. Br J Obstet Gynaecol. 1985;92:39-
45.
for their technical and editorial assistance in the
13. Zimmermann P, Eirio V, Koskinen J, Kujansuu E, Ranta
preparation of this manuscript. T. Doppler assessment of the uterine and uteroplacental
circulation in the second trimester in pregnancies at high
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J Obstet Gynecol 1988;159:559-61. relationship with umbilical venous blood gas measured
38. Ertan A, Jost W, Hendrik H, Lauer S, Uhrmacher S, at cordocentesis. Am J Obstet Gynecol 1990;162:115-20.
Schmidt W. Perinatal events and neuromotoric 52. Gudmundsson S, Dubiel M. Doppler velocimetry in the
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editor. 2nd World Congress of Perinatal Medicine. 53. Campbell S, Vyas S, Nicolaides K. Doppler investigation
Bologna: Monduzzi Editore Spa; 1993. p. 1049-52. of the fetal circulation. J Perinat Med 1991;19:21-26.
 Doppler Sonography in High Risk Pregnancy 779
54. Biagiotti R, Sgambati E, Brizzi E. Placental morphometry 68. Divon MY, Girz BA, Sklar A, Guidetti DA, Langer O.
in pregnancies complicated by intrauterine growth Discordant twins—a prospective study of the diagnostic
retardation with absent or reversed end diastolic flow value of real-time ultrasonography combined with
in the umbilical artery. Ital J Anat Embryol 1999;104:201- umbilical artery velocimetry. Am J Obstet Gynecol
07. 1989;161:757-60.
55. Kingdom J, Huppertz B, Seaward G, Kaufmann P. 69. Gaziano E, Gaziano C, Brandt D. Doppler velocimetry
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Reprod Biol 2000;92:35-43. dizygotic twins. Am J Obstet Gynecol 1998;178:1359-67.
56. Rizzo G, Pietropolli A, Capponi A, Arduini D, Romanini 70. Hecher K, Campbell S, Doyle P, Harrington K, Nicolaides
C. Chromosomal abnormalities in fetuses with absent K. Assessment of fetal compromise by Doppler
end-diastolic velocity in umbilical artery: analysis of risk ultrasound investigation of the fetal circulation. Arterial,
factors for an abnormal karyotype. Am J Obstet Gynecol intracardiac, and venous blood flow velocity studies.
1994;171:827-31. Circulation 1995;91:129-38.
57. Valcamonico A, Danti L, Frusca T, Soregaroli M, Zucca 71. Senat MV, Schwarzler P, Alcais A, Ville Y. Longitudinal
S, Abrami F et al. Absent end-diastolic velocity in changes in the ductus venosus, cerebral transverse sinus
umbilical artery: risk of neonatal morbidity and brain and cardiotocogram in fetal growth restriction.
damage. Am J Obstet Gynecol 1994;170:796-801. Ultrasound Obstet Gynecol 2000;16:19-24.
58. Neilson JP, Alfirevic Z. Doppler ultrasound for fetal 72. Lingman G, Marsal K. Fetal central blood circulation in
assessment in high risk pregnancies. Cochrane Database the third trimester of normal pregnancy—a longitudinal
Syst Rev 2000;CD000073. study. I. Aortic and umbilical blood flow. Early Hum.Dev.
59. Baschat AA, Gembruch U, Viscardi RM, Gortner L, 1986;13:137-50.
Harman CR. Antenatal prediction of intraventricular 73. Hecher K, Spernol R, Szalay S, Stettner H, Ertl U.
hemorrhage in fetal growth restriction: what is the role Reference values for the pulsatility index and the
of Doppler? Ultrasound Obstet Gynecol 2002;19:334-39. resistance index of blood flow curves of the umbilical
60. Wienerroither H, Steiner H, Tomaselli J, Lobendanz M, artery and fetal aorta in the 3d trimester. Ultraschall Med
Thun-Hohenstein L. Intrauterine blood flow and long- 1989;10:226-29.
term intellectual, neurologic, and social development. 74. Soothill PW, Nicolaides KH, Bilardo K, Hackett GA,
Obstet Gynecol 2001;97:449-53. Campbell S. Utero-placental blood velocity resistance
61. Ertan AK, Jost W, Mink D, Schmidt W. Neuromotoric index and umbilical venous pO2, pCO2, pH, lactate and
development of children after AED-Flow during erythroblast count in growth-retarded fetuses. Fetal Ther.
pregnancy. In: Kurjak A, Latin V, Rippmann E, editors. 1986;1:176-79.
Advances on the pathophysiology of pregnancy. Milano: 75. Jouppila P, Kirkinen P. Blood velocity waveforms of the
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62. Farrell T, Chien PF, Gordon A. Intrapartum umbilical Obstet Gynecol 1986;67:856-60.
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perinatal outcome: a systematic review. Br J Obstet flow in pregnancies complicated by intrauterine growth
Gynaecol. 1999;106:783-92. retardation. Obstet Gynecol 1987;69:895-902.
63. Sijmons EA, Reuwer PJ, van Beek E, Bruinse HW. The 77. Hackett GA, Campbell S, Gamsu H, Cohen-Overbeek T,
validity of screening for small-for-gestational-age and Pearce JM. Doppler studies in the growth retarded fetus
low-weight-for-length infants by Doppler ultrasound. Br and prediction of neonatal necrotising enterocolitis,
J Obstet Gynaecol. 1989;96:557-61. haemorrhage, and neonatal morbidity. Br Med J (Clin
64. Beattie RB, Dornan JC. Antenatal screening for Res Ed) 1987;294:13-16.
intrauterine growth retardation with umbilical artery 78. Arabin B, Siebert M, Jimenez E, Saling E. Obstetrical
Doppler ultrasonography. BMJ 1989;298:631-35. characteristics of a loss of end-diastolic velocities in the
65. Goffinet F, Paris-Llado J, Nisand I, Breart G. Umbilical fetal aorta and/or umbilical artery using Doppler
artery Doppler velocimetry in unselected and low risk ultrasound. Gynecol Obstet Invest 1988;25:173-80.
pregnancies: a review of randomised controlled trials. 79. Tonge HM, Wladimiroff JW, Noordam MJ, van Kooten
Br J Obstet Gynaecol. 1997;104:425-30. C. Blood flow velocity waveforms in the descending fetal
66. Giles WB, Trudinger BJ, Cook CM, Connelly A. Umbilical aorta: comparison between normal and growth-retarded
artery flow velocity waveforms and twin pregnancy pregnancies. Obstet Gynecol 1986;67:851-55.
outcome. Obstet Gynecol 1988;72:894-97. 80. Bonatz G, Schulz V, Weisner D, Jonat W. Fetal heart rate
67. Gaziano EP, Knox H, Ferrera B, Brandt DG, Calvin SE, (FHR) pathology in labor related to preceeding Doppler
Knox GE. Is it time to reassess the risk for the growth- sonographic results of the umbilical artery and fetal aorta
retarded fetus with normal Doppler velocimetry of the in appropriate and small for gestational age babies. A
umbilical artery? Am J Obstet Gynecol 1994;170:1734-41. longitudinal analysis. J Perinat Med 1997;25:440-46.
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81. Marsal K, Laurin J, Lindblad A, Lingman G. Blood flow pattern in the human fetus. Am J Obstet Gynecol
in the fetal descending aorta. Semin.Perinatol 1996;174:1645-47.
1987;11:322-34. 91. Vyas S, Nicolaides KH, Bower S, Campbell S. Middle
82. Ley D, Tideman E, Laurin J. Abnormal fetal aortic cerebral artery flow velocity waveforms in fetal
velocity waveform and intellectual function at 7 years hypoxaemia. Br J Obstet Gynaecol. 1990;97:797-803.
of age. Ultrasound Obstet Gynecol 1996;8:160-65. 92. Mari G, Adrignolo A, Abuhamad AZ, Pirhonen J, Jones
83. Ley D, Laurin J, Bjerre M, Marsal K. Abnormal fetal aortic DC, Ludomirsky A et al. Diagnosis of fetal anemia with
velocity waveform and minor neurological dysfunction Doppler ultrasound in the pregnancy complicated by
at 7 years of age. Ultrasound Obstet Gynecol 1996;8:152- maternal blood group immunization. Ultrasound Obstet
59. Gynecol 1995;5:400-05.
84. Divon MY, Ferber A. Doppler evaluation of the fetus. Clin 93. Mari G, Deter RL, Carpenter RL, Rahman F, Zimmerman
Obstet Gynecol 2002;45:1015-25. R, Moise KJ, Jr. et al. Noninvasive diagnosis by Doppler
85. Mari G, Detti L. Doppler ultrasound application to fetal ultrasonography of fetal anemia due to maternal red-
medicine. In: Fleischer A, Manning F, Jeanty P, Romero cell alloimmunization. Collaborative Group for Doppler
R, editors. Sonography in Obstetrics and Gynecology Assessment of the Blood Velocity in Anemic Fetuses. N
Engl.J Med 2000;342:9-14.
(Principles and Practice). New York, USA: McGraw Hill;
94. Zimmerman R, Carpenter RJ, Jr., Durig P, Mari G.
2001. p. 247-83.
Longitudinal measurement of peak systolic velocity in
86. Mari G, Moise KJ, Jr., Deter RL, Kirshon B, Carpenter
the fetal middle cerebral artery for monitoring
RJ, Jr., Huhta JC. Doppler assessment of the pulsatility
pregnancies complicated by red cell alloimmunisation:
index in the cerebral circulation of the human fetus. Am
a prospective multicentre trial with intention-to-treat.
J Obstet Gynecol 1989;160:698-703.
BJOG. 2002;109:746-52.
87. Vetter K. The significance of Doppler blood flow 95. Mari G, Detti L, Oz U, Zimmerman R, Duerig P, Stefos
measurement in recognizing placental insufficiency. Arch T. Accurate prediction of fetal hemoglobin by Doppler
Gynecol Obstet 1988;244 Suppl:S12-S18. ultrasonography. Obstet Gynecol 2002;99:589-93.
88. Arabin B, Bergmann PL, Saling E. Simultaneous 96. Huisman TW. Doppler assessment of the fetal venous
assessment of blood flow velocity waveforms in system. Semin.Perinatol 2001;25:21-31.
uteroplacental vessels, the umbilical artery, the fetal 97. Laurichesse-Delmas H, Grimaud O, Moscoso G, Ville Y.
aortaand the fetal common carotid artery. Fetal Ther. Color Doppler study of the venous circulation in the fetal
1987;2:17-26. brain and hemodynamic study of the cerebral transverse
89. Strigini FA, De Luca G, Lencioni G, Scida P, Giusti G, sinus. Ultrasound Obstet Gynecol 1999;13:34-42.
Genazzani AR. Middle cerebral artery velocimetry: 98. Yoshimura S, Masuzaki H, Miura K, Muta K, Gotoh H,
different clinical relevance depending on umbilical Ishimaru T. Diagnosis of fetal pulmonary hypoplasia by
velocimetry. Obstet Gynecol 1997;90:953-57. measurement of blood flow velocity waveforms of
90. Sepulveda W, Shennan AH, Peek MJ. Reverse end- pulmonary arteries with Doppler ultrasonography. Am
diastolic flow in the middle cerebral artery: an agonal J Obstet Gynecol 1999;180:441-46.
 55
Effect of Exercise on
Fetoplacental Doppler Flow

H Alper, A Kubilay Ertan, Werner

THE EFFECTS OF MATERNAL EXERCISE ON it increases the rate of placental bed blood flow at rest.
PLACENTAL BED BLOOD FLOW If this inference is correct then exercise training during
pregnancy should actually increase the glucose and
Sustained bouts of maternal exercise have both acute
oxygen delivery to the placental site throughout mid-
and chronic effects on placental bed blood flow.
and late-pregnancy.
During exercise, blood flow is diverted away from
The main concern about exercise in pregnancy is
the viscera to the exercising muscle and skin.1 The
that reduced uterine blood flow may cause hypoxia
magnitude of the reduction in flow is directly
in the fetus. 7 Recent studies using Doppler
proportional to exercise intensity and the muscle mass
ultrasonography found an increase in the systolic/
used (which varies with the type of exercise), and with diastolic (S/D) ratio of uterine circulation, indicating
common types of exercise performed at usual exercise an increase in resistance of the main vessels that
intensities, the reduction usually exceeds 50%. This supply the uterus.8,9
exercise-induced decrease in visceral flow persists Although uteroplacental blood flow may decrease
throughout pregnancy but, in late-pregnancy, the with exercise, compensatory mechanisms may exist
magnitude of the decrease is blunted in women who to ensure adequate fetal oxygenation. In studying
continue to exercise regularly. 2-4 Once the exercise ewes, Chandler reported an increase in uterine
ceases, flow rapidly returns to normal. Thus, during extraction of oxygen that occurred with the decreased
a routine exercise session both glucose and oxygen uterine blood flow after maternal exercise.10 Curet et
delivery to the placental site are acutely reduced and al. reported altered distribution of uterine blood flow
the magnitude of the decrease varies with exercise in favor of the placenta in ewes.11
type and intensity, maternal fitness and the time point
in pregnancy when the exercise is carried out.4,5 COMPLICATED PREGNANCIES AND EXERCISE
However, women who perform weight-bearing Two worrisome antenatal complications of pregnancy
exercise regularly during pregnancy augment the are intrauterine growth restriction and preterm labor.
pregnancy-associated increases in plasma volume, Strenuous exercise in pregnancy has been assessed
intervillous space blood volume, placental volume and is not harmful to the mother or the fetus in healthy
and cardiac output,5,6 The fact that regular weight- women if it is of limited duration. Heavy work or
bearing exercise augments the changes in these exercise also does not appear to increase the risk of a
parameters by between 10 and 50% also suggests that preterm delivery or intrauterine growth restriction in
782 Textbook of Perinatal Medicine

women at low risk for an adverse pregnancy hypertension, IUGR fetus, or both) in the third
outcome.12 trimester of singleton pregnancies. The patients
The influence of exercise during pregnancy and underwent a bicycle exercise test during which pulsed
its effect on birth weight and pregnancy outcome Doppler sonographic assessment of the uteroplacental
remains uncertain. The most recent technical bulletin circulation was performed. Exercise appeared to
from the ACOG13 suggests that lower birth weights increase the pulsatility of the uteroplacental Doppler
are observed among vigorously exercising women, waveform in all cases. The changes in the waveforms
but there is no information linking exercise with an were more exaggerated in the complicated
adverse outcome of the fetus. The effect of maternal pregnancies, particularly when the resting waveform
exercise on prenatal complications is also unknown. had been abnormal. These changes indicate an
A recent review from the Cochrane Database was increase in uteroplacental vascular resistance with
unable to demonstrate important benefits or risks to exercise, suggesting a deleterious effect of physical
the mother or fetus with exercise in pregnancy. 12 exertion in the third trimester, particularly in the
Small patient numbers or failure to take into presence of hypertension or IUGR fetus.
consideration the confounding variables in larger The effect of physical exertion on the fetoplacental
samples hampers the studies assessing exercise with unit in pregnancies complicated by intrauterine
birth weight and pregnancy outcome. Because the growth retardation or hypertensive disorders is of
labor force is composed of more working women, special clinical interest, because these fetuses are
many who exercise at conception and continue during known to be at risk for long-term neurological
pregnancy, the impact of exercise on pregnancy morbidity.
outcome in working women is very important.
Influences of exercise, stress, and occupation on Clinical Study on Exercise During Complicated
pregnancy outcome are difficult to examine because Pregnancy and Doppler Sonography32
of confounding variables not taken into account in
We conducted a study including measurements of the
large investigations and the lack of an adequate
fetal aorta, fetal middle cerebral artery, umbilical
sample size in smaller studies.
artery and uteroplacental vessels in appropriate-for-
As physical stress is relatively easy to standardize,
gestational-age fetuses (AGA) and intrauterine
several groups have studied changes in pregnant
growth retarded fetuses (IUGR) to investigate changes
women as a result of sporting exertion, particularly
of the fetoplacental unit after defined maternal
the measurable physiological changes in the
exercise in the third trimester of pregnancy.
organisms of the mother and child. Although using
different types of exercise - produced by ergometer, Materials and Methods
treadmill and running tests - all authors came to the
conclusion that light and medium physical exercise A total of 33 pregnant women with AGA fetuses and
has no significant adverse effect on the mother or the ten patients with IUGR fetuses in the third trimester
fetus.14-16 were examined. Multiple pregnancies, cases with
Doppler flow measurements of the fetoplacental maternal renal disease, maternal diabetes, maternal
unit after physical exercise of the mother have been cardiovascular pathology other than hypertension
performed with varying results by several and fetuses with chromosomal or structural anomalies
investigators.16-30 Only one study compared Doppler were excluded from evaluation. IUGR was defined
flow in uncomplicated and complicated pregnancies as a fetal abdominal circumference <5th percentile for
after physical exercise of the mother. 31 In this study gestational age of our reference ranges.33
Hackett et al. studied thirty-four women (12 The exercise period began with an acclimatization
uncomplicated and the other 22 complicated by period of three minutes (30 W), followed by ten
 Effect of Exercise on Fetoplacental Doppler Flow 783
minutes of moderate exertion (1.25 W/kg body Glucose and lactate levels were measured in
weight for each women). A bicycle ergometer from capillary blood samples taken from the finger pad
Mijnhardt (Mijnhardt-Jäger b.v., Bunnik, The before and after exercise (“Monotest-Lactat in
Netherlands) was used. Halbmicro-Technik”, Boehringer Mannheim). The
Immediately after the exercise period Doppler pulse and blood pressure of the mother was
flow measurements were performed. The test period automatically registered at three-minute intervals
was 35 minutes. In the IUGR group fetal heart rate during the test (Dinamap, Critikon).
monitoring (FHR) was performed for additional 15 The Wilcoxon pair difference test for associated
minutes before and after the exercise. random samples was used for statistical evaluation.
Doppler flow recordings of the umbilical arteries,
fetal aorta, middle cerebral and the uterine arteries Results
were performed. During all Doppler examinations the Normal pregnancies: The mean performance on the
patients were positioned semi-recumbent to avoid bicycle ergometer was 79 W (± 11 W). Gestational age
“Vena Cava Syndrome”. at delivery was 40.0 weeks (± 8 days). The mean birth
Doppler flow velocity waveforms were obtained weight was 3270 g (± 383 g).
from a free-floating central part of the umbilical artery Mode of delivery: Twenty four (73%) women
in the absence of body movements, fetal breathing or delivered vaginal spontaneously, 1 (3%) vaginal
cardiac arrhythmia with the sample volume covering operative and 8 (24%) by cesarean section.
the whole vessel. Care was taken to keep the
Doppler flow results of normal pregnancies
insonation angle in the umbilical artery at the lowest
(n=33) (Table 55.1)
possible angle. The fetal aorta was localized in its
abdominal part at the origin of the renal arteries. The Umbilical artery: The observed RI was within the
angle between ultrasound beam and fetal aorta was normal range before and after exertion. However, in
kept below 55°. The middle cerebral artery was 4 (12%) fetuses the measurements reached the
visualized at about 1cm of its origin in the circle of threshold range after exercise.
Willis in an axial view. The insonation angle in the
Fetal aorta: The mean RI before exercise was 4.9 (±1.3).
middle cerebral artery was always below 15°. Care
In 8 (24%) fetuses the RI was at the threshold range
was taken to minimize fetal head compression,
(RI between 0.83 and 0.86) and in 1 (3%) fetus at the
because this is known to influence the flow velocity
pathological range (RI>0.86). A significant increase in
waveforms of the middle cerebral arteries. the RI was determined following exertion (p<0.01).
For uterine artery Doppler the transducer was However, the mean value did not reach the
placed in the right or left lower part of the abdomen. pathological level. An increase in the RI of the aorta
Color Doppler imaging was used to localize the main shortly after exertion was observed in 21 (63%) fetuses
uterine artery cranial to the crossing of the external (In 5 [24%] within the threshold range, in 16 (76%) in
iliac artery. The examination was repeated on the the pathological range).
opposite side. The insonation angle was kept below
55° at the uterine arteries. Middle cerebral artery: Before exercise, RI was in the
Abnormal umbilical, uterine and fetal aorta normal range in all cases. A significant reduction in
Doppler results were those >2 SD above the mean for the RI was determined shortly after the exertion phase
gestational age of our local reference ranges 34. Fetal (p<0.01). Twenty minutes after exertion, the results
brain sparing was supposed when the RI was <2 SD were almost the same as the baseline records.
below the mean of our local reference ranges for the Uterine artery: The observed RI was within the normal
middle cerebral artery.34 range before and after exertion.
784 Textbook of Perinatal Medicine

Table 55.1: Changes of RI during exercise in AGA pregnancies (n = 33)

RI (Mean ± SD)

Before exertion After exertion

(baseline) 1.-6. min 7.-12. min 13.-18. min
Fetal Aorta 0.8 ± 0.21 0.82 ± 0.29 0.81 ± 0.22 0.82 ± 0.26
p value p<0.01 ns p<0.05

Middle cerebral artery 0.82 ± 0.48 0.77 ± 0.32 0.84 ± 0.54 0.83 ± 0.41
p value p<0.01 ns ns

Umbilical artery 0.62 ± 0.12 0.6 ± 0.12 0.62 ± 0.12 0.62 ± 0.1
p value ns ns ns

Uterine artery 0.44 ± 0.15 0.41 ± 0.1 0.44 ± 0.12 0.44 ± 0.1
p value ns ns ns

RI: Resistance index

ns: difference not significant
SD: Standart deviation

FHR: The fetal heart rate remained nearly unchanged The maternal glucose levels decreased by 21%
before and after exertion (Fig. 55.1). In one case fetal (p<0.001) after exercise, while the lactate values
bradycardia (lasting approximately two minutes at increased almost two-fold from 14.6 mg% to
the end of the exertion phase) was observed. This 27.6 mg% (p<0.001).
patient developed preeclampsia in the last two weeks
IUGR pregnancies: The mean performance on the
of pregnancy.
bicycle ergometer was 68 W (± 10 W). Gestational age
Maternal parameters: The maternal blood pressure and at delivery was 37.6 weeks (± 19 days). The mean birth
the maternal heart rate increased during the exertion weight was 2065 g (± 526 g).
phase but returned to the initial values at the end of
Mode of delivery: Five (50%) women delivered vaginal
the test.
spontaneously and 5 (50%) by cesarean section.
Doppler flow results of IUGR pregnancies (n=10)
(Table 55.2)
Umbilical artery: In 3 (30%) fetuses the baseline value
was in the threshold and in another 3 (30%) fetuses it
was pathological. After exercise the RI was in the
threshold range in one (10%) fetus and pathological
in 4 (40%) fetuses.
The RI in the umbilical artery was pathologic in 3
fetuses already before exercise. This had a marked
influence on the mean RI value, because of the very
small sample size. Thus, the calculated mean values
Fig. 55.1: Fetal heart rate during the test period (mean ± SD) of all measurements were in the pathological range
in AGA (squares) and in IUGR (circles) pregnancies from the beginning. After exclusion of these 3 cases,
 Effect of Exercise on Fetoplacental Doppler Flow 785
Table 55.2: Changes of RI during exercise in IUGR pregnancies (n = 10)

RI (Mean ± SD)

Before exertion After exertion

(baseline)

1.-6. min 7.-12. min 13.-18. min

Fetal Aorta 0.85 ± 0.37 0.87 ± 0.42 0.89 ± 0.51 0.89 ± 0.51
p value p<0.05 p<0.05 p<0.05

A. cerebri media 0.8 ± 0.38 0.77 ± 0.29 0.74 ± 0.11 0.76 ± 0.33
p value p<0.05 p<0.05 p<0.05

A. umbilicalis (all) 0.82 ± 0.82 0.83 ± 0.81 0.84 ± 0.72 0.77 ± 0.39
p value ns ns ns

A. umbilicalis (without 0.64 ± 0.11 0.66 ± 0.18 0.64 ± 0.09 0.69 ± 0.17
extremes)
p value ns ns ns

A. uterinae 0.41 ± 0.19 0.52 ± 0.2 0.47 ± 0.12 0.47 ± 0.07

p value ns ns ns

RI: Resistance index

ns: difference not significant
SD: Standart deviation

the RI became normal and no significant changes in and made a “plateau” until 13 to 18 minutes after
the RI of umbilical arteries occurred during the test. exertion. In 6 (60%) fetuses the RI following exertion
was lower than the baseline values.
Fetal aorta: RI before exercise was within the
In growth retarded fetuses, the RI returned to
pathological range in 3 (30%) fetuses and in 2 (20%)
normal levels more slowly than in AGA fetuses. In
fetuses within the threshold range. The RI following
contrast to AGA fetuses, at the end RI in IUGR fetuses
exertion increased significantly (p<0.05).
remained well below the values registered at baseline
Four (40%), 5 (50%) and 6 (60%) fetuses Doppler
(p<0.05).
values were within the pathological range,
respectively for measurements after exertion between Uterine artery: There were no significant changes in
minutes 1-6, minutes 7-12 and minutes 13-18. RI of the uterine vessels during the test.
The mean values of fetal aortic RI values in IUGR FHR: The FHRs before and after exercise remained
fetuses were higher than in AGA fetuses (p<0.05). In unchanged (Fig. 55.1).
contrast to the AGA group, in the IUGR group all RI
Maternal parameters: Maternal blood pressure and
values after exercise were within the threshold or the
heart rate increased during exercise but regained
pathologic range and did not return to normal values
normal values rapidly after exercise. The maternal
after exercise.
glucose levels decreased about 24% (p<0.001), while
Middle cerebral artery: The RI revealed a stepwise the lactate concentrations doubled from 11.6 mg% to
reduction until 7 to 12 minutes after exertion (p<0.05) 24.2 mg% (p<0.001).
786 Textbook of Perinatal Medicine

Discussion maternal exercise. After exclusion of those cases, RI

values in the umbilical artery were in the
This study reports Doppler flow measurements of the
physiological range during the test in AGA and IUGR
placental vascular bed, the fetal aorta, umbilical artery
fetuses. These findings are in good accordance to
together with the fetal cerebral arteries in the human
results reported in the literature.30,36-41 Furthermore,
AGA and IUGR fetus after physical exercise of the
fetal heart rate remained unchanged after maternal
mother.
exercise in AGA and IUGR fetuses. This is partly in
There is conflicting data regarding the question of
accordance with previous studies.30,42-47 Differences
uteroplacental supply during and after physical
in study protocols might account for these differences.
exercise of the mother in uneventful pregnancies and
The presented results support evidence of fetal
pregnancies at risk. The main hypothesis for guiding
cerebral vasodilatation leading to redistribution of
this study was that maternal exercise has both acute
fetal blood volume to the cerebrum as a physiologic
and chronic effects on placental bed blood flow.
answer after moderate maternal exercise during the
During the exercise maternal blood flow is diverted
third trimester of pregnancy. In IUGR fetuses, cerebral
away from the viscera to the exercising muscle and
vasodilatation (brain sparing phenomenon) lasted
skin (fetoplacental blood steal-effect). The magnitude
longer than in AGA fetuses and did not return to
of the reduction in flow is directly proportional to
initial levels during the test period, pointing towards
exercise intensity and the muscle mass used (which
an altered fetal oxygenation under these
varies with the type of exercise), and with common
circumstances. Furthermore, our results suggest that
types of exercise performed at usual exercise
maternal exercise does not significantly alter uterine
intensities, the reduction usually exceeds 50%. This
and umbilical perfusion in AGA and IUGR
exercise-induced decrease in visceral flow persists
pregnancies suggesting absence of change in the
throughout pregnancy.35
uterine vascular bed resistance.
The present Doppler flow results of the fetal aorta
and fetal middle cerebral arteries in normal
OTHER STUDIES CONCERNED WITH
pregnancies showed significant differences before and
DOPPLER SONOGRAPHY DURING EXERCISE
after exertion. The RI in the aorta increased following
IN PREGNANT WOMEN
exertion and remained higher for a considerable time
(approx. 20 minutes), although the findings did not In 1956 Morris et al48 already studied changes in
become pathological. In IUGR fetuses the increase of uterine circulation following physical exertion by the
the RI in the fetal aorta was more important with mothers. The authors found a statistically significant
resistance indices being in the pathological range lengthening of the uterine clearance half-time of NaCl
during the time period of the test. and hence a reduction in circulation during exertion.48
The RI in the cerebral artery reduced significantly At rest, by contrast, the clearance half-time was
following exercise and returned very quickly shorter and uterine circulation improved. The main
approximately to its initial value in AGA fetuses. In critic point to the results of this study was that during
IUGR cases reduction of the RI could be observed examination procedure the patient rested in supine
until the end of the test without return to pre-test position, thus inducing possible vena cava occlusion
values, thus indicating an initially decreased fetal syndrome.
cerebral circulation in IUGR cases after maternal Several investigators reported of unchanged
exercise. RI of the placental vascular bed and the uteroplacental blood flow and umbilical perfusion
umbilical arteries remained unchanged throughout after bicycle stress test in the third trimester.30,49-52
the test period. In three cases of IUGR we found Morrow et al. found higher resistance indices in the
elevated RI values in the umbilical artery prior to uterine arteries and elevated fetal heart rates after
 Effect of Exercise on Fetoplacental Doppler Flow 787
exercise of the mother in the third trimester. The RI lower birth weights are noted among offspring of
in the umbilical artery however, was unaltered. 53 women who exercise during pregnancy, these birth
Erkkola et al demonstrated in a series of weights are still within normal ranges. Currently
uncomplicated pregnancies an increase in RI of the there are no data to confirm that exercise during
uterine arteries and the maternal blood pressure after pregnancy has deleterious effects on the fetus.
exercise, whereas no change in the RI occurred in the 2. Maternal exercise does not significantly alter
umbilical artery. Of note, the fetal heart rate increased uterine and umbilical perfusion in AGA and IUGR
significantly after exercise.54 pregnancies suggesting absence of change in the
The predictive value of maternal aerobic exercise uterine vascular bed resistance. However,
for pregnancy-induced hypertension was studied by submaximal maternal exercise was followed by a
Hume et al in a small series.55 Preeclampsia developed fetal cerebral vasodilatation and an increase of
in four patients with RI values being elevated in the resistance in the fetal aorta which was more
umbilical artery after recovery in these four patients. evident in IUGR fetuses. This might be due to a
It was concluded, that aerobic exercise of the mother slight fetal hemoglobin desaturation in those cases.
might be a valuable tool in predicting hypertensive These findings underline the need of close
pregnancy complications.56 On the other hand antenatal surveillance of IUGR fetuses by Doppler
decreased umbilical artery RI values were reported flow measurements in order to detect circulatory
after maternal exercise in the third trimester, thus deterioration in those fetuses and to reduce long-
indicating an improved placental circulation term morbidity. This is an important and relevant
following exercise in healthy women.28 task of modern perinatal medicine.
Hackett et al57 performed a bicycle exercise test in
thirty-four woman in the third trimester. Twelve ACKNOWLEDGEMENT
pregnancies were uncomplicated, whereas 22 of the
The authors acknowledge Mr. Aykut BARUT, MD
cases were complicated by small-for-gestational-age
(Zonguldak/Turkey), Hakan SADE, MD (Zonguldak/
fetuses or maternal hypertension. Increase in
Turkey), and Mehmet Vural, MD (Zonguldak/Turkey)
pulsatility indices was more prominent in
for their technical and editorial assistance in the
complicated pregnancies than in uncomplicated
preparation of this manuscript.
gestations, thus indicating an important reduction of
uteroplacental blood flow by maternal exercise in
complicated pregnancies.58 In a more recent study a REFERENCES
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7. Ezmerli NM. Exercise in pregnancy. Prim.Care Update response to graded maternal aerobic exercise and
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11. Curet LB, Orr JA, Rankin HG, Ungerer T. Effect of waveform changes in fetal, uteroplacental and large
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28. 26. Moore DH, Jarrett JC, Bendick PJ. Exercise-induced
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healthy low-risk pregnant working women. Obstet 1988;5:94-97.
Gynecol 2002;99:466-72. 27. Steegers EA, Buunk G, Binkhorst RA, Jongsma HW, Wijn
13. ACOG Committee opinion. Number 267, January 2002: PF, Hein PR. The influence of maternal exercise on the
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15. Pijpers L, Wladimiroff JW, McGhie J. Effect of short-term
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dynamics. Br J Obstet Gynaecol 1984;91:1081-86.
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16. Revelli A, Durando A, Massobrio M. Exercise in
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pregnancy: a review of maternal and fetal effects. Obstet
Doppler ultrasound studies before and following short-
Gynecol Survey 1992;47:355-63.
term maternal stress in late pregnancy. Z Geburtshilfe
17. Manders MA, Sonder GJ, Mulder EJ, Visser GH. The
Perinatol 1988;192:173-77.
effects of maternal exercise on fetal heart rate and
31. Hackett GA, Cohen-Overbeek T, Campbell S. The effect
movement patterns. Early Hum Dev 1997;48:237-47.
18. Bonnin P, Bazzi-Grossin C, Ciraru-Vigneron N, Bailliart of exercise on uteroplacental Doppler waveforms in
O, Kedra AW, Savin E et al. Evidence of fetal cerebral normal and complicated pregnancies. Obstet Gynecol
vasodilatation induced by submaximal maternal 1992;79:919-23.
dynamic exercise in human pregnancy. J Perinat Med 32. Ertan AK, Schanz S, Tanriverdi HA, Meyberg R, Schmidt
1997;25:63-70. W. Doppler examinations of fetal and uteroplacental
19. Veille JC. Maternal and fetal cardiovascular response to blood flow in AGA and IUGR fetuses before and after
exercise during pregnancy. Semin Perinatol 1996;20:250- maternal physical exercise with the bicycle ergometer. J
62. Perinat Med 2004;32:260-65.
20. Erkkola RU, Pirhonen JP, Kivijarvi AK. Flow velocity 33. Schmidt W, Hendrik H, Gauwerky J, Junkermann H,
waveforms in uterine and umbilical arteries during Leucht W, Kubli F. Diagnosis of intrauterine growth
submaximal bicycle exercise in normal pregnancy. Obstet retardation by intensive ultrasound biometry. Geburtsh
Gynecol 1992;79:611-15. Frauenheilk 1987;42:543-48.
21. Ruissen C, Jager W, von Drongelen M, Hoogland H. The 34. Ertan A, Hendrik H, Tanriverdi H, Bechtold M, Schmidt
influence of maternal exercise on the pulsatility index of W. Fetomaternal Doppler sonography nomograms.
the umbilical artery blood velocity waveform. Eur J Perinatoloji 2001;9:174-80.
Obstet Gynecol Reprod Biol 1990;37:1-6. 35. Clapp J. The effects of maternal exercise on fetal
22. Hume RF, Jr., Bowie JD, McCoy C, Magarelli PC, Gall oxygenation and feto-placental growth. Eur J Obstet
M, Hertzberg BS et al. Fetal umbilical artery Doppler Gynecol Reprod Biol 2003;110:80-85.
 Effect of Exercise on Fetoplacental Doppler Flow 789
36. Erkkola RU, Pirhonen JP, Kivijarvi AK. Flow velocity 48. Morris N, Osborn S, Wright H, Hart A. Effective uterine
waveforms in uterine and umbilical arteries during blood flow during exercise in normal and preeclpamtic
submaximal bicycle exercise in normal pregnancy. Obstet pregnancies. Lancet 1956;361:481-83.
Gynecol 1992;79:611-15. 49. Veille JC. Maternal and fetal cardiovascular response to
37. Ruissen C, Jager W, von Drongelen M, Hoogland H. The exercise during pregnancy. Semin.Perinatol. 1996;20:250-
influence of maternal exercise on the pulsatility index of 62.
the umbilical artery blood velocity waveform. Eur J 50. Ruissen C, Jager W, von Drongelen M, Hoogland H. The
Obstet Gynecol Reprod Biol 1990;37:1-6. influence of maternal exercise on the pulsatility index of
38. Veille JC, Bacevice AE, Wilson B, Janos J, Hellerstein HK. the umbilical artery blood velocity waveform. Eur J
Umbilical artery waveform during bicycle exercise in Obstet Gynecol Reprod Biol 1990;37:1-6.
normal pregnancy. Obstet Gynecol 1989;73:957-60. 51. Moore DH, Jarrett JC, Bendick PJ. Exercise-induced
39. Morrow RJ, Ritchie JW, Bull SB. Fetal and maternal changes in uterine artery blood flow, as measured by
hemodynamic responses to exercise in pregnancy Doppler ultrasound, in pregnant subjects. Am J Perinatol
assessed by Doppler ultrasonography. Am J Obstet 1988;5:94-97.
Gynecol 1989;160:138-40. 52. Steegers EA, Buunk G, Binkhorst RA, Jongsma HW, Wijn
40. Moore DH, Jarrett JC, Bendick PJ. Exercise-induced PF, Hein PR. The influence of maternal exercise on the
changes in uterine artery blood flow, as measured by uteroplacental vascular bed resistance and the fetal heart
Doppler ultrasound, in pregnant subjects. Am J Perinatol rate during normal pregnancy. Eur J Obstet Gynecol
1988;5:94-97. Reprod Biol 1988;27:21-26.
41. Steegers EA, Buunk G, Binkhorst RA, Jongsma HW, Wijn 53. Morrow RJ, Ritchie JW, Bull SB. Fetal and maternal
PF, Hein PR. The influence of maternal exercise on the hemodynamic responses to exercise in pregnancy
uteroplacental vascular bed resistance and the fetal heart assessed by Doppler ultrasonography. Am J Obstet
rate during normal pregnancy. Eur J Obstet Gynecol Gynecol 1989;160:138-40.
Reprod Biol 1988;27:21-26. 54. Erkkola RU, Pirhonen JP, Kivijarvi AK. Flow velocity
42. Erkkola RU, Pirhonen JP, Kivijarvi AK. Flow velocity waveforms in uterine and umbilical arteries during
waveforms in uterine and umbilical arteries during submaximal bicycle exercise in normal pregnancy. Obstet
submaximal bicycle exercise in normal pregnancy. Obstet Gynecol 1992;79:611-15.
Gynecol 1992;79:611-15. 55. Hume RF, Jr, Bowie JD, McCoy C, Magarelli PC, Gall M,
43. Ruissen C, Jager W, von Drongelen M, Hoogland H. The Hertzberg BS et al. Fetal umbilical artery Doppler
influence of maternal exercise on the pulsatility index of response to graded maternal aerobic exercise and
the umbilical artery blood velocity waveform. Eur J subsequent maternal mean arterial blood pressure:
Obstet Gynecol Reprod Biol 1990;37:1-6. predictive value for pregnancy-induced hypertension.
44. Veille JC, Bacevice AE, Wilson B, Janos J, Hellerstein HK. Am J Obstet Gynecol 1990;163:826-29.
Umbilical artery waveform during bicycle exercise in 56. Hume RF, Jr., Bowie JD, McCoy C, Magarelli PC, Gall
normal pregnancy. Obstet.Gynecol. 1989;73:957-60. M, Hertzberg BS et al. Fetal umbilical artery Doppler
45. Morrow RJ, Ritchie JW, Bull SB. Fetal and maternal response to graded maternal aerobic exercise and
hemodynamic responses to exercise in pregnancy subsequent maternal mean arterial blood pressure:
assessed by Doppler ultrasonography. Am J Obstet predictive value for pregnancy-induced hypertension.
Gynecol 1989;160:138-40. Am J Obstet Gynecol 1990;163:826-29.
46. Moore DH, Jarrett JC, Bendick PJ. Exercise-induced 57. Hackett GA, Cohen-Overbeek T, Campbell S. The effect
changes in uterine artery blood flow, as measured by of exercise on uteroplacental Doppler waveforms in
Doppler ultrasound, in pregnant subjects. Am J Perinatol normal and complicated pregnancies. Obstet Gynecol
1988;5:94-97. 1992;79:919-23.
47. Steegers EA, Buunk G, Binkhorst RA, Jongsma HW, Wijn 58. Hackett GA, Cohen-Overbeek T, Campbell S. The effect
PF, Hein PR. The influence of maternal exercise on the of exercise on uteroplacental Doppler waveforms in
uteroplacental vascular bed resistance and the fetal heart normal and complicated pregnancies. Obstet Gynecol
rate during normal pregnancy. Eur J Obstet Gynecol 1992;79:919-23.
Reprod Biol 1988;27:21-26.
790 Textbook of Perinatal Medicine

APPENDIX • Persistent second- or third-trimester bleeding

• Placenta previa after 26 weeks of gestation
Guidelines for Exercise During Pregnancy
• Premature labor during the current pregnancy
The American College of Obstetricians and Gynecologists • Ruptured membranes
(ACOG) has published a set of guidelines for exercise during • Preeclampsia/pregnancy-induced hypertension
pregnancy and the postpartum period. The most recent ACOG
guidelines are listed in Table 55.3. These recommendations are Relative Contraindications to Aerobic Exercise During
made for women who do not have any additional risk factors Pregnancy
for adverse maternal or perinatal outcome.13
• Severe anemia
Contraindications to Exercise • Unevaluated maternal cardiac arrhythmia
• Chronic bronchitis
According to ACOG13 conditions that should be considered • Poorly controlled type 1 diabetes
contraindications to exercise during pregnancy include the • Extreme morbid obesity
following: • Extreme underweight (BMI <12)
• History of extremely sedentary lifestyle
Absolute Contraindications to Aerobic Exercise During • Intrauterine growth restriction in current pregnancy
Pregnancy • Poorly controlled hypertension
• Hemodynamically significant heart disease • Orthopedic limitations
• Restrictive lung disease • Poorly controlled seizure disorder
• Incompetent cervix/cerclage • Poorly controlled hyperthyroidism
• Multiple gestation at risk for premature labor • Heavy smoker

Table 55.3: American college of obstetricians and Warning Signs to Terminate Exercise While Pregnant
gynecologists’ guidelines for exercise during • Vaginal bleeding
pregnancy and postpartum • Dyspnea prior to exertion
• Dizziness
1. Regular exercise (at least three times per week) is • Headache
preferable to intermittent activity.
• Chest pain
2. Avoid exercise in the supine position after the first • Muscle weakness
trimester. This position is associated with decreased • Calf pain or swelling (need to rule out thrombophlebitis)
cardiac output in most pregnant women, causing a • Preterm labor
decreased distribution of blood to splanchnic beds • Decreased fetal movement
including the uterus. • Amniotic fluid leakage
3. Pregnant women should stop exercising when fatigued
and not exercise to exhaustion. Conclusions and Recommendations of ACOG for Exercise
4. Non–weight-bearing exercises such as cycling or During Pregnancy13
swimming will minimize the risk of injury and facilitate
• Recreational and competitive athletes with uncomplicated
the continuation of exercise during pregnancy.
pregnancies can remain active during pregnancy and
5. Adequate diet should be ensured. should modify their usual exercise routines as medically
6. Avoid types of exercise in which loss of balance could indicated. The information on strenuous exercise is scarce;
be detrimental to maternal or fetal well-being, especially however, women who engage in such activities require
in the third trimester. Further, any type of exercise close medical supervision.
involving the potential for even mild abdominal trauma • Previously inactive women and those with medical or
should be avoided. obstetric complications should be evaluated before
7. Adequate hydration, appropriate clothing, and optimal recommendations for physical activity during pregnancy
environmental surroundings during exercise should be are made. Exercise during pregnancy may provide
ensured. additional health benefits to women with gestational
8. The physiologic and morphologic changes of pregnancy diabetes.
persist 4–6 weeks postpartum. Thus, prepregnancy • A physically active woman with a history of or risk for
exercise routines should be resumed gradually based on preterm labor or fetal growth restriction should be advised
a woman’s to reduce her activity in the second and third trimesters.
 56
Doppler Velocimetry in Intrauterine
Growth Restriction

Mandruzzato GP, Meir YJ, Maso GP

INTRODUCTION that intrauterine growth restriction can be responsible

also of diseases occurring in adult life.
Intrauterine growth restriction (IUGR) according to
Chronic fetal hypoxaemia induces changes in
the current definition is that of a fetus that fails to
many fetal vital functions (haemodynamics, heart
reach his potential growth. The term IUGR should be
activity, fetal movements and behaviour, amniotic
only used in regard to the fetus, while SGA (small for
fluid turnover) and one of the first to be observable
gestational age) should be used only in regard to the
is blood flow redistribution. As Doppler technology
newborn.1 This distinction must be kept in mind very
enables us to study in a non invasive way these
clearly. It is true that perinatal mortality and
changes it has become a fundamental tool for
morbidity are significantly increased in cases
assessing the fetal oxygenation and the fetal response
presenting a birthweight inferior to the 10th percentile to hypoxaemia becoming a useful guide in clinical
for gestational age (therefore defined as SGA) and also management of IUGR fetuses.
inferior to the 15th percentile2 but it has been shown
that symptoms of hypoxaemia are observable in cases CHARACTERISTICS OF DOPPLER VELOCITY
presenting a birthweight also superior to the 50th WAVEFORM(DVWF)
percentile, but showing a restriction of growth by The DVWF reflects the velocities of blood during a
ultrasound biometry during fetal life, with the same cardiac cycle. The so called “angle indipendent
frequency as in SGA newborns. 3 IUGR can be parameters” are commonly used for studying the
associated to many conditions (malformations, characteristics of the DVWF. The velocities of the
kariotype aberrations, infections, maternal diseases) systolic phase is compared to that of the diastolyc one
but the most frequent and most dangerous according to different formulas. The most simple is
complications is represented by chronic fetal the S/D ratio obtained by dividing the two. The
hypoxaemia. This is the consequence of obliterative resistance index (RI) is obtained by dividing the
placental vasculopathy that reduces first maternal- systolic velocity for the systolic minus the diastolic.
fetal supply of nutrients and later on of oxygen. This Probably the most comprehensive parameter is the
ominous condition is encountered in about 30% of pulsatility index (PI) because it takes into
IUGR fetuses and is the cause of the poor perinatal consideration not only systolic and diastolic velocities
outcome (intrauterine death or damage, acute but also the mean of the velocities. Anyway the
hypoxaemia in labour, neonatal death and morbidity characteristics of the DVWF and so the different
early and late as well. Moreover it has been postulated parameters are mainly influenced by the diastolic
792 Textbook of Perinatal Medicine

phase therefore reflecting the peripheral resistance fetal hypoxaemia consequence of the placental
downstream the explored segment of the vessels, obliterative vasculopathy. Due to the capacity of
especially in case of investigation performed on Doppler technology it is possible to study
arteries. When the peripheral resistance is markedly the haemodynamic changes occurring in this
increased the forward blood flow can be absent or also condition in umbilical arteries and those occurring in
reverted. These particular patterns of the DVWF are fetal arteries.
called ARED Flow (Absent/Reverse End Diastolic The first step of the fetal adaptation to hypoxaemia
Flow). After the introduction of Color Flow Mapping is represented by blood flow redistribution inducing
(CFM) technique it became possible to identify also vasoconstriction in somatic arteries and
very tiny vessels and vascular structures that can be vasodilatation on the cerebral arteries. This
sampled by Doppler technique. As a consequence it phenomenon is called “brain sparing effect” and is
has been possible to build a map of fetal haemo- finalized to preserve sufficient oxygenation to the
dynamic patterns in normally evolving pregnancies central nervous system. It has been postulated that
and in those affected by hypoxaemia as well. such a “sparing effect” occurs also at the level of
adrenal and coronary arteries. Therefore peripheral
FETAL AND UMBILICAL HAEMODYNAMICS IN resistance is increased in somatic and splancnic
NORMAL PREGNANCIES arteries and reduced in cerebral.
In case of normally evolving pregnancy Doppler When placental obliterative vasculopathy occurs
investigation on somatic and cerebral fetal arteries the peripheral resistance is also increased in umbilical
shows a fairly constant pattern of the DVWF arteries. It has been shown that PI elevation is
indicating an almost stable peripheral resistance or a proportional to the obliteration of the placental
small progressive reduction. When studying with the vascular bed.4
same technology the umbilical arteries a significant From the clinical point of view by using Doppler
progressive reduction of peripheral resistance is investigation it is possible to assess both the cause
observable possibly related to the increasing need of (umbilical arteries) and the effect (fetal arteries) of
nutrients and oxygen for the growing fetus. hypoxaemia.
Object of the studies have been first umbilical
DOPPLER PATTERNS OF IUGR
arteries and fetal thoracic descending aorta. With the
progress of the Ultrasound Imaging technology and Doppler study on umbilical arteries and fetal thoracic
the use of CFM, allowing to identify and sample also descending aorta has been performed in 653 IUGR
tiny vessels, many other arteries like cerebral (internal fetuses. In all the cases gestational age has been
charotid and middle and anterior cerebral), renal, established on the basis of ultrasonic biometry carried
mesenteric, adrenal, splenic, iliac aortic arch and out in early pregnancy (by meauring CRL) and not
coronary have been object of investigation. later than 20 gw (by measuring the biparietal
As a consequence a very comprehensive overview diameter). IUGR has been diagnosed if the fetal
of the fetal physiologic haemodynamics has been biometry (abdominal circumference) showed a
obtained that is a fundamental basis for studying and discrepancy in defect major than 2 weeks from the
understanding the possible changes occurring in expected curve of growth that have been established
pathologic pregnancies. in our institute. Cases presenting fetal abnormalities
(anatomical and/or chromosomal) have been
ARTERIAL DOPPLER CHANGES IN excluded from this study. After IUGR recognition
HYPOXAEMIC IUGR Doppler investigation has been applied at a weekly
As already said the most frequent and severe or minor interval according to the severity of the
complication of IUGR is represented by the chronic growth restriction and of the maternal clinical
 Doppler Velocimetry in Intrauterine Growth Restriction 793
conditions by measuring the PI values. Cases consequence of increased peripheral resistance
presenting PI values superior to the 2nd standard provoked by placental obliterative vasculopathy.
deviation were considered as abnormal. Fetal Practically by studyng haemodynamics on
biometry has been performed weekly if severe umbilical arteries we can assess the cause of chronic
restriction was observed and/or abnormal PI were fetal hypoxaemia while studying fetal vessels we can
present, and at 14 day interval in cases presenting assess the phenomenon of fetal adaptation to the
normal Doppler values. Computer assisted reduced oxygen supply.
cardiotochography (CTG) according to the Oxford As already said it has been shown that PI values
System 8002 has been performed for monitoring fetal are proportional to the obliteration of the placental
conditions. vascular bed but evidence has also been given that
The IUGR cases have been divided in 4 groups DVWF becomes altered only when at least 60% of the
according to the characteristics of Doppler patterns. placental vascular bed is obliterated5 and oxygen
In the 1st group 71 cases presenting absent or reverse supply to the fetus strongly reduced. As a
diastolic flow (ARED) have been included (10.8%). consequence the specificity of PI on UA is much
In the 2nd group are collected the cases (n. 64, 9.8%) higher than that observable on FA.
presenting abnormal PI ( over the 2nd SD) in both Therefore, according to the Doppler patterns, the
vascular district. In the 3rd group are the cases (n. 85, first group (ARED) represents a condition of
13%) presenting abnormal PI only in aorta while still restriction of oxygen supply to the fetus inducing a
depicting normal values in umbilical arteries. The severe hypoxaemia. Unfavourable perinatal
fourth group is represented by cases showing normal outcome(death or handicaps in survivors) has been
PI values in both aorta and umbilical arteries (n. 433, observed only in this group. The second and third
66.3%). groups represent a condition of reduced oxygen
The prevalence of fetal distress (FD) has been supply and fetal adaptation and possible FD. The
calculated for each group. FD has been diagnosed on fourth group represents IUGR fetuses not affected by
the basis of short term variation (ST) below 3 ms in chronic hypoxaemia.
pregnancy and on the presence of late decelerations The clinical consequences can be indicated as
or bradicardia and/or fetal acidemia on FBS during follows:
labor requiring cesarean delivery. Overall the Group 1 Timing of prompt delivery should be
prevalence of FD was 31% but with a statistically taken into consideration.
significative difference in the 4 groups. Group 2 and 3 Close surveillance and timing of the
FD has been observed in 100% of the cases in the delivery according to fetal
1st group. This prevalence is reduced to 74% in the monitoring. Maternal corticosteroids
2nd group and even more, 33% , in the 3rd. In the 4th administration if gestational age is
group this figure is 12%. . lower than 34 weeks. Vaginal
Sensitivity and specificity of Doppler for delivery after spontaneous onset of
predicting FD has been calculated separately for FA labor is possible in about 50% of the
and UA. The sensitivity is 62.69 for FA and 35.18 for cases .
UA. Group 4 Clinical and instrumental control at
The specificity is 81.56 for FA and 96.71 for UA. weekly or 14 days interval.In the
The reason for that difference depends on the majority of the cases vaginal
pathophisiological background of haemodynamics delivery after spontaneous onset of
changes of the two vascular districts. Fetal vessels, labor occurs.
like aorta, changes represent the adaptation to A particular attention should be deserved to IUGR
hypoxaemia while umbilical arteries changes are the cases when ARED flow are observed. This
794 Textbook of Perinatal Medicine

haemodynamic condition is encountered in about 10 of the fetal adaptation if CFH is present. Fetal thoracic
of IUGR fetuses and is usually associated with a low descending aorta is easy to be identified and sampled
gestational age, as a mean 30 weeks. by using pulsed Doppler.
As the outcome is largely different in case of End According to the patterns of the DVWF and PI
Diastolic Flow Absent (EDFA) as compared to Reverse values it is possible to distinguish the IUGR fetuses
Flow (RF), being better in the first condition, the affected by CFH from those that are not. As a
characteristics of the management should be different. consequence the characteristics of the control can be
In fact it has been shown that perinatal mortality and differiantiated.
handicaps rates are significantly higher in case of RF. 6 Moreover, if CFH is present, it is possible to
monitor its evolution obtaining information of clinical
CONCLUSION practical validity in order to optimise the
IUGR can be associated with many fetal adverse management and the timing of the delivery if
conditions (malformations, chromosomal aberrations, necessary.
infections) but the most important cause of both
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easily observable by using Doppler technology by
4. Giles W Trudinger B. Baird P Fetal umbilical artery flow
analysing the characteristics of the DVWF. velocity waveforms and placental resistance:
As CFH occurs in about 30% of IUGR, therefore pathological correlation. Br J Obstet Gynaecol 1985;92:31.
requiring close control and possibily active manage- 5. Trudinger B Cook CM Doppler umbilical and uterine
ment, the crucial point, after IUGR recognition, is flow waveforms in severe pregnancy hypertension. Br J
Obstet Gynaecol 1990;97:142.
represented by identification or exclusion of CFH. By 6. Mandruzzato GP Bogatti P Fisher-Tamaro L. Gigli C. The
studying DVWF on umbilical and fetal arteries it clinical signoficance of absent or riverse end diastolic
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from mother to the fetus and to monitor the aspects Obstet Gynaecol 1991;1:192.
 57
Doppler Evaluation of
Fetal Venous System

Maso Gianpaolo, Conoscenti Giancarlo, Mandruzzato Giampaolo

INTRODUCTION liver. They merge with the cardinal veins, the third
pair of embryonic veins, which originate from the
Fetal blood flow measurements have become an
body of the embryo and open into the right and left
important tool in the surveillance of high risk
horns of the sinus venosus of the primitive heart.
pregnancies. There is a vast amount of literature on
The fetal liver and its development in the septum
umbilical arteries and fetal arterial system, but fetal
transversus play an important role in modifying the
venous circulation has only recently been evaluated.
primitive vitelline and umbilical veins into their final
The introduction of high-resolution ultrasono-
morphology.
graphy, combined with color-Doppler imaging (CDI),
With the rapid growth of the liver, the umbilical
offered a breakthrough in the study of the fetal venous
veins connect with the liver sinusoids. The
system, considerably enhancing our understanding
asymmetric development of the heart and the rotation
in normal physiologic conditions, as well as in
of the intestinal tract cause the major change in the
abnormal circumstances.
venosus circulation by forming a single venosus blood
This review will focus on the embryologic,
stream from left to right.
anatomic and physiological characteristics of the fetal
In the 6 mm-embryo, the complete right umbilical
venous circulation. The knowledge of the develop-
vein, the cranial part of the left umbilical vein, the
ment and physiology represents the basis to
left vitelline vein and part of the anostomoses
understand the structural anomalies and the
obliterate and a new vessel, the ductus venosus (DV),
haemodynamic changes that occur in the venous
develops. This is a shunt vessel between the left
district in pathological conditions.
umbilical vein and the right hepatocardinal channel,
which will become the upper inferior vena cava (IVC).
EMBRIOLOGY OF THE FETAL VENOUS
At this stage all the placental blood enters the right
SYSTEM
atrium through the left distal umbilical vein (UV), DV
In a 4-week embryo three pairs of veins are found. and proximal right vitelline vein, which by pass the
The vitelline veins run from the yolk sac to the liver sinusoids. The upper two anostomoses of the
sinus venosus via liver sinusoid, and are connected distal vitelline veins fuse to form the portal vein,
to each other via anastomoses around the duodenum. whereas the distal anostomoses form the superior
The umbilical veins transport oxygenated blood mesenteric and splenic veins and the proximal parts
from the chorion to the sinus venosus, by-passing the become the hepatic veins (Fig. 57.1).
796 Textbook of Perinatal Medicine

Fig. 57.2: Embryology of inferior and superior vena cavae

(reprinted with permission from Ultrasound Obstet Gynecol
2000; 15: pp.231-241)

Fig. 57.1: Embryology of umbilical, portal, and hepatic venous taking blood from the liver to the heart (Fig. 57.3).
system (reprinted with permission from Ultrasound Obstet
Gynecol 2000; 15: pp.231-241) The DV shunts oxygenated blood from the umbilical-
portal system directly to the heart.
In the afferent venous system, the UV enters the
Inferior vena cava and superior vena cava (SVC) abdomen within the falciform ligament, ascending
originate from the cardinal veins that are the main steeply towards the liver and runs along its surface
drainage system of the embryo’s body (Fig. 57.2). The in cephalad direction. It then joins a confluence of
anterior and posterior cardinal veins drain the cranial vessels termed the portal sinus. This is a wide L-
and caudal part of the body of the embryo, shaped vessel at the distal part of the UV, connecting
respectively. The left brachiocephalic vein is formed the right and left intrahepatic portal veins. These
during the eighth week from the right anterior and perfuse the right and left hepatic lobes, respectively.
right common cardinal veins, through left to right There are two main left (superior and inferior)
anostomoses, whereas the left anterior cardinal vein intrahepatic portal veins. The right intrahepatic portal
disappears. Azygos and hemyazigos veins originate vein shows a more abundant branching pattern. The
from the upper portion of the division of the vein originating from the confluence of the splenic
supracardinal veins, whereas the caudal part becomes and superior mesenteric veins outside the liver
the caudal part of the IVC.1-4 represents the extrahepatic portal vein.
The DV originates from the portal sinus as the
ANATOMY OF THE FETAL VENOUS SYSTEM
latter turned at an almost right angle into the right
Two venous systems can be identified within the fetal lobe of the liver. The diameter of the DV is
liver: an afferent system, or umbilical-portal system, approximately one-third that of the UV. This is a
taking blood from the placenta and gut to the liver, branchless, hourglass-shaped vessel ascending in the
and an efferent system, given by the hepatic veins, direction of the diaphragm, which joins distally with
 Doppler Evaluation of Fetal Venous System 797
The efferent system is represented by a number of
vessels arising from the right and left hepatic lobes
(right, middle and left hepatic veins), which drains
into the subdiaphragmatic vestibulum. The hepatic
veins, DV and IVC open into the subdiaphragmatic
vestibulum, an inverted funnel shaped, vascular space
just below the diaphragm, ending into the right
atrium.3-5

PHYSIOLOGY OF THE FETAL VENOUS SYSTEM

The anatomical relationship in the hepatic afferent
venous system supports the well established concept
that oxygenated blood flow from the placenta is
distributed through the UV to the portal sinus, which
supplies the left and right intrahepatic portal veins
and the DV. Deoxygenated blood from the
Fig. 57.3: Representation of fetal umbilical and hepatic venous extrahepatic portal veins is diverted almost
system. The arrows indicate the direction of flow. The colors exclusively to the right hepatic lobe. The alignment
show the degree of oxygenation (red=high, purple=medium, of UV and DV, although not in anatomical continuity
blu=low). FO, foramen ovale; RA, right atrium; DV, ductus
for the interposed portal sinus, favours the
venous; UV, umbilical vein; HV, hepatic veins; IVC, inferior vena
cava; PS, portal sinus; LPV, left portal vein; RPV, right portal preferential streaming of oxygenated blood to the DV
vein; EPV, extrahepatic portal vein; GB, gallbladder (reprinted and consequently to the heart (Figs 57.3 and 57.4).
with permission from Ultrasound Obstet Gynecol 2001; 18: Approximately 50% of the UV blood flow enters the
pp.598-604)
DV and accounts for 98% of the blood flow through
the DV. The portal blood is mainly directed to the right
the hepatic left vein and the IVC, just proximal to the lobe of the liver.
entrance into the right atrium (Fig. 57.4). The existence As far as the vessels of the efferent venous system
of a “sphincter” that regulates the blood flow through is concerned, it is possible to observe that the right
the DV to the heart has been postulated, and it has hepatic vein runs parallel to the IVC, while the left
been supposed that the control of this anatomic and middle hepatic veins run parallel to the DV. It
structure is oxygen concentration-dependent. has been postulated that this spatial rearrangement
is the consequence of distribution of more oxygenated
blood flow. The left hepatic lobe, in fact, is primarily
supplied with the blood flow from the UV via the left
portal vein.
UV
HV Moreover it has been shown that there is
streamlining of blood flow within the thoracic IVC:
RA PS blood from DV and left hepatic vein flows in the
DV dorsal and leftward part, whereas blood from the
IVC
SVC right lobe, distal IVC, and right hepatic lobe flows in
the ventral and rightward stream part of IVC. The
Fig. 57.4: Sagittal view of the fetal venous system. RA, right
atrium; DV, ductus venous; UV, umbilical vein; HV, hepatic veins; ventral and rightward stream, together with blood
IVC, inferior vena cava; P, portal system; SVC, superior vena from SVC, is directed to the right atrium and through
cava the tricuspid valve into the right ventricle, ejected into
798 Textbook of Perinatal Medicine

the main pulmonary artery and shunted, via ductus

arteriosus, into the descending aorta. The dorsal and
leftward stream is directed towards the foramen ovale
thereby delivering well-oxygenated blood flow
directly to the left heart and, via ascending aorta, to
the myocardium and the brain.3,6,7

NORMAL DOPPLER FINDINGS

The application of high resolution and color Doppler
ultrasonography has allowed the structural and
functional evaluation of fetal venous system.
At sonography, the UV can be detected in a sagittal
or transverse section of the abdomen. In the transverse
section it curves towards the right side of the upper
Fig. 57.6: Midsagittal view of the fetal upper abdomen. DV and
abdomen (Fig. 57.5). hepatic vein merge into the IVC forming the subdiaphragamatic
The DV can be visualized in its full length in a infundibulum, a funnel shaped, vascular space just below the
midsagittal longitudinal section of the trunk or in an diaphragm, ending into the right atrium
oblique transverse section through the upper
abdomen. Its origin from the UV can be found where
CDI indicates higher velocities compared with the
flow in UV, and sometimes this produces an aliasing
effect. The blood flow velocities accelerate due to the
narrow lumen of the DV, the maximum inner width
of the narrowest portion being 2 mm (Figs 57.6 and
57.7).

Dx

Fig. 57.7: Midsagittal section of the fetal trunk: DV is visualized

in its full length arising from UV. The CDI indicates higher
velocities compared with the flow in the UV: aliasing effect is
present
U
The IVC could be well evaluated either in the
Ant. Post. longitudinal and coronal section; it runs anterior, to
the right of and nearly parallel to the descending aorta
(Fig. 57.8).
The hepatic veins can be visualized either in a
transverse scan section through the upper abdomen
or in a sagittal-coronal section through the hepatic
Sin lobes (Fig. 57.9).
Fig. 57.5: Transverse view of the fetal abdomen. The UV The typical waveform for blood flow in the venous
curves towards the right side vessels, excluding the UV and portal veins, consists
 Doppler Evaluation of Fetal Venous System 799

Fig. 57.8: Coronal plane of the upper abdomen: the IVC runs Fig. 57.9: Coronal section through the right hepatic lobe. The
anterior, to the right of and nearly parallel to the descending right hepatic vein and IVC merge into the subdiaphragmatic
aorta infundibulum

in three phases related to the cardiac cycle (Fig. 57.10). a second forward peak flow. The lowest velocities (a)
The highest pressure gradient between the venous in fetal venous vessels can be observed during the
vessel and the right atrium occurs during ventricular atrial contraction of the late diastole (peak A of the
systole (S), resulting in the fastest blood flow velocities biphasic atrio-ventricular flow waveform).
forward the fetal heart. Early diastole (peak D) with The DV flow pattern is characterized by a triphasic
opening of the atrio-ventricular valves and passive forward flow (Fig. 57.11): it is directed toward the
early filling of the ventricles (peak E of the biphasic heart through the whole cardiac cycle. Even in early
atrio-ventricular flow waveform) is associated with pregnancy, there is no retrograde flow during atrial
contraction.

5 Diastole Late
Early(D) , (Atrial Contraction)
(a)
Systole(S) HV/IVC HV/IVC HV/IVC
=
5
,

=
DV DV DV

AVvalves AVvalves

Fig. 57.10: Doppler waveform patterns in the DV, HV, and IVC, and their relationship with the cardiac cycle (AV, atrioventricular
valves; S, systole; D, early diastole). A physiologic reverse flow is evident in IVC/HV during atrial contraction (a) (with permission
from Hecher K. The fetal venous circulation. In Harrington, K. and Campbell S Eds. A colour atlas of Doppler ultrasonography in
Obstetrics, pp 71-9)
800 Textbook of Perinatal Medicine

to the outlet into IVC. It has been established that the

inlet part of DV should be evaluated for Doppler
waveform analysis.
As for the IVC, large standard deviations for
various Doppler waveform variables and a mixture
of overlapping signals from different bloodstreams
have been shown at the subdiaphragmatic venous
infundibulum. It has been established that the site of
sampling is between the renal vein and DV: this is
the place of the highest reproducibility. 6-9
More than ten different angle- independent indices
of the IVC and DV have been proposed and references
ranges have been built (Fig. 57.14). Pulsatility Index
for Veins and Peak Velocity Index for Vein are now
Fig. 57.11: Triphasic forward Doppler flow waveform in the DV.
commonly used for the highest correlation with
It is directed toward the heart through the whole cardiac cycle. adverse outcome variables, such as fetal acidemia and
A nadir of forward flow is observed during atrial contraction perinatal mortality. 9,10,11 Even if flow volume and
absolute velocity measurements can be evaluated, it
has been demonstrated to have higher inaccuracy and
In the IVC and hepatic veins (Figs 57.12 and 57.13) intra-observer variation compared to qualitative
a physiological reverse flow during atrial contraction ratios. This is mainly due to vulnerable errors of the
is observed. The percentage of reverse flow in IVC evaluation of vessel diameter measurements and
decreases with advancing gestational age. unreliable or high angle of insonation.
As for the site of sampling, this is of main The mean and peak velocities increase significantly
importance in the evaluation of fetal venous system. in venous vessels with advancing gestational age. The
It has been shown that the highest velocities of the highest and lowest velocities are found in the DV and
DV are at the inlet, immediately above the UV, respect right hepatic vein, respectively.

Figs 57.12 and 57.13: Doppler flow waveforms in the HV and IVC:
a physiological slight reversal flow is recorded during atrial contraction (a)
 Doppler Evaluation of Fetal Venous System 801
measurements during fetal breathing movements.
Changes in intrathoracic pressure during breathing
movements have significant effects on Doppler
waveforms. Inward movement of the abdominal wall
during inspiration is accompanied by an increase of
blood flow velocities, whereas a decrease in velocities
is evident during expiration. As the shape of Doppler
waveforms shows changes during the breathing
movements, indices or velocity ratios should be
evaluated during fetal apnea (Figs 57.15 and
57.16).6,7,12
The easiest vessel to investigate is the UV.
Reference ranges for quantitative umbilical vein blood
Fig. 57.14: Angle-independent indices reported in the literature
for the IVC and DV. S, systole; D, diastole; A, atrial contraction;
flow has been also built, according to the formulas:
TVI, time velocity integral; PV, peak velocity; PLI, preload index; UV volume flow (mL/min)=Time Averaged Velocity
PVIV, peak velocity index for vein; PIV, pulsatility index for vein (mm/s) × Cross-sectional vessel area (mm 2); UV
absolute flow (mL/min)= vessel cross sectional area
Conversely, the angle-independent indices decrease (mm 2) × Mean velocity × 60. However,
during gestation and this is consistent with a methodological differences in blood flow study have
reduction in cardiac afterload due to the decrease in limited the quantitative evaluation of the UV in
placental resistance. It may also reflect increased clinical practice. Qualitative analysis of the UV
ventricular compliance. The reduction in cardiac waveform in normal conditions shows a continuous
afterload causes a decrease in end-diastolic forward flow without pulsations after the first
ventricular pressure and therefore an increase in trimester (Fig. 57.17). Mild sinusoidal pulsations
venous blood flow velocity towards the heart during synchronous with the fetal heart rate have been
atrial contraction.10,11 described in some normal fetuses between 34 and 38
As shown for arterial Doppler evaluation, from a weeks and during fetal breathing movements (20%
methodological point of view, it is essential to avoid of the cases in the free-loop portion). These have to

Figs 57.15 and 57.16: Doppler flow waveforms during breathing movements in the DV e IVC
802 Textbook of Perinatal Medicine

The abnormal development of fetal venous vessels

may be related to either of two different pathogenesis:
the primary failure to transform or to form the critical
anastomoses and the secondary occlusion of an
already transformed system.
Four major groups of anomalies can be identified
on the basis of the aetiology (primary or secondary),
the vessel involved, and the embryologic precursor
(Table 57.1):
1. abnormal connection of the cardinal veins;
2. abnormalities of the UV;
3. abnormalities of the vitelline veins;
4. anomalous pulmonary venous connection (not
Fig. 57.17: Qualitative analysis of the UV waveform: a discussed in this chapter).
physiologic continuous forward flow without pulsations is Anomalies of the fetal venous system may be also
observed after the first trimester
classified simply considering either
1. the abnormalities of the caval venous system, or
be distinguished from the pathological pulsations in 2. the anomalies of umbilical, portal and hepatic
cases of severe fetal compromise and non-immune veins
hydrops (Fig. 57.18).6,13,14,15 The abnormal connections of the cardinal veins are part
of the heterotaxy syndromes.
STRUCTURAL ANOMALIES OF THE FETAL An interrupted or absent IVC with azygos vein
VENOUS SYSTEM continuation or the persistence of left SVC are the
A short review of the embryologic landmarks has been
given in order to understand the fetal venous system Table 57.1: Classification of fetal venous system
structural anomalies (section 2 of this chapter). anomalies (reprinted with permission from J Ultrasound
Med 2002; 21:pp.1145-1158)

A. Cardinal Veins
a. Complex malformations, heterotaxic syndrome
b. Isolated malformation

B. Umbilical veins
a. Primary failure to create critical anostomoses
– Complete: abnormal connection of UV (venosus
shunts) into iliac vein, IVC, SVC, and right
atrium
– Partial: Persistent of right umbilical vein (PRUV)
with or without DV
b. Secondary occlusion

C. Vitelline veins
a. Primary failure to create critical anasotomoses
– Complete agenesis of portal system
– Partial agenesis of right or left portal branch
Fig. 57.18: Umbilical vein pulsations with notches synchronous
(portosystemic shunt)
with atrial contractions. Diphasic pulsations due to the increased
central venous pressure and/or opening of the DV may be
D. Anomalous pulmonary venous connection (total or
secondary to congestive hear t failure or imminent fetal
partial)
hypoxaemia/acidaemia
 Doppler Evaluation of Fetal Venous System 803
result of primary failure to create the anastomoses in a prolonged hypoperfusion of the liver that may lead
embryologic period and may be a sign of cardio- to portal hypertension.2,3,4,17,18,19
splenic syndromes. Partial failure to form critical anostomoses in left
The anatomical correlations of aorta to IVC and and right veins is quite common. Persistence of the
the spine, and the venous connections to the atria are right umbilical vein (PRUV) is the most common
very helpful to diagnose left and right atrial anomaly observed. Three types may be identified:
isomerism. In situs solitus the aorta is located to the 1. the intrahepatic form (the UV is connected with
left of the spine, whereas in situs inversus the location the right portal vein instead of the left portal
is reversed. In right isomerism the aorta and IVC are vein);
on the same side of the spine, either right or left. 2. the RUV is connected directly to the iliac vein,
Aplasia of the spleen should be a sign of right IVC or right atrium;
isomerism. In the left isomerism the aorta runs medial 3. both the UVs persist.16,17
to the spine, the IVC is not identified and the azygos The first type is commonly identified as an isolated
finding, and is considered a benign variant, whereas
vein runs dorsal and lateral to the aorta, either on the
the other two are often associated with complex
right or on left side. In this subtype of heterotaxy
structural anomalies, especially cardiac mal-
syndrome, multiple spleens are usually present. A
formations, or signs of congestive heart failure.
situs ambiguus is a common finding in both types of
The pathophysiologic mechanisms of PRUV,
isomerism: the stomach can be in a left, or right, or
primary or secondary, seem to be related to occlusion
medial position. The position of the liver can be
by thromboembolic events arising from the placenta.
variable, as well.2,3,4,6,16,17
Teratogenic agents have been advocated as inducing
Abnormalities of the IVC and SVC are often
primary failure of the critical anastomoses.
associated with major impairments of the heart
The anomalies of the vitelline veins are extremely rare
development, intestinal tract and body symmetry, and only few cases have been reported in prenatal
influencing significantly the prognosis. 2,3,4,6 literature. Primary failure to form the critical
The anomalies of the umbilical veins represent the anastomoses may lead to complete agenesis of the
major and most common group of the fetal venous portal system or to partial agenesis of the right or left
system structural anomalies. portal vein. In the complete form, enterohepatic
Primary failure to form the critical anostomoses circulation is shunted systemically.
results with an aberrant vessel that shunts the blood Partial forms of absence of the portal system might
flow from the placenta to the systemic veins. This represent a more benign form of the vitelline veins
spectrum of anomalies may involve the iliac vein, the abnormalities.2-4
IVC or SVC, or the direct connection with the right
atrium. Agenesis of DV is a common feature of these VENOUS SYSTEM DOPPLER AND FETAL
groups of anomalies. Two forms may be identified. DISEASES
The first one is represented by the direct Umbilical vein pulsations with moderate to severe
connection of the UV with the systemic venous notches synchronous with atrial contraction have been
circulation, by passing the liver. This is often described as an ominous sign. They are associated
associated with Noonan Syndrome, pleural effusion, with various fetal pathological conditions such as,
and hydrops. non-immune hydrops (NIH), fetal arrhythmia, fetal
The second form includes cases in which the UV congestive heart failure, placental anomalies, fetal
is adequately connected with the portal vein, but fails growth restriction (FGR), absent/reverse end diastolic
to establish a communication with the persistent flow (ARED) in umbilical artery (UA) and abnormal
proximal part of the right vitelline vein. The result is fetal heart rate patterns.
804 Textbook of Perinatal Medicine

Different pathophysiological mechanisms may lead expected during the heart cycle. In cases of premature
to UV pulsations. Single pulsation, caused by changes beats of ventricular origin, the reverse flow is evident
in forward flow from the placenta, might be related at the moment of end diastole, with a typical lag
to ARED flow in UA during diastole or bradicardia, pattern in blood flow velocity after ventricular
umbilical cord occlusion, and true knot on the cord premature beat.6-20
during systole. Diphasic pulsations, due to increased Venous Doppler analysis is also essential to
central venous pressure and/or opening of the DV, manage supraventricular tachycardia. From the
can be secondary to congestive heart failure or observation of venous flow patterns (IVC, DV), it is
imminent fetal hypoxaemia/acidaemia (Fig. 57.18).20 possible to delay antyarrhytmic treatment if the heart
Non immune hydrops fetalis is a severe clinical rate is below 210 beats/min. Above this critical heart
condition of varying etiologies with poor prognosis. rate frequency, an abnormal monophasic forward flow
Differentiating between NIHF caused by congestive is observed in DV and IVC. This pattern is related to
heart failure and other non-cardiac causes is essential direct impediment of diastolic filling causing
to formulate a prognosis. elevation of atrial and venous pressure. Due to the
In presence of NIHF and umbilical pulsations, the presence of a parallel fetal flow circuitry, the increase
right ventricular shortening fraction is significantly of the left atrial pressure leads to right side congestive
decreased, and abnormal venous return to the heart heart failure and ventricular dysfunction.6,21,22
is consistent with decreased cardiac output, leading Fetuses with intra uterine growth restriction (IUGR)
to congestive heart failure and poor fetal outcome.
are usually delivered on the basis of abnormal results
Structural heart diseases involving ventricular
of non stress tests such as fetal heart rate (FHR)
outflow, with or without hydrops, are frequently
monitoring, biophysical profile or the presence of
associated with abnormal venous blood flow. Altered
maternal pathological conditions. Although
pump function with increased workload causes a
introduction of arterial Doppler ultrasound
decrease or even reversal blood flow during atrial
evaluation has resulted in a significant decrease in
contraction. In cases with tricuspid regurgitation,
perinatal mortality and morbidity, the transition
increased reversed phase in IVC is frequently
between adaptation and decompensation due to fetal
associated to fetal hydrops. Increased central venous
hypoxaemia/acidemia is difficult to identify
pressure due to regurgitant flow into the atrium can
accurately.
cause hydrops, which implies poor prognosis.
The decision regarding the optimal time of
The diagnosis of the different types of fetal
arrythmias is possible by simultaneous waveform delivery, to avoid iatrogenic delivery of a mild affected
recordings from abdominal aorta and IVC. High- premature neonate before irreversible asphyxia-
velocity reverse flow due to increased right pressure related damage, is still a dilemma. The arterial
is found either in atrial contraction against a closed multivessel evaluation (umbilical artery, descending
tricuspid valve, or in tricuspid regurgitation. The first aorta, middle cerebral artery) is commonly used in
occurs during premature atrial contraction and with clinical practice to assess fetal well-being in high risk
complete atrioventricular block, the second during pregnancy. However this assessment has a limited
premature ventricular contraction. value in determining the time of delivery. 6,23,24,25,26,27,28
Premature beats of supraventricular or ventricular Although maximal decrease in vascular cerebral
origin can be differentiated depending on the resistance has been found to precede the onset of late
characteristic differences in blood flow velocity decelerations by an average of two weeks, it has been
waveforms of the venous vessels (IVC) during atrial insuitable to monitor IUGR fetuses closely during the
contraction. During premature beats of atrial origin last two weeks preceding the occurrence of acute
an exaggerated reverse flow is recorded earlier than distress or intrauterine death.
 Doppler Evaluation of Fetal Venous System 805
The Doppler study of the fetal venous blood flow biophysical profile, and computerized cardio-
in IVC and DV and other venous vessels (sinus tocography, in the timing of delivery and the
trasversus, right hepatic vein) have raised new physiopathological sequence of the deterioration.
expectations by investigating fetal haemodynamic Besides promising results, it has not been yet assessed
changes more accurately. what is the best method for timing the delivery of
Two mechanisms can be considered for the onset preterm severe IUGR fetuses.30-32
of abnormal venous Doppler waveform: the increase The widely held view that, in any case, venous
of right ventricular afterload, and the myocardial Doppler abnormalities would precede deterioration
failure. As long as the fetus is able to compensate for of biophysical parameters has not been observed.
reduced placental supply by redistribution, Ferrazzi et al30 reported that more than 50% of the
preferential myocardial oxygenation delays the fetuses delivered because of an abnormal FHR pattern
development of right heart failure, despite an did not have venous Doppler abnormalities.
increasing afterload. Progressive changes in fetal Hecher et al31 observed that among fetuses born
venous circulation may indicate failure of the before 32 weeks’ gestation, persistent abnormalities
compensatory mechanism and herald the in FHR tracings preceded the occurrence of an
development of right heart failure due to myocardial abnormal DV pulsatility index in about 53% of the
hypoxaemia.6,9,10 cases, and simultaneous anomalies were detected in
It has been shown that evaluation of Doppler 5% of the cases.
venous waveforms are correlated to computerized Muller et al27 found that absent/reverse flow in
analysis of FHR monitoring: reverse flow in DV is DV in a group of cases with umbilical artery ARED
significantly correlated with values of short term flow was significantly predictive of poor outcome.
variation below 3.5ms, ominous sign of hypoxaemia/ Delivery was indicated by non reassuring status
acidaemia (Fig. 57.19).29,30 defined as either cardiotocographic (CTG)
Recent studies are focusing on the role of fetal pathological pattern or when suspicious FHR traces
venous Doppler evaluation, combined or integrated were associated with absent or reverse in DV flow
with other methods of fetal surveillance, such as during atrial contraction. However it is not indicated
how many cases of normal DV Doppler flow
waveforms were delivered for abnormal CTG pattern.
Baschat et al32 reported that the deterioration of
arterial/venous parameters occurred before an
abnormal biophysical profile within 24 hours in the
majority of the cases.
This data show that haemodynamic changes of
blood flow and decompensation, as detected by an
abnormal FHR trace, biophysical profile or venous
Doppler, are widely variable among fetuses and do
not follow a predictable physiopathological cascade.
It has been postulated that many variables have to be
considered in the clinical practice. It has been shown
that gestational age has a significant impact on the
predictive value of venous Doppler for the timing of
delivery. Moreover, in managing cases of severe
Fig. 57.19: Abnormal DV waveform: reversal flow during atrial
contraction is the consequence of increased end-diastolic preterm IUGR it has to be considered the high risk
pressure for the sequelae of prematurity.33
806 Textbook of Perinatal Medicine

Probably the combination of Doppler evaluation 3. Fasouliotis SJ, Achiron R, et al. The Human fetal venous
system: normal embryologic, anatomic, and physiologic
of the fetal circulation, to assess cardiac function, and
characteristics and developmental abnormalities. J
biophysical parameters/computerized CTG, as Ultrasound Med 2002 21(10):1145-58.
reflection of central nervous system involvement, 4. Achiron R, Hegesh J, M Yagel, et Al. Abnormalities of
should allow more precise information about the the central veims and umbilico-portal system:prenatal
ultrasonographic diagnosis and proposed classification.
pathophysiology and assessment of fetal growth Ultrasound Obstet Gynecol 2000 16:539-48.
restriction. A multicenter randomized clinical trial 5. Mavrides E, Moscoso G, Caravalho JS. et al The anatomy
should be addressed to assess what is the best method of the umbilical, portal and hepatic venous systems in
the human fetus at 14-19 weeks of gestation.
to monitoring and timing the delivery of severe
6. Hecher K, Campbell S. Characteristics of fetal venous
premature growth restricted fetuses, and actually two blood flow under normal and during fetal disease.
on going trials, GRIT (Growth Restriction Intervention Ultrasound Obstet Gynecol 1996 7:68-83.
Trial) and TRUFFLE (Trial of Umbilical and Fetal Flow 7. Moll W. Venous return in the fetal-placental cardio-
vascular system. Eur J Obstet Gynaecol 1999.
in Europe) studies, might clarify this issue. 33,34,35 8. Hecher K, Campbell S, Snijders R et al. Reference ranges
for fetal venous and atrioventricular blood flow
CONCLUSION parameters. Ultrasound Obstet Gynecol 1994 4:381-90.
9. Hecher K, Snijders R, Campbell S et al. Fetal venous,
In recent years, high resolution sonography, combined intracardiac, and arterial blood flow velocities in
with CDI has advanced our ability to investigate the intrauterine growth restriction: relationship with fetal
blood gases. Am J Obstet Gynecol 1995 173:10-5.
fetal venous system. These non invasive techniques
10. Rizzo G, Capponi A, Arduini D et al. The value of fetal
have enhanced our understanding of the fetal venous arterial, cardiac and venous flows in predicting pH and
circulation in physiologic condition and provide us blood gases measured in umbilical blood at cordocentesis
the possibility to evaluate circulatory changes in in growth r etarded fetuses Br J Obstet Gynecol
1995;102(12):963-9.
abnormal circumstances. 11. DeVore GR, Horenstein J. Ductus venosus index: a
From the literature, it can be speculated that fetal method for evaluation of right ventricular preload in the
venous Doppler may be a helpful diagnostic tool and second trimester. Ultrasound Obstet Gynecol 1993;3:338-
may influence the management of fetal diseases such 42
12. Gardiner H, Brodszki J, Marsal K. Ventriculovascular
as cardiovascular pathologies, hydrops and fetal physiology of the growth-restricted fetus. Ultrasound
growth restriction. Obstet Gynecol 2001;18(1):47-53.
As for the latter condition, the longitudinal 13. Ferrazzi E, Rigano S, Bozzo M et al. Umbilical vein blood
flow in growth-restricted fetuses. Ultrasound Obstet
Doppler analysis of fetal arterial and venous districts Gynecol 2000;16(5):432-8.
provides us essential information about the 14. Reed KL, Anderson CF. Changes in umbilical venous
progressive deterioration that occurs in chronic velocities with physiologic perturbation. Am J Obstet
hypoxaemia. Even though abnormal venous Doppler Gynecol 2000;182(4):738-40.
15. Boito S, Struijk PC, Ursen NT et al. Umbilical venous
has a high likelihood of perinatal mortality/ volume flow in the normally developing and growth-
morbidity, further studies are needed to clarify the restricted human fetus. Ultrasound Obstet Gynecol
role of fetal venous Doppler in the timing of delivery. 2002;19(3):229-34.
16. Volpe P, Marasini M, Caruso G et al. Prenatal diagnosis
The understanding of the variables that affect the
of ductus venosus agenesis and its association with
physiopathological changes in severely compromised cytogenetic/congenital anomalies Prenatal Diagn
fetuses should provide us this crucial information. 2002;22(11):995-1000.
17. Jaeggi ET, Fouron JC, Hornberger LK et al. Agenesis of
the ductus venosus that is associated with extrahepatic
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vein drainage: prenatal features and clinical outcome.
1. Hamilton WJ, Mossman HW. Human Embriology, 4th Am J Obstet Gynecol 2002;187(4):1031-7.
edn.Cambridge:Heffer 1972:272-82. 18. Cohen SB, Lipitz S, Mashiach S et al. In utero
2. Hoffstetter C., Plath H., Hansmann M. Prenatal diagnosis ultrasonographic diagnosis of an aberrant umbilical vein
of abnormalities of the fetal venous system Ultrasound associate with hepatic hyperechogenicity. Prenatal Diagn
Obstet Gynecol 2000 15(3):231. 1997 17(10):978-82
 Doppler Evaluation of Fetal Venous System 807
19. Baz E, Zikulnig L, Hackeloer BJ et al. Abnormal ductus short-term perinatal outcome. Acta Obstet Gynecol Scand
venosus blood flow: a clue to umbilical cord 2002;22(9):786-91.
complication. Ultrasound Obstet Gynecol 1999;13(3):204- 28. Baschat AA, Gembruch U, Reiss I et al. Relationship
6. between arterial and venous Doppler and perinatal
20. Gudmunsson S. Importance of venous flow assessment outcome in fetal growth restriction. Ultrasound Obstet
for clinical decision-making. Eur J Obstet Gynecol Gynecol 2000;16(5):407-13.
Reprod Biol 1999;84(2):173-8. 29. Senat MV, Schwarzler P, Alcais A et al. Longitudinal
21. Gembruch U, Krapp M, Germer U et al. Venous Doppler changes in the ductus venosus, cerebral transverse sinus
in the sonographic surveillance of fetuses with and cardiotocogram in fetal growth restriction.
supraventricular tachycardia Eur J Obstet Gynecol Ultrasound Obstet Gynecol 2000 16(1):19-24.
Reprod Biol 1999;84(2):187-92. 30. Ferrazzi E, Bozzo M, Rigano S, Bellotti M, Morabito A,
22. Gembruch U, Krapp M, Baumann P. Changes of venous Pardi G, Battaglia FC, Galan HC. Temporal sequenze of
blood flow velocity waveforms in fetuses with abnormal Doppler changes in the peripheral and central
supreventricular tachycardia. Ultrasound Obstet Gynecol circulatory systems of the severely growth-restricted
1995;5(6):394-9. fetus. Ultrasound Obstet Gynecol 2002;19:140-146.
23. Ozcan T, Sbracia M, d’Ancona RL et al. Arterial and 31. Hecher K., Bilardo CM., Stigler RH et al Monitoring of
venous Doppler velocimetry in the severely growth-
fetuses with intrauterine growth restriction: a
restricted fetus and associations with adverse perinatal
longitudinal study. Ultrasound Obstet Gynecol
outcome. Ultrasound Obstet Gynecol 1998;12(1):39-44.
2001;18(6):564-70.
24. Baschat AA, Gembruch U, Reiss I et al. Demonstration
32. Baschat AA, Gembruch U, Harman CR et al. The
of fetal coronary blood flow by Doppler ultrasound in
sequence of changes in Doppler and biophysical
relation to arterial venous and flow velocity waveforms
parameters as severe growth restriction worsens
and perinatal outcome “the heart sparing effect”
Ultrasound Obstet Gynecol 2001;18(6):598-604.
Ultrasound Obstet Gynecol. 1997;9(3):162-72.
25. Tchirikov M, Rybakowski C, Huneke B et al. Umblical 33. Bilardo CM, Wolf H, Stigter RH, Ville Y, Baez E, Visser
vein blood volume flow rate and umbilical arterial GHA, Hecher K. Relationship between monitoring
pulsatility as “venous-arterial index” in the prediction parameters and perinatal outcome in severe, early
of neonatal compromise. Ultrasound Obstet Gynecol intrauterine growth restriction. Ultrasound Obstet
2002;20(6):580-5. Gynecol 2004;23:119-125.
26. Hofstaetter C, Gudmundsson S , Hansmann M. Venous 34. Romero R., Kalache KD., Kadar N Timing the delivery
Doppler velocimetry in the surveillance of severely of the preterm severely growth-restricted fetus: venous
compromised fetuses. Ultrasound Obstet Gynecol 2002 Doppler, cardiotocography or the biophysical profile?
20(3):233-9. Ultrasound Obstet Gynecol 2002;19(2):118-21.
27. Muller T, Nanan R, Rehen M et al. Arterial and ductus 35. Baschat AA. Integrated fetal testing in growth restriction:
venosus Doppler in fetuses with absent or reverse end- combining multivessel Doppler and biophysical
diastolic flow in the umbilical artery: correlation with parameters. Ultrasound Obstet Gynecol 2003;21:1-8.
 SECTION 7
Basic Science
H Nakano, Y Murata
 MECHANISM OF LABOR

58 Molecular Background
of Parturition:
Lessons from Knockout Models
Tadashi Kimura, Kazuhide Ogita, Tateki Tsutsui,
Koichiro Shimoya, Masayasu Koyama, Yuji Murata

INTRODUCTION critical these functions were for maintenance of

pregnancy, as well as initiation and progress of
Parturition, which is the last step of new life in their
parturition in vivo. The biggest advantage using mice
motherhood, is considered the result of multiple
knockout model is to elucidate the actual function of
biochemical and physiological steps. For example,
these molecules in vivo by disrupting the specific gene
during the first 9 month of human gestation, the
responsible for the phenotype. In some cases, natural
uterus is in a quiescent state, and unresponsive to
human disease caused by the gene deletion/mutation
contractile stimuli (Phase 0). After this prelude to
would also give us a clue for elucidating the function
parturition, the uterus should prepare for labour
of the genes and substrates for parturition. This
(Phase 1). During labour, the uterus contracts to dilate
chapter will focus the reproductive phenotypes of
cervix and to force the fetus through the birth canal
gene-targeted mice or human genetic diseases in
(Phase 2). After final process of labor, the uterus
which genes that were deleted are suspected of
involutes to normal size (Phase 3).1 Beginning of
having functions for reproduction.
parturition can be considered as transition from phase
0 and phase 1, which is undetectable clinically. The
ENDOCRINE SYSTEM
initiation of labour is the transition from phase 1 and
phase 2, which is determined clinically by onset of Drastic change of endocrine milieu occurs during
regular and painful uterine contraction leading to pregnancy. For example, plasma oestrogen concent-
cervical dilatation and descendence of fetal presenting rations at term of pregnancy are over 1.000-fold of
part. those in non-pregnant period. Steroid hormones play
At phase 0 and phase 1, various endocrine and crucial roles for development of reproductive organs.
immunological factors should control uterine function Most of knockout mice models related to steroid-
in order to keep its quiescence and to prepare for genesis showed underdevelopment of sexual organs
labour. At phase 2 and 3, stimulating molecules for and infertility, which were inadequate for analysis of
uterine smooth muscle contraction and molecules parturition. Some of peptide hormones are mainly
related to uterine contractile systems must play secreted from brain, and they modulate functions of
crucial roles (Fig. 58.1). Tons of papers had been peripheral organs. The peptide hormone oxytocin,
appeared which described up- and down-regulations which directly activates uterine contractilities, will be
of these molecules, although few of them told us how discussed later.
812 Textbook of Perinatal Medicine

Beginning of parturition Beginning of labour Delivery

Phase 0 Phase 1 Phase 2 Phase 3

Quiescence Prepare for labour Active labour Involution

Endocrine factors Uterotonic factors Uterotonic factors

Endocrine factors CRH oxytocin
oestrogens relaxin PGs
progestagens E/P ratio Connexins
relaxin Immunological factors Ion cnannels
LH/CGR? cytokines?
NOS COX, PGs and receptors
Connexins
Innate immunity?
TNF α?

Fig. 58.1: Various molecules have been reported to regulate four phases during pregnancy and postpartum. In phase 0, uterine
smooth muscle should keep its quiescence even under severe distention and stretch by the conceptus. Transition of phase 0
to phase 1 is clinically undetectable, albeit this is the true initiation of parturition. Once process of phase 1 start, the fate to
deliver is irreversible. Transition of phase 1 to phase 2 can be recognized as an onset of labour, however the attempt to stop
labour at this point could already be impossible, as shown by a lot of papers described about tocolysis (Modified from Cunningham
et al.1)

Steroid Hormones the mother suffered from progressive virilization

during pregnancy7 and the other case the mother was
Oestrogen and its Receptors administered tocolytic reagent for several weeks.2 In
In the endocrine system, steroid hormones both cases, labour occurred spontaneously in term
(oestrogens, progestagens, glucocorticoids and and the mothers delivered their babies vaginally.
androgens) and their receptors have been considered Maternal oestradiol and oestriol concentrations near
to involve in the regulation of parturition. Near term term were <3% and <1%, respectively. These results
of pregnancy, concentrations of circulating oestrogens from natural “knockout” human model indicated that
are drastically elevated. In humans at near term of extremely high amount of oestrogens during the third
pregnancy, there is more than 100-fold increase of trimester are not necessary for process of human
plasma oestrogen concentrations. High concentrations parturition. Aromatase knockout (ArKO) female mice
of oestrogens are believed to enhance uterine were completely infertile because of hypoplastic
sensitivity and to induce labour stimulating mole- uterus and ovary.8 Adult male and female ArKO mice
cules. As most of the oestrogens are synthesized by had higher concentrations of testosterone and
aromatase (P450arom, cyp19) in the placenta of near androstendione, the precursors for oestrogens.
term in human and higher primates, the antenatal Concentrations of these androgens at fetal and
histories of the aromatase deficient patients are of neonatal period were not evaluated.
great interest. Among 16 cases reported, all appeared The oestrogen effect is mediated by two distinct
to be born at term with labour.2-7 Gestational courses nuclear receptors, namely oestrogen receptor (ER)a
of two cases were precisely described. In one case, and ERb. ERa knockout mice showed hypoplastic
 Molecular Background of Parturition: Lessons from Knockout Models 813
uterus and females were completely infertile. 9 there were no observations of preterm birth or other
Although they were infertile and implantation did not parturition failure in these cases, as well in GR+/- or
occur, decidualization could be induced with GR-/- pregnant females.15 These observations reveal
mechanical stimulation by progesterone dependent that knockout mouse models involving oestrogen,
manner.10 On the other hand, female ERb knockout progestagen and glucocorticoid systems are unsui-
mice possessed hormonally responsive uterus and table for study of parturition. Natural human model
grossly normal ovaries, and they were subfertile in (fetuses suffering from aromatase deficiency) suggests
term of the frequency and size of litters. Their that extremely high concentrations of oestrogens in
parturition was not disturbed. The nature of this the third trimester are not necessary for maintenance
subfertility was caused by ovarian dysfunction.11 ERa of pregnancy and initiation of labour. To elucidate
is necessary for development and function of uterus the function of oestrogens, progesterone and gluco-
and ovary, however ERb appears to play roles that corticoid for parturition using gene targeting mice
are more limiting on ovary. model, development of novel tissue- and phase
specific gene targeting strategy such as Cre-loxP plus
Progesterone and its Receptors tet-off system should be mandatory.
In rodents, progesterone withdrawal is the most
Androgens
important trigger for parturition. As progesterone is
the fundamental precursor of all other steroidgenesis, Androgens may also play important roles in parturi-
it is impossible to down-regulate progesterone tion. Infusion of androstendione into pregnant rhesus
synthesis without disturbing other steroidgenesis by monkeys increased uterine contractility, maternal
specific gene disruption. There are two progesterone plasma oestradiol and oxytocin concentrations, as
receptor isoforms, progesterone receptor (PR)-A and well as an increase of fibronectin in the amniotic fluid,
PR-B. It is hypothesized PR-B acts as competitive and then induced preterm birth.16 In human, there
manner to PR-A function. PR-A knockout (PRAKO) were two reports of mothers of P450 aromatase
female mice revealed extensive abnormalities, deficiency and a mother of congenital adrenal
including anovulation, defective sexual behaviour, hyperplasia patient caused by mutant P450 oxido-
hypertrophic uterus and underdevelopment reductase. In both papers, the mothers suffered from
mammary glands, and these abnormalities leaded to virilisation with hyperandrogenism in their antenatal
infertility.12 PR-B knockout (PRBKO) female mice periods.7,17 However, these mothers did not expe-
were fertile, and sustained normal parturition at rience preterm birth. Therefore, excess of circulating
term.13 androgens, of which levels caused virilisation of adult
women, might have no effect on human parturition.
Glucocorticoid and its Receptor The most potent form of androgens is dehydro-
In sheep, up-regulation of fetal glucocorticoid triggers testosterone, which is converted from testosterone by
their parturition.14 In mice, glucocorticoid receptor steroid 5α-reductases. There are two isoforms of the
(GR) knockout caused severe respiratory failure after enzyme, type 1 and type 2. Steroid 5α-reductase
birth, and more than 80% of GR-/- pups died. type 2 mutation in human and mice causes male
Impaired feedback loop of hypothalamo-pituitary- pseudohermaphroditism, characterized by normal
adrenal axis leaded higher plasma corticosterone internal genitalia but with external genitalia resemb-
concentrations (approximately 2.5-fold) in GR-/- and ling those of female. Steroid 5α-reductase type 1
GR+/- neonates. After mating GR+/- male and GR+/ knockout (5αR1-null) mice showed normal reproduc-
- female, 75% of pups are expected to have higher tive behaviour both in male and female, and female
glucocorticoid concentrations in utero. However, became pregnant normally. However, approximately
814 Textbook of Perinatal Medicine

70% of pregnant 5αR1-null mice failed to undergo indicated that both fetal and maternal hypothalamo-
delivery at term.18 These mutant mice showed normal pituitary-adrenal axis does not play crucial roles in
luteal regression, withdrawal of circulating pro- mouse parturition. However, maternal glucocorticoid
gesterone, and normal uterine contractility to oxytocin administration helps fetal lung maturation similar to
and prostaglandin F 2α. Administration of anti- human’s clinical settings for preterm baby.
progestin RU 486 or ovariectomy recovered parturi-
tion in 5αR1-null mice. Steroid 5α-reductase type 1 Relaxin and its Receptor
localized in the endometrial epithelium and cervical Relaxin is a polypeptide hormone composed of two
epithelium. Progesterone and 20α-hydoxyproges- amino-acid chains as a member of insulin family. The
terone concentration in uterine tissue were higher in effect of relaxin has been believed to promote
5αR1-null mice at term of pregnancy. Cervix of 5αR1- maturation uterine cervix at parturition. Recent meta-
null mice failed to ripe at term and relaxin administ- analysis of recombinant or porcine relaxin administ-
ration prevented their parturition defect by enhancing ration on pregnant women indicated that there was a
cervical ripening.19 These observations suggest that reduction in the risk of the cervix remaining
parturition defect in 5αR1-null mice was caused by unfavourable or unchanged with induction, with
local aberrant progesterone metabolism, rather than relaxin administration. However, cesarean rate was
systemic androgen metabolism. similar. 24 Relaxin-null mutant mice have been
developed, and they were fully fertile. Some of
Peptide Hormones relaxin-null pregnant female revealed protracted
labour, although mean gestational period was similar
Corticotrpin-Releasing Hormone (CRH)
to the wild type. Relaxin-null dams showed exhibited
In primate and human pregnancy, placenta produces normal nursing behaviour, and the pups could not
large amount of CRH. McLean et al.,20 reported that suckle milk from breast because of underdevelop-
CRH may act as a ‘placental clock’, i.e. serum ment of nipples.25 In pregnant relaxin-null mice,
concentration of CRH could predict preterm birth or decrease of collagen content was not observed in
timing of labour in human. CRH was shown to nipples and vagina. Increase of water content in pubic
potentiate both oxytocin and PGF2α induced myo- symphysis was smaller than that observed in wild
metrial activity,21,22 however the actual function of type mice, suggesting the female reproductive tract
CRH in pregnant uterus is still unclear. In rodents, and nipples were harder than the wild type mice.26
placenta does not produce CRH. CRH deficient In relaxin-null mice, myometrial oxytocin receptor
mouse might not be a good model for testing placental and estrogen receptor-a expressions in late pregnancy
CRH function, however still it could help to under- (day 18.5) were attenuated.27 LGR7, which was at first
stand the function of fetal hypothalamo-pituitary- cloned as orphan receptor with structural homology
adrenal axis at parturition, as Liggins suggested.14 to gonadotrophin and thyrotrophin receptors, was
CRH-/- mice born from CRH+/- female mated with proved a receptor for relaxin.28 LGR7 knockout female
CRH+/- male grew normally and were fertile without mice exhibited normal fertility but some of pups
glucocorticoid replacement. CRH-/- female mated (approximately 15%) died at parturition. Protracted
with CRH-/- male delivered their pups between 19- delivery was also observed in LGR7-null mouse.
20 days of gestation, although the authors did not Gestational length was similar to wild type mice.
compare the date with wild type mothers. The CRH- Underdevelopment of nipple was also observed.29
/- pups born from CRH-/- dams died because of Taken together, relaxin plays some role for prepa-
severe lung dysplasia, and maternal glucocorticoid ration for parturition, although it is not a critical factor
substitution rescued the pups.23 These observations for completion of birth.
 Molecular Background of Parturition: Lessons from Knockout Models 815
Growth Hormone Receptor (GH) IMMUNOLOGICAL SYSTEM
Growth hormone/IGF-1 system exerts direct and There is an idea that parturition resembles to
indirect effects on gonadal function and reproductive “rejection of conceptus as a semiallograft” from the
system. However, the phenotypes on parturition for mother. However, if maternal immune recognition is
GH deficient patients are not well documented. In crucial for parturition, neither strained mice or SCID
mice, female reproduction of GH receptor/GH mice could deliver their pups. Classical T-cell-
binding protein deficient (GHR-KO) mice was mediated adapted immunity does not seem to play a
precisely investigated. GHR-KO mice had fewer significant roles in preterm labour and term
numbers of ovulatory follicles and corpola lutea. parturition in human and mice, because gestation
When they become pregnant, GHR-KO mice con- length does not decrease in proportion to number of
ceived fewer pups, and the pups were smaller. On previous deliveries. There are various reports
the other hand, their placentas were larger than wild suggesting the relation between physiological or
type mice. The date of parturition was delayed for 1 pathological parturition and cytokines, chemokines,
day, however the mechanism of this delay was not growth factors and their receptors. We suspect these
characterized.30,31 phenomena reflect that reproductive system may
employ inflammation reaction for maternal adapta-
Gonadotrophin Receptors tion or modulation to maintain pregnancy and/or
parturition.
There are two dominant gonadotrophin receptors,
namely FSH receptor (FSHR) and LH/CG receptor Interleukins
(LH/CGR). FSHR null mice showed infertility due
to hypoestrogenism. FSHR +/- mice revealed age Interleukin (IL)-1 and its Receptor
dependent reproductive deficits and developed IL-1 is one of the central modulator of immune
unilateral uterine masses.32 LH/CGR null female mice reaction/inflammation. Systemic administration of
showed hypoplastic uterus and ovary. Follicular IL-1 can induce preterm birth in mice36 and pretreat-
growth beyond antral stage was arrested. Replace- ment of IL-1 receptor antagonist (IL-1ra) prevents this
ment therapy with oestradiol and progesterone IL-1 induced preterm labour.37 Knockout model mice
rescued hypoplastic uterus completely, although disrupting IL-1 system (IL-1β-null mice; 38 IL-1β
female mice were infertile.33 In human, activation and converting enzyme-null mice;39 IL-1 type 1 receptor-
inactivation mutants of FSHR and LHR were null mice)40 were fully fertile. In IL-1β type 1 receptor-
reported. Similar phenotypes to knockout mice were null mice, litter size was significantly smaller than
reported in both patients having inactivating FSHR wild type mice. 41 Intracervical or intrauterine
and LH/CGR mutations.34 It has been shown that challenge of lipopolysaccharides or heat-killed
LH/CGR expressed in the human uterus. Very Ecshericia coli is considered as a model for intraute-
preliminary experiment suggests that administration rine infection. Preterm delivery could be induced in
of hCG to the patients of preterm labour might both IL-1β-null 42 and IL-1 type 1 receptor null
decrease incidence of birth.35 If the patients with LH/ pregnant mice43 by the intrauterine infection model.
CGR inactivation mutation will be conceived by The challenge to delivery periods were similar to
oocyte donation -IVF-ET program, the clinical course those observed in wild type mice. Up-regulation of
of her pregnancy could reveal the importance of IL-1 induced cytokine/growth factors (IL-6, TNF-α,
uterine LH/CGR functions on maintenance of IFN-γ) and constitutive NF-κB p65 protein expression
pregnancy and parturition. were attenuated in IL-1β-null mice.44 These data
816 Textbook of Perinatal Medicine

suggest that the intrauterine infection-induced parturition was not disturbed. uNK cells are majour
preterm birth in murine model does not require cellular component of decidua, and have been
maternal IL-1 signaling system. considered to play important roles limiting normal
trophoblast invasion, and immunological modulation
IL-6 of feto-maternal interface (for example, reviewed by
IL-6 has numerous biologic activities, including Croy et al.54). The pregnant course, observed in uNK
induction of acute-phase proteins, regulation of cell deficient mice, raised a big question about the
haematopoiesis, and terminal differentiation of B- functional significance of these cells.
cells. Various reports indicated induction of IL-6 in IL-10 inhibits proliferation and cytokine synthesis
chorioamnionitis/intrauterine infection, which cause in type 1 T cells and can induce immunological
preterm labour.45,46 IL-6-null mice were fully fertile nonresponsiveness or anergy, acting preferably for
and no disturbance in parturition.47 Signal transduc- Th1/Th2 balance hypothesis during pregnancy.
tion of IL-6 is mediated by the gp130 protein, a However, IL-10-null mice conceived with larger
subunit signal transducer molecule of the dimeric IL- numbers of implantation sites, heavier pup’s weight
6 receptor, and also a subunit of the receptors for and similar gestation length. There was no tendency
leukaemia inhibitory factor (LIF), oncostatin M, IL- to increase resorption of the fetus during pregnancy
11, ciliary neurotrophic factor (CNTF) and cardio- and preterm birth.55
trophin 1. gp-130-null mice were lethal in utero, due Tumor necrosis factor-alpha (TNF-α) was impli-
to hypoplastic myocardium and impaired haemato- cated in the aetiology of preterm birth. Amniotic fluid
poiesis.48 Administration of exogenous IL-6 to wild levels of TNF-α were elevated in the patients with
type pregnant mice did not lead to preterm birth. preterm labour or intrauterine infection. Recently, a
Intrauterine bacterial inoculation into IL-6 null- relation between polymorphism in the promoter
pregnant mice induced preterm birth, which revealed region of TNF-α gene and preterm rupture of
similar rate to wild type mice.49 These observations membrane 56 or bacterial vaginosis 57 has been
revealed that IL-6 is neither necessary nor sufficient reported. TNF-α-null mice were fully fertile.58 There
for murine intrauterine infection-preterm birth model. are two types of TNF receptors, and TNF receptor
type 1-null mice showed early senescence and poor
Other Interleukins and their Receptors fertility, due to ovarian dysfunction.59 However, these
IL-8 is considered to play important roles on cervical experimental models showed normal parturition
ripening before and during labour in the human process, although the number of pups was apparently
uterus [reviewed in 50]. However, mice lacking IL-8 smaller in TNF receptor type 1-null mice.59
receptor homologue revealed normal phenotype on
Innate Immune System
their reproduction.51 IL-2 receptor g chain is shared
for multiple cytokine receptors for IL-2, IL-4, IL-7, IL- Innate immune system, which recognizes non-specific
9, and IL-15. Mice lacking IL-2 receptor γ chain gene pathogen derived molecules by toll-like receptors,
showed irregular oestrous cycle, however they were causes inflammatory response including various
fertile. Interestingly, IL-2 receptor g chain-null mice cytokines and metalloproteinases production. Unique
lack uterine natural killer cells (uNK cells) on day 13 target molecules for each toll-like receptors (TLR) has
of gestation, however their parturition, litter size and been determined. For example, TLR-2 recognizes di-
body weights of offsprings were similar to the wild and tri-palmitoylated peptides, TLR-3 recognizes
type mice.52 IL-15-null mice, which lack natural killer double strand RNAs, and TLR-4 recognizes the lipid-
differentiation in lymphoid tissue, also had no uterine A component of lipopolysaccharides. Myeloid
natural killer cells. 53 Their pregnant course and differentiation factor 88 (MyD88), the downstream
 Molecular Background of Parturition: Lessons from Knockout Models 817
adapter molecule, plays crucial roles for signal amnesia (less developed social memory) and
transduction from TLRs to inflammation reaction. aggression, 71,72 although their sexual behaviour
These molecules are expressed in placenta,60 and one appeared to be normal.
genetic polymorphism for TLR-4 (Asp 299 Gly) In mice, initiation of labour is primary determined
resulting in decreased receptor function may associate by luteolysis, and corpus luteum expresses oxytocin
with a predisposition to preterm birth in human.61 receptor. Continuous infusion of oxytocin to wild-
Various knockout mice had already established for type or oxytocin null mice revealed that oxytocin can
TLRs and MyD88, all of them were healthy and fertile either delay labour at low doses and initiate preterm
(reviewed in62). Knockout mice of the molecules labour at high doses. Low dose of oxytocin prevented
related to innate immune system might provide luteolysis, and retarded progesterone withdrawal.
useful models with which to analyse susceptibility to The dose required to prevent luteolysis was lower in
preterm birth resulting from infection. oxytocin-null mice than wild type mice, probably due
to up-regulation of the oxytocin receptor in corpus
MOLECULES STIMULATE/MODULATE luteum of oxytocin-null mice.73 In wild-type and
UTERINE CONTRACTILITY oxytocin-null mice, contrary to the up-regulation of
oxytocin receptor in term myometriun, the receptor
Oxytocin and its Receptor in corpus luteum was down-regulated at term of
Oxytocin is one of the most potent uterotonic agents pregnancy, which leaded to luteolysis, and initiation
identified and is widely used in routine clinical of labour. The substances, which compensate
settings for augmentation and induction of labour. contractile activity of oxytocin, should further be
Oxytocin has also been considered essential for milk elucidated.
let-down during lactation. Oxytocin is synthesized not There was a personal communication that the
only in the hypothalamic paraventricular and oxytocin receptor knockout mice were lethal. 74
supraoptic nuclei, but also in the pregnant uterine However, Nishimori’s group successfully developed
endometrium, 63 and fetal membrane. 64 As the oxytocin receptor-null mice, and their phenotype on
oxytocin receptor up-regulation is observed in term parturition appeared to be similar to oxytocin-null
myometrium65 as well as in term decidua,66 oxytocin mice (Takayanagi et al., in preparation). Further
may act by both endocrine and paracrine manner investigations of their phenotype about reproduction,
to promote labour. Oxytocin null mice were parturition and behaviour are on going.
produced67,68 and they were fully fertile, able to
deliver litters at term. Their milk ejection reflex was Prostaglandins (PGs) and their Receptors
severely disturbed, leading to the death of the pups PGs are synthesized from arachidonic acid, which is
by starvation. If the pups were at nurse, they could mainly released from cell membrane phospholipids
survive. It was speculated that endogeneous Arg8- by the activity of cytosolic phosholipase A2. The
vasopressin compensated the oxytocin action, because arachidonic acid is then converted to PGH2, which is
the dissociation constant of Arg8-vasopressin and the precursor for other PGs, prostacyclin (PGI2) and
oxytocin to oxytocin receptor are similar. However, thromboxane A2, via the action of cyclooxygenase
physiological responsiveness of oxytocin receptor to (COX)-1 or –2. Then specific PG isomerases/
Arg8-vasopressin was 1/10~1/100 of the oxytocin synthetases convert PGH2 to the specific forms. PGs
responses,69,70 meaning that pharmacological dose of are widely synthesized and distributed in the body.
vasopressin is required to induce physiological Particularly around parturition, they are synthesized
uterine contraction. Therefore, this hypothesis is and secreted from placenta, fetal membrane and
unlikely. Oxytocin null male mice showed social uterine myometrium. Numerous reports have been
818 Textbook of Perinatal Medicine

indicated an up-regulation of PGE2 and PGF2a (or luteolysis, with smaller amount of PGF2α and without
other PGs) and modulation of their receptors around oxytocin in COX-1/oxytocin-null mice.
parturition (reviewed by Olson et al.74). COX-2-null mice showed severe renal pathology
(dysplasia) and female infertility.78,79 The uterus of
Cytosolic Phospholipase A2-α (cPLA2-α) COX-2-null mice could not decidualize after typical
cPLA2-α preferentially hydrolyses fatty acids and pseudopregnant stimuli, and showed implantation
lysophoshplipids to provide precursors for PGs and failure when wild-type fertilized eggs were trans-
platelet activating factor (PAF). cPLA2-α-null females ferred.80 Pharmacological inhibition of COX-2 by
could not deliver between day 18.5 and day 20.5; selective COX-2 inhibitor (celecoxib) in COX-1-null
instead, they delivered a smaller number of live mice induced complete implantation failure, suggest-
pups at days 21.5-22.5, and the offspring did not ing COX-2 is necessary for preparation of uterine
survive.75,76 Caesarian section at term was able to receptivity.81 Actual function of COX-2 for murine
yield viable neonates. Administration of a pro- parturition can not be analysed by gene targeting
gesterone antagonist RU486 was able to rescue models. Administration of lipopolysaccharides
parturition defect of cPLA2-α-null mice, and restored induced preterm birth in COX-1-null mice, with
pups’ viability. These observations suggest that the induction of COX-2 mRNA and PGF2α in the uterus.
parturition defect of cPLA2-α-null mice was caused Selective COX-2 inhibitor was more potent to inhibit
mainly by the defect of luteal regression, rather than lipopolysaccharide-induced preterm birth than
by the shortage of PGs as uterine stimulating selective COX-1 inhibitor. These pharmacological and
substrates. using COX-1-null mice studies suggested that COX-
2 plays pivotal role when preterm birth was induced
Cyclooxygenases (COX) by infection.82

COX-1 carries out “house keeping” functions such as

Membrane Proetaglandin Receptors
cytoprotection of stomach mucosa, platelet aggre-
gation and regulation of blood flow. COX-1 is After first molecular cloning of the receptor for
expressed in many cell types and in general, it shows thromboxane (TX) A 2, the receptors for prosta-
constitutive activity. COX-1-null female mice showed glandins prostanoids have been cloned by homology
normal fertility, but their parturition was delayed, screening. They are classified as G-protein linked
leading to neonatal death. Bolus administration of rhodopsin receptor family with seven transmembrane
PGF2α at day 19.5 resulted in labour within 24 hours domains (reviewed by Narumiya et al.83). Specific
and restored pups’ viability.77 In wild type mice, they receptors for PGD2, TXA2, PGI2, PGE2, and PGF2α
showed up-regulation of COX-1 and oxytocin have been cloned and referred as DP, TP, IP, EP, and
receptor in the uterus near term of pregnancy, and FP, respectively. There are four subtypes for EP
induction of both molecules was diminished in COX- (EP1~EP4). Several isoforms of EP1, EP3, FP and TP
1-null mice. Double knockout of COX-1 and oxytocin have also been reported. PGF2a action is mediated by
restored their parturition at term.77 This observation FP, which is coupled with G-protein, leading to the
supported the idea that oxytocin acts as a luteo- increase of intracellular calcium [Ca2+]i concentration
supportive factor to corpus luteum in pregnant and stimulate myometrial contraction. PGE2 action
mice. 73 Uterine PGF 2α production at term was is more complex. Activation of EP1, EP3A and EP3D
impaired in both of COX-1-null and COX-1/oxytocin- leads to elevation of [Ca2+]i whereas EP2 and EP4
null mice, and uterine PGF2α concentrations were very activate adenylate cyclase, which leads to myometrial
low in both of mice. It is very interesting what relaxation. In myometrium, it has been reported that
molecule compensates the uterotonic function after up-regulation of EP2 and suppression of FP during
 Molecular Background of Parturition: Lessons from Knockout Models 819
pregnancy [84] and increase of FP, EP3 and prostaglandins compensate the uterine stimulative
suppression of EP285 at the onset of labour. As cyclic activity, although there is no FP in myometrium.
AMP induces uterine muscle relaxation and elevation
of [Ca2+]i activate the uterus, these observations are Nuclear Prostaglandin Receptors
reasonable for maintenance of uterine quiescence and
stimulate the parturition during the course of Recently, existence of specific prostaglandin trans-
pregnancy. porters, which mediate influx of PGs into the cells has
Mice lacking EP1, EP2 and EP3 genes are healthy been demonstrated. Moreover, trafficking of COX-2
and fertile. In EP3-null mice, febrile response induced to nuclear envelope was also determined. These data
by IL-1β was attenuated.86 Most of EP4-null mice died suggests the existence of specific nuclear receptors for
due to a persistent ductus arteriosus. Less than 5% of PGs (reviewed by Helliwell et al.92). Peroxisome
EP4-null mice were survived and they were fertile.87,88 proliferator activated receptors (PPARs) are putative
No authors mentioned precisely the course of targets for the nuclear action of PGs and other
parturition of EP-deficient mice. eicosanoids.
In contrast, mice lacking FP gene were fertile, but It has been shown that PPARγ preferentially binds
female could not deliver pups at term. This prolonged to 15d-PGJ2, the final metabolites of PGD2. As human
pregnancy caused degeneration of placenta, and gestational tissues contain PGD synthases (PGDS) and
intrauterine fetal death. By caesarian section, fetus PGD2 in amniotic fluid,93 the function of PPARg in
could be rescued, however administration of PGF2α the pregnant uterus is of great interesting. PPARγ
or oxytocin at term was not effective to induce labour. is also considered as a target molecule of thiazoli-
Up-regulation of the oxytocin receptor in the uterus dinedione drugs, which are widely used as insulin
at term was abolished. Oophorectomy on day 19 sensitizers. PPARγ-null mice were lethal in utero, due
recovered the parturition process of FP-null mice, and to defects in placental vascularization.94 Using Cre-
they delivered pups normally. Oophorectomy also loxP recombination system, conditional PPARγ
restored the oxytocin receptor up-regulation in the knockout mice were obtained. Female mice, which the
pregnant uterus at term.89 In FP-null nice, induction PPARγ gene was conditionally deleted in epithelial
of COX-2 in the uterus on day 20 was totally cells, T- and B-cells, and ovary cells, showed impaired
abolished. On the other hand, COX-1 in the uterus fertility with smaller litter size. In this mouse strain,
was up-regulated on day 17 and decreased at the time uterine PPARγ was intact and parturition was not
of parturition in wild type mice, however this decline disturbed.95
of COX-1 level was also disturbed in FP-null mice. PPARδ-null mice also showed high (approxi-
Induction of uterine connexin 43 mRNA was mately 90%) embryonic lethality. The connections
abolished in FP-null mice. After oophorectomy on day between placenta and decidua were abnormally loose.
19, COX-2 up-regulation, COX-1 down-regulation The labyrinth was smaller, however the vascular
and connexin 43 up-regulation at the time of structure was fully developed, different from the
spontaneous labour normalized to the wild type level. placentas observed in PPARγ-null mice.96 PGI2 was
Administration of exogenous progesterone after considered as a mediator for embryo implantation,97
oophrectomy in FP-null mice inhibited parturition. and PGI 2 is revealed one of natural ligand for
Treatment with COX-nonselective or COX-2 selective PPARδ.98 In contrast to these observations, surviving
inhibitors to FP-null mice after oophrectomy also PPARδ-null mice were generally healthy and fertile,
prolonged the time from oophrectomy to delivery.90,91 albeit they display more than a 60% reduction in
These findings suggest that the progesterone adipose mass. PPARα-null mice showed normal
withdrawal is the critical factor to determine the onset fertility.99 Taken together, PPARs (especially PPARγ
of mouse parturition, and COX-2-derived and PPARδ) plays important roles during placen-
820 Textbook of Perinatal Medicine

tation. Their function on parturition has not been shows overexpression of SK3 gene and protein
determined from knockout mice models, although (approximately 3-fold). Phenotype after down-
plenty amount of their natural ligands (various regulation by doxycyclin was almost neglectable.
eicosanoids and unsaturated fatty acids) were On the other hand, homozygous female showed
detected in gestational tissues during pregnancy. protracted labour and majority (7/10) of the pups
died during parturition in utero. In adult mice,
Connexins respiratory response during hypoxic attack was
Connexins are the protein subunits of intracellular abnormal; they could not increase respiratory rate and
gap junction channels. In mammals, there are at least occurred apnea. Doxycyclin administration, which
15 connexin family genes. Among them, connexin abolished the SK3 expression, rescued these
(Cx) 43 is up-regulated in pregnant myometrium at phenotypes.102 Overexpression of Ca2+-activated K+
term and this induction is considered to ensure channel most severely affected the uterine contracti-
coordinate contraction of uterine smooth muscle lity at parturition.
during labour to produce expulsive force effectively.
Nitric Oxide Synthases (NOS)
Mice lacking Cx43 died postnatally because of
congenital obstruction of the right ventricular Nitric oxide may play important role for regulation
outflow.100 Another subtype of connexins, Cx32 or Cx of myometrial relaxation and cervical ripening. Three
40 genes were ‘knocked-in’ into the Cx43-null mice majour isoforms of NOS, i.e., neuronal NOS (nNOS),
to elucidate the functional specificity of connexins. endothelial NOS (eNOS), and inducible NOS (iNOS),
Both of Cx43-null heterozygous CX 32 or hetero- are expressed in non-pregnant and pregnant uterus.
zygous Cx40 knock-in mice (-/cx32 or -/cx40) could Knockout mice of these three NOSs were reported to
deliver their pups, suggesting these molecules are be fertile and there were no abnormalities on their
possibly compatible in uterine function at parturition. parturition.103-105 Calcitonin gene-related peptide
Cx43-null heterozygous Cx32 knock-in dams failed (CGRP) inhibits contractile activities of smooth
to nurse their pups, due to impairment of milk muscles. CGRP-induced vascular smooth muscle
ejection. 101 These model mice could not tell the relaxation was mediated by nitric oxide. CGRP also
necessity of gap junction in term myometrium for inhibited KCl-induced contraction in uterine
regulation of uterine contraction. myometrium. However, this inhibition was observed
in all of nNOS-null, eNOS-null, and iNOS-null mice
Ion Channels models equivalently to the wild type mouse.106 These
Ion channels are necessary for proper electrophysio- observations suggest that nitric oxide-NOSs system
logical responses of excitatory organs (nerves, may not be necessary to ensure the myometrial
muscles, etc), however few reports are available about relaxation during pregnancy, although there is a
their gene targeting model and reproduction. possibility that the another type of NOS could
SK channels are potassium-selective, voltage- compensate the function of the targeted NOS.
independent, and activated by increases of [Ca2+]i ,
CONCLUSION
that occurs during an action potential and induce
repolarization of membrane potential. There are three Since our first review about knockout mice model and
subtypes of SK channels. A tetracyclin-based genetic parturition,107 various gene targeting model mice
switch sequence was introduced into the 5’-flanking were produced. Especially after finishing human
of mouse SK3 gene. Administration of doxycyclin to genome project in 2002 and near completion of mouse
the mouse abolished the SK3 gene transcription genome project, knockout mice are ultimate strategy
effectively. On the other hand, homozygous mutant to investigate the genes of unknown functions. All of
 Molecular Background of Parturition: Lessons from Knockout Models 821
observations listed here and another reviews,108,109 who are suffering from genetic disorders, even when
indicate that a few of deficient genes, which are they showed normal sequence.
conventionally considered as a very important factor For the future, unexpected phenotype can be
to regulate parturition, successfully disturbed their obtained from double- or triple gene knockout mice.
parturition. Moreover, in most of the knockout mice Good example was reported by Embree-Ku and
whose parturition were intruded, the process of Boekelheide,110 indicating that absence both of p53
luteolysis rather than the uterotrophic or uterotonic and FasL genes in female mice led to dystocia. Further
action was actually impaired (Fig. 58.2). Gene analysis should be done to determine the unexpected
targeting of endocrine system often resulted in pathway from these apoptosis-related genes to uterine
infertility, because of hypoplastic reproductive contraction at parturition. Using the available
system. Most of gene targeting mice related to resources of knockout model mice, we could further
immune system and the substrates related to uterine analyse the mechanism of parturition with some
contraction could successfully deliver their pups. physiological and/or pharmacological manipulation.
Conventional uterotonic pathway such as oxytocin, We also expect to find novel strategies against
and prostaglandin system could be preserved by preterm birth through these experimental models,
redundant manner except the function of targeted which is still a leading cause of mortality and
molecule concerned with luteolysis. Some interesting morbidity of infant.
knowledge could be obtained from human diseases
from gene mutations, such as fetal aromatase ACKNOWLEDGEMENT
deficiency. We clinicians should observing precisely We thank Ms. Naoko Hagino for excellent secretary
the pregnant and parturition courses of the patients help. This work was supported in part by Grants-in-

Corpus luteum

cPLA2α-null
FP-null
COX-1-null

Myometrium/
Contraction
SK3-overexpression
p53/FasL-null ?

Susceptability to
interauterine infection
Cervix
X: IL-1 null
X: IL-6 null 5α-reductase type 1-null
Relaxin-null ?

Fig. 58.2: Summary of gene targeted mice affected to their phenotype on parturition. Notice that most of target points of knockout
mice were corpus luteum; failure of luteolysis. Relationship between deficiency of immunological system and susceptibility to
infection-induced preterm birth is of great interest, however only negative data are available
822 Textbook of Perinatal Medicine

Aid for Scientific Research (Nos. 14571557, 15390505, 12. Lydon JP, MeMayo FJ, Funk CR, Mani SK, Hughes AR,
Montogomery CA, Shymaia G, Conneely OM, O’Malley
15591746 and 16390476) from the Ministry of
BW. 1995 Mice lacking progesterone receptor exhibit
Education, Science and Culture of Japan (Tokyo, pleiotropic reproductive abnormalities. Genes Dev 9:2266-
Japan). 2278.
13. Mulac-Jericevic B, Lydon JP, DeMayo FJ, Conneely OM.
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PM, Corry SA, Trzaskos JM. 1995 Renal abnormalities and 90. Tsuboi K, Sugimoto Y, Iwane A, Yamamoto K, Yamamoto
an altered inflammatory response in mice lacking S, Ichikawa A. 2000 Uterine expression of prostaglandin
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79. Morham SG, Langenbach R, Loftin CD, Tiano HF, prostaglandin F receptor-deficient mice. Endocrinology
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failures in cyclooxygenase 2-deficient mice. Cell 91:197- 92. Helliwell RJA, Berry EBE, O’Carroll SJ, Mitchell MD. 2004
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81. Reese J, Zhao X, Ma WG, Brown N, Maziasz TJ, Dey SK. parturition? Prostagl Leukotri Ess Fat Acids 70:149-165.
2001 Comparative analysis of pharmacologic and/or 93. Shiki Y, Shimoya K, Tokugawa Y, Kimura T, Koyama M,
genetic disruption of cyclooxygenase-1 and cyclo- Azuma C, Murata Y, Eguchi N, Oda H, Urade Y. 2004
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receptors: structures, properties, and functions. Physiol peroxisome proliferation-activated receptor gamma
Rev 79:1193-1226. (PPARg) does not affect mammary development and
84. Matsumoto T, Sagawa N, Yoshida M, Nori T, Tanaka I, propensity for tumor formation but leads to reduced
Mukoyama M, Kotani M, Nakao K. 1997 The prosta- fertility. J Biol Chem 277:17830-17835.
glandin E2 and F2 alpha receptor genes are expressed in 96. Barak Y, Liao D, He W, Ong ES, Nelson MC, Olefsky JM,
human myometrium and are down-regulated during Boland R, Evans RM. 2002 Effects of peroxisome
pregnancy. Biochem Biophys Res Commun 238:838-841. proliferator-activated receptor d on placentation,
85. Brodt-Eppley J, Myatt L 1998 Changes in expression of adiposity, and colorectal cancer. Proc Natl Acad Sci USA
contractile FP and relaxatory EP2 receptors in pregnant 99:303-308.
rat myometrium during late gestation, at labor, and 97. Lim H, Gupta RA, Ma WG, Paria BC, Moller DE, Morrow
postpartum. Biol Reprod 59:878-883. JD, DuBois RN, Trzaskos JM, Dey SK. 1999 Cyclo-
86. Ushikubi F, Segi E, Sugimoto Y, Murata T, Matsuoka T, oxygenase-2-derived prostacyclin mediates embryo
Kobayashi T, Hizaki H, Tuboi K, Katsuyama M, Ichikawa implantation in the mouse via PPARdelta. Genes Dev
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febrile response in mice lacking the prostaglandin receptor 98. Forman BM, Chen J, Evans RM. 1997 Hypolipidemic
subtype EP3. Nature 395:281-284. drugs, polyunsaturated fatty acids, and eicosanoids are
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1997 The prostaglandin receptor EF4 triggers remodeling 99. Lee SS, Pineau T, Drago J, Lee EJ, Owens JW, Kroetz DL,
of the cardiovascular system at birth. Nature 390:78-81. Fernandez-Salguero PM, Wdstphal H, Gonzalez FJ. 1995
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Targeted disruption of the alpha isoform of the peroxisome 104. Laubach VE, Shesely EG, Smithies O, Sherman PA. 1995
proliferator-activated receptor gene in mice results in Mice lacking inducible nitric oxide synthase are not
abolishment of the pleiotropic effects of peroxisome resistant to lipopolysaccharide-induced death. Proc Natl
proliferators. Mol Cell Biol 15:3012-3022. Acad Sci USA 92:10688-10692.
100. Reaume AG, de Sousa PA, Kulkarni S, Langille BL, Zhu 105. Shesely EG, Maeda N, Kim H-S, Desai KM, Krege JH,
D, Davies TC, Juneja SC, Kidder GM, Rossant J. 1995 Laubach VE, Sherman PA, Sessa WC, Smithies O. 1996
Cardiac malformation in neonatal mice lacking connexin Elevated blood pressures in mice lacking endothelial nitric
43. Science 267:1831-1834. oxide synthase. Proc Natl Acad Sci USA 93:13176-13181.
101. Plum A, Hallas G, Magin T, Dombrowski F, Hagendorff 106. Naghashpour M, Dahl G. 2000 Relaxation of myometrium
A, Schumacher B, Wolpert C, Kim J, Lamers WH, Evert by calcitonin gene-related peptide is independent of nitric
M, Meda P, Traub O, Willecke K. 2000 Unique and shared oxide synthase activity in mouse uterus. Biol Reprod
functions of different connexins in mice. Curr Biol 10:1083- 63:1421-1427.
1091. 107. Kimura T, Ogita K, Kusui C, Ohashi K, Azuma C, Murata
102. Bond CT, Sprengel R, Bissonnette JM, Kaufmann WA, Y. 1999 What knockout mice can tell us about parturition.
Pribnow D, Neelands T, Storck T, Baetscher M, Jerecic J, Rev Reprod 4:73-80.
Maylie J, Knaus H-G, Seeburg PH, Adelman JP. 2000 108. Gross G, Imamura R, Muglia LJ. 2000 Gene knockout mice
Respiration and parturition affected by conditional in the study of parturition. J Soc Gynecol Investig 7:88-95.
overexpression of the Ca2+-activated K+ channel subunit, 109. Muglia LJ. 2000 Genetic analysis of fetal development and
SK3. Science 289:1942-1946. parturition control in the mouse. Pediatr Res 47:437-443.
103. Huang PL, Dawson TM, Bredt DS, Snyder SH, Fishman 110. Embree-Ku M, Boekelheide K. 2002 Absence of p53 and
MC. 1993 Targeted disruption of the neuronal nitric oxide FasL has sexually dimorphic effects on both development
synthase gene. Cell 75:1273-1286. and reproduction. Exp Biol Med 227:545-553.
 59 Mechanism of Human
Uterine Contraction

Tatsuhiko Kawarabayashi, Yoshihito Inoue

INTRODUCTION example, stomach and trachea are classified in poorly

excitable muscles, and vas deferens and ureter in
Uterus is one of the smooth muscle organs which quiescent, but highly excitable muscles. As for the
carry out their physiological roles through contractile myometrium, it is placed in the group of spon-
activities those are tonic and/or phasic contractions taneously active and readily excitable muscles like the
which vary according to the function of each organ. taenia of caecum, intestine and portal vein. The
The contractile activities are characterized by three contractility of this muscle group is greatly influenced
elements which are amplitude, duration and fre- by changes in electrical activity. However, one of the
quency, and their combinations determine the type most important roles of the uterus is to retain a fetus
of motility. On the other hand, the arrangement of by suppressing contractility until such time as
the smooth muscle bundles which are composed of adequate fetal growth can be achieved, and then to
smooth muscle cells determines the direction of the expel the fetus by rhythmic contraction. Long-term
force. The contractile properties of smooth muscle and short-term control mechanisms are essential to
organ are generally correlated with the electrical achieve this dual role. The activity of the myometrium
activity of the plasma membrane, however the is highly influenced by hormonal conditions to keep
influence of electrical activity varies from organ to the fetus in utero, and by a variety of stimulants
organ. Some muscles do not generate action poten- (oxytocin, prostaglandins, catecholamines, etc.) which
tials, while others produce active responses. As for promote expulsion of the fetrus. The course of
the relationship between action potential and pregnancy and parturition vary between different
contraction, it can be said that the pattern, duration species and myometrial functions would be expected
and frequency of action potentials determine the to show similar variation. In the human, a periodicity
pattern of contractions including each duration and consisting of one-minute of contraction and a few
frequency. Moreover, differences in electrical minutes of relaxation is essential for both mother and
properties might be expected to correlate with the fetus. The mother can perform pushing efforts during
different mechanisms by which bioactive substances the contraction phase, and the fetus can recover from
and drugs affect the activity of each smooth muscle the hypoxic state during the relaxation phase. This
organ. Therefore, the various types of smooth muscle periodicity probably determines the fundamental
can be classified according to their excitability. For characteristics of human uterine contractility.
828 Textbook of Perinatal Medicine

ELECTRICAL ACTIVITY IN micoelectodes, tip-potentials of the microelectrodes,

THE HUMAN MYOMETRIUM stretching of the tissue, bathing temperature and so
on, all affect the membrane potential. Therefore, it is
Few studies have recorded the intracellular electrical
difficult to compare date reported by different
activity of the human myometrium, though there
investigators even for the same tissue. The actual
have been many studies on the electrophysiological
valuue of the resting membrane potential in term-
properties of animal myometrium. In 1971, Nakajima
pregnant human myomtrium is about -46 to –50 mV
reported intracellular action potential of human
(Nakajima, 1971; Inoue et al., 1990), and this is
isthmic myometrium using a microelectrode. His
compatible with the values in term-pregnant rat
description was limited to the mean resting potential
myometrium (Kuriyama & Suzuki, 1976; Anderson,
(-46.4 mV), and the configuration of the action
Kawarabayashi & Marshall, 1981). Even in isolated
potential (plateau-type). In 1982 therefore, we
pregnant human myometial cells dissected from the
initiated electrophysiological experiments in human
incisional edge of the lower uterine segment at the
myometrium using the single sucrose-gap method.
time of Cesarean delivery, the mean resting
The specimens consisted of small strips of pregnant
membrane potential is -49.4 mV, the same as in intact
human isthmic myometrium dissected from the lower
tissue (Pressman et al., 1988).
uterine segment at the time of term Cesarean section
The resting membrane potential of the myo-
with patients under epidural anesthesia under the
metrium is highly influenced by external potassium
informed consent, prior to the administration of
and sodium in animals. In the rat, when potassium is
oxytosis. This material can be easily and consistently
increased from the normal concentration (5.9 mM in
obtained from the human uterus without compli-
Krebs solution), the membrane gradually depolarizes
cations. We used the single sucrose-gap method to
(Kanda & Kuriyama, 1980). On the other hand, when
make a simultaneous record of spontaneous electrical
sodium is decreased, the membrane depolarizes and
and mechanical activity; this is the most stable method
contracture develops in pregnant mouse (Osa, 1971)
for recording long-term activities.
and rat (Kanda & Kuriyama, 1980) myometrium. It is
Passive Electrical Properties considered that the contracture produced by sodium
removal is largely calcium dependent, and that an
Resting Membrane Potential increase in calcium conductance, secondary to
The resting membrane potential of a spontaneously membrane depolarization and sodium-calcium
active smooth muscle, such as intestine and myo- exchange, is involved in the calcium-dependent
metrium, is lower than a non-spontaneously active contracture (Masahashi & Tomita, 1983). In pregnant
smooth muscle. In these muscles, the resting potential human myometrium, the resting membrane potential
is defined as the maximum polarization between is primarily influenced by permeability for potassium
action potentials recorded by the microelectrode ion, but sodium permeability also has an important
method. If the tissue shows bursts of spontaneous role (Inoue et al., 1990).
activity, the value obtained during the quiescent
period is taken as the membrane potential. In Length Constant
pregnant human myometrium, it is easier to measure We can get the electrical response of pregnant human
the resting membrane potential because of the long- myometrium evoked by varios intensities of stimu-
lasting quiescent period, since the frequency of the lation recorded at three different distances from the
action potential is very low in comparison with that stimulating partition. The amplitudes of the electro-
of the rat. However, it is obvious that many factors, tonic potentials show outward rectification. Linear
such as faulty impalement, deficiencies in the relations between the applied inward current
 Mechanism of Human Uterine Contraction 829
intensities and the amplitudes of the electrotonic because of the stimulatory influence of the sex steroids
potential were seen at more than three places. There and the muscle distention caused by fetal growth
was a long-linear relationship between spatial decay (Cole & Garfield, 1989). Measurements of longitudinal
of the electrotonic potential produced by a given muscle cells isolated from the uteri of 21-day pregnant
current intensity and the distances from the partition. rats (delivering day), showed an average size of
This indicates an exponential decay of the electrotonic 232±74 µm × 16.2±7.0 µm (Tsukamoto et al., 1991).
potential along the tissue. The lengh constant Hormones, especially estrogen, and muscle distention
describes the efficiency with which a current will also affect the electrical properties of the myometrium
spread through the tissue. This content is significant (Kawarabayashi & Marshall, 1981). In rat, the resting
in determining the propagation of action potentials membrane potential gradually depolarizes (from -43
through the tissue. The mean values of the length to -36 mV in circular, -45 to -41 mV in longitudinal
constant was 1.0±0.1 mm, which was the distance at muscle), and there is a progressive increase in the
which the electronic potential decayed to 1/e. This length constant (from 2.5 to 2.9 mm in longitudinal
value is shorter than that measured in the longitudinal muscle) and the time constant (from 180 to 228 ms in
muscle of term-pregnant rat myometrium (2.9 mm) longitudinal muscle) throughout pregnancy and
(Kuriyama & Suzuki, 1976), but is similar to that delivery (Kuriyama & Suzuki, 1976; Anderson et al.,
observed in the circular muscle of mid-pregnant rat 1981). Thus a spontaneous action potential is more
myometrium (1.02 mm) (Kawarabayashi, 1978). easily generated and propagated through the
myometrium as pregnancy progress. The overall
Mambrane Time Constant excitability of the myometrium in late pregnancy
culminates in the initiation and progress of labor. The
The mambrane time constant is calculated from the
same may occur in human myometrium, though this
relationship between the time to reach the half
has not been verified because of the difficulty in
amplitude of the electrotonic potential at the steady
obtaining early and mid-pregnancy myometrium.
sate and the distance between the recording electrode
and the stimulating electrode. The slope of the line
Active Electrical Properties
represents the relationship of τ w/2λ, where τ m and
λ are the time constant of the membrane and length Action Potentials
constant of the tissue, respectively. The time constant
In a small animal with a bicornuate uterus, such as
is used as an indecator of membrane resistance. An
the rat or mouse, the myometrium consists of a well-
increase in membrane permeability can therefore be
defined outer longitudinal layer and an inner circular
measured as a decrease in τ m. The time constant of
layer separated by an extensive vascular plexus; the
pregnant human myometrium is 396±46 ms (Inoue
electrophysiological characteristics of each muscle are
et al., 1990); this value is larger than that of pregnant
different. The predominant types of action potentials
rats (180-228 ms)(Kuriyama & Suzuki, 1976; Sims,
in rat uteri at mid-pregnancy are spike in the
Daniel & Garfield, 1982).
longitudinal muscle and plateau in the circular muscle
(Kawarabayashi & Osa, 1976). In human myometriun,
Effect of Reproductive State on
it is difficult to dissect the longitudinal and circular
Passive Electrical Properties
muscle and therefore difficult to distinguish the action
The cells of the myometrium are spindle-shaped, potentials characteristic of these two layers. However,
ranging in size from 2 to 10 µm in diameter and from spike- and plateau-type action potentials can be
200 to 600 µm in length, depending on the species and distinguished from the pattern of traces using the
hormonal state of the individual. The muscle cells are microelectrode method (Inoue et al., 1990) and single
largest during the later stages of pregnancy, primarily sucrose-gap method (Kawarabayashi et al., 1986a).
830 Textbook of Perinatal Medicine

Plateau potentials are more frequently observed, but by a slow depolarization of the muscle cell membrane
these do not allow prediction of whether the pattern culminating in generation of the action potential. As
of action potentials will be spike or plateau type the pacemaker cells are not localized to a specific area
before the onset of spontaneous activity. However, of the myometrium, these cells can only be recognized
all contractions are well synchronized with the action by the pattern of electrical activity. It is said that all
potential, even a single spike effectively triggers a uterine muscle cells are capable of becoming
small contraction; the tension does not revert to the pacemakers (Marshall, 1973). The frequency of
resting level but summated to a fused tetanus if the pacemaker activity determines the rate of contraction.
intervals between spikes are short enough. The In pregnant rat myometrium, the slow depolarization
amplitude of the contraction depends on the fre- is associated with a gradual increase in membrane
quency of the spike potentials. In the plateau-type, resistance, presumably due to a reduction in
the initial spike triggers the contraction and the potassium conductance, as judged from the increase
duration of the contraction is considerably prolonged in amplitude of the electrotonic potential recorded
in proportion to the plateau duration, though the from a single cell (Kuriyama & Suzuki, 1976). It is also
amplitude is not greatly increased (Kawarabayashi possible that the slow depolarization results from an
et at., 1986a). increase in sodium permeability, since the pacemaker
The configuration of spontaneous action potentials potential is dependent upon the presence of sodium
in human myometrium is very similar to the pattern in the external environment and is unaffected by the
observed in rats; however, the time courses are removal of calcium (Reiner & Marshall, 1976).
remarkably different (about 10 sec in rat vs 60 sec in Recently, we found hyperpolarization (below -60
human). The duration of both plateau- and spike-type mV)-activated inward currents (Ih) in circular but not
action potentials gradually decreases and finally in longitudinal muscle in pregnant rat uterus under
disappears in excess calcium (7 mM) and calcium-free voltage-clamp conditions. Since Ih is activated at the
solutions, as well as with application of the calcium resting membrane potential, it is likely that this
antagonist, diltiazem (Kawarabayashi, Kishikawa & current contributes spontaneous activity in circular
Sugimori, 1986b). Moreover, superfusion with muscle cells of late pregnant rats (Okabe et al., 1999).
sodium-deficient (15.5 mM) and calcium-free solution The pacemaker potential is also observed in
increases the amplitude of the electrotonic potential pregnant human myometrium. The membrane
and inhibits any active response, in comparison with potential gradually depolarizes and the action
the responses in the calcium-free solution (Inoue et potential is ultimately evoked. Though steady current
al., 1990). Calcium ions can therefore be considered pulses are applied, evoked potentials are not regular
to play an essential role in constituting the action and the pattern gradually changes in accordance with
potential, and sodium ions influence the generation the periodicity of the membrane. The pacemaker
of the action potential (Kawarabayashi, 1978). potential is greatly influenced by temperature; the
frequency of spontaneous contractions increased
Pacemaker Potentials markedly, but their duration decreased when
Myometrium is a spontaneously active and highly temperature of the bathing fluid was increased from
excitable muscle. Most of the uterine muscles show 26oC to 39oC. External magnesium ion suppresses the
spontaneous rhythmic action potentials which arise gradient of the pacemaker potential and the duration
in pacemaker cells, and are transmitted over the organ of each action potential (Kawarabayashi et al., 1984;
as a whole. As in other visceral smooth muscles and Kawarabayashi, Kishikawa & Sugimori, 1988a;
the heart, uterine pacemaker activity is characterized Kawarabayashi, Kishikawa & Sugimori, 1989).
 Mechanism of Human Uterine Contraction 831
Ion Channels in the Human Myometrium during pregnancy. These results suggest that the
Calcium channels: It is well known that contractions expression levels of L-type channels change dyna-
of the myometrium are related to an increase in the mically, and it may contribute directly to the
concentration of intracellular free calcium ion, and it regulation of cell excitability and that the T-subtype
is also known that a large difference in calcium that increases during pregnancy differs between
concentrations exists between the extracellular fluid longitudinal and circular muscle cells (Ohkubo, et al,
(~10-3 M) and intracellular cytosol (~10-7 M). There- 2004).
fore, calcium influx from the extracellular space into In pregnant human myometrium, two different
the cytosol is very important in regulating myometrial types of voltage-dependent calcium channels have
contractility. Two types of channels for calcium influx been observed at the single-channel level using the
have been suggested (Bolton, 1979). One is a potential- patch clamp technique (Inoue et al., 1990), and the
sensitive calcium channel that opens when the inward calcium current was characterized by
membrane depolarizes and is normally responsible activation and inactivation properties (Young,
for the action potential. The other type is a receptor- Herndon-Smith & Anderson, 1991b). One of these had
operated channel which is controlled or operated by a single-channel conductance of 12 pS, and was only
a receptor for a stimulant substance. Nowadays, it is activated by depolarizing pulses from a holding
well known that voltage-dependent calcium channels potential of -100 mV; this channel was inactivated at
(VDCC) represent the major machinery for intra- a holding potential of -60 mV. The second type had a
cellular calcium mobilization and two types of VDCC, single-channel conductance of 29 pS activate by
L (long-lasting)-type (dihydropyridine-sensitive) and depolarizing pulses from a holding potential of -60
T (transient)-type, are identified. Therefore, we mV. Summate currents also showed different time
evaluated the difference in the expression of mRNA courses for current relaxation; i.e. the 12 pS calcium
of two types of calcium channels between longitudinal channel (transient type; T-type) was rapidly inacti-
and circular muscle layer of rat myometrium during vated, whereas the 29 pS calcium channel (long-
pregnancy. Changes in the expression of mRNA lasting tyoe: L-type) was slowly inactivate. The
encoding L-type (α1C) and T-type (α1G, α1H, and majority of the 12 pS calcium channels are likely to
α1I) calcium channels in longitudinal and circular be inactivated at a normal resting potential of about
muscle cells of the rat myometrium were examined -50 mV,as indicated by experiments that used the
using a comparative kinetic RT/PCR method. During whole-cell voltage clamp technique (Inoue et al.,
the course of pregnancy, α 1C mRNA expression 1990). The physiological importance of the L-type
showed an N-shaped change in longitudinal muscle, current must be related to the formation of plateau
but simply increased after mid-pregnancy in circular potential, judging from its higher threshold potential
muscles. The mRNAs for α1G and α1H, but not that and slower inactivation. Activation of the T-type
for α1I, were expressed in both longitudinal and calcium channel may be responsible for the spike
circular muscles. In longitudinal muscle, the change component, and it may trigger activation of the long-
in α1H mRNA was similar to that in α1C mRNA lasting-type calcium channel. Recently, Three types
during gestation, but the expression of α1G mRNA of T-type channel α1 subunits, α1G (Cav3.1), α1H
changed significantly only at term (day 22). In circular (Cav3.2), and α1I (Cav3.3), have been cloned and we
muscle, α1H mRNA expression was stable at any examined the electrophysiological characteristics of
stage during pregnancy, but α1G mRNA significantly three cloned human α1H isoforms of T-type calcium
increased on day 15 and at term. No relationship was channel Cav3.2 expressed in pregnant human uterus.
observed between VDCC mRNA expressions and Then, our results suggested that molecular-structure
either proliferation or hypertrophy of circular muscle variation within the III-IV linker influenced the
832 Textbook of Perinatal Medicine

voltage-dependence of activation and inactivation, membrane potential can affect the initiation of the
and kinetics. Although the role of T-type calcium action potential and hence contraction. In pregnant
channels in uterus remains unknown, changes in the human myometrium, it is believe that the changes in
uterine expression of these α1H isoforms may potassium permeability primarily affect the resting
influence the physiological function during preg- potential (Inoue et al., 1990), and that this might be
nancy (Ohkubo et all., in submission). involved in the action of catecholamine β2-agonist and
the effect of high calcium on the duration of action
Sodium channels: Sodium ions may play an impor-
potentials (Kawarabayashi et al., 1984; Kawara-
tant role in generating the pacemaker potential and
bayashi et al., 1986b). Though a single channel
the action potential in uterine muscle. In the
potassium current has not yet been recorded from the
longitudinal muscle layer of pregnant rat myo-
human myometrium, several studies of potassium
metrium, a fast sodium channel current (tetrodotoxin
current obtained from the myometrial cells of
sensitive) was recorded from freshly isolated single
experimental animals by the patch-clamp technique
cells using whole cell voltage-clamp technique, ant it
have been reported (Coleman & Parkington, 1987;
was suggested that the fast sodium channel current
Kihara et al., 1990; Toro, Stefani & Erulkar, 1990a). It
might play a role in cell-to-cell conduction and
has been suggested that calcium-activated potassium
possibly in regulation of spontaneous electrical
channels, which are controlled by intracellular
activity (Ohya & Sperelakis, 1989).
calcium, are not activated by calmodulin but rather
In cultured cells obtained form pregnant human
that calcium binds directly to the gating site for
myometrium, a large voltage-activated inward
channel activation (Kihara et al., 1990). Furthermore,
current was identified as sodium channel conduc-
three potassium currents (fast, intermediate and slow)
tance by the following criteria: (1) removal of sodium
are found in rat myometrium; the fast current is
from the bath eliminated the current; (2) the current
predominant in cells from estrus rats, whereas
was blocked by the sodium-channel-blocking agent,
intermediate current is more frequent in cells from
tetrodotoxin; (3) the current was observed in the
diestrus rats. In addition, norepinephrine potentiates
absence of calcium (Young & Herndon-Smith, 1991a).
the fast current and reduces the intermediate current
The sodium current was large (maximal inward
(Toro et al., 1990a). Using rat or pig myomtrial
current 7.2 µA/cm2) and of short duration (decayed
potassium channels incorporated into lipid bilayers,
within 10 ms); the onset of activation was -40 mV,
it has been shown that myometrial β-adrenergic
with a peak inward current at -10 mV. Steady-state
receptors may be coupled to a GTP-dependent protein
voltage inactivation of this channel showed half-
that can directly gate calcium-activated potassium
maximal inactivation at -67 mV, indicating that this
channels (Toro, Ramos-Franco & Stefani, 1990b).
channel is largely inactivated at normal resting
Current research is directed at understanding the
potentials. The sodium currents do not appear to
mechanisms of potassium channels through the
contribute to the rising phase of the action potential
molecular biological technique. One of the most
in human myocytes (Young & Herndon-Smith,
conspicuous channels is the high (big) conductance
1991a). Further study is required to clarify the
potassium channel, BK channel. It has a large single
physiological role of sodium channels.
channel conductance of around 250 pS and is a
Potassium channels: The potassium channels are calcium-activated channel (KCa). A major role for BKCa
involved in terminating action potentials and in channels is likely to be the restoration of resting
returning the membrane potential to its resting level. conditions following an action potential. Thus, the
Furthermore, the resting potential is primarily set by calcium influx and depolarization occurring during
the permeability to potassium ion, and changes in the the action potential in smooth muscle would both
 Mechanism of Human Uterine Contraction 833
contribute to an increase in the probability of opening estradiol produces a plateau potential (Kuriyama &
of BKCa channels resulting in repolarization of the Suzuki, 1976). Although sex steroids affect membrane
membrane. This would decrease the probability of properties, the changes which occur during preg-
opening of the voltage-dependent calcium channels nancy cannot be explained by the action of such
and in this way reduce excitability and facilitate hormones. There is only one report which describes
relaxation (Parkington & Coleman, 2001). As for the electrical activity of human myometrium in early
human myometrium, it is reported that the mRNA pregnancy (Kawarabayashi et al., 1986a). The action
for BKCa channels is abundant in human myometrium potential is composed of a long plateau potential or
(Wallner et al., 1995). As the other potassium channels, abortive spikes superimposed on the long plateau.
delayed rectifier potassium channel (Miyoshi et al., The duration tends to be longer than in term
1991; Knock et al., 1999), transient-A-type potassium pregnancy.
channel (Inoue et al., 1993) and ATP sensitive
potassium channel (KATP) (Hamada et al., 1994) are RELATIONSHIP BETWEEN ELECTRICAL
reported. ACTIVITY AND CONTRACTION
Contraction of the myometrium is related to the
Effect of Reproductive State
concentration of intracellular free calcium ion; the
on Active Electrical Propertie
increase in intracellular calcium might arise from an
Near the end of pregnancy the circular muscle influx of calcium from the extracellular space, the
activities of the rat uterus exhibit characteristic translocation of calcium ions in or near the cell
changes that are a prerequisite for normal delivery. membrane and/or the release of calcium from internal
These changes consist of a progressive alteration in stores. Pregnant human myometrium usually
the configuration of action potentials form a single, generates spontaneous action potentials and extra-
plateau-type in early and mid-pregnancy to a cellular calcium might enter the cell through the
repetitive train discharge at term (Osa & Fujino, 1978; calcium channels during these action potentials. In
Anderson et al., 1981). The action potentials cause our sucrose-gap experiments, contractions were
brief, irregular contractions during early and mid- always synchronized with the corresponding action
pregnancy and regular contractions of longer potentials. Therefore, the amount of calcium which
duration at term. Furthermore, uterine volume enters during the action potential is sufficient to
(muscle stretching) and circulating estrogens may be activate the contractile mechanism and to release
more important than the fetoplacental unit in the additional calcium from internal stores, thereby
evolution of circular muscle activity in the pregnant amplifying the transmembrane signals (Parkington &
rat (Kawarabayashi & Marshall, 1981). The protein Coleman, 1990). On the other hand, the periodicity
synthesis inhibitor, cycloheximide, can suppress the of one-minute contraction and a few minutes of
evolution of activity and delay parturition (Maruta relaxation is essential for mother and fetus during the
& Osa, 1986). The action potential of longitudinal stress of parturition. A long and hypertonic contrac-
muscle exhibits a burst discharge of spikes and the tion decreases uteroplacental blood flow, causes fetal
pattern does not change throughout pregnancy. hypoxia, and small contractions cannot expel the fetus
However, estradiol hyperpolarizes the membrane and further. The myometrium has a spontaneous
a burst of spikes is generated from sustained periodicity and thereby generates action potentials
depolarization. Progesterone, by contrast, slightly and contractions of appropriate duration. Under
hyperpolarizes the membrane and typical burst physiological conditions, the contractility of the
discharges occur without sustained depolarization. uterus is regulated by changing the electrical activity.
Simultaneous treatment with progesterone and It might be very easy to regulate the frequency,
834 Textbook of Perinatal Medicine

duration, and probably amplitude of spontaneous contractions in labor were evaluated by a double
contractions evoked by each action potential by guard-ring tocodynamometer attached to the fundus
changing the resting membrane potential. and the caudal part of the uterus. The synchronizing
In obstetric practice both periodic contractions and ratio of two contraction waves was significantly
sufficient periods of relaxation are the most important higher in the active phase than in the latent phase of
factors for the well-being of the fetus and the progress labor, and nearly regular upward or downward
of the delivery. Considering these fundamental observed in each case (Nakahara et al., 1986).
characteristics of the human uterine contraction, Furthermore, the percentages of both concurrent and
relaxation mechanisms are essential for the fetus and synchronous contractions were higher than those of
the mother, and should be better understood, along Braxton Hichs contractions, and both values increased
with the stimulation of the contractions. A reduction significantly between 5 and 6 cm of cervical dilation
in intracellular calcium is essential for relaxation. (Shinmoto et al., 1991). On the other hand, small
Currently, two pathways are speculated for the contraction waves (30 seconds or less duration of each
myometrium to lower the intracellular calcium ions wave) recorded by a guardring tocodynamometer
to produce relaxation. One of them is a calcium pump were observed in 7.5% of the cardiotocographs
in the plasma membrane or the membrane of the examined, and the rate of small-wave appearance in
sarcoplasmic reticulum, and the other is a sodium- each gestational week tended to decrease gradually
calcium exchange mechanism that is an antiporter as the pregnancy progressed. This was not observed
present in the plasma membrane carrying sodium in after 41 weeks of gestation and was frequently
one direction and calcium in the other. In pregnant observed in cases of effective β2-stimulant intravenous
human myometrium, we suggested the presence of infusion for the treatment of preterm labor
the sodium-calcium exchange mechanis m and the (Kawarabayashi et al., 1988b). The synchronizing ratio
specific inhibitory effect of magnesium ion. This of peaks of small contraction waves was almost the
mechanism might prevent the long tonic contractions, same as the ratio in the active phase of labor
to protect the fetus from hypoxia during pregnancy (Nakahara et al., 1986). Thus synchronization of local
and parturition (Morishita et al., 1995). contractions results in the effective contractions of
human parturition. However, the uterus does not
PROPAGATION OF EXCITATION have any specific conduction pathways for excitation.
In human uterus, the resting tonus maintains uterine Instead, the action potential spreads into the
shape and fetal position. Resting tonus is maintained surrounding cells in three-dimensions in accordance
by random activation of the myometrium by action with their cable-like properties. The length constant
potentials. However, well-coordinated contraction is of the membrane gradually increases throughout
essential for successful expulsion of the fetus after the pregnancy in the rat, as described earlier, and the
onset of labor. In order to achieve this coordination, conduction velocity of the action potential in
many myometrial cells have to contract at the same longitudinal preparations of pregnant rat myo-
time, and local contractions obtained by the coordi- metrium increases from 9.2 cm/s at late pregnancy
cation of the cells have to synchronized over the whole to 10.5 cm/s during delivery (Miller, Garfield &
of the uterus as parturition progresses. Since small Daniel, 1989). Gap junctions, which are assumed to
muscle strips of pregnant human myomtrium exhibit be the structure involved in electrical and chemical
spontaneous periodicity with one-minute contraction communication between cells, increase during
and a few minutes relaxation, this periodicity may parturition and disappear after delivery in experi-
facilitate coordinated contraction. In our clinical mental animals (Garfield, 1984). This structure is
study, the qualitative characteristics of uterine observed in human myometrium from women in pre-
 Mechanism of Human Uterine Contraction 835
term labour (Garfield & Hayashi, 1981).These changes in low calcium solution (Kawarabayashi et al., 1986b,
may contribute to the propagation of excitation 1989).
during parturition.
Magnesium
EFFECTS OF IONS AND DRUGS ON
Magnesium sulfate has been used as a tocolytic agent
ELECTRICAL ACTIVITY AND CONTRACTION
to prevent pre-term labor. The effect of magnesium
Calcium on the spontaneous electrical and mechanical
activities of the circular muscle of term pregnant rat
Extracellular calcium has been shown to play an
uterus suggests that the effect is largely due to
important role in the activation of smooth muscle and
suppression of the plateau potential (Osa &
the amplitude of the tension can be related to the
Ogasawara, 1983). According to the whole-cell voltage
external calcium concentration and consequently to
clamp method on freshly isolated single pregnant rat
the calcium influx in pregnant rat myometrium
myometrial cells, magnesium inhibits the calcium
(Mironneau, 1973; Bengtsson, Chow & Marshall,
current, affecting mainly the transient component
1984). Moreover, the inward calcium current may
(Ohya & Sperelakis, 1990). In pregnant human
affect potassium conductance during the plateau
myometrium, frequency, amplitude, and duration of
potential in the circular muscle of pregnant rat
spontaneous contractions all decrease with increases
myometrium, and the potassium conductance
in external magnesium; the frequency change is the
provides the plateau duration, and consequently the
most significant (Kawarabayashi et al., 19891).
duration of the contraction (Osa & Kawarabayashi,
Magnesium ion suppresses the gradient of pacemaker
1977). In pregnant human myometrium, spontaneous
potential, and consequently the frequency of contrac-
contraction is strongly affected by external calcium;
tion (Kawarabayashi et al., 1984).
2.5 mM calcium in Krebs solution is the most efficient
concentration in terms of frequency, amplitude, and
Oxytocin
duration of whole conctractions. Both excess calcium
and low calcium suppress the generation of spon- The initiation of either term or preterm labor is
taneous contraction; however, the mechanism of these considered to be a final common phenomenon
two types of suppression may differ. Calcium ions induced by augmented uterine contractions, regard-
may play dual roles in the electrical activity of the less of the incipient cause. And it is well known that
myometrium; an excitatory role in action potential oxytocin plays an important role in the initiation of
and an inhibitory role accomplished by membrane labor in both term and preterm parturients. However,
stabilization and calcium-mediated potassium a satisfactory direct comparison of the functional roles
activation. Therefore, the effects of excess calcium on of oxytocin in term and preterm labor had not been
spontaneous contractions may depend on the balance elucidated. We had demonstrated that the inhibitory
of excitatory and inhibitory effects. If the increase of effects of both peptidyl and nonpeptidyl oxytocin
calcium influx during the action potential is predomi- antagonists on spontaneous uterine contractions of
nant, the amplitude of the contraction will increase; pregnant rats became greater as the pregnancy
however, the contraction will be diminished if the progressed. This change was accompanied by a
generation of action potentials is suppressed by significant increase in myometrial oxytocin receptor
membrane stabilization and activation of the outward density (Kawarabayashi et al., 1996). Then we made
potassium current. By contrast, low calcium may a direct comparison of the functional roles of oxytocin
decrease the influx of calcium and consequently in term and preterm labor in rats. Firstly, we
suppress the contraction, since both the amplitude determined the myometrial oxytocin receptor density
and duration of contraction are generally decreased and maternal plasma concentrations of oxytocin and
836 Textbook of Perinatal Medicine

progesterone on gestational days 18, 20 and 22 is short and the contraction is small in the presence
(morning) and at the onset of delivery (day 22 of diltiazem (calcium antagonist).The results of the
afternoon) in rats with labor at term and at the onset potassium contracture experiment also suggest that
of delivery (day 20 afternoon) in rats in preterm labor oxytocin evokes a contracture in the absence of an
induced by the combined use of bilateral ovariectomy action potential by releasing calcium from intra-
and estradiol injection. We also evaluated the effects cellular storage sites.
of a nonpeptidyl oxytocin antagonist on the initiation This possibility is supported by our another study
of both term and preterm labor. Consequently, the measuring intracellular calcium using Fura-2 in
number of tritiated oxytocin binding sites in myo- isolated cells of pregnant rat myometrium
metrial membranes rapidly increased on gestational (Tsukamoto et al., 1991). Then, we examined changes
day 22 (morning). Plasma progesterone level in responsiveness of freshly isolatedlongitudinal
decreased in an inverse fashion. A rapid increase in muscle cells from rat uterus to oxytocin during
circulating oxytocin concentration was observed at gestation were investigated through measuring
the onset of delivery, and both the plasma oxytocin contractility as well as intracellular free calcium
concentration and the receptor density had the same concentration. We have demonstrated the pregnant
values in rats with preterm labor as in rats with term stage-dependent contraction of freshly isolated
labor. The oxytocin antagonist delayed the initiation myometrial cells in response to an extracellular
of labor in rats with term and preterm labor in a dose- hormone, oxytocin, in Ca2+-containing medium. The
dependent manner (Kobayashi et al., 1999). oxytocin effect appeared to be through oxytocin
On the other hand, the direct effect of oxytocin on receptor since the effect could be blocked by a specific
spontaneous electrical and mechanical activities in oxytocin antagonist. The magnitude of the contraction
pregnant human myometrium has been investigated of the isolated cells in response to extracellular
using the single sucrose-gap method (Kawarabayashi, oxytocin was in the order of 21 day >>18day > 15day
Kishikawa & Sugimori, 1986c). Oxytocin potentiates pregnant rat longitudinal muscle cells. In a concent-
spontaneous contractions by enhancing the plateau ration dependent manner, oxytocin elicited a rapid
part of action potentials; the spike-type configuration increase in intracellular calcium ion of longitudinal
becomes plateau. This potentiation depends on the muscle cells isolated from different stages of the
external calcium concentration, and the effects on pregnant rat uterus, especially at the term of
frequency and amplitude of contractions may vary. pregnancy. The time (4-5 s) required to reach a
In our microelectrode experiments, two types of maximum increase in intracellular calcium ion of the
spontaneous action potentials were seen in pregnant isolated longitudinal muscle cells in response to
human myometrium; a long plateau and a spike-like oxytocin was the shortest among all previously
action potential. With no change in the resting reported studies. The results also indicated that the
membrane potential, low concentrations of oxytocin freshly prepared longitudinal muscle cells maintained
either evoked an action potential with plateau phase, their functional calcium signaling system. The order
increased the amplitude and duration of the plateau of the responsiveness of the isolated longitudinal
potential, or increased the frequency of generation of muscle cells to oxytocin was 21day >> 18day > 15day
action potentials. Oxytocin also lowered the threshold pregnant rats in terms of rate, affinity and magnitude.
for evoking an action potential. Higher concentrations Oxytocin appears to transmit its signal mainly
depolarized the membrane with an associated through stimulating a voltage-dependent and/or
reduction in membrane resistance (Nakao et al., 1997). receptor operated nonselective calcium channel.
Oxytocin evokes action potentials and contractions However, the possibility that a part of the oxytocin
in high frequency; the duration of the action potential action occurs through stimulating the release of
 Mechanism of Human Uterine Contraction 837
calcium from intracellular store sites of longitudinal rat at mid-pregnancy longitudinal muscle possesses
muscle still remains (Kawarabayashi et al., 1997). mainly β-adrenoceptors, while circular muscle has α-
The excitatory effect of oxyttocin is modified by adrenoceptors (Kawarabayashi & Osa, 1976).
external magnesium ion in pregnant human myo- However, in late gestation, activation of the α-
metrium. Relatively high magnesium (2.4 mM) adrenoceptors occurs in the longitudinal muscle,
suppresses the spontaneous activities; however, while the circular muscle switches from α- to β-
oxytocin enhances the contractions and the plateau adrenoceptor dominance (Kishikawa, 1981).
part of action potentials to a greater extent than does In pregnant human myometrium, noradrenaline
the magnesium-free solution. In the potassium always exhibits α-excitatory action at 10-12~10-6 g/ml;
contracture experiment, the oxytocin-induced however β-inhibition of β2-stimulant is also observed
contracture during the tonic phase is potentiated by (Kawarabayashi et al., 1984). It is suggested on the
magnesium. Magnesium may potentiated the basis of animal studies that activation of α-receptors
excitatory effect of oxytocin at superficial sites of the in the longitudinal muscle is mainly mediated by slow
plasma mambrane, allowing the possibility of depolarization of the membrane (due to an increase
intracellular action (Kawarabayashi et al., 1990a). The in chloride conductance) which leads to an increase
interaction between calcium and magnesium is in spike frequency; in the circular muscle it is
probably very significant in the regulation of the mediated by prolongation of the plateau of action
action of oxytocin on uterine contractility. potentials (due to an increase in calcium conductance).
It is obvious that oxytocin is involved in the α-action of the myometrium also includes membrane
initiation and progress of labor in many species and hyperpolarization due to an increase in potassium
also plays an important role in lactation. From another conductance and an increase in cAMP production
point of view about the initiation of labor and underlies the suppression of spontaneous contraction
lactation, we clarified the possibility that oxytocin (Bulbring & Tomita, 1987). Catecholamine action may
might modulate oxytocin neurons in the para- fundamentally affect uterine contractility during
ventricular nuclei of female rats throughout preg- pregnancy and parturition.
nancy and parturition. Our results show that the firing In obstetric practice, adrenergic β2-stimulants have
rates of paraventricular neurons in virgin and been widely used as tocolytic agents to prevent
pregnant rats decreased in activity, however the preterm delivery. However, commercially available
neurons of delivering and lactating rats exhibited tocolytic agents often have severe adverse effects
excitatory responses. This excitation reversed to (such as tachycardia, tremor of the hands, and lung
inhibition again after the lactating period ended. It is edema) because they simultaneously exert weak α
suggested that negative feedback by oxytocin in and β1 effects on the cardiovascular system. Another
virgin and pregnant rats might reverse to positive concern about β2-stimulants as tocolytic agents is that
feedback in delivering and lactating animals as a their tocolytic effect is inconsistent among patients
result of changes in hormonal conditions. This reverse and the so-called myometrial desensitization pheno-
might be closely related to the initiation of delivery menon in which the recurrence of contractions might
(Kawarabayashi et al., 1993a). be related to a decrease in cAMP production
(Kawarabayashi et al., 1993b). Recently, we produced
Catecholamines a new β 2 -stimulant (KUR-1246) with a higher
The effects of catecholamines on the myometrium selectivity for uterine β2-receptors (and thus weaker
differ among animal species, and even in the same side effects)(Kobayashi et al., 2001). Then, we
animal, depending on the hormonal status of the performed the experiment to evaluate the usefulness
individual and each muscle layer. For example, in a of this new β2-adrenergic stimulant as a tocolytic
838 Textbook of Perinatal Medicine

agent and to clarify the mechanisms that underlay the and complex interactions might be involved in the
diverse inhibitory effects of β2-stimulants that were initiation and potentiation of contractions in vivo
seen in human myometria in vitro. Consequently, (Kawarabayashi & Sugimori, 1985).
KUR-1246 was approximately 80 times and 7 times
more selective for β2-receptors than isoproterenol and CONCLUSION
ritodrine, respectively. The inhibitory effect of KUR-
The myometrium has spontaneously active and
1246 was as strong as the inhibitory effect of the
highly excitable membrane with many voltage
conventional β2-adrenergic stimulants. A wide range
dependent ion channels. Contractility of the myo-
of inhibitory effects was observed, even when high
metrium is regulated by the electrical activity of this
concentrations of isoproterenol or KUR-1246 were
membrane. The main external controlling factors are
applied. There was a correlation between the degree
sex steroid hormones. The balance of estrogen and
to which isoproterenol suppressed contractions and
progesterone, and the changes during the course of
the number of [3H] dihydroaloprenolol binding sites
the menstrual cycle, pregnancy and parturition,
on the membrane in each muscle strip. These results
changes the resting membrane potential, the pattern
suggest that KUR-1246 should be a very useful β2-
of action potentials and the effects of drugs such as
adrenergic stimulant for use as a tocolytic agent
catecholamines and oxytocin. Hormones also affect
because of its high selectivity for the β2-receptor and
the conduction of excitation and produce morpho-
its potent inhibitory effect. The diversity of the
logical changes of cell size. All of these changes lead
inhibitory effects that are induced by β2-stimulants is
to synchronized contractions which are effective in
at least partly due to differences in β2-receptor density
expulsion of the fetus. It is particularly important for
among term-pregnant human myometria (Sakakibara
the fetus that the periodicity of the phasic contractions
et al., 2002).
is strictly maintained.
Other Drugs
ACKNOWLEDGEMENT
There are few studies on the electrophysiological
action of other drugs on the human myometrium. The author is grateful to Miss Aki Ueno and Miss
Prostagrandin F2α (PGF2α) and methylergometrine Sayako Kawarabayashi, a daughter of mine, for
maleate (methergin) potentiate the plateau part of the typewriting the manuscript.
action potential and contraction of pregnant human
myometrium (Kawarabayashi & Sugimori, 1985; BIBLIOGRAPHY
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action of methergin is not inhibited by phentolamine Effect of indomethacin and aspirin on uterine activity in
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(1984). Effects of magnesium and catecholamines on adrenergic receptors under long-term application of
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and prostaglandin F2α on pregnant human myometrium effects of peptide and nonpeptide oxytocin antagonists on
recorded by the single sucrose-gap method- Comparison radioligand binding and uterine contractility of rats during
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(1986a). Spontaneous electrical activity and effects of Sugimori H. (1997). Changes in responsiveness of freshly
noradrenaline on pregnant human myometrium recorded isolated longitudinal muscle cells from rat uterus towards
by the single sucrose-gap method. Acta Physiologica oxytocin during gestation: contractility and calcium
Hungarica, 67,71-82. signaling. Molecular and Cellular Endocrinology, 128,
18. Kawarabayashi T., Kishikawa T., Sugimori H. (1986b). 77-84.
Effects of external calcium and calcium antagonist, 29. Kihara M., Matsuzawa K., Tokuno H., Tomita T. (1990).
diltiazem, on isolated segments of pregnant human Effects of calmodulin antagonists of calcium-activated
myometrium. Asia-Oceania Journal of Obstetrics and potassium channels in pregnant rat myometrium. British
Gynaecology, 12, 409-17. Jounal of Pharmacology, 100, 353-9.
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30. Kishikawa T. (1981). Alterrations in the properties of the 43. Nakajima A. (1971). Action potention of human
rat myometrium during gestation and post partum. myometrial fibers. American Journal of Obstetrics and
Japanese Journal of Physiology, 31, 515-36. Gynecology, 111, 266-9.
31. Knock G.A., Smirnov S.V., Aaronson P.I. (1999). Voltage- 44. Nakao K., Inoue Y., Okabe K., Kawarabayashi T., Kitamura
gated K+ currents in freshly isolated myocytes of the K. (1997). Oxytocin enhances action potentials in pregnant
pregnant human myometrium. Journal of physiology, 518, human myometrium- A study with microelectrodes.
769-81. American Journal of Obstetrics and Gynecology, 177,
32. Kobayashi M., Akahane M., Minami K., Moro M., Ajisawa 222-8.
Y., Inoue Y., Kawarabayashi T. (1999). Role of oxytocin in 45. Ohkubo T., Kawarabayashi T., Inoue Y., Kitamura K.
the initiation of term and preterm labor in rats: Changes (2005). Differential expression of L- and T-type calcium
in oxytocin receptor density and plasma oxytocin channels between longitudinal and circular muscles of the
concentration and the effect of an oxytocin antagonist, L- rat myometrium during pregnancy. Gynecologic and
366,509. American Journal of Obstetrics and Gynecology, Obstetric Investigation, 59, 80-5.
180, 621-7. 46. Ohkubo T., Inoue Y., Kawarabayashi T., Kitamura K.
33. Kobayashi M., Takeda K., Murata S., Kojima M., Akahane Identification and electrophysiological characteristics of
M., Inoue Y., Kitamura K., Kawarabayashi T. (2001). isoforms of T-type calcium channel Cav3.2 expressed in
Pharmacological characterization of KUR-1246, a selective pregnant human myometrium. 2005 in submission.
uterine relaxant. Journal of Pharmacology and Experi- 47. Ohya Y., Sperelakis N. (1989). Fast Na+ and slow Ca2+
mental Therapeutics, 297, 666-71. channels in ingle uterine muscle cells from pregnant rats.
34. Kuriyama H., Suzuki H. (1976). Changes in electrical American Journal of Physiology, 257, C408-12.
properties of rat myometrium during gestation and 48. Ohya Y., Sperelakis N. (1990). Tocolytic agents act on
following hormonal treatments. Journal of Physiology, calcium channel current in single smooth muscle cells of
260, 315-33. pregnant rat uterus. Journal of Pharmacology and
35. Marshall J.M. (1973). The physiology of the myometrium. Experimental Therapeutics, 253, 580-5.
in The Uterus, pp.89-109, Willians & Wilkins, Baltimore. 49. Okabe K., Terada K., Kitamura K., Kuriyama H. (1987).
36. Maruta K., Osa T. (1986). Blockage by cycloheximide of Features of 4-amniopyridine sensitive outward current
the prepartum changes in membrane activity and observed in single smooth muscle cells from the rabbit
adrenergic response of the circular muscle of rat uterus. pulmonary artery. Pflugers Archieves, 409, 561-8.
Japanese Journal of Physiology, 36, 971-83. 50. Okabe K., Inoue Y., Kawarabayashi T., Kajiya H., Okamoto
37. Masahashi T., Tomita T. (1983). The contracture produced F., Soeda H. (1999). Physiological significance of
by sodium removal in the non-pregnant rat myometrium. hyperpolarization-activated inward currents (I h) in
Journal of Physiology, 334, 351-63. smooth muscle cells from the circular layers of pregnant
38. Miller S.M., Garfield R.E., Daniel E.E. (1989). Improved rat myometrium. Pflugers Archives, 439, 76-85.
propagation in myometrium associated with gap junctions 51. Osa T. (1971). Effect of removing the external sodium on
during parturition. American Journal of Physiology, 256, the electrical and mechanical activities of the pregnant
C130-41. mouse myometrium. Japanese Journal of Physiology, 21,
39. Mironneau J (1973). Excitation-contraction coupling in 607-25.
voltage clamped uterine smooth muscle. Journal of 52. Osa T., Kawarabayashi T. (1977). Effects of ions and drugs
Physiology, 233, 127-41. of the plateau potential in the circular muscle of pregnant
40. Miyoshi H., Urabe T., Fujiwara A. (1991). Electro- rat myometrium. Japanese Journal of Physiology, 27,
physiological properties of membrane currents in single 111-21.
myometrial cells isolated from pregnant rats. Pflugers 53. Osa T., Fujino T. (1978). Electrophysiological comparison
Archieves, 419, 386-93. between the longitudinal an circular muscles of the rat
41. Morishita F., Kawarabayashi T., Sakamoto Y., Shirakawa uterus during the estrous cycle and pregnancy. Japanese
K. (1995). Role of the sodium-calcium exchange Journal of Physiology, 28, 197-209.
mechanism and the effect of magnesium on sodium-free 54. Osa T., Ogasawara T. (1983). Effects of magnesium on the
and high-potassium contractures in pregnant human membrane activity and contraction of the circular muscle
myometrium. American Journal of Obstetrics and of rat myometrium during late pregnancy. Japanese
Gynecology, 172, 186-95. Journal of Physiology, 33, 485-95.
42. Nakahara H., Kawarabayashi T., Ikeda M., Uchiumi Y., 55. Parkington H.C., Coleman H.A. (1990). The role of
Sugimori H., Nakano H. (1986). Synchronization of uterine membrane potential in the control of uterine motility. In
contractions recorded by guard-ring tocodynamometer. Uterine Function: Molecular and Cellular Aspects. Ed.
Asia-Oceania journal of Obstetrics and Gynaecology, 12, M.E. Carsten and J.D. Miller, pp.195-248, Plenum Press,
137-42. New York.
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56. Parkington H.C., Coleman H.A. (2001). Excitability in Proceedings of the National Academy of Sciences, USA,
uterine smooth muscle. In The Endocrinology of Parturi- 87, 2892-5.
tion. Basic Science and Clinical Application. Ed. R. Smith, 62. Toro L., Ramos-Franco J., Stefani E. (1990b). GTP-
pp 179-200, Karger, Basel. dependent regulation of myometrial K-Ca channels
57. Pressman E.K., Tucker Jr. J.A., Anderson Jr. N.C., Young incorporated into lipid bilayers. Journal of General
R.C. (1988). Morphologic and electrophysiologic charac- Physiology, 96, 373-94.
terization of isolated pregnant human myometrial cells. 63. Tsukamoto T., Kawarabayashi T., Kaneko Y., Kumamoto
American Journal of Obstetrics and Gynecology, 59, T., Sugimori H. (1991). Intracellular calcium of longitu-
1273-9. dinal muscles isolated from pregnant rat myometrium.
58. Reiner O., Marshall J.M. (1976). Action of prostaglandin Cell Biology International Report, 15, 637-44.
PGF 2α on the uterus of the pregnant rat. Naunyn- 64. Wallner M., Mccra P., Ottolia M., Kaczorowski G.J.,
Schmiedeberg’s Archives in Pharmacology, 292, 243-50. Latorre R., Garcia M.L., Stefani E., Toro L. (1995).
59. Shinmoto M., Kawarabayashi T., Ikeda M., Sugimori H. Characterization of and modulation by a beta-subunit of
(1991). Qualitative evaluation of uterine contractions a human maxi KCa channel cloned from myometrium.
recorded by a double guard-ring tocodynamometer. Receptors Channels, 3, 185-99.
American Journal of Obstetrics and Gynecology, 165, 65. Young R.C., Herndon-Smith L. (1991a). Characterization
1282-6. of sodium channels in cultured human uterine smooth
60. Sims S.M., Daniel E.E., Garfield R.E. (1982). Improved muscle cells. American Journal of Obstetrics and
electrical coupling in uterine smooth muscle is associated Gynecology, 64, 175-81.
with increased numbers of gap junctions at parturition. 66. Young R.C., Herndon-Smith L., Anderson Jr. N.C. (1991).
Journal of General Physiology, 80, 353-75. Passive membrane properties and inward calcium current
61. Toro L., Stefani E., Erulkar S. (1991a). Hormonal regulation of human uterine smooth muscle cells. American Journal
of potassium currents in single myometrial cells. of Obstetrics and Gynecology, 164, 1132-9.
 BASIC ASPECTS OF FETAL DEVELOPMENT
AND FETAL ANOMALY
60
Animal Studies of
Fetal Maturation

Norio Shinozuka

INTRODUCTION 2. Animal studies in normal developmental and

maturational course of cardiovascular function.
In perinatal research fields. we are investigating a
3. Chronic fetal stressed model to study fetal reaction
continuously growing organism in adjusting and
for investigating maturation.
developing its vital functions from womb to extra-
uterine life.1 The matured fetus means that the fetus
ANIMAL STUDIES IN FETAL PHYSIOLOGY.
reached at a certain stage of functional growth and
METHODOLOGY USING CHRONIC ANIMAL
development, where a fetus obtains an ability to live
MODEL
outside the womb alone in a clinical term. In a fetal
physiological study, unlike the other, we must As for a clinician in perinatal medicine, the major
emphasize the feature of the fetus. Following concern in animal studies could be the interpretation
specification must taken into account in fetal study; of the results to human fetal physiology. Dynamic
Fetal status are continuously changing as pregnancy changes in fetal developmental course, namely
progressed. The gestational age is an important factor maturation, has been targets for our researches.
in development. The environment of fetus is affected The chronic fetal study, which is more complicated
by both maternal and fetal factors. The fetus respond and invasive method compared with acute model, is
to the insults from outside with variety of reactions. an essential procedure for animal experiment for
Glucocorticoids play a main role in development and investigating ‘maturation”. A lot of basic researches
maturation throughout the fetal life.2,34,5 Thus, when have been carried out to establish a chronic state
we study some fetal physiological response at certain animal model of the fetus. At the beginning of fetal
gestational age, the result means the degree of the physiological researches, an acute fetal preparation
developmental or maturational stage of the fetus. procedure had been used.6-8 From 1960’s, a sheep fetal
The respiratory, cardiovascular and neurological preparation procedure has been applied for the
functions are the major functions to support life. The chronic study model, In 1970’s to 80’s, this metho-
development of lung function was described in dology of fetal chronic preparation, namely
another section, following issues related to studies in ‘unanesthetized fetus9-12 in utero’, was established for
fetal cardiovascular and neurological maturation are the standard procedure for investigating fetal
outlined: physiology.13-17 No objection could be raised that an
1. Animal studies in fetal physiology. Methodology ideal animal model for perinatal research purposes
using chronic animal model. should be a non-human primate model applying a
 Animal Studies of Fetal Maturation 843
baboon or a rhesus monkey. However, a non-human electrodes using stainless wires terminating in metal
primate fetal studies requires a lot of complicated pins or screws are placed bilaterally through fetal
system such as a special cage, a tether system to cranial frontal bone into touch the dura mater. The
connect cables and catheters for maintain preparation, character of ECoG signals is low voltage, low
a special animal care and so on, and, above all, a great frequency and noisy bioelectric signal. To obtain high
deal of expenses. In contrast, when we consider an quality ECoG signals, some techniques such as
availability of pregnant ewes, the total cost, easiness application of sealed cables like coaxial cables,
of animal care, surgical preparation and management, placement of an indifferent and a ground electrodes
the advantage of the sheep chronic experiment is clear are required. For recording myometrial activities
even if the physiological difference among species is (uterine contraction) several wire electrodes were
taken into account. Thus fetal preparation using sewn to the myometrium. Following surgical
pregnant ewe has been a widely approved basic preparation of the ewe and fetus, all fetal catheters
procedure for investigating fetal physiology. and leads were grouped to exit the lateral abdominal
wall of the ewe at a single point. Surgical closure was
The Chronic Preparation of the Sheep Fetus accomplished in layers. During and the days
The term of the fetal sheep is around 145 to 150 days following surgery, the antibiotics were given to the
of gestation (dGA). Birth weight at term is around ewe and fetus.
4.0 to 4.5 kg in the Rambouillet-Columbia sheep. Maintenance: A heparin solution (10 units ml-1 of
Depend on the study protocol, the fetal preparation physiological saline) was continuously infused at a
is usually done around at 100 to 125 dGA. The size of rate around 0.5 ml h-1 into each vascular catheter to
sheep fetus is appropriate for surgical preparation ensure that it remained open. Fetal condition, well-
(approximately 2.0 kg at around 110dGA). being status, is usually checked by using fetal arterial
The techniques have been described in detail blood gas data. When the other fetal biophysical data
elsewhere, a brief outline of the procedure is given in such as ECoG, or fetal heart rate(FHR) are recorded,
this section.18-22 these data are also the parameters to assess fetal well-
Usually, the ewes bred on a single occasion only being status.
and carrying a fetus of known gestational age are used Data acquisition: The biological signals have been
for experiments. The gestational age was counted recorded using the analog recording charts. Recently,
from the mating period and confirmed by ultrasound all data are usually recorded by means of computer
later. Prior to the surgery, the ewe is housed in a assisted data acquisition system (DAS) that equipped
metabolic stall in a room with controlled light/dark biological amps, frequency filters, analog top digital
cycles. Surgery is performed under halothane general converters and so on. Fetal blood pressure is
anesthesia. measured using the pressure transducer and the
The uterus is exposed through a midline abdo- actual fetal pressure values are calibrated by amniotic
minal incision. Hysterotomy is performed and fetuses cavity pressure. All data are stored digitally for
are instrumented with several catheters and elec- further analysis. The scenes of sheep experiments are
trodes. The polyvinyl vascular catheters are placed shown in Figs 60.1 and 60.2.
via the carotid artery and jugular vein and/or femoral
ANIMA STUDIES IN NORMAL
artery and vein. An amniotic cavity catheter is also
DEVELOPMENTAL AND MATURATIONAL
placed. For recording fetal biophysical and neuro-
COURSE OF CARDIOVASCULAR FUNCTION
logical activities, several electrodes are attached. For
electro cardio gram, usually the steel electrodes are The conceptual schema of fetal maturation with
placed at the chest wall. For exploring fetal neuro- gestational age is shown in Fig. 60.3. The degree of
logical activity the electoro corticogram (ECoG) functional maturation must be represented as an
844 Textbook of Perinatal Medicine

Fig. 60.1: The sheep experiments: The fetus is Fig. 60.2: Example of Data acquisition system: The biological
instrumented with several catheters and electrodes signals form fetus are recorded digitally to the computer aided
system for further analysis

functional 50
maturation

Cortisol
40

30
ng/ml

delivery 20

90 100 110 120 130 140 150 dGA 10

0.6 0.7 0.8 0.9 1.0

Fig. 60.3: The conceptual schema of fetal maturation with 0

gestational age: Example of Sheep (Term at around145 to 150 128 130 132 134 136 138 140
dGA)
dGA
exponential growth curve as reported in the cortisol Fig. 60.4: The cortisol level at fetal sheep plasma
level with gestational age 4,23 (Fig. 60.4). Basic
researches of sheep experiments suggest that the
fetal organic maturation is accelerated around (FHR) deceases steadily.26, 27, 30-32 Typical changes in
120dGA.24-30 Although developmental stage of 120 fetal blood pressure and heart rate with gestational
dGA, which means 0.8 dGA, is not simply translated age in sheep is shown in Fig. 60.5. It has been assumed
to that of to 32 weeks at human fetus, the process to that the BP increases during the last of gestation as a
functional development and maturation should be result of both an increase in cardiac output and a rise
similar. in peripheral vascular resistance, whereas the
decrease in FHR has been referred to a function of
Cardiovascular Maturation
the baroreflex to the increased BP. The baroreflex
In the sheep fetus during late gestation, arterial blood induced by increased parasympathetic function via
pressure (BP) increases steadily and fetal heart rate the vagus on basal FHR.
 Animal Studies of Fetal Maturation 845
60 200 variability of arterial pressure and heart rate.26, 39
For these reasons, the ontogenic changes in baro-
reflex function in fetal cardiovascular maturation
50 180
must be characterized. In this section, study

FHR (bpm)
MAP (mmHg)

related to the ontogenic changes in baroreflex

40 160 function in fetal sheep is introduced.

Study Design
30 140
105 110 115 120 125 130 135 140 145 Ontogenic Changes on Broreflex Function
dGA
Tewnty fetal sheep were instrumented and following
Fig. 60.5: Mean fetal arterial blood pressure (MAP) and fetal
heart rate (FHR): MAP increased from 110 to 140 days baroreflex protocol was carried from 110 dGA to 140m
gestation (dGA), whereas FHR decreased steadily from 110 dGA with 5 days interval.
to 140 dGA. bpm, (Beats/min)
Cardiovascular Changes in
Steroid Administration to the Fetus
It has been shown that influences of sympathetic
and parasympathetic activity on baseline FHR Stating at 133±1 dGA, saline (control group: CNTL)
increase with gestational age in the sheep fetus. The or betamethasone (Beta) was administrated to the fetal
hormones that have stimulatory effects on the fetal juglar vain at a rate of 10mg h-1 over the next 48 h.
cardiovascular system increase with gestational Betamethasone infusion was started at 1800 h.
age.26,27, 30-32 The roles of the fetal endocrine, auto- baroreflex protocol was carried out after 40 h at Bata
nomic nerve system, and baroreflex control on the infusion.
fetal cardiovascular system have not yet been charac-
Baroreflex Study Protocol40, 41
terized. In clinical medicine, FHR monitoring is an
important procedure for fetal managements. How- Since baroreflex has been shown to operate an
ever, for understanding physiological meaning of important role at late gestation fetal sheep, much
FHR, we must consider the biophysical background researches have been reported to understand the
factor ie the degree of development, gestational age, control of the fetal circulation. Several method have
intrauterine environment and so on. been used for evoke baro-reflex response of the fetus,
Previous animal studies have been reported the The sensitivity of the baroreflex elicited depend on
specification of fetal cardiovascular developments as the method used. We used Sodium nitroprusside
follows: (SNP) for induce hypotension and Phenylephrine (PE)
1. Cardiac output increased in proportion to fetal for induce hypertension. SNP is known to act as a
gestational age, fetal weight.33-35 vasodilator, both arterial and venous vessels,
2. The cardiac output in the fetus is controlled almost resulting in reduced peripheral vascular resistance
solely by alteration of heart rate.34, 36 and venous return.42 PE acts as an alpha agonists that
3. The fetal heart is operating near the upper limit of increase force of contraction, vascular smooth muscle
the Frank-Starling Curve.37, 38 contraction, increase peripheral resistance and reduce
4. The fetal heart has a limited ability of changing heart rate by vagal reflex.43 Adding both hypotension
stroke volume (inotropic action).33-35 and hypertension trial data with above mentioned
5. Baroreflex has been shown to operate in late logistic procedure, baroreflex function was analyzed.
gestation and plays an important role in regulating Detailed procedure is as follows;
846 Textbook of Perinatal Medicine

Hypotension Ontogenic Changes in Baroreflex Function

After 1h basal recording, SNP (10 mg ml -1 ) was Hypotension induced by SNP
infused intravenously to the fetus at 0.1-6.4 ml
An initial baroreflex action during hypotension
min-1 with 2 min at each increment. Infusion was
induced by SNP was to increase FHR (shortening of
stopped when fetal blood pressure (FBP) had
R-R interval) against dropping FBP due to vasodi-
decreased by 30% or FHR fell below 100 bpm or
latation. Increase in FHR by FBP fall is sympathetic
arrhythmia appeared. Fetal arterial blood samples
activity.
were taken at –5, end of infusion and +10 minutes.
Compensatory tachycardia was reversed as SNP
dosage increased. This phenomena is not clear until
Hypertension
115 dGA, is distinguished at 120 dGA and most
After at least 1h of recovery period was taken form ominous at 135 dGA This breakdown bradycardia
above hypotension experiment, fetuses received PE assume to be caused by decreased volume in venous
(25 mg ml-1 ) intravenously at 0.1-1.6 ml min-1 with 2 return and vagal activity. The difference in response
min at each increment, until FBP increased 30% or to SNP infusion at each gestational ages suggests a
FHR fell below 100 bpm or arrhythmia appeared. developmental degree and a balance between
Fetal arterial blood samples were taken at –5, end of sympathetic and parasympathetic control of cardiac
infusion and +10 minutes. function. However, since cardiac out put is defined
FBP and electrocardiogram (EKG) data were by stroke volume and heart rate, the factor of inotropic
recorded with DAS at 250Hz sampling rate. Mean function, even if it is limited, must be taken into
arterial pressure (MAP) and R-R interval from EKG consideration. The significant difference in response
signals were used for later analysis. Baroreflex between 135 and 145 dGA must be a caused by the
function was analyzed using logistic model as shown ability of inotropic function. Moreover, this result
in Fig. 60.6.44 suggest that 135dGA is a most critical period at

A Model of Baroreflex Response

R-R interval (msec)
500

450 A1 y A1 A4
400 Slope A2 1 exp A2(x A3)
350

300 y: R-R interval (msec)

x : Mean Arterial Pressure (mmHg)
A4 A3
250
A1: Range of R-R interval (msec)
20 30 40 50 60 70
A2: Slope sensitivity
Mean Arterial Pressure (mmHg) A3: Centering point in arterial pressure (mm Hg)
A4: minimum point of R-R interval in reflex
response (msec)

Maximum gain (msec / mmHg) =A2/A1 x 0.25

Saturation (mmHg) = 1.317/A2+A3
Threshold (mmHg)= -1.317/A2+A3

Fig. 60.6: Mathematical model in analyzing baro-reflex response: Using a logistic model,
maximum gain, saturation and threshold are assessed as indices of baro-reflex function
 Animal Studies of Fetal Maturation 847
baroreflex development. The vagal refelex is most at each gestational age, the character of maturational
sensitive and the breakdown bradycardia is easily course is clear. The summary of the developmental
induced (Fig. 60.7). changes in baroreflex function were shown in Fig.
60.9. Two critical point of 115 to 120 dGA and 135 to
Hypertension Induced by PE 140 dGA were distinguished in baorlefrex develop-
During PE induced hypertension trial, R-R interval ment. Significant changes in Max gain at 135 to 140
prolonged linearly according to FBP rise. PE acts dGA, in Saturation at both 115 to 120 dGA and 135 to
mainly as an alpha agonists, and heat rate falls is 140 dGA , and thresholds at 115 to 120 dGA . As stated
induced by vagal reflex The difference in baro-reflex above, these critical point at maturational course
slope might be the activity and sensitivity in pressure might be caused by the degree of developmental
of vagal function. Significantly higher FBP achieved activity, sensitivity, and balance between sympathetic
against similar FHR at slope saturation at late and parasympathetic nerves, peripheral vessel
gestation, suggests the development of cardiac activity, as well as the ability of inotropic action
contractility function. must also be considered. (contractility of the heart).

Analysis of Baroreflex Funtion Effect of Gulcocorticoids on

(ongogenic study) Cardiovascular Function

Using the data obtained from SNP induced hypoten- Previous studies showed that glucocorticoids
sion and PE induced hypertension, the baroreflex administration to the sheep fetus increase in FBP and
curve was studied (Fig. 60.8). When we look at the increase femoral vascular resistance. However,
speculation in range and slope of baroreflex curves precise effects of cardiovascular baroreflex response
to glucocorticoids have not yet been clarified. An
example of studies on betamethsone effect on the fetal
Hypotension induced by SNP baroleflex function at 135 dGA is shown.
600

135
550

500 Ontogenic changses in baroreflex curve

140 130
450 650
125 130
400 600 135
120
125 140
350 115
550 120

500
300 110
450
250
10 20 30 40 50 60 400
MAP (mmHg) base line MAP
350 115

Fig. 60.7: Hypotension by SNP: Open circle shows baseline 300

110
(starting point). Initial reaction of SNP infusion is increase in
FHR (shortening of R-R interval) against FBP fall. 250
20 30 40 50 60 70 80 90 100
Compensatory tachycardia was reversed as SNP dosage MAP (mmHg)
increased. Then, the breakdown bradycardia caused by
decreased volume in venous return and vagal activity was Fig. 60.8: Ontogenic changes in baroreflex curve: The apparent
appeared This phenomenon of breakdown bradycardia difference in range and slope of baroreflex curves at each
appeared after 120 dGA and most omunious at 135dGA gestational is found
848 Textbook of Perinatal Medicine

Ontogenic changes in Barorefrex parameters

Maximum Gain Saturation

30 80
*

25

70
*
20
60 **
15 * *

**
50
10

5 40
Range of R-R interval Thresholds
400 60

350

50
300
250 40
*

200
30
150 *
100 20
110 120 130 140 dGA 110 120 130 140 dGA

Fig. 60.9: Summary of changes ontogenic changes in baroreflex function: Two critical point of 115 to 120 dGA and 135 to 140
dGA were found in baorlefrex development. Significant changes in Max gain at 135 to 140 dGA, in Saturation at both 115 to 120
dGA and 135 to 140 dGA, and thresholds at 115 to 120 dGA . ** * p< 0.05

FBP and FHR Changes in Namely baroreflex curve shifted right and handling
Betamethasone Infusion range was expanded. All parameters of baroreflex
function were significantly altered by betamethasone
FBP was constantly increased after betamethasone
(Fig. 60.11).
(Beta) infusion to the fetuses. In Beta group, FBP was
Recent studies show an elevation of FBP after
statistically higher after 7h of infusion compared with
infusion of glucocorticoids directly to the fetus.45-49
the base line FBP of past 24h before infusion. FBP was
The mechanisms producing an increase in fetal blood
also statistically higher in Beta group after 8 h of
pressure during betamethasone have been discussed
infusion compared with control (CNTL) group. In
as the mediation of an increase in fetal total peripheral
contrast to the fetuses in CNTL showed nominal 24 h
vascular resistance and/or fetal cardiac output.45-49
variation in FHR, Beta fetuses showed significant
Betamethasone may accelerates fetal cardiovascular
decrease in FHR after betemethasone infusion. FHR
maturation, chronological FHR changes in Beta
fall in Beta fetuses from 5 to 9 h after infusion were
fetuses suggest that there are at least two steps of
significant compared the base line FHR of past 24h
cardiovascular alterations induced by betamethasone.
before infusion. FHR from 5 to 12 h after infusion in
Initial FHR decreaseInitial cardiovascular response to
Beta fetuses were significantly lower compared with
increased FBP and significant decrease in FHR in first
CNTL fetuses (Fig. 60.10). After 12h of infusion, FHR
12 h of betamethasone might be caused by basic baro-
in Beta fetuses gradually recovered to base line FHR
reflex response to FBP rise. The second step of FHR
level. No statistical difference was found after 24 h of
recovery against FBP rise may be mainly caused by
infusion between Beta and CNTL fetuses.
resetting of baro-reflex responsibility including
sympathetic and parasympathetic autonomic nervous
Baroreflex Function at 40 h
activity . In addition, at this stage, changes in cardiac
after Beta Administration
output by betamethasone must be taken into account.
Beta fetus showed much wider range of FBP change The newborn lamb has the ability of the heart to alter
with relatively narrower range of FHR change. inotropic state. Thus, near term fetus must have ability
 Animal Studies of Fetal Maturation 849
65 CNTL 180

60
170

55 160

50 150

45 140
-28 -24 -20 -16 -12 -8 -4 0 4 8 12 16 20 24 28 32 36 40 -28 -24 -20 -16 -12 -8 -4 0 4 8 12 16 20 24 28 32 36 40
time (h) time (h)

Betamethasone

180
65

170
60

55 160

50 150

45 140
-28 -24 -20 -16 -12 -8 -4 0 4 8 12 16 20 24 28 32 36 40 -28 -24 -20 -16 -12 -8 -4 0 4 8 12 16 20 24 28 32 36 40
time (h) time (h)

Fig. 60.10: Changes in MAP and FBP by Betamethasone administration on fetus: Stating at 133±1 dGA, saline (control
group:CNTL) or betamethasone (Beta) was administrated to the fetal vain at a rate of 10… g h-1 over the next 48 h. Hourly fetal
blood pressure (FBP) , fetal heat rate (FHR) in control group (CNTL) and betamethasone-treated (Beta) fetuses. Values shown
are means ± SEM. for every hour. Time 0 was settled at the beginning of vehicle or betamethasone infusion Filled bar represents
hours of darkness (2100h –0700h). Shadowed bar represents the infusion periods

to use inotropic action of the heart, even if it is limited,

Baroreflex changes by betamethasone
and the magnitude of the inotropic ability would
750 indicate the degree of maturation of the fetal heart
Beta
function. The other study using betamethasone
650
CNTL treated fetus showed that fetal femoral blood flow and
550
CNTL Beta
femoral vascular resistance tend to recover at the end
Max.gain•@•@24.1•}2.9•@17.3•}1.6 * of 48 h betamethasone infusion. Therefore, the second
450 range 292•}28 431•}55 *
thres . 54.3•}1.8 58.5•} 3.3•@ step cardiovascular alteration also mediated by
350
sat . 63.2•}3.1•@•@74.3•}3.4*
p< 0.05
betamethasone administration to the fetuses.
Above results suggest that there exist several
250
40 50 60 70 80 90 100 important period of gestational age in the course of
MAP (mmHg)
cardiovascular maturation and the process of
Fig. 60.11: Baroreflax changes by betamethasone: Siginificant maturation is mediated and modified by gluco-
changes in each parameters of baroreflex function are found. corticoid. One of the major current concepts of
The curve shifted to right and expanded range of handling programming cardiovascular system states that the
850 Textbook of Perinatal Medicine

precise timing and sequence of maturational events In this section we introduce a long term light
during fetal life are fundamental to normal develop- stressed fetal model by means of increased uterine
ment. activity of oxytocin (LTOT model).

CHRONIC FETAL STRESSED MODEL LTOT Model41, 61-63

TO STUDY FETAL REACTION FOR
Myometrial contractures are characterized by long-
INVESTIGATING MATURATION
lasting low amplitude epoch of myometrial contrac-
From the clinical point of view, major interest in fetal tility occurring throughout pregnancy in sheep.
physiology have been fetal hypoxia. A lot of studies Contractures induce a fall in fetal arterial oxygen
have been carried out to clarify variety of reaction of pressure (PO2) a decrease in uterine blood flow, and
the fetus to acute hypoxia insult in utero. Much also produce mechanical stress to the fetus by
knowledge related to biophysical background in compression. Previous study showed oxytocin (OT)
perinatal medicine such as deceleration in heat rate induced contractures in late gestation sheep altered
monitoring, behavioral state alterations and so on fetal pituitary-adrenal 61, 62 functions and might
have been obtained from animal experiments. Recent accelerate neurological development as revealed in
epidemiological studies, as Baker stated, indicate that ECoG voltage amplitude. 64, 65 Since fetal hypo-
an adverse intrauterine environment affects fetal thalamic - pituitary - adrenal axis plays essential role
physiological development and may be the origins in ovine parturition, these kind of neuroendcrine
of later disease much attention comes to pay the fetal alteration by increased myometrial contractures
environment in the womb. Do the chronic changes in should be associated with alteration of physiologic
environment, in other words, the chronic stress to the function. We hypothesized that long-term increased
fetus really alter the fetal maturational course and myometrial contracture frequency, namely long-term
beyond ? Restricted maternal nutrition have been frequent light stress to the fetus, would alter fetal
shown to have an apparent effects on fetal cardio- physiological development and fetal responses to
vascular function. Animal studies in rats and sheep acute stress episodes. We, therefore exposed pregnant
have been demonstrated hypertensive offspring sheep with repeated pulses of oxytocin from 96 to 131
induced by maternal nutrient restriction and dGA. OT dose not cross the ovine placenta. Thus, no
differences in fetal growth were associated with direct effects on the fetus of OT are responsible for
changes in cardiovascular control any fetal changes.66
Several chronic stressed fetal model have been The LTOT protocol is shown in Fig. 60.12. Ewes
reported. As an altered fetal environment model, received ether saline (control group: CNTL), or
prolonged hypoxia in chronic sheep studies50-55 have oxytocin (600 mU.kg -1.min -1 . long term oxytocin
been demonstrated long-term and short-term effects group: LTOT) infusions into maternal jugular vein at
on fetal cardiovascular function. A long term fetal 0.033 mL min-1 as 5 minutes pulses stating at 96 dGA.
placental embolization model56-58 have been demonst- Oxytocin pulse infusion was stopped a day before
rated umbilical blood flow and heart rate pattern fetal surgery and recommenced 2 days after fetal
alterations and caused hypertension and myocardial surgery. By this procedure of oxytocin pulses,
hypertrophy. A repeated cord occlusion model59, 60 myometrial contracture frequency increased by
have been reported the response alteration in slightly over one hundred percent ewes in LTOT
hormonal and cardiovascular responses. However, a compared with CNTL ewes (Table 60.1).
few studies have been reported related to the Using LTOT model, following issues are studied:
experimental model of long-term environmental 1. Hormonal environment (Cotisol and ACTH)
alteration/stress to the fetus. 2. Blood and arterial blood gas environment
 Animal Studies of Fetal Maturation 851
LTOT protocol

Maternal Fetal
surgery surgery Necropsy

OT pulses OT pulses

91 96 120 122 124 141

dGA
Saline (CNTL) or oxytocin (600 U.kg -1 .min-1 ) (LTOT) was infused into the maternal jugular vein as 5-
5 - min pulses every 20 min.

Fig. 60.12: LTOT protocol: Ewes received ether saline (control group: CNTL), or oxytocin (600µU.kg-1.min-1. long term oxytocin
group: LTOT) infusions into maternal jugular vein at 0.033 mL min-1 as 5 minutes pulses stating at 96 dGA. Oxytocin pulse
infusion was stopped a day before fetal surgery and recommenced 2 days after fetal surgery

Table 60.1: Effect of Oxytocin pulses (LTOT) or vehicle 3. Response to acute fetal hypoxemia (1h) induced
control (CNTL) on the number of conractures h -1 . by administrating nitrogen to the ewe through
Contracute frequency was counted every day and (131±1 dGA)
averaged in each animal to obtain representative values
4. Ontogenic cardiovascular changes and baroreflex
for each period. Mean ± SEM * p < 0.01
alteration.
CNTL LTOT 5. Behavioral alterations.
126-130 dGA 1.35 ± 0.13 * 3.34 ± 0.06 *
Hormonal Environment (Fig. 60.13)
131-135 dGA 1.45 ± 0.09 * 3.21 ± 0.07 *
Basal fetal plasma ACTH and cortisol values during
136-140 dGA 1.52 ± 0.13 * 3.13 ± 0.06 *
study period are presented in Fig. 60.13. There were

A C T H C o r t is o l
50 50

a a
40 40

30 30

20 20

10 10

0 0
128 130 132 134 136 138 140 128 130 132 134 136 138 140

dG A dG A

Fig. 60.13: Fetal plasma ACTH and cortisol concentrations in CNTL (…) and LTOT („).
Mean ±SEM a: p<0.05 compared with 128 to 138 dGA
852 Textbook of Perinatal Medicine

Table 60.2: Arterial blood gas values of CNTL and LTOT during study period. Blood samples were taken at 9:00 –10:00
every day. Data were averaged in each animal to obtain representative values for each period. Mean ± SEM * p < 0.05
CNTL vs LTOT
CNTL LTOT
126-130 dGA pH 7.36 ± 0.001 7.36 ± 0.001
PCO2 (mmHg) 47.3 ± 0.23 48.6 ± 0.09
PO2 (mmHg) 24.3 ± 0.09 * 22.4 ± 0.17 *
Hb (mg/dl) 10.8 ± 0.07 11.1 ± 0.07
O2 sat (%) 64.5 ± 0.33 62.9 ± 0.37
O2 content (ml/dl) 9.3 ± 0.05 9.5 ± 0.05
131-135 dGA pH 7.35 ± 0.001 7.35 ± 0.001
PCO2 (mmHg) 47.5 ± 0.23 49.9 ± 0.09
PO2 (mmHg) 22.4 ± 0.09 * 20.6 ± 0.18 *
Hb (mg/dl) 11.3 ± 0.07 12.2 ± 0.07
O2sat (%) 57.2 ± 0.33 59.2 ± 0.38
O2content (ml/dl) 8.6 ± 0.05 * 9.8 ± 0.05 *
136-140 dGA pH 7.34 ± 0.001 7.35 ± 0.001
PCO2 (mmHg) 48.7 ± 0.28 48.5 ± 0.16
PO2 (mmHg) 20.9 ± 0.06 20.1 ± 0.21
Hb (mg/dl) 12.6 ± 0.07 13.1 ± 0.12
O2sat (%) 52.7 ± 0.49 55 ± 0.34
O2content (ml/dl) 8.7 ± 0.07 * 9.6 ± 0.05 *

no significant difference in ACTH and cortisol values Fetal pO2 was significantly lower and O2 content
between CNTL and LTOT. However, cortisol / ACTH was significantly higher in LTOT at baseline. No
ratios (ng/pg) were significantly lower in LTOT at difference was found in maternal blood gas and pH
128 to 132 dGA (CNTL: 0.13±0.02, 0.24±0.09, 0.21±0.08, values at baseline (Table 60.3). At the end of 60 min.
LTOT: 0.06±0.03, 0.08±0.04, 0.08±0.04). Cortisol is hypoxemia, fetal pH, O2 saturation, O2 content were
higher in 140 dGA in both CNTL and LTOT significantly higher in LTOT, although pO2 did not
differ between two groups (Table 60.4). At 120 min.
Blood and Arterial Blood Gas Environment (60min. after acute hypoxemia insult), blood gas
Fetal arterial blood gas values are summarized in
Table 60.2. PO2 was lower in LTOT at 126 to 135dGA Table 60.3: Baseline fetal and maternal blood gas data
and O2 content was higher in LTOT at 131 to 140 dGA. (mean ± SD)
CNTL LTOT
Response to Acute Fetal Hypoxemia FETUS
Acute fetal hypoxemia insult was induced at 131±1 pH 7.359 ± 0.015 7.363 ± 0.014 N.S.
PCO2 (mmHg) 47.4 ± 5.6 48.8 ± 4.2 N.S.
dGA by administrating nitrogen to the ewe through pO2 (mmHg) 23.6 ± 2.8 21.8 ± 2.3 p<0.05
a tracheal tube for 1 hour, beginning at the start of Hb (g/dl) 11.3 ± 1.3 12.0 ± 1.5 N.S.
oxytocin or saline pulse. Maternal and fetal arterial Sat O2 (%) 60.0 ± 6.5 60.2 ± 5.4 N.S.
O2 content (ml/dl) 8.9 ± 0.8 9.8 ± 1.2 p<0.05
blood samples (0.5 ml) were taken at -60, -15, -5, 5,
10, 20, 30, 40, 60 and 120 minutes. Blood samples were MOTHER
pH 7.476 ± 0.026 7.465 ± 0.021 N.S.
measured using an blood gas analyzer. Oxygen
PCO2 (mmHg) 34.8 ± 3.5 33.8 ± 4.4 N.S.
saturation (%) and hemoglobin (mg dl -1 ) were pO2 (mmHg) 108.5 ± 12.8 117.4 ± 11.2 N.S.
measured with a hemoximeter. O2 content (ml.dl-1) Hb (g/dl) 10.4 ± 1.8 9.8 ± 1.2 N.S.
was calculated from hemoglobin (Hb), O2 saturation Sat O2 (%) 96.6 ± 2.3 97.7 ± 2.4 N.S.
O2 content (ml/dl) 13.7 ± 2.2 12.8 ± 1.6 N.S.
and pO2 values.
 Animal Studies of Fetal Maturation 853
Table 60.4: Fetal blood gas data at the end of 60 min. Table 60.5: Fetal blood gas data at 120 min.
acute hypoxemia (mean ± SD) (60 min after acute hypoxemia insult) (mean ± SD)
FETUS CNTL LTOT FETUS CNTL LTOT
pH 7.355 ± 0.029 7.384 ± 0.006 p<0.05 pH 7.355 ± 0.018 7.372 ± 0.012 N.S.
PCO2 (mmHg) 42.3 ± 1.3 42.2 ± 3.1 N.S. PCO2 (mmHg) 47.6 ± 2.6 46.6 ± 1.8 N.S.
pO2 (mmHg) 14.1 ± 1.0 14.3 ± 2.8 N.S. pO2 (mmHg) 21.1 ± 2.8 20.8 ± 2.3 N.S.
Hb (g/dl) 11.7 ± 1.5 11.3 ± 2.1 N.S. Hb (g/dl) 11.0 ± 0.7 112 ± 1.1 N.S.
Sat O2 (%) 29.4 ± 3.8 38.7 ± 7.2 p<0.05 Sat O2 (%) 55.4 ± 10.5 58.0 ± 6.4 N.S.
O2 content (ml/dl) 4.6 ± 0.7 5.8 ± 1.1 p<0.05 O2 content (ml/dl) 8.2 ± 1.5 8.8 ± 1.2 N.S.

values in both group returned to normal value and LTOT (Fig. 60.15). Linear model analysis proved that
no difference was found between two groups (Table the model of same slope with different intercept by
60.5). LTOT or not was best fitting model and the effect of
Relationship between maternal and fetal pO2 and LTOT was statistically significant (p<0.001).
O2 content showed lower pO2 but higher O2 content During hypoxemia and recovery period, fetal
at same maternal oxygen delivery in LTOT. Linear pH tend to shift higher and it’s variability was less
model analysis showed statistically significant LTOT in LTOT compared with CNTL (pH variability
effect (P<0.001 Fig. 60.14). expressed as coefficient of variation (CV) : CNTL:
O2 content at pO2 was significantly higher in LTOT 0.33±0.15, LTOT: 0.12 ± 0.06, mean ± SD P< 0.05) (Fig.
and O 2 saturation at pO 2 , which expressed O 2 60.16).
dissociation curve, was obviously sifted to the left in

A B

A B 14 80
35 14
70
12
Fetal O2 saturatin (%)

30 12
Fetal O2 content (ml/dl)

60

25 10 10



50

20

8
8





40


15 6


6



30
10 4


4

20
5 2


0 0 2 10
0 20 40 60 80 100 120 140 2 4 6 8 10 12 14 16 18 20 5 10 15 20 25 30 5 10 15 20 25 30
Maternal pO2 (mmHg) Maternal O2 content (ml/dl) Fetal pO2 (mmHg) Fetal pO2 (mmHg)
Y=0.45xX - 0.034xXxA -1.16 Y=3.04x X - 3.10xA -9.44
Y=0.12x X + 0.0092xXxA + 8.56 Y=0.59x X - 0.055xXxA -0.03 A=+1 when CNTL A=+1 when CNTL
A=+1 when CNTL A=+1 when CNTL A=-1 when LTOT P<0.001
A=-1 when LTOT P<0.001
A=-1 when LTOT P<0.001 A=-1 When LTOT P<0.001

CNTL LTOT CNTL LTOT

Fig. 60.14: Fetal and maternal PO2 (A) fetal and maternal O2 Fig. 60.15: Fetal O2 saturation (A) and fetal O2 content (B) in
content (B) before and during hypoxemia … CNTL z LTOT (A) relation to fetal pO2 before and during hypoxemia. … CNTL z
Y=0.12 × X + 0.0092 × X × Z + 8.56 (CNTL Z=+1:Dashed line, LTOT (A) Y=3.04 × X - 3.10 × Z -9.44 (CNTL Z=+1:Dashed
LTOT Z=-1: straight line, P<0.001) (B) Y=0.59 × X - 0.055 × X line, LTOT Z=-1: straight line, P<0.001) (B) Y=0.45 × X - 0.034
× Z -0.03 (CNTL Z=+1:Dashed line, LTOT Z=-1: straight line, × X × Z -1.16 (CNTL Z=+1:Dashed line, LTOT Z=-1: straight
P<0.001) line, P<0.001)
854 Textbook of Perinatal Medicine

7.5 55

50 * * *
7.45

FBP (mmHg)


45

7.4


40
pH

7.35


35

124 128 132 136 140
dGA

7.3
200

7.25
8 10 12 14 16 18 20 22 24 26 28 30 180

FHR (bpm)
Fetal pO2 (mmHg)
Fig. 60.16: Fetal pH values before and during acute
hypoxemia … CNTL, z LTOT 160

* * * * * *
Ontogenic Cadiovascular Changes
140
and Baroreflex Alteration 124 128 132 136 140
FBP was significantly higher from 126 to 128 dGA in Fig. 60.17: Ontogenic changes in FBP and FHR in CNTL and
the fetuses of LTOT ewes compared with the fetuses LTOT. CNTL(€) and LTOR(z), mean±SEM p<0.05 compared
of CNTL. FHR was significantly lower in the fetuses with CNTL
of LTOT from 126 to 131 dGA (Fig. 60.17). The slope
of daily FBP changes (CNTL 0.76±0.21, LTOT 600
0.27±0.06 mmHg dGA-1) and FHR (CNTL -1.91±0.20,
LTOT -0.70±0.41 bpm dGA-1) was significantly lower
in LTOT (Fig. 60.18).
R-R interval (msec)

There was no difference in the fall in FBP at the 500

end of SNP infusion. FBP dropped by 31 to 37 %.
However, total SNP dosage (adjusted by fetal weight)
required to produce this fall in FBP was significantly
400
higher in LTOT (CNTL 21.1±3.7, LTOT 34.7±4.6 µg/
kg). Initially, fetus tried to compensate FBP fall by
increasing FHR. In contrast to CNTL fetuses tend to
show early breakdown of compensatory reaction and 300
fall into bradycadia. The breakdown point to fall into 20 30 40 50
bradycardia was significantly different between
MAP (mmHg)
CNTL and LTOT (CNTL:41.6±0.6 bpm, 328±10 msec,
LTOT: 38.7±1.4 bpm, 328 ±16 msec) (Fig. 60.18). PO2 Fig. 60.18: Hypotension by SNP: The breakdown point to fall
into bradycardia was significantly different between CNTL and
and O2 saturation values was significantly lower at LTOT (CNTL:41.6±0.6 bpm, 328±10 msec, LTOT: 38.7±1.4
the end of SNP infusion in CNTL. No difference was bpm, 328 ±16 msec) LTOT fetus showed resistive reaction to
found in blood gas during experiment in LTOT hypotension insults
 Animal Studies of Fetal Maturation 855
Table 60.6A: Arterial blood gas values of CNTL and LTOT Table 60.6B: Arterial blood gas values of CNTL and
during SNP induced hypotention. Mean ± SEM * p < 0.05 LTOT during PE induced hypertention. Mean ± SEM
compared with baseline (-5min)
CNTL LTOT
CNTL LTOT
Baseline (-5) pH 7.34 ± 0.01 7.34 ± 0.01
Baseline (-5) pH 7.34 ± 0.002 7.33 ± 0.01 PCO2 (mmHg) 50.4 ± 3.2 50.3 ± 1.9
PCO2 (mmHg) 48.4 ± 3.4 49.2 ± 1.1 PO2 (mmHg) 21.5 ± 2.8 23.0 ± 3.1
PO2 (mmHg) 22.6 ± 1.4 21.1 ± 1.9 Hb (mg/dl) 12.7 ± 2.0 13.7 ± 1.4
Hb (mg/dl) 12.0 ± 0.5 12.6 ± 0.8 O2sat (%) 52.7 ± 7.9 56.9 ± 6.7
O2sat (%) 58.7 ± 3.2 57.9 ± 4.4 O2content (ml/dl) 8.9 ± 1.0 10.1 ± 0.6
O2content (ml/dl) 9.4 ± 0.3 9.5 ± 0.5 End of infusion pH 7.36 ± 0.007 7.35 ± 0.01
End of infusion pH 7.34 ± 0.005 7.34 ± 0.01 PCO2 (mmHg) 47.8 ± 2.2 48.9 ± 1.8
PCO2 (mmHg) 50.9 ± 0.8 50.5 ± 1.2 PO2 (mmHg) 22.1 ± 1.7 23.0 ± 2.6
PO2 (mmHg) 18.9 ± 1.3 * 21.2 ± 2.0 Hb (mg/dl) 13.5 ± 0.9 13.8 ± 1.3
Hb (mg/dl) 12.1 ± 1.1 12.8 ± 1.2 O2sat (%) 59.1 ± 1.7 56.0 ± 7.2
O2sat (%) 46.3 ± 2.3 49.6 ± 5.3 O2content (ml/dl) 10.7 ± 0.62 10.2 ± 1.3
O2content (ml/dl) 7.59 ± 0.9 * 8.3 ± 0.7 +10 min. pH 7.34 ± 0.008 7.34 ± 0.01
+10 min. pH 7.34 ± 0.003 7.34 ± 0.01 PCO2 (mmHg) 48.2 ± 2.4 49.3 ± 1.6
PCO2 (mmHg) 50.1 ± 0.5 47.0 ± 1.4 PO2 (mmHg) 21.5 ± 1.1 23.2 ± 2.9
PO2 (mmHg) 21.1 ± 1.5 22.9 ± 2.0 Hb (mg/dl) 12.5 ± 0.3 13.4 ± 1.3
Hb (mg/dl) 12.3 ± 1.1 12.3 ± 0.9 O2sat (%) 54.8 ± 4.6 55.7 ± 7.2
O2sat (%) 54.1 ± 4.6 55.4 ± 6.2 O2content (ml/dl) 9.2 ± 0.7 9.8 ± 1.1
O2content (ml/dl) 8.8 ± 0.6 8.9 ± 0.7
ACTH Cortisol
200 40

a a
150 30 a b
pg/ml

ng/ml

100 20

50 10

0 0
Baseline End +10 min Baseline End +10 min
Fig. 60.19: ACTH and cortisol response during SNP infusion CNTL (…) and LTOT („).
Mean ±SEM a: p<0.05 compared with base line. b: p<0.05 CNTL vs LTOT

fetuses (Table 60.6). ACTH and cortisol response to shown in Fig. 60.21. ECoG activity represents basic
hypotension showed attenuated response. (Fig. 60.19). behavioral rhythm, little is known about diurnal
However, no differences was found in cortisol / variation of ECoG pattern. Characteristic ECoG
ACTH ratios (ng/pg) between CNTL and LTOT. pattern have been discussed with alternation between
Baroreflex curve was shifted to right and showed low voltage fast activity (LV) state and high voltage
mature pattern in LTOT fetuses. Maximum gain slow activity (HV) state. As pregnancy progressed the
(msec/mmHg) was significantly different between amplitude increased and the difference between HV
CNTL and LTOT (CNTL 24.4 ± 2.7, LTOT 16.6 ± 2.3). state and LV state becomes clear.
The ECoG characteristic changes were analyzed
Behavioral Alterations by means of ECoG power spectral distribution
ECoG has been used for analyzing fetal neurological analysis. 3 hour Raw ECoG data sampled at 250 Hz
activity. Example of analog ECoG recording were were analyzed using conventional Fast Fourier
856 Textbook of Perinatal Medicine

600 140 dGA and low frequency was statistically lower

550 at 126 and 130 dGA Defference The HV and LV peak.

The mature pattern in ECoG spectra was found in in
500
LTOT fetus compared with LTOT.

450 In addition, HV-LV ECoG cyclicity analysis 21 was

done with following procedurss; 1): Denoising by
400
Wavelet transform filtering; 2) HV-LV ECoG cyclicity


350 by periodogram analysis. Hourly Peak cycle and cycle
300 were calculated by using period gram, Daily data at
40 45 50 55 60 65 70 130, 135 and 140 dGA were studied (Fig. 60.23). Peak
CNTL
MAP (mmHg)
LTOT
HV-LV cycle frequency in CNTL was changed to
lower by gestational age where as that in LTOT was
Fig. 60.20: Baroreflex alteration by LTOT: Baroreflex curve was
shifted to right and showed mature pattern in LTOT fetuses already low at 130 dGA and no difference was found
by gestational age. Peak HV-LV cycle frequency was
statistically lower in LTOT at 130 and 135 dGA.
Transform (frequency resolution at 0.04Hz, range 0- FBP and FHR in each HV and LV state at 130 and
41.6Hz). Spectral edge frequency (90%) was calcu- 140dGA were shown in Fig. 60.24. Mean FBP was
lated. 3 hour data (recorded at 10:00-14:00) at 126, 130, significantly higher and FHR was significantly lower
135, 140 dGA were studied (Fig. 60.22) ECoG power in both HV and LV state in LTOT compared with
spectra analysis by calculation spectral edge fre- CNTL.
quency distribution <Szeto, 1982 #587; Szeto, 1985 FHR was increased in HV state from 130 dGA.
#309; Szeto, 1990 #305> showed apparent distinction Both FBP and FHR were increased in HV state at at
between low frequency peak and high frequency peak 140 dGA. The difference in state characteristics
in LTOT (Fig. 60.22). In LTOT, high Spectral edge becomes apparent by plotting on the one chart. LV
frequency was statistically higher in LTOT at 126 to and HV state difference in FBP and FHR in CNTL

Fig. 60.21: Typical ECoG recording at 110, 125 and 135 dGA
 Animal Studies of Fetal Maturation 857
A) CNTL B) LTOT
12 12
126 dGA 126 dGA
8 8

4 4

0 0

12 130 dGA 12 130 dGA

Relative distribution (%)

Relative distribution (%)

8 8

4 4

0 0

12
135 dGA 12 135 dGA
8 8

4 4

0 0
12 12
140 dGA 140 dGA
8 8

4 4

0 0
0 5 10 15 20 25 0 5 10 15 20 25

Fig. 60.22: ECoG spectral edge frequency at each gestational age: ECoG power spectra analysis by calculation spectral edge
frequency distribution showed apparent distinction between low frequency peak and high frequency peak in LTOT (Fig. 60.2).
In LTOT, high Spectral edge frequency was statistically higher in LTOT at 126 to 140 dGA and low frequency was statistically
lower at 126 and 130 dGA Defference The HV and LV peak
*
2.5 and LTOT was summarized in Fig. 60.25. The pattern
of cardiovascular changes in behavioral state is shifted
to right in LTOT fetus suggest acceleration of
maturation in LTOT
In those LTOT studies, no difference was found
Cyclicity (cycle/h)

2.0 * at necropsy in body weight, organ weight adn

placenta between CNTL and LTOT.

WHAT HAPPENED IN LONG-TERM

LIGHT STRESS TO THE FETUS?
1.5 A single contracture produced in response to a single
pulse of OT administrated to the pregnant ewe in late
gestation stimulates the release of fetal ACTH. A
longer period of fetal exposure to contractures at an
earlier stage of maturation altered the sensitivity of
1.0 the fetal adrenal to ACTH both under basal and
Fig. 60.23: Peak HV-LV cycle frequency following exposure to hypoxemia, hypotension and
858 Textbook of Perinatal Medicine

60

55
FBP (mmHg) 50

45

40
HV LV HV LV
200

180
FHR (bpm)

160

140
HV LV HV LV

130 dGA 140 dGA

Fig. 60.24: FBP and FHR in HV and LV state at 130 and 140dGA

200
hypertension. In LTOT study, fetal PO2 was lower and
O2 content higher in LTOT fetuses than CNTL fetuses.
190
This finding indicating that LTOT fetus were not
hypoxemic. They adapted to repeated mild stress and
180 13 developed compensatory mechanisms by altering
0 oxygenation accompanied by a shift of the oxygen
FHR (bpm)

130
170 dissociation curve to the left.
135 We also found an alteration in cardiovascular
160 140 ontogenic change and baro-receptor response in
135 LTOT fetuses. The baroreflex curve in LTOT showed
150 14 right shift and mature pattern that indicated from
0 previous ontogenic studies. From obtained results, we
140 speculate that LTOT fetus have more ability of
40 45 50 55 60 isotropic function than CNTL fetuses. Fetal cardio-
FBP (mmHg)
vascular maturation during the final month of
LTOT LV LTOT HV pregnancy is characterized by a rise in FBP and a fall
CNTL LV CNTL HV in FHR. Higher FBP and lower FHR in LTOT fetuses
compared with gestation matched controls suggests
Fig. 60.25: LV and HV state difference in FBP and FHR in
CNTL and LTOT: The pattern of cardiovascular changes in
an acceleration of fetal cardiovascular maturation.
behavioral state is shifted to right in LTOT fetus suggest ECoG is one of the main indices of fetal neurolo-
acceleration of maturation in LTOT gical function. Biological variation is dependent upon
 Animal Studies of Fetal Maturation 859
behavioral states in late gestation. Difference in FBP early environmental stimulation changes a develop-
and FHR in each HV-LV state indicates the degree of mental course and induces later physiological
state maturation. The alteration of ontogenic changes alteration. The environmental interactions in early
in the relationship of FBP and FHR to fetal ECoG development lead to change in the physiological and
states. (HV/LV states) following LTOT suggests an physical phenotype of the developing embryo or fetus
acceleration of fetal neurological maturation.67, 68 in expectation of future advantage in a particular
Above all results, we speculate that the altered predicted adult environment. The word “program-
intrauterine environment induced by increased ming” sounds like that the biological process is
uterine contracture activity accelerates endocrino- commanded and corded. Gluckman and Hanson use
logical, neurological and functional maturation either the term of “predictive adaptive responses” (PARs)
by altered fetal oxygenation, glucocorticoid activity to describe environmental responses.71
and/or physical stimulation of the fetus. In the period before birth, the environmental
factors play an important roll in biological process of
FETAL MATURATION, ADAPTATION OR fetal maturation and some future life is possibly
ADJUSTMENT BY THE VARIOUS defined. Studying fetal maturation and it’s alteration
STRESS TO THE FETUS by environmental stimulation, we can catch on a part
Through above mentioned animal studies, there rises of future process in development and health.71 18, 72
hypothesis that any stress to the fetus, environmental For these reasons, much attention should be paid to
or congenital, could induce an acceleration of investigate fetal physiology and biomedical sciences.
functional maturation. Initial compensatory response
of the fetus to the environmental stress would be the REFERENCES
acceleration of the maturation.
1. S TAVE U. Maturation, Adaptation, and Tolerance. In:
An adequate stress such as uterine contracture Stave U, ed. Perinatal Physiology. New York: Plenum
must be a necessary factor to fetal stimulation. For Publishing, 1970.
clinician, not only the gestational age but the matu- 2. LIGGINS GC. Premature delivery of foetal lambs infused
rational age must be a desirable index to assess fetal with glucocoticoids. J Endocr 1969;45:515-523.
3. LIGGINS GC, FAIRCLOUGH RJ, GRIEVES SA, KENDALL JZ, KNOX
well-being taken into account. Yet to further basic DS. The mechanism of initiation of parturition in the ewe.
research are required to answer those questions. Recent Prog Horm Res 1973;29:111-159.
There is currently much interest in the effects of 4. CHALLIS JRG, LYE SJ. Perturition. In: Knobil E, Neill JD, eds.
The Physiology of Reproduction, Second Edition. New
the quality of the intrauterine environment. Recent
York: Raven Press, 1994.
epidemiological studies indicate that an adverse 5. CHALLIS JRG, PATRICK JE. Fetal and maternal estrogen
intrauterine environment affects fetal physiological concentrations throughout pregnancy in the sheep. Can J
development and may be the origins of later adult Physiol Pharmacol 1981;59:970-978.
6. DAWES GS. Changes in the circulation at birth. Br Med Bull
disease.69-71 18, 72 Restricted maternal nutrition have 1961;17:148-53.
been shown to have an apparent effects on fetal 7. DAWES GS. The umbilical circulation. Am J Obstet Gynecol
cardiovascular function. Animal studies have been 1962;84:1634-48.
demonstrated hypertensive offspring induced by 8. DAWES GS. Placental development and umbilical blood
flow. J Obstet Gynaecol Br Emp 1962;69:815-7.
maternal nutrient restriction and differences in fetal 9. NATALE R, CLEWLOW F, DAWES GS. Measurement of fetal
growth were associated with changes in cardio- forelimb movements in the lamb in utero. Am J Obstet
vascular control. Barker hypothesis,69, 70 namely, fetal Gynecol 1981;140:545-51.
10. C LEWLOW F, D AWES GS, J OHNSON B, M., W ALKER DW.
origins of adult disease is an important key word in
Changes in Breathing, Electrocortical and Muscle Activity
perinatal biomedical science. This concept has been in Unanesthetized Fetal Lamb. J Physiology 1983;341:463-
called as fetal programming, which means that an 476.
860 Textbook of Perinatal Medicine

11. DAY MA, DARBY P, HAGIN S. Autoradiographic analysis of 27. HANSON MA. The inportance of baro- and chemoreflexes
regional brain glucose utilization in chronically monitored in the control of the fetal cardiovascular system. J Dev
unanesthetized fetal sheep. Brain Res 1983;313:133-6. Physiol 1988;10:491-511.
12. SZETO HH. Effects of narcotic drugs on fetal behavioral 28. DAWES GS, FOX HE, LEDUC BM, LIGGINS GC, RICHARDS RT.
activity: acute methadone exposure. Am J Obstet Gynecol Respiratory movements and rapid eye movement sleep
1983;146:211-6. in the foetal lamb. J Physiol 1972;220:119-43.
13. SOMA LR, WHITE RJ, KANE PB. Surgical preparation of a 29. C LEWLOW F, D AWES GS, J OHNSTON BM, W ALKER DW.
chronic maternal-fetal model in pregnant sheep: a Changes in breathing, electrocortical and muscle activity
technique for the measurement of middle uterine blood in unanaesthetized fetal lambs with age. J Physiol
flow, umbilical blood flow, and fetal sampling in the 1983;341:463-76.
awake sheep. J Surg Res 1971;11:85-94. 30. BODDY K, DAWES GS, FISHER R, PINTER S, ROBINSON JS. Foetal
14. G RESHAM EL, R ANKIN JH, M AKOWSKI EL, M ESCHIA G, respiratory movements, electrocortical and cardiovascular
BATTAGLIA FC. An evaluation of fetal renal function in a responses to hypoxaemia and hypercapnia in sheep. J
chronic sheep preparation. J Clin Invest 1972;51:149-56. Physiol 1974;243:599-618.
15. DAWES GS. Fetal circulation and breathing. Clin Obstet 31. DAWES GS. The control of fetal heart rate and its veiability
Gynaecol 1974;1:139-49. in lambs. In: Kunzel W, ed. Fetal heart rate monitpring.
16. DAWES GS. Fetal breathing movements and sleep in sheep. Berin: Springer-Verlag, 1985.
Ann Rech Vet 1977;8:413-7. 32. UNNO N, WONG CH, JENKINS SL, et al. Blood pressure and
17. DAWES GS. The central control of fetal breathing and heart rate in the ovine fetus: ontogenic changes and effects
skeletal muscle movements. J Physiol 1984;346:1-18. of fetal adrenalectomy. Am J Physiol 1999;276:H248-56.
18. N ATHANIELSZ PW, BAILEY A, POORE ER, THORBURN GD, 33. RUDOLPH AM, HEYMANN MA. Cardiac output in the fetal
HARDING R. The relationship between myometrial activity lamb. The effect of spontaneous and induced changes of
and sleep state and breathing in fetal sheep throughout heart rate on right and left ventricular output. Am J Obstet
the last third of gestation. Am J Obstet Gynecol 1980;138: Gynecol 1976;124:183-192.
653-9. 34. RUDOLPH AM, HEYMANN MA. Fetal and neonatal circulation
19. ROBINSON SR, WONG CH, ROBERTSON SS, NATHANIELSZ PW, and respiration. Ann Rev Phyisol 1974;36:187-207.
SMOTHERMAN WP. Behavioral responses of the chronically 35. RUDOLPH AM, HEYMANN MA. Circulatory Changes during
instrumented sheep fetus to chemosensory stimuli Growth in the Fetal Lamb. CIrc. Res. 1970;26:289-299.
presented in utero. Behavioral Neuroscience 1995;109:551- 36. R UDOLPH AM. Organization and Control of thr Fetal
62. CIrculation. In: Jones CT, Nathanielsz PW, eds. The
20. DERKS JB, GIUSSANI DA, JENKINS SL, et al. A comparative Physiological Development of the Fetus and Newborn.
study of cardiovascular, endocrine and behavioral effects New York: Academic Press, 1985.
of betamethasone and dexamethasone administration to 37. WALKER AM, FLEMING J, SMOLICH R, STRUDEN R, HORNE R,
fetal sheep. J Physiol 1997;499.1:pp217-266. MALONEY J. Fetal oxygen consumption, umbilical circula-
21. SHINOZUKA N, NATHANIELSZ PW. Electrocortical activity in tion and electorocortical activity transitions in fetal lambs.
fetal sheep in th last seven days of gestation. J Physiol J Developmental Physiology 1984;6:267-274.
1998;513.1:273-281. 38. GIRBERT RD. Control of the fetal cardiac output during
22. UNNO N, WONG CH, JENKINS SL, et al. Blood Pressure and changes in blood volume. Am J Physiol 1980;238:H80-H86.
Heart Rate in the Ovine Fetus: Ontogenic Changes and 39. ITSKOVIZ J, LAGAMMA EF, RUDOLPH AM. Baroreflex control
Effects of Fetal Adrenalectomy. Am J Physiol 1998;276: of the circulation in chronically instrumented fetal lambs.
H248-H256. Circ Res 1983;52:589-596.
23. MAGYAR DM, FRIDSHAL D, ELSNER CW, et al. Time-trend 40. S HINOZUKA N, Y EN A, N ATHANIELSZ PW. Increased
analysis of plasma cortisol concentrations in the fetal sheep myometrial contracture frequency produced by pulse
in relation to parturition. Endocrinology 1980;107:155-159. administration of Oxytocin to the pregnant ewe from 96
24. HYMAN AI, HAWORTH G, BOWE ET, DANIEL SS, JAMES LS. to 131 days gestation alters fetal oxygenation and
Effects of sympathetic blockade on the fetal responses to responses to acute hypoxemia. Am J Obstet Gynecol 1999.
asphyxia. Biol Neonate 1972;21:1-8. 41. S HINOZUKA N, Y EN A, N ATHANIELSZ PW. Increased
25. VAPPAVOURI EK, SHINEBOURNE EA, WILLIAMS RL, HEYMANN myometrial contracture frequency at 96-140 days
MA, R UDOLPH AM. Development of cardiovascular accelerates fetal cardiovascular maturation. Am J Phyiol
responses to autonomic blockade in intact fetal and 2000;278:H41-49.
neonatal lambs. Biol Neonate 1973;22:177-188. 42. BENOWITZ NL. antihypertensive agents. In: Katzung BG,
26. HANSON MA. The control of heat rate and blood pressure ed. Basic & Clinical Pharmacology 7th Ed. Stamford:
in the fetus: theoretical considerations. In: Hanson MA, Appleton & Lange, 1998.
Spencer JAD, Rodeck CH, eds. Fetus and Neonate: 43. HOFFMAN BB. Adrenoceptor-Activating & Other Sympatho-
physiology and clinical apprications. Cambridge: mimetic Drugs. In: Katzung BG, ed. Basic & Clinical
Cambridge University Press, 1993 (vol 1). Pharmacology 7th Ed. Stamford: Appleton & Lange, 1998.
 Animal Studies of Fetal Maturation 861
44. KENT BB, DRANE JW, BLUMENSTEIN B. Mathamatical Model 59. GIUSSANI DA, UNNO N, JENKINS SL, et al. Dynamics of
to Access Changes in Barorecepter Reflex. Cardiology cardiovascular responses to repeated partial umbilical
1976;57:295-310. cord compression in late-gestation sheep fetus. Am J
45. WOOD CE, CHEUNG CY, BRACE RA. Fetal Heart rate arterial Physiol 1997;273:H2351-60.
pressure, and blood volume response to cortisol infusion. 60. GIUSSANI DA, SPENCER JAD, MOORE PJ, BENNET L, HANSON
Am J Physiol 1987;253:R904-R909. MA. Afferent and efferent components of the cardio-
46. DERKS JB, MULDER EJH, VISSER GHA. The Effect of Maternal vascular reflex response to acute hypoxia in term fetal
Betamethasone Administration on the fetus. Br J Obstet sheep. J Physiol 1993;461:431-449.
Gyneac 1995;102:40-46. 61. OWINY JR, SADOWSKY DW, ZARECZNY S, NATHANIELSZ PW.
47. DERKS JB, GIUSSANI DA, VAN DAM LM, et al. Differential Effect of Pulsatile Intravenous Oxytocin Administration
Effects of Betamethasone and Dexamethasone Fetal to the pregnant Sheep over the Last Third of Gestation on
Administration of Perturition in Sheep. J SOc Gyecol Invest Fetal ACTH and Cortisol Response to Acute Hypotention.
1996;3:336-341. J Soc Gynecol Invest 1995;2:13-18.
48. DODIC M, W INTOUR EM. Effects of prolonned (48 H) 62. OWINY JR, JENKINS SL, SADOWSKY DW, NATHANIELSZ PW.
infusion of cortisol on blood pressure, renal function and Effect of Pulsatile Oxytocin Administration to the pregnant
fetal fluids in the immature ovine foetus. Clin Exp. ewe in the Last Third of Gestation on Fetal ACTH and
Pharmacol. Physiol 1994;21:971-980. Cortisol Response to Acute Hypoxemia. J Soc Gynecol
49. TANGALAKIS K, LUMBERS ER, MORIZ KM, TOWSTOLESS MK, Invest 1995;2:673-677.
WINTOUR EM. Effect of cortisol on blood pressure and 63. SHINOZUKA N, YEN A, NATHANIELSZ PW. Alteration of fetal
vascular reactivity in the ovine fetus. Exp Physiol oxygenation and responses to acute hypoxemia by
1992;77:709-717. increased myometrial contracture frequency produced by
50. KITANAKA T, GILBERT RD, LONGO LD. Maternal responses pulse administration of oxytocin to the pregnant ewe from
to long-term hypoxemia in sheep. American Journal of 96 to 131 days’ gestation. Am J Obstet Gynecol 1999;180:
Physiology 1989;256:R1340-7. 1202-1208.
51. KITANAKA T, ALONSO JG, GILBERT RD, SIU BL, CLEMONS GK, 64. SADOWSKY DW, MARTEL JK, JENKINS SL, POORE MG, CABALUM
LONGO LD. Fetal responses to long-term hypoxemia in T, NATHANIELSZ PW. Pulsatile oxytocin administered to
sheep. American Journal of Physiology 1989;256:R1348- ewes at 120 to 140 days gestational age increases the rate
54. of maturation of the fetal electrocorticogram and nuchal
52. A LONSO JG, O KAI T, L ONGO LD, G ILBERT RD. Cardiac activity. J Dev Physiol 1992;17:175-81.
function during long-term hypoxemia in fetal sheep. 65. S ADOWSKY DW, M ARTEL J, C ABALUM T, P OORE MG,
American Journal of Physiology 1989;257:H581-9. NATHANIELSZ PW. Oxytocin given in a pulsatile manner to
53. LONGO LD, DALE PS, GILBERT RD. Uteroplacental Os Uptake: the ewe at 120 to 140 day’s gestational age increases fetal
continuous measurements during uterine quiesence and plasma cortisol. Am J Obstet Gynecol 1992;166:200-205.
contractions. Am J Physiol 1986;250:R1099-R1107. 66. GLATZ TH, WEITZMAN RE, NATHANIELSZ PW, FISHER DA.
54. ALLEN WW, POWER GG, LONGO LD. Fetal O2 changes in Metabolic clearance rate and transplacental passage of
response to hypoxic stress: a mathematical model. Journal oxytocin in the pregnant ewe and fetus. Endcrinology
of Applied Physiology: Respiratory, Environmental & 1980;106:1006-11.
Exercise Physiology 1977;42:179-90. 67. WAKATSUKI A, MURATA Y, NINOMIYA N, MASAOKA JG, TAYNER
55. UENO N, ZHAO Y, ZHANG L, LONGO LD. High altitude- JG, KUTTY KK. Autonomic nervous system regulation of
induced changes in alpha1-adrenergic receptors and baseline heart rate in fetal lamb. Am J Obstet Gynecol
Ins(1,4,5)P3 responses in cerebral arteries. American 1992;167:519-523.
Journal of Physiology 1997;272:R669-74. 68. WAKATSUKI A, MURATA Y, NINOMIYA N, MASAOKA JG, TAYNER
56. MUROTSUKI J, BOCKING AD, GAGNON R. Fetal heart rate JG, KUTTY KK. Physiologic barorecepter activity in fetal
patterns in growth-restricted fetal sheep induced by lamb. Am J Obstet Gynecol 1992;167:820-827.
chronic fetal placental embolization. Am J Obstet Gynecol 69. BARKER DJP. Fetal origins of cornary heart desease. Br Med
1997;176:282-90. J 1995;311:171-174.
57. GAGNON R, MUROTSUKI J, CHALLIS JR, FRAHER L, RICHARDSON 70. BARKER DJP. Fetal nutrition and cardiovascular disease in
BS. Fetal sheep endocrine responses to sustained later life. Br Med Bull 1997;53:96-108.
hypoxemic stress after chronic fetal placental emboli- 71. GLUCKMAN PD, HANSON M. The Fetal Matrix Evolution,
zation. Am J Physiol 1997;272:E817-23. Development and Disease. Cambridge: Cambridge
58. G AGNON R, JOHNSTON L, M UROTSUKI J. Fetal placental University Press, 2005.
embolization in the late-gestation ovine fetus: alterations 72. NATHANIELSZ PW, BERGHORN KA, DERKS JB, et al. Life before
in umbilical blood flow and fetal heart rate patterns. Am birth: effects of cortisol on future cardiovascular and
J Obstet Gynecol 1996;175:63-72. metabolic function. Acta Paediatr 2003;92:766-72.
 61
Basic Background of Congenital
Anomalies: Neural Tube Defects

Keiya Fujimori, Akira Sato

INTRODUCTION more sites, or failure of two sites to meet. Neural

tube closure is normally complete by the end of the
Neural tube defects (NTDs) are the second most
fourth week after conception (6 weeks after the last
common class of congenital anomalies after cardiac
menstrual period), a time when many women do not
defects. A worldwide incidence of isolated (ie,
yet realize they are pregnant.
nonsyndromic) NTDs is 1.4 to 2.0 per 1,000 love
The most common types of NTDs are listed in
births.1 They can also occur as part of a genetic
Table 1.4 Anencephalus is the most severe defect, in
syndrome or constellation of abnormalities. They are
which the forebrain, meninges, valt of the skull, and
a major cause of stillbirth, neonatal and infant death,
scalp all fail to form. It is lethal, resulting in stillbirth
and lifelong severe handicap. Anencephaly accounts
or early neonatal demise. Spina befida involves
for one half of all cases of NTDs and is incompatible
failure of fusion of caudal portion of neural tube,
with life. With treatment, 80 to 90 percent of infants
usually of 3-5 contiguous vertebrae and spinal cord
with isolated spina bifida survive with varying
or meninges or both exposed to amniotic fluid.
degree of handicap. Factors that influence eventual
Meningocele is the protrusion of the meninges and
neurological function include the size and location
cerebrospinal fluid into a sac covered by epithelium.
of the defect, trauma to exposed neural tissue, timing
Myleomeningocele is most common and serious
of surgical closure, degree of associated
defects that include the spinal cord, nerve roots,
ventriculomegaly, and occurrence of complication
meninges, and cerebrospinal fluid. Commonly it
such as infection. It is well known that NTDs are occurs in the lumbar area. As meninges or neural
preventable disease among the few birth defects. tissue plus meninges are exposed to the amniotic fluid
Preconceptional counseling and folic acid and eventually to the environment, neural tissue is
supplementation are very important. damaged, causing the structures supplied by the
damaged nerves to be dysfunctional. Lesions in the
EMBRYOLOGY AND TYPES OF NTDS
lumbosacral area can lead to paraplegia and lack of
The neural folds in the brain and spinal cord regions bowel or bladder control. The level of the lesion in
fuse in the midline, converting the neural tube by usually reflected in severity of the clinical deficit,
days 26 to 28 of embryonic life.2 Recent data indicate with higher lesions having more pronounced deficits.
that closure occurs in separate regions that then fuse.3 Open defect are often associated with
Clinical data suggest five possible closure sites. NTDs ventriculomegaly or hydrocephalus as a result of a
likely result from either failure of closure in one or block to cerebrospinal fluid circulation. The increased
 Basic Background of Congenital Anomalies : Neural Tube Defects 863
intracranial pressure may cause pressure atrophy of considered that Valproic acid impair folate absorption
the developing brain, although neurological of act as antagonists. Aminopterin and isotretinoin
dysfunction cannot be reliable estimated from the also have been associated with anencephaly or
thickness of the compressed cortical mandle. encephalocele.
Rachischisis describes the situation in which none of Some inherited syndromes known to include
the vertebral arches fuse, and the entire spine is open. NTDs include Meckel-Gruber, Roberts-SC
This condition is generally incompatible with life. phocomelia, Jarco-Levin, and Harde syndrome, as
well as trisomy 13, trisomy 18, and triploidy. These
ETIOLOGY autosomal recessive diseases have 25 % recurrence
Many risk factors of NTDs are known so far risk, and trisomies 13 and 18 and triploidy have a 1
including family history, exposure to certain % recurrence risk. 13 Cloacal extrophy and
environmental agents, genetic syndromes and racial sacrococygeal teratoma may be associated with spina
or ethnic groups. Main and Mennuti presented the bifida, and amniotic bands may cause spina bifida or
recognized causes of neural tube defects in Table 2.5 anencephaly.13
Family history is the most important risk factor Some geographic regions and racial or ethnic
groups are associated with NTDs. The United
for NTDs. Because they are multifactorial in
Kingdom has the highest frequency of NTDs, with
inheritance, the risk to a first-degree relative is
an incidence of almost 1% compared with 0.2 % in
approximately 2 to 3 percent. While this is lower than
the United Staes.14
the risk of autosomal dominant or recessive disorder,
China, Egypt and India also have a very high
it is 20 to 30 times higher than the risk of NTDs in
incidence. The reasons of these high incidences are
the general population. The level of risk is directly
considered to be related both the ethnic (genetic)
related to the number of affected relatives and their
background of the inhabitants and environmental
degree of relatedness of the fetus.6,7 However, only
influences such as diet. For example, Sikhs living in
5% of NTDs occur in families with a positive family
India have more than twice the incidence of NTDs
history.8 More than 90% occur in families with no
as Sikhs living in Canada.7
prior history.9
Certain ethnic and racial groups also appear to
Exposure to certain environment agents has been be at high risk. For example, a study using of
implicated in neural-tube defect formation. Exposure population-based data from California found that
must occur during the first 28 days of gestation when incidence of NTDs of Hispanic women was higher
the neural tube is developing. Hyperglycemia, from than Caucasian women (1.12 vs.0.96 per 1,000).
insulin-dependent diabetes increases the risk for African-American and Asian women were at low risk
neural-tube defect.9 Although this may be inhibit fetal (0.75 and 0.75 per 1,000).15
glycolysis, functional deficiency of arachidonic acid Several investigators reported that obese women
or myoinositol in the developing embryo, or had a two-to threefold risk for NTDs as well as other
alterations in the yolk sac,10 the exact mechanism is anomalies.16-18. Subsequently, Shaw et al. found a
unknown. Hyperthermia (high maternal body significant twofold increased incidence of NTDs in
temperature) during neural-tube formation has also women whose body mass index (BMI) was 30 or
been implicated to cause defects. Maternal fever and higher.19,20
sauna baths have both been reported to increase the Although, there is no firm evidence that influenza
relative risk up to sixfold.11 virus causes congenital malformation,21 Lynberg et
Anticonvulsants, most notably valproic acid and al. reported in a case-control study that children born
carbamazepine, induced NTDs. Especially, fetuses to women with influenza early in pregnancy had a
exposed to valproic in the first trimester a 1 to 2 threefold risk of NTDs. This may be related to
percent of risk of spina bifid. 12 The reason in associate hyperthermia.22
864 Textbook of Perinatal Medicine

The most important environment influence in autoantibodies against folate receptors in women
NTDs formation appears to be related to the dietary could be associated with pregnancy complicated by
intake of folic acid, because pregnancies complicated a NTD.29
by a fetal NTD have lower maternal plasma levels of
folate than pregnancies that are unaffected. Recently, DIAGNOSIS
a specific gene defect associated with folic acid Alpha-Fetoprotein (AFP)
metabolism has been implicated. A thermolabile
Prior to the late 1970s, there was no way to identify
variant of 5,10-methylentetrahydrofolate reductase
NTDs during pregnancy, but then it was discovered
(MTHFR) has themutation 677C®T, which results in
that amniotic fluid and maternal serum alfa-
a substitution of valine for alanine. This variant
fetoprotein was a marker for pregnancy of NTDs.
enzyme has reduced activity leading to altered
AFP is a fetal-specific globlin similar to albumin in
homocysteine metabolism. Hyperhomocystinemia
molecular weight and is synthesized early in gestation
increases the risk for fetal NTDs, atherosclerosis,
by the yolk sac and subsequently by the
thromboembolism, and recurrent miscarriage. 23
gastrointestinal tract and fetal liver. The kidney and
Several studies have shown that parents who have
placenta also produce trace amounts of AFP. The level
had a pregnancy complicated by a NTD and their
of fetal plasma AFP peaks between 10 and 13 weeks
affected offspring are more likely to carry a mutation of gestation and declines exponentially from 14 to
in the gene encoding the enzyme methylentetrahy- 32 weeks and then more sharply until term. AFP
drofolate reductase (MTHFR) than the unaffected enters the fetal urine and is excreted into the amniotic
population. For example, in the Netherlands, 14-16% fluid. Peak levels of amniotic fluid AFP (AFAFP) are
of mothers, 10-15% of fathers, and 13-18% of children reached between 12 and 14 weeks of gestation,
with spina bifida are homozygous for the MTHFR decline between 10 and 15 percent per week during
mutation compared with 5% of the general the second trimester, and are almost non-detectable
population.24-26 Other mutations in this enzyme with at term.30 AFP passes into the maternal circulation
similar effects also have been reported.26 Therefore, by diffusion across the placental membranes and may
it seems possible that folic acid supplementation helps also be transported via the placental circulation.31
to overcome the effects of this enzyme mutation, AFP levels in maternal plasma or serum rise above
resulting in more normal levels of homocysteine and non-pregnant levels as early as the 7 th week of
adequate production of methionine. The Medical gestation. Although, maternal serum levels are
Research Council Vitamin Study Research Group significantly lower than amniotic fluid levels, these
published the results of a large, prospective, increase during gestation.32 When there is a fetal
randomized, double-blind study of folic acid abnormality such as an opening uncovered by
supplementation conducted at 33 centers in seven epitherium in the body or number of other problems,
countries. 27 The results showed that folic acid then maternal AFP serum level are increased. Brock
supplementation reduced NTDs recurrences by 70 and Sutcliffe showed that amniotic fluid AFP levels
%.27 Czeizel and Dudas subsequently showed that were much higher in pregnancies complicated by fetal
periconceptional folic acid supplementation anencephaly. 33 Subsequently, Brock et al.
decreased the risk of a first occurrence of a NTD.28 demonstrated that maternal serum AFP levels were
But, folic acid supplementation dose not prevent all also elevated in affected pregnancies.34 The first large
cases, other unknown genes or factors are presumed prospective trial for maternal serum AFP screening
to cause some cases. Recently, Rothenberg et al. was the UK Collaborate Study on Alpha-fetoprotein
showed that autoantibodies against folate receptors in Relation to Neural Tube Defects.35 Subsequently,
were present in sera from women whose pregnancies other investigators confirmed the effect of screening
are complicated by a NTD. They hypothesized that forNTDs. 36-38
 Basic Background of Congenital Anomalies : Neural Tube Defects 865
Maternal serum alpha-fetoprotein (MSAFP) Raising the twin cutoff to 5.0 MoM decrease the false-
screening for NTDs is ideally performed between positive rate 3 % but also decreases the detection of
16 and 18 weeks of gestation. MSAFP is measured in anencephaly to 83 % and open NTDs to 39 %. Wapner
ng/ml and reported as a multiple of median (MoM) et al. reported that a detection rate was 50 to 85 %
of the unaffected population. MoM is used because and a 5 % false-positive rate using a cutoff of 4.5
AFP levels do not follow a Gaussian distribution, MoM. 44 Because serum screening for fetal
and because it aids comparison of results form abnormalities in multiple gestation will always be
different laboratories and populations. Cutoffs limited by the inability to confirm which fetus is
between 2.0 to 2.5 MoM (for most laboratories) as affected, many centers do not offer serum screening
upper limits indicate an increased risk for a fetal NTD in multiple gestation even for NTDs.
of other structural anomaly (and warrants further Women with MSAFP levels higher than cutoff
evaluation). It is considered that the detection rates level of 2-2.5 MoM should be referred for genetic
are almost 100 % for anencephaly and 85 to 92 % for counseling and consideration of a diagnostic test. The
open spina bifida, with a false-positive rate between diagnostic test offered to women with a positive
2 and 5 %.39 A number of factors can influence the MSAFP test result is genetic amniocentesis. If the
interpretation of an MSAFP value. The most AFAFP level is elevated, an assay is performed to
important factor for efficient MSAFP screening is the determine the presence or absence of
accuracy of the gestational age determination. acetylcholineesterase. Acetylcholineesterase is
Consequently, a first trimester ultrasound (especially predominately neuronally derived, giving it
measurement of crown lump length; CRL) is the additional specificity for nervous system lesions.
preferable means of documenting gestational age. Therefore, elevated AFAFP together with the
And femur length and biparietal diameter should be presence of acetylcholineesterase is considered
measured to confirm gestational age for AFP diagnostic for a fetal NTD. A combined use AFP and
screening. Maternal weight affects the MSAP acetylcholineesterase together identified 100 % of
concentration. The heavier the women, the lower the cases of anencephaly, 100 % of cases of open spina
MSAFP value as a result of dilution in the larger blood bifida, and 20 % of ventral wall defects, with a false-
volume. Maternal ethnicity may also alter the positive rate of 2.2 per 1,000 amniocentesis.45 One
interpretation of an MSAFP level, because black advantage of amniocentesis is that amniotic fluid also
women have a 10 to 15 % higher MSAFP than non- can be obtained for determination of the fetal
blacks.40 This is important because the incidence of karyotype. In pregnancies complicated by an elevated
NTDs in blacks is lower. Pregnant women with MSAFP level, the incidence of fetal aneuploidy is 0.61
insulin-dependant diabetes mellitus have MSAFP % in ultrasounographically determined normal
values that are significantly lower than non-diabetic fetuses and 16 % in abnormal fesuses.46,47
women in the second trimester, which requires Women already known to be at high risk of having
adjustments in the interpretation.41.42 This is critical a fetus with a NTD because of a previously affected
because there is up to a 10-fold higher frequency of pregnancy, a positive family history, medication
NTDs in the offspring of these patients. MSAFP also exposure, diabetes, or other risk factors, can be
must be altered in multiple gestations. Because the offered a diagnostic test directly. Performing a
maternal serum AFP level is approximately doubled genetic amniocentesis in all those women would
in normal twin pregnancy, different cutoffs are result in a 98 % detection rate for NTDs and a 100
needed to interpret this test in multiple gestation. % detection rate for aneuploidy. However, all high-
When a 2.5 MoM cutoff in twin pregnancy is used, risk women for NTDs would undergo amniocentesis
99 % of cases of anencephaly and 89 % of open NTDs unnecessarily. Although second trimester
are detected but generate a 30 % false-positive rate.43 amniocentesis is a relatively safe procedure, it is
866 Textbook of Perinatal Medicine

associated with a post procedure pregnancy loss rate

of approximately 1 in 200.48

Ultrasound
The ultrasound diagnosis of neural tube defects is
based upon soft tissue and bone findings with the
recognition of associated abnormalities in the skull
and brain. The soft tissue findings include absence
of skin covering the defect and presence of a round
sac (Fig. 61.1) that may correspond to a meningocele
or myelomeningocele. The bone findings are derived
from the vertebral abnormalities associated with spina
bifida. Fig. 61.2: Severe ventriculomegaly in 30th week of gestation
is present on the transverse view of head with
Spina bifida is associated with a variety of typical meningomyelocele.
intracranial abnormalities, including ventri-
culomegaly (Fig. 61.2) and hypoplasia of the posterior
fossa structures. The associated abnormalities include
frontal bone scalloping (lemon sign; Fig. 61.3)49 and
obliteration of the cisterna magna with either an
absent cerebellum or abnormal anterior curvature
of the cerebellar hemispheres (banana sign; Fig.
61.4).49 The fruit signs are very helpful for early
diagnosis of the open spina bifida.
There are three main scanning sections used in
the evaluation of the spine: sagittal, transverse, and
coronal.50 In the sagittal section, the normal spine
appears as two parallel lines converging in the
sacrum. Sagittal scans are also useful for evaluating Fig. 61.3: Axial ultrasound in the fetal head demonstrated
bifrontal deformity of the calvaria (arrows) (Lemon sign)

Fig. 61.4: Obliteration of the cisterna magna with either

Fig. 61.1: A sagittal scan of the spine reveling a abscent cerebellum or abnormal anterior curvature of the
meningomyelocele (arrows) overlying a spinal defect. cerebellar hemispheres (Banana sign)
 Basic Background of Congenital Anomalies : Neural Tube Defects 867
the spinal curvatures of which exaggeration may be is uncertain. In the RADIUS (routine antenatal
an indirect sign of spina bifida. In the coronal section, diagnostic imaging with ultrasound) trial, in which
the normal spine appears as either two or three routine ultrasound was performed in conjunction
parallel lines. Spina bifida is typically characterized with maternal AFP screening, the sensitivity was
by a widening of the two external lines due to a 80%.52 In a survey of European centers, Boyd et al.
divergent separation of the lateral processes of the reported overall sensitivity of 75%, but large variation
vertebrae (Fig. 61.5). Sagittal and coronal views are between centers from 33% to 100% 53 . In one
most useful in this evaluation. In the transverse retrospective study conducted in Great Britain, the
section, the neural canal appears as a closed circle. In estimated sensitivity was marginally higher for serum
the presence of a defect, the posterior laminae are AFP screening, 84% to 92%, than for ultrasound
typically absent, and the lateral processes are set screening, 70% to 84%54. In all of these studies, it is
apart (Fig. 61.6).51 The presence of a sac certainly is unclear whether the cranial signs of fetal spina bifida
helpful the diagnosis of the spinal defect whereas were systematically researched. In a more recent
the absence of a sac can make detection difficult. This retrospective multicentric study using the cranial
myelomeningocele sac should not be confused for a signs, the sensitivity of ultrasound was 85%.55 Careful
skin-covered defect. It is a common belief that scanning of the rest of the fetus should be performed
indirect signs of spina bifida, such as paralysis of the to exclude associated abnormalities.
lower extremities and bladder distention, can be Several authors have reported on the accuracy of
useful in the diagnosis of the lesion. the prenatal diagnosis of spina bifida by ultrasound.
The accuracy in the diagnosis of spina bifida Table 3 shows the results of the three largest series
depends on the experience of the sonographer, the available for study.50
quality of the equipment, and the amount of time Regarding the diagnosis of the other NTDs using
dedicated to the scan. It is believed that the accuracy ultrasound, anencephaly was the first congenital
of referral centers should be close to 100%, in large anomaly identified in utero with ultrasound.56 The
part due to recognition of associated cranial findings. diagnosis relies on the failure to demonstrate the
The accuracy of routine non-targeted examinations cranial vault. The anencephalic fetus has a typical

Fig. 61.6: Transverse scan of the body of a fetus affected by

a large spinal defect (arrows). The cystic and irregular echoes
Fig. 61.5: Colonal plane demonstrating lateral splaying of the arising posteriorly from the defect suggested the presence
lateral process with widening of the spinal canal (arrows) of meningomyelocele.
868 Textbook of Perinatal Medicine

froglike appearance and usually has a short neck (Fig. 1. cephaloceles are often associated with
61.7). The diagnosis can probably be made within hydrocephaly
the ten weeks of gestation by transvaginal 2. brain tissue can be seen in some cephaloceles
ultrasound. 3. cystic hygromas usually have multiple septa, are
Cephalocele is also to be diagnosis by transvaginal often associated with other signs of hydrops, and
ultrasound within the ten weeks of gestation. Specific have a paracervical origin, and
findings in diagnosis of the cephalocele are to identify 4. severe scalp edema can be confused with a
the soft tissue masses from scalp and the skull defect cephalocele, but usually a sagittal scan can identify
(Fig. 61.8). The helpful findings for differential an intact skull and the diffuse nature of the
diagnosis are: condition.57

ROUTE OF DELIVERY
NTDs remain controversial as to whether the route
of delivery influences outcome. Theoretically, a
vaginal delivery may be further damaged by the
mechanical forces of labor and by amniotic fluid
contamination of the cerebrospinal fluid because of
exposed neural tissue during labor. In the early 1980s,
Chervenak, et al. reported that infants with NTDs
delivered by elective cesarean section (CS) have a
better outcome in a small series of infants. 58
However, in a retrospective study of children with
spina bifida, significant differences in any of several
Fig. 61.7: Acrania/anencephaly. Transvaginal scan in colonal
neurologic functions were not noted regardless of
plane shows protruding brain (arrows) with absent calvaria.
This has a “Mickey Mouse” shape on coronal scans. route of delivery. In early 1990s, two papers
published conflicting results from large populations
of affected infants. A prospective series in 1991 by
Luthy, et al. compared infants with spina bifida
delivered by CS before labor, CS after labor, and
vaginal delivery. 59 Level of motor deficit was
assessed for each child as their motor level in relation
to their radiologically determined anatomic level with
degree of deficit and then evaluated across delivery
categories. A significantly greater degree of motor
loss, regardless of the anatomic level of the lesion,
was noted in children delivered after labor, either
by CS or vaginally. The greatest preservation of
motor skills was noted in children delivered by CS
before the onset of labor. In contrast, another review
of outcomes in a similar, relatively large series of
infants with NTDs did not reveal significant
differences among routes of delivery.60 As endpoints,
Fig. 61.8: Encephalocele. Transvaginal scan of cranium
shows large amount of brain protruding posteriorly (thin this study assessed neurologic level and method of
arrows) and a bony defect (big arrow). community locomotion. Infants were broadly
 Basic Background of Congenital Anomalies : Neural Tube Defects 869
grouped into functional neurologic levels of L2, L3- with a two-hit hypothesis in these fetuses. The first
4, and below L5 levels. Although vaginal delivery “hit” is the defect itself, and the second comes from
initially seemed to be more neurologically continued exposure to amniotic fluid. 65 An
deleterious to breech infants, even this significance experimental evidence from both animal and human
was lost on follow-up of these infants. However, as studies suggests that early gestational repair of open
breech presentation, resulting from neurologic spina bifida may help preserve neurological function
dysfunction of hydrocephalus with an enlarged head, that might be lost due to in utero mechanical and
is common in pregnancies complicated by fetal spina chemical trauma. Animal studies involving primates,
bifida, cesarean delivery is standard for the breech rats, and pigs have demonstrated that, compared to
fetus with an NTD.60 The best delivery rout for the an untreated group, surgical closure successfully
vertex fetus remain controversial. No prospective preserved neurologic function.66-68
randomized trial of vaginal delivery versus cesarean Moreover, several investigators theorized that
delivery for vertex fetuses with spina bifida has been antenatal closure or coverage of the spine defect
performed. All studies of vaginal versus cesarean might prevent some of the neurological damage.
delivery are retrospective and all suffer from various Recently, both open surgical closure and laparoscopic
biases.59,61,62 Theoretically, cesarean delivery possibly techniques are being evaluated. Harrison’s group,
avoids mechanical trauma and infection of the fetal by using the fetal sheep model, has shown that repair
spine. of induced fetal spine defects prevent tissue damage
Because it is still not clear whether or how the and improve neurological function.69 Bruner et al.
method of delivery significantly affects neurologic described four human fetuses whose open lower
outcome in these infants, American College of spine defects were covered endoscopically with a
Obstetricians and Gynecologists recommends that maternal skin graft at 22 to 24 weeks.70 It was hoped
decisions about the timing and route of delivery that this would prevent herniation of the hindbrain
should be made individually in consultation with into the foramen magnum with obstruction and
personal with experience and knowledge of such ventriculomegaly, the Arnold-Chiari malformation.
complications, which may include maternal-fetal They also compared 10 fetuses that underwent open
medicine specialists, neonatologists, and pediatric surgical repair at 26 to 30 weeks with 20 fetuses
neurosurgeons.4 without antenatal repair. 71 The surgically treated
Generally, delivery at term is optimal. However, fetuses had a significantly decreased need for
rapidly increasing ventriculomegaly may prompt ventriculoperitoneal shunt placement after delivery.
delivery before term so that a shunting procedure Johnson et al at Children’s Hospital of Philadelphia
can be performed. (CHOP) also suggests that a reversal of the hindbrain
The fetus with spina bifida should be delivered herniation and a decreased incidence of neonatal
at a hospital with neonatal intensive care facilities ventriculoperitoneal shunting for hydrocephalus can
and personal capable of managing the spine defect be achieved.72
and any immediate complications. 63 Because Open maternal-fetal surgery for NTD was initially
individuals with a NTDs are at risk of developing a undertaken at four centers in the United States as an
severe, potentially life-threatening allergy to latex, investigative procedure under the guidance of
clinicians handling the infant should wear latex-free institutional review boards. Many centers believe the
gloves.64 procedure to be an innovative therapy that should
not be ethically withheld. However, a survey of
FETAL SURGERY (IN UTERO REPAIR) almost 1000 members of the Society for Maternal-
Isolated open spina bifida often results in permanent Fetal Medicine indicated that 56% felt the procedure
neurological damage. Observations are consistent has still not been validated.73
870 Textbook of Perinatal Medicine

Fetal surgical repair of open spina bifida exposes PREVENTION

the mother to the risks of anesthesia, hemorrhage,
The risk of having a NTD pregnancy can be reduced
chorioamnionitis and sepsis, thrombosis, tocolytic
by raising folic acid consumption around the time of
induced pulmonary edema, and uterine rupture.
conception. 79-81 But, how much folic acid
Additionally, preterm labor, preterm premature
supplementation is enough to prevent NTDs is still
rupture of membranes, and oligohydramnios may
controversial. Women in Western countries typically
occur in up to 50% of patients.74 Because of concerns
have a baseline folate level of 5 ng/ml (normal rage;
about the safety and unproven benefits, fetal surgery
6-20ng/ml).82 The Food and Drug Administration in
for the correction of open spina bifida should be
U.S.A. established standard fortifying cereal and
considered investigational. This surgery should only
grain products such as cereal, bred, rice and pasta
be conducted in a collaborative research setting in
with folic acid. By putting 140µ g of folic acid into
highly specialized centers.75 The randomized trial has
each 100g of grain products, it was established that
begun in the face of strong physician and patient
the folic acid intake would increase 100µ g per day.83
belief that maternal-fetal surgery for NTD is a proved
Although women of reproductive age should be
and beneficial technique. If clinical outcomes are not
advised to ingest a diet that includes folate-rich
improved by the intervention, future open surgical
foods, several studies have shown that diet alone is
procedures for this condition should be abandoned.76
not effective in increasing serum folate levels.
It also remains controversial because spina bifida is
Therefore, folic acid supplementation should be
not a lethal defect.
encouraged.
The ingestion of supplement 0.2mg of folic acid
MANAGEMENT
each day would reduce the incidence of NTDs by
Although recent reports indicate that NTDs in utero only 20 %.82 These calculations are supported by data
repair may improve neurologic function and reduce from the U.S. Public Health Service that confirm since
morbidity from hydrocephalus and the Arnold- grain fortification began, the incidence of NTDs in
Chiari II malformation by reversal of the hindbrain the United State has decreased by only 19 %.84 It is
herniation component, the treatment of NTDs has recommended that women of reproductive age take
been performed by postnatal surgical management. 0.4mg of folic acid supplement each day. This would
Postnatal surgery is aimed at covering the exposed reduce the incidence of NTDs by 36 %. Intake of a
spinal cord, preventing infection, and treating 4mg supplemental dose is recommended for women
hydrocephalus with a ventricular shunt. Steinbok et with high risk for an offspring with NTDs. For
al. reported a 91 % shunt rate in 101 children after example, if previous pregnancy has been complicated
minimum follow-up period of 8.6 years. 77 The by a NTD, the mother’s intake of folic acid
children’s Hospital of Philadelphia published shunt supplement should be 4mg per day in the next
rate among 189 children treated for spina bifida pregnancy, starting at least 4 weeks before conception
between 1983 and 2000.78 One hundred percent (35/ and continuing through the first 3 months of
35) of children with thoracic level lesion’s received pregnancy.85 This would reduce the incidence of
shunts, compared with 88 % (100/114) of children NTDs by 82 %. A 5 mg a day supplement dose in
with lumbar lesion and only 68 % (27/40) of children predicted to reduce the incidence of NTDs by 85 %.82
with lesions confined to the sacrum. In recently Although folic acid is considered nontoxic even a
treated patients, the upper level of the spina bifida very high doses and is rapidly excreted in the urine,
lesion appears to be a major determinant of the need there seems to be minimal risk associated with a high
for shunt placement. Fewer neurosurgeons are supplementation of 5 mg of folic acid per day.
automatically placing shunts at the same time as the Supplementation folic acid could mask the symptoms
spinal lesion is closed. of pernicious anemia. However, folic acid cannot
 Basic Background of Congenital Anomalies : Neural Tube Defects 871
mask the neuropathy typical of this diagnosis. PROGNOSIS AND OUTCOME
Currently, 12 % of patients with pernicious anemia The estimated 23 % of NTD pregnancy is aborted.94,95
present with neuropathy alone.86 With folic acid Despite aggressive intervention, nearly 14 % of all
supplementation, this proportion may be increased, spina bifida neonates do not survive past 5 years of
but there is no evidence that initiating treatment after age, with the mortality rate rising to 35 % in those
the development of a neuropathy results in with symptoms of brainstem dysfunction secondary
irreversible damage.87 to the Arnold-Chiari malformation.96 Mothers who
The March of Dimes contracted the Gallop choose to continue the pregnancy must prepare for
Organization to conducted a random-digit-detailed a child with significant care needs and high medical
telephone survey of a national sample of 2001 women expenses. Unfortunately many healthcare
aged 15 to 45 years to assess knowledge about folic professionals have considered that the fetus with
acid use.88 Less than a third of women of childbearing spina bifida would be mentally retarded, never walk,
age consume a daily supplement containing folic acid. and suffer bladder and bowel incontinence. Recently,
Only 13 % of women knew that folic acid helps Mirzai et al. commented that the majority of children
prevent birth defects, and only 7 % knew that folic with myelomeningocele could have a normal IQ and
acid should be taken before pregnancy. a socially acceptable degree of continence and be able
Without folic acid supplementation, the empirical to walk.97 The greatest concern is whether the child
recurrence risk after one affected child is 3 to 4 %, of spina bifida will ever walk. In a 25-year follow up
and after two affected children it is 10 %. With of 71 patients treated at birth in an aggressive, non-
supplementation, the risk after one affected child is selective manner, Bowman et al. observed that 46 %
less than 1 %.14 of young adults (33/71) ambulated the majority of
In humans, the only source of folic acid is the diet, the time (75-100%). 63 An additional 13 % (9/71)
and absorption occurs primarily in the proximal ambulated 25-50% of the time. Forty-one percent (29/
jejunum. Before folic acid can be absorbed, it must 71) ambulated only with the aid of wheelchair. When
be reduced to the monoglutamate form.89 Pancreatic stratified by lesion level, patients with lower defects
conjugates within the intestine are responsible for were more likely to ambulate the majority of the time.
this process. The activity of conjugate is decreased Next problem of fetus with spina bifida is
by anticonvulsants, oral contraceptives, alcohol, and intelligence. Bowman et al. reported that 85 % of the
sulfa drugs. So, women taking antiepileptic agents 71 young adults followed by their group were
decrease absorption of folic acid resulting to folic attending or had graduated from high school and/
acid deficiency. 90-92 or college, and 63 % attended regular classes.63 Forty-
Folic acid supplementation may not decrease the five percent were actively employed, and almost 10
risk of NTDs in women with high first trimester % worked as volunteers. Most of the 71 patients lived
blood glucose levels, or high first trimester maternal with their parents, although 11 lived independently
temperature, or in women who take valproic acid. and two were married. Mirzai et al. noted that 60 %
In women with high glucose levels, high maternal of their young adults had normal IQ and
temperature, the exact mechanism is unknown. First development.97 However, a normal IQ was seen in
trimester valproic acid use results in a 1-2 % risk of 76 % without hydrocephalus. McLaurin et al.
having a fetus with spina bifida, but the mechanism reported that 70 % of myelomeningocele had a normal
may be different from that of other antiepileptic IQ.98 Steinbok et al. observed that 58 % of their cohort
agents. 93 Fetuses with aneuploidy or genetic attended public school, and were in the appropriate
syndromes may have NTDs as a results of their grade for their age.77 So, most children with spina
specific generic abnormality. These NTDs are not bifida are not mentally retarded. Concern about
prevented by folic acid. bladder and bowel incontinence, Bowman et al.
872 Textbook of Perinatal Medicine

noted that 85 % of their young adults (60/71) used 3. Golden JA, Chernoff GF. Multiple site of anterior neural
tube closure in humans: Evidence from anterior neural
clean intermitted catheterization (CIC), and 90 % of
tube defects (anencephaly). Pediatrics 1995;95:506-10.
those (54/60) performed their own catheterization. 4. American Collage of Obstetricians and Gynecologists,
For those patients on CIC, 15 % always had urinary Committee on Practice Bulletin: Neural tube defects.
continence, 68 % were dry the majority of the time No44. July, 2003.
5. Main DM, Mennuti MT. Neural tube defects: Issues in
(75-100%), and 7 % were dry 50 % of the time. Fifty- perinatal diagnosis and counseling. Obstet Gynecol
two percent of the young adults reported bowel 1986;67:1-16.
control the majority of the time, and 52 % reported 6. Bonaiti-Pellie C, Smith C. Risks tables for genetic
100 % social bowel continence. 63 Steinbok et al. counseling in some common congenital malformations.
J Med.Genet 1974;11:374-77.
reported 75 % social continence of urine, defined as 7. Nussbaum RL, McInnes RR, Willlard HF.. Genetics of
the ability to remain dry and odor-free without the disorders with complex inheritance. In: Thompson and
use of a diaper, and 86 % social continence of bowel.77 Tompson genetics in medicine.6th ed.Philadelphia: WB
Saunders 2001;289-310.
It should be obvious form these report that most
8. Aitken DA, Crossley JA, Spencer K. Prenatal screening
affected children will grow into young adults will for neural tube defects and aneuploidy. In: Rimsui DL,
normal intelligence, walking, and with social Connor JM, Pyerutz RE, Kort BE. ed.Emery and Rimoin’s
continence of both bladder and bowel. Bruner and principles and practice of medical genetics,4th ed. New
York : Churchill and Livingstone, 2002;763-801.
Tulipan emphasized that, although a small number 9. Becerra JE, Khoury MJ, Cordero JF, Erickson JD. Diabetes
of affected children would experience devastating mellitus during pregnancy and the risks for specific birth
sequelae, equal number would be apparently normal, defects : A population based study. Pediats 1990;85:1-9.
and prenatal imaging was becoming increasingly 10. Reece EA, Hobbins JC. Diabetic embryopathy:
Pathogenosis prenatal diagnosis and prevention. Obstet
sophisticated in identifying the extent of disease and Gynecol Surv 1986;41:325-35.
likely long-term outcomes.99 11. Milunsky A. Genetic disorders and the fetus :
Diagnosis,Prevetion and treatment, 3rd ed. Balimore,
RECURRENCE RISK Johns Hopkins University Press 1992;1-12.
12. Robert E, Robert JM, Lopras C. Is valproic acid
Several types of NTDs appear to have a unique teratogenic? Rev.Neural 19831;39:445-47.
recurrence risk. Hall et al. reported 7.8 % recurrence 13. Jones KL. Smith’s Recognizable Pattern of Human
Molformation,5th ed., Philadelphia, Sanders, 1997.
risk with high spina bifida, 0.7 % with low spina 14. Williams Obstetrics: Prenatal diagnosis and fetal therapy,
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15. Feuchtboum LB, Currier RJ, Riggle S, Roberson M, Lorey
incidence of neural tube defects based on specific FW, Cunningham GC. Neural tube defect prevalence in
factors in the United State (Table 4.).5 The common California (1990-1994) : eliciting patterns by type of defect
risk factor, family history, varies with the underling and maternal race / ethnicity.Genet.test 1999;3:265-72.
16. Mikail,L.N.,Mittendorf.R.,Walker,C.K. : The association of
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17. Waller DK, Mills JL, Simpson J.L., Cunningham GC,
Conley MR, Lassman MR, Phoads GC: Are obese woman
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congenital anomalies (eds: Romero R, et al.), Appleton & paralysis associated with myelomeningocele: clinical and
Lange, Norwalk 1988;36-43. experimental data implicating a preventable spinal cord
51. Campbell S. Early prenatal diagnosis of neural tube injury. Neurosurgery 1990;26:987-992.
defects by ultrasound. Clin Obstet Gynecol 1977;20:351- 66. Michejda M. Intrauterine treatment of spina bifida:
59. primate model. Z Kinderchir 1984;39:259-61.
52. Crane JP, LeFevre ML, Winborn RC, Evan JK, Ewigman 67. Heffez DS, Aryanpur J, Rotellini NA, Hutchis G, Freeman
BG, Bain RP, Frigottetto FD, McNellis D, the RDIUS Study JM. Intrauterine repair of experimental surgically created
Group. A randomized trial of prenatal ultrasonographic dysraphism. Neurosurgery. 1993;32: 1005-1010.
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Group. Am J Obstet Gynecol 1994;171:392-99. rescues neurological function at birth in sheep with spina
53. Boyd PA, Wellesley DG, de Walle HEK, Tenconi R, Garcia- bifida. Nat Med 1995;1:342-47.
Minaur S, Zandwijken GRJ, Stoll C, Clementi M. 69. Meuli M, Meuli-Simmen C, Yingling CD, Hutchins GM,
Evaluation of the prenatal diagnosis of neural tube defects Timmel GB, Harrison MR, Adzick NS: In utero repair of
by fetal ultrasonographic examination in different centres experimental myelomeningocele saves neurological
across Europe. J Med Screen 2000;7:169-74. function at birth. J Pediatr Surg 1996;31:397-402.
54. Williamson P, Alberman E, Rodeck C, Fiddler M, Church 70. Bruner JP, Richards WO, Tulipan NB, Arney TL:
S, Harris R. Antecedent circumstances surrounding neural Endoscopic coverage of fetal myelomeningocele in utero.
tube defect births in 1990-91. The Steering Committee of Am J Obstet Gynecol 1999;180:153-8.
the National Confidential Enquiry into Counseling for 71. Bruner JP, Walsh WF, Boehm FH, Paschall RL, Reed GW,
Silva SR, Vrabcak EK, Tulipan N: Open fetal repair of
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myelomeningocele improves neurologic outcome in the
55. Sebire NJ, Noble PL, Thorpe-Beeston JG, Snijders RJM,
neonate. Am J Obstet Gynecol 19th Annual Meeting of
Nicolaides KH. Presence of the “lemon” sign in fetuses
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Gynecol 1997;10:403-407.
Flake AW, Howell Lj, Hedrick HL, Wilson RD, Adzick
56. Campbell S, Johnstone FD, Holt EM, May P. Anencephaly:
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73. Lyerly AD, Cefalo RC, Socol M, Fogarty L, Sugarman J.
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maternal-fetal surgery. Am J Obstet Gynecol
Lange, Norwalk 1988;46-50.
2001;185:1052-8.
58. Chervenak FA, Berkowitz R, Tortora M, Hobbins JC. The 74. Bruner JP, Tulipan N, Paschall RL, Boehm FH, Walsh WF,
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1985;151:933-42. surgery for myelomeningocele and the incidence of
59. Luthy DA, Wordinsky T, Shurtleff DB, Hollenbach KA, shunt-dependent hydrocephalus. JAMA 1999;282:1819-
Hickok DE, Nyberg DA, Beneditti TJ. Cesarean section 1825.
before onset of labor and subsequent motor function in 75. ACOG Committee Opinion. No. 252. Fetal surgery for
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N.Engl.J.Med 1991;324:662-66. 76. Moise KJ. Maternal-fetal surgery for spina bifida: On the
60. Cochrane D, Aronyk K, Sawatzky B, Wilson D, Steinbok brink of new era? Am J Obstet Gynecol 2003;189:311.
P. The effects ob labor and delivery on spinal cord 77. Steinbok P, Irvine B, Cochrane DD, Irwin BJ. Long-term
function and ambulation in patients with outcome and complications of children born with
meningomyelocele. Childs Nerv. Syst 1991;7:312-15. meningomyelocele. Childs Nerv. Syst 1992; 8:92-6.
61. Bensen JT, Dillard RG, Burton BK. Open spina bifida: Does 78. Rintoul N, Sutton LN, Hubbard AM, Cohen B, Melchionni
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Obstet.Gynecol. 1988;71:532-4. myelomenisgoceles: Functional level, vertebral level,
62. Sakala EP, Andree I. Opimal route of delivery for shunting and the implications for fetal intervention.
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63. Wilkins-Haug L. Consideration for delivery of infants 79. Wald N, Sneddon J, Densem J, Frost C, Stone R.
with congenital abnormalities. Obstet. Gynecol. Clin North Prevention of neural tube defects: results of the MRC
Am.1999;26:399-412. Vitamin Study. Lancet 1991;338:132-37.
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80. Botto LD, Moore CA, Khoury MJ, Erickson JD. Neural- 91. Iyengar L, Babu S. Folic acid absorption in pregnancy.
tube defects. N Engl J Med 1999;341:1509-19. Br.J.Obstet.Gynecol 1975;82:20-23.
81. Wald N. Folic acid and the prevention of neural tube 92. Johan E, Magnus EM. Plasma and red blood cell folate
defects: maternal nutrition and pregnancy outcome. Ann during normal pregnancy. Acta Obstet.Gynecol.Scand
NY Acad.Sci.1993; 678:112-29. 1981;60:247-51.
82. Wald NJ, Law HR, Morris JK, Wald DS. Quantifying the 93. Lindhout D, Omtzigt JG, Cornel MC Spectrum of
effect of folic acid. Lancet 2001;358: 2069-73. neural tube defects in 34 infants prenatally exposed
83. Food standards: Amendment of identify for enriched to antiepileptic drugs. Neurology 42(suppl 5)1992;
grain products to require standards of addition of folic 111-18.
acid FDA.Final rule. Fed Regist 1996;61:8781-97. 94. Roberts HE, Moore CA, Cragan JD. Impact of prenatal
84. Honein MA, Paulozzi LJ, Mathews TJ, Ericson JD, Wong diagnosis on the birth prevalence of neural tube defects.
LY. Impact of folic acid fortification of the US food supply Atlanta.1990-1991. Pediatrics 1995;96:880-83.
on the occurrence of neural tube defects. JAMA
95. Velie EM, Shaw GM. Impact of prenatal diagnosis and
2001;285:2981-86.
elective termination on prevalence and risk estimates of
85. American College of Obstetricians and Gynecologists:
neural tube defects in California, 1989-1991.
Folic acid for the prevention of recurrent neural tube
Am.J.Epidemiol 1996;144: 473-79.
defects. ACOG Committee Opinion 120.Washington,
D.C.: ACOG, 1993. 96. Worley G, Schuser JM, Oakes WJ. Survival at 5years of a
86. Lindenbaum J, Healton EB, Savage DG, Brust JC, Garrett cohort of newborn infants with myelomeningocele.
TJ, Podell ER. Neuropsychiatric disorders caused by Dev.Med.Child.Neurol 1996;38:816-22.
cobalamin deficiency in the absence of anemia or 97. Mirzai H, Ersahim Y, Mutluer S, Kayahan A. Outcome of
macrocytosis. N.Engl.J.Med.1988;318:1720-28. patients with meningomylocele. Childs Nerv.Syst
87. Wald NJ, Bower C. Folic acid, pernicious anemia, and 1998;14:120-3.
prevention of neural tube defects. Lancet 1994;343:307. 98. McLaurin RL. Myelomeningocele: Outcome and large
88. Centers for Disease Control and Prevention: Knowledge complication. In Pediatric neurosurgery: Surgery of the
and use of folic acid by woman of childbearing age – developing nervous system, 2nd.ed.Section of Pediatric
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1999;48:325-7. Neurological Surgeons(ed). Philadelphia, Saunders,
89. Herbent V, Colman N, Spivack M, Ocasio E, Ghanta V, 1989;53-70.
Kimmel K, Brenner L, Frendlick J, Scott J. Folic acid 99. Bruner JP, Tulipan N. Tell the truth about spina bifida.
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1970;211:1982-84. 1988;43:827-37.
 62
Genetic Aspects of
Congenital Heart Disease

Toru Kanzaki

EPIDEMIOLOGY embryopathies. Risk factor for CHD can be grouped

into two main categories, fetal and maternal factors.
Congenital heart disease is the most common severe
(Table 62.2)
congenital abnormality with an incidence of about 8.8
in 1.000 live births. Epidemiologic studies that have
excluded patent ductus arteriosus in premature Table 62.1: Comparison of disease seen
in infant and fetal series
infants have suggested an overall lower incidence of
CHD (3.7 in 1000 live births). Brompton NERICP fetal
Diagnosis (%) (%) (%)
A clear difference on the proportion of individual
anomalies between fetal and infant can bee seen in Ventricular septal defect 15.4 15.7 5
Complete transposition 10.4 9.9 2
Table 62.1.1 This is because these are all lesions readily Tetralogy of Fallot 9.9 8.9 3
detectable during the screening four-chamber scan. Coarctation 10.5 7.5 3
In contrast, the rate of detection of ventricular septal HLHS 3.7 7.4 11
Mitral atresia 0 0 5
defects, complete transposion and teratology of Fallot
Critical aortic stenosis 1.1 1.9 4
is lower than infancy because these lesions are not AVSD 3.9 5.0 17.5
readily detectable on routine scan. Nevertheless, CHD Pulmonary stenosis/atresia 4.9 6.4 5
remains the most common severe abnormality in the Atrial septal defect 0.5 2.9 0
TAPVC 3.6 2.6 <1
newborn. Its prenatal diagnosis allows for better Cardiomyopathy 2.7 2.6 4
pregnancy counseling and improved neonatal Tricuspid atresia 4.7 2.6 4
outcome. Double-inlet ventricle 4.3 2.4 2
Double-outlet ventricle 3.0 1.5 3
Trunk 2.1 1.4 1.5
CONGENITAL HEART DISEASE AND
Ebstein’s malformation 0 0 7
CHROMOSOMAL ABNORMALITIES Tumor 0 0 1
Corrected transposition 0.8 0.9 <1
Traditionally the etiology of most congenital heart Miscellaneous 11.3 10.4 <1
defects has been considered multifactorial, with
AVSD = atrioventricular septal defect; Brompton = Royal
interaction between genetic and environmental Brompton Hospital, London; HLHS = hypoplastic left heart
factors. Only about 10 to 15% of all congenital heart syndrome; NERICP = New England infant Cardiac Care
defects have been attributed to known chromosomal program; TAPVC = totally anomalous pulmonary venous
abnormalities, genetic syndromes, and teratogenic connection.
 Genetic Aspects of Congenital Heart Disease 877
Table 62.2: Risk factors for congenital heart disease Table 62.3: Congenital heart disease and associated
chromosomal abnormalities
Fetal
Chromosomal abnormalities Fetuses aneuploid infants aneuploid
Extracardiac anatomic abnormalities Cardiac defect total fetuses total infants
Nonimmune hydrops fetalis
Atrioventricular 193 75 186 133
Fetal cardiac arrhythmia
septal defect
Maternal
Ventricular septal 70 34 542 47
Family history of congenital heart disease
defect
Maternal metabolic disorders
Hypoplastic left 168 10 108 3
Maternal teratogen exposure
heart syndrome
Pulmonary atrersia/ 61 3 201 1
The frequency of chromosomal abnormalities in stenosis
Transposition of 22 0 119 0
infants with congenital heart disease has been esti- great arteries
mated as 5 to 10% from postnatal data. Some atudies Aortic atresia/stenosis 42 2 73 3
suggested that up to 39% of fetuses with congenital Tricuspid atresia 46 2 19 0
Truncus srteriosus 15 2 68 1
heart defects diagnosed by fetal echocardiogram at
Coarctation of aorta 114 33 132 11
18 to 20 week’s gestation have a chromosomal Tetralogy of Fallot/
anomaly, although chromosomal account for only 5% Double outlet 86 19 159 20
of congenital heart defects in liveborns. This discre- right ventricle
pancy is attributed to inutero losses of aneuploid
fetuses Table 62.4 is a list of the most common chromo-
Cardiac defects tend to be specific common somal abnormalities and their associated congenital
chromosomal abnormalities and their associated cardiac defects.2 Data obtained from postnatal studies
congenital cardiac defects (Table 62.3).2 In general, suggest that in incidence of cardiac defects is 40 to
malformations of the right side of the heart are rarely 50% in trisomy 21, 25 to 45% in Turner’s syndrome,
associated with karyotypic abnormalities. The and more than 90% in trisomies 13 and 18.
diagnosis of transposition of the great vessels and
tricuspid atresia are not usually associated with SINGLE-GENE DISORDERS ASSOCIATED
chromosomal abnormalities. On the other hand, trio WITH CONGENITAL HEART DISEASE
ventricular septal defect, perimembranous ventricular Although the etiology of many syndromes remain
defect, Tetralogy of Fallot, double outlet right unknown, approximately 3% of congenital heart
ventricle and hypoplasitic left heart syndrome are defects are attributed to single-gene defects. Table 62.5
associated with chromosomal abnormalities. is a list of the more common genetic syndromes of

Table 62.4: Incidence and type of congenital heart disease in chromosomal aneuploidy
Chromosomal Incidence at Associated Common cardiac
Abnormality live birth cardiac abnormality abnormalities
Trisomy 21 1:800 40-50% Atrioventricular septal defect
Ventricular septal defect
Trisomy 18 1:8000 >90% Ventricular septal defect
Double outlet right ventricle
Trisomy 13 1:20,000 >80% Ventricular septal defect
Atrial septal defect
45,X 1:10,000 25-45% Coarctaion of aorta
Bicuspid aortic valve
878 Textbook of Perinatal Medicine

Table 62.5: Single-Gene disorders associated with congenital heart defects

Other anomalies detected
Syndrome Associated cardiac defect prenatally Inheritance
Holt-Oram Septal defect, Coarctaion Absent thumb, upper extremity AD, sporadic
of the aorta, HLHS phocomelia, Syndactyly
Noonan Septal defect, Pulmonary Cystic hygroma, AD
Stenosis, PDA micrognathia
CATCH-22 Conotruncal heart defect Cleft lip, cleft palate AD
microcephaly
Ellis-van Creveld Atrial septal defect, Cleft lip, postaxial polydactyly AR
Single atrium Dandy-Walker malformation
Treacher-Collins Septal defects, PDA Micrognathia AD
Kartagener Dextrocardia Situs inversus, communicating AR
hydrocephalus
Kippel-Feil Ventricular septal defect Sacral agenesis AD, Sporadic
Williams Aortic stenosis, Unilateral renal agenesis, AD, sporadic
Septal defects IUGR

Table 62.6: Empiric estimation of recurrence risk for congenital heart defects
Individual(s) Affected
Defect One Siblings Two Siblings Mother Father
Ventricular septal defect 3 10 6-10 2
Patent ductus arteriosus 3 10 4 2.5
Atrial septal defect 2.5-3.2 8 4-4.5 1.5
Tetralogy of Fallot 2.5 8 2.5 1
Pulmonary stenosis 2 6 4-6.5 1.5
Coarctation of the aorta 2-8 6 2 2
Aortic stenosis 2 6 13-18 3
Transposition great vessels 1.5 5
Endocardial cushion defects 3 10
Hypoplastic left heart 2 6
Ebstain anomaly 1 3
Pulmonary atresia 1 3

unknown etiology and their associated cardiac and in child of the affected rather than siblings, and
extracardiac features.3 increase significantly with each additional affected
relative. Affected mothers are also at higher risk for
RECURRENCE RISK affected offspring than affected father. These data are
In general, recurrence risk of 1 to 5% is estimated for summarized in Table 62.6.4
the majority of congenital cardiac abnormalities. For REFERENCES
the majority of cases the exact cause of the congenital 1. LD Allan, et al. prospective diagnosis of 1,006 consecutive
heart defect is unknown, making it difficult to cases of congenital disease in the fetus JACC 1994;23:1452-
precisely predict whether the anomaly will occur 8
2. Abuhamad Alfred “A practical guide to fetal echocardio-
again in a future pregnancy. Large population studies graphy” Lippincott-Raven 1997
of isolated defects provide the most practical 3. Online Mendelian Inheritance of Man: http://
recurrence risks, though they may not always the www.ncbi.nlm.nih.gov/Omim/
4. KK Welch et al. The role of genetic counseling in the
applicable and their limitation should be outlined to
management of prenatally detected congenital heart
the patients. In general, recurrence risks are higher defects. Seminars in perinat 2000;24:373-9
 63
Clinical and Genetical Approach
to Skeletal Dysplasia

Keiichi Ozono, Noriyuki Namba, Yoko Miyoshi, Kazuko Wada, Toshimi Michigami

INTRODUCTION them are reviewed in this chapter.1-7 Moreover, the

defects of these factors lead to skeletal dysplastic
Skeletal dysplasias comprise of more than 200
diseases.
diseases and are not infrequent as a whole. However,
The manifestation of patients with skeletal
each entity of skeletal dysplasias is rather rare and
dysplasia is various. In utero, polyhydroamnios and
many pediatricians are unfamiliar with the recent
growth retardation of fetus is often associated with
advances in understanding of the pathogenesis and
skeletal dysplasias. After birth, respiratory difficulty
the medical management of these diseases. Skeletal
dysplasias are clinically important, especially for is the primary issue to be solved in patients with
neonatologist since the respiratory complications severe skeletal dysplasias. Characteristic faces and
sometimes result in neonatal death. Recent advances disproportionate short stature are often the hallmarks
in the research on bone and cartilage metabolism have of skeletal dysplasias in childhood. Extraskeletal
shed light on the molecular mechanisms of skeletal features including hypoplastic hair, skin legions and
diseases and made a great contribution to the immunological abnormality imply specific skeletal
management of patients with skeletal dysplasia.1-3 dysplasia.
The identified genes responsible for skeletal The wide variation in phenotypic severity is one
dysplastic diseases are increasing in number (Table. of features of skeletal dysplasia. Sometimes the names
63.1).4-8 Importantly, several new techniques have of diseases are distinct to describe the difference in
developed for diagnosis and treatment of patients phenotype even when the same gene is responsible
with skeletal dysplasias. for the diseases. Such diseases are allelic and have
Bone formation or skeletogenesis consists of two similar features, although the severity and the
different pathways, membranous bone formation and survival rate are quite different. For example,
enchondral bone formation. The former process is mutations of the FGF receptor 3 (FGFR 3) gene are
direct bone formation from mesenchymal cells associated not only with achondroplasia, the most
without a cartilage mold. The skull is the common chondrodysplasia, but also with
representative bone formed via membranous bone thanatophoric dysplasia and hypochondroplasia.9
formation. In contrast, most bones including long Another example is the case of the defects in the type
bones and vertebrae are formed by enchondral bone II collagen gene including hypochondrogenesis,
formation. Several important factors have been spondyloepiphyseal dysplasia, Kniest and Stickler
identified to be involved in this process and some of diseases.10
880 Textbook of Perinatal Medicine

Table 63.1: Skeletal dysplasia and its responsible gene

1. FGF receptor or FGF
Achondroplasia FGFR3 (G1138A,C)
Hypochondroplasia FGFR3 (C1659A,G; C1620A)
Thanatophoric dysplasia FGFR3 (I: C742T, II: A1948G)
Pfeiffer syndrome FGFR1 (C755G); FGFR2 (T1036C; G1037A)
Crouzon syndrome FGFR2 (G1037A; T1036C,A; C1073G, etc)
Jackson-Weiss syndrome FGFR2
Apert syndrome FGFR2 (C934G; C937G)
Beare-Stevenson cutis gyrata syndrome FGFR2
Muenke craniosynostosis FGFR3 (C749G)
Hypophosphatemic rickets, AD FGF23
2. Collagen
Osteogenesis imperfecta COL1A1; COL1A2
Achondrogenesis type II COL2A1
Hypochondrogenesis COL2A1
Spondyloepiphyseal dysplasia COL2A1
Kniest dysplasia COL2A1
Stickler dysplasia COL2A1; COL11A2
Stickler dysplasia type2 COL11A1
Spondyloepimetaphyseal dysplasia COL2A1
(Strudwick type)
Multiple epiphyseal dysplasia type2 COL9A2
Metaphyseal dysplasia (Schmid) COL10A1
3. Matrix protein
Pseudoachondroplasia COMP
Multiple epiphyseal dysplasia COMP
Shprintzen-Goldberg syndrome FBN1
Keutel syndrome MGP
Multiple epiphyseal dysplasia MATN3
4. Hormone, Hormone receptor, Signal transducer
Metaphyseal dysplasia (Jansen) PTH/PTHrP receptor (gain)
Blomstrand chondrodysplasia PTH/PTHrP receptor (loss)
Albright osteodystrophy Gsa
McCune-Albright syndrome Gsa
Vitamin D dependency type I 1alpha-hydroxylase
Vitamin D dependency type II Vitamin D receptor
Osteoporosis-pseudoglioma LRP5 (loss)
High bone mass LRP5 (gain)
Familial expansile osteolysis TNFRSF11A
Juvenile Paget’s disease OPG
5. Enzyme
Hypophosphatasia TNS Alkaline phosphatase
Osteopetrosis Carbonic anhydrase II, TCIGR1, CLCN7, GL
Pycnodysostosis Cathepsin K
Smith-Lemli-Opitz syndrome ∆7-sterol reductase
Mucopolysaccharidoses (Hurler, Morquio, —) lysosome enzyme
X-linked recessive chondrodydplasia punctata arylsulfatase E
Rhizomelic chondrodysplasia punctata PEX7
Coffin-Lowry syndrome RSK-2
Noonan syndrome PTPN11
SEMD Pakistani type PAPSS2

Contd...
 Clinical and Genetical Approach to Skeletal Dysplasia 881
Contd...

Osteolysis Torg type MMP2

Wolcott-Rallison syndrome EIF2AK3
OLEDAID NEMO
6. Transcription factors
Boston-type craniosynostosis MSX2
Campomelic dysplasia SOX9
Cleidocranial dysplasia CBFA1
Saethre-Chotzen syndrome TWIST
Polysyndactyly type II HOXD-13
Greig syndrome GLI3
Polydactyly type A GLI3
Ulnar-mammary syndrome TBX3
Holt-Oram syndrome TBX5
Townes-Brocks syndrome SALL1
Nail-patella syndrome LMX1B
Tricho-rhino-phalangeal dysplasia type1 TRPS1
Ellis-van Creveld EVC
EEC syndrome p63
Trichodentooseeous syndrome DLX3
Leri-Weill dyschondrostosis SHOX
7. Others
Diastrophic dysplasia sulphate transporter (DTDST)
Achondrogenesis type IB sulphate transporter (DTDST)
Atelosteogenesis type 2 sulphate transporter (DTDST)
Craniometaphseal dysplasia pyrophosphate transporter (ANK)
Chondrodysplasia growth/differentiation factor-5
(Hunter-Thompson, Grebe) (CDMP-1)
osteosclerosis SOST
Brachydactyly type C CDMP-1
Camurati-Engelmann TGFB1
SED tarda SEDL (ER-Golgi transport)
Cartilage-hair hypoplasia RMRP
Kenny-Caffey syndrome TBCE (chaperone protein)
Multiple synostosis syndrome Noggin
Spondylocostal dysostosis DLL3
Brachydacyly A1 IHH
Osteoporosis-pseudoglioma syndrome LRP5
Progressive pseudorheumatoid dysplasia WISP3
Brachydacyly B2 ROR2
Dyggve-Melchior-Clausen dysplasia FLJ90130
Shwachman-Diamond SBDS
(common mutations are described in parenthesis)

In general, phenotype is severe in patients with treatments for childhood cases of skeletal dysplasias
skeletal dysplasias found in perinatal period, and long have been improved such as growth hormone for
survival is not achieved in many of them mainly due achondroplasia, bisphosphonate for osteogenesis
to respiratory problems. Elucidation of the imperfecta and bone marrow transplantation for
relationship between the skeletogenesis and lung malignant osteopetrosis. Thus, the opprotunity has
development may lead to better treatments for severe increased for pediatricians to treat patients with
forms of skeletal dysplasias. In contrast, the skeletal dysplasia.
882 Textbook of Perinatal Medicine

In this manuscript, we take an overview of some tissue (primary spongiosa) replaces cartilage. During
of key players in the enchondral bone formation and the chondrocytic differentiation, the main
their implication in skeletal diseases. We aim to help components of the matrix are changed from collagen
clinicians to manage patients with skeletal dysplasia type II to collagen type I via collagen type X. Recently,
with better understanding of the diseases. At first, many molecules including SOX9, FGF receptor 3
molecular mechanisms of the proliferation and (FGFR3) and parathyroid hormone-related peptide
differentiation of chondrocytes in growth plate are (PTHrP) have been found to play important roles in
reviewed. Then, recent advances in genetics and the process.1-3 These integrated networks of such
clinical aspects are described in several representative bioactive factors tightly control enchondral bone
skeletal dysplastic diseases. Clinical approach to development in the limb. Moreover, the genes
skeletal dysplasia is mentioned in the last part of the encoding these molecules are responsible for several
manuscript. types of skeletal dysplasias. The process of
chondrocytic differentiation is terminated by the
DEVELOPMENT OF CARTILAGE AND BONE death of hypertrophic chondrocytes, followed by
Enchondral bone formation is a multistep process blood vessel invasion, which promotes replacement
where chondrocytes proliferate and differentiate step of the cartilaginous matrix by the primary spongiosa.
by step, resulting in layered structure, namely resting, The first step of chondrocytic differentiation or
proliferating, hypertrophic and calcifying zones (Fig. chondrogenesis is the mesenchymal cell condensation
63.1).3 After the extracellular matrix is calcified, bone of undifferentiated progenitor cells. The
differentiation of mesenchymal precursor cells into
Collagen II SOX9 chondrocytes requires a transcription factor, Sox9.11,
FGF 12
Sox9 is a member of the Sox family of transcription
Resting zone
BMPs, IGF-1, Ihh
factors that contain high-mobility-group (HMG)-box
FGFR3 DNA-binding domain. Sox9 up-regulates the
Proliferating zone
BMPs, Runx2
expression of characteristic cartilaginous matrix genes
PTHrP Ihh
such as collagens type II, IX, and XI, and aggrecan. In
Hypertrophic zone humans, haploinsufficiency of the Sox9 gene causes
Collagen X
Calcifying zone ALP
campomelic dysplasia (MIM 114290), which is
VEGF, MMP characterized by deformities of long bones.13 Most
Chm-1
Primary spongiosa affected neonates die from respiratory failure due to
osterix cbfa1
hypoplastic tracheal and rib cartilage. Interestingly,
Collagen I
some XY patients with campomelic dysplasia exhibit
Fig. 63.1: Enchondral bone formation: Chondrocytes form the male-to-female sex reversal because Sox9 is involved
layer structure according to the stage of differentiation in growth
not only in chondrogenesis but also in mammalian
plate and eventually cartilage is replaced by bone matrix,
primary spongiosa. In the process of the enchondral bone sex determination as a downstream regulator of the
formation, chondrocytes proliferate and differentiate into transcription factor, SRY.
hypertrophic chondrocytes, then matrix is calcified. The main FGFR3, as the other FGFRs, is a membrane bound
matrix proteins which are underlined are changed from collagen
type II to collagen type I via collagen type X. Many molecules protein, consisting of three immunoglobulin-like
including SOX9, PTHrP and FGFR3 have been found to play domains in the extracellular portions, a
an important role in the process as shown in the Figure. transmembrane domain and two tyrosine kinase
FGF: fibroblast growth factor, BMP: bone morphogenic protein,
domains in the intracellular portion. 14 FGFR3 is
IGF-1: insulin-like growth factor, Ihh: Indian hedgehog, FGFR3:
FGF receptor 3, PTHrP: PTH-related peptide, ALP: alkaline expressed in the proliferating chondrocytes. Its
phosphatase, VEGF: vascular endothelial growth factor, MMP: ligands, most importantly FGF18, bind to the FGFR3
matrix metaroproteinase, Chm-1: chondromodulin-1 and activate the receptor by its autophosphorylation
 Clinical and Genetical Approach to Skeletal Dysplasia 883
and the phosphorylation of other substrate proteins.15 osteoblast lineage.22 Ihh induces the expression of
The major signaling pathways of FGFR3 are thought PTHrP and inhibits differentiation of hypertrophic
to be the Mitogen activating protein kinase (MAPK) chondrocytes followed by the delay of the
pathway and the STAT-1 pathway. These signals mineralization of cartilage matrix. This effect of Ihh
mediate the inhibitory effects of FGFs on the on chondrocytic differentiation is mediated by
proliferation and differentiation of chondrocytes. increasing PTHrP production in the growth plate.
The importance of FGF signaling in skeletal Because PTHrP keeps chondrocytes in the
development was firstly revealed with the discovery proliferative pool and suppresses Ihh production,
that a point mutation in the transmembrane domain PTHrP and Ihh establish a negative-feedback loop
of FGFR3 causes achondroplasia (MIM 100800).14 The that maintains a balance of chondrocyte proliferation
abnormality of the FGFR3 gene is also associated with and differentiation.22 Ihh is also a potent stimulator
hypochondroplasia (MIM 146000), thanotophoric of chondrocyte proliferation, and conversely an
dysplasia (MIM 187600), and severe achondroplasia inhibitor of chondrocyte maturation.23 In this sense,
with developmental delay and acanthosis nigricans Ihh has the positive effect on normal chondrocyte
(SADDAN) syndrome.16 proliferation in a PTHrP-independent manner.
PTHrP was initially discovered as a causal factor Heterozygous missense mutations in the Ihh gene
of humoral hypercalcemia of malignancy.17 However, have been recently identified as a cause of autosomal
gene-targeting experiments has revealed that PTHrP dominant form of brachydactyly type A1 (MIM
plays an important role in chondrogenesis via a local 112500)(24). This type of brachydactyly is
action.18 PTHrP-null mice, for example, exhibit a characterized by the shortening or the absence of
severe disorder of enchondral bone formation, middle phalanges.
characterized by shortened bones and premature Runx2, also called cbfa1, belongs to the Runt
maturation and ossification of the cartilaginous transcription factor family.25-27 Runx2 was initially
tissues.19 Mice lacking the parathyroid hormone discovered as an essential molecule for osteoblast
(PTH)/PTHrP receptor exhibit the similar differentiation.25-27 It has been shown that inactivating
phenotypes. PTHrP and PTH, the latter of which is mutations of one allele of the human Runx2 gene
one of the main regulators of calcium and bone cause cleidocranial dysplasia (MIM 119600). 25
metabolism share the PTH/PTHrP receptor. However, further experiments revealed that Runx2
Therefore, the PTH/PTHrP receptor mediates both is also expressed in chondrocytes, and severe delays
the endocrine actions of PTH and the auto/paracrine of chondrocyte maturation is found in genetically
actions of PTHrP. The PTH/PTHrP receptor is mainly manipulated mice lacking this factor.28
expressed in the transitional zone between Hypertrophic chondrocytes are the most
proliferating and hypertrophic cells (i.e., the pre- characteristic in shape and produce the specific matrix
hypertrophic zone) in growth plate. PTHrP regulates protein, collagen type X. Then, the matrix is calcified
the transition from proliferation to differentiation in and replaced by bone tissue. In other words, an
chondrocytes. avascular cartilage template is reconstructed into
Indian hedgehog (Ihh), a member of a family of highly vascularized bone tissue. In contrast to
proteins that are important for embryonic patterning, immature chondrocytes which secrete angiogenic
is highly expressed in the pre-hypertrophic zone and inhibitors, hypertrophic chondrocytes produce
in the upper hypertrophic chondrocytes.20, 21 Actually, angiogenic stimulators such as vascular endothelial
Ihh is secreted by pre-hypertrophic and early growth factor (VEGF) and FGF, and become a target
hypertrophic chondrocytes. The mice Ihh-/- show for capillary invasion.29 The invasion of blood vessels
abnormal chondrocytic differentiation and a failure is critical in the last stage of chondrocyte maturation.
to specify appendicular perichondrial cells to the The mammalian growth plate is highly hypoxic and
884 Textbook of Perinatal Medicine

expresses the transcription factor hypoxia-inducible structurally related polypeptides that play a critical
factor 1 (HIF-1), which belongs to the PAS subfamily role in a variety of biological processes. The FGFRs
of bHLH (basic helix-loop-helix) transcription factors represent a family of four tyrosine kinase receptors
and is known to induce the VEGF expression in many (FGFR1–4) that bind FGFs with variable affinity.
tissues and cells.30 HIF-1 is not sufficient to induce Achondroplasia is the most common form of
VEGF expression in cartilage or other factor(s) blocks rhizomeric dwarfism with a rate of one per 15000-
the inducible activity of HIF-1 before the maturation 30000 births. The disease is inheritated in an
of chondrocytes becomes complete. autosomal dominant manner, but more than 90% of
The degradation of calcified cartilage matrix is the cases are sporadic. Advanced paternal age is
another important event for enchondral bone reported in sporadic cases. Its clinical features are
formation. During hypertrophic change, chondrocytes short stature caused by rhizomelic shortening of the
synthesize type X collagen, which is associated with limbs, characteristic faces with frontal bossing and
denaturation and loss of type II collagen resulting mid-face hypoplasia, exaggerated lumbar lordosis,
from increased collagenase activity. The transcription and trident hand. As typical radiologic features,
factor Cbfa1 has been shown to regulate expression caudal narrowing of the interpediculate distance,
of matrix metalloproteinase (MMP) 13 (collagenase- rather than the normal caudal widening, and a
3).31 MMP-9 is also important enzyme for matrix notchlike sacroiliac groove are found in children with
degradation.32 Remarkably, inactivation of matrix achondroplasia. Interestingly, the same mutation of
metalloproteinase-9 (MMP-9) resulted in bone the FGFR3 gene is the cause of achondroplasia in
phenotype similar to that found in VEGF-knockout almost all patients (G to A transition at nucleotide
mouse, suggesting the involvement of proteinases as 1138).34,35 This mutation causes the substitution of
well as VEGF in the processes of vascular invasion in amino acid 380 (Gly380Arg), and can be recognized
growth plate and endochondral ossification. Indian by PCR followed by digestion with restriction enzyme
hedgehog plays an important role in skeletal SfcI. The same mutation of FGFR3 was also found in
angiogenesis and calcification of cartilage.33 Japanese patients with achondroplasia. The detection
As described in this section, enchondral bone of this mutation is especially helpful in the diagnosis
formation is elaborately regulated by many factors of neonatal patients with this disease. Other minor
such as transcription factors, growth factors, enzymes mutations are also reported (G to C at nucleotide 1138
and matrix proteins. Moreover, the defect in the and G to T at nucleotide 1123).
regulation leads to dysplastic bone and cartilage In our experience, some patients with
formation both in human and mice. achondroplasia are not recognized prenatally even
when routine examination with ultrasonography is
CLINICAL AND GENETICAL ASPECTS undertaken. This is partly because the disproportion
OF SKELETAL DYSPLASIAS develops more prominently after birth. In our study
Skeletal Dysplasias Associated in which the relationship between age and clinical
with FGFR Abnormality data (height, arm span and measurements of skeletal
The abnormality of FGFR3 gene is associated with radiographs) were statistically analyzed in 27
achondroplasia, hypochondroplasia, thanatophoric achondroplasia patients with the G380R genotype, the
dysplasia and the most rare form, SADDAN.14-16 Its height standard deviation score decreased with age.
cognate ligand remains unclear, but FGF18, 17 and 8 In making a clinical diagnosis of achondroplasia in
are likely to elicit its signal via binding to the FGFR3.15 early infancy, it should be noted that short stature and
These ligands are produced in the perichondrium. squared pelvis deformity are not prominent in some
The FGF family of proteins consists of at least 23 cases.36
 Clinical and Genetical Approach to Skeletal Dysplasia 885
To treat the short stature of patients with feature in thanatophoric dysplasia is the protrusion
achondroplasia, recombinant human growth of perichondrium into the growth plate. The growth
hormone (GH) has been administered. First-year plate is irregular and narrow, as in other
response is typically a 2-3 cm increase in growth chondrodysplasias. An anomaly of the brain
velocity in prepubertal children.37 However, the effect (abnormal fissure in the temporal lobe) is also
of GH treatment on the final adult height is not observed. Thanatophoric dysplasia is divided into
conclusive so far. GH treatment, at least in the two subtypes according to the finding of the shape of
prepubertal period, seems to influence degree of the femur (I: curved femur, II: straight femur) (Fig.
disproportion. The activating mutation of FGFR3 63.2). A cloverleaf-like deformity of the skull is often
promotes apoptosis of chondrocytes. Insulin-like associated with type II but may also be present in type
growth factor (IGF)-I, which is a mediator of GH, may I. The most common mutations in type I and II of
reduce apoptosis of chondrocytes expressing mutated thanatophoric dysplasia were reported to be
FGFR3.38 More recently, it has been reported that c- Arg248Cys and Lys650Glu, respectively.
type natriuretic peptide is effective to prevent Hypochondroplasia is a relatively mild disease,
shortening of long bones in the mice model for manifested as short stature. The head is not affected.
achondroplasia.39 The spinal canal narrows in its caudal portion as is
Achondroplasia can be associated with respiratory true in achondroplasia. Fingers are short, although
difficulty in early infancy and childhood, although hands are not of the trident type. Asn540Leu is
the degree of the difficulty is usually not so severe. reported to be the most common mutation found in
One of the respiratory difficulties is manifested as this disease.
sleep apnea syndrome.40, 41 Although a large scale The other form in this family is called SADDAN,
study on sleep apnea syndrome in achondroplasia is which stands for severe achondroplasia with
lacking, but approximately 30% patients with developmental delay and acanthosis nigricans. The
achondroplasia suffer from sleep anpea syndrome. In patients with SADDAN survive infancy without
serious situation, sleep apnea syndrome leads to prolonged life-support measures. The FGFR3
hypoxia, pulmonary hypertension, heart failure and
sudden death. The causes of sleep apnea syndrome Telephone receiver Cloverleaf skull
in achondroplasia are both obstruction of air way and (femur)
failure of central control of respiration. The
obstructive sleep apnea is derived from the small oral Type I + + or -
cavity with a relatively large tongue, hypertrophy of
tonsilla and adenoid as well as weakness of trachea. Type II - +
Neurological problems including hydrocephalus and
compression of the spinal cord due to a small foramen
magnum are relatively common in achondrolasia and
may cause central sleep apnea syndrome.
Polysomnography is used to make a diagnosis of sleep
apnea syndrome. Symptomatic patients require
type I type II
tonsillectomy, adenoidectomy or continuous positive
airway pressure therapy. Fig. 63.2: Two types of thanatophoric dysplasia: Thanatophoric
dysplasia type 1 and 2 are characterized by telephone receiver-
Thanatophoric dysplasia, a lethal form of like bended femur and straight femur, respectively as x-ray
dwarfism, is also caused by mutations of the FGFR3 figures are shown in the bottom. Cloverleaf skull is often
gene. In histological analyses, the most characteristic associated with type 2 and sometimes with type1.
886 Textbook of Perinatal Medicine

mutation (A1949T, Lys650Met) occurs at the fracture leads to deformity of long bones and chronic
nucleotide adjacent to the TD type II (TD2) mutation bone pain. It was classified into four forms by Sillence
(A1948G: Lys650Glu) and results in a different amino et al.45: a dominant form with blue sclerae, type I; a
acid substitution in the kinase domain activation loop. perinatally lethal OI syndrome, type II; a
All these disorders are autosomally dominant, progressively deforming form with normal sclerae,
mainly sporadic, and are caused by gain-of-function type III; and a dominant form with normal sclerae,
mutations, leading to a constitutively active FGFR3. type IV. However, Type IV is rather heterogeneous
The degree of activation of FGFR3 correlates well with and includes patients with a moderate to severe
the severity of the chondrodysplasia; the mutated disease who do not fit types I or III. Thus, other types
FGFR3 found in thanatophoric dysplasia is the most of OI (V, VI, and VII) without identifiable collagen
activated form. This relationship provides the first type I mutations have been recently described.43
evidence for negative regulation of chondrogenesis There is no curative treatment for osteogenesis
by FGFR3. Several animal models have established imperfecta. However, the therapy using pamidronate,
that FGFR3 negatively regulates chondrocyte a derivative of bisphosphonate, has recently
proliferation. MAPK is a major downstream effecter developed and successfully alleviated symptoms in
of FGFR3 activity. Indeed, chondrocytes expressing children with OI. In short, cyclic intravenous
a constitutively active form of MEK, the MAPK administration of pamidronate improved bone
activator, present an achondroplasia phenotype mineral density and reduced the frequency of bone
similar to that observed with constitutively active fracture. However, there are few studies reporting the
FGFR3. Conversely, blockade of MAPK activation outcome measures of bisphosphonate therapy in
rescues achondroplasia obtained with constitutively children with OI. Glorieux et al. observed that in
active FGFR3. In addition, it has been shown that patients with severe osteogenesis imperfecta aged 3
FGFR3 represses chondrocyte proliferation through to 16 years, intravenous pamidronate (mean annual
activation of the transcription factor STAT1 by a yet dose 6.8 mg/kg) increased lumbar vertebral bone
unknown mechanism. mineral density (BMD) by an average of 42% per
year.46 The same group also demonstrated that in
Collagenopathy children with OI types III or IV less than 2 years of
Type I collagen is the most abundant protein in bone. age, a 12-month treatment with pamidronate at a
This type of collagen is synthesized as the mean dose of 12.4 mg/kg increased lumbar
heterotrimer of procollagens a1(I) and a2(I). vertebral BMD by 86 to 227%. Recently, Astrom and
Heterozygous mutations in the two genes for Soderhall reported that monthly infusions of
procollagen a1(I) and a2(I). (COL1A1 and COL1A2) pamidronate for 2 to 9 years resulted in gradual
have been found in patients with osteogenesis increase in total body and lumbar spine bone density
imperfecta (MIM 166200, 166210, 166220, 166230).42, in children with OI.47
43 As another novel treatment for patients with
These mutations cause a change either in the
structure of the protein or in the number of collagen severe osteogenesis imperfecta, transplantation of
molecules made. The severe forms of osteogenesis bone marrow cells containing adult mesenchymal
imperfecta are reported to have a glycine substitution stem cells has been attempted.48 Mesenchymal stem
within the Gly-X-Y amino acid repeat. Mutated cells can differentiate into multiple cell types present
collagens interfere with the formation of collagen in several tissues, including bone, fat, cartilage, and
fibrils. In contrast, null mutations of COL1A1 cause muscle, making them ideal candidates for cell-based
the mild form of osteogenesis imperfecta.44 therapies. More recently, mesenchymal cell therapy
Osteogenesis imperfecta is characterized by low using isolated mesenchymal stem cells has been
bone mineral density with fragility, and frequent bone reported.49 In the report, donor marrow-derived
 Clinical and Genetical Approach to Skeletal Dysplasia 887
mesenchymal cells were administrated to treat six mutation in the COL11A1 (MIM 604841). Multiple
children who had undergone standard bone marrow epiphyseal dysplasia (MIM 132400) is caused by a
transplantation for severe osteogenesis imperfecta. mutation in the COL9A1 or the COMP gene.54, 55 The
Five of six patients showed engraftment in one or COMP gene is also responsible for pseucoachondro-
more sites, including bone, skin, and marrow stroma, plasia (MIM 177170), which is one of the most
and had an acceleration of growth velocity during the frequent skeletal dysplasias and resembles
first 6 months post-infusion. achondroplasia except for head and face.55
Adult stem cells can be used after the ex vivo
genetic manipulation to correct genetical disorders. Other Chondrodysplasias
For osteogenesis imperfecta, one study in which The chondrodysplastic disease, achondrogenesis is
adeno-associated viral vectors were used to disrupt characterized by severely impaired chondrogenesis
dominant-negative mutant COL1A1 collagen genes with extremely short limbs and narrow thorax,
in mesenchymal stem cells from patients with a severe leading to the perinatal death of patients with this
form of osteogenesis imperfecta was reported.50 It disease. Fetal hydrops and hydroamnios are also
seems that the gene was successfully targeted in adult associated with achondrogenesis. Although
human stem cells. achondrogenesis has been subtyped in several ways,
Collagen type II, IX, X and XI are expressed in the the definition reported by Borochowitz et al., based
cartilaginous tissue. Collagen type II specific to on detailed analyses of clinical, radiological and
cartilage matrix is synthesized as the homotrimer of morphological studies, seems to have received
collagen a1(II). Mutations in the single gene for type consensus: type I (MIM 200600) A (Houston-Harris),
II procollagen have been found in patients with type IB (Fraccaro) and type II (Langer-Saldino, MIM
II achondrogenesis (MIM 200610)-hypochondro- 200610). A histological analysis of cartilaginous tissue
genesis, spondyloepiphyseal dysplasia (MIM 183900), is very helpful, especially to make the diagnosis of
Kniest dysplasia (MIM 156550) and Stickler achondrogenesis type IB.56 Achondrogenesis type IB
(hereditary arthro-ophthalmopathy) syndrome (MIM is caused by the mutations of the diastrophic
108300). 51 The platyspondylic lethal skeletal dysplasia (DTDST ) gene.57
dysplasias (PLSD), Torrance type (MIM 151210) was The DTDST gene encodes a sulfate transporter,
found to be caused by COL2A1 mutations.52 The which is required for the synthesis of sulfated
platyspondylic lethal skeletal dysplasias is a proteoglycans in cartilage with other name,
heterogeneous group of chondrodysplasias SLC26A2.58 It is not surprising that defects of this gene
characterized by severe platyspondyly and result in a chondrodysplasia phenotype, although the
shortening of limbs. Interestingly, the most common precise mechanism whereby the impaired sulfation
form of PLSD is thanatophoric dysplasia (TD), which of proteoglycans causes abnormal enchondral
is caused by mutations in the FGFR3 as described ossification remains to be elucidated. Several
previously. mutations of the DTDST gene were reported in
Type X collagen is a homotrimeric, short-chain, patients with achondrogenesis type IB, the most
nonfibrillar extracellular matrix component. The severe form, atelosteogenesis type II or neonatal
expression of type X collagen is restricted to osseous dysplasia (MIM 256050), an intermediate
hypertrophic chondrocytes. The mutation in the form and the mildest form of the diseases, diastrophic
COL10A1 is associated with Schmid metaphyseal dysplasia (MIM 222600). The recessive multiple
chondrodysplasia (MIM 156500).53 It is reported that epiphyseal dysplasia (MIM 226900) is also caused by
Stickler syndrome type 2 with a different vitreo- the mutations of DTDST. Homozygous mutant mice
retinal phenotype from that of type 1 is caused by a for the gene were characterized by growth
888 Textbook of Perinatal Medicine

retardation, skeletal dysplasia and joint contractures, Leri-Weill dyschondrosteosis (LWD)

thereby recapitulating the essential aspects of the (OMIM127300) is caused by the haploinsufficiency of
diastrophic dysplasia phenotype in man. The skeletal the short stature homeobox-containing (SHOX)
phenotype included reduced toluidine blue staining gene.62, 63 LWD is an autosomal dominant form of
of cartilage, chondrocytes of irregular size, delay in mesomeric dysplasia first described by Leri and Weill
the formation of the secondary ossification center and in 1929. Patients with this condition demonstrate short
osteoporosis of long bones. stature due to shortening of the lower legs and
The cartilage hair hypoplasia (CHH, MIM 250250) Madelung deformity of the forearm. The abnormality
or spondylometaphseal dysplasia McKusick type is of the SHOX also causes Turner skeletal features and
characterized by disproportionate short stature, a certain proportion of idiopathic short stature. The
hypoplastic hair, ligamentous laxity, defective SHOX gene was cloned from the pseudoautosomal
immunity, hypoplastic anemia, and neuronal region of the sex chromosome (Xp22 and Yp11.3) and
dysplasia of the intestine (Hirschsprung disease). affects the adult height. It is exclusively expressed in
CHH was found to be caused by mutations in the the first and second pharyngeal arches and in the
ribonuclease mitochondrial RNA processing gene developing distal limb bones of the human embryo.
(RMRP).59 The untranslated RMRP gene encodes the The expression of SHOX is in the hypertrophic zone
RNA component of a ribonucleoprotein endoribo- and less intensely in proliferating zone in growth
nuclease. Normally the RNase MRP complex is plate. Although the function of SHOX in growth plate
involved in multiple cellular and mitochondrial is to be elucidated, it may be involved in the fusion
functions. of growth plate and affect the growth at the pubertal
The difference between the Japanese and other stage.
ethnic groups is remarkable in terms of the mutations
and polymorphisms in RMRP gene. Four novel Abnormality in PTH/PTHrP
mutations were reported in two patients with typical Receptor or G Protein
and atypical CHH.60 A patient with typical CHH had The family of G protein has many members, and Gsa
a 17-bp duplication at +3 and a de novo 182G > A. is the representative protein which has been shown
The other patient with atypical CHH had a 17-bp to cause bone diseases.64 G protein is a signal effector
insertion at -20 and a 218A > G. molecule, typically forming heterotrimeric guanine
The X-linked spondyloepiphyseal dysplasia tarda nucleotide-binding proteins. Mutations in Gsa protein
(SEDT; MIM 313400) has the features consisting of are divided into two groups, gain of function
disproportionately short trunk, short stature, mutation and loss of function one. McCune-Albright
characteristic radiological findings of the spine syndrome and Albright osteodystrophy combined
(posterior hump, end plate sclerosis, and disc space with pseudohypoparathyroidism are the diseases
narrowing) and the hips (short and thick femoral caused by these mutations, respectively.65
necks), and positive family history. The linkage The PTH/PTHrP receptor is a G protein-coupled
analyses revealed that the SEDL gene on X membrane-bound receptor and its best-characterized
chromosome is responsible for the disease.61 The second messenger is cAMP. Although cAMP activates
SEDL gene product, known as sedlin is a 140 amino- protein kinase A (PKA) as a downstream of PTHrP
acid protein with a putative role in endoplasmic receptor, but it is still not clear what molecules
reticulum-to-Golgi transport. However, function of responsible for delay of chondrocytes maturation
sedlin in bone and mineral metabolism remains to be serve as the substrates of PKA. In the growth plate,
characterized. the PTH/PTHrP receptor mRNA is expressed in
 Clinical and Genetical Approach to Skeletal Dysplasia 889
prehypertrophic chondrocytes at higher levels. The or Ollier and Maffucci diseases (MIM 166000).
critical role of the PTH/PTHrP receptor in Enchondromas are common benign cartilage tumors
endochondral bone development is highlighted by the of bone that can occur as solitary lesions or, in
discovery that two rare forms of chondrodysplasias, enchondromatosis, multiple lesions. This type of
Blomstrand lethal chondrodysplasia (MIM 215045) mutated receptor is constitutively active in vitro.
and Jansen’s metaphyseal chondrodysplasia (MIM However, others reported that no mutations of the
156400) are caused by mutations of this receptor. PTH/PTHrP receptor gene found in patients with
Blomstrand lethal chondrodysplasia is caused by enchondromatosis.
inactivating mutations of the PTH/PTHrP receptor, Pseudohypoparathyroidism, especially type Ia, is
while the mutated receptors found in Jansen’s associated with the loss of function-type mutations
metaphyseal chondrodysplasia are constitutively in the Gsa gene (GNAS1). 65 In patients with the
active.66, 67 The former disease is characterized by disease, no response to PTH is observed in the
prenatal lethality, premature and abnormal bone excretion of phosphate and cAMP. In contrast to
mineralization and ossification, and shortened limbs. McCune-Albright syndrome, the mutations are
Endochondral bone formation is markedly advanced scattered along the entire gene, including missense
in fetuses with Blomstrand chondrodysplasia, and the mutations and deletions. This disease is inherited in
columnar proliferative layer in the mutant growth a dominant fashion, and the mutation is found in a
plate is virtually absent. The disease appears to have single allele. Albright hereditary osteodystrophy
an autosomal recessive pattern of inheritance. Jansen’s (AHO), which consists of short stature, shortening of
metaphyseal chondrodysplasia is an autosomal the fourth and fifth metacarpals, round face, obesity
dominant disorder characterized by short-limbed and ectopic calcification is associated with
dwarfism secondary to severe abnormalities of the pseudohypoparathyroidism type Ia (MIM 103580).
growth plate and hypercalcemia. The laboratory Since the GNAS1 gene is an imprinted gene, the
findings in patients with Jansen’s metaphyseal transmission of the disease to the next generation is
chondrodysplasia are reminiscent of primary characteristic. Maternal transmission of Gsa
hyperparathyroidism. According to the original mutations leads to AHO associated with resistance
report, the genomic DNA from 10 JMC patients has to parathyroid hormone (pseudohypoparathyroidism
been examined: seven patients had the H223R type Ia), while paternal transmission leads only to the
heterozygous nucleotide exchange, and three patients AHO phenotype (pseudopseudohypopara-
had distinct heterozygous mutations in the PTH/ thyroidism). Pseudohypoparathyroidism type Ib
PTHrP receptor (T410P, T410R, and I458R). (MIM 603233) has the resistance to PTH only in
When chondrocytes are forced to express either kidney, and a region responsible for the disease is also
PTHrP or an activated form of its receptor, cartilage associated with the GNAS1 locus. PHP-Ib is caused
maturation is dramatically inhibited and bone by heterozygous mutations disrupting a long-range
formation delayed. Mice lacking either PTHrP or its imprinting control element. Recently, deletions that
receptor, in contrast, exhibit dwarfism of their long remove the differentially methylated region
bones due to premature chondrocyte maturation. encompassing exon NESP55 and exons 3 and 4 of the
Therefore, PTHrP signaling negatively regulates the antisense transcript, those are located near GNAS1
switch from a proliferative immature chondrocyte to region. Thus, it is confirmed that epigenetic defects
a post-proliferative mature hypertrophic chondrocyte. in the imprinted GNAS1 cluster are associated with
More recently, a heterozygous missense mutation pseudohypoparathyroidism type Ib.68
Arg150Cys has been identified in the PTH/PTHrP McCune-Albright syndrome is characterized by
receptor gene of two patients with enchondromatosis three major symptoms, café au lait pigmentation,
890 Textbook of Perinatal Medicine

multiple fibrous dysplasia and endocrine disorders phatasia.73 The severity of the disease is generally well
including precocious puberty, hyperthyroidism, correlated with the onset of the disease, except for
autonomous adrenal hyperplasia and growth odontohypophosphatasia, where only the teeth are
hormone secreting pituitary adenoma. This syndrome affected. The patients with the perinatal type of
is caused by the somatic mutation in the GNAS1gene, hypophosphatasia almost always die around birth
leading to elevated levels of cyclic AMP in cells. This due to impaired development of the lung and the
gene has a hot spot of mutation at Arg of codon 201 severe hypomineralization of their bones. However,
(Arg201His or Arg201Cys).69 Since these mutations the classification of these subgroups is not definite,
are somatic, mosaicism for a mutation in the GNAS1 and there is diversity in the phenotype which forms
gene is found in patients with McCune-Albright so-called spectrum. For example, we have previously
syndrome. Cells obtained from the lesions with reported a patient who achieved long-term survival
fibrous dysplasia secreted a significant amount of without respiratory failure in spite of having fetal
interleukin (IL)-6 and exhibited an impaired response onset.74 Since these patients survive longer despite
of IL-6 secretion to IL-1 in patients with McCune- their fetal onset, we should pay more attention to take
Albright syndrome.70 In response to the elevation of care of them and to genetic counseling. The presence
cAMP, IL-6 is produced perhaps through the cAMP of such a case may depend on the development of a
response element of the IL-6 gene promoter. Fibrous diagnosis procedure or on the specificity of the
dysplasia is a focal and benign fibrous bone lesions, genotype. However, this benign form of hypophos-
which is caused by the activating mutation in the phatasia found in the Japanese patients is surmised
GNAS1gene. Hypophosphatemic rickets is sometimes to be associated with a specific mutation, F310L,
observed as a complication of McCune-Albright whose product retained approximately 70% of its
syndrome. Two hypotheses have been put forward enzymatic activity. The relatively high activity of the
to explain the pathogenesis of hypophosphatemic mutant enzyme may contribute to this relatively mild
rickets associated with McCune-Albright syndrome. form. On the other hand, mutations found in the
One of them supposes the hypersensitivity to PTH in severe form of the disease do not tend to be associated
the renal tubules due to the mutation in the with restricted positions, although the three-
GNAS1gene, based on the inhibitory effect of PTH dimensional model study showed that most of the
via cAMP on phosphate transport in the kidney. The severe missense mutations were localized in crucial
other hypothesizes humoral factor(s) from the bone domains, such as the active site.75 Elucidation of the
lesions which inhibit(s) phosphate reabsorption. In molecular heterogeneity underlying hypophos-
fact, Riminucci et al. recently reported the elevated phatasia may contribute to our understanding of the
plasma FGF-23 levels in patients with McCune- clinical heterogeneity observed in hypophosphatasia
Albright syndrome.71 and the improvement of treatment, especially in
patients with severe forms of hypophosphatasia.
Hypophosphatasia The patients with the classical perinatal form of
hypophosphatasia almost always die in utero or the
Hypophosphatasia (MIM 146300, 171760, 241500, neonatal period. Therefore, the perinatal form is a
241510) is characterized by the hypomineralization synonym for the lethal form. The second most severe
of bone associated with the impaired activity of tissue- form, the infantile type of the disease, is still
nonspecific alkaline phosphatase (TNSALP). 72 associated with high mortality because of the
Hypophosphatasia has diverse phenotypes, and is impairment of respiratory function and
usually classified into five subtypes based on the age hypercalcemia.76 The patients with other types of
of onset and clinical features; perinatal, infantile, hypophosphatasia usually do not suffer from life-
childhood, adult type, and odontohypophos- threatening complications.
 Clinical and Genetical Approach to Skeletal Dysplasia 891
To date, more than a hundred mutations have cells is necessary before the cell-based therapy
been reported in the TNSALP gene in patients with becomes standard as treatment of severe
hypophosphatasia, mainly in Caucasians and hypophosphatasia.
Japanese.77 However, the mutations are scattered in
the whole coding region, and only a few mutations Craniometaphyseal Dysplasia
have been recognized to occur frequently in the gene. Craniometaphyseal dysplasia (MIM 123000) is a
Moreover, although the relationship between the genetic syndrome characterized by the sclerotic
clinical features and the mutation of the corres- change of cranial and tubular bones that commonly
ponding gene has also been analyzed, only a few present at a young age, often with facial abnormalities
reports detected the positive correlation between the and otolaryngologic manifestations such as a
mutations and severity.75 The mutations responsible conductive hearing loss. Craniometaphyseal
for mild hypophosphatasia may not cause a complete dysplasia is defective in ANK, the pyrophosphate
loss of ALP function, suggested by several transporter. 80 Thus, this disease supports the
reconstruction experiments in which mutated ALP inhibitory role of pyrophosphate in mineralization.
activity was examined.
Although hypophosphatasia is usually inherited Diseases with High or
in an autosomal recessive manner, autosomal Low Bone Mineral Density
dominant inheritance is also recognized in some
families with the mild form of the disease. Bone mineral density is determined by both genetic
Interestingly, the mutations in those families have and environmental factors. The genetical approach
been reported to show the dominant negative effect has shown that multiple genes have effects on bone
on the wild-type ALP activity, as one of the mineral density. Recent developments in molecular
remarkable results of the recent progress in molecular genetics and genomics have dramatically increased
biology.78 a power to identify genes which affect bone mineral
The mechanism for which the defect of ALP density. The sclerosing bone dysplasias can be
activity causes hypomineralization is not fully classified into two groups such as increased trabecular
understood. There are three main assumptions for the bone density (osteosclerosis) and a cortical bone
role of ALP in mineralization process. First, ALP thickening (hyperostosis). There are several diseases
increases local phosphate concentration, leading to the which belong to sclerosing bone dysplasias, e.g.,
acceleration of mineralization. Second, ALP decreases osteopetrosis, pycnodysostosis and osteopoikilosis.
the concentration of local pyrophosphate, a substrate Osteopetrosis characterized by a marked increase
of ALP and an inhibitor of mineralization. Finally, in bone mass is a heterogeneous disorder of the
ALP controls gene expression including osteopontin skeleton in several animal species.81 In humans, the
through the increase in intracellular phosphate disease is inherited as either an autosomal dominant
concentration and affects the mineralization. or autosomal recessive trait. The autosomal dominant
In patients with the infantile form of form exhibits mild symptoms only in adults
hypophosphatasia, bone marrow cell transplantation (McKusick MIM 166600). The autosomal recessive
was tried to avoid the expected poor prognosis.79 The form consists of three types; a mild type (MIM
patient was given T-cell-depleted, haplo-identical 259710), a lethal type (MIM 259720) which is rare, and
marrow from her healthy sister. Chimerism in infantile malignant osteopetrosis (MIM 259700)
peripheral blood and bone marrow became 100% characterized by severe symptoms such as diffuse
donor. The patient survived and some clinical osteosclerosis of all bones, extramedullary
improvement was observed. More experience with hematopoiesis associated with bone marrow failure,
transplantation of bone marrow or mesenchymal stem and sensorineurogenic impairment in infancy. It is
892 Textbook of Perinatal Medicine

caused by defects in bone resorption by osteoclasts, Buchem disease (MIM 239100) turned out to be due
resulting in increased bone mass and narrowing of to loss-of-function mutations of the SOST gene, most
the bone marrow cavity. Impaired bone resorption, likely increasing bone morphogenetic protein
as seen in the various forms of autosomal recessive signaling. In addition, osteoprotegerin and receptor
osteopetrosis (MIM 259700), can be due to mutations activator of NF kappa B (RANK), whose gene is
in a subunit of the vacuolar H+ pump (TCIRG1 gene) TNFRSF11A, are responsible for juvenile Paget’s
or to mutations in the chloride channel CLCN7 gene disease and familial expansile osteolysis.91, 92
in human.82, 83 Another form of osteopetrosis is caused Infantile cortical hyperostosis (Caffey disease,
by carbonic anhydrase II deficiency, and associated MIM114000) is characterized by radiological evidence
with renal tubular acidosis and cerebral calcification of cortical hyperostosis, soft tissue swellings, fever
(MIM 259730).84 Very recently, mutation in the GL and irritability.93 Caffey disease was first reported in
gene, the gene responsible for spontaneous mouse 1945 by Caffey and Silverman. Its principle features
gray-lethal whose phenotype is a coat color defect and include acute inflammatory manifestations and the
severe autosomal recessive form of osteopetrosis, early onset time, usually in the first year of life. The
leads to severe recessive osteopetrosis in human.85 X- cause of the disease remains unclear and the disease
linked recessive anhidrotic ectodermal dysplasia with is self-limiting.
immunodeficiency, osteopetrosis and lymphoedema Further, it was recently shown that the gene
(OL-EDA-ID, MIM300301) is caused by hypomorphic encoding the low-density lipoprotein receptor related
mutations in NEMO, the regulatory subunit of the protein 5 (LRP5) is one of the regulators of peak bone
IKK (IkappaB kinase) complex encoded in the IKBKG mass in vertebrates. 94 The autosomal recessive
gene.86 Germline loss-of-function mutations in IKBKG osteoporosis pseudoglioma syndrome (MIM 259770),
are lethal in male fetuses. a disorder causing both skeletal and eye
Hematopoietic stem cell transplantation seems to abnormalities, is due to inactivating mutations in the
be the most effective and rational therapy for LRP5 gene.95 Besides the neonatal blindness, children
malignant osteopetrosis at the moment, because it with OPPG have a very low bone mass and are very
provides normal osteoclast precursors.87 However, sensitive to fractures and skeletal deformities. The
several kinds of treatment including high dose of disease is not caused by abnormal collagen matrix,
active vitamin D and long-term therapy with and this differentiates it from the severe osteogenesis
interferon gamma (IFN-g), also have been reported imperfecta, although it shares similar phenotype with
to be effective. osteogenesis imperfecta. Of interest, obligate carriers
Cathepsin K has been cloned as an osteoclast- of OPPG mutations show an increased incidence for
specific cysteine protease. The abnormalities in this osteoporotic fractures, indicating a dominant effect
gene were reported in patients with pycnodysostosis of this gene on bone mass. Targeted disruption of the
(MIM 265800).88 The characteristic features of this LRP5 gene in mice also produces osteoporosis
disease are disproportionate short stature, front- postnatally. On the other hand, in a family that
occipital prominence, high-arched palate, proptosis, includes phenotypically normal individuals with
a pointed nose and sclerotic bones. exceptionally dense bones (high bone mass MIM
In addition to impaired bone resorption, increased 601884), a gain-of-function mutation (G171V) in the
bone formation can result in sclerosing bone LRP5 gene has been described.96 The same mutation
disorders. Recently, it is reported that the increased was found in another kindred with other phenotypic
TGF-b signaling results in Camurati-Engelmann abnormalities, such as torus palatinus and a wide,
disease (MIM 131300).89 The increased bone formation deep mandible in addition to high bone density. LRP5
in sclerosteosis (SOST MIM 269500)90 and in Van acts as a coreceptor for Wnt proteins and is expressed
 Clinical and Genetical Approach to Skeletal Dysplasia 893
in osteoblasts, where it is required for the osteoblast The main facial findings of Noonan syndrome are
proliferation and functions in a Runx2-independent hypertelorism with down-slanting palpebral fissures,
manner. These findings demonstrate that the LRP5 ptosis, and low-set posteriorly angulated ears with a
signaling pathway plays an important role in the thickened helix. Cardiovascular diseases including
regulation of bone mass in vertebrates. valvular pulmonary stenosis, atrial septal defect and
LRP6 is another coreceptor of canonical Wnt hypertrophic cardiomyopathy (HCM) are observed
pathway. Thus, it is interesting whether LRP6 is in 50%~80% of patients with Noonan syndrome.
involved in bone metabolism, although a human Other symptoms are webbed neck, chest deformity,
disease caused by the abnormality of LRP6 has not mild mental retardation, cryptorchidism, feeding
been identified. Lrp6-null mice is embryonic lethal difficulties, bleeding diathesis, and lymphatic
and not suitable for the analysis of bone metabolism. dysplasias. The incidence of Noonan syndrome is
We found that a novel spontaneous mutation, estimated to be between 1:1,000 and 1:2,500 live births.
ringelschwanz (rs) in the mouse is in the Lrp6 gene.97 Recently, heterozygous missense mutations in the
While heterozygous rs animals appear normal, PTPN11 gene, located on chromosome 12 (12q24),
homozygous rs mutants show malformations in the have been identified in 33%~60% of affected familial
vertebral column, digits and the neural tube as in or sporadic cases of Noonan syndrome.99-102 The
Lrp6-null mutants, these phenotypes are less severe product of the PTPN11 gene, SHP-2, is widely
as compared to those in null mutants. The rs mutation expressed in various tissues and is involved in several
is regarded as a hypomorphic allele of Lrp6. The Lrp6 signal transduction pathways in cooperation with
dysfunction in rs leads to a delay in ossification at growth factors, cytokines, and hormones. Thus,
birth and to a low bone mass phenotype in adults. mutations in the PTPN11 gene could cause the wide
Thus, LRP6 is certainly involved in bone metabolism range of clinical features in Noonan syndrome. SHP-
as well as LRP5. 2 is composed of two tandemly arranged src
homology 2 domains, N-SH2 and C-SH2, at the amino
Noonan syndrome terminus, a single central phosphatase domain (PTP)
Noonan syndrome (MIM 163950) is an autosomal and a carboxy-terminal tail (Fig. 63.3). In steady state,
dominant disorder characterized by a variable N-SH2 domain binds to PTP domain and suppresses
phenotype comprising proportional short stature, its phosphatase activity. In contrast, the binding of
congenital heart defects, and minor facial anomalies.98 both domains is loose and PTP exerts its activity in

Exon numbers of the PTPN11 gene

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

N-SH2 C-SH2 PTP

3-104aa 112-216aa 221-524aa

Structure of SHP-2 encoded by the PTPN11 gene

Fig. 63.3: The structure of the PTPN11 gene and functional domain structure of SHP-2 are illustrated in the Figure. The gene
consists of 15 exons and the function domains of the SHP-2 protein comprise two tandemly arranged SH2 domains at the N
terminus (N-SH2 and C-SH2) followed by a protein tyrosine phosphatase (PTP). The frequent mutations associated with Noonan
syndrome are detected in Exons 3, 7 and 13 in the gene.
894 Textbook of Perinatal Medicine

mutant SHP-2 found in Noonan syndrome. In other of 2120 cases of newborns hospitalized (0.66%).104
words, gain-of-function type mutation is found in the Among them, 4 patients (28.27%) belong to the group
PTPN11 gene in patients with Noonan syndrome. The considered by the European Society of Pediatric
structure of the PTPN11 gene corresponding to the Radiology as lethal. Representative lethal types of
functional domain structure of SHP-2 is also depicted skeletal dysplasia and the corresponding causal genes
in the Fig. 63.3. The gene consists of 15 exons. The are described in the Table 63.2. The genes responsible
frequent mutations are detected in Exons 3, 7 and 13 for osteogenesis imperfecta, thanatophoric dysplasia
in the gene. and hypophosphatasia are type I collagen gene,
To date, more than 70 mutations in the PTPN11 FGFR3 gene and tissue non-specific ALP gene,
gene have been described. Tartaglia et al. reported respectively, which are essential for the development
patients with PTPN11 mutations were associated with of cartilage and bone, as described in the previous
pulmonary stenosis, while those without PTPN11 section. Other important molecules in enchondral
mutations were with HCM.103 Two other reports bone formation such as SOX9 and PTHrP receptor are
support the conclusion that HCM is found more also responsible for lethal type chondrodysplasia.
frequently in patients with Noonan syndrome Patients with campomelic dysplasia caused by SOX9
without PTPN11 mutation. However, Sarkozy et al. mutations often have respiratory difficulties. Other
showed LEOPARD syndrome (MIM 151100) with lethal forms of short limb dwarfism consist of a lethal
HCM was highly related to the mutations in exon 7 form of arthrogryposis multiplex congenita (MIM
or exon12 of the PTPN11 gene,102 suggesting that 108110), platyspondylic lethal osteochondrodysplasia,
HCM could be associated with PTPN11 mutations. short rib syndrome and atelosteogenesis.
As mentioned above, SHP-2 is widely expressed Atelosteogenesis type 2 (AO2) (MIM 256050) is a
in various tissues and cell types, and has been neonatally lethal chondrodysplasia characterised by
implicated in diverse signaling pathways including severe limb shortening and deficient ossification of
those initiated by growth factors, cytokines and parts of the skeleton. The disease is caused by
hormones. SHP-2 has compound signaling functions. mutations of the DTDST gene and its phenotypic
For instance, SHP-2 directly interacts with growth overlap with non-lethal diastrophic dysplasia. The
factor and cytokine receptors when its ligand induces heterogeneous group of platyspondylic lethal skeletal
rapidly tyrosine phosphorylation. It can also interact dysplasias (PLSD) originally included thanatophoric
with a variety of signaling intermediates such as Grb2, dysplasias (TD1/2: MIM 187600, 187100) as the most
and Gab1 and 2. As a PTP, SHP-2 is believed to common forms of this condition, as well as TD
function by dephosphorylation of its associated variants San Diego type (PLSD-SD: MIM 270230) and
signaling molecules, thus diminishing local signals. Torrance-Luton type (PLSD-TL: MIM 151210). The
However, the ultimate effect of SHP-2 in most
signaling pathways is to enhance the signal Table 63.2: Skeletal dysplasia, lethal type
transduction, for example it activates the Ras-Raf- and responsible genes
MAP kinase cascade. In most circumstances, SHP-2 Disease Gene
plays a positive role in transducing signals relayed
Osteogenesis imperfecta type II COLI
from tyrosine kinase-containing receptors.103 Thanatophoric dysplasia FGFR3
Hypophosphatasia lethal type TNSALP
PERINATAL PERIOD Achondrogenesis COLII
Hypochondrogenesis COLII
Skeletal Dysplasia, Lethal Type Achondrogenesis IB DTDST
Camptomelic dysplasia SOX9
The study in the St. John Hospital in Rome reported Blomstrand chondrodysplasia PTHR1
14 cases of constitutional osteochondrodysplasias out Short rib syndrome ?
 Clinical and Genetical Approach to Skeletal Dysplasia 895
FGFR3 gene mutations have been identified in TD1/ epiphysis of femur. We previously reported the
2 and PLSD-SD, while PLSD-TL is caused by relationship between the number of calcified bones
COL2A1. The metatropic dysplasia group includes and the gestational week. In hypophosphatasia,
fibrochondrogenesis, Schneckenbecken dysplasia and achondrogenesis and some forms of chondrodyplasia,
various forms metatropic dysplasia.105 The perinatally calcification of bones is extremely delayed. In contrast,
lethal metatropic group of conditions consists of lethal a mild decrease in number or normal development
metatropic dysplasia (Type 2) or hyperchondro- of calcified bones is observed in patients with
genesis, lethal hyperplastic metatropic dysplasia osteogenesis imperfecta and thanatophoric dysplasia.
(Type 1) and fibrochondrogenesis. In our experience, These results suggest the difference in the
osteogenesis imperfecta and thanatophoric dysplasia pathogenesis of each skeletal dysplasia.
were the most frequent lethal skeletal diseases.
CLOSING COMMENTS
Amnionic Fluid
Due to the limitation of length of this review, the
Clinical analysis of patients with skeletal dysplasias, review cannot provide readers a whole picture
lethal type revealed several characteristic phenotypes accounting for the recent development of investi-
in each disease. For example, polyhydramnios is gations on skeletal dysplasia. Apparently
known as one of the features in patients with identification of genes responsible for skeletal
congenital anomaly. However, osteogenesis dysplasia contributes to better understanding of the
imperfecta and thanatophoric dysplasia were quite process in which chondrocytes, osteoblasts and
different in terms of association with polyhydra- osteoclasts proliferate, differentiate and interact with
minios in our patients. In 11 patients with each other. Because the opportunity for pediatrician
osteogenesis imperfecta, no polyhydramnios was to take care of patients with skeletal dysplasia has
observed. In contrast, nine out of 11 patients with increase, pediatrician should understand biological
thanatophoric dysplasia were complicated with and developmental aspects of bone and chondrocytes
polyhydramnios. as well as clinical advance of treatment of patients
with skeletal dysplasia.
Intrauterine Growth Retardation (IUGR)
ACKNOWLEDGMENT
IUGR is often observed in fetus with severe skeletal
dysplasia. Short limb associated with skeletal I thank Drs. Masahiro Nakayama, Osaka Medical
dysplasia tends to underestimate the expected body Center and Research Institute for Maternal and Child
weight of the fetus. In contrast, hydrops, sometimes Health. I also thank Drs. Hitomi Okabe, Kunihiko
associated with achondrogenesis and thanatophoric Takahashi, Shigetoyo Kogaki and Shigeo Nakajima,
dysplasia, affects the weight. Patients with Osaka University Graduate School of Medicine.
osteogenesis imperfecta are often skinny and show
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electrophoresis identifies only COL1A1 mutations in 15 60. Ridanpää, M., van Eenennaam, H., Pelin, K., et al., 2001.
patients with osteogenesis imperfecta type I, identification Mutations in the RNA component of RNase MRP cause a
of common sequences of null-allele mutations. Am. J. pleiotropic human disease, cartilage-hair hypoplasia. Cell.
Hum. Genet. 62, 98-110. 104, 195-203.
46. Sillence, D.O., Senn, A., Danks, D.M., 1979. Genetic 61. Nakashima, E., Mabuchi, A., Kashimada, K., et al., 2003.
heterogeneity in osteogenesis imperfecta. J. Med. Genet. RMRP mutations in Japanese patients with cartilage-hair
16, 101-116. hypoplasia. Am. J. Med. Genet. A. 123, 253-256.
47. Glorieux, F.H., Bishop, N.J., Plotkin, H., et al., 1998. Cyclic 62. Gedeon, A.K., Colley, A., Jamieson, R., et al., 1999.
administration of pamidronate in children with severe Identification of the gene (SEDL) causing X-linked
osteogenesis imperfecta. N. Engl. J. Med. 339, 947-952. spondyloepiphyseal dysplasia tarda. Nature. Genet. 22,
48. Astrom, E., Soderhall, S., 2002. Beneficial effect of long 400-404.
term intravenous bisphosphonate treatment of 63. Shears, D.J., Vassal, H.J., Goodman, F.R., et al. 1998.
osteogenesis imperfecta. Arch. Dis. Child. 86, 356-364. Mutation and deletion of the pseudoautosomal gene
49. Chamberlain, J.R., Schwarze, U., Wang, P.R., et al., 2004. SHOX cause Leri-Weill dyschondrosteosis. Nat. Genet. 19,
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50. Millington-Ward, S., Allers, C., Tuohy, G., et al., 2002. in dyschondrosteosis (Leri-Weill syndrome). Nat. Genet.
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67. Schipani, E., Kruse, K., Juppner, H., 1995. A constitutively of the mouse progressive ankylosis gene, result in
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68. Jobert, A.S., Zhang, P., Couvineau, A., et al., 1998. Absence Osteopetrosis. N. Engl. J. Med. 351, 2839-2849.
of functional receptors for parathyroid hormone and 83. Frattini, A., Orchard, P.J., Sobacchi, C., et al., 2000. Defects
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69. Bastepe, M., Frohlich, L.F., Linglart, A., et al., 2005. osteopetrosis. Nat. Genet. 25, 343-346.
Deletion of the NESP55 differentially methylated region 84. Kornak, U., Kasper, D., Bosl, M.R., et al., 2001. Loss of the
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27. 85. Sly, W.S., Whyte, M.P., Sundaram, V., et al., 1985. Carbonic
70. Weinstein, L.S., Shenker, A., Gejman, P.V., et al., 1991. anhydrase II deficiency in 12 families with the autosomal
Activating mutations of the stimulatory G protein in the recessive syndrome of osteopetrosis with renal tubular
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86. Chalhoub, N., Benachenhou, N., Rajapurohitam, V., et al.,
71. Yamamoto, T., Ozono, K., Kasayama, S., et al., 1996.
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Increased IL-6 production by cells isolated from the fibrous
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bone dysplasia tissues in patients with McCune-Albright
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87. Doffinger, R., Smahi, A., Bessia, C., et al., 2001. X-linked
72. Riminucci, M., Collins, M.T., Fedarko, N.S., et al., 2003.
anhidrotic ectodermal dysplasia with immunodeficiency
FGF-23 in fibrous dysplasia of bone and its relationship
is caused by impaired NF-kappaB signaling. Nat. Genet.
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27, 277-285.
73. Whyte, M.P., 1994. Hypophosphatasia and the role of
88. Wilson, C.J., Vellodi, A., 2000. Autosomal recessive
alkaline phoshatase in skeletal mineralization. Endocr.
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Rev. 15, 439-461.
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74. Mornet, E., 2000. Hypophosphatasia, the mutations in the 89. Gelb, B.D., Shi, G.P., Chapman, H.A., et al., 1996.
tissue-nonspecific alkaline phosphatase gene. Hum. Pycnodysostosis, a lysosomal disease caused by cathepsin
Mutat. 15, 309-315. K deficiency. Science. 273, 1236-1238.
75. Cai, G., Michigami, T., Yamamoto, T., et al., 1998. Analysis 90. Kinoshita, A., Saito, T., Tomita, H., et al., 2000. Domain-
of localization of mutated tissue-nonspecific alkaline specific mutations in TGFB1 result in Camurati-
phosphatase proteins associated with neonatal Engelmann disease. Nat. Genet. 26, 19-20.
hypophosphatasia using green fluorescent protein 91. Brunkow, M.E., Gardner, J.C., Van Ness, J., et al., 2001.
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 IMMUNOLOGICAL BASIC ASPECTS
DURING PREGNANCY
64
Implantation

Shigeru Saito

INTRODUCTION UNIQUE HLA EXPRESSION

ON TROPHOBLASTS
Human pregnancy represents a semi-allograft to the
maternal host. 1 However, the semi-allogeneic The mechanism for maintenance of pregnancy has
embryo/fetus is not rejected by the mother. When a been proposed. Cytotoxic T cells, which induce
donated embryo is transplanted to a surrogate rejection, recognize antigeneic peptites expressed on
mother, the fetus is an allograft to the mother, but major histocompatibility antigen (MHC) class I or
the allogeneic fetus is not rejected by the mother: class II on target cells. Interestingly, villous
Pregnancy is thus a mysterious biological trophoblasts lack MHC class I and class II molecules
phenomenon. Recent studies suggest that endometrial on their surface. As a result, villous trophoblasts can
(maternal) lymphocytes play some roles in the not be recognized by maternal T cells, resulting in
maintenance of pregnancy via immune mediators prevention of rejection.
such as cytokines. 2 It has been postulated that Natural killer (NK) cells are lymphocytes of the
tolerance to paternal antigens must be present during innate immune system that are involved in the early
pregnancy. Some regulatory lymphocytes and defences against foreign cells.3 NK cell activation is
regulatory cytokines play very important roles for controlled by a dynamic balance between
preventing allograft rejection. However, these complementary and antagonistic pathways. NK cells
mechanisms are not so rigid. The absence of these express an array of activating cell surface receptors
regulatory factors is involved in multiple that can trigger cytolytic programs, as well as cytokine
implantation failure, pregnancy loss and pre- or chemokine secretion. NK cells also express cell
eclampsia. The low rate of successful implantation in surface inhibitory receptors that antagonize activating
humans suggests that the expression of these pathways through protein tyrosine phosphatases. The
cytokines and their biologic signals should be optimal, classical MHC class I molecules HLA-C, and the non-
precise and synchronized. In recent years, classical class I molecules HLA-E and HLA-G, interact
accumulating evidence has emerged that many with inhibitory receptors, such as killer-cell
factors, including cytokines, growth factors and immunoglobulin-like receptors (KIRs) and CD94/
maternal lymphocytes, contribute to the success of NKG2. A wide range of MHC class I molecules such
embryo implantation and maintenance of pregnancy. as HLA-G also bind ILT2 and ILT4, which are
 Implantation 901
members of the immunoglobulin-like transcript (ILT) complement regulatory proteins on trophoblasts.
family. Interestingly, extravillous trophoblasts, which However, complement deposition is recognized at the
invade the uterus, express HLA-C, HLA-E and HLA- feto-maternal interface in miscarriage cases. Survival
G.3 Maternal NK cell-cytotoxic activity is suppressed of Crry-/- embryos was compromised because of
by inhibitory receptors resulting in the fetus being complement deposition and concomitant placental
protected from maternal NK cell attack. A unique inflammation.6 Interestingly, breeding with C3-/- mice
characteristic of HLA-G is the generation of multiple rescued Crry-/- mice from lethality, suggesting that
spliced variants. Alternative splicing of the HLA-G the regulation of complements is critical in fetal
mRNA yields different membrane- bound and soluble control of the maternal process that mediates tissue
isoforms. Interestingly, soluble HLA-Gs which is damage.6
produced by villous trophoblasts, is an In humans, antiphospholipid syndrome (APS) is
immunosuppressive molecule inducing apoptosis of characterized clinically by fetal loss and thrombosis
activated- CD8+ T cells and down- modulating CD4+ and serologically by the presence of autoantibodies
T cell proliferation. 4 Therefore, soluble HLA-G to lipid-binding protein. Recent data suggested that
probably plays very important roles in the complement activation, especially C5a and C5R
maintenance of pregnancy at the feto-maternal interaction, is necessary for thrombosis of the
interface. Soluble HLA-G may also contribute to the placental vasculature.7 APS is generally treated with
control of implantation. It has been reported that anticoagulation therapy. Recent studies demonstrated
human implantation was strictly related to soluble that treatment with heparin prevented complement
HLA-G secretion by pre-implantation embryos. 5 activation in vivo and in vitro and protected mice
Fuzzi et al. reported that after in vitro fertilization from pregnancy complications induced by
(IVF) or intracytoplasmic sperm injection (ICSI), only antiphospholipid antibodies.8 These data suggest that
transfer of embryos secreting HLA-G could lead to inhibition of complement activation is essential for
pregnancies. In contrast, no pregnancy occurred after maintenance of pregnancy.
transfer of soluble HLA-G-negative embryos. Soluble
HLA-G appears to be a key molecule at the time of FAS–FAS LIGAND (FAS L) SYSTEM
implantation, and in early and late placentation. The Fas /Fas L pathway plays a critical role in
promoting apoptosis and regulation of immune
EXPRESSION OF COMPLEMENT REGULATORY
responses. The Fas/Fas L system appears to
PROTEINS ON TROPHOBLASTS
contribute to the immune privilege of the maternal-
Activation of a complement promotes cell lysis fetal interface. The maternal decidua and fetal
mediation by the membrane attack complex (MAC). trophoblasts express Fas L, and expression might
Complements also bind and attack self tissues, prevent trafficking of reactive maternal cells into the
especially in areas of inflammation. However, cells fetal circulation and vice versa. T cells specific for fetal
are protected from the deleterious effects of antigens (Ags) decrease in an Ag-specific manner
complement activation by complement regulatory during pregnancy, consistent with clonal deletion in
proteins such as CD46 (MCP), CD55 (DAF), CD59 and the maternal immune system. Placental trophoblasts
Crry. Crry, present only in rodents, regulates the which express Fas L can induce Fas-mediated death
deposition of activated C3 and C4 on the surface of of maternally activated T cells, and this clonal deletion
autologous cells. Decreased expression of is one mechanism of tolerance to the fetal allograft.9
complement regulatory molecules has been found in The Fas/Fas L system also plays important roles in
different inflammatory disorders. Complement implantation. Embryonic trophoblasts and maternal
activation is regulated by excessive expression of decidua produce conticotropin-releasing hormone
902 Textbook of Perinatal Medicine

(CRH) and CRH induces Fas L expression.11 Female T cells can be classified into CD4+ T cells and CD8+
rats treated with a CRH receptor type 1 antagonist, T cells by their surface markers (Fig. 64.2). CD4+ T
antalarmin, showed a marked decrease in cells are also classified into Th1 cells, which produce
implantation sites and live embryos, along with IL-2, IFN-g and TNF-b, and Th2 cells which produce
diminished endometrial Fas L expression. Embryos IL-4, IL-5 and IL-13. Th1 cells are involved in cellular
from mothers that lacked T cells or from syngeneic immunity such as rejection or cytotoxic T cell
matings were not rejected when the mothers were responses. On the other hand, Th2 cells are involved
given antalarmin.10 These data suggest that locally in immunoglobulin production. Based on these
produced CRH promotes implantation and findings, Wegmann et al. hypothesized that
maintenance of early pregnancy by killing activated physiological protection from maternal rejection is
T cells. due to a Th2- type response at the materno-fetal
interface. 12 In a mouse model, Th1 cells induced
TH1/TH2 BALANCE DURING PREGNANCY miscarriage and implantation failure. However, in
The blastocyst and maternal endometrium develop humans, the peripheral blood Th1/Th2 balance in
an exquisite dialogue during the implantation normal pregnancy is controversial, because the
window. Successful embryo implantation requires the amplitude of this balance is very small in peripheral
synchronization of embryo development and uterine blood. On the other hand, the Th1/Th2 ratios in the
preparation. In mice, this period begins at day 3 and endometrium or decidua change dramatically during
is complete by day 5 (Fig. 64.1). Pseudopregnancy at the menstrual cycle and pregnancy. For example, it
day 2 in mice does not represent the receptive phase has been reported that the Th1/Th2 ratio was 147.5
for implantation of embryos. Takabatake et al. during the proliferative phase of the endometrium,
reported that in recipient pseudopregnant mice 37.4 during the secretory phase and 1.3 in early
injected intravenously with splenocytes or culture pregnancy decidua.13 Furthermore, the numbers and
supernatant on day 2, blastocyst transfer was formed population of Th2 cells are increased at the decidua
on day 2. 11 The successful implantation rate was basalis compared to those at the decidua parietalis,
markedly higher in the pregnancy day 4- and day 8- suggesting that Th2 cells accumulate at the
splenocytes- injected groups. They further clarified implantation site.14
that a significant increase in the implantation rate was Hill et al. first reported that Th1 type immunity is
observed when pregnancy day 4- CD4+ T cells were present in women with recurrent pregnancy loss, and
injected into the uterus. These data suggest that CD4+ Piccinni et al. first reported defective production of
T cells during early pregnancy could contribute to Th2 cytokines by decidual T cells in unexplained
changing the implantation window and increase the T cell receptor Surface marker Cytokine production
chance of implantation. Th0 (IL-4+, IFN-γ +)
CD4+ CD25- Th1 (IL-4-, IFN-γ +)
CD4 Th2 (IL-4+, IFN-γ -)
close (implantation failure)? implantation window close (implantation failure)?
? ? Tαβ Th3 (IL-10+, TGF-β+++)
Tr1 (IL-10+++, TGF- β+)
Pseudopregnant day1? ? day2? ? ? day3 ? ? day4 ? day5 day6 day7 day8 day9 day10

CD4+CD25+ regulatory T (IL-10+/-, TGF-β+/- )

T Tc0 (IL-4+, IFN-γ +)

Tc1 (IL-4-, IFN-γ +)
CD8
Blastocyst transfer Tc2 (IL-4+, IFN-γ -)
+? CD8+ Tr (IL-10++, TGF-β+/-)
splenocytes CD56+ TCRγ δ+ IL-10++, TGF- β+ (Tr1 like)
thymocytes Tγ δ
CD4? -T cells? TCRγ δ+ IL-10+++, TGF-β++ (Tr1 like)

Fig. 64.1: Implantation window in mice Fig. 64.2: T cell subsets classified by their surface markers
and cytokine profiles
 Implantation 903
recurrent spontaneous abortion. Michimata et al. first maternal tolerance to the fetus by increasing the
reported decreased Th2 cells in the decidua basalis number of CD4+CD25+ Treg cells.
in recurrent spontaneous abortion with normal
embryo, although accumulation of Th2 cells was INDOLEAMINE 2,3- DIOXYGENASE (IDO)
observed in the decidua basalis in recurrent EXPRESSION DURING PREGNANCY
spontaneous abortion with abnormal chromosomal Indoleamine 2,3- dioxygenase (IDO) is an enzyme for
content.15 These data suggested that accumulation of tryptophan catabolism and it is expressed in the
Th2 cells at the decidua basalis is important in blastocyst, syncytiotrophoblasts, extravillous
maintaining pregnancy. trophoblasts, macrophages and endometrial gland
cells. Pharmacologic inhibition of IDO activity
REGULATORY T CELLS IN PREGNANCY
resulted in dramatically decreased rates of successful
Recent data demonstrated that immunoregulatory allogeneic pregnancy due to maternal T cell response
activity specific for donor alloantigens is enriched in to fetal alloantigens. 19 IDO is a key immuno-
the CD4+CD25+ regulatory T (Treg) cell population suppressive mechanism in normal pregnancies,
(Fig. 64.2). CD4+CD25+ Treg cells play a critical role although IDO- deficient mice can become pregnant
in peripheral tolerance, transplantation tolerance and and do not abort.
maternal tolerance to the fetus. The population of Cytotoxic T lymphocyte- associated antigen 4
CD4+CD25+ Treg cells increase in iliac lymph nodes, (CTLA-4) plays a critical role in peripheral tolerance,
inguinal lymph nodes, in the spleen, in decidua, and and it is well known that CD4 +CD25+ Treg cells
in blood, and these cells suppress alloreactive express CTLA-4 on their surfaces. Interestingly,
proliferation in vitro.16,17 Alubihare et al. injected 2 x CTLA-4 induces IDO enzyme activity in dendritic
107 lymphocytes or an equal numbers of cells from a cells and regulates tryptophan catabolism.20 These
CD25-depleted cell preparation (CD25-) into BALB/ findings suggest that decidual CD4+CD25+ Treg cells,
C nu/nu mice that lacked T cells. 16 All recipient which express CTLA-4 on their surface, interact with
BALB/C nu/nu female mice were mated with dendritic cells. As a result, these signals enhance IDO
C57BL/6 male mice on the day after adoptive transfer. activity resulting in maintenance of pregnancy. The
As a result, all the fetuses were aborted in allogeneic cross talk between CD4+CD25+ Treg cells and the IDO
pregnancy when CD25- cells were injected, while this enzyme may induce successful pregnancy.
treatment did not induce fetal resorption in syngeneic
pregnancy. These findings suggest that CD25+ cells, CYTOKINE PROFILE IN DECIDUAL NK CELLS
perhaps CD4 + CD25 + T cells, mediate maternal The Th1/Th2 paradigm has been further developed.
tolerance to the fetus. T cell subsets which produce the immunoregulatory
In human pregnancy, CD4+CD25bright Treg cells cytokines IL-10 and TGF-b have been clarified. Th3
are increased in the early pregnancy decidua, but this cells predominantly produce TGF-b, while Tr1 cells
elevated CD4+CD25bright Treg cell ratio decreases to predominantly produce IL-10. They achieve
a non-pregnancy level in miscarriage cases. 17 immunoregulation via their cytokine production. NK
Therefore, CD4+CD25+ Treg cells are crucial to the cells also classified into NK1, NK2, NK3 and NKr1
maintenance of tolerance in pregnancy. Recently, cells by their cytokine profiles (Fig. 64.3).
Polanczyk et al. reported that estrogen augmented It is well known that NK cells are the main
Foxp3 expression, which is an essential factor for the population of lymphocytes in early pregnancy
development of CD4 +CD25 + Treg cells, and that decidua. NK cells can be classified into CD16+CD56dim
treatment with estrogen increased the CD4+CD25+ NK cells and CD16-CD56bright NK cells. The main
Treg cell number in mice.18 Estrogen might promote population of peripheral blood NK cells is
904 Textbook of Perinatal Medicine

Fig. 3 NK cell subsets by their cytokine profiles • Absence of classical MHC class I and class II molecules on
trophoblasts
NK1 (IFN-γ+, TNF-α+) • Expression of HLA-C, HLA-G, and HLA-E on trophoblasts
• Expression of complement regulatory proteins on trophoblasts
NK2 (IL-4+, IL-5+, IL-13+) (CD46, CD55, and CD59)
NK • Fas ligand, Fas receptor system
NK3 (TGF-β+) • Immunosuppressive factors (α2 glycoprotein, AFP, and TGFβ)
CD16+CD56dim NK cell
• uNK (CD16-CD56bright NK cells) (GMG cells in mice)
CD16-CD56bright NK cell
• Cytokines (Th2 type cytokines) and hormones
NKr1 (IL-10+)
• regulatory T cells (CD4+CD25+ T cells, Th3, Tr1)
• regulatory NK cells (NK3, NKr1)

Fig. 64.4: Proposed mechanism for

Fig. 64.3: NK cellsubsets by their cytokine profiles maintenance of pregnancy

CD16 + CD56 dim NK cells, whereas the main clearly change during implantation and pregnancy.
population of endometrial and decidual NK cells is These dramatic and synchronized changes are present
CD16-CD56bright NK cells. In the peripheral blood of at the local implantation site. A better understanding
non-pregnant subjects, IFN-g-producing of these sequential events could improve clinicians’
CD16+CD56dim NK cells and CD16-CD56bright NK cells ability to treat disorders related to these processes,
are the main populations. After pregnancy, the including infertility and early pregnancy loss.
populations of IL-10-producing NKr1 cells in
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10. Makrigiannakis A, Zoumakis E, Kalantaridou S, Coutifaris 1528.
C, Margioris AN, Coukos G, Rice KC, Gravanis A, 16. Alubihare VR, Kallikourdis M, Betz AG. (2004) Regulatory
Chrousos GP. (2001) Corticotropin-releasing hormone T cells mediate maternal tolerance to the fetus. Nat.
promotes blastocyst implantation and early maternal Immunol. 5; 266-271.
tolerance. Nat Immunol 2:1018-1024. 17. Sasaki Y, Sakai M, Miyazaki S, Higuma S, Shiozaki A, Saito
11. Takabatake K, Fujiwara H, Goto Y, Nakayama T, Higuchi S. (2004) Decidual and peripheral blood CD4+CD25+
T, Maeda M, Mori T. (1997) Intravenous administration regulatory T cells in early pregnancy subjects and
of splenocytes in early pregnancy changes the spontaneous abortion. Mol. Hum. Reprod. 10; 347-353.
implantation window in mice. Hum Reprod 12:583-585. 18. Polanczyk MJ, Carson BD, Subramanian S, Afentoulis M,
12. Wegmann TG, Lin H, Guilbert L, Mosmann TH. (1993) Vandenbark AA, Ziegler SF, Offner H. (2004) Estrogen
Bidirectional cytokine interactions in the maternal-fetal drives expansion of the CD4+CD25+ regulatory T cell
relationship: is successful pregnancy a TH2 phenomenon? compartment. J Immunol 173:2227-2230.
Immunol Today 14:353-356. 19. Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ,
13. Saito S, Tsukaguchi N, Hasegawa T, Michimata T, Tsuda Marshall B, Brown C, Mellor AL. (1998) Prevention of
H, Narita N, Ichijo M. (1999) Distribution of Th1, Th2 and allogeneic fetal rejection by tryptophan catabolism. Science
Th0 and the Th1/Th2 cell ratios in human peripheral and 281; 1191-1193.
endometrial T cells. Am J Reprod Immunol 42:240-245. 20. Grohmann U, Orabone C, Fallarino F, Vacca C, Calcinaro
14. Michimata T, Tsuda H, Sakai M, Fujimura M, Nagata K, F, Falorni A, Candeloro P, Belladonna ML, Bianchi R,
Nakamura M, Saito S. (2002) Accumulation of CRTH2- Fiaretti MC, Puccetti P. (2002) CTLA-4-Ig regulates
positive T-helper 2 and T-cytotoxic 2 cells at implantation tryptophan catabolism in vivo. Nat Immunol 3:1097-1101.
sites of human decidua in a prostaglandin D2- mediated 21. Higuma-Myojo S, Sasaki Y, Miyazaki S, Sakai M, Shiozaki
manner. Mol Hum Reprod 8:181-187. A, Miwa N, Saito S. Cytokine profile of natural killer cells
15. Michimata T, Sakai M, Miyazaki S, Ogasawara MS, in early human pregnancy. Am J Reprod Immunol in
Suzumori K, Aoki K, Nagata K, Saito S. (2003) Decrease press.
 PLACENTA AND TROPHOBLASTS

65
Endocrinological Aspect

Norimasa Sagawa

INTRODUCTION unit (Jaffe, 1999). The individual adult steroid-

producing glands are capable of the formation of
The production of steroid and protein hormones by
progestins, androgens, and estrogens, but this is not
human trophoblasts is the largest in amount and
true of the placenta. There is a constant interplay of
diversity among endocrine organs in all mammalians.
fetus, placenta, and mother to form the bulk of the
A unique and obligatory interrelationship is present
sex steroids in pregnancy (Jaffe, 1999). For estrogen
between the hyperestrogenic state of human
formation by the placenta to occur, precursors must
pregnancy and the fetal adrenal secretion of large
reach it from both the fetal and maternal
amount of C19 steroids which serve as precursors for
compartments, whereas placental progesterone
estrogen synthesis in the placenta. Human
formation is accomplished in large part from
syncytiotrophoblast takes up maternal plasma low-
circulation maternal low-density lipoprotein
density lipoprotein (LDL)-cholesterol as a substrate
cholesterol (Carr et al., 1982). In the placenta,
for progesterone biosynthesis in the placenta.
cholesterol is first converted to pregnenolone and then
The human placenta also synthesizes an enormous
rapidly and efficiently to progesterone (Pion et al.,
amount of protein and peptide hormones including
1965). Production of progesterone reaches
human chorionic gonadotropin (hCG), human
approximately 250 mg/day by the end of pregnancy,
chorionic somatomammotropin (hCS), chorionic
when the circulating levels are on the order of 130 ng/
adrenocorticotropin (ACTH), and others.
ml (Johanson et al., 1979). The placenta also produces
STEROIDOGENESIS IN THE estrogens by aromatization of circulating androgens.
FETOPLACENTAL UNIT The major precursor in placental estrogen formation
is dehydroepiandrosterone sulfate (DHEA-S), mainly
Steroid Fromation from the fetal adrenal gland. The abundant sulfatase
enzyme in the placenta converts DHEA-S to free
Estrogen
(unconjugated) DHEA, when it reaches the placenta.
The placenta is an incomplete steroid-producing DHEA is further converted to androstenedione,
organ. It must rely on precursors reaching it from the thereafter to testosterone, and finally to estrone and
fetal and maternal circulations. The unique 17b-estradiol. However, the major estrogen formed
interdependence of fetus, placenta, and mother arose in the human pregnancy is neither estrone nor
the concept of an integrated fetoplacental-maternal estradiol but another estrogen, estriol. Estriol is not
 Endocrinological Aspect 907
secreted by the ovary of nonpregnant women but of estriol, 16a-hydroxy DHAS is predominantly
constitutes more than 90% of the known estrogen in originated from fetus reflecting fetal adrenal and liver
pregnancy urine. Concentrations increase with function. Thus, increase in the maternal plasma estriol
advancing gestation and reach to 35 to 45 mg/24 hr concentration in late pregnancy is the reflection of total
at term (Frandsen and Stakeman, 1963). Estriol is also functions and development of fetal adrenal, fetal liver
found in the amniotic fluid and maternal circulation and the placenta.
(Schindler and Siiteri, 1968). The concentration of Sulfatase deficiency occurs in male babies at the
estriol in the maternal circulation is between 8 and 13 incidence of 1/15,000 pregnancies, in which 16a-
ng/ml at term (Goebelsmann, et al., 1973). hydroxy DHAS is not hydrolyzed and is not further
Estriol is produced by a unique biosynthetic converted to estriol. The infant with sulfatase
process, which forms the interdependence of three deficiency later develops X-linked ichthyosis
compartments, fetus, placenta and mother (Fig. 65.1). (Bradshaw and Carr, 1986). Anencephalus lacking
Maternal cholesterol is transported as LDL-cholesterol pituitary does not secrete ACTH and then estriol
to the placenta. Cholesterol is converted to production is very low, approximately 10% of normal
pregnenolone in the placenta and fetal adrenal. Fetal fetus. When the fetus dies in utero the precursor of
adrenal further metabolizes pregnenolone to estriol is not provided from fetal adrenal and the
dehydroepiandrosterone sulfate (DHAS), which is estriol levels declines significantly (Jaffe, 1999).
metabolized to 16a-hydroxy DHAS by 16a- However, changes in the maternal plasma or urinary
hydroxylase in the fetal liver. DHAS and 16a-hydroxy estriol levels are too slow and do not reflect real time
DHAS are hydrolyzed by placental sulfatase in the fetal vaiability. In Down syndrome, maternal plasma
placenta and resulting DHA is further metabolized unconjugated estriol levels are low, because the
to estrone and estradiol, and 16a-hydroxy DHA to production of precursor of estriol synthesis in the fetal
estriol by placental aromatase. The precursor of adrenal is not adequate. Based on this fact, serum
placental estrone and estradiol is derived from both estriol levels in the late first trimester are utilized as
maternal and fetal adrenals. In contrast, the precursor one of serum markers of Down syndrome.

Mother Placenta Fetus

LDL Cholesterol
Pregnenolone
Adrenals

sulfate
Cholesterol Pregnenolone
Dehydroepi-
Acetate Progesterone androsterone
sulfate
Liver

16 -hydrxylase
16 -hydroxy-
Dehydroepi- sulfatase
androsterone 16 -hydroxy-
Estriol
Liver

Dehydroepi-
glucosiduronate aromatase androsterone
Estriol sulfate

Excretion
into urine
Fig. 65.1: Estriol biosynthesis in fetoplacental-maternal unit
908 Textbook of Perinatal Medicine

Glucocorticoid administration suppresses placental placenta. Cortisol level in the amniotic fluid increases
estrogen synthesis because glucocorticoid suppresses as fetus maturate due to cortisol excretion into fetal
ACTH secretion in both mother and fetus and urine. Maternal plasma cortisol level increases
consequently decreases DHAS secretion from both secondary to the increase in cortisol binding globulin
maternal and fetal adrenals. (CBG) in maternal plasma. When utero-placental
blood flow decreases in the pregnant women
Progesterone complicated with preeclampsia, chronic hypertension
Placenta is the main source of progesterone in the or severe diabetes mellitus, blood flow in the placental
maternal plasma (Simpson and MacDonald, 1981). intervillous space decreases resulting in the diffusion
Precursor of progesterone synthesis, cholesterol is of placental steroid hormone to the fetus, increase in
predominantly derived from maternal plasma LDL the steroid hormone levels in the umbilical cord. The
cholesterol, since cholesterol synthesizing enzymes are increased cortisol might accelerate fetal lung
not expressed in the placenta. Thus, progesterone maturation in case of fetal compromise associated
synthesis is dependent on maternal and placental with impaired utero-placental perfusion.
bioactivities but not on fetal viability (Liu and Rebar,
1999). This is the reason why the progesterone levels Biological Function of Steroid
in maternal sera do not reflect acute fetal compromise
as compared to that of estrogen. Placenta does not Estrogens
metabolize progesterone. Major part of placental The functional role of placental estriol in pregnancy
progesterone is secreted to fetal circulation and further has caused a great deal of speculation. In many
metabolized to glucocorticoids such as cortisol and biologic systems, estriol is a weak estrogen. Its potency
aldosterone. Rest of the placental progesterone is is approximately 0.01 times of estradiol and 0.1 times
secreted to maternal plasma. Plasma concentration of of estrone on a weight basis. However, estriol is
progesterone in the late first trimester is reported to be as effective as other estrogens in one
approximately 30 - 40ng/ml and further increases to function; its ability to increase uteroplacental blood
130 ng/ml (secretion: 250 mg/day) which is flow. Therefore, this may be a primary function of
approximately 10 times of corpus luteum production. large amount of placental estriol. Its relatively weak
Porgesterone production in the syncytiotrophoblast estrogenic function on other organ systems may be
during early first trimester is still low and is not beneficial to specifically increase urtoplacental blood
enough to maintain the pregnancy. Thus, corpus flow. Although acute administration of estriol is
luteum is necessary for the maintenance of pregnancy ineffective as an estrogen and does not demonstrate
until 6-7 weeks of gestation. Half life of progesterone extensive binding to estrogen receptors, prolonged
is much more shorter than that of hCG. Therefore, exposure to estriol does produce estrogen effects and
plasma level of progesterone decreases much earlier binding occurs. Estrogens exert their biological effect
than that of hCG when spontaneous termination of on blood flow by stimulating prostaglandin
pregnancy occurs in early pregnancy. biosynthesis (Resnik et al., 1974).
Estradiol stimulates protein synthesis, cell
Corticoids
proliferation in the endometrium, myometrium and
Progesterone produced in the placenta is metabolized mammary gland. It is also involved in the regulation
to either cortisol or aldosterone because fetal adenal of vascular permeability and fluid balance. The
lacks 3b-hydroxysteroid dehydrogenase (3bHSD). increase in blood volume and extracellular fluid
Cortisol is further converted to cortisone by 11b- volume is mediated by estrogen. Fetus is also the
hydroxysteroid dehydrogenase (11bHSD) in the target of placental estrogen and its growth and
 Endocrinological Aspect 909
development are affected by estrogen. implantation (Hay and Lopata, 1988). HCG is a
Estrogens are also important for initiation of glycoprotein of heterodimer with molecular weight
parturition at an appropriate time. Estrogen stimulates of 36.7 kD. It is composed of two subunits, 92-amino
phospholipids synthesis and turnover, prostaglandin acids a-subunit and 145-amino acid b-subunit. The a-
production and lysosome formation in the uterine subunit is homologous to thyroid-stimulating
endometrium, and modulate adrenergic mechanisms hormone (THS), luteinizing hormone (LH), and follicle
in uterine myometrium, thereby contributing to the stimulating hormone (FSH). The a-subunit gene is
onset of labor (Casey et al., 1983). localized to chromosome 6. The b-subunit is similar
to LH and the β-subunit gene is located on the
Progesterone chromosome 19, fairly close to the LH-b gene. In
contrast to LH, hCG contains sialic acid residues
Progesterone induces the secretory endometrium,
which account for its half life (24 hours) longer than
which is required for implantation. Progesterone is
that of LH (2hours).
also important in maintaining uterine quiescence
Clinically, hCG can be detected in either the serum
during pregnancy by suppressing uterine smooth
or urine 7 to 8 days after fertilization and is the earliest
muscle contractility (Roberts et al., 1984). It also
biochemical marker for pregnancy. Studies during in
inhibits prostaglandin synthesis in the uterus (Cane
vitro fertilization cycle suggest that embryos
and Villee, 1975). Progesterone has also been proposed
expressed hCG mRNA as early as eight-cell stage but
to be essential hormone of mammalian pregnancy
that intact hCG was not until 8 days after egg retrieval.
because it inhibits T lymphocyte cell-mediated
The increase in hCG levels between days 5 and 9 after
responses involved in tissue rejection (Siiteri et al.,
ovum collection is principally due to free b-hCG pro-
1977). In this theory, it is suggested that a high local
duction, while by day 22 most of the circulating hCG
(intrauterine) concentration of progesterone can
is in the dimmer form. After implantation hCG is
effectively block cellular immune responses to foreign
produced principally by the syncytiotrophoblast layer
antigens. Therefore, progesterone has been aptly
of chorionic villi and is secreted into the intervillous
called the “hormone of pregnancy” because it appears
space. Cytotrophoblasts also can produce hCG.
to be essential for maintenance of pregnancy in all
These observations are in accordance with the in
mammals examined, and its presence has been
vitro studies that suggest dimmer hCG synthesis is
detected in species representing all classes of
controlled in a two-phase manner through a supply
vertebrates. The essential nature of progesterone for
of subunits. In contrast to LH secretion in the pituitary
pregnancy maintenance has been demonstrated by
gland, hCG is secreted constitutively as subunits are
experiments in which abortion was induced after the
available and is not stored in secretory granules as in
administration of drugs that either inhibit
the case of pituitary LH (Muyan and Boime, 1997).
progesterone synthesis or compete with progesterone
The immature syncytiotrophoblast produces free b-
for receptor binding or the administration of
hCG subunit while the ability to produce the a-subunit
progesterone antibodies. The specificity of the
by cytotrophoblast appears to lag by several days
abortifacient effect was demonstrated by the
(Hay, 1985). As the trophoblast matures, the ratio of
concurrent administration of progesterone in some of
a-subunit to b-subunit reaches a 1:1 ratio, and the hCG
those experiments.
concentration reaches a peak value of 100,000 mIU/
mL around the 9 to 10 weeks of pregnancy. Placenta
HUMAN CHORIONIC GONADOTROPIN
produces more a-subunit as gestation advances, and
Human chorionic gonadotropin hCG) is the earliest the ratio of a-subunit to hCG is approximately 10:1 at
product of the cells which form embryo representing term (Takemori etr al., 1981).
the first signal of the embtyo even prior to The doubling time of serum hCG levels during
910 Textbook of Perinatal Medicine

early gestation is approximately 30 hours (Lenton and HUMAN CHORIONIC SOMATOMAMMOTROPIN

Woodward, 1988). The hCG doubling time has been (HCS) (HUMAN PLACENTAL LACTOGEN; HPL)
utilized as a clinical marker to differentiate normal
Human chorionic somatomammotropin (hCS) was
from abnormal pregnancies such as ectopic pregnancy
initially isolated in 1962 as human placental lactogen
or spontaneous abortions. When vaginal ultrasono-
(hPL) (Josinovich and MacLaren 1962). hCS has
graphy cannot detect intrauterine gestational sac even
structural similarity to both pituitary human growth
after the hCG levels reach 1,100 to 1,500 mIU/mL, an
hormone (hGH) and prolactin (PRL). hCS is consisted
ectopic pregnancy is strongly suggested. On the other
of 191 amino acids with molecular weight of
hand, higher hCG levels suggest the presence of molar
approximately 22 kD and contains two disulfide
pregnancy or multiple gestations. bonds. It shares up to 96 % homology with hGH and
The major biologic function of hCG during early 67 % homology with PRL (Bewley et al., 1972; Cooke
pregnancy is to rescue corpus luteum from its et al., 1081). hCS and hGH genes locate on the same
premature demise while maintaining progesterone portion of chromosome 17, which is consisted of five
production. Until the luteal-placental shift in genes, two coding for hGH and three coding for hCS
progesterone synthesis occurs at 7th week of (Owerbach et al., 1980). hCS is produced only in the
pregnancy, hCG is required for rescue and syncytiotrophoblast and at a constant rate throughout
maintenance of the corpus luteum. This is supported gestation (McWilliams and Boime, 1980; Hoshina
by the report that immunoneutralization of hCG et al., 1982). Consequently, serum hCS concentration
resuts in early pregnancy failure (Stevens, 1975). In correlate well with placental mass and viability. At
the explant experiment with first trimester chorionic term, Placenta produces hCS approximately 1-4 g/day
tissue, intermittent administration of gonadotropin and maternal serum hCS levels range from 5 – 15 mg/
releasing hormone (GnRH) enhanced the pulsatile mL.
secretion of hCG from the explant tissue, implicating Despite the large amount of production during
placental GnRH as a paracrine regulator of hCG pregnancy, the physiological function of hCS has not
secretion (Barnea et al., 1991). When pregnancy is not fully clarified. hCS has been suggested to have major
established, the corpus luteum is preprogrammed to metabolic effect on the mother to ensure that the
undergo luteolysis. hCG also stimulate the production nutritional demands of the fetus are met, functioning
of estradiol, 17-hydroxyprogesterone and other as a growth hormone of pregnancy (Grumbach et al.,
peptides, such as relaxin, inhibin, from corpus luteum. 1966). During pregnancy, maternal plasma glucose
Ovarian progesterone is essential for maintenance levels are decreased, plasma free fatty acids (FFAs)
of early pregnancy. When progesterone action is are increased, and insulin secretion is increased with
blocked with a competitive progesterone antagonist, resistance to endogenous insulin as a consequence of
such as mifepristone (RU 486), pregnancy is the GH-like and contra-insulin effects of hCS.
terminated. Removal of corpus luteum before, but not Peripheral glucose uptake is suppressed in the mother
after 7th week of gestation resulted in subsequent but it crosses the placenta freely by a facilitated
abortion (Csapo et al., 1973; Csapo and Pulkkinen, diffusion mechanism. Amino acids are transported
1978). Removal of coupus luteum after 9th week of across the placenta by an active transport mechanism
pregnancy had little or no influence on pregnancy. against the concentration gradient. Transplacental
Thus, progesterone supplementation is required when passage of fatty acids is slow. Consequently, when the
corpus luteum function is compromised prior to 9th mother is in the unfed or starved state, glucose should
to 10th weeks of pregnancy. During later pregnancy, be reserved largely for the fetus and free fatty acids
progesterone production in placenta is sufficient for would be used preferentially by the mother. Insulin
the maintenance of pregnancy. and other protein hormones do not cross the placenta.
Regulation of placental secretion of hCS is poorly
 Endocrinological Aspect 911
understood. Factors that regulate pituitary GH rate of PTH secretion by the adult parathyroid is
secretion are not effective in placenta. Although hCS modulated by plasma Ca2+ concentration. PTH-rP
has structural homology to hGH and PRL, it does not secretion from the placenta is regulated by calcium
have growth promoting or lactogenic activity in concentration (Hellman et al., 1992).
humans (Grumbach et al., 1966). There are several case Relaxin is also expressed in the human placenta
reports on the healthy newborn from hCS deficient (Bogic et al., 1995). Relaxin is synthesized as a single
pregnancy (Nielsen et al., 1979; Parks et al., 1985). 105 amino acids preprorelaxin which is cleaved to
Thus, it is possible that hCS is not essential for form two chains A and B. Relaxin is structurally
pregnancy but may serve as an evolutionary similar to insulin and nerve growth factor. Relaxin acts
redundancy for pituitary GH and PRL. However, it on myometrial smooth muscle to stimulate adenylate
remains to be clarified whether pregnancies without cyclase and to promote uterine relaxation.
hCS production would have a good outcome even in Placenta produces chrionic thyrotropin, but its
the state of nutritional deprivation. biological significance in normal human pregnancy
is yet be clarified.
OTHER PLACENTAL PROTEIN HORMONES Growth hormone-variant (hGH-V) is expressed in
the placenta but not in the pituitary (Cunningham
Chorionic Adrenocorticotropin (ACTH)
et al., 1999). The gene is located in the growth
A protein similar to pituitary adrenocorticotropic hormone –prolactin gene cluster. The variant of hGH,
hormone (ACTH) has been isolated from the placenta. sometimes referred to as placental growth hormone,
ACTH, lipotropin, and β-endorphin are recovered is a 191 amino acid protein that differs in 15 amino
from placental extract, presumably from the same or acids from hGH. hGH-V is synthesized in placenta,
similar 31 kD precursor proopiomelanocortin (POMC) presumably in the syncytiotrophoblasts. hGH-V is
(Odagiri et al., 1979). It is also reported that ACTH is present in the maternal plasma by 21 to 26 weeks of
secreted from dispersed placental cells (Liotta et al., pregnancy, increases in concentration to about 36
1977). Dexamethasone treatment does not alter the weeks of pregnancy and remains relatively constant
production of ACTH in the placenta. thereafter. The maternal plasma levels of hGH-V
The physiological significance of placental ACTH correlate well with those of insulin-like growth factor-
is unclear. ACHT plasma levels during pregnancy are 1. Secretion of hGH-V from trophoblast is inhibited
lower than in non-pregnant women; nonetheless, the by glucose in a dose-dependent manner (Patel et al.,
concentration increases as gestation advances (Carr 1995). The biological activity of hGH-V is similar to
et al., 1981). Placenta secretes ACTH into both that of hCS.
maternal and fetal circulations, but it does not cross
the placenta. The administration of dexamethasone HYPOTHALAMIC-LIKE RELEASING HORMONES
to pregnant women does not suppress urinary free
Gonadotropin-releasing Hormone (GnRH)
cortisol levels as effectively as it does in men or non-
pregnant women. Corticotropin releasing hormone Placenta secretes relatively large amount of GnRH
stimulates the synthesis and release of ACTH from (Siler-Khodr, 1988). GnRH is present only in the
chorionic tissue in vitro (Riley et al., 1991). cytotrphoblast but not in the syncytiotrophoblast.
Placental GnRH is suggested to act as hCG releasing
Parathyroid Hormone-related Protein (PTH-rP) hormone (Siler-Khodr, 1983). First trimester chorionic
and other Protein Hormones tissue secretes hCG in response to GnRH much more
Parathyroid hormone-related protein (PTH-rP) is than that of term placenta (Currie et al., 1993).
synthesized in various tissues including pregnant Receptor for GnRH is expressed in both
uterus, myometrium, endometrium and placenta. The cytotrophoblast and syncytiotrophoblast. Trophoblast
912 Textbook of Perinatal Medicine

secretes inhibin and activin and regulates GnRH The mRNA for GHRH has been identified in the
production in a paracrine manner. Human placenta human placenta (Berry et al., 1992). The biological
can also synthesize thyrotropin releasing hormone function of placental GHRH is not known.
(TRH) in vitro (Gibbons et al., 1975; Khodr and Siler-
Khodr, 1980). OTHER PLACENTAL PEPTIDE HORMONES

Corticotropin-releasing Hormone (CRH) Neuropeptide Y (NPY)

The same CRH gene expressed in hypothalamic Neuropeptide Y (NPY), 36-amino acid peptide is
tissues is also expressed in the trophoblast, amnion, originally isolated in the brain. It also is present in
chorion leave, and decidua. Plasma levels of CRH in sympathetic neurons innervating the cardiovascular,
non-pregnant women are 15 pg/mL. Maternal plasma respiratory, gastrointestinal, and genitourinary
CRH levels increase to 250 pg/mL at early third systems. NPY is also expressed in the placenta and
trimester, and to 1000 pg/mL abruptly during the last localized in cytotrophoblasts (Petraglia et al., 1989).
5 to 6 weeks of pregnancy (Goland et al., 1988). After Receptors for NPY are also present in the placenta,
labor onset, maternal plasma CRH levels increase which secrete CRH by stimulation with NPY.
further to about two- to three-folds (Petraglia et al.,
1989). The biological function of uterine CRH Inhibin and Activin
including placental CRH is not clear yet. Receptors
Inhibin is a glycoprotein hormone that acts on the
for CRH are present in many tissues including fetal
pituitary and inhibit FSH release. Inhibin is a
adrenal, placenta and myometrium. Only very small
heterodimer with dissimilar α- and β-subunits. The
amount of placental CRH can enter fetal circulation
inhibin β-subunit is composed of one of two distinct
suggesting relatively insignificant role in fetal adrenal
peptides, bA or bB. Activin is closely related to inhibin
steroidogenesis. Large amount of CRH is secreted into
and is formed by the combination of two β-subunits.
maternal circulation, however, there is also a large
This peptide hormone is produced by various tissues
amount of CRH-binding protein in maternal plasma.
including testis, granulosa cells of the ovary, corpus
The bound form of CRH is biologically inactive and
luteum. The placenta can produces inhibin a-, βA-,
targeted for degradation. The possible biological
and βB-subunits at the maximal rate at term (Petraglia
function of placental CRH is the relaxation of both
et al., 1987; Petraglia et al., 1991). Placental inhibin, in
uterine and vascular smooth muscles and
conjunction with large amount of sex steroid
immunosuppression. Physiological reverse of CRH
hormones produced in the placenta, may serve to
function, the induction of myometrial contraction (i.e.,
inhibit FSH secretion and thereby block ovulation
the initiation of parturition by CRH) has been
during pregnancy. Serum activin levels decline
proposed (Wadhwa et al., 1998). CRH increases
rapidly after delivery (Petraglia et al., 1994). Receptors
prostaglandin synthesis in placenta, amnion, chorion
for activin are present in placenta and amnion. Inhibin
leave, and decidua (Jones and Challis, 1989). In the
may act via GnRH to regulate hCG production in
hypothalamus, glucocorticoids inhibit CRH release,
placenta (Petraglia et al., 1987).
however, in the trophoblast, glucocorticoids do
stimulate the expression of the CRH gene, two- to
Natriuretic Peptides
threefold increases in CRH mRNA and protein
expression after treatment of human trophoblast in Atrial natriuretic peptide (ANP), 28 amino acid
culture (Robinson et al., 1988). Thus, in the placenta, peptide is predominantly produced in the atrial
positive feed back loop of CRH, ACTH and myocytes, but is also produced in the placental
glucocorticoids is proposed (Riley et al., 1991). trophoblast (Lim and Gude, 1995). Brain natriuretic
Growth Hormone-releasing Hormone (GHRH): peptide (BNP), predominantly produced in the heart
 Endocrinological Aspect 913
is also secreted from amnion cells (Itoh et al., 1993). secretion from the hypothalamus (Chehab et al., 1996;
These natriuretic peptides induce natriuresis, diuresis, Yura et al., 2000). It also modulates glucose
and relaxtion of smooth muscle. The receptors for metabolism by increasing insulin sensitivity and
natriuretic peptides are also expressed in the human activates sympathetic nervous system (Ogawa et al.,
placenta as well as in the myometrium suggesting a 1999; Sheck et al., 1998). In humans, leptin is also
possible role of ANP and BNP in the uterine relaxation produced by placental trophoblasts and is secreted
during pregnancy (Itoh et al., 1994). into both maternal and fetal circulations (Masuzaki
et al., 1997). Leptin production in the placenta is
Leptin increased in pregnancies complicated with several
Maternal insulin sensitivity is regulated by various pathologic conditions(Sagawa et al., 1997; Mise et al.,
factors including placenta-derived hormones (Fig. 1998; Leprecq et al., 1998). Plasma leptin levels are
65.2). Several placenta-derived hormones, such as significantly elevated in molar pregnancy (Sagawa et
prolactin, human chorionic somatomammotropin al., 1997). Leptin gene expression in the placenta is
(hCS or placental lactogen; hPL) and steroid augmented in severe preeclampsia, and maternal
hormones, have been considered to decrease insulin plasma leptin levels in severe preeclampsia are
sensitivity (Abrams and Pickett, 1999). Placental significantly higher than those in normotensive
production of these hormones is increased in pregnant women. (Mise et al., 1998) Leptin production
accordance with the increasing size of the placenta. in the placenta is also increased in diabetic pregnancy
Recently, novel peptide hormones, leptin and resistin, with insulin treatment (Leprecq et al., 1998). Leptin is
originally identified as adipocytokines and regulate also proposed to play a functional role in implantation
glucose and energy metabolism have been reported by virtue of its stimulatory effect on matrix
to express in the human placenta. (Masuzaki et al., metalloproteinase expression in cytotrophoblast
1997; Yura et al., 2003). (Castellucci et al., 2000).
Leptin is initially identified as an adipocyte-
Resistin
derived hormone that decreases food intake and body
weight via its receptor in the hypothalamus (Zhang Resistin is a newly identified adipocyte-derived
et al., 1994). Subsequent animal studies revealed hormone that decreases insulin sensitivity and
various physiological function of leptin (Campfield increases plasma glucose concentration, thus
et al., 1995; Hallaas et al., 1995). Leptin plays an contributing the development of type II diabetes
essential role in reproduction by regulating GnRH mellitus (Steppan et al., 2001). Resistin is proposed to

Suppressor of Insulin Sensitivity

Human Chorionic Somatomammotropin (hCS)

Prolactin
Steroid Hormones
Resistin•
Placenta

Enhancer of Insulin Sensitivity

Leptin

Fig. 65.2: Regulation of maternal insulin sensitivity by placental hormones

914 Textbook of Perinatal Medicine

link obesity to insulin resistance (Flier, 2001). pp.122-131. Pennsylvania: W.B. Saunders company.
2. Barnea ER, Kaplan M, Naor Z: Comparative stimulatory
Adipocyte secretes various substances that modulate
effect of gonadotropin-releasing hormone (GnRH) and
insulin sensitivity, such as free fatty acid, TNF-a, and GnRH agonist upon pulsatile human chorionic
leptin. Resistin is recently cloned by Steppan et al. gonadotropin secretion in superfused placental explants:
(2001) as a substance which expression in the adipose Reversable inhibition by a GnRH antagonist. Hum Reprod,
6:1063-1069, 1991.
tissue decreases by the treatment with 3. Berry SA, Srivastava CH, Rubin LR, Phipps WR, Pescovtz
thiazolidinedione, an anti-diabetic drug. Thus, resistin OH: Growth hormone releasing hormone-like messenger
is proposed to be a major factor that induces insulin ribonucleic acid and immunoreactive peptide are present
resistance and hyperglycemia in obese person. in human testis and placenta. J Clin Endocrinol Metab,
75: 281-288, 1992.
Northern blot analysis revealed resistin mRNA 4. Bewley TA, Dixon JS, Li CH: Sequence comparison of
expression in term placenta as well as in the amniotic human pituitary growth hormone, human chorionic
membrane (Yura et al., 2003). Resistin mRNA somatomammotropin, and ovine pituitary growth and
lactogenic hormones. Int J Pept Protein Res, 4: 281-289,
expression was also detected in a trophoblastic cell
1972.
line (BeWo cells) and a very faint band was detected 5. Bogic LV, Mandel M, Bryant-Greenwood GD: Relaxin gene
in decidua vera tissue. In situ hybrydizaion and expression in human reproductive tissues by in situ
immunohistochemistry suggest the expression of hybridization. J Clin Endocrinol Metab, 80:130-139, 1995.
6. Bradshaw KD, Carr BR: Placental sulfatase deficiency:
resistin in placental villi, mainly in syncitiotro- Maternal and fetal expressions of steroid sulfatase
phoblast. Resistin protein was secreted from cultured deficiency and X-linked ichthyosis. Obstet Gynecol Srv,
placental tissue (Yura et al, 2003). Resistin gene 68:505-509, 1986.
expression in term placental tissue was significantly 7. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P:
Recombinant mouse OB protein: evidence for a peripheral
larger than that in chorionic villous tissue in the first signal linking adiposity and central neural networks.
trimester. By contrast, the resistin gene was expressed Science, 269: 546-549,1995.
to a lesser degree in adipose tissue than in term 8. Cane EM, Villee CA: The synthesis of prostaglandin F by
human endometrium in organ culture. Prostaglandins,
placental tissue. Moreover, resistin gene expression
281-290, 1075.Carr BR, Simpson ER: Cholesterol synthesis
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resistin is supposed to induce insulin resistance and 9. Carr BR, Parker CRJr, Madden JD, MacDonald PC, Porter
JC: Maternal plasma adrenocorticotropin and cortisol
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Flier 2001), it is possible that placental resistin may Gynecol, 139: 416-420, 1981.
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metabolism in concert with various placental Endocrine regulation of the initiation and maintenance of
parturition. Clin Perinatol, 10: 709-725, 1983.
hormones including leptin (Fig. 65.2). 11. Castellucci M, Matteis R, Meisser A, Cancello R, Monsurro
However, the regulatory mechanism of resistin V, Islami D, Sarzani R, Marzioni D, Cinti S, Bischof P:
gene expression in the human placenta is not yet Leptin modulates extracellular matrix molecules and
metalloproteinases: possible implications for trophoblast
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 66
Regulation of Extravillous
Trophoblast Differentiation

Kotaro Fukushima, Kiyomi Tsukimori, Hitoo Nakano

INTRODUCTION DIFFERENTIATION OF
CYTOTROPHOBLAST (CT)
During early development, cytotrophoblast (CT)
differentiation contributes to organization of the feto– During the early phase of human pregnancy, CT cells
maternal interface. One layer of the differentiated are derived from trophectodermal cells of the
trophoblast, which is marked by an invasive blastocyst and contribute to organization of the feto–
phenotype, is called extravillous trophoblast (EVT). maternal interface through cell proliferation and
EVT invades decidual tissue and the maternal uterine differentiation. Differentiation of CT proceeds by two
wall. Recent evidence shows that EVT invasion has a pathways that result in morphologically and
crucial role in organizing and maintaining feto- functionally distinct trophoblast populations (Fig.
placental circulation. In this chapter, we focus on 66.1). One population consists of multi-nucleated,
interstitial and endovascular invasion and their non-replicating syncytiotrophoblast cells (ST),
regulatory mechanisms during EVT differentiation. beneath which lie immature, replicating, mononuclear

Column Decidua Myometrium

Villi

invasion

G10W

Fig. 66.1: Microscopic appearance of extravillous trophoblast in placenta in early gestation during invasion.
H&E stained placental tissue from patients with cervical cancer who underwent radical hysterectomy at
10 weeks of gestation. Arrow, invaded extravillous trophoblast; arrow head, maternal vessel replaced by
trophoblast
 Regulation of Extravillous Trophoblast Differentiation 919
villous cytotrophoblast. After the blastocyst attaches distribution during invasion. Not only integrin
to the endometrium, mononuclear CT cells that adhesion receptors, but also E-cadherin expression,
surround the embryonic disc fuse to ST to form a are altered during the invasive pathway6. Expression
syncytial layer. This layer covers the intravillous space of E-cadherin, the cell-cell adhesion molecule, is
and transports nutrients, wastes, and gases between strong in CT stem cells and weak in differentiating
fetal and maternal blood1. and invading EVT cells 7 . These findings are
The other population is the extravillous summarized in Fig. 66.27,8.
trophoblast (EVT), and these cells have invasive EVT invasion is a biochemically active process
properties. EVT cells leave the cellular column to because invading cells have to secrete proteases
intrude into the decidua and uterine wall, and they including serine protease, cathepsin, and
are observed as cytokeratin-positive cells in the metalloproteinases. Matrix metalloproteinases
decidua, the intima of the spiral arteries, and the (MMPs) have 15 family members that are classified
proximal third of the myometrium. It is thought that by substrates and structure into four subgroups. The
interstitial invasion of the placental bed by EVT MMPs are inactivated by tissue inhibitor of
promotes placental anchorage. Interstitial invasion is metalloproteinases (TIMP). The TIMP family consists
accompanied by endovascular invasion, in which of four members: TIMP-1, -2, -3, and -4. Among all of
some invading EVT cells interact, resulting in these enzymes, MMP-2 and MMP-9 are considered
replacement of endothelium and the muscular tunica to be the most important for EVT invasion10,11. Several
of maternal vessels, including the spiral arteries. This pieces of evidence have shown that ECM and integrin
replacement substantially decreases vascular can affect the activity of MMPs and behavior of EVT
resistance and results in increased blood flow toward cells12,13. MMP-9 is up-regulated at deeper sites as in
the intervillous space2,3. the case of integrin α1â114. Damsky et al 5 investigated
the effect of integrin-ECM interaction on EVT invasive
ALTERATION OF ADHESION MOLECULES
DURING INTERSTITIAL INVASION Differentiation markers in EVT
Examination of tissue sections of human placental bed Villi column interstitial endovascular
biopsies shows that EVT cells switch integrin Integrins
phenotype during differentiation and invasion4. The 6 4
CT stem cells, which are anchored to the basement 5 1
1 1??
membrane, express α6b4 integrin. Formation of the 3
cell column is accompanied by α5â1 up-regulation, 5
and as EVT cells intrude into the uterine wall they
E-cadherin
express the α1â1 subunit as well as the α5â1 subunit. VE-cadherin
Generally, α6b4 staining is weak and discontinuous
at the uterine wall4. During this normal trophoblast ECM
Collagen IV
invasion, the extracellular matrix (ECM) undergoes Laminin
a transition from laminin (Ln) to fibronectin (Fn) and Fibronectin
collagen type IV (C4). Ln is abundant in the superficial (Modified from Zhou et al, 1993, 1997a)
areas that face the villous trophoblast. In contrast, C4
Fig. 66.2: Alteration of adhesion molecules expressed in EVT
and Fn are more abundant at deeper sites4,5. Thus, it
during invasion. Scheme of the alteration of integrin and
can be assumed that EVT cells alter their integrin cadherin expression and distribution of extracellular matrix at
expression in parallel with the variation in ECM each placental site during invasion. (Modified from Refs. 8,9)
920 Textbook of Perinatal Medicine

properties using antibody-inhibition to matrigel reduced staining for adhesion receptors characteristic
invasion assay. Antibodies against Ln and C4 blocked of stable monolayer epithelial cells and showed
EVT invasion. The anti-α6 antibody did not inhibit enhanced staining for adhesion molecules
EVT invasion, whereas anti-α1 antibody did inhibit characteristic of endothelial cells. CT in cell columns
invasion. When combined, these antibodies acted show reduced E-cadherin staining and express VE-
synergistically. In contrast, anti-Fn antibodies cadherin, PECAM-1, VCAM-1, and a4-integrins. EVT
stimulated rather than blocked invasion. Thus, the cells in the uterine interstitium and maternal vessels
EVT-ECM interaction that subsequently arouses start to express αVâ3 integrin. These molecules (αVâ3
integrin conversion seems to be important in and VE-cadherin) enhance CT invasiveness9. In a later
controlling EVT phenotype. report, Zhou et al. showed that preeclamptic CT does
The significance for normal placentation of CT not stain for most of the endothelial-type adhesion
differentiation is highlighted by the fact that in molecules that are expressed by control CT cells17.
preeclampsia, in which both interstitial and Inhibitors of αVâ3 or αVâ5 show anti-angiogenic
endovascular invasion are abnormally shallow, CT activity in many models 18. Indeed, a humanized
cells show significant defects in differentiation8,14-16. version of LM609, a monoclonal antibody that blocks
Furthermore, CT cells in women with preeclampsia áVâ3 signaling, has entered clinical trials for use in
increase expression of the á5â1 subunit, but fail both treatment19. Although genetic studies in mice have
to up-regulate α1â1 and to down-regulate α6b45,16. provided several controversial points, it is believed
Thus, the cells appear arrested in their differentiation that these integrins play an important role in
and express an ECM receptor phenotype that may not angiogenesis20. Thus, these endothelial cell-related
be optimal for invasion9. Taking all of these findings molecules are considered to play important roles in
together, it is likely that expression of these integrin endovascular differentiation in EVT.
subunits is involved in regulation of normal EVT The vascular endothelial growth factor (VEGF)
differentiation. family members and their receptors (VEGFR) seem
to have important actions during the initial stages of
ALTERATION OF ADHESION MOLECULES angiogenesis21. EVT cells in early gestation express
DURING ENDOVASCULAR INVASION VEGF-A, VEGF-C, placental growth factor (PlGF),
Angiogenesis plays a crucial role both in normal VEGFR-1, and VEGFR-3. When binding of VEGF-A,
physiological and pathological conditions including PlGF, and VEGF-PlGF heterodimer to VEGFR-1 is
placental development. During invasion, EVT finally inhibited, tube-like formation on matrigel is impaired
replaces the endothelial cells in uterine vessels. and expression of integrin α1â1 is decreased. This
Moreover, EVT cells also intrude into the vascular effect is enhanced when VEGF-C binding to
muscles. This endovascular differentiation induces endogenous VEGFR-3 is blocked. This result suggests
remodeling of spiral arteries to increase blood flow that the signal from VEGFR1/3 is involved in
toward the intervillous space, which is covered by alteration of integrin switching. The same research
syncytiotrophoblast, the other form of differentiated group also reported that CT responds to VEGF
CT. As in the case of interstitial invasion, integrin ligands by the autocrine system 22. Dunk et al 23
subunits expressed in EVT dramatically change. reported that angiopoietin 1 and angiopoietin 2 can
Along with endovascular differentiation, the adhesion act as a mitogen and stimulate nitric oxide release
molecule repertories change in a comprehensive from first trimester trophoblast, as well as VEGF23-26.
manner that mimics the pattern for endothelial cells9. These angiogenic factors also influence the angiogenic
Zhou et al. 9 reported that EVT in vivo showed state of maternal blood vessels27.
 Regulation of Extravillous Trophoblast Differentiation 921
EFFECT OF CYTOKINES AND GROWTH Transforming Growth Factor
FACTOR ON EVT INVASION (TABLE 66.1) Transforming Growth Factor beta (TGFβ) stimulates
synthesis of matrix glycoproteins 39 and TIMP
Interleukins
secretion through down-regulation of urokinase,
Interleukin-1(IL-1) increases MMP-9 secretion and plasmin, and plasminogen activator 40-42 . TGFα
stimulates MMP-9 activities28,29. IL-1 or its receptors inhibits cellular proliferation and migration37,43,44,
are important for implantation of the blastocyst30. whereas TGFá promotes EVT differentiation through
Thus, IL-1 is a positive regulator of trophoblast the invasive pathway42.
differentiation along the invasive pathway31 IL-6
activates MMP-2 and MMP-9 in trophoblasts 32 . α)
Tumor Necrosis Factor Alpha (TNFα
Circulating levels of IL-6 are increased in patients with TNFα levels are elevated in patients with
preeclampsia 33,34 . IL-10 down-regulates MMP-9 preeclampsia 45,46 , and TNFα has been shown to
activity and EVT invasiveness. IL-15 increases ETV regulate progesterone, estradiol, and human
invasion and migration, as well as MMP-1 production chorionic gonadotropin (hCG) production in
by Jeg-3 cells35. IL-10 and IL-15 seem to regulate cytotrophoblasts47. TNFá stimulates trophoblastic
trophoblast invasiveness by autocrine mechanisms.35- MMP-9, MMP-1, and MMP-3 production in human
37
Wang et al. reported lower levels of expression of chorionic cells 48, whereas TNFá decreases TIMP
IL-8 and IL-15 in preeclamptic placentas38. secretion32,49. TNFα induces apoptosis 50, integrin

Table 66.1: Summary of biological effects of soluble factors on cytotrophoblast:

IL, interleukin; TNF, tumor necrosis factor,; TGF, transforming growth factor; LIF, leukemia inhibitory factor; IGF,
insulin-like growth factor; IGFBP, IGF binding protein; VEGF, vascular endothelial growth factor; Ang, angiopoietin.
Biological effect on cytotrophoblast(and/ or EVT) References
promote invasion
Lala, 1994; Librach, 1994
IL1 increase MMP9 secretion
Meisser, 1999a
promote defferentiation in invasive pathway
increased circulating level in preeclamptic patients Conrad, 1997:98
IL6
activate MMP2 and 9 Meisser, 1999b
IL8 lower level of expression in preeclamptic placenta Wang, 1999

IL10 inhibit invasion Roth et al.,1998, 1999

lower level of expression in preeclamptic placenta Wang, 1999

IL15
increase invasiveness Zygmunt, 1998

progesteron, hCG, estradiol synthesis Li, 1994

stimulates MMP1, 3, 9, decreaseTIMP So,1992, Takahashi, 1993, Meisser, 1994b
TNFƒ ¿ induce integrin subunit conversion Fukushima, 2003
induce apoptosis Levy R, 2000
elevated lcirculating level and expression in preeclamptic patients and placenta Hamai, 1997, Rinehart, 1999

stimulate matrix glycoproteins Finebarg, 1994

Graham CH, 1992; Khoo NK, 1998; Roth 1999
TGFƒ À inhibit cellular proliferation and migration Graham and Lala, 1991, Graham, 1994, Irving and Lala, 1995
stimulate TIMP secretion by downregulate urokinase, plasmin, plasminogen activator

TGFƒ ¿ promote differeintiation Irving and Lala, 1995

LIF inhibit gelatinolytic activity Bishof, 1995

IGF2 stimulates differntiation and migration Irving and Lala, 1995

IGFBP1 increase cell migration, invasion, TIMP1 secretion and gelatinolytic activity Irving and Lala, 1995, Hamilton, 1998; Bischof, 1998

increase proliferation and NO release Charmock- J ones, 1994, Athanassiades, 1998, Ahmed 1997
VEGF
involved in tube- like formation in matrigel (VEGFR) Zhou, 2002
Ang2 increase proliferation and NO release Dunk, 2000
922 Textbook of Perinatal Medicine

subunit conversion, and functional activation in EVT a)

cell lines51.
TNF 0 100pg/ml
Insulin-like Growth Factors and Relatives Time 0 6 12 24
Insulin-like growth factor (IGF)-II promotes tropho- 1
blast differentiation along the invasive pathway.
Hamilton et al.52 showed that IGF-II promotes cell 6
migration. IGFBP-1 increases trophoblast cell
migration 42 , invasion 52 , TIMP-1 secretion, and
b)
gelatinolytic activity53.

Other Soluble Factors

Leukemia inhibitory factor (LIF) is important for
implantation of the blastocyst30 . LIF inhibits the (?) 100pg/ml
gelatinolytic activity of trophoblasts bearing a laminin Fig. 66.3: TNFα induces integrin subunit switching in TCL1
receptor54. cells. (A) Immunoblot analysis using anti- α1 and -α6 integrin
subunits. TCL1 cells were seeded and grown at 37°C. After 1
TNF, VEGF, AND ECM AS COLLABORATIVE day of incubation, the medium was replaced with fresh,
complete medium containing 10% fetal calf serum and 20 or
REGULATORS IN EVT DIFFERENTIATION 100 pg/mL TNFα for the indicated times. Cellular proteins were
extracted then analyzed by immunoblotting. (Reproduced from
As discussed above, many growth factors and
Ref. 51) (B) TNFα strengthens integrin adhesive functions.
cytokines have been shown to have an ability to TCL1 cells were seeded on Collagen type I–coated coverslips.
produce certain effects on trophoblast function; The cells were incubated with or without 100 pg/mL TNFα for
however, the mechanism to regulate integrin subunit 24 hours. Cells were then fixed and stained with an anti-α1
integrin subunit monoclonal antibody. The white arrows indicate
conversion has been unclear. Fukushima et al 51
integrin α1 subunit aggregation (Reproduced from Ref. 51).
reported that TNFá suppressed á6 integrin expression
and enhanced á1 integrin expression in a dose-
dependent manner in a human EVT cell line; TNFα
also induced apoptosis, which is suppressed by
Hypoxia
signals via integrin â1, with aggregation also induced Inflammatory responses
by TNFα (Fig. 66.3). Because integrins comprise a
large family of cell surface receptors that recognize a TNF VEGF
Spiral artery
variety of ECM components55, these results suggest
Villi
that TNFα and ECM might collaboratively regulate
EVT differentiation through integrin signaling (Fig. 6 1 V 3 Endovasucular
66.4). EVT cells alter their integrin expression in ECM alteration differentiation

parallel with varied ECM distribution during Interstitial invasion

invasion4,5. Thus, it has been suggested that alteration
of integrin expression during differentiation of EVT Invasiveness Apoptosis
may be responsible for mediating distinct signals to
EVT upon adhesion to ECM. In other words, ECM Fig. 66.4: A hypothetical paradigm for TNFα/VEGF/ECM
regulates EVT differentiation; however, at the same collaboration during EVT differentiation. See text for detail.
time, this is an adaptation for EVT. ECM, extracellular matrix.
 Regulation of Extravillous Trophoblast Differentiation 923
We should note physiological microenvironments phenotype, and there are probably other key mole-
surrounding EVT during early pregnancy. Hypoxia cules that are essential for invasive phenotype, e.g.
and oxidative stress caused by hypoperfusion and regulation of MMP secretion and activity. It is neces-
transient ischemia affect cytokine production.56-58 sary to take into account cross-talk among these mole-
Placental VEGF expression is up-regulated by cules in the course of a normal pregnancy. Much more
hypoxia59. Hypoxia also induces pro-inflammatory data is needed in order to integrate the current pieces
cytokines including TNFα60. TNFα plays a pivotal of research evidence for this very interesting field.
role in pregnancy61 and seems to be necessary for fetal
ACKNOWLEDGMENT
development because it is expressed in normal tissues
of a wide range of organs in the human fetus62. Zhou This work was supported in part by a grant-in-aid
et al. 22 suggested that the signal from VEGF-VEGFR from the Ministry of Education, Japan (16790609),
is involved in alteration of integrin switching. We Kanzawa Medical Research Foundation and Inamori
have found that TNFα and VEGF induce integrin Foundation.
αVâ3 expression and aggregation in an immortalized
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 67 Trophoblast Dysfunction and
Maternal Endothelial Cell
Dysfunction in the
Pathogenesis of Preeclampsia
Kiyomi Tsukimori, Kotaro Fukushima, Hitoo Nakano

INTRODUCTION intervillous space.5,6 In preeclampsia, extravillous

trophoblast (EVT) cell invasion of the uterus is
The etiology and pathogenesis of preeclampsia
shallow, and endovascular invasion does not progress
remain poorly understood. Several investigators have
beyond the terminal portion of the spiral arteries (Fig.
suggested that poor placentation is an important
67.1).5 Myometrial segments of these arteries remain
predisposing factor of preeclampsia and that
anatomically intact and undilated; in addition,
endothelial cell dysfunction underlies disease
adrenergic nerve supply to the spiral arteries is not
manifestations.1-4 In response to reduced placental
affected. The mean external diameters of the uterine
perfusion due to poor placentation, the placenta may
spiral arteries in women with preeclampsia are less
promote release of various factors that initiate
than one half the diameters of similar vessels from
systemic endothelial cell dysfunction, leading to an
uncomplicated pregnancies. The failure of EVT
increase in both vascular resistance and arterial
invasion in preeclampsia results in a reduction in
pressure and activation of the coagulation cascade
uteroplacental perfusion. Because the process of EVT
associated with preeclampsia. In this manuscript, we
invasion of spiral arteries is normally completed by
focus on functional abnormalities of the placenta and
weeks. We ative phenotype, α5β1, but fail both to
trophoblast in preeclampsia, as well as the potential
upregulate adhesion molecules that promote
cellular and molecular mechanisms that contribute to
invasion, α1β1, and to downregulate molecules that
the maternal endothelial cell dysfunction seen in this
inhibit invasion, α6β4 (Table 67.1).9-12 Thus, the cells
disorder.
appear arrested in their differentiation and express
an ECM receptor phenotype that may not be optimal
POOR PLACENTATION
for invasion.12 In addition, endovascular invasion
During early pregnancy, cytotrophoblast (CT) cells seems to require the ability of endovascular
invade the uterus and its spiral arteries (in interstitial trophoblast cells to alter phenotype to resemble
and endovascular invasion, respectively). As a result vascular endothelial cells. 13 In preeclampsia,
of endovascular invasion, CT cells replace the trophoblast cells in decidual vessels do not express
endothelial layers of spiral arteries with destruction the endothelial antigens vascular adhesion molecule-
of the medial elastic, muscular, and neural tissue. This 1 (VCAM-1) and platelet endothelial adhesion
replacement substantially decreases vascular resis- molecule-1 (PECAM-1). 12 When these data are
tance, resulting in increased blood flow toward the considered together, this overall dysfunctional
 Trophoblast Dysfunction and Maternal Endothelial Cell Dysfunction 927
Normal pregnancy
Preeclampsia
Cytotrophoblast

Adequate blood flow

Poor blood flow

Syncytiotrophoblast

Cytotrophoblastic
cell column
Decidua Musculo-
elastic coat
Trophoblast Trophoblast
invasion invasion
Poor
placentation
Myometrium
Spiral artery

23
Fig. 67.1: Trophoblast invasion in normal and preeclamptic pregnancies (Modified from Saito et al., 2003 )

Table 67.1: Integrin expression by cytotrophoblasts in normal and preeclamptic pregnancies

Change from villus to placental bed

Integrin receptor ECM ligands Functional link Normal pregnancy Preeclampsia

6/ 4 BM ligand (Ln ?) Inhibit invasion Downregulated Unchanged

5/ 1 Fn Initial proliferation Upregulated Upregulated
3 / 1? Ln, Fn, Col Proliferation Uniformly expressed Uniformly expressed
1 / 1??? Ln, Col IV, Col I Promote invasion Upregulated Not expressed
(weakly expressed)

Abbreviations: ECM, extracellular matrix; BM, basement membrane; Ln, laminin; Fn, fibronectin; Col, collagen. (Modified
from Zhou et al., 199312)

expression of adhesion molecules may be responsible reported that placental villi cultured under hypoxic
for the pathological findings of impaired interstitial conditions showed variable syncytial degeneration
and endovascular invasion in preeclampsia. and a marked increase in the number and growth-
promoting activity of CT cells.14 More recently, using
FACTORS INVOLVED IN POOR PLACENTATION an in vitro organ culture model, CT maintained under
hypoxic conditions failed to express integrin α1 and
Hypoxic Environment
VE-cadherin.15,16 These findings suggest that under
Several studies suggest that oxygen tension can hypoxic conditions CT cells enter a proliferative
modulate trophoblast differentiation. Fox and Path pathway and do not differentiate to the invasive
928 Textbook of Perinatal Medicine

phenotype. The adhesion molecule phenotype of and cytotoxic T cells, resulting in the inadequate
these cells mimics that of CT from women with trophoblast invasion seen in preeclampsia. Recently,
preeclampsia.12 Saito and colleagues reported that preeclampsia is
In vitro, hypoxia stimulates production of associated with a Th1 predominant immunity.35 Th1-
inflammatory cytokines and other mediators such as type cytokines such as IL-2, IFNβ, TNFα, and TNFβ
tumor necrosis factor-α (TNFα), Interleukin (IL)-1α, activate cytotoxic T cells and NK cells. Activated
IL-1β,17 and transforming growth factor-β (TGFβ)18 cytotoxic T cells and NK cells can attack invading
by trophoblasts. TNFα induces apoptosis,19 integrin trophoblasts, causing a failure of trophoblast invasion.
subunit conversion, and functional activation in an
EVT cell line.20 TGFβ also inhibits cellular prolife- Genetic Factors
ration and migration.21-23 In addition, trophoblasts There is evidence of an increased incidence of
under hypoxic conditions increase production of preeclampsia among sisters, mothers, and daughters.
soluble fms-like tyrosine kinase 1 (sFlt-1), an Some studies have implicated several genes as risk
antagonist for both vascular endothelial growth factor factors for preeclampsia including angiotensin, 36
(VEGF) and placental growth factor (PlGF).24 The endothelial nitric oxide synthase (eNOS),37 TNFα,38
enzyme sFlt-1 is involved in an alteration of integrin the factor Leiden mutation, 39 and hyperhomo-
switching that decreases cell invasiveness. 25 In cysteinemia.40 Recent data focused on feto-placental
placentas from women with preeclampsia, there is rather than maternal acting genes suggest that feto-
increased production of TNFα,17 TGFβ,18 and sFlt- placental genes may carry an associated risk. These
1,25,26 as well as decreased production of VEGF.25 could be genes encoding factors associated with CT
Taken together, this evidence suggests that hypoxia invasion. The risk of preeclampsia increases with a
induces production of inflammatory cytokines and/ change in partner, 41) implying the importance of
or growth factors and then modulates cytotrophoblast paternal genes. By following both men and women
differentiation and adhesion antigen expression, who were products of preeclamptic pregnancy, it has
resulting in the inadequate invasion seen in been suggested that both maternally and paternally
preeclampsia. inherited genes play a contributory role,42 possibly
by contributing to the genetic constitution of the
Immunologic Factors
placenta.
Epidemiological evidence indicates that first preg-
nancy, change of partner, donor insemination, and use BIOLOGICAL CHANGES
of barrier contraceptives all increase the risk of OF PLACENTAL FUNCTION
preeclampsia, suggesting that a prior immune
Poor placentation causes a reduction in uteroplacental
response to foreign or paternal antigens protects
perfusion, causing placental ischemia/hypoxia.
against development of preeclampsia. 27-29 In
Placental ischemia/hypoxia is known to induce
preeclampsia, human leukocyte antigen (HLA)-G, a
several mediators such as reactive oxygen species
surrogate auto-antigen known to prevent recognition
(ROS) and inflammatory cytokines. Several biochemi-
by natural killer (NK) cells, is not expressed in
cal abnormalities have been reported in placentas
trophoblasts.30,31 HLA-G downregulates NK cell-
obtained from women with preeclampsia (Table 67.2).
mediated cytotoxicity32 and suppresses IL-2–induced
cell damage. 33 The soluble HLA-G1 isoform also
Increased Oxidative Stress
downregulates CD8-positive T cell (cytotoxic T cell)
reactivity.34 These findings suggest that invasive Increased superoxide (O2-) synthesis rates have been
trophoblast lacking HLA-G is attacked by NK cells noted in placentas from women with pre-
 Trophoblast Dysfunction and Maternal Endothelial Cell Dysfunction 929
Table 67.2: Biological changes in preeclamptic placenta

Marker or Activity Location Reference No.

Increased oxidative stress:

Increased superoxide synthesis Placental tissue and trophoblast cells (43,44)
lncreased xanthine oxidase expression lnvasive cytotrophoblast (45)
lncreased nitrotyrosine immunostaining Invasive cytotrophoblast (46,47)
Increased MDA level Placental homogenate (49,50)
Increased 8-isoprostane level and production Placental tissue pieces (51)
Increased protein carbonyl level Placental and decidual homogenate (52)
Increased lipid peroxide production Trophoblast cells and villous tissue (51,53,54)
Decreased glutathione peroxidase activity Placental homogenate (55)
Decreased vitamine E level Placental homogenate (55)
Decreased Cu/Zn-SOD activity and Trophoblast cells (44)
mRNA expression

Altered cytokine production:

Increased TNF production and mRNA expression Placental tissue (56,57)
Increased IL-1 mRNA expression Placental tissue (56)
No-change for inflammatory cytokine (TNF , IL-1 , Placental homogenate (58)
IL-1 , IL-6) mRNA expression
Decreased IL-8 production Placental villous tissue (59)
Decreased IL-10 immunostaining Villous trophoblast cells (60)
Decreased IL-15 production Placental tissue and trophoblast cells (61)

Increased vasoconstriction:
Increased thromboxane production Placental tissue and cytotrophoblast (62,63)
Increased ET-1 production and mRNA expression Trophoblast cells (64,65)
Increased NKB mRNA expression Outer syncytiotrophoblast (68)
Decreased prostacyclin production Placental tissue and cytotrophoblast (62,63)
Decreased iNOS mRNA expression Trophoblast cells (64)
Abbreviations: MDA, malondialdehyde; TNF, tumor necrosis factor; IL, interleukin; ET, endothelin; NKB, neurokinin B; iNOS,
inducible nitric oxide synthase

eclampsia.43,44 The expression of xanthine oxidase, antioxidant levels such as vitamin E, as well as the
which is an important source of O2- generation, is also activities of glutathione peroxidase,55 and both mRNA
enhanced in placentas from women with pre- expression and enzyme activity for Cu/Zn-super-
eclampsia.45 As an indirect indication of excessive oxide dismutase (SOD), are decreased in pre-
generation of ROS, nitrotyrosine content, a stable eclampsia.44 Thus, the placenta represents a state of
marker for peroxinitrite (ONOO-), is increased in oxidative stress in preeclampsia.
placentas from women with preeclampsia.46,47 When
oxygen free radicals are not eliminated by anti- Altered Cytokine Production
oxidants, lipid peroxide formation is induced. 48
Placental levels of lipid peroxidation products, as well Expression of inflammatory cytokines such as TNF-
as other markers of oxidative stress such as α and IL-1β is increased in preeclamptic placentas.56,57
malondialdehyde (MDA), 49,50 8-iso-PGF2α, 51and However, Benyo and colleagues failed to observe
protein carbonyl52 are increased. In vitro production increased mRNA levels of both TNF-α and IL-1β in
of lipid peroxides is also increased in trophoblasts preeclamptic placenta.58 Placental levels of IL-8,59 IL-
from women with preeclampsia. 51,53,54 Placental 10,60 and IL-1561 are decreased in preeclampsia. Thus,
930 Textbook of Perinatal Medicine

although the picture is not entirely clear, placental indicative of endothelial dysfunction are increased in
cytokine production is altered in preeclampsia. the blood of women with preeclampsia including
cellular fibronectin (cFN), 81-83 von Willebrand
Increased Vasoconstriction Factor,84,85 thrombomodulin,86,87 and vascular cell
Placental thromboxane production is increased, adhesion molecule-1 (VCAM-1).88,89 Many of these
whereas placental PGI2 production is decreased in substances including serum soluble VCAM-190 and
preeclampsia.62,63 Endothelin (ET)-1 expression and cFN 83 are elevated weeks before preeclampsia
production are increased in trophoblasts obtained becomes clinically evident.
from women with preeclampsia.64,65 Regarding nitric
LINKAGE BETWEEN PLACENTAL
oxide (NO) production, Napolitano and colleagues
DYSFUNCTION AND MATERNAL
reported that inducible nitric oxide synthase (iNOS)
ENDOTHELIAL DYSFUNCTION
expression, which represents the main source of NO,
is decreased; conversely, endothelial nitric oxide To link placental dysfunction with the generalized
synthase (eNOS) expression is increased in tropho- endothelial dysfunction seen in preeclampsia, the
blasts obtained from women with preeclampsia.64 In existence of factor X, released from the placenta into
contrast, other investigators have failed to observe the maternal circulation, was proposed. Indeed, we
increased eNOS activity66 and eNOS immunostaining and other investigators have reported that serum
levels.67 Page and colleagues reported that expression from women with preeclampsia has a cytotoxic effect
of neurokinin (NK) B is increased in trophoblasts from on cultured endothelial cells.91,92 The factor seems to
women with preeclampsia.68 Thus, in preeclampsia modulate endothelial cell function rather than
placental vasoconstrictor production is increased, damage the cells directly. In response to serum or
whereas placental vasodilator production is plasma from women with preeclampsia, production
decreased. of PGI293,94 and NO95-97 is altered, and increases are
seen in cFN production,98,99 mitogenic activity,100,101
MATERNAL ENDOTHELIAL CELL uptake of fatty acids,102 and expression of platelet–
DYSFUNCTION IN PREECLAMPSIA derived growth factor (PDGF). 103 Many of these
Several pieces of evidence indicate that adverse activities are not only elevated weeks before
changes in structure and function of the maternal preeclampsia becomes clinically evident, but, as with
vascular endothelium account for the altered vascular the clinical signs of the syndrome, they disappear
reactivity, activation of the coagulation cascade, and shortly after delivery. 91,99-101 Initially, Factor X was
multisystem damage that occurs in preeclampsia.69,70 thought to be a single factor, but increasing evidence
Pathologic changes in endothelial cells that line the suggests the presence of several interacting factors.
renal glomerular capillaries (glomerular endo- Several candidate factors have been proposed,
theliosis) are a consistent feature in women with including oxidative damage products, proinflam-
preeclampsia.71-73 Structural changes of the endo- matory cytokines, syncytiotrophoblast microvesicles
thelium have been found in uteroplacental vessels.74 (STBM), and angiogenic factors.
In addition, functional evidence of endothelial
Oxidative Damage Products
alteration has been reported. The level of the
endothelial prostanoid prostacyclin (PGI2) is reduced Circulating levels of lipid peroxidation products such
weeks before as well as during clinically evident as MDA104-106 and 8-iso-PGF2α50,107 are increased in
preeclampsia.75-77 Vessels removed from women with preeclampsia. As described above, these products are
preeclampsia manifest reduced endothelial-mediated elevated in concentration in trophoblasts from women
vasodilator function. 78-80 A variety of substances with preeclampsia. Increased lipid peroxidation
 Trophoblast Dysfunction and Maternal Endothelial Cell Dysfunction 931
increases endothelial monolayer permeability to constitutional factors, such as genetic, behavioral, and
protein108 and increases incorporation of fatty acids environmental factors would predispose to pre-
into endothelial cell membranes.109 Free 8-iso-PGF2á eclampsia. These constitutional factors, likely
is also a biologically active vasoconstrictor in vivo.110 influenced by the unique physiological changes of
Nitrotyrosine staining, a stable marker for ONOO- is pregnancy, would interact with placental factors
increased in sera from women with preeclampsia111 induced by placental ischemia/hypoxia to bring
and in preeclamptic placenta.46,47 The free radical about the pathophysiological changes of pre-
ONOO- is one of the most potent reactive species, and eclampsia.1,134
it can lead to increases in lipid peroxides and direct
or indirect cellular damage.112 Constitutional Factors
Preexisting hypertension, diabetes, obesity, and
Proinflammatory Cytokines
increased insulin resistance, as well as African descent
Proinflammatory cytokines such as TNF-α and IL-1β and increased blood homocysteine concentration, are
can produce endothelial dysfunction either directly already known to be predisposing factors. 135
or by activating maternal leukocytes. 3,113,114 In Interestingly, these are also risk factors for other
preeclampsia, circulating levels of IL-6, TNF-α,115-117 endothelial diseases, in particular atherosclerosis. The
and its two soluble receptors (p55 and p75 TNF-R)117 concept of common risk factors for the two disorders
are increased. Expression of placental cytokines is supported by the relationship of preeclampsia to
including TNF-α and IL-1β is also increased in cardiovascular disease in later life.136,137 In addition,
preeclampsia.56,57 In contrast, Benyo and colleagues preeclampsia and atherosclerosis share common
demonstrated that placental levels of inflammatory alterations of lipid profile including elevated
cytokines (e.g., TNF-α, IL-1α, IL-1β, and IL-6) are not triglycerides, 104 reduced HDL-cholesterol,138 and
altered, 58 suggesting that tissues other than the increased small dense LDL-cholesterol. 139 LDL
placenta, such as activated leukocytes or endothelium, particles are smaller than those of normal controls,
may be involved in the elevation of inflammatory which may facilitate their oxidation.140,141
cytokines found in the circulation of women with
preeclampsia. Hung and colleagues reported that Pregnancy-specific Changes
hypoxia–reoxygenation of placental tissue in vitro It is well known that a neutrophilic leukocytosis
increases production of TNF-á and causes endothelial occurs in pregnancy.142 Sacks and colleagues used
dysfunction.118 Interestingly, recent evidence suggests whole blood flow cytometric techniques to report that
that TNFα also stimulates release of sFlt-1 from normal third-trimester pregnancy is characterized by
placental explants.131 remarkable activation of peripheral blood leukocytes,
an activation that is further increased in pre-
MATERNAL AND PLACENTAL INTERACTIONS
eclampsia. 143 We and other investigators have
IN PATHOGENESIS OF PREECLAMPSIA
demonstrated that isolated neutrophils from women
Abnormal placentation is not uniquely associated with preeclampsia synthesize more superoxide than
with preeclampsia. For example, infants with those of normotensive pregnant women.144-146 In an
intrauterine growth restriction132 and one third of investigation of the mechanism of extreme neutrophil
infants with preterm birth 133 manifest abnormal activation in preeclampsia, Aly and colleagues
features of placentation identical to those seen in demonstrated that STBM, which are present in blood
preeclampsia. It has been proposed that abnormal in elevated levels in preeclampsia,119 lead to activation
placentation must interact with maternal factors to of maternal neutrophils. 147 Maternal neutrophils
cause the clinical features of preeclampsia. Maternal could also be locally activated during passage of
932 Textbook of Perinatal Medicine

maternal blood through the placenta. 117,148 In secrete or elaborate substances into the maternal
addition, we have reported that sera from women circulation that directly or indirectly cause systemic
with preeclampsia enhance superoxide production of vascular endothelial cell dysfunction. In addition,
neutrophils in vitro. 144 The interaction of these pregnancy-specific changes (e.g. activation of
activated neutrophils with endothelium would then neutrophils) combined with maternal constitutional
result in release of reactive oxygen species and factors (e.g. genetic disposition and circulating
endothelial injury.149 Taken together, this evidence lipoproteins) are also involved in development of
suggests that activated neutrophils, occurring as a preeclampsia. It is necessary to clarify the mechanisms
usual component of maternal response to pregnancy, involved in placental and maternal endothelial
could provide a link between the placental dysfunc- dysfunction and to identify the factor(s) connecting
tion and maternal endothelial cell dysfunction seen them in order to understand, treat, and eventually
in preeclampsia. prevent preeclampsia.

CONCLUSION ACKNOWLEDGMENT
The two central pathophysiological themes of
This work was supported in part by a grant-in-aid
preeclampsia are placental trophoblast dysfunction
from the Japanese Ministry of Education (16790609
and endothelial cell dysfunction within the maternal
and 16591666).
systemic vasculature. As discussed above, it has been
proposed that multiple factors (e.g. hypoxic environ-
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vessels. Am J Obstet Gynecol 1989; 161: 735-741. serum vascular endothelial growth factor immuno-
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89. Higgins JR, Papayianni A, Brady HR, Darling MRN, induces vascular cell adhesion molecule-1 expression on
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90. Krauss T, Kuhn W, Lakoma C, Augustin HG. Circulating growth factor mRNA and protein expression by cultured
endothelial cell adhesion molecules as diagnostic markers human endothelial cells. Am J Reprod Immunol 1991; 25:
for the early identification of pregnant women at risk for 105–108.
development of preeclampsia. Am J Obstet Gynecol 1997; 104. Hubel CA, McLaughlin MK, Evans RW, Hauth BA, Sims
177: 443-449. CJ, Roberts JM. Fasting serum triglycerides, free
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endothelial cells. Am J Obstet Gynecol 1988; 159: 908-914. within 48 hours post partum. Am J Obstet Gynecol 1996;
92. Tsukimori K, Maeda H, Shingu M, Koyanagi T, Nobunaga 174: 975–982.
M, Nakano H. The possible role of endothelial cells in 105. Hubel CA. Dyslipidemia, iron, and oxidative stress in
hypertensive disorders during pregnancy. Obstet Gynecol preeclampsia: assessment of maternal and feto-placental
1992; 80: 229-233. interactions. Semin Reprod Endocrinol 1998; 16: 75–92.
93. Baker PN, Davidge ST, Barankiewicz J, Roberts JM. Plasma 106. Wang Y, Walsh SW, Guo J, Zhang J. The imbalance
of preeclamptic women stimulates and then inhibits between thromboxane and prostacyclin in preeclampsia
endothelial prostacyclin. Hypertension 1996; 27: 56–61. is associated with an imbalance between lipid peroxides
94. deGroot DJM, Davidge ST, Friedman SA, McLaughlin MK, and vitamin E in maternal blood. Am J Obstet Gynecol
Roberts JM, Taylor RN. Plasma from preeclamptic women 1991; 165: 1695–1700.
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without changes in enzyme activity or mass. Am J Obstet Michael CA. Plasma and urinary 8-iso-prostane as an
Gynecol 1995; 172: 976–985. indicator of lipid peroxidation in pre-eclampsia and
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JM. Distinct factors in plasma of preeclamptic women J Obstet Gynecol 1992; 167: 440–447.
increase endothelial nitric oxide or prostacyclin. Hyper- 110. Roberts LJ, Morrow JD. The isoprostanes: Novel markers
tension 1996; 28: 758–764. of lipid peroxidation and potential mediators of oxidant
98. Roberts JM, Edep ME, Goldfine A, Taylor RN. Sera from injury. Adv Prostaglandin Thromboxane Leukot Res 1995;
preeclamptic women specifically activate human umbilical 23: 219-224.
vein endothelial cells in vitro: morphological and 111. McCord N, Ayuk PT, Sargent IL, Redman CWG, Boyd
biochemical evidence. Am J Reprod Immunol 1992; 27: CAR. Evidence of increased oxidative stress in pre-
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99. Taylor RN, Casal DC, Jones LA, Varma M, Martin JN Jr, 112. Lowe DT. Nitric oxide dysfunction in the pathophysiology
Roberts JM. Selective effects of preeclamptic sera on of preeclampsia. Nitric Oxide 2000; 4: 441-458.
human endothelial cell procoagulant protein expression. 113. Pober JS, Cotran RS. Cytokines and endothelial cell
Am J Obstet Gynecol 1991; 165:1705-1710. biology. Physiol Rev 1990; 70: 427– 451.
100. Musci TJ, Roberts JM, Rodgers GM, Taylor RN. Mitogenic 114. Redman CWG, Sucks GP, Sargents IL. Preeclampsia, an
activity is increased in the sera of preeclamptic women excessive maternal inflammatory response to pregnancy.
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101. Taylor RN, Heilbron DC, Roberts JM. Growth factor 115. Conrad KP, Benyo DF. Placental cytokines and the
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119. Knight M, Redman CWG, Linton EA, Sargent IL. Shedding 131. Ahmad S, Ahmed A. Elevated placental soluble vascular
of syncytiotrophoblast microvilli into the maternal endothelial growth factor 1 receptor-1 inhibits
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factor in preeclampsia. Circ Res 2002; 90: 1274-1281. 137. Sibai B, El-Nazer A, Gonzalez-Ruiz A. Severe preeclampsia
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Caldwell RB. Vascular endothelial growth factor signals in normal and hypertensive pregnant women. Obstet
endothelial cell production of nitric oxide and prostacyclin Gynecol 1995; 85: 353–356.
through flk-1/KDR activation of c-Src. J Biol Chem 1999; 139. Sattar N, Bendomir A, Berry C, Shepherd J, Greer IA,
274: 25130-25135. Packard CJ. Lipoprotein subfraction concentrations in
126. Polliotti BM, Fry AG, Saller DN, Mooney RA, Cox C, Miller preeclampsia: pathogenic parallels to atherosclerosis.
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factor and vascular endothelial growth factor for 140. Hubel CA, Shakir Y, Gallaher MJ, Mclaughlin MK, Roberts
predicting severe, early-onset preeclampsia. Obstet JM. Low density lipoprotein particle size decreases during
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sepsis. Am J Obstet Gynecol 1998; 179: 80-86. Parry S. Neutrophils are stimulated by syncytiotro-
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 68
Basic Aspect of
Trophoblastic Disease

Norio Wake, Kazuo Asanoma, Takao Matsuda, Hideori Kato

GENETICS OF HYDATIDIFORM MOLES derive from the two paternal alleles in some gene loci,
whereas the allele derives from one of two paternal
Hydatidiform moles that have grossly swollen villi
alleles in the remaining loci. The genetic features
are divisible into two entities; the classical complete
shown in these moles are compatible with fertilization
mole and the partial mole. The complete mole
of an empty egg by two spermatozoa. Dispermy
presents as a rapidly progressing hydatidiform
would result in an XX, XY or YY sex chromosome
change affecting the whole placenta, with widespread
constitution, in a 1:2:1 ratio. Again, YY moles are
and gross trophoblastic hyperplasia in the absence of
lethal.
an embryo and its covering amnion. The majority of
In addition to androgenesis, occasional complete
complete moles have a 46,XX karyotype. Inspection
moles that are diploid but biparential in origin have
of karyotype from a mole and its parents readily
been described. While androgenetic complete moles
discloses that both members of chromosome pairs of
are usually sporadic, biparental complete moles are
the complete mole are traceable to one paternal associated with a predisposition to recurrent molar
chromosome. Thus, these moles result from pregnancies and frequently occur in more than one
duplication of a paternal haploid set in a functionally member of a family. Women with biparental complete
empty ovum, a process called androgenesis. Most mole have a much greater risk of further complete
probably these moles develop from fertilization of an mole than woman with androgenetic complete mole
empty ovum by a haploid sperm followed by the or partial mole and have an appreciable risk of
duplication of its chromosomes. 1-6 The maternal persistent trophoblastic disease. Biparental complete
nuclear complement is either eliminated or mole arises from an unusual pregnancy associated
inactivated in an empty ovum. This mechanism with a failure to set maternal imprints within the
would account for the preponderance of XX moles, ovum. The gene, mutated in woman with biparental
because their YY counterparts are probably lost complete mole, shows an autosomal recessive mode
during early cleavage stages. of inheritance and has been mapped to chromosome
The rare 46,XY moles can also be found. 7-9 19q 13.4.
Estimates for the total number of these moles range In the partial moles there is a slow hydatidiform
from 4–20% in a small series. Southern blots of change that affects only some of the villi. There is
polymerase chain reaction (PCR) products clearly focal, moderate, trophoblastic hyperplasia,
demonstrate that both alleles shown in the mole irrespective of the survival of the embryo. An
940 Textbook of Perinatal Medicine

accumulation of cytogenetic data has shown that MALIGNANT TROPHOBLASTIC NEOPLASMS

dispermic triploids that were products of an intact WITH DIFFERENT MODES OF ORIGIN.
ovum fertilized by two spermatozoa were responsible
for these partial moles.10-13 We have encountered It is well-known that the complete mole has a
unusual cases of partial moles in the course of propensity to malignancy. However, there has been
systematic cytogenetic studies of partial moles each no direct proof in the majority of patients that
with a tetraploid karyotype. These rare partial moles choriocarcinoma indeed derived from a complete
result from the combination of a haploid ovum with mole. The androgenetic origin of complete moles
three paternal haploid sets as a result of trispermic provides us with a method for determining the origin
fertilization.14-16 The majority of partial moles result of choriocarcinomas. The genome of choriocarcinoma
from dispermic triploids. Tetraploids with one should reflect that of the pregnancy from which the
maternal and three paternal haploid sets provide tumour arose. After a live birth or spontaneous
unequivocal morphological examples of partial abortion, both maternal and paternal contributions
moles. In addition to these, complete moles that to the genome should be present in the tumour
involve the whole placenta in hydatidiform changes genome. Choriocarcinoma after complete mole
are androgenetic in origin. These findings illustrate conceptions should carry only the paternal genome.
an intriguing correlation between a molar phenotype The absence of a paternal contribution in the tumour
and the ratio of paternal to maternal genome in the genome is a feature of non-gestational
conceptus. In this connection, the fact that benign choriocarcinoma. Based on these genetic
ovarian teratomas are parthenogenetic in origin leads backgrounds, a small number of choriocarcinomas
to the possibility that the maternal and paternal have been examined so far.17-23 However, the number
genome are not functionally equivalent. The teratoma of cases reported is too small to show whether there
that consists of embryonic tissue elements in the is a predominant association of complete mole with
absence of extra-embryonic tissues has two choriocarcinoma or not. Thus, we examined the
maternally derived haploid sets. These findings point genetic origin of a relatively large number of
to some dependence of the extra-embryonic tissues, trophoblastic tumours in order to demonstrate the
notably trophoblast, on the paternal genome, while propensity to malignancy of complete mole.
some maternal genes are apparently required for the Genomic DNAs obtained from 24 fresh or paraffin-
development of the embryo proper. Only male plus embedded tumours were successfully amplified by
female diploid combinations of pronuclei would give PCR.24 Based on pregnancy history, these tumours
rise to normal embryos. Particular sets of genes included: (i) 9 post-molar trophoblastic tumours, (ii)
undergo a separate specific imprinting during 12 tumours preceded by live birth or abortion and
oogenesis and spermatogenesis, respectively. Most (iii) 3 non-gestational tumours. PCR polymorphism
probably, disruption of imprinted regulation for a data revealed the absence of a maternal genome in
particular set of genes in complete and partial moles eight post-molar trophoblastic tumours (Table 68.1).
contributes to the formation of molar phenotypes, but This was contrasted with the presence of a maternal
these remain to be identified. Histopathological genome in all 12 tumours preceded by live birth or
criteria to differentiate partial and complete moles are abortion and in the three non-gestational tumours.
inconsistent among countries. In addition, histological Thus, these eight post-molar trophoblastic neoplasms
features overlap significantly between these moles developed from malignant transformation of
especially when the moles are evaluated in early complete moles. Six tumours were homozygous at
gestational stage. These indicate the necessity of three or more gene loci in which the partners were
genetic demonstration of each class of moles. heterozygous. A female sex chromosome constitution
 Basic Aspect of Trophoblastic Disease 941
Table 68.1: PCR-polymorphism analysis of choriocarcinomas and invasive mole
(antecedent pregnancies were complete moles) and Pa (parents)
Patients DNA D1S80 ApoB D5S107 DRB D9S43 RB D17S30 DMD SRY
1 P f/g a/- a/b 4/- a/- a/b c/- I {j I {j
T f/g a/c b/c 4/12 a/b a/b c/-
M e/f b/c b/c 9/12 b/- b/- c/-
2 P b/d a/c a/b 2/3,6 a/c a/b c/f I {j I|j
T b/d a/c a/- 2/- a/- a/b c/f
M a/- a/c b/c 2/4 a/- b/c a/e
3 P b/g a/b c/d 4/- b/- a/- b/e I {j I|j
T b/- a/- d/- 4/- b/- a/- b/-
M a/g a/c c/d 2/4 c/d a/b e/f
4 P d/h d/h a/c c/- 2/3,6 a/b c/- I {j I|j
T d/- d/- a/- c/- ND b/- c/-
M c/- c/- a/c e/f 3,6/- b/c a/b
5 P a/b a/b e/f 4/- c/d a/b d/f I {j I|j
T a/- b/- f/- 4/- c/- b/- d/-
M d/e b/- b/d 2/- d/e a/d f/g
6 P i/- a/- b/d 4/2 b/f c/- d/- ND ND
T i/- a/- b/- 4/- b/- c/- d/-
M i/j a/- b/c 3,6/- b/g a/b c/d
8 P a/b a/- a/b 1/- f/g ND d/f I {j I|j
T b/- a/- a/- 1/- g/- f/-
M c/d a/c c/- 4/12 f/- a/b
9 P h/f a/- a/b 11/9 ND ND b/- I {j I|j
T h/- a/- a/- 11/- b/-
M h/- a/c b/- 4/9 b/c
*
10 P d/- a/c a/b 4/8 b/h a/- b/d I {j I {j
T d/- a/- b/- 4/8 b/- a/- b/d
M a/b a/c a/b 4/9 b/f a/- a/-

was anticipated because PCR failed to amplify any A B

fragment specific to the SRY (which is specific to the M T P M T P
Y chromosome) gene sequence in these tumours.
These genetic features may be compatible with those
of the complete mole that results from fertilization of
an empty egg by an X-bearing sperm. The
heterozygosity was recognized in two tumours at a
←a
few gene loci. The 240 base-pair (bp) PCR product ←b ←a
←b
←d ←c
specific to the SRY gene sequence was present in one
tumour but not in the other. It seemed likely that the
two tumours originated from an XX or XY dispermic,
androgenetic mole (Fig. 68.1). Amplified gene(locus) MCT118 (D1S80) 3-beta (ApoB)
The remaining choriocarcinoma contained an Location 1p36-p35 2p24-p23
Technique VNTR VNTR
allele derived from the patient at a few gene loci. This
finding is compatible with the assumption that the Fig. 68.1: PCR-polymorphism of two chonocarcinomas. The
tumour did not arise from an complete mole. A full- tumour showed two bands that were absent in maternal DNA,
suggesting an androgenic in origin. P=PCR products from
term delivery prior to a complete mole conception
paternal DNA; T=from tumour DNA; M=from maternal DNA;
would explain this tumour development. VNTR=variable number of tundem repeat.
942 Textbook of Perinatal Medicine

All 12 tumours in class (ii) had alleles of both committed to cell growth control, in order to
paternal and maternal contribution. However, characterize the regulatory circuitry for cell
discordance of sex between the antecedent pregnancy proliferation in complete moles. Complete moles are
product and the tumour was recognized in three characterized by hyperplastic trophoblast and have
choriocarcinomas. The absence of a paternal a high propensity to give rise to choriocarcinoma.
contribution suggested a parthenogenetic origin for Characteristic alterations in gene expression profiles
the three non-gestational choriocarcinomas. The were observed when compared with normal villi. A
findings that PCR polymorphisms were either total of 57 genes were significantly up-regulated in
homozygous in certain loci or heterozygous in others complete moles. These involved the Ras/MAP
may mean that the tumour was derived from a germ kinaseIII, JAK/STAT5 and Wnt signal pathways,
cell after meiosis I. As a result, at least three subtypes implicating growth factor or cytokine-mediated signal
with different modes of origin were demonstrated in pathways in the trophoblastic hyperplasia of complete
the 24 trophoblastic tumours. Although more than moles. Several genes associated with anti-apoptosis,
half of the trophoblastic tumours collected here had cell structuring and/or cell attachment were also up-
a maternal contribution to their genomes, the data still regulated in complete moles. In contrast, relatively
support the suggestion that of all forms of pregnancy fewer genes were down-regulated and these involved
that predispose patients to choriocarcinoma, the most insulin growth factor binding proteins (IGFBPs),
likely is the complete mole. Versican, Interleukin-1, tumour necrosis factor
receptor, CD44 and Rad 52. The genes identified as
MOLECULAR MECHANISMS ASSOCIATED
being up or down-regulated may help to elucidate
WITH TROPHOBLASTIC DISEASES
the regulation mechanisms of trophoblastic
Gene Expression Profile in Complete Mole proliferation and the mechanisms causing a
Kato et al (2002) 25 used microarray analysis to pathological phenotype in complete moles (Fig.
investigate the expression profiles of 589 genes 68.2).25

villi mole

STAT5B

Cy3(mole)
villi mole

Cy5(villi)
IGFBP5
Fig. 68.2: A log plot of microarray experiment demonstrating distribution of 425-gene expression in normal and molar villi.
Fluorointensity of Cy-3, which labelled to mRNA from complete mole, is plotted vertically. That of Cy-5, from normal villi, is
horizontally plotted. Up-regulation of STAT5B expression and down-regulation of 1GFBP5 expression in mole were shown. x:
Control file: mole red Cy3; y: non-control file: norma; villi green Cy5.
 Basic Aspect of Trophoblastic Disease 943
Silencing of NECC1 / Hop placental villi expressed NECC1, but all of the
Expression in Choriocarcinoma choriocarcinoma cell lines examined and most of the
surgically removed choriocarcinoma tissue samples
Choriocarcinoma is a highly invasive tumour
failed to express it. Asanoma et al26 transfected this
consisting of markedly anaplastic trophoblasts totally
gene into choriocarcinoma cell lines and observed
lacking residual villous structures. Demonstration of
remarkable alterations in cell morphology and
a predominant association between complete mole
suppression of in vivo tumorigenesis. Induction of
and choriocarcinoma suggests that the molecular
chorionic somatomammotropin hormone 1 (CSH1)
events of mole and choriocarcinoma development are
and remarkable alteration in cell morphology
related, since the putative forerunner carries unique
including multinucleation by NECC1 expression
genetic features (as mentioned previously). The
suggested differentiation of choriocarcinoma cells to
monoallelic contribution shown in the complete mole
syncytiotrophoblasts (Fig. 68.3).
would render a certain gene susceptible to functional
The tumour suppressive ability of NECC1 does not
inactivation by ‘one-hit’ kinetics. Alternatively,
require the 3rd/4th helix and the C-terminal domain.
uniparental transmission of genes that are subject to
The inhibitory effect of mutant NECC1, which deletes
parental imprinting in humans would impair their
the 3rd/4th helix and the C-terminal domain, on
regulation. Thus, the features exhibited by complete
choriocarcinoma cell growth properties, is analogous
mole would be associated with inactivation of
to that of wild-type NECC1. The results imply that
particular tumour suppressor genes, contributing to
the DNA binding capability of NECC1 is not required
the propensity to malignancy.
for choriocarcinoma cell differentiation and the
Many tumour suppressor genes are inactivated by
resultant tumorigenic suppression. This unexpected
intragenic mutations in one allele, accompanied by
finding may be supported by the previously reported
the loss of a chromosomal region containing the
evidence that several homeobox genes exhibit their
remaining allele; this is termed loss of heterozygosity.
biological functions in the absence of DNA binding.
Mapping such deleted regions has been used to
The data suggest that loss of NECC1 expression is
identify sequences involved in malignancies.
involved in the malignant conversion of placental
However, the monoallelic contribution exhibited by
trophoblasts.
the complete mole and its transformant would mask
Human chromosome 7 carries a putative tumour
the chromosomal region where the allelic loss
suppressor gene involved in choriocarcinoma.
frequently occurs. To resolve this difficulty, Asanoma
To determine which chromosome carries a
et al.26 constructed a PCR-subtracted fragmentary
putative tumour suppressor gene, microcell-hybrids
cDNA library between normal placenta villi and the
were isolated following fusion of choriocarcinoma
choriocarcinoma cell line (CC1) and isolated a
cells with microcells from mouse A9 cells containing
candidate choriocarcinoma suppressor gene. This
a single human chromosome, 1, 2, 6, 7, 9 or 11.
gene comprised an open reading frame of 219
Microcell-hybrids with the introduction of
nucleotides (nt) encoding 73 amino acid residues and
chromosome 7 were suppressed or modulated for
contained a homeodomain as a consensus motif, being
tumorigenicity and exhibited altered in vitro growth
identical with homeodomain only protein (HOP),
properties. Introduction of chromosomes 1, 2, 6, 9 or
which is essential for cardiomyocyte development.27-
28 11 had no effect. Tumorigenic revertants isolated from
This gene, designated as N ot Expressed in
microcell-hybrids with the introduced chromosome
Choriocarcinoma clone 1 (NECC1)26 is located on
7 contained reduced numbers of chromosome 7. These
human chromosome 4q11-q12. NECC1 expression is
findings suggest that chromosome 7 contains a
ubiquitous in the brain, placenta, lung, smooth
putative tumour suppressor gene for
muscle, uterus, bladder, kidney and spleen. Normal
944 Textbook of Perinatal Medicine

cell line tissue sample case

NUC-1

Bewo

JEG3

CC1
CC3
CC2
NJG

JAR
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
D7S
22 531
513
21 484
15.3 493
15.2 EGFR
15.1
14 519
13 478
12 499
11.2 494
11.1
11.1 520
11.21 502
11.22
11.23 482
663
21.1
639
21.2
21.3 645
22 502
31.1 ELN
31.2 524
31.3 486
CFTR
32 530
33 495
34 483
35
550
36

Fig. 68.3: Map of homozygous deletions on chromosome 7. Close squares represent

homozygous deletions. Open squares mean the retention of a single or both alleles.

choriocarcinoma. Changes in the phenotypes seen in balance may lead to hyperplastic proliferation of the
microcell-hybrids were not associated with the trophoblast, which characterizes molar pregnancies.
presence of either the ERV3 or the H-plk locus on the Based on this hypothesis, it is likely that genomic
introduced chromosome 7, indicating that the imprinting, which is disrupted in the androgenetic
putative tumour suppressor gene is outside the ERV3 mole, may play a pivotal role in the development of
and H - p l k gene loci. Furthermore, we obtained choriocarcinoma. H19 and IGF2 are two classic
evidence for defining a critical region on chromosome examples of related imprinted genes. A high level of
7 (7p12-7q11.23) that was frequently lost in surgically H19 expression, in contrast to a considerably lower
removed choriocarcinoma tissues and cell lines. Using level of IGF2 expression, was demonstrated in
a panel of microsatellite markers, biallelic deletions choriocarcinoma.30 P57KIP2 may also play a role in the
were observed, which strongly suggests the presence pathogenesis of gestational trophoblastic disease
of a tumour suppressor gene within this critical region (GTD)31 P57KIP2 is a cyclin-dependent kinase inhibitor
(Fig. 68.4).29 and is imprinted with the maternal allele being
expressed. P57KIP2 was found to be highly expressed
Genome Imprinting in proliferating trophoblast of normal placenta, but
expressed at a low level in complete mole and
It has been clearly established that both paternal and choriocarcinoma. This is in accordance with what is
maternal contributions are necessary for maintaining expected, on the basis of the imprinting of the
a balanced development of both embryonic and extra- maternal allele. However, at present, their exact role
embryonic tissues, and the disruption of such a and diagnostic usefulness are not clear.
 Basic Aspect of Trophoblastic Disease 945

Vector alone Deletion mutant Wild type

NECC1 NECC1

250µm

CSH1

50µm

Fig. 68.4: Morphology and immunofluorescent staing of NECC1transfected BeWo cells. BeWo cells transfected with vector
only, deletion mutant NECC1, and wild type NECC1 were photographed using phase-contrast microscopy at 40•~. Lower
photographs were immunofluorescent staing of CSH1. NECC1 deletion mutant and wild-type transfectants expressed abundant
CSH1. CSH1=choriomammotropin hormone 1.

Other Molecular Events Involved in proto-oncogene expression by abnormal trophoblast

Trophoblastic Diseases is hard to evaluate since several proto-oncogenes are
already expressed at high levels in normal placentas.
Malignant transformation in hydatidiform mole is a
Epidermal growth factor receptors (EGFR) are
multistep process involving the accumulation of
expressed more strongly in molar placentae than in
several genetic events, including activation of
normal placentae of similar gestational age. Tumours
oncogene and/or loss of tumour suppressor genes.
with a histological diagnosis of invasive mole and
A small number of oncogenes and tumour suppressor
choriocarcinoma show very strong binding of EGFRs.
genes have been found to play putative roles in the
EGFR expression has been associated with the
pathogenesis of GTD. For example, the oncogenes c-
secretion of human chorionic gonadotrophin (hCG).
m y c, c-erb-B-2, bcl-2 and m d m - 2, 32 the GTPase-
Following exposure to chemotherapy, EGFR binding
activating protein genes, p53, p21WAF1/KIP1, Rb,
sites have been noted to be diminished in
and the tumour suppressor gene DOC-2/hDab233
choriocarcinoma cells.36
have all been listed as candidates.
There are reports of increased c-fms RNA in
SUMMARY
complete mole compared with normal placentas34 and
c-myc and ras RNA in choriocarcinomas. 35 The The complete mole is androgenetic in origin. The vast
significance of such simple quantitative changes in majority of complete moles result from the
946 Textbook of Perinatal Medicine

fertilization of an egg devoid of nuclei (an empty egg) 7. K. Ohama, T. Kajji, E. Ikamoto et al., Dispermic origin of
XY hydatidiform moles. Nature 292 (1981), pp. 551–552.
by a haploid spermatozoon. Fertilization of an empty
8. N. Wake, T. Seki, H. Fujita et al., Malignant potential of
egg by two spermatozoa is responsible for a rare class homozygous and heterozygous complete moles. Cancer
of complete mole. The genome of choriocarcinoma Research 44 (1984), pp. 1226–1230.
should reflect that of the pregnancy from which the 9. N. Wake, T. Fujino, S. Hoshi et al., The propensity to
malignancy of dispermic heterozygous moles. Placenta 8
tumour arose. Thus, the predominant association of (1987), pp. 319–326.
complete mole with choriocarcinoma suggests that 10. P. Vassilakos, G. Riotton and T. Kajii, Hydatidiform mode:
the molecular events for the formation of a complete two entities. A morphologic and cytogenetic study with
mole and the malignant conversion of trophoblasts some clinical considerations. American Journal of
Obstetrics and Gynecology 127 (1977), pp. 167–170.
are related. The monoallelic contribution shown in 11. A.E. Szulman and U. Surti, The syndromes of
complete mole would render a certain gene hydatidiform mole. I. Cytogenetic and morphologic
susceptible to functional inactivation by ‘one-hit’ correlations. American Journal of Obstetrics and
Gynecology 131 (1978), pp. 665–671.
kinetics. Alternatively, uniparental transmission of
12. A.E. Szulman, E. Philippe, J.G. Bou’e and A. Bou’e, Human
genes that are subject to parental imprinting in triploidy: association with partial hydatidiform moles and
humans would impair their regulation. Loss of non molar conceptuses. Human Pathology 12 (1981), pp.
NECC1 expression, biallelic deletions at the critical 1016–1021.
13. S.D. Lawler, R.A. Fisher, V.J. Pickthall et al., Genetic
(7p12-7q11.23) region and enhanced H19 expression studies on hydatidiform moles. I. The origin of partial
in choriocarcinoma would reflect the genetic features moles. Cancer Genetics and Cytogenetics 5 (1982), pp. 309–
exhibited by the putative forerunner, complete mole. 320.
In addition, alterations in gene expression profiles 14. D.M. Sheppard, R.A. Fisher, S.D. Lowler and S. Povey,
Tetraploid conceptus with three paternal contributions.
accompanied by malignant conversion of trophoblasts Human Genetics 62 (1982), pp. 371–374.
would facilitate choriocarcinogenesis from complete 15. U. Sutri, A.E. Szulman, K. Waquer et al., Tetraploid partial
mole. In future, identification of molecular targets hydatidiform moles: two cases with a triple paternal
contribution and a 92, XXXY karyotype. Human Genetics
down- or up-regulated in choriocarcinoma will
72 (1986), pp. 15–21.
provide us with the management tools for gestational 16. L.O. Vejerslev, R.A. Ficher, U. Surti and N. Wake,
trophoblastic diseases. Hydatidiform mole: cytogenetically unusual cases and
their implications for the present classification. American
Journal of Obstetrics and Gynecology 157 (1987), pp. 180–
REFERENCES 184.
17. N. Wake, K. Tanaka, V. Chapman et al., Chromosomes
1. T. Kajii and K. Ohama, Androgenetic origin of
and cellular origin of choriocarcinoma. Cancer Research
hydatidiform mole. Nature 268 (1977), pp. 633–634.
41 (1981), pp. 3137–3143.
2. N. Wake, N. Takagi and M. Sasaki, Androgenesis as a
18. R.A. Fisher, S.D. Lawler, S. Povey et al., Genetically
cause of hydatidiform mole. Journal of the National Cancer homozygous choriocarcinoma following pregnancy with
Institute 60 (1978), pp. 51–57. hydatidiform mole. British Journal of Cancer 58 (1988),
3. N. Wake, Y. Shina and K. Ichinoe, A further cytogenetic pp. 788–792.
study of hydatidiform mole, with reference to its 19. R.S.K. Chaganti, P.R.K. Koduru, R. Chakraborty and W.B.
androgenetic origin. Proceedings of the Japan Academy Jones, Genetic origin of a trophoblastic choriocarcinoma.
54 (1978), pp. 533–537. Cancer Research 50 (1990), pp. 6330–6333.
4. S.D. Lawler, V.I. Pickthall, R.A. Fisher et al., Genetic 20. R.A. Fisher, F.J. Paradinas, E.S. Newland and G.M. Boxer,
studies of complete and partial hydatidiform moles. Genetic evidence that placental site trophoblastic tumours
Lancet 2 (1979), p. 580. can originate from a hydatidiform mole or a normal
5. K. Yamashita, N. Wake, T. Araki et al., Human lymphocyte conceptus. British Journal of Cancer 65 (1992), pp. 355–
antigen expression in hydatidiform mole/: androgenesis 358.
following fertilization by a haploid sperm. American 21. R.A. Fisher, E.S. Newlands, A.J. Jeffreys et al., Gestational
Journal of Obstetrics and Gynecology 135 (1979), pp. 597– and nongestational trophoblastic tumours distinguished
600. by DNA analysis. Cancer 69 (1992), pp. 839–845.
6. P.A. Jacobs, C.M. Wilson, J.A. Sprenkle et al., Mechanism 22. T. Arima, T. Imamura, S. Amada et al., Genetic origin of
of origin of complete hydatidiform moles. Nature 268 malignant trophoblastic neoplasms. Cancer Genetics and
(1980), pp. 714–716. Cytogenetics 73 (1994), pp. 95–102.
 Basic Aspect of Trophoblastic Disease 947
23. S. Sasaki, P.K. Katayama and M. Roesler, Cytogenetic 31. M. Chilosi, E. Piazzola, M. Lestani et al., Differential
analysis of choriocarcinoma cell lines. Acta Obstetricia et expression of p57 KIP2 , a maternally imprinted cdk
Gynecologica Japonica 34 (1982), pp. 2253–2256. inhibitor, in normal human placenta and gestational
24. T. Arima, T. Imamura, N. Sakuragi et al., Malignant trophoblastic disease. Laboratory Investigation 78 (1998),
trophoblastic neoplasms with different modes of origin. pp. 269–276.
Cancer Genetics and Cytogenetics 85 (1995), pp. 5–15. 32. V. Fulop, S.C. Mok, D.R. Genest et al., c-myc, c-erbB-2, c-
25. H. Kato, Y. Terao, M. Ogawa et al., Growth-associated fms and bcl-2 oncoproteins. Expression in normal
gene expression profiles by microarray analysis of placenta, partial and complete mole, and choriocarcinoma.
trophoblast of molar pregnancies and normal villi. Journal of Reproductive Medicine 43 (1998), pp. 101–110.
International Journal of Gynecological Pathology 21 33. V. Fulop, C.V. Colitti, D. Genest et al., DOC-2/hDab2, a
(2002), pp. 255–260. candidate tumor suppressor gene involved in the
development of gestational trophoblastic diseases.
26. K. Asanoma, T. Matsuda, H. Konda et al., NECC1, a
Oncogene 17 (1998), pp. 419–424.
candidate choriocarcinoma suppressor gene that encodes
34. T. Maruo and M. Mochizuki, Immunohistochemical
homeodomain consensus motif. Genomics 81 (2003), pp.
localization of epidermal growth factor receptor and myc
15–25.
oncogene product in human placenta: implication for
27. C.H. Shin, Z.P. Liu, R. Passier et al., HOP, an unusual
trophoblast proliferation and differentiation. American
homeodomain protein. Cell 110 (2002), pp. 725–735. Journal of Obstetrics and Gynecology 156 (1987), pp. 721–
28. F. Chen, H. Kook, R. Milewski et al., Hop is an unusual 727.
homeobox gene that modulates cardiac development. Cell 35. A.N. Cheung, G. Srivastava, S. Pittaluga et al., Expression
110 (2002), pp. 713–723. of c-myc and c-fms oncogenes in trophoblastic cells in
29. T. Matsuda, M. Sasaki, H. Kato et al., Human chromosome hydatidiform mole and normal human placenta. Journal
carries a putative tumour suppressor gene(s) involved in of Clinical Pathology 46 (1993), pp. 204–207.
choriocarcinoma development. Oncogene 15 (1997), pp. 36. S. Sarkar, B.M. Kacinski, E.I. Kohorn et al., Demonstration
2773–2781. of myc and ras oncogene expression by hybridization in
30. T. Arima, T. Matsuda, N. Takagi et al., Association of IGF2 situ in hydatidiform mole and in the BeWo
and H19 imprinting with choriocarcinoma development. choriocarcinoma cell line. American Journal of Obstetrics
Cancer Genetics and Cytogenetics 93 (1997), pp. 39–47. and Gynecology 154 (1986), pp. 390–393.
 69
The Placenta

Kurt Benirschke

THE NORMAL PLACENTA the decidua and, somewhat later, the endometrial
(spiral) arterioles. This infiltration stops before the
In the idealized menstrual cycle of 28 days,
myometrium is reached, thus it normally leaves a thin
fertilization takes place on day 14, the developing
layer of decidua basalis to remain between villi and
blastocyst develops in the Fallopian tube, travels
myometrium. It is at this interface where the Nitabuch
through the tube to the endometrial cavity and
and Rohr fibrinoid layers are produced, eosinophilic
implants on approximately day 6½ 1 . It usually
substances that are produced by the extravillous
implants on the anterior or posterior surface of the
trophoblast. The latter cells, because of their formerly
upper endometrium, invades the decidualizing
uncertain origin (maternal or fetal) have also been
endometrium by ingesting its cells through
called the “X-cells”; they often produce small cysts
trophoblastic activity and becomes interstitially
containing major basic protein. The major basic
implanted; that is to say, it becomes completely
protein (MBP) is similar to that found in the granules
surrounded by endometrium. At first, mostly
of eosinophilic polymorphonuclear cells, and it is
trophoblastic proliferation takes place around a large
secreted into the maternal circulation, like hCG. Its
cavity, the blastocystic cavity that contains a gel and
function is completely unknown.
the tiny embryo. From the gradually developing
The embryo then lengthens and folds. From the
embryo, the three layers (ectoderm, mesoderm and
edges of its ectodermal plate the amnionic cavity
endoderm) develop; the mesoderm expands into the
forms which then gradually fills with clear fluid. As
future umbilical cord, and then comes to line the
the embryo folds in all directions, the edges of the
blastocystic cavity thus making it the future chorionic
ectoderm and amnion come to meet over the
membrane, and thence the mesoderm proliferates into
developing umbilical cord mesenchyme and the
the gradually developing villi, from inside outwards.
amnion fuses with this mesenchyme tightly. As the
The trophoblast, initially polyploid, differentiates into
amnion fills with fluid (perhaps derived from that
cytotrophoblast from which the syncytiotrophoblast
contained in the extraembryonic coelom), it expands
develops on the villous surfaces. The cytotrophoblast
and gradually becomes passively attached to the inner
differentiates into two components, the villous
surface of the chorionic membrane. It completely fuses
cytotrophoblast (also called the “Langhans’ layer”)
with this membrane at about 12 weeks of gestation2.
that underlies the syncytium, and the extravillous
Prior to that fusion, it is being held in position by the
trophoblast. It is the latter group of cells that assumes
gel of the extraembryonic coelom (Fig. 69.1).
the infiltrative arm of the expanding shell; it infiltrates
 The Placenta 949
It is important to realize that the amnion has an vessels also differentiate in situ in the placental villi
inner epithelial layer that sits on a complex connective or whether they progress only from the fetus towards
tissue layer, but it does not ever contain blood vessels. the periphery. Thus, ultimately two umbilical arteries
Moreover, the amnion can usually be dislodged from progress from the fetus through the umbilical cord
the chorionic surface of the placenta and is thus often to the villous circulation, ramifying over the chorionic
so disrupted by the manipulations at delivery. plate of the placenta. They are readily distinguished
Furthermore, if the amnion were to disrupt prior to as arteries or veins by their position: the major arterial
it’s becoming affixed to the chorion (before 12 weeks), branches pass o v e r the veins. They are virtually
then amnionic bands may form that ultimately can indistinguishable histologically. The vessels can be
disrupt parts of the fetus3. followed toward the periphery where they are seen
From the endodermal layer of the embryo to dip into the villous tissue and, generally, a single
develops the yolk sac. Its epithelium provides the vein returns to the same location as the arterial branch.
precursors for liver, hematopoietic cells and germ Each such branch establishes a single fetal
cells, aside from producing the intestines after the cotyledonary district whose circulation does not
embryo has folded. Having folded, the rotation of the merge with adjacent cotyledons4.
intestines inside the embryo gradually pulls the yolk The extravillous cytotrophoblast arrodes the
sac into the fetal abdominal cavity; it is there maternal arterioles, grows into them and there causes
connected to possible remains of Meckel’s the “physiologic change”, altering these maternal
diverticulum. Also, from the distal part of the yolk arterial blood vessels by removing their musculature
sac a small, temporary extension develops into the and depositing fibrinoid. At first thick columns
developing umbilical cord, the primitive allantoic virtually occlude the lumens, later they hollow out
diverticulum. It is very transitory in humans while a and the complete intervillous circulation is then
true sac develops in many other mammals and serves established (Figs 69.2 and 69.3). Needless to say, fetal
as a receptacle for fetal urine. In human placentation and maternal circulations are separated by the
the fetal urine accumulates in the amnionic cavity. trophoblast and a thin layer of connective tissue.
Blood vessels infiltrate the villi and establish the fetal
circulation somewhat later in the expansion of the GROSS EXAMINATION
villous tissue. It is not quite certain whether these The placenta should be inspected after the baby is
delivered and some minimal observations should be

Fig. 69.1: Eight weeks conceptus in utero. The arrows denote

the edge of the expanding amnion. Note that the dome of the
placental membranes is not attached to the opposite side of Fig. 69.2: Extravillous trophoblast growing
the uterus. within a decidual spiral arteriole.
950 Textbook of Perinatal Medicine

be made immediately and it needs to be studied by

the Kleihauer-Betke technique3. If infarcts or other
unusual findings are made, the placenta should be
sent for pathologic examination. Special circum-
stances are to be observed in multiple pregnancy and
these are discussed in a subsequent section.

UMBILICAL CORD
The normal cord insertion is somewhere near the
center of the placental disk. In about 5% of normal
gestations it inserts at the placental margin, and in
~1% of placentas it is located in the membranes
(“velamentous insertion”). The latter is of significance
in that it is often a cause of fetal growth restriction
and also, because the fetal vessels ramifying in the
membranes have lost their protection by Wharton’s
jelly and may become disrupted, leading to massive
fetal hemorrhage. The length of the umbilical cord is
Fig. 69.3: The placental floor in early implantation. The darker important and it can rarely be reassessed after the
cells are extravillous trophoblast that intermingle with the placenta is sent for study. Thus, it should at least be
decidual cells
estimated, if not measured, at the time of delivery. In
the normal term gestation the umbilical cord is
charted. It is our practice also to save the placenta in approximately 55 cm long, and 85% have a counter-
a refrigerator for several days as its examination may clockwise (left) twist. The reason for this “chirality”
be valuable for pathologists in cases where the infant is unknown but I suspect that it relates to the fetal
is abnormal or fails to thrive. The important movements because immobile fetuses, such as found
observations to be made at the time of delivery are with osteogenesis imperfecta cases which have
the following features: 1) The length and insertion of usually no twists. The cord in those cases is also
the umbilical cord should be ascertained; 2) The unusually short (Fig. 69.4). In contrast, when knots
presence or absence of retroplacental clot (abruptio in the cord exist or when there are nuchal cords, it is
placentae) needs to be looked for; 3) The color of the often significantly lengthened. This may be the result
fetal surface (meconium staining or opacification from of excessive fetal movements. It is also important to
chorioamnionitis) need to be charted, and 4) The color ascertain in unusually long cords whether there is
of the villous tissue should be inspected. The latter excessive twisting of the cord on the surface of the
observation is important as it can denote whether a fetus, the place where it inserts on the abdomen. It is
baby has lost blood through transplacental not uncommon that excessive twisting leads to fetal
hemorrhage. The color of the villous tissue is almost demise, even abortions (Fig. 69.18). In addition, one
totally a reflection of the fetal hemoglobin content. may find “false knots” which represent redundancies
Thus, an anemic neonate has a very pale villous tissue of vessels or excess Wharton’s jelly, unimportant
that may reflect erythroblastosis, Parvovirus B19 features.
infection, hemoglobinopathy or, importantly, The normal umbilical cord contains three blood
significant fetal blood loss. If it is unusually pale (and vessels, two arteries and one vein. In some 1% of
the obstetrician of course needs to be acquainted with neonates only one artery is found (SUA) and this is
the normal colors), then a maternal blood film should frequently associated with congenital anomalies (~
 The Placenta 951
At the site of rupture one often finds blood clot and
some inflammation can occur here from the processes
of labor. Histologically there is then deciduitis, and
thrombosis may be present in the decidual blood
vessels. While this may be grossly interpreted as
representing an abruptio placentae, that is not quite
correct, as the blood is accumulated only behind the
membranes, not behind the villous tissue. Of course,
since chorioamnionitis is so much more common in
immature placentas, these features are much more
frequently found in such births. For the pathologist,
the study of the deciduas capsularis is best
Fig. 69.4: Length of umbilical cord in excessively short cord undertaken when a membrane roll is made so as to
syndromes. The line represents the normal length. increase the chances of finding abnormalities. These
are principally findings of “atherosis” (alterations of
decidual arteries in preeclampsia to be discussed
45%) and also with fetal trisomies. While the presence below) aside from the inflammation. Since atherosis
of SUA may signal to the neonatologist that special is so frequently found in these vessels, this has raised
attention should be paid to possible internal the question of where the vascular supply of the
anomalies (heart, kidney), it is important to realize deciduas capsularis originates. It is usually assumed
that many babies with SUA are entirely normal. True that the expanding membranes are merely pressed
knots in the umbilical cord usually form early during against the deciduas vera of the opposite side of the
development and they are now often recognized uterus and that there is perhaps no ingrowth of
sonographically. They may lead to complete decidua vera into the decidua capsularis, but
obstruction of blood flow and to fetal demise. In other definitive studies have not been made. Macroscopic
cases, true knots have so impeded the venous findings of early placentas negate this suggestion of
(oxygenated blood) return from the placenta that true ingrowth from the deciduas vera (Fig. 69.1).
surface thrombi will be observed on the placenta It is important for the pathologist to recognize that
which can even be calcified. Obviously, such features the amnion consists of a single layer of epithelial cells
may determine whether major sequelae develop in (that occasionally have patches of squamous
the fetus, such as CNS destruction and cerebral palsy. metaplasia) which are situated on a dense, avascular
connective tissue membrane. When the amnion
THE MEMBRANES
disrupts spontaneously before it attaches to the
The free membranes are referred to as the chorion chorion in early pregnancy, the amnion fails to grow
leave but, in the older placental literature, all of the subsequently and may become entangled in fetal
placenta and its membranes were referred to as the extremities when the fetus moves about. This is the
“membranes” or “secundines”. The “free” mechanism for amnionic bands and its many
membranes as we know them now have an outer layer complications, primarily digital amputations. The
of deciduas capsularis which is followed by atrophied cause of such disruptions is unknown but does not
villi in between extravillous trophoblast, then comes usually relate to trauma or any antecedent event that
the chorion and innermost is the amnion. When the has been elucidated. In such cases one can invariably
membranes have a measurable portion between the find a rim of amnion at the reflection of the umbilical
site of rupture and the placental disk, then it cannot cord, as it is here firmly affixed to the mesenchyme
have been a placenta previa if it is delivered vaginally. of the cord. Amnion nodosum is the other
952 Textbook of Perinatal Medicine

pathological condition worthy of note. In the absence bleeding somewhere in the gestational sac; it must
of amnionic fluid (as in renal agenesis, polycystic therefore be critically appraised.
kidneys, urethral obstruction, etc.) fetal urine fails to
fill the sac and focal degeneration of the amnionic VILLOUS TISSUE
epithelium takes place. Amnion nodosum is most The villous tissue changes with the maturation of the
pronounced on the placental disk, never on the cord placenta. In young organs, the villi are relatively large,
and only rarely on the free membranes. At the sites have numerous cells and the fetal capillaries are
of this epithelial disruption, vernix caseosa embeds dispersed peripherally beneath the trophoblast. The
and forms microscopic nodules, the amnion villi look “edematous” and this changes with maturity
nodosum. This is of course possible only after the fetus as more villi sprout peripherally (Fig. 69.6). In the
has made sufficient vernix to be embedded, and it is term placenta then the most peripheral villi are small
thus not found in very immature fetuses with renal and contain mostly 3-4 capillaries with few connective
agenesis (Fig. 69.5). tissue elements. There are also some macrophages
Meconium staining of the membranes is common. within the villi, the so-called Hofbauer cells, and they
It occurs in nearly 15% of our placentas and is usually are more readily seen in immature organs. They are
the result of post-term gestations. Numerous clinical important cells in the elimination of antigens and
impressions have suggested that meconium discharge assist in the removal of focal hemorrhage as they occur
is the result of fetal hypoxia, but other studies indicate for instance in CMV infections. They may then contain
that this may not be so. For instance, most stillborn hemosiderin.
fetuses, assuredly having died from hypoxia, are not The surface of villi is covered by trophoblast. There
stained. Moreover, elevated levels of motilin (the GI is an inner layer of cytotrophoblast (the “Langhans”
hormone that regulates bowel movements) are layer) in which mitoses occur that produce the
present. Meconium can be recognized histologically cytoplasm and the nuclei for the covering
in the macrophages of amnion and chorion by their syncytiotrophoblast. The syncytium, however, is the
yellow pigmentation and enlargement. It must be actual organ of exchange. It is a single, uninterrupted
cautioned also that this pigment disappears quickly membrane covering all villi, has no cell borders, and
when slides are exposed to light. Slides must thus be
examined soon after their preparation. Moreover, the
pigment may also be due to hemosiderin from chronic

Fig. 69.6: Immature villi with numerous nucleated red blood

cells within the capillaries. The stroma is “loose” and appears
Fig. 69.5: Placental surface in renal agenesis with amnion edematous, but that is normal. A few syncytial buds are in the
nodosum; at the arrow is the degenerated, calcified remains process of detaching. The cytotrophoblastic Langhans’ layer
of the yolk sac (a normal feature) is visible beneath the superficial syncytium.
 The Placenta 953
the nuclei have become incapable of mitosis. The Wiedemann syndrome, associated with
syncytiotrophoblast has a fine brush border of chorangiomas, and a few other conditions (diabetes).
microvilli and its cytoplasm possesses numerous When such alterations are found one should also look
transport vesicles, and its surface has many receptor for the presence of nucleated red blood cells (NRBCs)
sites for nutrient exchange. Importantly, the in the fetal capillaries; they are not present in placentas
syncytium expresses no HLA antigens that could after about 25 weeks and, when present, they may
potentially excite a maternal rejection process. So far also signal prolonged intrauterine hypoxic states.
as is now known, only HLA-G is expressed and this
is not antigenic to the mother. The cytotrophoblast is INFECTIONS
easily visible in young placentas but it is difficult to
recognize these cells at term, although they are always One of the most important aspects of obstetrics today
there when studied by the electron microscope. Since is ascending infection with chorioamnionitis and
cytotrophoblast continues to produce new syncytium, premature birth ensuing. This is an especially
the cells and cytoplasm of the latter bunch up and important feature for the 20-30 week gestations as the
form so-called knots, or sprouts. These increase in often associated severe prematurity may lead to fetal
number towards term and then they are recognized infection and, most importantly, to CNS damage with
on about 30% of peripheral villi. They also often cerebral palsy the outcome. Chorioamnionitis is
detach and are carried away in the intervillous common and it often recurs in subsequent
(maternal) circulation and swept to the maternal lung. pregnancies. I believe that it results mainly from the
Here they die, as they have no reproductive capacity. deficiency of endocervical mucus that normally
When the villi shrink, as is the case in preeclampsia protects the intrauterine environment from vaginal
because of deficient water transfer to the fetus, there organisms. This, in turn, probably reflects severe
is more “buckling” of the syncytium and more knots chronic endocervicitis. While septic distribution of
are found; this is referred to as the “Tenney-Parker” some maternal organisms occurs (listeriosis,
change. cytomegalovirus infection, toxoplasmosis) these are,
A number of conditions cause histologically numerically speaking, unimportant entities.
recognizable changes in villi, the most important and The endocervical canal produces copious amounts
frequent of which is infarction. Death of villi, usually of dense mucus in normal pregnancy that contains
of larger districts, is caused by the obliteration of abundant antibodies and protective immunocytes.
spiral (decidual) arterioles. This occurs most The canal is also normally closed and narrow until
commonly in preeclampsia and may be associated labor commences. When organisms are allowed to
with abruption of the placenta from bleeding into the cause endocervicitis and proliferate here, the
deciduas basalis. But infarcts are also common at the inflammatory process generates enzymes (mainly a
edge of the placenta and then they are usually without phospholipase) that lead to the local production of
consequence. Edema of villi is a frequent finding in prostaglandin with dilatation of the cervix and lower
fetal anemia (erythroblastosis, hemoglobinopathy) uterine segment following. This, in turn, leads to
and of course in hydatidiform moles. In addition, one deciduitis of the “forelying” decidua capsularis and
may find inflammatory cells within villi in the the organisms may then enter the amnionic cavity,
condition known as “villitis of unknown etiology” with or without the rupture of membranes. Once they
(VUE), in CMV infections and in syphilis. are in the amnionic cavity, the leukotactic property
Finally, there may be too many capillaries within of the organisms leads to a series of inflammatory
the terminal villi. This condition, known as sequelae, first on the surface of the placenta, then the
chorangiosis, is seen in chronic hypoxia (e.g. in umbilical cord and, when inhaled, the infection may
placentas from high altitude), in the Beckwith- cause fetal pneumonia (Fig. 69.7). The first effect is
954 Textbook of Perinatal Medicine

the emigration of maternal leukocytes from the Thus it becomes more important to anticipate the
intervillous space beneath the chorionic surface of the infection, especially its recurrent nature, and treat
placenta; then inflammation of surface vessels follows, with antibiotics prior to the dilatation of the cervix.
thereafter umbilical phlebitis and finally umbilical The pathologist observes placentas with an opacified
arteritis takes place. This pus that obscures the fetal (“cloudy”) fetal surface and, histologically, by the
surface of the placenta and makes it to be “cloudy” presence of numerous polymorphonuclear leukocytes
(opaque) is thus of mixed origin, maternal and fetal. in chorion and amnion (Fig. 69.7). Later there is
Studies of gastric aspirates and lung exudate have exudation from the umbilical vein and then the
shown this admixture definitively. In time, after days arteries. The remainder of the placenta, especially its
of aspiration of this infective material, the fetal lung villous structures, is entirely normal, but usually
reacts with infiltration of a lymphocytic response. immature. The membranes, however, are markedly
Often it is possible to identify some bacterial altered. The deciduitis and often decidual necrosis are
organisms, but this is generally uncommon. The severest near the point of membrane rupture which
reason for our inability to recognize organisms is so close to the endocervical canal. There may be
histologically lies in the nature of the inciting antigens. fresh clot attached at this site and it is occasionally
They are frequently not visible in histologic sections mislabeled as representing an abruption. In twin
(such as Trichomonas, Mycoplasma, Ureaplasma, gestations it is invariably twin A, lying closest to the
Chlamydia) but they can be cultured if efforts are endocervix that has the infection and severest
made. An exception is found in the infections with inflammation. Chlamydial organisms are the
group B streptococci. Because of their toxins commonest cause of genital infection nowadays,
(hemolytic and cytolytic), one may identify numerous causing urethritis, salpingitis (with infertility
organisms but find only relatively little inflammation ensuing), cervicitis and occasionally a disseminated
with this common infection. infection. Since this organism is not visible in routine
Numerous attempts have been made to treat this preparations of histologic slides, it must be considered
ascending infection when it is recognized by a dilating when chorioamnionitis is present.
cervix or by maternal fever, but that is usually too Disseminated infections represented by lesions in
late in the course of the disease. Moreover, most the placenta are found in listeriosis. This gram
efforts to treat the fetus in utero with administration positive coccobacillus causes maternal sepsis and
of antibiotics to the mother have been unsuccessful. disseminates into the fetus probably most commonly
via abscess formation in the placenta. Numerous
epidemics have been described that have usually been
of a food-borne origin, as the organism is widespread
and proliferates well in the refrigerated state. The
placenta may show small abscesses and many
organisms are commonly found on the placental
surface. When the fetus is thus infected, the condition
known as “granulomatosis infantiseptica’ may result,
with disseminated abscesses, meningitis, dermatitis
and other sequelae. Since the organism is highly
susceptible to ampicillin, early diagnosis is essential.
Toxoplasma organisms of placenta and fetus are
Fig. 69.7: Placental surface in marked, long-standing
chorioamnionitis. The dense leukocytic infiltrate is seen beneath
commonly acquired parenterally from the fecal
the amnion. contamination originating from cats. In felines, the
 The Placenta 955
intestines propagate the organism and, when feces are in the placenta of growth-restricted fetuses and in
dry and subject to dust contamination, the pregnant stillbirths. Worse, it often recurs in subsequent
mother may become infected. That is an important pregnancies. When large districts of the placenta are
reason for cleaning litter boxes while the fecal material so affected, fetal demise is common but there are no
is still moist. Toxoplasma cysts of a congenital abnormal findings of any infectious nature in the fetal
infection may be seen in the chorion and even more tissues. The villi in VUE are probably infiltrated by
commonly in Wharton’s jelly of the umbilical cord, maternal T-cells and macrophages. They here cause
but they are sparse. The fetus may develop an obliteration of the capillary beds and the restrictive
hydrocephalus and a variety of other pathologic cause of fetal growth is therefore readily understood.
states. The infection is easily preventable but difficult But the precise cause of why the maternal
to treat once it is diagnosed. lymphocytes invade the placenta is as yet unknown.
Cytomegalovirus infection is also common and it It has been speculated that this is akin to a “rejection”
may be sexually transmitted at times. It infects the phenomenon but why the fetal HLA type should be
villi of the placenta and can then disseminate into the recognized by the mother’s immune cells is so far
fetus. The outcome is highly variable but is often obscure.
associated with growth restriction, cerebral
manifestations, jaundice and other complications. The TUMORS AND MICROCHIMERISM
usually small placenta may show characteristic The commonest tumor of the placenta is the
changes. In early infections one finds inclusion bodies chorangioma6. It is frequently found only accidentally
within villi, thrombosis of capillaries and occasional in sections prepared at random. Angiomas occur in
villous hemorrhages. Plasma cells then infiltrate villi as an expansion of the fetal capillary and
which are otherwise very unusual features of normal mesenchymal cells; they form nodules that can be
placentas; eventually the villus atrophies and seen grossly and which are easily shelled out of their
hemosiderin pigment deposits in Hofbauer cells. The beds. Interestingly, their surface is usually covered
antigen is easily demonstrated with modern by a single layer of trophoblast that suggests the
techniques of antibody-marked histologic staining, as expansion of fetal vessels being very focal in nature.
is of course the case also with the determination of Chorangiomas occur more frequently at high altitude
serum antibodies. When the infection is longstanding
and when it is severe, thrombi may develop even in
the larger surface vessels (Fig. 69.8), and these may
be calcified as well.
Only a few other disseminated infections are of
importance. Thus, varicella infection has been
described rarely, hepatitis antigens can cross the
placenta, Coxsackie viruses have been transmitted
with few placental lesions visible, and the placenta
may also contain numerous intervillous malaria
organisms during a malaria attack. Transmission to
the fetus transplacentally, however, of the widespread
malaria infection is extremely rare.
A final comment must be made about a reasonably Fig. 69.8: Placenta in severe CMV infection with extensive
common condition known as “villitis of unknown venous thromboses at arrows. The thrombi were at least
etiology” (VUE). This condition is frequently found partially calcified.
956 Textbook of Perinatal Medicine

and are often also associated with “chorangiosis”, an The situation differs with fetal cells disseminating into
increase of the normal number of capillaries in the the mother transplacentally. It is now recognized that
peripheral villi. They are benign tumors despite their fetal cells often traverse the placenta in small
frequently great cellularity. In fact, chorangiomas numbers. These are mostly red blood cells but
have been mislabeled in the past as being sarcomas, nucleated elements have also reached the maternal
mesenchymomas or have been assigned other circulation, perhaps even fetal stem cells. In the
appellations, but they have never metastasized. Large maternal organism these elements may live for many
chorangiomas may protrude on the fetal surface (Fig. years and, perhaps as determined by their antigenic
69.9); they may be one cause of hydramnios and they expression, they may be destroyed in the mother.
may also infarct from thrombosis with cessation of Recent studies, however, have also shown that some
the hydramnios resulting. Recent studies have shown of these fetal cells themselves may impart an
that they are at least in part the result of increased antibody/rejection response against the mother. This
angiopoietin expression 7 . On rare occasions the “microchimerism” is now thought to be the cause of
angioma may be associated with an excessive degree some maternal autoimmune diseases such as systemic
of trophoblastic proliferation. This condition has been sclerosis and postpartum thyroiditis. Indeed, it has
labeled “chorangiocarcinoma”, but its true nature and been shown that the maternal thyroid epithelium may
degree of malignancy are still poorly defined. on occasion be replaced by fetal cells when
Maternal tumors have also been found to have set postpartum thyroiditis has occurred.
metastases in the placenta occasionally, perhaps most Choriocarcinoma “in situ” has been described a
commonly the carcinoma of the breast. They may few times in otherwise normal placentas and this
focally destroy placental tissue but most of them do tumor has even been disseminated into the mother.
not disseminate into the fetus. This only contrasts with Macroscopically such tumors have given the
the occasional metastatic melanomas which can travel impression of being infarcts, and only histologic
into the fetus but here, the metastases are usually preparations have shown them to be malignant
“rejected” in neonatal life. Maternal B-cells neoplasms. In some cases, the tumor has caused
lymphomas have been described recently as having villous destruction with exsanguination of the fetus
disseminated into villi and they have caused neonatal into the mother. This entity is completely unrelated
deaths from tumor dissemination. Most maternal to the usual cause of choriocarcinoma that may follow
leukemias, however, do not spread to villi or the fetus. the presence of a hydatidiform mole, and its
chromosomes have not yet been studied. The reason
for their occurrence is obscure.

MOLES
When the villi swell up with much fluid from the
intervillous space by transport through the
syncytium, they swell and may become so swollen
as to take on a grape-like configuration that is grossly
visible. We refer to this as hydatid swelling and it is
doubtlessly related to the deficient movement of the
accumulated fluid to the fetus because the fetus has
died and the fetal placental circulation has ceased. The
Fig. 69.9: Large chorioangioma bulging result is the formation of a) “hydatid degeneration”
from the placental surface at left. of the placenta in abortion, and b) hydatidiform
 The Placenta 957
moles. (“Mole” merely means mass). Because not the The distension is mostly within the terminal villi and
entire placental tissue may have become transformed these can often be traced to thinner and firmer
into grape-like masses, we speak of “partial structures represented by the former stem villi that
hydatidiform moles” (PHM) and also of “complete do not participate so much in the swelling. The
hydatidiform moles” (CHM). The former may amount of trophoblastic development varies greatly
represent a variety of conditions; triploidy of the in CHM; at times it is massive and suspicious of tumor
conceptus is the commonest antecedent condition but development. But the former method of “grading
“PHM” may also be due to a set of twins, the placenta moles”, depending on the amount and nature of
of one having become truly molar i.e. a CHM. trophoblastic proliferation, has been abandoned as it
The differentiation of these two types of moles is has proven to have little prognostic significance. The
not always easy but it should be attempted. When villi of CHM have no capillaries, in contrast to what
two separate masses or a distinctly divided placenta is often the case in PHM. Since the revolutionary
is present, twinning is the most likely origin. But the insight gained by Kajii and Ohama8 it is now accepted
differentiation of PHM and CHM may often present that CHM are “androgenetic”. That is to say, their
difficulties for the pathologist and the strong chromosomes are o n l y derived from the
recommendation has been made to submit some of spermatozoon. They are also 2n = 46,XX because a Y-
the abnormal tissue for ploidy analysis that is most bearing sperm would lead to a 2n = 46,YY conceptus
efficiently done by flow cytometry, or for cytogenetic and those cells are not viable. Thus, one can easiest
study. Flow cytometry is the easiest and quickest way understand the development of a CHM by visualizing
for this differential diagnosis. It quickly identifies the fertilization by an X-bearing spermatozoon of an
triploidy (3n) from diploidy (2n) and this is relevant “empty” egg, i.e. an oocyte that has lost its nucleus.
primarily because triploid moles are only The 23,X chromosomes (from the spermatozoon) of
exceptionally rarely followed by gestational the newly fertilized oocyte would then duplicate. But,
trophoblastic neoplasms (GTNs). because of imprinting features, an ovum fertilized by
Partial moles (PHM) are most commonly the result o n l y male chromosomes does not develop a
of fertilization of one oocyte by two spermatozoa. This functional embryo; it can only produce a placenta.
imbalance leads to defective fetal development and, When early complete moles have been carefully
usually, the embryo dies early while the placenta examined, diminutive embryos are found
continues to grow and accumulates fluid. It is much occasionally; they are severely stunted and would
less common that a polar body (two maternal
components – gynogenic) provides the additional set
of chromosomes. In such pregnancies there is
considerably better fetal development. Nevertheless,
the embryo develops somewhat abnormally and
shows numerous anomalies that are invariably lethal
soon after birth. One of the more characteristic
anomalies is the fusion of two fingers and often also
of toes. The placentas of PHM are enlarged,
irregularly molar and the villi have scalloped borders
that often lead to trophoblastic inclusions. These
inclusions are not truly invasive features but represent
tangential sections through infolded surfaces.
The c o m p l e t e h y d a t i d i f o r m m o l e (CHM) is Fig. 69.10: Uterus filled with a “complete hydatidiform mole”.
similarly enlarged but more uniformly so (Fig. 69.10). The ovaries are enlarged because of gonadotropin stimulation
958 Textbook of Perinatal Medicine

soon have vanished. Thus, CHMs have generally no Exaggerated placental site) so that they have now all
fetus and no vasculature, and there is also no been comprised as “gestation trophoblastic
recognizable amnionic cavity. For completeness sake neoplasias” (GTNs). Nevertheless, the
it must be mentioned that a few exceptions have been choriocarcinoma is the best recognized and the most
reported. Thus, a rare gynogenic mole has been found; frequent of these tumors. It is composed solely of
also rarely, a diploid spermatozoon has led to the trophoblast, cytotrophoblast and syncytiotrophoblast,
formation of moles and, equally amazing, a small and most commonly it follows complete moles.
portion of CHMs fertilized by two sperms was found Because the choriocarcinoma continues to produce
to be 2n = 46,XY. These aberrations from the usual, chorionic gonadotropin, it is easily screened for and
however, have not had different sequelae. the follow-up of moles is usually undertaken with
Because the swelling of terminal villi and the serial determination of gonadotropin levels. The other
enlargement of a molar placenta obviously take time unusual feature of these tumors, especially the
to develop, really early CHMs may be difficult to choriocarcinoma, is that it is highly susceptible to
identify; they may appear to be spontaneous methotrexate and actinomycin D therapy. Even
abortions, i . e . “blighted ova”. In addition, metastatic lesions are mostly treated successfully now
spontaneous intermixtures of normal villi and molar when they are recognized early enough.
villi have been observed in chimeras. All of these are While choriocarcinoma most commonly follows a
uncommon features, however. They merely indicate CHM, it may also arise from abortions, even from
that detailed study may be needed to unravel what ectopic pregnancies. And it may be present
is otherwise a great biologic complexity. Furthermore, accidentally in an otherwise normal placenta and is
nobody has described an “empty egg” that we then referred to a “choriocarcinoma in situ”. It then
hypothesize as being the starting point for molar looks like some bland infarct but may of course have
development. We thus assume that some abnormality serious sequelae. What causes choriocarcinoma to
in the maternal oocyte nucleus exists that prevents it develop is uncertain, although it would appear that
from participating in embryonic development. What excessive proliferation of trophoblast is a precursor,
this is, that is being studied. Occasional chromosomal as it is engendered often in moles. The tumor is
errors and genetic defects have thus been identified, usually very hemorrhagic and metastases occur
but that is in a minority of cases so far. We may need anywhere but they are most feared when they occur
more information on the reasons for the great in the brain.
geographic/racial differences in the occurrence of The other tumorous lesions referred to above are
CHMs to attain a better understanding of its real more characteristically produced by the extravillous
causes. Genetic errors have been identified on trophoblast, the “X-cells” whose main purpose is the
occasion as the basis for familial moles. But why it is invasion of the uterus and the modulation of the
that CHMs occur in European/American stock with uterine vessels. By and large, these tumors are much
a frequency of ~1:2,000 and in the Japanese population less common; they usually behave in a less malignant
for instance as commonly as in ~1:350 that is not fashion and can often be treated by excision.
known now.
MULTIPLE PREGNANCIES
TROPHOBLASTIC TUMORS
Twinning is common and monozygotic (MZ -
Choriocarcinoma is the most malignant, albeit “identical”) and dizygotic (DZ - “fraternal”) twins
uncommon outcome of hydatidiform moles. But other occur (Fig. 69.11). When higher multiple pregnancies
neoplastic entities are now recognized (Epithelioid take place, MZ and DZ multiples may be admixed.
trophoblastic tumor; Placental site nodule; In order to understand the placenta of monozygotic
 The Placenta 959
twins it is necessary that one visualizes the stages at The placenta of dichorionic twins is easy to
which the “splitting” of the developing embryo can understand (Figs 69.11 to 69.13). The two blastocysts
occur (Fig. 69.12). Thus, when segregation of implant either side-by-side in the uterus or on
blastomeres takes place very early (during the first 3 opposite surfaces. Two fused placentas may thus arise
days), then two entirely separate placentas may which have a diamnionic, dichorionic “dividing
develop; but when it occurs later, a single chorion and membrane”. Sonographically this is commonly
two amnions develop; and when it occur later still, a recognized by the thickness of the membrane and by
monoamnionic sac can be produced. Eventually, after a small elevation of placental tissue at the meeting
13 days of development, twinning becomes point of the chorionic surface. The pathologist
impossible or else conjoined twins would develop. observes that these membranes are thicker, less
Therefore, the placenta of MZ twins may be dicho- translucent and that atrophied blood vessels may be
rionic (~20%) or monochorionic (~80%). This is what apparent in the dividing membranes. Anastomoses
is actually found and it is important as the between the two fetal circulations do not occur or are
classification of twins may depend on this; and so so rare that they warrant a case report. The umbilical
does the formation of blood vessels that may connect cords of both types of twins are much more often
the two fetal circulations. The anastomotic connec- marginally (or membranous-velamentous) inserted.
tions then occur only in MZ and monochorionic twins; That is also the case of occasional singleton placentas
DZ twins virtually never have such anastomoses and but in twins it may be the consequence of competition
are worthy of being reported. for space in an expanding placenta. Alternatively, it
The frequency of DZ twins depends largely on may be the result of improper early central implan-
genetic factors that control polyovulation. Polyovu- tation but the precise mechanics are undetermined.
lation is controlled by maternal FSH levels; it is very Importantly, such abnormal cord insertion may also
high in the Nigerian Yoruba tribe, but much lower in be found on the dividing membranes and the
Oriental people. Therefore, the percentage of MZ velamentous vessels then represent a danger of
twins is much higher in Japan than it is in African or disruption when these are ruptured during delivery.
European populations. The consequences of this are Monochorionic placentas in contrast nearly always
significant also as most problems in the placentation have blood vessel connections on the fetal surface.
of twins occur with monochorionic (MZ) twins. These take essentially three forms: Most common is
an artery-to-artery communication (Fig. 69.14); next

Fig. 69.11: Two uteri within which are 8 week-old twin fetuses.
At left are monochorionic (“identical”) twins with their amnionic
sacs. At right are two “fraternal”, dichorionic twins within Fig. 69.12: Conceptual drawing of early splitting of embryos/
adjacent placental implantations. placentas in the process of producing monozygotic twins.
960 Textbook of Perinatal Medicine

most commonly artery-to-vein connections occur, and communication prevents this syndrome in its worst
vein-to-vein anastomoses are least often found. The states.
connections are readily identified in the delivered In such monochorionic twin placentas (the
placenta. One may stroke blood back and forth in an majority is diamnionic, monochorionic – DiMo), the
A-A anastomosis; the recognition of A-V connections dividing membranes are composed of two amnions;
is much more difficult and it is also the most they are translucent and lack remnants of former
important and troublesome connection. Injection with vessels.
milk or other fluids makes it easy to recognize the The most important and frequent complication of
type anastomosis, and it is usually necessary to MZ twinning is the twin-to-twin transfusion
undertake such injections if the A-V anastomosis of syndrome (TTTS). It then comes about by the presence
the twin-to-twin-transfusion syndrome (TTTS) is to of a single “shared (common) cotyledon” (Fig. 69.15).
be understood. As has been said earlier, arteries An artery from the donor enters one cotyledon and
generally cross over the veins, especially in the larger this is drained to the “recipient” who becomes fluid-
vessels. They are thus easily recognized and their overloaded and because of excessive urination that
course can be followed by careful gross inspection. recipient develops hydramnios. That is how the
Generally speaking, in the normal placenta an arterial syndrome usually becomes symptomatic, most
branch distributes blood to a single cotyledon. When frequently between 20 and 30 weeks of gestation. The
this branch is followed to its end, the artery suddenly donor urinates little or not at all and becomes the
stops, bends down into the villous and then perfuses “stuck twin”. Hydramnios usually terminates the
one cotyledon. Nearby, a vein emerges from this pregnancy unless it is treated by the modern method
cotyledon and sends blood back to the umbilical vein. of laser obliteration of the offending vessels. In order
In the TTTS, however, this vein sends blood back to to do this surgery one requires considerable
the other twin, thus establishing the basis for the knowledge of the vascular features of the placental
TTTS. One needs to inject these suspect terminal surface and it should not be attempted unless this
arterial branches, fill the cotyledon completely and detailed knowledge is acquired. It must also be
see the injected material emerge in the vein of the appreciated that even large inter-twin anastomoses
“recipient” twin in order to establish the basis for the may have other serious sequelae. Thus, when one
TTTS. There may be several such “common districts”
(they have been referred to as the “third circulation”)
and they may even have different directions. Their
net size determines the severity of the TTTS; it is
generally held now that the co-existence of an A-A

Fig. 69.13: Diagram to show the membrane relationship in

monochorionic twin placentas (left) and dichorionic twin Fig. 69.14: Monochorionic twin placenta with a single large
placentas (right) artery-to-artery anastomosis (at arrows)
 The Placenta 961
DiMo twin dies in utero, blood may be transferred Acardiac twins occur in many forms; some are
rapidly from the surviving twin back into the now nearly perfectly formed babies, but most are severely
dead fetus. This can lead to an at least temporary abnormal and they may even grossly appear as
deficient CNS perfusion in the survivor and thus, though they were skin-covered teratomas. Most
cerebral palsy in one of surviving twins is relatively acardiacs also have a single umbilical artery. They are
common. Such a mechanism is also implored in always monozygotic, or “identical”, although they
understanding the death of the later-dying original represent the worst-possible congenital abnormality
“Siamese” twin pair (Eng). imaginable. The formation of acardiacs is best
Monoamnionic twins are always monochorionic explained by the presence of both, an A-A and V-V
(MZ) and thus suffer the possibility of entangling of anastomosis in the surface of the placenta (Fig. 69.17).
their umbilical cords. Complex knots may develop We believe that in very early embryonic development
early in fetal life and they may become constrictive the normal twin causes a reversal of blood flow
and cause fetal demise (Fig. 69.16). At times one find through the A-A connection and the V-V thus
thrombi in such umbilical cords or in blood vessels returning the blood in the opposite direction; perhaps
of the chorionic surface from the chronically restricted they were then already of different sizes. Because
blood flow during intrauterine life. Moreover, blood from the artery now enters the developing
chorangiosis is often observed in such placentas. acardiac fetus at its abdomen, the legs develop more
adequately, while the cephalic end is usually most
deficiently developed. And, because of the reversal
of flow, the heart of the “acardiac” develops poorly
(it may be two-chambered) or not at all. These
acardiac fetuses are chromosomally generally normal
and of the same sex as the co-twin. It might be
mentioned also that such acardiacs have been
reported quite accidentally in many different species.
When many more fetuses are implanted, a
condition that is now much more common with the
practice of “assisted reproductive technology” (ART),
Fig. 69.15: Drawing to show the “shared cotyledon” in a
monochorionic twin placenta with the twin-to-twin transfusion
syndrome

Fig. 69.16: Monoamnionic twin placenta with extensive Fig. 69.17: Drawing to show the set-up of the vascular
entangling of umbilical cords that led to fetal demise connections that lead to the development of an acardiac twin.
962 Textbook of Perinatal Medicine

the placentas may be closely packed and have no

blood vessel connections. They generally have
abnormal cord insertions and, depending on their
number, many are born prematurely. It has also been
our observation that frequently one or more of the
fetuses are surgically eliminated by KCl injection and
a fetus papyraceus is then found in the membranes
with a markedly atrophied placenta. What is amazing
in such specimens is the marked spiraling of their
cords, as this must have originated very early in
development. Finally, the placentas of such ART
pregnancies present challenging problems in that
more fetuses and placentas may be found than
embryos originally implanted into the uterus. Thus,
Fig. 69.18: Abortus with an excessively long and heavily twisted
monochorionic twins are admixed and can only be
umbilical cord and the even more excessive twisting on the
explained by assuming that one embryonic precursor abdominal surface of the fetus.
has split early in gestation. Perhaps the practice of
embryonic culture in vitro for several days is on the abdominal surface which must be observed to
responsible for this spontaneous MZ twinning event. understand this cause of embryonic demise.

ABORTIONS PLACENTAL AND FETAL HYDROPS

Spontaneous abortions are very common in human The placenta of hydropic fetuses is much enlarged
development they are much more common than in and most commonly it is very water-logged. The villi
most species that have been studied in detail. The vast are swollen and often contain prominent Hofbauer
majority occurs during the first 3 months of gestation cells (macrophages). There are many causes for
and the majority is due to chromosomal errors. hydrops and depending on their nature, the
Generally, a deformed or macerated embryo is found histopathology differs. In erythroblastosis and in the
on examination of the specimen but equally often, placentas of the fetal thalassemias, the capillaries
especially in the earliest abortions, the amnionic sac contain nucleated red blood cells in profusion; in
is empty and the fetal vasculature of the placenta has transplacental infection with parvovirus B19, one may
atrophied; these specimens are often referred to as find characteristically nuclear inclusion bodies that
“blighted ovum”. The placenta is otherwise atrophied are found most often within the nucleated red cells.
and may have focal hydatid changes of the villi. The But, at later stages, they may be inconspicuous and
trophoblast is unremarkable or atrophied. Occasional identification of the etiology of hydrops will
retroplacental hemorrhages accompany these commonly depend on serologic findings or on
specimens. A frequent cause of spontaneous abortion staining the tissue with specific antibodies. When the
is the presence of an excessive long umbilical cord hydrops is caused by fetal anomalies such as left heart
with severe twisting (Fig. 69.18). The causes of the hypoplasia, cystic adenomatous malformation of the
twisting and excessive length of the cord are unknown lung, sacrococcygeal teratoma etc., and then the
but I speculate that this is the result of excessive placenta is merely large, edematous and pale. Some
movements in early life. It often leads to severe of the other fetal conditions that lead to hydrops are
twisting on the surface of the umbilical cord insertion summarized below.
 The Placenta 963
MATERNAL AND FETAL DISEASES AFFECTING of recent origin, they still have fetal blood remaining
THE PLACENTA and they are red. As infarcts age, they lose the fetal
hemoglobin and become pale and, eventually white.
Preeclampsia They are firm and sharply delimited from the spongy
The cause of preeclampsia (or pregnancy-induced adjacent placenta tissue. In contrast to the more
hypertension – PIH) is still unknown, but speculations common marginal infarcts seen in normal placentas,
about its origin abound. Less controversial are the infarcts of PIH are distributed centrally. They also
placental sequelae in PIH. Generally speaking, the may surround focal intervillous thrombi which are
placenta is smaller and exhibits what is called characterized by a laminated appearance due to the
“advanced maturation”. This is a misnomer, however, “lines of Zahn” in a thrombus. The occlusion of
and merely applies to the histologic features of such maternal spiral arterioles also causes the degeneration
placentas as having smaller villi; they appear to be of decidua basalis and destruction of maternal veins.
more mature than would be expected at the usually This may lead to hemorrhages and the condition
immature gestational age. The villi are not only known as abruptio placentae (Fig. 69.20). While
smaller but also, they have less mesenchymal fluid abruption is commonest in PIH, it also can occur in
content. As a consequence, the superficial cover of traumatic injuries to the placenta. For instance,
trophoblast buckles and more “knots” or “sprouts” amniocentesis occasionally needs to be done by
of syncytium become apparent. This is referred to as trespassing the placental tissue and that can disrupt
the Tenney-Parker change after the first authors to major blood vessels. More common though is
describe this feature. This increased number of abruption of the placenta in automobile accidents, for
sprouts (more than 30% of terminal villi) also leads instance when a seat belt injures the pregnant uterus.
to their more frequent deportation in the maternal Very rarely an abruption was caused by external
circulation and was thus witnessed as a peculiarity version of a breech presentation thus it needs to be
of women dying in eclampsia as they had more such borne in mind that such can occur when versions are
elements in their pulmonary capillaries. attempted. It is not uncommon that small
Preeclampsia is associated characteristically with retroplacental hematomas are found on careful
the presence of “atherosis” in the maternal, decidual examination, especially adjacent to placental infarcts.
spiral arterioles. It is conceived that the normal When they are as large and sudden as shown in Fig.
transformation of these blood vessels does not occur 69.20, however, they are lethal for the fetus.
because of inadequate extravillous trophoblastic
infiltration in early development. The atherosis is
reasonably characteristic for PIH and may be found
in the decidua basalis and also (often easiest) in the
decidua capsularis of the membranes. But, not in all
cases of even severe PIH can one find this change; it
can also be associated with thrombosis. Atherosis
affects only the maternal arterial bed; it spares the
veins. Characteristically, it consists of the deposition
of foam cells (cholesterol-laden macrophages) in the
lumen and wall of the arterioles (Fig. 69.19). This
lesion may obstruct blood flow, as thrombosis would
also do and thereby lead to placental/fetal hypoxia Fig. 69.19: Atherosis in the spiral arteriole
and typically to placental infarcts. When infarcts are of a patient with severe pre-eclampsia
964 Textbook of Perinatal Medicine

in blood clot and it is occasionally accompanied by

inflammation. Also, because of insufficient
decidualization of the higher endocervical canal,
placenta previa is often associated with focal placenta
accreta.
When deeper infiltration of the myometrium by
placental tissue has occurred, we speak of placenta
Fig. 69.20: Abruptio placentae with fetal demise in increta and when it has penetrated, we refer to it as
preeclampsia. Not the compression of nearly one-half of the “placenta percreta”. These terms are frequently
placenta. Infarcts are also present. misinterpreted to mean that the placenta has actually
invaded the myometrium to destroy it and “grow
through the endometrium”, to emerge on the
One feature of placental infarcts differs from peritoneal surface. This is really true only of ectopic
infarcts occurring in other organs (e.g. the kidney), pregnancies in the fallopian tube. When they rupture,
namely the dead tissue does not become “organized” this is due to placenta percreta but primarily so
in the usual sense. That is to say, blood vessels from because there is only minimal or absent
the adjacent tissues do not enter the infarct and the decidualization, thus assuring that a placenta percreta
dead tissue is also not removed by macrophage can form; and because of the thinness of the tubal wall,
activity. rupture may occur when the conceptus enlarges. It
must be said, however, that ever so rarely a full term
Placenta Percreta gestation takes place in the tube. Moreover, all
It is normal for placentation that a small amount of abdominal implantations are placentas accreta and it
decidua basalis separates the villi from the is for that reason that the placenta will not detach
myometrium. It is not fully understood why it is that upon delivery. It has also recruited an enormous
the trophoblast stops invading or destroying the blood supply from the neighborhood.
endometrium at that point, as one can readily find Placenta percreta has become more common in
“X-cells” in the myometrium underlying most recent years and it is now often diagnosed
placental sites and they are found in myometrial sonographically. Virtually invariably this is the result
blood vessels beneath the placenta. Only when there of a prior Cesarean section. When the uterus is
is insufficient decidua present does the villous portion sutured, usually by a single layer of resorbable fibers,
of the placenta attach itself to the myometrium and the edges of the prior incision are poorly aligned and
then forms a placenta accreta. I believe that this occurs since there is no new growth of myometrium to
most commonly because prior disease (e . g . connect the edges, repair occurs by connective tissue.
tuberculosis or chronic endometritis) has destroyed When a new pregnancy takes place, this scar widens
the endometrium and endometrial repair does not and thins; when a placenta is attached directly over
take place by lateral growth of endometrium. Thus, the site, it may appear as though it has penetrated
when a placenta implants over a prior curettage site, the uterus, but that occurs only by separating the
the development of focal placenta accreta may occur. myometrial edges from the prior Cesarean section.
It is generally witnessed only by the disruption of the Thus, having implanted on connective tissue (instead
placenta floor when the placenta is examined or of the normal decidua), the placenta may even attach
clinically by postpartum bleeding. When thus itself to the posterior surface of the urinary bladder.
placental tissue remains attached to a focus of On occasion some bladder wall is removed at the
myometrium, a placental “polyp” may form that is excision of such specimens and it appears as though
composed of fragments of placental tissue enmeshed a true invasion has taken place. But that is no more
 The Placenta 965
than the usual infiltration of extravillous trophoblast syndrome. More important are fetal neuroblastoma
into the uterine musculature that occurs in all and sacrococcygeal teratoma; both may present as
pregnancies. In other words, while it is theoretically hydrops with typical swelling and edema of the villi.
possible that an occasional placenta may truly invade, In neuroblastoma, however, the neuroblasts are seen
the common placentas percreta are the result of to plug many capillaries and occasional rosettes may
insufficient healing of a prior section scar. It might be identified.
be mentioned parenthetically that, when a pathologist
has the opportunity to examine the hysterectomy REFERENCES
specimens of such percretas, the endocervical canal 1. Hertig AT. Human Trophoblast. Springfield: Charles C
is tough to cut, it is firmly closed, and it is filled with Thomas, 1968.
that sticky mucus that normally prevents ascending 2) Boyd JD, Hamilton WJ. The Human Placenta. Cambridge:
infection of the amnionic cavity. W Heffer, 1970.
3. Benirschke, Kaufmann P. The Pathology of the Human
Placenta, 4th edn. New York: Springer-Verlag, 2000.
Fetal Storage Diseases
4. Wigglesworth JS. Vascular anatomy of the human placenta
Numerous storage diseases of the fetus, the so-called and its significance for placental pathology. J Obstet
Gynaecol Br Commonw 1969;76:979.
“errors of metabolism”, affect the placental 5. Landing BH. Amnion nodosum: a lesion of the placenta
morphology. One of the first to be recognized was apparently associated with deficient secretion of fetal
“I-cell disease” in which the trophoblastic cells show urine. Am J Obstet Gynecol 1950;60:1339.
diffuse vacuolation. The same is true of many other 6. Benirschke K. Recent trends in chorangiomas, especially
those of multiple and recurrent chorangiomas. Pediatr
storage diseases and, to differentiate among them, it Developm Pathol 1999;2:264.
is necessary to undertake enzyme studies. Fetal 7. Guschmann M. Solitary and multiple chorangiomas –
leukemia occurs occasionally and can be recognized clinical consequences, expression of growth factors and
differences in the growth rate. Z Geburtsh Neonatol
by the circulating nucleated cells but care must be
2003;207:6.
taken not to over-interpret these as they may be 8. Kajii T, Ohama K. Androgenetic origin of hydatidiform
transitory phenomena for instance in Down’s mole. Nature 1977; 268:633
 70
Clinically Significant
Pathology of the Placenta

Beata Hargitai, Tamas Marton

INTRODUCTION PLACENTA REFERRAL TO THE

HISTOPATHOLOGY LABORATORY
Histopathological examination of the placenta can
contribute to determine the causes of fetal demise, The increased workload of perinatal pathology
growth restriction, or neonatal condition. Recently departments would not allow examination of all
several guidelines1-3 and books have been published placentas, which is not even necessary, except those
in the subject of placenta pathology.4,5 The ever- well defined conditions when placenta referral is
growing evidence based knowledge requires indicated. This “minimal list” can be extended in
recapitulation of the clinico-pathologic correlation. selected centres with specific research project. Referral
The benefits of placenta examination include is decided at the delivery suit. The indications of
recognition of maternal conditions having effect on placenta referral are as follows1:
subsequent pregnancies (autoimmune disease,
Fetal conditions, when referral is indicated: IUGR
antiphospholipid syndrome, thombophylia) or may
have medico-legal implications (e.g. concerning the (birthweight below 2.5 kg or 3rd centile), prematurity
aetiology of long-term neuro-developmental sequelae (less than 37 weeks gestation), placental abruption,
or the approximate timing of an intrauterine death.6,7 fetal hydrops, fetal developmental abnormality,
Timing of the lesions and fetal damage can be chromosome aberration, stillbirth, severe fetal distress
estimated and possibly vital clues obtained concern- requiring admission to NNU, Rhesus (and other)
ing the aetiology of the fetal or neonatal condition. isoimmunisation, morbidly adherent placenta, twins
Many features of the placenta can be judged only in / other multiple pregnancy (complicated or uncom-
the clinico-pathological context, partly because of the plicated), abnormal placental shape (if clinically
occasionally loose correlation between the histological relevant, including placental tumours) or other
changes and the clinical symptoms and partly because postnatally diagnosed disorders of the placenta
of the large reserve capacity of the placenta. It is also (haematoma, too large or too small placenta,
apparent that satisfactory clinical information infarction, discoloration of membranes), umbilical
improves the rate of recognised histological features, cord, containing two vessels, Premature Rupture of
which underlines the importance of the submitted Membranes (PROM) (more than 36 hours).
clinical information to the pathologist.8 Diseases of the neonate with possible IU origin
This chapter attempts to highlight clinico- include neonatal infection (Pneumonia, or sepsis
pathological associations bearing great importance in within 72 hours) and neonates with neurological
the everyday obstetrical and neonatal care. signs.
 Clinically Significant Pathylogy of the Placenta 967
It is also recommended to examine the placentas THE NORMAL PLACENTA
from pregnancies with maternal diseases that might
Normal human placenta has a range of features that
have consequences in the neonate. These are, maternal
are dependent on many factors including maternal
pyrexia and maternal group B streptococcus, pre-
size, ethnic origin, geographic area, age, parity etc.
eclampsia, hypertension, severe diabetes, including
All placentas are examined at the delivery suit
gestational diabetes, maternal thrombopathies-
after birth macroscopically.
thrombophilias, other metabolic disease, maternal
The membranes can loose the transparency,
autoimmune disease, maternal tumour and storage
become mat/murky and thickened in chorio-
disease.
amnionitis, subchorionic haemorrhage. Small, white-
Generally referral is NOT indicated for chole-
grey granular nodules appear in oligohydramnios
stasis of pregnancy (with no further complication),
and this alteration is referred as amnion nodosum,
Hepatitis B, HIV infection (seropositivity with no
can be mixed up with squamous metaplasia
manifest disease), other maternal disease with normal
macroscopically, but the latter is a normal variant.
pregnancy outcome, normal pregnancy, placenta
Circumvallate placenta presents with a yellow-
praevia, post partum haemorrhage.
whitish rim on the fetal surface. The significance of it
In the pathology laboratory placentas are selected for is uncertain, some correlate it with IUGR.
pathologic examination: A full examination of the The normal placenta is ovoid, and the fetus/
placenta includes macrosocopic and histological placenta weight ratio ~ 7 at term, growing gradually
examination of representative samples of the placenta, from 1 at 14/40 weeks of gestation. Normal thickness
membrane and umbilical cord. The indications for is approximately 1.5-2.5 cm. Irregular placental shape,
examination of the placentas are as follows1: multilobed placenta can be a sign of disturbed
Rhesus isoimmunisation with admission to the implantation, or developmental abnormality of the
neonatal unit, in any intrauterine death/stillbirth uterus. The placenta weight correlates with the fetal
(even if a post mortem examination of the baby does weight and a small placenta is prone to result in
not take place), anaemia requiring intrauterine placenta insufficiency and subsequent fetal demise.
transfusion, morbidly adherent placenta, maternal Large placenta is usually associated with fetal
pyrexia, neonatal infection, prematurity (<34weeks overgrowth syndromes and genetic disorders
and not PET/IUGR), severe fetal distress, any (Beckwith-Wiedeman syndrome, Congenital
admission to the neonatal unit, IUGR, prematurity nephrosis syndrome of the fetus). Other underlying
(<34weeks) due to PET/IUGR, severe PET, abruption, conditions are maternal diabetes, maternal and fetal
hydrops and fetal anomaly. The goal in this group is anaemia, and feto-placental hydrops.9
to demonstrate the placental consequences of the The fetal surface has to be searched for vessels
clinical condition, in other instances to identify the leaving the disc, but not returning to it, because that
aetiology. can be a sign of a retained cotyledon. Generally the
The rest of placentas belong to a risk group for fetal surface reflects the changes that can be seen in
neonatal disease, so storage is recommended (in the membrane or on the subchorionic surface. The
unfixed state, for 2 weeks, 4°C, urgent examination colour of the normal placenta varies between red and
on clinical request). These placentas are from dark red, which depends on the time of clipping the
pregnancies with PROM, prematurity (34-36 weeks), umbilical cord. In a normal placenta palpation is
uncomplicated gestational diabetes, Rhesus negative spongy and homogenous, does not suggest any focal
mother, maternal group B streptococcus and lesions (except for small, peripheral infarcts or
uncomplicated pre-eclampsia. perivillous fibrin deposition in term placentas).
968 Textbook of Perinatal Medicine

After turning the placenta, the maternal side has frequently observed placental features were increased
to be checked for completeness. The umbilical cord placental weight, overcoiled cord, true knots and
length is 40-70 cm at term, with one coil over 5 cm in congestion. Cord prolapse causing fetal distress
average.10 The normal umbilical cord has 3 vessels occurred also more often with a long umbilical cord.11
and is inserted on the placental disc, preferably in Marginal cord insertion shows correlation with
central or paracentral position. IUGR, still birth, neonatal death, premature birth, low
birthweight. A possible explanation is that a disturbed
Twin Placentas implantation is behind the atypical cord insertion. The
It is essential to determine the chorionicity of twin same is true for velamentous cord insertion.
placentas, because of the increased morbidity and Over- or undercoiling of the cord has an increased
mortality rate of the monochorionic gestation. The risk for fetal demise, fetal intolerance to labour, IUGR,
commonest type is the dichorionic placenta. It can chorioamnionitis. 10 It is apparent that extremely
have both a single disc (either fused or non- overcoiled umbilical cord has an elevated vascular
separated), or two separated discs. While dichorionic resistance and vascular obstruction is often behind
twins can be both di- and monozygotic, mono- the fetal loss in these cases.
chorionic twins are always monozygotic. Mono- A true knot can cause fetal death (associated with
chorionic, diamniotic twins represent the second most perinatal mortality of 10%), whereas loose knot per
frequent twinning. There is always a single placenta se does not cause harm to the fetus. (Fig. 70.1.) Long
disc. Chorionicity can be easily identified with the umbilical cord is a risk factor of both knot and
help of two forceps’s: The septum needs to be increased coiling.
separated into two layers. In case of two thin, equally Single umbilical artery12 has an association with
translucent webs the twin placenta is monochorionic, fetal malformation chromosome aberration in 25-50%.
whereas in uneven separation, having one smooth, In normally formed infants IUGR is frequent and
opaque, thin layer and a thicker one with uneven there is also an increased perinatal mortality.
surface, the pregnancy is dichorionic. Thrombosis of the umbilical vessels has a very
The rarest finding is the monochorionic, mono- poor prognosis4, but survival can also occur.
amniotic twin placenta (with a single placenta disc). Beside the well known consequences of
intrauterine infection (see the paragraph below),
CLINICOPATHOLOGICAL CORRELATIONS umbilical cord vessel vasculitis and funisitis are
associated with cord vessel thrombosis and
Umbilical Cord vasospasm of cord vessels.5 Necrotising funisitis is
The umbilical cord is short by definition, if measures
less than 40 cm. Short umbilical cord carries and
increased risk for fetal/neonatal morbidity or
mortality and there is an increased rate of
neurological abnormality. The cord is considered to
be long, if it is longer than 70 cm. Long umbilical cord
has a correlation with maternal factors, such as
systemic diseases, delivery complications and
increased maternal age. According to Baergen et al.,
fetal factors included non-reassuring fetal status,
respiratory distress, vertex presentation, cord
entanglement, male sex, increased birth weight. Other Fig. 70.1: Tight knot of the umbilical cord.
 Clinically Significant Pathylogy of the Placenta 969
usually seen with acute chorioamnionitis. Candida,
Streptococci, Herpes and Syphilis are reported to play
role in the pathogenesis of necrotising funisitis. (Fig.
70.2.)4

Membranes
Acute chorioamnionitis (including “subchorial
intervillositis”) has a strong association with
premature rupture of the membranes and preterm
delivery.13 Fetal intrauterine infection may occur. Fig. 70.2: Necrotising funisitis. See the whitish necrotic
Maternal pyrexia and tachycardia are described as areas in the umbilical cord.
maternal effects, but may be asymptotic. Recently
chorioamnionitis has been implicated as a risk factor
for periventricular leukomalacia and cerebral palsy.14 intervillous fibrin deposition, villitis of unknown
Chronic chorioamnionitis has been observed in origin and trisomies. 9 Placental weight shows
prolonged rupture of membrane and Herpes virus correlation with the fetal weight, a small fetus has
infection.4 generally smaller placenta than a large fetus, but a
Amnion epithelial vacuolization can be artifact, small placenta may lead to growth restriction.
but lipid containing droplets in the epithelium are The placenta is thin (the medical term is: Placenta
specific for gastroschisis.4 annulare or placenta membranacea) by definition if
In contrast to the common belief pigmented the average thickness is less than 2 cm and the
macrophages and the presence of meconium staining placenta has a large membranous area. While the fetal
are not necessarily associated with adverse fetal outcome is usually favorable, there is a risk of
outcome. Meconium staining indicates the danger of maternal bleeding, placenta praevia, placenta accreta.
meconium aspiration and with other histologic signs Often premature delivery occurs and possibly it is
of fetal distress may underline the diagnosis. more frequent in IUGR.16
Vasospasm of cord vessels and fetal chorionic vessels The haemorrhages of the placenta include
are reported as a consequence of meconium retroplacental haematoma. A large retroplacental
exposure.15 haematoma causes a crater (Fig. 70.3.) and extensive
Acute and chronic deciduitis, decidual necrosis in infarction involving sufficient proportion of villous
the parietal decidua are frequently associated with tissue with secondary fetal hypoxia and/or perinatal
ascending infiltrations of the placental membranes, death. An early separation (placental abruption) can
may be non-significant in isolation. In retroplacental be lethal if extensive. An elevated maternal serum
haematoma severe, necrotising acute deciduitis is a AFP level can be associated with old haematomas.
common finding. The significance of chronic Subchorionic haematoma (Fig. 70.4.) usually has
deciduitis with scattered infiltration of lymphocytes no clinical significance when patchy, focal or present
is uncertain.4 as a thin diffuse layer. Although rarely, in extreme
cases, a massive haematoma (massive subchorial
Placenta thrombosis, Breus’ mole) can result in abortion.
Placenta praevia is usually diagnosed by
Macroscopic Alterations of the Placenta
ultrasound before delivery. If undetected and causes
Low placenta weight, below 10th centile for gestational bleeding, it can be life threatening for both mother
age occurs in IUGR, pre-eclampsia, increased and fetus.
970 Textbook of Perinatal Medicine

Fig. 70.4: Lamellated subchorionic haematoma can be

seen on the fetal surface of this placenta
Fig. 70.3: The crater in the middle of the placenta was
caused by a retroplacental haemorrhage
be extremely elevated.17,18 There are two special
patterns of the fibrin deposition: Massive basal
Placenta accreta, increta and percreta are plate perivillous fibrin deposition is termed as
potentially life threatening clinical conditions, causing “Maternal floor infarct” and known to be
uterine rupture, and massive postpartum associated with high mortality and IUGR.4,5,19,20
haemorrhage, or leading to caesarean section if The massive perivillous fibrin deposition in a
prenatally diagnosed. Placenta creta is often an netlike pattern (Figs 70.6A and B) is the “Gitter
indication of postpartum hysterectomy because of the infarct”. “Gitter infarct” and “Maternal floor
excessive bleeding. To make the pathologic diagnosis infarct” are historical names, none of them a true
of a placenta accreta, examination of the entire uterus infarct, but a special type of perivillous fibrin
is necessary as a post hysterectomy specimen. deposition.
3. Abnormalities of the fetal vessels: Fetal chorionic
Microscopic Alterations of the Placenta
vessels and fetal stem vessels of the placenta may
Abnormalities of the placental chorionic villi, the contain fresh or organized thrombus. The
intervillous space and chorionic vessels that result in organized thrombus can calcify, or contains small
a reduced functional capacity of the placenta: vascular spaces if recanalised. Obstruction of fetal
1. A placental infarct (Figs 70.5A and B) has no vessels (Fig. 70.7) is associated with groups or
significance if it is single, marginal and/or fields of hyalinized, avascular villi. These villi can
involves less than about 5% of the villous tissue. not take apart in the blood gas exchange for the
If a placental infarction involves more than 10% complete lack of capillaries. Presence of extensive
of the placental volume is regarded as extensive avascular villi (Fig. 70.8), due to fetal vessel
infarct and can have serious clinical consequences thrombosis, was reported in association with
such as fetal hypoxia, IUGR, stillbirth, pregnancy stillbirth, IUGR, maternal and fetal coagulopathy
induced hypertension, abruptio placentae, and fetal thromboembolic disease leading to
neurological abnormalities because of the reduced cerebral palsy.7 Intimal fibrin cushion, a non-
size villous tree.4 symmetric intimal swelling with endothelial
2. Extensive perivillous fibrin deposition, involving disruption, is described in neonatal asphyxia, in
more than 20-30% of the villous tissue and association with disseminated capillary thrombi
functional placenta, is an important histological of fetal vessels. The severity of the fetal
entity, associated with IUGR and fetal death. In consequences depends more on the accompanying
these cases often 70-80% of villous population is vascular lesions, mainly on fetal vessel
enveloped by fibrin. The maternal serum AFP can thrombosis.15 If there are large areas of avascular
 Clinically Significant Pathylogy of the Placenta 971

A B
Figs 70.5: Multiple fresh infarcts in a term placenta A: Macroscopic picture; B: Microscopic image representing necrotic villi

A B
Fig. 70.6: Netlike fibrin deposition in the placenta A. Macroscopic picture;
B. Microscopic image shows villi entrapped by fibrin

Fig. 70.8: A group of avascular villi around a stem villus.

Fig. 70.7: Stem vessel occlusion The stem villi show haemorrhagic endovasculitis.
972 Textbook of Perinatal Medicine

villi, the prognosis is dependent on the proportion may be due to reduced fetal perfusion and
of the placenta as described above. placental hypoxia or can be the sign of accelerated
Haemorrhagic endovasculitis (HEV) is a maturation if the duration of pregnancy was less
controversial entity, which was reported to be a than 40 weeks.
post-mortem artifact and was doubted as being a 2. Elevated number of nucleated red blood cells
specific disease. The histological appearance is (NRBC-s) may occur in many causes of chronic
characterized by thrombotic-recanalised stem hypoxia (Fig. 70.9.), IUGR, stillbirth, acute and
vessels and extravasated, fragmented red blood chronic fetal blood loss or anaemia, maternal
cells. HEV was found to be associated with diabetes and erythroblastosis fetalis.4
meconium staining and postmaturity. Earlier 3. An increase of VSM (vasculo-syncytial membrane)
report revealed association with stillbirth, IUGR, is described in pregnancies at high altitude, pre-
neurological disability, maternal hypertension. eclampsia, maternal heart failure, and maternal
HEV was reported also in livebirths, associated anaemia. VSM deficiency was reported in pre-
with perinatal complications, fetal distress and eclampsia, materno-fetal rhesus incompatibility,
IUGR. Interlesional relationships exist between maternal diabetes, low birth weight and
thrombotic, chronic inflammatory and chronic stillbirths.4,5
vaso-occlusive lesions.4 4. Extensive stromal fibrosis occurs in terminal
4. Most frequently intervillous haemorrhage and villous deficiency, in IUGR, and in avascular villi
thrombus are related to maternal vessel lesion and due to fetal stem vessel thrombosis.
is of maternal origin. Small and focal lesions have 5. Placentas from pregnancies with hydrops fetalis
no clinical importance. Large and multiple lesions may show a combination of immaturity and
may cause fetal compromise or demise depending oedema. Villous oedema occurs also in infections
on the functional placenta parenchyma loss and (Syphilis, CMV, Toxoplasma, Parvovirus) (Figs
the rest of the unaffected placenta. Quite often it 70.10A and B) and in hydatidiform moles. Oedema
can be seen in preeclamsia and is surrounded by may be within normal limits, when focal.4
infarct as a rim. In some cases intervillous 6. A failure of villous maturation was found to be
haemorrhage and thrombus is sign of fetal associated with fetal hypoxia, IUGR, maternal
bleeding into the maternal circulation as described diabetes and materno-fetal Rhesus
by Kline. Only a minority of these alterations lead incompatibility. Maturation failure may lead to
to large amount of fetal blood loss and stillbirth intrauterine death.5,21
or severe anaemia followed by ischaemic lesions
of parenchymal organs.
Changes of the chorionic villi secondary to
preeclampsia, intrauterine hypoxia, or fetal conditions
and maternal spiral artery changes:
1. Increased number of syncytial knots occurs in
preeclampsia, hypertension, diabetes mellitus,
maternal anaemia, pregnancy at high altitude. It
can also be seen in a thick histologic section
(artifact). Despite of the fact that it occurs in
preeclampsia, correlation between increased
syncytial knotting and fetal hypoxia has not been
proved. Excessive increase of syncytial knotting Fig. 70.9: Nucleated red blood cells in a terminal villus.
 Clinically Significant Pathylogy of the Placenta 973

A B
Fig. 70.10: Placenta oedema A. Macroscopic picture- the placenta bulky. B. Oedematous terminal villi

7. Accelerated villus maturation (maturitas praecox)4 associated with IUGR and preterm birth, and tends
can be observed in prematurely delivered to recur during subsequent pregnancies.4
placentas in pre-eclampsia and the features are 3. Chronic histiocytic intervillositis, (chronic
related to chronic ischaemia. perivillositis) is characterized by dense histiocytic
8. Abnormalities of the maternal vessels are usually intervillous infiltrate, and is reported in association
associated with preeclamptic toxaemia. with elevated maternal serum AFP, recurrent
Uteroplacental or decidual arteriopathy is a abortion, IUGR, preterm delivery. Malaria
failure of physiological adaptation of maternal infection should be excluded.23
vessels. Uteroplacental vessel fibrinoid necrosis, Miscellaneous conditions of the chorionic villi:
acute atherosis and uteroplacental vessel 1. Mesenchymal dysplasia is the hallmark of
thrombosis is closely related with pregnancy Beckwith-Wiedeman syndrome.24
induced hypertension, maternal essential
hypertension, pre-eclampsia and resulting in fetal
complications such as IUGR, SGA, stillbirth. It is
associated with APA, SLE and thrombophilia.4,5,22
Inflammatory processes involving the placental villi
or intervillous space
1. Acute villitis is usually associated with severe
maternal infection, preterm delivery and might
lead to intrauterine infection and IUD.4
2. The etiology of chronic villitis is usually not
known (villitis of unknown origin, VUO or villitis
of unknown etiology, VUE). (Fig. 70.11.) In about
15% of cases CMV, toxoplasma, syphilis infection
is the underlying cause of chronic villitis. Fig. 70.11: Villitis of unknown etiology (VUE). Chronic
Chronic villitis is associated with IUGR and/or inflammatory cells infiltrate the villus, the chorionic epithelium
stillbirth. Chronic villitis of unknown etiology is is damaged.
974 Textbook of Perinatal Medicine

2. Perinatal death and congenital malformation and CONCLUSION

cerebral palsy were found to be associated with
In conclusion we would like to emphasis the
chorangiosis as a response to low-grade tissue
importance of placental referral to the pathology
hypoxia. Although others have supported this
laboratory and the placenta examination. We also
observation, it still remained a question how does
would like to encourage communication between
the chronic hypoxia result in increased
clinicians and pathologists to discover further clinico-
vascularisation. The significance of this alteration
pathological correlations for the benefit of the
needs further investigation.25
patients.
3. Chorangioma is a tumour-like lesion, resembling
infantile haemangiomas. (Fig. 70.12.) It is most REFERENCES
likely of hyperplastic origin, arising from the
1. Hargitai B, Marton T, Cox PM. Examination of the human
subtrophoblastic reticular tissue of the immature placenta. Best practice No 178. J Clin Pathol 2004;
stem villi. Large lesions can lead to cardiac failure, Accepted.
hydrops and death of the fetus due to high output 2. Khong TY. A topographical and clinical approach to
cardiac failure. Other possible complications are examination of the placenta. Pathology 2001; 33(2):174-
186.
transplacental bleeding, and fetomaternal 3. Langston C, Kaplan C, Macpherson T, Manci E, Peevy K,
transfusion leading to anaemia. Chorangioma was Clark B et al. Practice guideline for examination of the
reported to be associated with pre-eclampsia, placenta: developed by the Placental Pathology Practice
Guideline Development Task Force of the College of
multiple gestation, premature delivery, fetal
American Pathologists. Arch Pathol Lab Med 1997;
thrombocytopenia and fetal angiomas (Kasabach- 121(5):449-476.
Merritt syndrome).4 4. Benirschke K, Kaufmann P. Pathology of the human
4. Umbilical cord haemangioma is a rare entity and placenta. 4 ed. New York, Berlin, Heidelberg: Springer-
Verlag, 1999.
its complications are related to the size of the 5. Fox H. Pathology of the placenta. 2 ed. London,
lesion. It can be associated with elevated AFP level, Philadelphia, Toronto, Sydney, Tokyo: W.B. Saunders
fetal DIC, fetal hydrops as well as fetal demise Company Ltd, 1997.
have been described.26 6. Altshuler G. Placenta within the medicolegal imperative.
Arch Pathol Lab Med 1991; 115(7):688-695.
7. Kraus FT. Cerebral palsy and thrombi in placental vessels
of the fetus: insights from litigation. Hum Pathol 1997;
28(2):246-248.
8. Redline RW, Boyd T, Campbell V, Hyde S, Kaplan C,
Khong TY et al. Maternal vascular underperfusion:
nosology and reproducibility of placental reaction
patterns. Pediatr Dev Pathol 2004; 7(3):237-249.
9. Naeye RL. Do placental weights have clinical significance?
Hum Pathol 1987; 18(4):387-391.
10. Machin GA, Ackerman J, Gilbert-Barness E. Abnormal
umbilical cord coiling is associated with adverse perinatal
outcomes. Pediatr Dev Pathol 2000; 3(5):462-471.
11. Baergen RN, Malicki D, Behling C, Benirschke K.
Morbidity, mortality, and placental pathology in
excessively long umbilical cords: retrospective study.
Pediatr Dev Pathol 2001; 4(2):144-153.
12. Chow JS, Benson CB, Doubilet PM. Frequency and nature
of structural anomalies in fetuses with single umbilical
arteries. J Ultrasound Med 1998; 17(12):765-768.
13. Gibbs RS, Romero R, Hillier SL, Eschenbach DA, Sweet
Fig. 70.12: Microscopic appearance of chorangioma with RL. A review of premature birth and subclinical infection.
small capillary-like vessels and sinusoids. Am J Obstet Gynecol 1992; 166(5):1515-1528.
 Clinically Significant Pathylogy of the Placenta 975
14. Wu YW, Colford JM, Jr. Chorioamnionitis as a risk factor 21. Stalmach T, Hebisch G, Meier K, Dudenhausen JW,
for cerebral palsy: A meta-analysis. JAMA 2000; Vogel M. Rescue by birth: defective placental maturation
284(11):1417-1424. and late fetal mortality. . Obstet Gynecol 2001; 97(4):505-
15. Altshuler G. Some placental considerations related to 509.
neurodevelopmental and other disorders. J Child Neurol 22. Magid MS, Kaplan C, Sammaritano LR, Peterson M,
1993; 8(1):78-94. Druzin ML, Lockshin MD. Placental pathology in systemic
16. Ahmed A, Gilbert-Barness E. Placenta membranacea: a lupus erythematosus: a prospective study. Am J Obstet
developmental anomaly with diverse clinical presentation.
Gynecol 1998; 179(1):226-234.
Pediatr Dev Pathol 2003; 6:201-203.
23. Boyd TK, Redline RW. Chronic histiocytic intervillositis:
17. Redline RW, O’Riordan MA. Placental lesions associated
a placental lesion associated with recurrent reproductive
with cerebral palsy and neurologic impairment following
term birth. Arch Pathol Lab Med 2000; 124(12):1785-1791. loss. Hum Pathol 2000; 31(11):1389-1396.
18. Görbe É, Rigó JJr, Marton T, Kõhalmi B, Csabay L, Csapó 24. Jauniaux E, Nicolaides KH, Hustin J. Perinatal features
Zs. Maternal floor infarct”, gleichzeitiges Auftreten von associated with placental mesenchymal dysplasia.
intrauteriner Fetusretardierung und hohem mütterlichen Placenta 1997; 18:701-706.
AFP-Spiegel. Z Geburtshilfe Neonatol 1999; 203(5):218- 25. Altshuler G. Chorangiosis. An important placental sign
220. of neonatal morbidity and mortality. Arch Pathol Lab Med
19. bane AL, Gillan JE. Massive perivillous fibrinoid causing 1984; 108(1):71-74.
recurrent placental failure. BJOG 2003; 110(3):292-295. 26. Kamitomo M, Sueyoshi K, Matsukita S, Matsuda Y, Hatae
20. Naeye RL. Disorders of the placenta, fetus and neonate: M, Ikenoue T. Hemangioma of the umbilical cord: stenotic
Diagnosis and clinical significance. St Louis: Mosby Year change of the umbilical vessels. Fetal Diagn Ther 1999;
Book, 1992. 14(6):328-331.
 SECTION 8
Fetal Diagnosis and Therapy
W Holzgreve, M Evans
978 Textbook of Perinatal Medicine
 Non-Invasive Prenatal Diagnosis of the Maternal Blood 979

71Non-Invasive Prenatal Diagnosis of the

Maternal Blood: Further Improvements
for the Clinical Everyday Life
Olav Lapaire, Bernhard Zimmermann, Xiao Yan Zhong,
Sinuhe Hahn and Wolfgang Holzgreve

ABSTRACT age distribution of the studied population. Down

One of the major topics of prenatal research today is the syndrome is the most common chromosome
genetic analysis of fetal cells or fetal DNA / RNA, which can abnormality among live births and is the most
be accumulated from the blood of pregnant women. It is the frequent form of mental retardation caused by a
intention of the clinician and scientists of the laboratory to chromosomal aberration. Prenatal protocols for
offer a risk-free diagnostic method for pregnant women in
order to reduce the number of invasive interventions (e.g. Down syndrome screening have been introduced for
amniocentesis (AC), chorionic villi sampling (CVS)) and the several reasons:
procedure related risk of fetal loss, as well as to provide • Trisomy 21 has a high prevalence (1 in 700 births
additional new markers in prenatal screening programs. Up in the absence of prenatal intervention)
to now the technical problems of cell enrichment have
prevented a routine use of fetal cell sampling in the clinics. In • The morbidity and mortality in affected fetuses
contrast, fetal cell-fee DNA in maternal plasma can now be and the consecutive socio-economic burdens
used for the extremely reliable identification of fetal genetic • The area-wide availability of diagnostic tests to
traits, clearly distincted from maternal sequences (e.g. the fetal detect this chromosomal abnormality
rhesus status) or inherited polymorphism. Only recently, a
new field of investigation has been opened by the • The availability all over the country of safe and
demonstration of the cell free form of fetal RNA in maternal accessible interventions to introduce abortions of
plasma, which is surprisingly stable and holds promise for affected fetuses.
non-invasive screening for fetal aneuploidies or pregnancy
There is the existent desire of the society for Down
associated disorders.
syndrome screening to be done as early as possible
in pregnancy, despite of the effectiveness of second
INTRODUCTION
trimester serum screening. First or early second
A routine clinical prenatal diagnosis with a view to trimester diagnosis of fetal abnormalities allows
identify fetal genetic disorders started in the1970’s. more time for decision making, greater privacy (the
Since its inception, the reason for prenatal diagnosis neighbourhood may not be aware of the pregnancy),
is the detection of fetal aneuploidy and and, if chosen by the couple, safer methods of
malformations. The overall risk of fetal chromosomal pregnancy termination. However, a number of issues
disorders is continuously rising due to the increasing must be addressed before earlier screening can be
average age of pregnant women in the western offered on a general population basis. These issues
world, especially in Europe. The maternal age alone include the availability and acceptability of early
as a screening marker has a low sensitivity of 30- invasive diagnostic methods (e.g., chorionic villus
40% for trisomy 21 (M. Down), dependent on the sampling1), and clinical effectiveness.
980 Textbook of Perinatal Medicine

Three screening markers, two serum, and one fetal villus sampling, depending on the routine of the
ultrasound marker have been shown to be performer and of the location of the placenta.
effective for first trimester screening for Down However, due to the procedure related risk of fetal
syndrome.2, 3 The two serum markers in combination loss, that is estimated to be 0.5-1% of all interventions,
with the maternal age constitute a first trimester a rising percentage of pregnant women opt not to
maternal serum screening test that achieves a have any invasive diagnostic procedures. Thus, the
senitivity of 63 percent at a 5 percent false positive rate of procedure-related unaffected fetal loss is
rate. 4 estimated to be 44-45 per 100,000 women screened
An improved performance can be attained by the when either first trimester screening (NT, free beta-
addition of sonographic analysis for increased fetal hCG, and PAPP-A) or a second trimester quadruple
nuchal translucency (NT). NT by itself is a strong test has been performed.
marker of Down syndrome and is associated with For that reason international projects in the field
detection rates between 60 to 70 percent at a 5 percent of prenatal medicine research for effective, risk free
false positive rate.5 When it is combined with the and reliable alternative methods and additional
pregnancy associated plasma protein A (PAPP-A), markers. Object of the research is to obtain fetal
free beta-hCG and the maternal age, an overall tissue, either with the enrichment of fetal cells or
sensitivity rate of approximately 85 percent at a 5 cell-free DNA and recently, RNA, extracted from
percent false positive rate can be obtained.6-8 the maternal blood. Fetal cells have been found in
The combination of serum and ultrasound markers the maternal blood, though in very low quantity.
at the end of the first trimester is better than any of Therefore the primary step was their detection,
the second trimester serum tests, that are nowadays enrichment, and characterisation with molecular-
available and, at least in a hypothetical model, are biologic methods.12 Beside fetal cells, also fetal cell-
more cost effective (screening plus liveborn costs).9 free DNA and as mentioned above, fetal RNA,
However, the performance of NT as a screening independent of fetal gender and genetic poly-
marker has not been consistent from study to study, morphismus status, was found in the maternal
probably because of the variability of operator’s plasma. With the progress in prenatal research and
expertise and different qualities of the equipment.10 technical advances, some results of non-invasive
Further studies as well as proper training and prenatal medicine research have already come into
ongoing quality management are necessary before a the clinical setting: as a diagnostic tool, fetal DNA,
noncritical widespread use of this screening regimen extracted from maternal plasma can now be used
can be implemented.11 for the extremely reliable identification of fetal
In case of a suspicious result (in Switzerland: genetic traits, that are absent in the maternal genome
overall risk for trisomy 21 > 1:380), an invasive (e.g. the fetal rhesus status or patients with an
testing, either with AC or CVS, is advised during a elevated risk for x-chromosomal inherited disorders
profound genetic counselling. Amniocentesis is the (e.g. haemophilia, fragile x-syndrome).
commonly used ultrasound guided technique for To examine fetal DNA, nowadays a polymerase
withdrawing amniotic fluid from the uterine cavity, chain reaction (PCR) is normally used for the first
using a needle via a transabdominal approach. step in the vast majority of DNA analyses. In a few
Chorionic villus sampling refers also to the invasive hours, an automated PCR can amplify a single DNA
procedures for prenatal diagnosis of genetic molecule a million-fold. The greatly amplified target
disorders, in which small specimens of the placenta DNA is subsequently analysed via other techniques.
are achieved for chromosome or DNA analysis. Two The recent detection of fetal RNA in the plasma
approaches are available for obtaining chorionic of pregnant women, has led to new opportunities.
tissue: a transcervical or a transabdominal chorionic Unlike fetal DNA, quantitative analysis of fetal RNA
 Non-Invasive Prenatal Diagnosis of the Maternal Blood 981
with PCR methods has the advantage of being maternal serum. It could be shown, that only 2-6 cells/
applicable to all gravidae, irrepective of fetal gender millilitre of maternal blood are present.15 Fetal cells
and genetic polymorphism.13 can be found in the blood of pregnant women from
To analyse fetal RNA, a reverse-transcriptase the first trimester on. However, a rapid, simple and
polymerase chain reaction (RT-PCR) is used for consistent procedure for their isolation for prenatal
transforming messenger RNA (mRNA) into non invasive testing has not been found. Almost any
complementary DNA (cDNA) by an RNA-dependent procedure available in experimental cell research for
DNA polymerase, specified as reverse transcriptase. cell enrichment has been used to isolate fetal cells
The cDNA complex is then changed into a double- out of maternal blood. For the multi step enrichment,
stranded DNA, and becoming so the template for a the density gradient centrifugation is always used
subsequent PCR reaction. as the first step16, fluorescent activated cell sorting
The main source of fetal RNA is thought to be (FACS))17, or magnetic activated cell sorting (MACS),
the Placenta. Fetal RNA is surprisingly stable in the see Fig. 71.1)18 follow as second step. A major effort
maternal plasma. Data indicate, that the measurement has been made during the last years to standardise
of circulating placental RNA may provide a new and validate these processes among different
method for noninvasive prenatal diagnosis and laboratories.
monitoring. The futural clinical application of this The latter method is easy to perform and has a
technology would be the application of RNA as an higher turnover of samples, as well as a higher
additional screening tool for chromosomal sensitivity than FACS (see Fig. 71.2). The third step
aneuploidies and other pregnancy associated includes either fluorescent in situ hybridisation,
disorders. culture or PCR. However, the cell culture, with or
without enrichment, as well as the multi-step
NON-INVASIVE CLINICAL DIAGNOSTICS USING enrichment procedure itself require many mani-
FETAL CELLS IN MATERNAL BLOOD SAMPLES pulations in which a certain amount of cells are lost.
A long sought goal of prenatal medicine has been New methods, such as automatic scanning are needed
the reduction of invasive diagnostic procedures for to install the cell enrichment in the routine clinical
fetal cell sampling, and its procedure related risk of use. Different populations of fetal cells can be
miscarriage, by isolating fetal cells from the maternal enriched from the maternal blood, CD 34+ hemato-
blood. poietic progenitor cells and cells from the trophoblast
In the 90ies of the last century, for the first time are used.19 Each of these cell lines has some specific
successful enrichment of fetal cells, extracted from disadvantages. For example it is not possible to
maternal blood, was published. The cells could be
checked for possible aneuploidies by fluorescent in
situ hybridisation (FISH). 14 FISH can identify
different chromosomal mutations including
deletions, duplications, aneuploidy and the presence
of derivative chromosomes. However, small
mutations, including small deletions and insertions
as well as point mutations, cannot be identified with
the FISH technique. When the DNA probes are
designated with a fluorochrome, a fast detection of
the fluorescent signal is possible via fluorescence
microscopy. The main difficulty of this method has Fig. 71.1: Transabdominal measurement of the fetal nuchal
been the very low concentration of fetal cells in the translucency (3.1 mm) at the end of the first trimester
982 Textbook of Perinatal Medicine

over conventional PCR: the data collection occurs

during amplification. The accumulation of PCR
products over time is measured directly, without post-
PCR modifications. Therefore it is less prone to
contamination, as the results are analysed auto-
matically without having to open the PCR reaction
vessel and there is no post PCR work. It also permits
the rapid analysis of numerous samples in one analytic
run and is therefore better for automation.
The quantitation of fetal DNA may obtain
additional knowledge regarding the pregnancy
outcome. Fetal DNA is elevated in specific pregnancy
associated disorders, like preeclampsia 22, hyper-
emesis gravidarum 23, or trisomy 21. 24. In case of
preeclampsia it could be demonstrated that the
Fig. 71.2: Aspect of a MACS system, used in our laboratory
severity of the disease correlates with the level of
fetal DNA in the blood of affected pregnant
cultivate nuclear erythrocytes. This fact doesn’t allow
women.25 These studies suggested, that an elevated
a metaphase analysis for chromosomal testing. On
concentration of fetal DNA may be a valuable marker
the other hand CD34+ cells can be cultivated.
for pregnancy associated diseases. 26 Because the
However, they persist postpartum in the maternal
majority (more than 90%) of free DNA in maternal
blood circulation and make a prenatal testing in the
serum derives from the mother, it has been difficult
next pregnancy more difficult. Furthermore, cells are
to differentiate the origin. Previously it was possible
not constantly present in the maternal circulation.
only to examine genetic traits, that are not present
The isolated cells have been investigated using either
in the maternal genome. However, with this non-
cytochemistry, soret band absorption microscopy,
invasive and risk free method it is now possible to
monoclonal antibodies for e- and g-chain-
detect y-specific sequences in pregnancies with an
haemoglobin, monoclonal antibody for i-antigen and
elevated risk for x-chromosomal inherited disorders
by fluorescent in situ hybridisation (FISH). For all
(e.g. haemophilia, fragile x-syndrome). Approxi-
those reasons, up to now the enrichment of fetal cells
mately 15% of Caucasian pregnancies are potentially
from the maternal blood is too laborious to be a at risk for severe intrauterine haemolytic disease,
serious alternative in the clinic and to supersede mainly due to Rhesus D incompatibility. The need to
prenatal invasive diagnostic procedures. Today, the know the Rhesus constellation, as well as the large
international research has partially turned its number of x-linked disorders, has prodded several
attention to the free fetal DNA and RNA. groups to develop non-invasive risk free methods
for diagnostic tests.
NON-INVASIVE PRENATAL DIAGNOSTIC
With the highly specific real time PCR method, it
TESTS WITH FETAL FETAL DNA
is nowadays possible to detect these fetal genetic
The first publication about fetal DNA, extracted from traits with an almost 100% sensitivity and specificity.
maternal blood dated from 1997.20 Quantitative A few laboratories offer routinely the detection of
investigations showed, that the concentration of fetal the fetal rhesus status. This is a success in the 15 year
DNA during pregnancy is much higher than that of old international research on this topic.
fetal cells.21 Quantitative levels can be measured with A recently published work of our laboratory
real time PCR. Real time PCR has several advantages demonstrated, that fetal DNA can be separated from
 Non-Invasive Prenatal Diagnosis of the Maternal Blood 983
maternal DNA, due to the difference of its size.27 A The presence of fetal DNA in maternal plasma
majority of fetal DNA has a size of <0.3 kb, whereas has revealed significant clinical potential for the
the maternal DNA, that constitutes more than 90% prenatal diagnosis of fetal genetic diseases and
of the amount of circulating DNA in the maternal pregnancy-associated complications.
blood, shows a size of > 1kb.28 The difference in size A caveat of the approach is that the DNA present
may account for the different origin. Fetal DNA in the circulation is predominantly of maternal origin
derives predominantly from the placenta, whereas and interferes with molecular analysis of the fetal
maternal DNA has its main origin in the haemato- DNA. Hence, paternally inherited fetal loci that are
poietic system.29,30 After size separation of the fetal clearly distinct from maternal genomic sequences can
DNA, it is possible to detect fetal microsatellite be readily examined. Paternally inherited mutant
markers with fluorescent polymerase chain genes in compound heterozygous genetic disorders
reaction.31 Up to now, this new technology has been may also be detected if the paternal mutation is
used for the determination of many disorders like dissimilar from the maternal allele. In general, the
myotonic dystrophy32 , achondroplasia33 and beta- detection of fetal single gene disorders is at least
thalassemia.34 cumbersome and often impossible with current
methods. Likewise does the determination of
NON-INVASIVE PRENATAL SCREENING TESTS chromosomal abnormalities require further
WITH FETAL FETAL DNA advancement in the technology before it is feasible
The current focus in research on fetal DNA in a non-invasive manner.
investigates it’s use as a maternal serum marker in Most studies generate data from pregnancies with
the second-trimester for fetal Down Syndrome and male fetuses as sequences on the Y chromosome are
other pregnancy associated disorders. The unique DNA markers absent in the maternal genome.
quantitative measurement of fetal DNA could This approach is only applicable to approximately 50
complement the second trimester serum markers. By percent of the pregnancies, but straightforward to
increasing the specificity of the screening it could perform. An impediment in the generation of accurate
help to prevent a considerable amount of data is the low number of fetal sequences in the
unnecessary invasive procedures. The median of fetal plasma, such that the samples quantified by the real-
DNA concentration is reported to be approximately time PCR have copy numbers close to the detection
two fold higher in pregnancies with Down Syndrome, limit and quantitative value of the results is reduced
compared with unaffected pregnancies, but the data by increased variability of method and sampling.
is disputed by other reports, and larger sample
NON-INVASIVE PRENATAL DIAGNOSTIC AND
numbers and meticulously accurate, standardized
SCREENING WITH FETAL RNA FROM
quantification are demanded to allow final
MATERNAL PLASMA, EXPRESSED FROM THE
conclusions.
PLACENTA
In order to use the fetal DNA as a screening
marker, a gender-independent fetal DNA marker A new development in prenatal screening research
that can be assayed by real-time PCR is needed. constitutes the measurement of fetal RNA in the
Polymorphic sequences are presently used in the maternal blood. It gives the possibility to screen for
clinical samples that are investigated for fetal rhesus sex-unspecific for disorders.35 Fetal RNA in maternal
status to ascertain the presence of adequate amounts plasma is surprisingly stable and holds promise for
of fetal DNA. Although a number of sequences has non-invasive gene expression profiling.36 Unlike fetal
to be examined in each pregnancy to ascertain DNA, extracted from maternal serum or plasma, fetal
distinction between fetal and maternal, this approach RNA can be used for prenatal testing irrespective of
is still relatively facile to implement. fetal gender and genetic polymorphism status. To
984 Textbook of Perinatal Medicine

date only a few reports present quantitative data on 9. Cusick W; Buchanan P; Hallahan TW; Krantz DA; Larsen
JW Jr; Macri JN. Combined first-trimester versus
this phenomenon. They indicate maternal plasma
second-trimester serum screening for Down syndrome:
RNA as a gender independent marker group that a cost analysis. Am J Obstet Gynecol 2003 Mar;
may by non-invasive gene-expression profiling be a 188(3):745-51.
suitable screening tool for pregnancy associated 10. Haddow JE; Palomaki GE; Knight GJ; Williams J; Miller
pathologies. It could be demonstrated, that not only WA; Johnson A. Screening of maternal serum for fetal
Down’s syndrome in the first trimester. N Engl J Med
fetal DNA, but also fetal RNA was present in elevated 1998;338:955-61.
concentrations in pregnant women with pre- 11. Mennuti, MT, Driscoll, DA. Screening for Down’s
eclampsia. 37 The presence of fetal RNA in the syndrome—too many choices?. N Engl J Med 2003;
maternal serum gives the possibility to investigate 349:1471.
12. Holzgreve W, Hahn S. Prenatal diagnosis using fetal
the expression of certain genes in analogy with the cells and free fetal DNA in maternal blood. Clin
nowadays used RNA markers in oncology.38 Perinatol 2001; 28:353-65.
The fast progresses and success in non-invasive 13. Poon LL, Leung TN, Lau TK, Lo YM. The presence of
prenatal research may give a futural prospect for fetal RNA in maternal plasma. Clin Chem 2000; 46:1832-
4.
valuable alternatives in regard to the prenatal
14. Hahn S, Sant R, Holzgreve W: Fetal cells in maternal
invasive diagnostics. blood: Current and future perspectives. Mol Hum
Reprod 1998; 4:515-21.
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DNA in maternal plasma and serum. Clin Chem 2002; 34. Chiu RW, Lau TK, Leung TN, Chow KC, Chui DH, Lo
48:650-3. YM. Prenatal exclusion of beta thalassaemia major by
26. Farina A, LeShane ES, Lambert-Messerlian GM, Canick examination of maternal plasma. Lancet. 2002;360:998-
1000.
JA, Lee T, Neveux LM. Valuation of fetal cell free DNA
35. Poon LL, Leung TN, Lau TK, Lo YM. Presence of fetal
as a second-trimester marker of Down syndrome
RNA in maternal plasma. Clin Chem 2000; 46:1832-34.
pregnancy. Clin Chem 2003; 49:239-42.
36. NG EK, Tsui NB, Lau TK, Leung TN, Chiu RW, Panesar
27. Li Y, Zimmermann B, Rusterholz C, Kang A, Holzgreve
NS, Lit LC, Chan KW, Lo YMD. MRNA of placental
W, Hahn S. Size separation of circulatory DNA in
origin is readily detectable in maternal plasma. Proc Natl
maternal plasma permits ready detection of fetal DNA
Acad Sci 2003; 100: 4748-4753, Lo YMD, Chiu RWK. The
polymorphisms. Clin Chem 2004; 50:1002-11.
biology and diagnostic applications of plasma rna. Ann
28. Lo YM, Tein MS, Lau TK, Haines CJ, Leung TN, Poon NY Acad Sci 2004; 1022:135-9.
PM. Quantitative analysis of fetal DNA in maternal 37. NG EK, Leung TN, Tsui NB, Lau TK, Panesar NS, Chiu
plasma and serum: implications for non-invasive RW, Lo YM. The concentration of circulating cortico-
prenatal diagnosis. Am J Hum Genet 1998; 62:768-775. trophin-releasing hormone mRNA in maternal plasma
29. Guibert J, Benachi A, Grebille AG, Ernault P, Zorn JR, is increased in preeclampsia. Clin Chem 2003; 49:727-
Costa JM. Kinetics of SRY gene appearance in maternal 31.
serum: detection by real time PCR in early pregnancy 38. Hasselmann DO, Rappl G, Rossler M, Ugurel S, Tilgen
after assisted reproductive technique. Hum Reprod W, Reinhold U. Detection of tumour-associated circu-
2003; 18:1733-6. lating mRNA in serum, plasma and blood cells from
30. Lui YY, Chik KW, Chiu RW, Ho CY, Lam CW, Lo YM. patients with disseminated malignant melanoma. Oncol
Predominant hematopoietic origin of cell free DNA in Rep 2001;8:115-8.
986 Textbook of Perinatal Medicine

72 Pregnancy Evaluation
by Ultrasonography

DV Surbek, S Tercanli, W Holzgreve

INTRODUCTION pregnancy where ultrasonography plays a major role

in the diagnostic procedure.
Since the introduction of ultrasound in prenatal
medicine, the prognosis of multiple pregnancies has
EARLY DIAGNOSIS OF MULTIPLE PREGNANCY
improved dramatically. Early and appropriate
diagnosis of multiplicity and chorionicity, detection Why should a multiple pregnancy be diagnosed
of discordant fetal growth, evaluation of fetal well- early? First, the number of fetuses, which can be
being by biophysical scoring and Doppler sonography confirmed by ultrasound, is a strong determinator
as well as planning of delivery mode by deter- of prognosis of a pregnancy which is generally best
mination of fetal presentation are some of the most for singletons and gets worse with higher order
important diagnostic advances which represent the multiplicity. Like in singleton pregnancies, gestational
basis of the adequate clinical management. Multiple age can be confirmed by an early ultrasound during
pregnancies are at increased risk for several the first trimester using growth charts of crown rump
complications during pregnancy and childbirth like length corresponding to gestational age.3 In the first
prematurity, fetal growth retardation, twin twin and second trimester of pregnancy, growth charts
transfusion syndrome, preeclampsia, stillbirth and for singleton pregnancies can be used appropriately
malpresentation. Therefore, early diagnosis of for twin pregnancies.4 More importantly, early
multiple pregnancy and in particular chorionicity is ultrasound allows for definitive diagnosis of
mandatory for the appropriate assessment of risk chorionicity which itself is also a strong predictor of
factors, for intensive prenatal care and early fetal outcome.
detection as well as treatment of complications. Usually, early diagnosis of multiple pregnancy by
Before the introduction of prenatal ultrasound, transvaginal sonography is easy.5 After the 5th week
detection rate of twin pregnancies before delivery of pregnancy (from the last menstrual period),
was lower than 50% 1, while in countries where different gestational sacs are visible in multichorionic
routine ultrasound in pregnancy is performed, the gestations, whereas in monochorionic twins only one
rate is close to 100%.2 Consequently, this has lead to chorionic cavity is visible. From the 6th or 7th week
decreased perinatal morbidity and mortality in twin of pregnancy, it is possible to identify the number of
and higher multiple gestations in the past thirty years. embryos and yolk sacs in multichorionic as well as
In the following chapter we will give an overview in monochorionic gestations. As soon as two or more
of the most important clinical issues of multiple embryos with heart activity are discernible, the
 Pregnancy Evaluation by Ultrasonography 987
diagnosis of multiple gestation is confirmed. In contrast, monozygotic twinning may result in
Although a false diagnosis of a singleton pregnancy dichorionic - diamniotic, monochorionic - diamniotic
may happen if a hurried scan is performed by an or monochorionic - monoamniotic placentation,
inexperienced examiner, the diagnosis at this stage depending on the age of division. The division of
is virtually error-free. Possible pitfalls may be chorial the embryo results in the following constellations:
hematomas or a decidual pseudosac mimicking a from day 1 to day 3 after fertilization: dichorionic-
second or third gestational sac, or conjoined twins diamniotic twins, from day 4 to day 6: dichorionic
mimicking a singleton pregnancy. - monoamniotic twins, and from day 7 to day 9:
Another issue in early diagnosis is the pheno- monochorionic - monoamniotic twins. If the division
menon of vanishing twins, which seems to happen happens after day 9, conjoined twins result.
in a significant proportion twin gestations6 and might Dichorionic placentation is found in 30 percent of
be the reason for discordant diagnosis in subsequent monozygotic pregnancies.8 As a rule, dizygous twins
ultrasound examinations. This phenomenon of are always dichorionic, although this dogma has
“vanishing embryos“ is especially well established recently been disproven. 9
from in vitro programs such as shown in Table 72.1 Virtually all monochorionic twins, which
which summarizes data obtained in pregnancies after represent about 20 percent of all twin pregnancies,
in vitro fertilization where intact heart action of the have vascular anastomoses in the placenta, whereas
embryos was the intake criterium for the prospective almost none of dichorionic (fused) placentas shows
study. “Vanishing embryos“ represent the sponta- such cross-circulation.10 These vascular shunts usually
neous abortion of a multiple gestation member in remain balanced, but occasionally, they might become
the first trimester either by expulsion or - more often functional, leading to typical monochorionic twin
- by complete resorption of the embryo. In many complications like discordant growth and twin-twin
cases it remains asympto-matic, though sometimes transfusion syndrome.11 Alternatively, in situations
it is accompanied by vaginal bleeding. Prognosis for with one intrauterine fetal demise complications from
the surviving twin seems excellent, although recently vascular anastomoses might arise in the surviving
it has been hypothezised that unexplained cerebral twin. These include severe conditions like multicystic
palsy might be the consequence in the survivor of a encephalomalacia and renal infarctions. In earlier
vanishing twin pair.7 publications, several authors postulated that embo-
lization of thromboplastin-like material across the
PRENATAL DIAGNOSIS OF ZYGOSITY, shared circulation followed by disseminated intra-
CHORIONICITY AND AMNIONICITY vascular coagulation is the cause of this phenomenon
which is also called the twin disruption syndrome.
Dizygotic twinning results in dichorionic - diamniotic
pregnancies, even though the placentae may be fused. More recent evidence however suggest another
pathophysiological mechanism, which is based on the
Table 72.1: Vanishing embryos in pregnancies with assumption that a sudden blood pressure gradient
multiples. The “intake criterium“ was intact heart action.
may occur at the moment of fetal demise, followed
All pregnancies are from the in vitro fertilization
program of Dr Robert Fischer, Hamburg by severe hypotension and exsanguination in the
Initial scan Cases 2nd trimester surviving fetus, leading to acute hypoxic organ
Twins 52 34 twins damage predominantly in the brain in up to 20% of
18 singletons survivors. 12 This phenomenon could be called an
Triplets 22 8 triplets acute twin-twin transfusion syndrome.13
11 twins
These complications do only occur in mono-
3 singletons
Quadruplets 4 2 quadruplets chorionic gestations. In particular, the fetal loss rate
2 triplets in monochorionic pregnancies is up to 4 times higher
988 Textbook of Perinatal Medicine

in monochorionic as compared to dichorionic twin chorionicity. A reliable diagnosis of chorionicity can

pregnancies. Chorionicity is thus the most important only be made if the fetuses are of opposite sex
factor influencing outcome of twin pregnancies. (dizygotic) or there are clearly two separated
Consequently, accurate prenatal diagnosis of placentae visible, which is often not the case in
chorionicity is of predominant importance for the dichorionic twins. Entanglement of umbilical cords
clinical management of twin pregnancies. represents a reliable sign confirming the presence of
As outlined above, monochorionic twins usually a single amniotic cavity in monoamniotic gestation.15
have a seperating membrane, thus being diamniotic. In cases with the same fetal sex, with one non-
Fewer than 2% of twins are monoamniotic. Besides seperated placenta and with a dividing membrane
complications of monochorionicity, these pregnancies between the fetuses, determination of chorionicity
are at high risk for cord accidents during pregnancy is difficult after the first trimester of gestation and
and birth, resulting in an extremely high fetal loss requires other criteria. Thickness of the dividing
rate of 50 to 75%. Delivery by early elective cesarean membrane measured by ultrasound is one criterium
section is therefore one of the important features of which is able to predict chorionicity, using a cutoff-
the management of monoamniotic twins. level of 2 milimeters.16 Another important sono-
Determination of chorionicity and amnionicity graphic feature is the number of layers identified in
before birth is made by ultrasonography. In early the dividing membrane. 17 While not always
pregnancy during the first trimester, it is usually easy technically possible, it remains a reliable criteria of
to differentiate the type of placentation by trans- dichorionic placentation if three or more layers are
vaginal sonography. If two gestational sacs with two present. Probably the best approach is the combi-
embryos are identified, the diagnosis of dichorionic nation of these criterias, reaching excellent predicting
twins can be made with certainty. On the other hand, values in the determination of chorionicity.18
if there is only one gestational sac with two embryos,
monochorionic twins are dia-gnosed. To seperate FETAL MALFORMATIONS AND
monoamniotic from diamniotic gestation, it is CHROSOMOMAL ANOMALIES IN
necessary to discern two amniotic membranes MULTIPLE PREGNANCY
surrounding the embryos, or, at a later stage, to Twins, above all monozygotic twins, are known to
identify a partition membrane between the fetuses. be at increased risk for malformations - not only
If there is no membrane visible, the sonographer has because the presence of two fetuses in one pregnancy
to be cautious as a seperating membrane might exist doubles the chance of a defect.19 The incidence of
but might be hardly visible on ultrasound scan, malformations is higher in monochorionic than in
particularily in cases of severe oligohydramnios or dichorionic twins and the highest in monoamniotic
anhydramnios of one twin combined with twins. Furthermore, the incidence of chromosomal
polyhydramnios in the other, as it is typically present aneuploidy seems to be higher in twin gestations as
in twin-twin transfusion syndrome (“stuck twin“). compatred to singletons.20 A detailed study of fetal
Later in the first trimester, from about 10 to 14 morphology in multiple pregnancy by ultrasound is
weeks gestation, the key to the differentiation of time consuming and sometimes much more difficult
mono- and dichorionic diamniotic twins is the “twin than in singletons, but it should be done during
peak“ sign or lambda sign was used to predict routine ultrasound surveillance. Emphasis should be
dichorionic twins if present.14 This latter finding put not only on typical anomalies unique to the
consists of chorionic tissue extending between layers twinning process, but also on other anomalies known
of the interfetal septum close to the placenta. to be increased in twin pregnancies.
In the second or third trimester of gestation, other Congenital anomalies specific to multiple
criterias become important in determination of gestation occur infrequently but are usually severe.
 Pregnancy Evaluation by Ultrasonography 989
The rate of conjoined twins is one in 50’000 birth.21 varying degrees of upper body reduction including
Prenatal diagnosis by ultrasonography including acardia and acranius.22 Doppler sonography may be
determination of type of anomaly and of shared helpful in identifiing cardiac structures, reversed
organs is important for the optimal management of perfusion and vascular anastomoses. 23 A different
those pregnancies in terms of appropriate deter- theory of pathogenesis is the primary existence of
mination of prognosis and plan of delivery route acranius - acardius malformation, which is supported
(cesarean section) and postnatal care. In severe cases by the fact that the malformed twin has been found
diagnosed early, termination of pregnancy is an to have a high prevalence of chromosomal anomalies.
option which many parents choose. Ultrasonographic Mortality in the reversely perfused twin is 100%. The
criteria for the detection of conjoined twins have been other fetus, the so-called “pump-twin“, is usually
proposed: a missing seperating membrane, a fixed severely compromised by a high-output heart failure
position of the twins towards each other and a lack which leads to a mortality of 50%. An intervention
of separate visualization of the fetuses in a specific might be necessary and indicated, which includes
anatomical region. Different patterns of physical ligation/coagulation of the cord or of intraabdo-
joining exist, resulting in different progonosis of the minal blood vessels of the acranius-acardius twin.
pregnancies. The symmetric complete form of Congenital anomalies not specifically related to
conjoined twinning is present when two fetuses are multiple gestation have the same ultrasonographic
anatomically almost “complete“ except the part of features like in singleton pregnancies. These
the body where they share a certain amount of tissue. malformations affect mainly the tracheoesophageal
These “diplopagi“ are described after the body anatomy, the genitourinary and central nervous
structure which is joined, namely craniopagi, system (neural tube defects), and the cardiovascular
thoracopagi (accounting for 57% of diplopagi), system.
omphalopagi, and pygopagi. Postnatal seperation is Chromosomal anomalies are also increased in
often possible in diplopagi except in cases where multiple gestations. The risk of chromosomal
gross parts of the heart or central nervous system anomalies in a twin pregnancy can be calculated using
are shared. The symmetric incomplete forms are maternal age, zygosity and nuchal translucency of
represented by twins with one trunk and a single the twin fetuses. In dichorionic twins, the detection
lower part of the body together with two heads rate of nuchal translucency measurements for
(dicephalus), or by twins with one head and upper chromosomal anomalies is similar as in singletons,
trunk and a double lower body (dipygus). Asym- whereas in monochorionic twins there are more false
metric forms are conjoined twins one of which is positives due to placentation-specific alterations of
severely malformed and often rudimentary (parasitic the nuchal translucency. In particular, care must be
twin) while the other is normally developed. taken if a large difference in nuchal translucency is
An extreme form of twin-specific asymmetric found in monochorionic twins because this could be
malformation is acranius-acardius, also known as an early manifestation of twin-twin transfusion
chorangiopagus parasiticus, or TRAP-sequence (twin syndrome and not of a karyotype anomaly. In
reversed arterial perfusion sequence). Numerous monozygous twins, the karyotype is the same in both
theories about pathogenesis of this syndrome, which twins, and calculations are used for both. In dizygous
occurs in a frequency of one in 35’000 birth, have twins, the risk must be calculated separately for each
been subject to discussion in the literature. Typical of the twins. Biochemical parameters such as free
features are functional vascular anastomoses between Beta-HCG and PAPP-A (in the first trimester) or
not-joined twins with reverse arterial perfusion of alpha-fetoprotein, free Beta-HCG, estriol and inhibin
the lower part of the malformed twin leading to (in the second trimester) can be used but are less
990 Textbook of Perinatal Medicine

useful yielding a lower detection rate of chromosomal selective termination, the risk of the latter procedure
anomalies in twins.24 Simple use of normative values for the surviving twin is lower the earlier the
from singleton pregnancies is not possible as medians selective fetocide of the co-twin is performed.
are different. Current studies are evaluating the If in a multiple pregnancy one child is proven by
validity of twin pregnancy-adjusted normative prenatal diagnosis to be affected with an untreatable
values. condition, e.g. trisomy 18 or 13 or a severe malfor-
If the parents wish prenatal karyotyping, both mation, a selective fetocide can be performed by
chorionic villus sampling (CVS) or amniocentesis can applying KCL directly to the fetal heart.29 This
be performed as possible options.25-27 The parents technique however may exclusively be used if
though must be informed in detail about the monochorionic placentation is excluded. The selective
difficulties and risks of karyotyping in multiple fetocide is ethically not much different from a
pregnancies. The procedure might be technically termination of a whole pregnancy in singletons,
difficult, leading to incomplete results (i.e., except for the fact that the pregnancy per se continues
karyotyping of only one fetus in twins). On the other and the dead fetus usually follows after the livebirth
hand, difficulties might arise if one fetus turns out of the co-twin together with the placenta.30
to be healthy while the other is affected by a severe In pregnancies with very high multiples, e.g.
chromosomal anomaly. In multiple gestation, CVS octuplet pregnancies, these would be bound to fail,
imposes specific problems due to a missing safeguard so that a “reduction“ of the number of living twins
in proving that identical karyotypes represent has been performed in order to avoid loss of the
monozygotic twins rather than sampling from the whole pregnancy spontaneously or through
same chorion frondosum. In multichorionic termination. This procedure is called multifetal
gestations, the placentas might be close to each other, pregnancy reduction and is performed by intra-
leading to difficulties in separate sampling. Further- cardiac injection of KCL in “muliple-chorionic”
more, contamination of one sample with the villi of multiples; again, monochorionicity must be excluded.
the other might happen. If fetal sex is different, it The outcome of the pregnancy after this procedure
could be safely determined that both fetuses have depends significantly on the starting number of
been karyotyped. When suspicion arises, “follow up“ fetuses, the finishing number and the operators
amniocentesis should be offered. Consequently, CVS experience.31 The primary aim however must be to
in twins should only be performed if individual avoid iatrogeneic higher order multiple pregnancy
samples can be guaranteed. Amniocentesis is the e.g. by controlled use of ovulation inducing drugs
alternative procedure, often preferred in multiple or by restriction of the number of transferred
gestation. After the puncture and retrieval of amniotic embryos to two during IVF procedure.
fluid of one amniotic sac, indigo carmine is injected
before the needle is retracted. In the following FETAL GROWTH IN MULTIPLE PREGNANCY
puncture of the second amniotic cavity, the aspirated As in all pregnancies, appropriate dating of
amniotic fluid is checked in colour to exclude reentry pregnancy is important in terms of determination of
of the amniotic cavity of the same fetus. With this fetal growth to differentiate growth restriction from
technique, amniocentesis in twins with a correct normal growth. Dating is best done in the first or
diagnosis of fetal karyotypes is feasible in most twin early second trimester by combining the date of the
pregnancies28 and has a somewhat lower loss rate as last menstrual period with fetal ultrasound
CVS. As a rule, the higher the risk for chromosomal measurements.
anomaly in a twin, the earlier the diagnosis should We mentioned before that in twin pregnancies,
be made, ideally by CVS. The reason for this is that growth charts of singletons can be used at least up
if one twin is affected and the parents opt for to the beginning of the third trimester, because
 Pregnancy Evaluation by Ultrasonography 991
normal growth in twins is the same as in singletons. Similarily, this technique might be used in twins as
Only after 28 to 30 weeks of pregnancy, intrauterine additional measure for detection of growth
growth gradually decreases compared to single- discordance and fetal compromise.38 Furthermore,
tons.4,32 It has been estimated that after 32 weeks of with color doppler placental anastomoses in twin-
pregnancy, weight gain of both fetuses in twin twin transfusin syndrome can be detected, which
pregnancy equals the weight gain of one singleton. might be helpful for intrauterine treatment by
Assessment of fetal growth in twin pregnancies fetoscopic laser-ablation of placental vessels (see
has been performed initially by measurements of below).39
biparietal diameter33, though it has been shown later, As in singletons, an individual biophysical profile
that biparietal diameter is not an appropriate including non-stress testing should be applied in both
measurement for detection of discordance in twins.34 twins in growth restricted twin pregnancies as an
Possible explanations for these difficulties might be important tool for assessment of fetal well-being.40
different fetal positions and overlaying fetal parts
of the other twin. Better estimates of fetal growth TWIN-TWIN TRANSFUSION SYNDROME
and prediction of discordance are accomplished by Twin-twin transfusion syndrome (TTS) is a condition
femur lenth and abdominal circumference35 where which develops in about 10-25% of monochorionic
technical difficulties in measuring seem to be of minor twin pregnancies. The underlying cause for this
importance. syndrome is imbalance of vascular anastomoses
If discordant growth in twin pregnancy (defined between the placental circulation of both twins within
by an estimated weight difference of 20 to 25% the single (monochorionic) placenta. This imbalance
between the fetuses) is diagnosed by prenatal leads to decreased feto-pacental blood volume in the
ultrasound, several possibilities exist. The most donor and increased volume in the recipient. The
common cause for the weight discordance is a definition of TTS includes polihydramnios-
constitutional weight difference in normal dizygotic oligohydramnios sequence. Typical sonographic
twins. In contrast, pathologic causes might result in features include in the donor fetus oligohydramnios
often severe growth difference between twins. The or anhydramnios (“stuck twin” phenomenon), small
prevalence of intrauterine growth restriction is up or absent bladder, and growth restriction, whereas
to 10 times higher in twins than in singletons, in the recipient shows polihydramnios and a large
particular in monochorionic twins. Pathologic bladder. In both twins, the condition can lead to
conditions include intrauterine growth retardation cardiac decompensation, detectable by ultrasound
affecting one or both twins, because of local utero- (including tricuspid regurgitation and negative
placental factors (which might happen in dichorionic ductus venosus A-wave in the recipient, pericardial
or monochorionic pregnancies), or twin-twin effusion, hydrops). Doppler flow measurements in
transfusion syndrome. In some cases, congenital umbilical arteries can be pathologic in both twins
anomaly of only one fetus might also lead to (absent or reversed enddiastolic flow). Ultimately,
discordant growth. An important question in fetal death in one or both twins can occur. Severe
discordant twins is chorionicity and amniotic fluid TTS has a 90% mortality and a high rate of neurologic
amount. Overall, perinatal morbidity and mortality longterm-morbidity (handycap) in surivors if
besides later intellectual sequelae are increased in untreated.
twin pregnancies irrespective of the underlying The severity of TTS can be assessed by ultrasound
cause.36 which correlates with the prognosis. Several criteria
Doppler velocimetry has proved to be predictive for classification have been proposed; the Quintero
of fetal hypoxia in growth-retarded singletons. 37 staging system being the most widely used.41
992 Textbook of Perinatal Medicine

Management options depend on severity of TTS, in patients with preterm labor, a recent multicenter
gestational age, and women’s preference and include study proved a correlation of cervical length
expectant management with close follow-up (in mild measured in the second trimester in asymptomatic
TTS), repetitive amniodrainage, needle septostomy patients with the risk of preterm delivery.45 A major
or endoscopic laser coagulation of anastomoses. finding in this study was that cervical length did seem
Cohort studies42 and a recent multicenter randomized to be a continuous variable rather than a dichotomous
trial43 suggest that laser treatment in severe TTS is variable, suggesting that cervical function might be
superior to repetitive amniodrainage regarding a continuum, in contrast to the earlier belief that the
neonatal mortality as well as morbidity. With regard cervix is either “competent“ or “incompetent“. Other
to the current evidence, laser treatment seems to be studies have shown that ultrasonography of the
the treatment of choice in severe TTS, but longterm cervix might be used as well in the follow-up after
neurologic outcome results of the randomized trial cervical cerclage, measuring the distance between the
must yet be awaited. cerclage suture and the internal cervical os.46
Though some of these studies have excluded
ULTRASONOGRAPHY FOR PREDICTION OF multiple pregnancies, others have specifically
PRETERM DELIVERIES IN MULTIPLE determined the predictive value in twin preg-
PREGNANCY nancies.47 One may conclude that ultrasonographic
Twin gestations are known to have a significantly determination of the cervix and the lower part of
increased risk of preterm delivery as compared to the uterus is an important additional tool in
singletons. Early diagnosis of preterm contractions predicting preterm delivery in multiple gestation,
and individual preterm delivery risk assessment is where the risk of prematurity is especially high.
therefore particularily important. Cevical ultrasound
INTRAPARTUM ULTRASONOGRAPHY
has recently been shown to be predictive of preterm
IN MULTIPLE GESTATION
delivery. Initial studies measuring cervical length by
transabdominal ultrasonography found a significant There is considerable controversy in the literature
correlation of a shortened cervix with preterm around intrapartum management of multiple
delivery. As shown by different examiners, trans- gestation.48 Multiple pregnancies of higher order are
abdominal measurement of cervical length has the usually delivered by cesarean section. In twins, the
disadvantage of being biased by the degree of single most important question is the route of
bladder filling, which led to the increased use of delivery in different subsets of twins and, addi-
transvaginal ultrasound probes in pregnancy.44 tionally, in different clinical situations like pre-
Beside the cervical length, dilatation of the internal maturity, growth retardation or preeclampsia. Above
cervical os, protrusion of membranes in the cervical all, the management plan for delivery has to take
canal, length of funneling and thickness of the wall presentation of the twins into consideration, which
of the lower uterine segment have been used more include all possible combinations of vertex, breech,
or less seccessfully to diagnose cervical incompetence transverse and oblique presentation of the first and
and to predict preterm birth. Ultrasonographic second twin.49 Ultrasonography can be reliably used
determination of cervical morphology has been for detection of these different presentations before
shown to be superior to digital examination of the onset of labor, during labor, after delivery of the
cervix for the prediction of preterm birth if there is first twin or after interventions like external or
no overt cervical dilatation of 2 cm or more. While internal version of the second twin. Again, ultrasound
some studies have used transvaginal ultrasound for examination is a most important tool in the
the prediction of the likelihood of preterm delivery peripartum management of of twin pregnancies.
 Pregnancy Evaluation by Ultrasonography 993
CONCLUSION 5. Holzgreve W, Westendorp J, Tercanli S. First trimester
ultrasound. In: Reproductive risks and prenatal
The aim of this chapter was to discuss the most diagnosis. Ed: Evans MI. Norwalk, USA, Appleton and
important clinical applications of ultrasonography in Lange 1992: 121-50.
6. Sampson A, de Crespigny LC. Vanishing twins: the
multiple gestation. Beginning with early gestation,
frequency of spontaneous fetal reduction of a twin
diagnosis of multiplicity, zygosity, chorionicity and pregnancy. Ultrasound Obstet Gynecol. 1992;2(2):107-
amnionicity are predominant tasks for determination 9.
of the risk of complications later in pregnancy. Typical 6a. Newton R, Casabonne D, Johnson A, Pharoah P. A case-
control study of vanishing twin as a risk factor for
complications of monochorionic twins with vascular cerebral palsy. Twin Res. 2003; 6(2):83-4.
anastomoses are being explained. Fetal congenital 7. Benirschke K, Chung KK. Multiple pregnancy. N Engl J
anomalies in multiple gestation are different in many Med 1973; 288: 1276 and 1329.
ways from singletons and represent another problem 7a. Souter VL, Kapur RP, Nyholt DR, Skogerboe K,
Myerson D, Ton CC, Opheim KE, Easterling TR, Shields
of primary importance in the routine medical care. LE, Montgomery GW, Glass IA. A report of dizygous
Multiple gestation-specific anomalies like conjoining monochorionic twins. N Engl J Med. 2003;349(2):154-8.
can be discerned from non-specific congenital 8. Robertson EG, Neer KJ. Placental injection studies in
twin gestation. Am J Obstet Gynecol 1983;147:170.
malformations which exist as well in singletons.
9. Blickstein I. The twin-twin transfusion syndrome. Obstet
Invasive procedures for prenatal chromosomal Gynecol 1990; 76: 714.
analysis are briefly discussed, being more difficult 9a. Pharoah PO, Adi Y. Consequences of in-utero death in
than in singletons as one has to deal with more than a twin pregnancy. Lancet 2000;355(9215):1597-602.
10. Fusi L, McParland P, Fisk N et al. Acute twin-twin
one maternal and one fetal karyotype. transfusion: a possible mechanism for brain damages
Discordant fetal growth is a major complication survivors after intrauterin death of a monochorionic
in multiple gestation. The diagnosis is usually twin. Obstet Gynecol 1991; 78: 517.
confirmed by ultrasonography; at the same time the 11. Finberg HJ. The twin peak sign: reliable evidence of
dichorionic twinning. J Ultrasound Med 1992; 11: 571.
underlying pathology like growth restriction based 12. Nyberg DA. Entangled umbilical cords: a sign of
on fetal malformation of one twin or twin-twin- monoamniotic twins. J Ultrasound Med 1984; 3:29.
transfusion syndrome might be evaluated. Cervical 13. Townsend RR, Simpson GF, Filly RA. Membrane
change assessed by vaginal ultrasonography has been thickness in ultrasound prediction of chorionicity of twin
gestations. J Ultrasound Med 1988; 7: 326.
shown to be predictive of spontaneous preterm 14. D’Alton ME, Dudley DK. The ultrasonographic
delivery in singletons; similarily this might be prediction of chorionicity in twin gestation. Am J Obstet
applicable in multiple gestation. Finally, peripartum Gynecol 1989; 160: 557.
15. Scardo JA, Ellings JM, Newman RB. Prospective
ultrasonography for the detection of presentation is
determination of chorionicity, amnionicity and zygosity
crucial in planning delivery and possible intrapartum in twin gestations. Am J Obstet Gynecol 1995; 173: 1376.
intervention in twins. 16. Bryan E, Little J, Burn J. Congenital anomalies in twins.
Baillières Clin Obstet Gynecol 1987; 1: 697.
REFERENCES 17. Lubs HA, Ruddle F. Chromosomal abnormalities in the
human population: estimation of rates based on New
1. Grennert L, Persson PH, Gennser G, and Kullander S. Haven newborn study. Science 1970; 169: 495.
Ultrasound and human-placental-lactogen screening for 18. Hanson JW. Incidence of conjoined twinning. Lancet
early detection of twim pregnancies. Lancet 1976; i: 4. 1975; ii: 1257.
2. Wenstrom KD, Gall SA. Incidence, morbidity and 19. Ash K, Harman CR, Gritter H. TRAP sequence -
diagnosis of twin gestations. Clin Perinatol 1988; 15: 1. successful outcome with indomethacine treatment.
3. Daya S. Accuracy of gestational age estimation using Obstet Gynecol 1990; 76; 960.
fetal crown-rump length measurements. Am J Obstet 20. Pretorius DH, Leopold GR, Moore TR et al. Acardiac
Gynecol 1993; 168: 903. twin. Report of Doppler sonography. J Ultrasound Med
4. Reece AE, Yarkoni S, Abdalla M et al. A prospective 1988, 7: 413.
longitudinal study of growth in twin gestations 20a. Spencer K, Nicolaides KH. Screening for trisomy 21 in
compared with growth in singleton pregnancies I. The twins using first trimester ultrasound and maternal
fetal head. II. The fetal limbs. J Ultrasound Med 1991; serum biochemistry in a one-stop clinic: a review of
10: 439 and 445. three years experience. BJOG. 2003;110(3):276-80.
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21. Jackson LG, Wapner RJ, Barr MA. Safety of chorionic 33. Giles WB. Doppler assessment in multiple pregnancy.
villus biopsy. Lancet 1986; i: 674. Semin Perinatol 1987; 11: 369.
22. Librach CL. Genetic amniocentesis in seventy twin 34. DeLia JE, Cruikshank DP, Keye WR. Fetoscopic
pregnancies. Am J Obstet Gynecol 1984;148:585. neodymium:YAG laser occlusion of placental vessels in
23. Wapner RJ, Johnson A, Davis G, Urban A, Morgan P, severe twin-twin transfusion syndrome. Obstet Gynecol
Jackson L. Prenatal diagnosis in twin gestations: a 1990; 75: 1046.
comparison between second-trimester amniocentesis 35. Lodeiro JG, Vintzileos AM, Feinstein SJ. Fetal biophysical
and first-trimester chorion villous sampling. Obstet profile in twin gestations. Obstet Gynecol 1986;67:824.
Gynecol 1993; 82: 49-56. 35a. Quintero RA, Morales WJ, Allen MH, Bornick PW,
24. Pruggmayer MRK, Jahoda MGJ, Van der Pol JG, Johnson PK, Kruger M. Staging of twin-twin transfusion
Baumann P, Holzgreve W, Karhut G, Lettan R, Eiben
syndrome. J Perinatol 1999;19:550-555.
B, Osmers R, Gola HW, Duda V, Polak P, Körner H,
35b. Hecher K, Plath H, Bregenzer T, Hansmann M,
Schulte-Valentin M, Schütte H. Genetic amniocentesis in
Hackeloer BJ. Endoscopic laser surgery versus serial
twin pregnancies: results of a multicenter study of 529
cases. Ultrasound Obstet Gynecol 1992; 2: 6-10. amniocenteses in the treatment of severe twin-twin
25. Westendorp A, Holzgreve W, Miny P. Selective fetocide transfusion syndrome. Am J Obstet Gynecol 1999;
of a twin with trisomy 18 by intracardial KCL 180:717-724
application. Arch Gynecol 1988; 244: 59-62. 35c. Senat MV, Deprest J, Boulvain M, Paupe A, Winer N,
26. Evans MI, Goldberg JD, Dumez Y, Wapner RJ, Lynch Ville Y. Endoscopic laser surgery versus serial
L, Dock BS, Golbus MS, Dommergues M, Holzgreve W, amnioreduction for severe twin-to-twin transfusion
Johnson MP, Berkowitz RL. Efficacy of second trimester syndrome. N Engl J Med. 2004;351(2):136-44.
selective termination (ST) for fetal abnormalities: 36. Anderson HF, Nugent CE, Wanty SD, Hayashi RH.
International collaborative experience among the Prediction of risk of preterm delivery by ultrasono-
world’s largest centers. Am J Obstet Gynecol 1993; 168: graphic measurement of cervical length. Am J Obstet
307. Gynecol 1990;163:859.
26a. Evans MI, Berkowitz RL, Wapner RJ, Carpenter RJ, 37. Iams JD, Goldenberg RL, Meis PJ, Mercer BM, Moawad
Goldberg JD, Ayoub MA, Horenstein J, Dommergues A, Das A, Thom E, McNellis D, Copper RL, Johnson F,
M, Brambati B, Nicolaides KH, Holzgreve W, Timor- Roberts JM, and the National Institute of Child Health
Tritsch IE. Improvement in outcomes of multifetal and Human Development Maternal Fetal Medicine Unit
pregnancy reduction with increased experience. Am J Network. The length of the cervix and the risk of
Obstet Gynecol. 2001;184(2):97-103. spontaneous premature delivery. N Engl J Med 1996;
27. McKeown T, Record RG. Observations on fetal grwoth
334:567.
in multple pregnancy in man. J Endocrinol 1952; 8:386.
38. Guzman ER, Houlihan C, Vintzileos A, Ivan J, Benito
28. Grennert L, Persson PH, Genser G. Intrauterine growth
C, Kappy K. The significance of transvaginal ultra-
of twins judged by BPD measurements. Acta Obstet
sonographic evaluation of the cervix in women treated
Gynecol Scand 1978;78:28.
29. Erkkola R, Ala-Mello S, Piiroinen O. Growth with emergency cerclage. Am J Obstet Gynecol 1996;
discordancy in twin pregnancies. A risk factor not 175: 471.
detected by measurements of biparietal diameter. Obstet 38a. Vayssiere C, Favre R, Audibert F, Chauvet MP,
Gynecol 1985; 66: 203. Gaucherand P, Tardif D, Grange G, Novoa A, Descamps
30. Brown CE, Guzick DS, Leveno KJ. Prediction of P, Perdu M, Andrini E, Janse-Marec J, Maillard F, Nisand
discordant twins using ultrasound measurement of I. Cervical length and funneling at 22 and 27 weeks to
biparietal diameter and abdominal perimeter. Obstet predict spontaneous birth before 32 weeks in twin
Gynecol 1987; 70: 677. pregnancies: a French prospective multicenter study.
31. Babson SG, Philips DS. Growth and development of Am J Obstet Gynecol. 2002;187(6):1596-604.
twins dissimilar in size at birth. N Engl J Med 1973; 289: 39. Cetrulo C. The controversy of mode of delivery in
937. twins: the intrapartum management of twin gestation.
32. Soothill PW et al. Relation of fetal hypoxia in growth Semin Perinatol 1986;23:533.
retardation to mean blood velocity in the fetal aorta. 40. Chervenak FA et al. Intrapartum management of twin
Lancet 1986; ii: 1120. gestation. Obstet Gynecol 1985;65:119.
 73
Chromosomal
Abnormality Screening
Mark I. Evans, James N. Macri,
Rosalinde Snijders, Robert S. Galen

PRINCIPLES OF SCREENING TESTS Table 73.1: Screening tests vs diagnostic tests

Screening for any disease process requires a Diagnostic Tests
fundamental understanding of the differences Performed only on “at risk” population
between diagnostic and screening tests. Diagnostic Commonly expensive
Commonly have risk
tests are meant to give a definitive answer to the Give definitive answer
question - Does the patient have this particular Screening Tests
problem? They are often complex and require Offered to general population of patients
Healthy patients
sophisticated analysis and interpretation. They are
Cheap
usually performed only on patients felt to be “at Easy
risk.” Because they tend to be expensive, in contrast, Reliable
screening tests are typically performed on healthy Quick
Define “at risk” population
patients and are often offered to the entire relevant Do not give definitive answer
population. They therefore need to be cheap, easy
to use, interpretable by everyone; their function is percentage of the patients test negative. Physicians
only to help define who, among the low risk group, are generally more interested in different questions,
is, in fact, at high risk. (Table 73.1) Screening test however, because only after a positive test does the
results are, by definition, not pathonomonic for the Disease
disease.1 Their role is to delineate who needs further + –
testing.
There are four key measures used in the Test + A B

evaluation of screening tests. (sensitivity, specificity,

positive predictive value, and negative predictive
– C D
value.) (Fig. 73.1) Sensitivity and specificity
fundamentally address the question from an
Sensitivity A/A+C
epidemiologic viewpoint. For example of all the
Specificity D/B+D
people with the disease, what percentage were
identified by the test? This is the definition of Positive Predictive Value A/A+B

sensitivity. Specifically is the converse, i.e. of all the Negative Predictive Value D/C+D
people who do not have the disease process, what Fig. 73.1: 2 × 2 Table of disease and tests
996 Textbook of Perinatal Medicine

HIV Testing in High Risk Big City STD Clinic HIV Testing in Low Risk Population

AIDS AIDS
+ – + –

HIV + 180 20 HIV + 18 20

Test Test

– 20 780 – 2 960

Sensitivity 180/200 = 90% Sensitivity 18/20 = 90%

Specificity 780/800 = 98% Specificity 960/980 = 99%

Positive Predictive Value 180/200 = 90% Positive Predictive Value 18/38 = 47%
Negative Predictive Value 780/800 = 98% Negative Predictive Value 960/962 = ~ 100%

Fig. 73.2: 2 × 2 Table in high risk population for Fig. 73.3: 2 × 2 Table in low risk population for
sensitivity and predictive values sensitivity and predictive values

patient usually get interested. Of all patients who the overall costs of the screening programs per se.2,3
have a positive test, what percentage of them actually The goal is to reduce the need for expensive costs of
have the disease? This is the positive predictive value. invasive testing that follow a positive screening, and
The negative predictive value is just the opposite, also, although not commonly mentioned, to reduce
i.e. of all the people who have a negative test, what the cost of the care of abnormal newborns who might
percentage of them are actually negative? as a result of screening be detected and terminated
A key point to remember is that, in general, at the wishes of the parents.1-5
sensitivity and specificity do not vary as a function
of prevalence; unless there is an influence of other SCREENING FOR CHROMOSOME
factors on the equation. However, positive and ABNORMALITIES
negative predictive values do. In a population in Merkatz et al. first published the association of low
which the prevalence is very low, the proportion of maternal serum alpha-fetoprotein with an increased
positives that will be false positive will be much risk of chromosome abnormalities, particularly Down
higher than in a population in which the prevalence Syndrome in 1984.6 Subsequently there was a gradual
is very high. In the former case the vast majority of acceptance of the association, as well as an eventual
positives will, in fact, be false positives. In both high understanding that Down syndrome is not the only
and low prevalence areas, the sensitivity and aneuploid condition association with low maternal
specificity of the tests should be the same. However, serum alpha-fetoprotein. For example, Trisomy 18
the positive and negative predictive values will be usually has even lower alpha-fetoprotein values.7
widely different. If a test is absolutely useless (no The adoption of wide scale screening with
better than chance) then the predictive value after maternal serum alpha-fetoprotein effectively doubled
testing will be the same as the population risk the potential detection of chromosome abnormalities
(prevalence) before testing. When this occurs, the in the population. Before the massive explosion of
test performs no better than a coin flip, and the infertility therapies, only about 20% of Down
sensitivity and specificity add to 100%. syndrome babies were born to women over age 35.
The past few years have seen continued More recent data suggest that the proportion of births
advancement in attempts to refine the sensitivity and to women over 35 has gone from about 5% to nearly
specificity of chromosomal screening, and to reduce 15%, and the proportion of Down Syndrome cases
 Chromosomal Abnormality Screening 997
in women over 35 is now more than 30%.8 The are of higher maternal weight16, and maternal weight
addition of a well coordinated maternal serum alpha- correction, per se, continues to be important.17,18
fetoprotein screening program as developed in the Over the past several years there have been
late 1980s could detect approximately 30% of the 75% numerous papers that have attempted to refine
of cases that are born to women under age 35. The methodologies of sample collection 21,22 and more
detailed mechanics of biochemical screening, i.e. with precisely explored the impact of various factors such
adjustments for gestational age, race, diabetic status, as more precise dating or the efficacy of Down
multiple gestation status, maternal weight, and Syndrome detection rates23,24 likewise with an ever
adjustments via a different database or correction increasing proportion of pregnancies resulting from
factors for maternal race, have been published infertility therapies, questions have risen as to
previously and will not be repeated here.9 whether modifications of risk or screening strategies
In 1988, Wald et al. suggested that a combination are required.25
of parameters including alpha-fetoprotein (AFP), beta A number of papers have suggested dimeric
human chorionic gonadotrophin (β-hCG), and inhibin A as an excellent marker that may raise the
unconjugated estriol (uE3) could significantly sensitivity by 3-7% for a given screen positive
increase the detection frequency of Down syndrome rate. 26-29 Out of this data have come calls for
to approximately 60% of the total.10 Multiple studies “quadruple” screening, and various combinations of
have corroborated the increased efficacy of multiple biochemical and biophysical (ultrasound) data. There
marker screening as opposed to AFP alone in are also paradigms that include different parameters
detecting chromosome abnormalities, particularly at different times combined. While preliminary data
Down syndrome.11-14 do suggest a high sensitivity with improved
Despite overwhelming data and recommen- specificity,30,31 hiding results from patients for up to
dations of national organizations such as the a month is ethically problematic in our opinion. No
American College of Obstetricians and Gynecologists doubt there will be multiple approaches to screening
that multiple numbers be offered, by the millennium that emerge, and there will be no one uniform
still nearly 20% of patients in the United States who standard approach.32
had screening were still just having AFP alone.15 A two-step approach has been the so called
Evans, et al. have investigated many of the “integrated” test.29-32 This is a combination of first
“dogmas” of three decades of biochemical screening trimester blood and ultrasound. The first trimester
and found that many of these are no longer valid. results are not communicated to the patient, who
We believe that the wide variance in results reported then waits for second trimester blood results before
from around the world is largely due to subtle and a risk assessment is completed. Two studies, the
sometimes not so subtle differences in laboratory “SURUSS” trial and the “FASTER” trial have data
methodologies.16-20 For example, the bitter arguments that suggest a reduced false positive rate for
about double versus triple screening are in part comparable sensitivity, but the trade off is the need
explained by wide differences in assays among labs for patients to wait as much as six weeks for start to
that particularly affect estriol. When the methods are finish of the screening process.30,31 For patients who
“standardized”, much of the variability disappears do not particularly care about the results, the delay
and will allow for an “apples vs. apples” as opposed may be fine, but our experience suggests that many
to “apples vs. oranges” comparison.20 Similarly, much anxious patients would find such delay intoler-
of the other reported variations in the literature able.33-36
likewise disappear with standardization, and the As reproductive techniques have dramatically
diabetic correction factor becomes unnecessary with increased the proportions of multiple pregnancies,
proper accounting for the fact that diabetic patients questions about the efficacy of screening tests have
998 Textbook of Perinatal Medicine

emerged. We and others have debated the data of on the motivation of the sonographer. Results were
biochemical screening on twins or more. There have compared from hospitals that used NT in clinical
been several papers that have promoted “pseudo practice (interventional) to those obtained in hospitals
risks” for twins by biochemical data. We continue to that recorded the measurements but did not act on
be concerned about the accuracy of these tests and the results (observational). In the interventional
believe that in multiples that biophysical data are group successful measurement of NT was achieved
more likely to be accurate.37-40 in 100% of cases and the measurement was >2.5 mm
in 2.3% of cases; the respective percentages in the
First Trimester observational group were 85% and 12%.43,44
The future of screening for Down Syndrome (and
other anomalies) lies in the first trimester. Substantial Guidelines
evidence now shows that free βHCG is reliably • Equipment to measure up to 0.1 mm and time
elevated and PAPP-A is diminished in Down’s allocated for each scan at least 10 minutes.
pregnancies.40-41 Data from multiple labs have been • Transabdominal or transvaginal route. The
consistent in suggesting 70% to even 90% detection
transabdominal route gives a success rate of 95%;
rates. In combination with ultrasound nuchal
in 5% of cases it is necessary to perform vaginal
translucency measurements, almost all publications
sonography.
in which the ultrasound component was performed
• Gestational age between 10+3 to 13+6 weeks (CRL
in a technically sound fashion have shown at least an
38-84 mm, BPD<27 mm). At these gestations the
70% sensitivity.42
success rate for obtaining a measurement is more
Several large scale studies – particularly the King
College group in London and the NICHD funded than 98%. From 14 weeks onwards the fetal
“BUN” and “FASTER” trials all essentially confirmed position (vertical) makes it more difficult to obtain
that 1st trimester data will be at least equal to routine measurements.45
2nd trimester double or triple screening.30,41 • Good sagittal section of the fetus, as for measure-
ment of fetal crown-rump length. An optimal
Measurement of Fetal Nuchal measurement is obtained when the fetus is in a
Translucency Thickness neutral position (neither in flexion nor in
Guidelines for measurement of fetal NT thickness extension).
have been drafted by the Fetal Medicine Foundation • Magnification so that the fetus occupies at least
(FMF). More than 300 centers around the world have 3/4rd and that each increment in the distance
adopted the FMF guidelines and they take part in between callipers is only 0.1 mm.
the quality control scheme. Quality control of ultra- • Distinguish between fetal skin and amnion (both
sound scans involves assessment of the distribution appear as thin membranes!) by waiting for
of NT measurements and assessment of randomly spontaneous fetal movement away from the
selected images in terms of magnification, section amniotic membrane. Alternatively, the fetus may
(sagittal or oblique), caliper placement, skin line be bounced off the amnion by asking the mother
(nuchal only or nuchal and back) and visualization to cough and/or by tapping the maternal
of the amnion separate from the nuchal membrane.35 abdomen.
The ability to measure NT and obtain repro- • Measure the maximum thickness of the
ducible results improves with training; good results subcutaneous translucency between the skin and
are achieved after 80 scans for the transabdominal the soft tissue overlying the cervical spine by
route and 100 scans transvaginally.42 The ability to placing the calipers on the lines as shown in the
achieve a reliable measurement of NT is dependent Figure underneath.
 Chromosomal Abnormality Screening 999
increased NT. Subsequent observational studies
examined in (high risk) pregnancies prior to invasive
testing the proportion of Down syndrome and
normal fetuses that present with increased NT.
Implementation studies then reported on the
feasibility of introducing screening by NT in routine
practice and, finally, centers that introduced the test
reported experience with screening based on the
Ultrasound measurement of the fetal neck at 12 wk combination of maternal age, gestational age and fetal
The umbilical cord may be round the fetal neck NT thickness.
in 5-10% of cases and this can produce an increased Observational Studies
NT as it adds about 0.8 mm to the measurement.46
Measurements of NT above and below the cord will In the early 1990s, several reports on fetuses with
increased NT demonstrated a possible association
be different and in the calculation of risk it is
between NT and chromosome defects in the first
appropriate to use the smaller measurement. It is well
trimester of pregnancy (Table 73.2).52-65 The mean
established that NT normally increases with
prevalence of chromosome defects in 14 series
gestational age.47-51 Therefore, the difference from
involving 1,457 patients was 28%. However, the
the normal median for gestation is used to determine
percentage ranged from 19 to 88%. This variation in
the factor by which the age-related risk is adjusted.
results presumably reflects differences in the
maternal age distributions and differences in the
Increased NT and Chromosome Defects
definition of minimum thickness of the abnormal
Studies that report on first trimester fetal NT translucency, ranging from 2 to 10 mm.
thickness and chromosome defects can be divided In subsequent studies NT thickness was assessed
in four groups. Initial observational studies examined immediately before fetal karyotyping, mainly for
the prevalence of chromosome defects in fetuses with advanced maternal age. Detection rates for trisomy

Table 73.2: Summary of reported series on first trimester fetal nuchal translucency (NT) providing data on
gestational age (GA) in weeks, criteria for diagnosis of increased NT thickness and the presence of
associated chromosome defects (T21 = trisomy 21, T18 = trisomy 18, T13 = trisomy 13).
Author GA (wk) NT (mm) N Abnormal karyotype
Total T21 T18 T13 45,X Other
Johnson 1993 -52 10-14 >2.0 68 41 (60%) 16 9 2 9 5
Hewitt 1993 -53 10-14 >2.0 29 12 (41%) 5 3 1 2 1
Shulman 1992 -54 10-13 >2.5 32 15 (47%) 4 4 3 4 0
Nicolaides 1992 -55 10-13 >3.0 88 33 (38%) 21 8 2 0 2
Pandya 1995 -56 10-13 >3.0 1,015 193 (19%) 101 51 13 14 15
Szabo and Gellen 1990 -57 11-12 >3.0 8 7 (88%) 7 0 0 0 0
Wilson et al 1992 -58 8-11 >3.0 14 3 (21%) 0 0 0 1 2
Ville et al 1992 -59 9-14 >3.0 29 7 (28%) 4 3 1 0 0
Trauffer et al 1994 -60 10-14 >3.0 43 21 (49%) 9 4 1 4 3
Nadel et al 1993 -61 10-15 >4.0 63 43 (68%) 15 15 1 10 2
Schulte-Valentin 1992 -62 10-14 >4.0 8 7 (88%) 7 0 0 0 0
Van Zalen-Sprock1992 -63 10-14 >4.0 18 5 (28%) 3 1 0 1 1
Cullen et al 1990 -64 11-13 >6.0 29 15 (52%) 6 2 0 4 3
Suchet 1992 -65 8-14 >10.0 13 8 (62%) 0 0 0 7 1
1,457 413 (28%) 198 100 24 56 35
55-56
1000 Textbook of Perinatal Medicine

Table 73.3: Summary of reported series on first trimester fetal NT before amniocentesis or CVS providing data on
gestational age (GA) in weeks, criteria for diagnosis of increased NT thickness, false positive rate (FPR),
detection rate (DR) and odds of an affected pregnancy (OAP) for trisomy 21
Author GA Nt cut-off N FPR DR trisomy 21 OAP trisomy 21
(wks)
Nicolaides et al 1994 67 10-13 >3 mm 1273 4% 84% (21/25) 1 in 4
Zimmerman et al 1996 68 10-13 >3 mm 1151 2% 67% ( 2/ 3) 1 in 12
Hewitt et al 1996 54 10-14 >3 mm 1312 4% 57% (12/21) 1 in 5
Comas et al 1995 69 9-13 >3 mm 487 1% 57% ( 4/ 7) 1 in 13
Salvodelli et al 1993 70 9-12 >3 mm 1400 <1% 54% (15/28) 1 in 2
Borell et al 1997 71 10-13 >3 mm 479 6% 44% ( 8/18) 1 in 5
Haddow et al 1998 51 9-15 95th 3308 5% 31% (18/58) 1 in 10
Brambati et al 1995 52 8-15 >3 mm 1819 2% 30% ( 8/26) 1 in 7
Scott et al 1996 72 9-13 95th 445 5% 30% ( 3/10) 1 in 8

21 varied from 30% to 84% (Table 73.3)66-71 with false Public Policy
positive rates ranging from 1% to 6%. Detection rates
Why then hasn’t first trimester screening already
were relatively low if measurements were taken
replaced the second trimester testing? The answers
before 10 weeks of gestation, and/or machines
are complex, but can be divided into several different
measured whole mm only.50,51
categories. Firstly many patients do not come for
prenatal care until the second trimester. It is well
Increased NT and Normal Karyotype
known that there are universal correlation between
Souka et al72 recently presented findings in 4,116 socioeconomic status and gestational age at first visit
chromosomally normal fetuses with increased NT for prenatal care. No matter how good a 1st trimester
together with a review of the literature. There are test is, it does no good for a patient first seen at 24
at least five conditions that may underlie increased weeks.77
NT and these include heart defects or heart failure, Secondly, even in 2001 with voluminous articles
intathoracic compression, altered composition of the and college opinions touting multiple markers, 20%
dermis, abnormal lymphatic system and neuro- of patients were still getting the 1980’s model of AFP
muscular abnormalities. alone. 15 Significant professional education will be
needed to leap frog the practice in 1st trimester
Heart Defects screening.
Two fetal echocardiographic studies at 10-16 weeks Thirdly, until immediate invasive testing is readily
of gestation reported that 16 (80%) of the 20 fetuses available and accepted, first trimester screening
with cardiac defects had abnormal collection of results would be worse than none if the patient then
nuchal fluid. 73,74 In addition, a study of 29,154 had to wait a month to have an amniocentesis for a
pregnancies demonstrated that the prevalence of Table 73.4: Prevalence of major cardiac defects in chromo-
cardiac defects increases with increasing NT. In somally normal fetuses with increased NT thickness
fetuses with a NT <95th percentile was 0.8 per 1000 NT thickness N Cardiac defects
compared to 15 per 1000 in the group with increased
<95th centile 27,332 0.8/1000 (~1 in 1,250)
NT thickness (Table 73.4). 75-76 Examination of 95th centile-3.4 mm 1,507 5/1000 (~1 in 200)
chromosomally normal pregnancies with a NT of 3.5 3.5-4.4 mm 208 29/1000 (~1 in 35)
mm or more (1% of the population) at 15-20 weeks 4.5-5.4 mm 66 91/1000 (~1 in 10)
>5.5 mm 41 195/1000 (~1 in 5)
by an echocardiographer identifies approximately
Total 29,154 1.7/1000
40% of significant cardiac defects.
 Chromosomal Abnormality Screening 1001
definitive answer.35-66 We see this as very problematic Cohorts of Down Syndrome risk were usually
for the “integrated” test that combines 1st and 2nd reported in five year groupings, and there was clearly
trimester lab results and ultrasound. CVS has long a big jump from the 30-34 to 35-39 age group. It was
since proven to be safe and effective in experienced only later when data were reported on a year age
hands. As the so called limb reduction defect scare specific curve that the slope of the curve was shown
has been shown to be false at appropriate gestational to be changing before age 35. Furthermore, the
ages hopefully the availability of CVS and acceptance difference from one year to the next was obviously
will swing the pendulum back towards the desire no where as dramatic as suggested in the 5 year
for 1st trimester screening for testing which as many cohorts. 9
advantages in the patient. We actually expect the Another dramatic development of the 1970’s was
concept of maternal age as a stand alone variable to changing laws in the USA concerning a woman’s right
be phased out over the next several years.77 to end a pregnancy. New York and California were
among the first states to repeal laws that made
Trisomy 18
abortion virtually impossible to obtain legally. In 1973
Although screening has generally focused on Trisomy the US Supreme Court ruled that in the first trimester
21, our data, and those of others has always shown a state had very little rights to interfere with a
a varied pattern of anomalies detected by screening.78 woman’s defined right of privacy in terminating a
A different pattern of analyte levels has been pregnancy.82-83 In the second trimester the state’s
observed in Trisomy 18. The values of AFP, hCG, interests were primarily only in ensuring the safety
and uE3 appear to be very low. 79 This suggests a of the procedure. It was only the third trimester that
different pathophysiology than for Down syndrome. the state could exert a compelling interest in protec-
In Down syndrome, the low AFP and uE3, and high ting the “rights” of the fetus over the mother’s
hCG can be explained as reflecting inappropriate wishes.
immaturity or dysmaturity of the fetus, i.e. all values The combination of new technology plus the
are consistent with a younger gestational age. In ability to terminate abnormal pregnancies led to a
Trisomy 18 however, that explanation does not surge of interest in prenatal diagnosis. As with most
work. 80 We have previously shown that there are new technologies, utilization was initially highest
different patterns of genomically directed intra- among patients of upper socioeconomic status who
uterine growth retardation in different aneu- had the knowledge of the availability of the
ploidies78 but how this translates into serum markers technology as well as the means to travel to far off
is unclear. Nevertheless some reports have shown centers to obtain such services.84
that an algorithm can be used to identify the majority The evidence is clearly that first trimester
screening followed by first trimester diagnosis by
of Trisomy 18 cases while adding about 0.75% to the
CVS can bring about a substantially higher sensitivity
population being offered amniocentesis.80,81
and specificity within the same time frame as AMA
THE END OF “ADVANCED MATERNAL AGE” offered CVS is overwhelming. The question thus
reduces to how and when to update the accepted
The association of advanced maternal age (AMA) “culture” in the United States to be consistent with
with increasing risks of chromosomal abnormalities the current scientific knowledge base.
particularly Down Syndrome has been appreciated There has to be the understanding that age is not
for decades. being discarded, but will merely become one of a
The choice of age 35 at least in the United States number of variables that can be assessed to give the
of America (USA) was an arbitrary compromise most accurate assessment of risk possible. With
determined in part by naivety in data collection. education, the ultrasound portion of the equation
1002 Textbook of Perinatal Medicine

Screening for Chromosomal

Abnormalities
100
90
80 Missed
70
% 60 Double/
Detection 50 Triple
40 MSAFP
30
20
10 MA 35
0
Fig. 73.4: Maternal age 35 identifies about 25% of Down Syndrome pregnancies. Low AFP brings the total to about 50%.
Double or triple screening raises that number to about 60%. Half of the 80% of cases occurring to women under 35 are
detectable.

will become more standardized to laboratory levels It is time for advance maternal age, as a stand
of quality assurance. Non profit organizations such alone criteria, for having invasive testing to go the
as the Fetal Medicine Foundation in London, and way of the buggy whip. The principal objection to
the Fetal Medicine Foundation in America as well as screening as entry to testing has been removed. It
certainly others will help coordinate the transition can all now be done in the first trimester. The science
and training needed to make such a reality. has evolved. It is now time for the culture and the
It is also not realistic to expect a shift of standards to follow.
“standards” and practice to change on a single day.
Thus, there will have to be a short phase in period, REFERENCES
under which wither the old or the new approach
1. Evans MI, Krivchenia EL, Yaron Y: Screening in Evans
will be considered acceptable. However, it is also
MI and Bui: Genomic Revolution and Obstetrics and
reasonable to expect that the insurance companies Gynecology. Balliere’s Clinical Obstetrics and
who will have to pay for such to vociferously and Gynecology 16:645-658, 2002.
clearly articulate to their subscribers and physicians, 2. Evans MI, Chik L, O’Brien JE, Chen B, Dvorin E, Ayoub
M, et al. MOMs and DADS: improved specificity and cost
that they are not about to vastly increase the numbers
effectiveness of biochemical screening for aneuploidy
of patients having tests. Thus, the right will be likely with DADS. Am J Obstet Gynecol 172:1138-1147, 1995
the “right” to pay out of one’s own pocket for testing 3. Evans MI, Chik L, O’Brien JE, Dvorin E, Johnson MP,
for AMA, per se. Krivchenia E, Sokol Rj. Logistic regression generated
 Chromosomal Abnormality Screening 1003
probability estimates for trisomy 21 outcomes from dependent diabetes in maternal serum alpha fetoprotein
serum AFP and BHCG: Simplification with increased testing has outlived its usefulness.Am. J. Obstet and
specificity. Mat Fetal Med 5:1-6, 1996 Gynecol 187:1084-6, 2002
4. Evans MI, Sobecki MA, Krivchenia EL, Duquette DA, 17. Evans MI, Harrison HH, O’Brien JE, Huang X,
Johnson MP, Drugan A, Hume RF. Parental decisions Chervenak FA, Henry GP, Wapner RJ. Maternal weight
to terminate/continue following abnormal cytogenetic correction for alpha fetoprotein: mathematical trun-
prenatal diagnosis: “What” is still more important than cations revisited. Genetic Testing. 6:221-223, 2002
“when. Am J Med Genet 61:353-355, 1996 18. Spencer K, Bindra R, Micolaides KH. Maternal weight
5. Pryde PG, Odgers AE, Isada NB, Johnson MP, Evans correction of maternal serum PAPP-A and free beta-hCG
MI. Determinants of parental decision to abort or MoM when screening for trisomy 21 in the first
continue for non-aneuploid ultrasound detected trimester pregnancy. Prenat Diagn 23(10):851-5, 2003.
abnormalities. Obstet Gynec 80:52-56, 1992 19. Evans MI, O’Brien JE, Dvorun E, et al: Standardization
6. Merkatz IR, Nitowsky FM, Macri JN, Johnson WE. An of methods reduces variability: explanation for the
association between low maternal serum alpha- historical discrepancies in Biochemical Screening. Genetic
fetoprotein and fetal chromosome abnormalities. Am J Testing 7:81-83, 2003.
Obstet Gynecol 148:886-894, 1984. 20. Spencer K. The influence of different sample collection
7. Nyberg DA, Kramer D, Resta RG, Kapur R, Mahony types on the levels of markers used for Down’s
BS, Luthy DA, Hickok D. Prenatal monographic findings syndrome screening as measured by the Kryptor
of trisomy 18: review of 47 cases. J Ultrasound Med Immunosassay system. Ann Clin Biochem 40(Pt 2):166-
2:103-113, 1993. 8, 2003.
21. Spencer K, Crossley JA, Aitken DA, Nix AB, Dunstan
8. Martin JA, Hamilton BE, Ventura SJ, et al. Births: Final
FD, Williams K. Temporal changes in maternal serum
data for 2001. National Vital Statistics Report 51, #2.
biochemical markers of trisomy 21 across the first and
National Center for Health Statistics, Hyattsville, MD
second trimester of pregnancy. Ann Clin Biochem 39(Pt
2002.
6):567-76, 2002.
9. Evans MI, Krivchenia EL, Yaron: Screening. In Evans,
22. Ghisoni L, Ferrazzi E, Castagna C, Levi Setti PE, Masini
MI, Bui, TH (eds). The Genome Revolution and
AC, Pigni A. Prenatal diagnosis after ART success: the
Obstetrics and Gynecology. Balliere’s Best Practice and
role of early combined screening tests in counseling
Research in Clinical Obstetrics and Gynecology.
pregnant patients. Placenta Suppl B:S99-S103, 2003.
Harcourt Brace Publishing Co., London, 16: 2002 16:624-
23. Donnenfeld AE, Icke KV, Pargas C, Dowman C.
657. Biochemical screening for aneuploidy in ovum donor
10. Wald NJ, Cuckle HS, Densem JW, Nanchahal K, Royston pregnancies. Am J Obstet Gynecol., Nov; 187(5):1222-5,
P, Chard T, et al. Maternal serum screening for Down 2002.
syndrome in early pregnancy. Br Med J 297:883-887, 24. Canick JA, Saller DN Jr, Lambert-Messerlian GM.
1988. Prenatal screening for Down syndrome: current and
11. Cheng EY, Luthy DA, Zebelman AM, Williams MA, future methods. Clin Lab Med 23(2):395-411, 2003.
Lieppman RE, Hickok DE. A prospective evaluation of 25. Silver HM, Lambert-Messerlian GM, Reis FM, diblasio
a second-trimester screening test for fetal Down AM, Petraglia P, Canick JA. Mechanism of increased
syndrome using maternal serum alpha-fetoprotein, maternal serum total activin a and inhibin a in
hCG, and unconjugated estriol. Obstet Gynecol 81:72- preeclampsia. J Soc Gynecol Investig 9(5):308-12, 2002.
77, 1993. 26. Wald NJ, Huttly WJ, Hackshaw AK. Antenatal screening
12. Aitken DA, McCaw G, Crossley JA, Berry E, Connor for Down’s syndrome with the quadruple test. Lancet
JM, Spencer K, et al. First-trimester biochemical 8;361(9360):835-6, 2003.
screening for fetal chromosome abnormalities and 27. Benn PA, Fang M, Egan JF, Horne D, Collins R.
neural tube defects. Prenat Diagn 13:681-683, 1993. Incorporation of inhibin-A in second-trimester
13. Wald N, Densem J, Stone R, Cheng R. The use of free screening for Down syndrome. Obstet Gynecol.
1993, ?-hCG -in antenatal screening for Down’s 102(2):413; author reply 413-4, 2003
syndrome. Br J Obstet Gynaecol 100:550-557, 1993. 28. Spencer K, Liao AW, Ong CY, Geerts L, Nicolaides KH.
14. Goodburn SF, Yates JRW, Raggatt PR, Caff C, Maternal serum levels of dimeric inhibin A in
Ferguson-Smith ME, Kershaw Ai, et al. Second-trimester pregnancies affected by Trisomy 21 in the first trimester.
maternal serum screening using alpha-fetoprotein, Prenat Diagn 21(6):441-4, 2001.
human chorionic gonadotrophin, and unconjugated 29. Malone et al: Faster trial. NEJM (In press) 2004.
oestriol: experience of a regional programme. Prenat 30. Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L,
Diagn 14:391-402, 1994. Mackinson AM. First and second trimester antenatal
15. Evans MI - Unpublished Data screening for Down’s syndrome: the results of the
16. Evans MI, Harrison HH, O’Brien JE, Dvorin E, Huang Serum, Urine and Ultrasound Screening Study
X, Krivchenia EL, Reece EA. Correction for insulin (SURUSS). J Med Screen 10(2):56-104, 2003.
1004 Textbook of Perinatal Medicine

31. Cuckle HS. Growing complexity in the choice of Down’s 44. Bower S, Chitty L, Bewley S, Roberts L, Clark T, Fisk
Syndrome screening Policy. Ultrasound Obstet Gynecol NM, Maxwell D, Rodeck CH. (1995) First trimester
19:323-326, 2002 nuchal translucency screening of the general population:
32. Souter VL, Nyberg DA, Benn PA, Zebelman A, Luthardt data from three centres [abstract]. 27th British Congress
F, Luthy DA. Correlation of second-trimester sono- of Obstetrics and Gynaecolology.
graphic and biochemical markers. J Ultrasound Med 45. Roberts LJ, Bewley S, Mackinson AM, Rodeck CH. First
23(4):505-11, 2004. trimester fetal nuchal translucency: Problems with
33. Cusick W, Buchanan P, Hallahan TW, Krantz DA, Larsen screening the general population 1. Br J Obstet Gynaecol
JW Jr, Macri JN. Combined first-trimester versus 1995;102:381-385.
second-trimester serum screening for Down syndrome: 46. Whitlow BJ, Economides DL. The optimal gestational age
a cost analysis. Am J Obstet Gynecol. 188(3):745-51, 2003. to examine fetal anatomy and measure nuchal
34. Muller F, Benattar C, Audibert F, Roussel N, Dreux S, translucency in the first trimester. Ultrasound Obstet
Cuckle H. First-trimester screening for Down syndrome Gynecol, 1998;11:258-261.
in France combining fetal nuchal translucency 47. Schaefer M. Laurichesse-Delmas H. Ville Y. The effect
measurement and biochemical markers. Prenat Diagn of nuchal cord on nuchal translucency measurement at
23(10):833-6, 2003.
10-14 weeks. Ultrasound Obstet Gynecol, 1998;11(4):271-
35. Nicolaides KH, Bindra R, Heath V, Cicero S. One-stop
3.
clinic for assessment of risk of chromosomal defects at
48. Pandya PP, Goldberg H, Walton B, Riddle A, Shelley S,
12 weeks of gestation. J Matern Fetal Neonatal Med
Snijders RJM, Nicolaides KH. The implementation of first
12(1):9-18, 2002.
trimester scanning at 10-13 weeks’ gestation and the
36. Crossley JA, Aitken DA, Cameron AD, McBride E,
Connor JM. Combined ultrasound and biochemical measurement of fetal nuchal translucency thickness in
screening for Down’s syndrome in the first trimester: a two maternity units. Ultrasound Obstet Gynaecol 1995a;
Scottish multicentre study. BJOG 109(6):667-76, 2002. 5:20-5.
37. Drugan A, O’Brien JE, Dvorin E, Krivchenia EL, Johnson 49. Pajkrt E. de Graaf IM. Mol BW. van Lith JM. Bleker OP.
MP, Sokol RJ, Evans MI. Multiple marker screening in Bilardo CM. Weekly nuchal translucency measurements
multifetal gestations: prediction of adverse pregnancy in normal fetuses. Obstet Gynecol, 1998;91(2):208-11.
outcomes. Fetal Diagnosis and Therapy 11:16-19, 1996. 50. Yagel S, Anteby EY, Rosen L, Yaffe E, Rabinowitz R,
38. O’Brien JE, Dvorin E, Yaron Y, Ayoub M, Johnson MP, Tadmor O. Assessment of first-trimester nuchal
Hume RF, Evans MI. Differential increases in AFP, HCG, translucency by daily reference intervals. Ultrasound
and uE3 in twin pregnancies: Impact upon attempts to Obstet Gynecol 1998 Apr;11:262-265.
quantify Down syndrome screening calculations. 51. Haddow JE, Palomaki GE, Knight GJ, Williams J, Miller
American Journal of Medical Genetics 73:109-112,1997. WA, Johnson A. Screening of maternal serum for fetal
39. Wald N, Cuckle H, Wu TS, George L. Maternal serum Down’s syndrome in the first trimester. N Eng J Med
unconjugated oestriol and human chorionic 1998;338:955-61.
gonadotrophin levels in twin pregnancies: implications 52. Brambati B, Cislaghi C, Tului L, Alberti E, Amidani M,
for screening for Down’s syndrome. Br J Obstet Colombo U, Zuliani G. First-trimester Down’s syndrome
Gynaecol 98(9):905-8, 1991. screening using nuchal translucency: a prospective
40. Cuckle H. Down’s syndrome screening in twins. J Med study. Ultrasound Obstet Gynecol 1995;5: 9-14.
Screen 5(1):3-4, 1998. 53. Johnson MP, Johnson A, Holzgreve W, Isada NB,
41. Wald NJ, Rish S, Hackshaw AK. Combining nuchal Wapner RJ, Treadwell MC, Heeger S, Evans M. First-
translucency and serum markers in prenatal screening trimester simple hygroma: Cause and outcome. Am J
for Down syndrome in twin pregnancies. Prenat Diagn Obstet Gynecol 1993;168:156-61.
23(7):588-92, 2003.
54. Hewitt BG, de Crespigny L, Sampson AJ, Ngu AC,
42. Wapner R, Thom E, Simpson JL, Pergament E, Silver R,
Shekleton P, Robinson HP. Correlation between nuchal
Filkins K, Plat L, Mahoney M, Johnson A, Hogge WA,
thickness and abnormal karyotype in first trimester
Wilson RD, Mohide P, Hershey D, Krantz D, Zachary J,
fetuses. Med J Aust 1996 Oct 7;165(7):365-8.
Snijders R, Greene N, Sabbagha R, MacGregor S, Hill L,
55. Shulman LP, Emerson D, Felker R, Phillips O, Simpson
Gagnon A, Ha llahan T, Jackson L; First trimester
maternal serum biochemistry and fetal nuchal J, Elias S. High frequency of cytogenetic abnormalities
translucency screening (BUN) study group. First- with cystic hygroma diagnosed in the first trimester.
trimester screening for trisomies 21 and 18. N Engl J Obstet Gynecol 1992;80:80-2.
Med 349(15):1405-13, 2003. 56. Nicolaides KH, Azar G, Snijders RJM, Gosden CM. Fetal
43. Braithwaite JM, Morris RW, Economides DL. Nuchal nuchal oedema: associated malformations and
translucency measurements: frequency distribution and chromosomal defects. Fetal Diagn Ther 1992;7:123
changes with gestation in a general population. Br J 57. Pandya PP, Altman D, Brizot ML, Pettersen H, Nicolaides
Obstet Gynaecol; 1996;103:1201-1204. KH. Repeatability of measurement of fetal nuchal
 Chromosomal Abnormality Screening 1005
translucency thickness. Ultrasound Obstet Gynaecol translucency across the first trimester. Pren Diagn
1995a;5:334-37. 1996;16:629-634.
58. Szabo J, Gellen J. Nuchal fluid accumulation in trisomy- 73. Souka AP, Nicolaides KH. Diagnosis of fetal abnor-
21 detected by vaginal sonography in first trimester. malities at the 10-14 week scan. Ultrasound Obstet
Lancet 1990;336:1133. Gynecol 1997;10:429-442.
59. Wilson RD, Venir N, Faquharson DF. Fetal nuchal fluid- 74. Souka AP, Snijders RJM, Novakov A, Soares W,
physiological or pathological?-in pregnancies less than Nicolaides KH. Defects and syndromes in chromo-
17 menstrual weeks. Prenat Diagn 1992;12:755-63. somally normal fetuses with increased nuchal
60. Ville Y, Lalondrelle C, Doumerc S, Daffos F, Frydman translucency thickness at 10-14 weeks of gestation.
R, Oury JF, Dumez Y. First-trimester diagnosis of nuchal Ultrasound Obstet Gynecol 1998;11:391-400.
anomalies: significance and fetal outcome. Ultrasound 75. Gembruch U, Knopfle G, Bald R, Hansmann M. Early
Obstet Gynecol 1992;2:314-6 diagnosis of fetal congenital heart disease by
61. Trauffer PL, Anderson CE, Johnson A, Heeger S, transvaginal echocardiography. Ultrasound Obstet
Morgan P, Wapner RJ. The natural history of euploid Gynecol 1993;3:310-317.
pregnancies with first-trimester cystic hygromas. Am 76. Achiron R, Rotstein Z, Lipitz S, Mashiach S, Hegesh J.
Obstet Gynecol 1994;170:1279-84. First-trimester diagnosis of fetal congenital heart disease
62. Nadel A, Bromley B, Benacerraf BR. Nuchal thickening by transvaginal ultrasonography. Obstet. Gynecol
or cystic hygromas in first- and early second-trimester 1994;84:69-72.
fetuses: prognosis and outcome. Obstet Gynecol 1993;82: 77. Hyett J, Perdu M, Sharland G, Snijders R, Nicolaides KH,
43-8. Using fetal nuchal translucency to screen for major
63. Schulte-Vallentin M, Schindler H. Non-echogenic nuchal congenital cardiac defects at 10-14 weeks of gestation:
oedema as a marker in trisomy 21 screening. Lancet population based cohort study. BMJ 1999;318:81-85.
1992;339: 1053. 78. Hyett J.A., Perdu M., Sharland G.K., Snijders R.S.,
64. Van Zalen-Sprock MM, Van Vugt JMG, Van Geijn HP. Nicolaides K.H. Increased nuchal translucency at 10-14
First-trimester diagnosis of cystic hygroma - course and weeks of gestation as a marker for major cardiac defects.
outcome. Am J Obstet Gynecol 1992;167; 94-8 Ultrasound Obstet Gynecol 1997;10(4):242-6
65. Cullen MT, Gabrielli S, Green JJ, Rizzo N, Mahoney MJ, 79. Evans MI, Macri JN, Galen RS, Drugan A: Biochemical
Salafia C, Bovicelli L, Hobbins JC. Diagnosis and
Screening in Evans MI, Johnson MP, Yaron Y, Drugan
significance of cystic hygroma in the first trimester.
A: Prenatal Diagnosis McGraw Hill Phil Co NY (In press)
Prenat Diagn 1990;10: 643-51.
80. Johnson MP, Barr Jr, M, Qureshi F, Drugan A, Evans
66. Suchet IB, Van der Westhuizen NG, Labatte MF. Fetal
MI. Symmetrical intrauterine growth retardation is not
cystic hygromas: further insights into their natural
symmetrical: the ontogeny of organ specific gravimetric
history. Can Assoc Radiol J 1992;6:420-4.
deficits in midtrimester and neonatal trisomy 18. Fetal
67. Nicolaides KH, Azar G, Byrne D, Mansur , Marks K.
Diagnosis and Therapy 1989 (released 1990);4:110-119.
Fetal nuchal translucency: ultrasound screening for
81. Drugan A, Dvorin E, Koppitch FC, Greb A, Krivchenia
chromosomal defects in first trimester of pregnancy. Br
EL, Evans MI. Counseling for low maternal serum
Med J 1992;304:867 69.
68. Zimmerman R, Hucha A, Savoldelli G, Binkert F, alpha-fetoprotein should emphasize all chromosome
Acherman J, Grudzinskas JG. Serum parameters and anomalies, not just Down Syndrome! Obstet Gynecol
nuchal translucency in first trimester screening for fetal 73:271-274, 1989.
chromosomal abnormalities. Br J Obstet Gynaecol 82. Palomaki GE, Haddow JE, Knight GJ, et al. Risk-based
1996;103:1009-1014. prenatal screening for trisomy 18 using alpha-
69. Comas C, Martinez JM, Ojuel J, Casals E, Puerto B, Borrell fetoprotein, unconjugated estriol, and human chorionic
A, Fortuny A. First-trimester nuchal edema as a marker gonadotropin. Prenat Diagn. 15:713, 1995.
of aneuploidy. Ultrasound Obstet Gynecol 1995;5:26-9. 83. Leporrier N, Herrou M, Morello R, Leymarie P. Fetuses
70. Savoldelli G, Binkert F, Achermann J, Schmid W. Ultra- with Down’s syndrome detected by prenatal screening
sound screening for chromosomal anomalies in the first are more likely to abort spontaneously than fetuses
trimester of pregnancy. Prenat Diagn 1993;13:513-8. with Down’s syndrome not detected by prenatal
71. Borell A, Costas D, Martinez JM, Delgado RD, Farguell screening. BJOG 110(1):18-21, 2003.
T, Fortuny A. Criteria for fetal nuchal thickness cut-off: 84. US Supreme Court: Roe vs. Wade 410 US, 113 (1973).
a re-evaluation. Pren Diagn 1997;17:23-29. 85. US Supreme Court: Doe vs. Bolton 410 US, 179 (1973)
72. Scott F, Boogert A, Sinosich M, Anderson J. Esta- 86. Evans MI, Hanft RS: The introduction of new techno-
blishment and application of a normal range for nuchal logies. ACOG clinical seminars 2:1-3, 1997.
1006 Textbook of Perinatal Medicine

74
Amniocentesis

S Tercanli, P Miny, W Holzgreve

INTRODUCTION Prior to any prenatal invasive test, patients should

be counselled. The risks and benefits of all invasive
Mid-trimester amniocentesis is the most commonly
and non-invasive tests must be discussed as well as
performed invasive technique in prenatal diagnosis.
Valenti et al. reported the first successful diagnosis the limitations of any procedure. In the cases of
of Down’s syndrome in 1968.1 Since that time the specific risk factors or abnormal ultrasound findings
number of mid trimester amniocentesis has increased the information should be as complete and
dramatically and amniocentesis is nowadays an appropriate as possible. Considering the current
established standard tool in the assessment of developments in prenatal diagnosis by performing
pregnancies that are at risk for a variety of advanced methods for individual risk calculation ,e.g.
chromosomal disorders, single gene defects, nuchal translucency measurement and biochemical
biochemical analysis and fetal infections etc. serum marker screening, counselling of pregnant
Chromosome analysis and tests related to risk women will become more and more important. It
screening for aneuploidy remain world wide by far can be assumed that in this context a more selective
the most common laboratory procedures in prenatal approach to invasive testing may result in the next
diagnosis. Conventional chromosome analysis has years. One of the significant problems in counselling
maintained its role as a gold standard for the primary pregnant women is still how to explain women (e.g.
exclusion of aneuploidy from amniotic fluid cells. social-economical, ethical, cultural variability) the
Frequent indications listed in table 1 for offering complex implications of risk calculation. Own
second trimester amniocentesis are pregnancies experiences showed that appropriate individual
considered to be at an increased risk (Table 74.1). counselling is more time consuming and requires
more appropriate methods.
Table 74.1: Common indications for amniocentesis
• Advanced maternal age (= 35 years old)
TECHNIQUE
• Family history for chromosome anomalies, single gene
defects etc. Mid trimester amniocentesis is commonly performed
• Abnormal maternal serum screening in the second
trimester
between 15-16 weeks of gestation (Figs 74.1 and 74.2).
• Increased risk for chromosomal anomalies following first Prior to the procedure ultrasound evaluation of the
trimester screening – if chorionic villus sampling is not uterus (e.g. exclusion of fibroids), the fetus, amniotic
available
fluid volume, and position of the placenta is
• Abnormal ultrasound findings
• Maternal infections potentially affecting the fetus recommended, because the failure rate can be
 Amniocentesis 1007

Fig. 74.2: Second - trimester amniocentesis

under ultrasound guidance

Operator experience may also prejudice the fetal loss

rate but this has not been definitively determined.6
Fig. 74.1: Diagram of amniocentesis. Transplacental
perforation should be avoided if possible However there is a general agreement that the
number of genetic amniocentesis needed to be
reduced by avoiding the removal of bloody fluid or trained and maintaining stable ongoing expertise is
multiple injections.2-4 Patients anxiety may be reduced recommended. 7-9 Exceptionally in multiple preg-
if adequate information is given to the patients during nancies amniocentesis should be performed by
the procedure at each step. After disinfection of the trained investigators. Amniocentesis in twin
maternal abdomen amniocentesis is performed under pregnancies consists in obtaining of amniotic fluid
direct ultrasound guidance generally using a 18-20 from both cavities. As recommended in the past dye
gauge needle. The obtained amniotic fluid volume injection in to the first punctured sac was performed
should be not more than 1 ml per gestational week. routinely.10 Advanced ultrasound technology allows
The first 2 ml of amniotic fluid should be rejected in the evaluation of both fetuses and makes dye
order to avoid maternal cell contamination. If bloody injection obsolete in experienced hands. Controversy
amniotic fluid is aspirated the analysis of the is ongoing whether both amniotic sacs should be
chromosomes from cultured cells will take longer injected in cases of monochorionic diamniotic twins.
time and there might be a slightly higher risk for In dichorionic twins a single needle insertion
misdiagnosis due to the risk of culturing maternal technique is often favoured, but may result in
cells from any other tissue other than blood cells. In cytogenetic problems. On the other hand it is
women with Rh-negative blood group Rh- immune unknown whether a single needle technique may
globuline must be administered, if the father of the induce a rupture of the membrane.
child is Rh-positive or his blood group is unknown.
CYTOGENETIC ASPECTS
Following the procedure it seems helpful to
demonstrate the fetus again to the mother by Compared to other methods for prenatal karyotyping
ultrasound evaluation. There is no clear evidence in the benefits of an amniocentesis are the simplicity of
the literature that ultrasound guidance itself will the implementation of the procedure and the
reduce the fetal loss rate, but these may lower the convenience of the analysis for the cytogenetic lab.
maternal fears. In contrast it is assumed that the In clinical practice the level of a-fetoprotein (AFP) in
abortion rate increases if the placenta is perforated.5 amniotic fluid is determined routinely. Currently it
1008 Textbook of Perinatal Medicine

is debated that these may not longer be needed fluid, vaginal bleeding, contractions, chorio-
because high resolution ultrasound is able to detect amnionitis, failure to obtain a sample, pregnancy loss,
neural tube defect and abdominal wall defects. and possibly fetal injury.5,16-23
However, the detection of spina bifida is depending Actual fetal loss rates related to genetic
on the experiences of the sonographer. Therefore amniocentesis vary among randomized studies and
evaluation of AFP in the amniotic fluid is still may be comixed by transplacental needle passage,
recommended. multiple needle insertion and use of larger needles
Cell culture as a prerequisite for conventional sizes.17-19
chromosome analysis on amniocytes causes a turn The total fetal loss rate related to the procedure
around time of at least one week. In practice the is often calculated to be around 0.5%.24 But in many
average processing time is probably close to two studies the source for this reported level of risk was
weeks in most of the labs. Ongoing trends in prenatal nondistinctive, and the background risk for
diagnosis aim at early and rapid diagnosis as well as miscarriage was unaccounted. In the three larger
at the improvement of risk-screening for aneuploidy. multicenter studies the risk for fetal loss following
Flourescent in situ hybridization (FISH) on interphase amniocentesis was approximately 1%, but bias due
amniocytes and quantitative fluorescence polymerase
to selection can not be excluded.3,7,22 These results
chain reaction (QF-PCR ) are efficient tools for the
were comparable with the former findings in the only
rapid exclusion of selected aneuploidies.11 Regarding
randomizied controlled trial reported by Tabor. 5
the overall detection rate of unbalanced chromosome
Recently Seeds reviewed 68,119 amniocenteses from
anomalies the same limitations apply for both
both controlled and uncontrolled studies providing
techniques with current approaches. It is suggested
straightforward arguments for several conclusions.25
that QF-PCR is advantageous at least in all centers
Currently midtrimester amniocentesis under
with access to the necessary hardware or those with
ultrasound guidance is associated with a procedure-
large sample numbers. We believe, however, that
for rapid karyotyping if available, direct preparation related rate of excess pregnancy loss of 0.33% (95%
from chorionic villi should be the method of first CI, 0.09, 0.56). Among only controlled studies, these
choice when there is an increased risk for unbalanced risk is 0.6% (95% CI, 0.31, 0.90). Adding the natural
chromosome anomalies i.e. after the ultrasound loss risk of about 1.08% among control groups the
diagnosis of fetal malformations. This method carries total rate of losses can be determined around 1.6%.
a false negative rate of below 1% as compared to up Application of ultrasound guidance may reduce
to 35% with interphase FISH or QF-PCR. 13 In the number of injections and may also lower the
conclusion it can be stated that FISH and QF-PCR incidence of blood stained fluid. Analysis of only
should be used as additional tests. controlled studies shows that this trend remains, but
Particularly in blood - stained probes maternal not statistically significant.
cell contamination of amniotic fluid cell is are rare Injury of the fetus is rare can not perfectly
but well known cause of diagnostic error in the prevented by using ultrasound guidance, but may
prenatal diagnosis of fetal disorders (<3/1000). 14 occur more frequently.
Using flourescent labelled microsatellites permits the Former reported experience of higher risks due
differentiation between maternal and fetal cells. to placental perforation does not support an
Mosaicism is one other remaining problem and is increased rate of miscarriage. As shown in the
seen in 1/1000 of samples.15 comprehensive overview other complications (such
as vaginal bleeding, infection or leakage of amniotic
COMPLICATIONS fluid) could not be analysed due to the limited
The risks which may be associated with second number of described terms or were not comparable.
trimester amniocentesis include leakage of amniotic Following the improvement of the technique and the
 Amniocentesis 1009
5. A.Tabor, M. Madsen, E. Obel, J. Philip, J. Bang and B.
Norgaard-Pedersen, Randomized controlled trial of
genetic amniocentesis in 4606 low-risk women, Lancet
1 (1986),1287–1293.
6. William B. Blessed MD, Helene Lacoste MD and Robert
A. Welch MD Obstetrician- gynecologists performing
genetic amniocentesis may be misleading themselves
and their patients.American Journal of Obstetrics and
Gynecology Volume 184, Issue 7 , June 2001, Pages 1340-
1344.
7. National Institute of Child Health and Human
Development National Registry for Amniocentesis
Study Group. Midtrimester amniocentesis for prenatal
diagnosis: safety and accuracy. JAMA 1976;236:1471-6.
8. Mennuti MT, Brummond W, Crombleholme WR,
Schwartz RH, Arvon DA. Fetal-maternal bleeding
associated with genetic am-niocentesis. Obstet Gynecol
Fig. 74.3: Gestational and amniotic sac at 12 weeks demonstrating
absence of fusion between amniotic membranes and the surrounding
1980;55:48-54.
cavitiy 9. Porreco RP, Young PE, Resnik R, Cousins L, Jones OW,
Richards T, et al. Reproductive outcome following
amniocentesis for genetic indications. Am J Obstet
laboratory methods there has been attempts in Gynecol 1982;143:653-60.
bringing forward the time of amniocentesis in the 10. Pijpers L, Jahoda MG, Vosters RP, Niermeijer MF, Sachs
past by performing early amniocentesis which is ES. Genetic amniocentesis in twin pregnancies.Br J
technically more demanding (Fig. 74.3). The both Obstet Gynaecol. 1988 Apr;95(4):323-6.
11. Kuo WL, Tenjin H, Segraves R et al. Detection of
randomised studies designed to assess the safety and aneuploidy involving chromosomes 13, 18 or 21 by
cytogenetic accuracy of early amniocentesis showed fluorescence in situ hybridization (FISH) to interphase
increased rate of fetal losses as well as an higher and metaphase amniocytes. Am J Hum Genet 1991;
rates of talipes equinovarus and oligohydramnios. 49:112-19
12. Fauth C, Speicher MR. Classifying by colors: FISH-based
Furthermore multiple needle insertions were genome analysis. Cytogenet Cell Genet 2001; 93:1-10.
performed in early pregnancies compared to mid- 13. Miny P, Tercanli S, Holzgreve W. Developments in
trimester amniocentesis. The rate of laboratory laboratory techniques for prenatal diagnosis.Curr Opin
failures following early investigations was arised. Obstet Gynecol. 2002 Apr;14(2):161-8.
14. Benn PA, Hsu LYF. Maternal cell contamination of
Comparing early vs. late amniocentesis it is suggested amniotic fluid cell cultures: results of a US nationwide
that the procedure in the second trimester is more survey. Am J Med Genet 1983;15:297-305.
favourable.26,27 15. Bui T-H, Iselius L, Lindsten J. European collaborative
study on prenatal amniotic fluid cell cultures. Prenat
Diagn 1984;4:145-62.
REFERENCES
16. P. Jeanty, F. Rodesch, R. Romero, I. Venus and J.C.
1. Valenti C, Schutta EJ, Kehaty T. Prenatal diagnosis of Hobbins, How to improve your amniocentesis
Down’s syndrome. Lancet. 1968 Jul 27;2(7561):220. technique, Am J Obstet Gynecol 146 (1983), pp. 593–596.
2. Romero, P. Jeanty, E.A. Reece, P. Grannum, M. Bracken 17. R.J. Carpenter, C.M. Hinkley and A.F. Carpenter,
and R. Berkowitz et al., Sonographically monitored Midtrimester genetic amniocentesis: use of ultrasound
amniocentesis to decrease intraoperative complications, direction vs. blind needle insertion, J Reprod Med 28
Obstet Gynecol 65 (1985);426–430. (1983), 35–40.
3. Simpson NE, Dallaire L, Miller JR, et al. Prenatal 18. R.A. Williamson, M.W. Varner and S.S. Grant, Reduction
diagnosis of genetic disease in Canada: report of a in amniocentesis risks using a real-time needle guide
collaborative study. Can Med Assoc J 1976;115:793-46. procedure, Obstet Gynecol 65 (1985), 751–755.
4. NICHD national registry for amniocentesis study 19. R. Romero, P. Jeanty, E.A. Reece, P. Grannum, M.
group. Midtrimester amniocentesis for prenatal Bracken and R. Berkowitz et al., sonographically
diagnosis. Safety and accuracy. J Am Med Assoc monitored amniocentesis to decrease intraoperative
1976;236:1471-6. complications, Obstet Gynecol 65 (1985), 426–430.
1010 Textbook of Perinatal Medicine

20. N.E. Simpson, L. Dallaire, J.R. Miller, L. Siminovick, J.L. 24. Centers for Disease Control and Prevention. Chorionic
Hamberton and J. Miller et al., Prenatal diagnosis of villus sampling and amniocentesis: recommendations for
genetic disease in Canada: report of a collaborative prenatal counseling, MMWR Morb Mortal Wkly Rep 44
study, CMAJ 115 (1976), 739–746. (1995), 1-4.
21. J. Philip and J. Bang, Outcome of pregnancy after 25. Seeds JW. Diagnostic mid trimester amniocentesis: How
amniocentesis for chromosome analysis, BMJ 2 (1978), safe? American Journal of Obstetrics and Gynecology
1183–1184. Volume 191, Issue 2, August 2004;607-615.
22. United Kingdom Medical Research Council: An 26. Randomised trial to assess safety and fetal outcome of
early and midtrimester amniocentesis. The Canadian
assessment of the hazards of amniocentesis: report of
Early and Mid-trimester Amniocentesis Trial (CEMAT)
the MRC Working Party on Amniocentesis, BJOG 85
Group. Lancet. 1998 Jan 24;351(9098):242-7.
(1978) (suppl 2), 1–41.
27. Sundberg K, Bang J, Smidt-Jensen S, Brocks V,
23. A. Antsaklis, N. Papantoniou, A. Xygakis, S. Mesogitis, Lundsteen C, Parner J, Keiding N, Philip J. Randomised
E. Tzortzis and S. Michalas, Genetic amniocentesis in study of risk of fetal loss related to early amniocentesis
women 20-34 years old: associated risks, Prenat Diagn versus chorionic villus sampling.Lancet. 1997 Sep
20 (2000), 247–250. 6;350(9079):697-703.
 75
Cordocentesis

Carl P Weiner

INTRODUCTION technically more difficult prior to 20 weeks, and the

loss rate is much higher prior to 16 weeks,
The development of high resolution ultrasound made
cordocentesis can be performed as early as 12 weeks.
it feasible to clearly image the umbilical cord. Daffos
The patient’s partner is encouraged to attend both
performed in the early 1980s the first intentional
the counseling session preceding the procedure, and
percutaneous umbilical blood sampling (cordo-
the procedure itself. The limitations and potential
centesis) under ultrasound guidance spurred by a
complications must be stated unambiguously before
desire to accurately diagnosis fetal toxoplasmosis.1
written informed consent obtained, and a targeted
The procedure rapidly gained favor with demons-
ultrasound examination performed.
tration of its safety 2-4 and directly spurred the
There are two methods for cordocentesis:
development of fetal medicine. A wide range of fetal
freehand and the use of a fixed needle guide. The
norms (hematological, endocrinological, immuno-
preferred location for umbilical cord puncture is the
logical, biochemical, and biophysical 5 ) were
placental origin where it is relatively fixed regardless
developed, a crucial step in the evolution of fetal
of technique. The first few centimeters of the fetal
medicine. And while many early indications for
origin of the umbilical cord are innervated, and
cordocentesis have been supplanted by less invasive
puncture there causes pain. The umbilical vein is the
techniques, there remain several indications for fetal
preferred target rather than the umbilical artery
blood sampling. The most common presently are the
because of its lower association with complications
assessment and treatment of red cell and platelet
discussed subsequently. A “no touch” philosophy is
alloimmunization, the antenatal diagnosis of inheri-
essential. If you do not touch the shaft of the needle,
ted blood or metabolic diseases, rapid karyotyping
you cannot contaminate it.
of malformed or severely growth restricted fetuses
The freehand technique employs an 18-20 gauge
in some countries, and rarely for the determination
spinal needle eight to twelve centimeters long1. The
of fetal acid base status. subcutaneous and deep layers are infiltrated with a
local anesthetic agent. The needle course is tracked
METHODS
by imaging the tip and shaft with the ultrasound
Cordocentesis is performed in the outpatient setting transducer held either in the opposite hand of the
by a single operator with or without an assistant. operator or by the assistant. Since the needle is not
There is no benefit of maternal fasting, sedation, fixed, the tip can move several centimeters in all axes
prophylactic antibiotics or tocolysis. Though it is should either the site of insertion be suboptimal or
1012 Textbook of Perinatal Medicine

the fetus move during the procedure. The operator I keep prepared a neuromuscular antagonist such
secures the needle after the vessel has been punctured pancuronium (0.3mg/kg EFW) on the sterile field
and the assistant aspirates a series of 1ml syringes. for every procedure, and routinely use it to eliminate
Pre-heparinization of the syringe is unnecessary fetal movement when performing a mid loop
unless a fetal blood gas is needed. The freehand puncture. The pancuronium is given either
technique remains most popular because of the intramuscular into the fetal buttock, or preferably,
flexibility it allows the operator. intravenously as soon as the vein is punctured; the
The author, however, prefers to perform effect here is evident within seconds. Vercuronium
cordocentesis using a fixed needle guide2 attached is preferred over pancuronium for simple diagnostic
to the base of the ultrasound transducer. Typically, procedures because its shorter half life allows a more
the transducer is held by the operator’s assistant. rapid return of fetal movement and heart rate
The predicted course of the needle, which can travel variability.6 In contrast, pancuronium is preferred
only in the vertical plane, is displayed on the for fetal transfusion because it maintains fetal cardiac
ultrasound screen, allowing the operator to select a output despite the volume load.
precise target for puncture. Deviation from the The volume of blood removed depends on the
predicted path occurs when there is an abrupt change gestation and indication for sampling. Five milliliters
in the relationship between the puncture site in the is typical, and adequate for a karyotype, umbilical
maternal abdominal wall and the uterus as the needle venous blood gas, and complete blood profile with
traverses between the two. The most common causes Kleihauer-Betke testing with 2mls remaining for use.
are abrupt patient movement or inspiration and
failure to hold the transducer surface flat against the MAJOR COMPLICATIONS AND RISK
maternal abdomen. Fetal movement is rarely an issue FACTORS FOR CORDOCENTESIS
because of the speed of the procedure. A smaller The major complications of cordocentesis are listed
gauge needle such as a 22 or 25 is used because lateral in Table 75.1. They include all complications
movement of the needle is not possible. I prefer to associated with amniocentesis plus fetal bradycardia,
target the umbilical cord longitudinally at the umbilical cord laceration, and thrombosis. Risk
“easiest” site for a direct approach. More than 50% factors for cordocentesis are noted in Table 75.2.
of the time I target a free loop. Placental puncture is Bradycardia is the major complication of
avoided whenever possible when the indication is cordocentesis. Essentially all emergency cesarean
alloimmunization (RBC or platelet) just as for deliveries and most perinatal losses are associated
amniocentesis. Local anesthesia is unnecessary for with a fetal bradycardia. Umbilical artery puncture
diagnostic procedures using a 22 gauge needle. A and hypoxia are the major risk factors for
local anesthetic should be used when the procedure bradycardia. In the absence of profound anemia or
is lengthy (e.g., intravascular transfusion). fetal heart failure, fetal hypoxia is associated with
Prophylactic antibiotics are not indicated for either an elevated umbilical artery resistance index and it
cordocentesis or intravascular transfusion. In my
experience, amnionitis complicates less than 1 in 800 Table 75.1: Complications of cordocentesis
diagnostic procedures when the “no touch” 1. Bradycardia or asystole
philosophy is rigorously adhered to and a needle 2. Premature rupture of membranes
guide is used (1 in 1200 procedures). 3. Premature labor
4. Umbilical hemorrhage
Fetal movement while the needle is intraluminal 5. Placental hemorrhage
increases the risk of umbilical cord trauma; it may 6. Chorioamnionitis
also either prevent a successful puncture or shorten 7. Umbilical thrombosis
the access time available regardless of technique. 8. Fetal to maternal hemorrhage
 Cordocentesis 1013
greater the decline. The decrease is associated with
Table 75.2: Risk Factors for Cordocentesis
prostacyclin release from the vascular endo-
1. Umbilical artery puncture (associated with bradycardia)
thelium.9,10 Endothelial adaptation to hypoxia also
2. Fetal hypoxemia- (associated with bradycardia)
3. Technique- freehand versus needle guide explains why hypoxemia is a risk factor for brady-
4. Gestational age- prior to 20 weeks, both techniques cardia.7 Rizzo et al demonstrated that endothelin is
5. Number of punctures (freehand technique only) released upon umbilical vein puncture of growth
6. Duration of procedure (freehand technique only)
7. Experience (freehand technique only, presumably restricted but not appropriately grown fetuses. 11
because of #4, 5) Fetuses who develop bradycardia release more
endothelin.
can be used as a risk marker. The incidence of It was generally accepted that the technique
bradycardia with absent and/or reversed diastolic selected was a matter of operator preference and
flow approaches 25%. Umbilical artery puncture had no impact on outcome. There is now evidence
increases the risk of fetal bradycardia 5-10 fold.3,40,7 to challenge that concept. The first line of evidence
The presence of either oligohydramnios or a 2-vessel is indirect. The often stated “advantage” of the
cord increases the risk of arterial puncture. freehand technique, its flexibility, may also increase
The observation the bradycardia is associated risk. Analogous to a lever, a small movement at the
with an elevated resistance index in one but not both hub of the needle amplifies the distance the tip moves.
umbilical arteries suggests localized vasospasm is the In association with this inescapable fact, freehand
cause. Pancuronium reduces the prevalence of cordocentesis produces a significantly greater
bradycardia in appropriately grown but not growth increase in the MSAFP than amniocentesis after
restricted fetuses7. It is possible some episodes of controlling for placental puncture.12 In contrast, the
bradycardia occur when fetal movement tugs on the incremental change in MSAFP when a needle guide
umbilical cord causing needle trauma and irritation is used is similar to amniocentesis.13 Further, the
to the underlying vascular smooth muscle. association between fetal thrombocytopenia and
Bradycardia after umbilical vein puncture may reflect bleeding from the umbilical puncture site after a
disruption of the adjacent umbilical artery smooth freehand cordocentesis is high enough to have
muscle as the tip traverses the cord. prompted a recommendation that all fetuses at risk
In the event of a bradycardia, vigorous fetal for alloimmune thrombocytopenia receive a
stimulation by palpation is beneficial as the heart will prophylactic platelet transfusion at cordocentesis.14
speed up and then slow again if the manual Yet, there is no relationship between the fetal platelet
stimulation is stopped too early. A variety of count and the bleeding time from the puncture site
chronotropes (e.g. atropine) and bicarbonate have when a needle guide is used.15 The latter may reflect
also been given as part of the fetal resuscitation either less lateral movement of the needle after
without predictable effect. puncture or the thinner gauge needle, or both. The
Umbilical cord laceration and thrombosis are loss rates reported after second trimester
associated with freehand procedures and not to date amniocentesis are lower when thinner needles are
reported when a needle guide was used.40 Though used.16 Not surprising, there are also reports which
bleeding from the umbilical puncture site is common, suggest that an amniocentesis performed with a
prolonged bleeding with sequelae is uncommon. needle guide is safer than one performed freehand.17
Even when performed at a mid loop, the fetus Though no single center has adequate volume for
does “react” to the cordocentesis. Umbilical artery a randomized trial, and comparisons of loss rates
resistance typically declines after either a diagnostic sustained by groups using the freehand and needle
procedure or a fetal intravascular transfusion.8 The guide techniques are problematic since it is hard to
higher the “normal” baseline resistance index, the separate procedure related losses from those
1014 Textbook of Perinatal Medicine

secondary to the natural progression of disease, there unrelated to the procedure. The perinatal loss rate
is evidence to suggest many losses are technique for these low risk procedures using the freehand
dependent. I examined the role of technique by technique was 3% (20/660). This rate is 15 times the
combining our experience with Professor Okamura needle guide rate (0.2%, 2/1021; p<000001) which
of Tokohu University who also uses a fixed needle includes fetuses with infection, hydrops and structural
guide for all procedures.40 Over 25 operators with malformations.
varying levels of experience performed 1260 Donner et al reported 759 diagnostic cordo-
diagnostic cordocenteses at a mean gestational age centeses with a known outcome using the freehand
of 29w. The umbilical vein (confirmed by the blood technique.19 Acknowledging several limitations (final
pressure reading) was punctured in 90% demons- diagnoses were not necessarily reported and 87%
trating the desired vessel can be targeted. A (34/39) of their perinatal losses were excluded as
procedure related loss was defined as any loss within being unrelated to the procedure), their stated loss
2 weeks of the procedure except those resulting from rate was 0.8% including 94 therapeutic terminations
elective pregnancy termination. Overall, there were in the denominator. Subtracting the terminations
12 losses (0.9%) (Table 75.3). from their total yields a loss of 1.1% (7/665). Of these
Though there are more recent studies, Ghidini et pregnancies, 160 were sampled because of severe
al provided adequate information for stratification early IUGR. We can identify their low-risk group by
and the low level of experience reported by the excluding the IUGR fetuses and assume all fetuses
involved centers may be more reflective of today’s with chromosomal abnormalities were either in the
reality.18 After deleting my experience from the growth restriction group, therapeutic termination
analyses, the overall loss rate was 7.2% (96/1,328) group, or the 1 fetus with trisomy 18 noted in the
with the freehand method. 18 This rate was signi- paper. This leaves a low risk group of 504 in which
ficantly higher than the overall loss rate when a there were 6 fetal/neonatal losses (1.2%). This rate
needle guide was used (0.9%, 12/1,260; p<0.00001). is significantly higher than that achieved in a similar
But this is a superficial comparison. group using a needle guide (p=0.03).
To exclude the contribution of the underlying These findings strongly suggest that many of the
pathology to the loss rate, procedures may be procedure related losses associated with cordo-
divided into high and low risk with the latter centesis are technique dependent. And while a few
excluding chromosomal abnormalities, nonimmune skilled operators might duplicate the results obtained
hydrops, intrauterine growth restriction and fetal with a needle guide, the majority of practitioners
infection. Such exclusions virtually eliminate all who perform only a few cordocenteses per year
abnormal fetuses that might be at risk for a loss would benefit from use of a guide.

Table 75.3: Frequency of major complications of cordocentesis when a needle guide is used
Final Diagnosis GA (weeks) at *Percent Emergency **Percent Death
cordocentesis Delivery Within 2 Weeks
RBC alloimmunization 28 ± 4 0.2 0.2
Uteroplacental dysfunction 32 ± 4 5.0 0.9
Chromosome abnormality 29 ± 6 7.7 9.9
All others 28 ± 6 0.3 0.2
*- Weiner, unpublished
**- from Weiner and Okamura, ref 400. Fetuses with a chromosome abnormality delivered by cesarean section were delivered
before the karyotype was completed.
 Cordocentesis 1015
INDICATIONS AND APPLICATIONS antibodies in a first sensitized pregnancy; (3) the
amniotic fluid bilirubin concentration; (4) the altered
Antenatal Diagnosis of Blood Disorders
morphometry of fetus and placenta; and (5) the
The use of recombinant DNA techniques on placental presence of pathological FHR patterns. However, the
biopsy material in the first trimester of pregnancy scatter of values around the regression lines
or amniocytes in the second for the diagnosis has describing the relationships between fetal anemia and
supplanted cordocentesis for the diagnosis of many the data obtained from these indirect methods of
of these conditions.20 Cordocentesis is still needed assessment was wide.31 And though the vast majority
for a phenotype diagnosis, in those patients requiring of fetuses with an elevated peak velocity in the
confirmation of normality based on a linked probe, middle cerebral artery are anemic, a sizable
those who lack key affected relatives, those who are percentage of anemic fetuses have normal velocities,
not informative by any of the available probes, and and the relationship between velocity and the
those in whom DNA analysis is not feasible because magnitude of the hemoglobin deficit varies greatly
of late referral. among fetuses.
The only accurate method for determining
Antenatal Diagnosis of Metabolic Disorders severity is blood sampling by cordocentesis with the
Antenatal diagnosis of over 100 of these disorders measurement of fetal hemoglobin concentration,
is now possible by the analysis of amniotic fluid, reticulocyte count, blood type, strength of the direct
placental tissue, or fetal blood. Cordocentesis is Coombs test and total bilirubin concentration.
particularly useful when the gestational age is close However, the timing of the first cordocentesis
to the local limit for abortion, as with late prenatal remains less than concrete. Invasive procedures
should be minimized not only because of the fetal
care or after failed chorionic villus or amniotic fluid
risk, but also because transplacental puncture
techniques.
enhances the risk of fetomaternal hemorrhage, 13,32
Red Blood Cell Alloimmunization increases maternal antibody titer, and worsens
disease. I prefer to avoid cordocentesis until the peak
Cordocentesis is not indicated in most instances of middle cerebral artery flow velocities are abnormal
maternal RBC alloimmunization for fetal blood in those pregnancies under 20w gestation. However,
typing. Accurate typing can now be accomplished since as many as half the fetuses with mild to moderate
by applying PCR to either trophoblast or amniocytes anemia have normal velocities, it is reasonable
obtained in the early second trimester when the risk depending on referral patterns and distances to
of exacerbating sensitization is lower.21-22 consider sampling all women with a history of severe
Fetal blood sampling made it possible to better disease, those with high antibody titers, and fetuses
understand the pathophysiology of this disease and with pathological FHR patterns.
allows for an improved method of assessment and A fetal blood sample is obtained, the hemoglobin
treatment.23-28 The net result of improved under- concentration measured, and an intravascular blood
standing is a improved perinatal outcome. The most transfusion given as necessary.33 The goal of the first
important advancement in the noninvasive manage- transfusion is to correct the hemoglobin deficit
ment of RBC alloimmune disease was the recognition completely unless there is hydrops. Immune hydrops
that most severely anemic fetuses have an elevated in the human fetus is almost always characterized
peak flow velocities in the middle cerebral artery.29- by an elevated umbilical venous pressure which is
30
Previously, the severity of fetal hemolysis was consistent with high output heart failure or left
estimated from (1) the history of previously affected ventricular dysfunction perhaps secondary to the low
pregnancies; (2) the level of maternal hemolytic oxygen carrying capacity.34 These fetuses tolerate the
1016 Textbook of Perinatal Medicine

first intravascular transfusion poorly, and should be known. ITP is the most common autoimmune
corrected initially to a hemoglobin level of no more disorder of reproductive age women; if true, there
than 8-9gm/dL. (We routinely monitor the fetal should be no controversy that thrombocytopenia
umbilical venous pressure to avoid over transfusion.) secondary to ITP posed a significant fetal risk during
The second transfusion is performed a few days later labor. Yet, the loss rate from cordocentesis in the
at which time the target hemoglobin for this and all best hands for a “low risk” fetus is 0.2%.40 Further,
subsequent transfusions is 18gm/dL. Subsequent there is no direct or indirect evidence that cesarean
transfusions are given at 3-4 week intervals until 34 section for autoimmune thrombocytopenia improves
to 36 weeks’ gestation, their timing based on the neonatal outcome.
findings in the middle cerebral artery and the There has been significant progress in the
knowledge that following a fetal blood transfusion management of severe fetal alloimmune thrombo-
the mean rate of decrease in fetal hemoglobin is cytopenia. 41-42 It is clear that medical therapy
approximately 0.3 g/dL/day. 33 Currently, the consisting of primarily high doses of IViG (1-2g/kg/
survival rate of red cell isoimmunized pregnancies week) with a prednisone rescue for suboptimal
treated with cordocentesis exceeds 90% in experi- responders is effective treatment for the majority of
enced hands, and virtually all losses are associated affected pregnancies.43 At risk pregnancies begin the
with immune hydrops fetalis.33 As important, we weekly infusion between 10-20 weeks depending on
have demonstrated normal long term neuro- past history. Most undergo a single cordocentesis
development despite the profound anemia prior to around 28 weeks to confirm normal platelet counts.
treatment. 35 When secondary to Pl(A1) platelet antigen
How often to repeat cordocentesis in the occa- incompatibility, fetuses with platelet counts > 20,000
sional affected fetus who is not anemic is determined at the initiation of therapy are predicted to maintain
by the change in the peak flow velocity in the middle their platelet count at the second fetal blood sampling
cerebral artery and by the ‘Hemolysis Pattern’ at > 20,000. The history of the previous sibling does
determined at the first sampling.36 This prospectively not predict the initial fetal blood sampling, the second
validated grading scheme is based on the reticulocyte fetal blood sampling, or the response to treatment.44
count and the strength of the positive Direct Coombs Even suboptimal fetal responders have a dramatic
test. Most fetuses do not require a second sampling. decrease in the risk of antenatal hemorrhage. Fetal
That said, nonanemic sensitized fetuses remain at platelet transfusion is associated with a high loss rate
risk for postnatal hyperbilirubinemia that is in direct when used for primary therapy (up to 17%45 ). Its
correlation to their antenatal bilirubin levels.37-38 role is now secondary, indicated for those fetuses
with extremely low platelet counts or those with a
Platelet Alloimmunization count <50,000 prior to a planned vaginal delivery.
Immune thrombocytopenia (ITP) is not an indication There is no relationship between the fetal platelet
for cordocentesis. 39 The assumed risk of fetal count and bleeding from the puncture site when a
intracranial hemorrhage during labor is not needle guide is used.15
supported by the aggregate experience of the last
Evaluation of Nonimmune Hydrops Fetalis
two decades. There is no more than one fetal loss
documented in the literature secondary to an Cordocentesis is central for the complete evaluation
intrapartum fetal hemorrhage. 39 Most losses of nonimmune hydrops since it allows the separation
attributed to ITP were associated with a maternal of cardiac from noncardiac etiologies.46 The umbilical
connective tissue disorder or a neonatal bleed. In venous pressure (UVP) is a surrogate for the central
almost all other instances, either the cause of death venous pressure. Studies of human fetuses47 indicate
or the timing of death is either not stated or not that is very similar to right sided heart pressure. An
 Cordocentesis 1017
elevated UVP is consistent with myocardial dys- 4. Maxwell DJ, Johnson P, Hurley P, Neales K, Allan L,
Knott P: Fetal blood sampling and pregnancy loss in
function whether caused by anemia (e.g. parvovirus
relation to indication. Br J Obstet Gynaecol 1991;98:892-
infection, hemolytic disease), or myocarditis, or 897.
obstructed cardiac return (thoracic mass effect). 5. Normal Values in Pregnancy. Ramsay MM, James DK,
Successful treatment of cardiogenic hydrops is Steer PJ, Weiner CP, Gonik B (Eds). 3rd Edition, WB
Saunders, Philadelphia, 2005.
associated with normalization of the UVP before the 6. Mouw RJC, Hermans J, Brandenburg HCR, Kanhai
hydrops resolves. Hydrops that is responsive to HHH. Effects of pancuronium or atracurium on the
shunting is caused by a shift of the mediastinum which anemic fetus during and directly after intrauterine
then obstructs cardiac return. An elevated UVP also transfusion (IUT): A double blind randomized study. Am
J Obstet Gynecol 1997,176 (2):S18.
predicts the fetus with hydrothorax and hydrops will 7. Weiner, C.P., Wenstrom, K.D., Sipes, S.L., Williamson,
be cured by a thoraco-amniotic shunt. If the UVP is R.A.: Risk factors for cordocentesis and fetal
neither elevated nor normalizes after draining the intravascular transfusions. Am J Obstet Gynecol, 1991
165:1020-1023.
chest, a shunt will not help. The underlying problem
8. Weiner, C.P., Anderson, T.: The acute effect of
lies elsewhere. cordocentesis with or without fetal curarization and of
intravascular transfusion upon umbilical artery
Miscellaneous waveform indices. Obstet Gynecol 73:219-224, 1989.
9. Weiner, C.P., Robillard, J.E.: Effect of acute intravascular
Not yet accepted but a likely valid indication for volume expansion upon human fetal prostaglandin
cordocentesis is presence of maternal thyroid concentrations. Am J Obstet Gynecol 161:1494-1497,
stimulating antibody (TSiG) or active maternal 1989.
10. Capponi A, Rizzo G, Pasquini L, Turri E, Arduini D,
Graves disease.48-49 Emerging evidence suggests even Romanini C. Indomethacin modifies the fetal hemo-
mild degrees of thyroid dysfunction is associated dynamic response induced by cordocentesis. Am J
with impaired long-term neurodevelopment. 50-52 Obstet Gynecol 1997;176(2):S19.
While there is a relationship between the degree of 11. Rizzo G, Capponi A, Rinaldo D, Arduini D, Romanini
C. Release of vasoactive agents during cordocentesis:
maternal and fetal thyroid suppression with such differences between normally grown and growth-
agents as propylthiouracil, it is common to find the restricted fetuses. Am J Obstet Gynecol 1996;175:563-70.
fetus is significantly over or under treated despite 12. Nicolini U, Kochenour NK, Greco P, Letsk-y EA,
the mother being euthyroid. For fetal hyper- Johnson RD, Contreas M, Rodeck CH: Consequences
of fetomatemal hemorrhage after intrauterine
thyroidism, the maternal PTU dose is increased and transfusion. BMJ 1988; 297:1379-1381.
the woman given thyroxine replacement. For 13. Weiner, C.P., Grant, S.S., Hudson, J., Williamson, R.A.,
hypothyroidism, the fetus can be given thyroxine Wenstrom, K.D.: Effect of diagnostic and therapeutic
intra-amniotically on a weekly basis.53 Women with cordocentesis upon maternal serum alpha fetoprotein
concentration. Am J Obstet Gynecol 161:706-708, 1989.
a history of Graves disease who have undergone 14. Paidas MJ, Lynch L, Lockwood CJ, Alvarez MA, Bussel
thyroid ablation should be screened for the presence J, Berkowitz RL: Alloimmune thrombocytopenia: Fetal
of TSiG. The fetus is at minimal risk if the TSiG study and neonatal losses related to fetal blood sampling. Am
is negative. J Obstet Gynecol 1995;172: 475-479.
15. Weiner, C.P.: Fetal blood sampling and fetal thrombo-
cytopenia. Fetal Diagn Therapy, 10:173-177, 1995.
REFERENCES 16. Tabor A, Philip J, Bang J, Madsen M, Obel EB, Norgaard-
1. Daffos F, Capella-Pavlovsky M, Forestier F. A new Pedersen B. Needle size and risk of miscarriage after
procedure for fetal blood sampling in utero: preliminary amniocentesis [letter]. Lancet, 1988 1(8578):183-4.
results of fifty-three cases. Am J Obstet Gynecol 1983, 17. Weiner, C.P., Williamson, R.A., Varner, M.W., Grant, S.:
146:985-7. Safety of second trimester amniocentesis. Lancet, 1986;ii:
2. Weiner, C.P.: Cordocentesis for diagnostic indications - 226.
two years experience. Obstet Gynecol 70:664-668, 1987. 18. Ghidini A, Sepulveda W, Lockwood CJ, Romero R:
3. Daffos F. Access to the other patient. [Review] Seminars Complications of fetal blood sampling. Am J Obstet
in Perinatology 1989;13:252-9. Gynecol 1993;168:1339-1344.37.
1018 Textbook of Perinatal Medicine

19. Donner C, Simon P, Karioun A, Avni F, Rodesch F: 33. Weiner CP, Williamson RA, Wenstrom KD, Sipes SL,
Experience of a single team of operators in 891 Widness JA, Grant SS, Estle L. Management of fetal
diagnostic funipunctures. Obstet Gynecol 1994;84:827- hemolytic disease by cordocentesis. II. Outcome of
831. treatment. Am J Obstet Gynecol. 1991;165:1302-7.
20. Boehm CD, Kazazian HH: Examination of fetal DNA 34. Weiner CP, Pelzer GD, Heilskov J, Wenstrom KD,
for hemoglobinopathies, in Alter BP (ed): Perinatal Williamson RA. The effect of intravascular transfusion
Hematology. New York, Churchill Livingstone, 1989, on umbilical venous pressure in anemic fetuses with and
pp 30–63. without hydrops. Am J Obstet Gynecol. 1989;161:1498-
21. Yankowitz J, Li S, Murray JC. Polymerase chain reaction 501.
determination of RhD blood type: an evaluation of 35. Swingle H.M., Harper D.C., Bonthius D., Weiner C.P.,
accuracy. Obstet Gynecol. 1995;86: 214-7. Widness J.A., Aylward G.A. Long-term Neuro-
22. Yankowitz J, Li S, Weiner CP. Polymerase chain reaction developmental Follow-up and Brain Volumes of
determination of RhC, Rhc, and RhE blood types: an Children following Severe Fetal Anemia with Hydrops.
evaluation of accuracy and clinical utility. Am J Obstet American Academy of Cerebral Palsy and Develop-
Gynecol. 1997; 176:1107-11. mental Medicine, Los Angeles 9/ 29-10/1, 2004.
23. Berkowitz RL, Chitkara U, Goldberg JD, et al: 36. Weiner CP, Williamson RA, Wenstrom KD, Sipes SL,
Intrauterine transfusion in utero: The percutaneous Grant SS, Widness JA. Management of fetal hemolytic
approach. Am J Obstet Gynecol 154:622, 1986. disease by cordocentesis. I. Prediction of fetal anemia.
24. Grannum PAT, Copel JA, Plaxe SC, et al: In utero Am J Obstet Gynecol. 1991 Sep;165(3):546-53.
exchange transfusion by direct intravascular injection in 37. Weiner CP, Wenstrom KD. Outcome of alloimmunized
severe erythroblastosis fetalis. N Engl J Med 314:1431, fetuses managed solely by cordocentesis but not
1986. requiring antenatal transfusion. Fetal Diagn Ther. 1994
25. Nicolaides KH, Rodeck CH, Kemp J, et al: Have Liley Jul-Aug;9(4):233-8.
charts outlived their usefulness? Am J Obstet Gynecol 38. Weiner CP. Human fetal bilirubin levels and fetal
155:90, 1986d. hemolytic disease. Am J Obstet Gynecol. 1992 May;
26. Nicolaides KH: Studies on fetal physiology and 166(5):1449-54.
pathophysiology in Rhesus disease. Semin Perinatol 39. Weiner C.P.: Why fuss over diagnosing fetal thrombo-
13:328, 1989c. cytopenia secondary to ITP? Contemp OB/GYN 1995
27. Weiner CP, Robillard JE. Atrial natriuretic factor, 40:45-50.
digoxin-like immunoreactive substance, norepinephrine, 40. Weiner, C.P., Okamura, K.: Diagnostic fetal blood
sampling - technique related losses. Fetal Diagnosis and
epinephrine, and plasma renin activity in human fetuses
Therapy 1996;11:169-175.
and their alteration by fetal disease. Am J Obstet
41. Radder CM, Brand A, Kanhai HH. Will it ever be
Gynecol. 1988 Dec;159(6):1353-60.
possible to balance the risk of intracranial haemorrhage
28. Soothill PW, Lestas AN, Nicolaides KH, et al: 2,3-
in fetal or neonatal alloimmune thrombocytopenia
Diphosphoglycerate in normal, anaemic and transfused
against the risk of treatment strategies to prevent it?
human fetus. Clin Sci 74:527, 1988.
Vox Sang. 2003 May;84(4):318-25.
29. Mari G, Moise KJ Jr, Deter RL, Carpenter RJ Jr. Flow
42. Bussel JB. Alloimmune thrombocytopenia in the fetus
velocity waveforms of the umbilical and cerebral arteries
and newborn. Semin Thromb Hemost. 2001
before and after intravascular transfusion. Obstet
Jun;27(3):245-52.
Gynecol. 1990;75:584-9.
43. Bussel JB, Berkowitz RL, Lynch L, Lesser ML, Paidas MJ,
30. Mari G, Deter RL, Carpenter RL, Rahman F, Huang CL, McFarland JG. Antenatal management of
Zimmerman R, Moise KJ Jr, Dorman KF, Ludomirsky alloimmune thrombocytopenia with intravenous
A, Gonzalez R, Gomez R, Oz U, Detti L, Copel JA, gamma-globulin: a randomized trial of the addition of
Bahado-Singh R, Berry S, Martinez-Poyer J, Blackwell low-dose steroid to intravenous gamma-globulin. Am
SC. Noninvasive diagnosis by Doppler ultrasonography J Obstet Gynecol. 1996 May;174(5):1414-23.
of fetal anemia due to maternal red-cell alloimmu- 44. Gaddipati S, Berkowitz RL, Lembet AA, Lapinski R,
nization. Collaborative Group for Doppler Assessment McFarland JG, Bussel JB. Initial fetal platelet counts
of the Blood Velocity in Anemic Fetuses. N Engl J Med. predict the response to intravenous gammaglobulin
2000;342:9-14. therapy in fetuses that are affected by PLA1 incom-
31. Nicolaides KH, Sadovsky G, Cetin E: Fetal heart rate patibility. Am J Obstet Gynecol. 2001 Oct;185(4):976-80.
patterns in red blood cell isoimmunized pregnancies. 45. Overton TG, Duncan KR, Jolly M, Letsky E, Fisk NM.
Am J Obstet Gynecol 161:351, 1989d. Serial aggressive platelet transfusion for fetal
32. Nicolini U, Kochenour NK, Greco P: Consequences of alloimmune thrombocytopenia: platelet dynamics and
fetomaternal haemorrhage after intrauterine trans- perinatal outcome. Am J Obstet Gynecol. 2002 Apr;
fusion. Br Med J 297:1379, 1988a. 186(4):826-31.
 Cordocentesis 1019
46. Weiner CP. Umbilical venous pressure measurement in 51. Kooistra L, van der Meere JJ, Vulsma T, Kalverboer AF.
the evaluation of nonimmune hydrops. Am J.Obstet Sustained attention problems in children with early
Gynecol 1993; 168:817-23. treated congenital hypothyroidism. Acta Paediatrica
47. Weiner Z, Efrat Z, Zimmer EZ, Iskovitz-Eldor J, Copel 1996, 85:425-9.
JA. Direct measurement of central venous pressure in 52. Weber G, Siragusa V, Rondanini GF, Prina Cerai LM,
human fetuses. Am J Obstet Gynecol 1997; 176:S19. Mora S, Colombini J, Medaglini S, Lia C, Locatelli T, Comi
48. Wenstrom, K.D., Weiner, C.P., Williamson, R.A., Grant,
G. Neurophysiologic studies and cognitive function in
S.S.: Prenatal diagnosis of fetal hyperthyroidism using
congenital hypothyroid children. Ped Res 1995, 37:736-
funipuncture. Obstet Gynecol 1990, 75:1-5.
40.
49. Yankowitz, J., Weiner, C.P.: Medical Fetal Therapy. Clin
Obstet Gynaecol, 1995, 9:553-570. 53. Van Loon AJ. Derksen JT. Bos AF. Rouwe CW. In utero
50. Salerno M, Di Maio S, Militerni R, Argenziano A, Valerio diagnosis and treatment of fetal goitrous hypo-
G, Tenore A. Prognostic factors in the intellectual thyroidism, caused by maternal use of propylthiouracil.
development at 7 years of age in children with congeni- Prenatal Diagnosis. 1995, 15:599-604.
tal hypothyroidism. J Endocrinol Invest 1995 18:774-9.
1020 Textbook of Perinatal Medicine

76 Perinatal Rh Hemolytic Disease and

Other Alloimmunizations:
Screening and Treatment
Prof Liliana S Voto

INTRODUCTION Rhnull individuals with membrane defects, are

erythroid specific and have a distinctive sequence
Severe hemolytic disease due to Rh incompatibility
homology. The RhD and non-D proteins show 92%
still constitutes a source of concern for obstetricians
sequence identity and a similar predicted membrane
and pediatricians. In Argentina, as well as in most
topology.
developing countries, this disease is one of the main
The Rh proteins D and Cc/Ee are encoded by the
causes of fetoneonatal morbidity and mortality due
RHD and RHCE genes, respectively, these genes are
to the lack of appropriate prophylaxis with post-
arranged in tandem on chromosome 1p34-p36 and
partum anti-D g.globulin and inadequate prenatal
probably result from the duplication of a common
control. 1
ancestral gene.
Perinatal hemolytic disease (PHD) represents one
The human RH locus is considered a two-gene
of the most significant examples in medicine of
model where all Rh-D positive haplotypes have two
successful management of a disease and adequate
structural genes (namely, RHD and RHCE) and most
profilaxis.
Rh-D negative ones have only one structural gene
By the first half of the century PHD accounted
(namely, RHCE). D protein is encoded by the RHD
for 45% of all perinatal deaths. Nowadays, this rate
gene, whereas the C/c and E/e proteins are encoded
has significantly decreased to 5%, as a result of in
by the RHCE gene. The relationship between blood
depth understanding of the etiology and patho-
group D epitopes and the amino acid polymorphisms
genesis of the disease, the advances in perinatal
of the Rh proteins still remains unclear, but it has
technology, the creation of sophisticated centers for
been found that the molecular basis for the C/c
high risk perinatal care and, mainly, from its
(Ser→Pro) and E/e (Pro→Ala) specificities result
prophylaxis.
from aminoacid polymorphisms at positions 103 and
THE RH BLOOD GROUP ANTIGENS 226, respectively. In the Rh system, polymorphism
and gene diversity seem to be produced mainly by
Biochemistry and Molecular Genetics gene conversion. But cases of gene deletion have also
A group of non glycosylated hydrophobic trans- been observed in the Rh system. Rhnull phenotypes
membrane proteins of 30-32 kDa are known to carry have been found to be caused by a mechanism of
the Rh blood antigens (D, Ce and Ee series). These transcriptional regulation which has not been clearly
proteins, which are not found in the red cells of rare described yet.
 Perinatal Rh Hemolytic Disease and Other Alloimmunizations 1021
In the cells of the Rhnull individuals, morpho- There are certain obstetric events that can increase
logical and functional abnormalities of cation the risk, such as placenta previa, ruptured placental
transport as well as phospholipid asymmetry have membranes, external version, Cesarean section,
been observed and are thought to lead to severe manual removal of placenta, and -in the early stages
clinical conditions. Also, Rh proteins and other of pregnancy-abortion, and ectopic pregnancy.
glycoproteins (such as Rh50 glycoprotein, CD47, All invasive procedures during pregnancy cause
glycophorin B, Duffy, LW) are either not present, or passage of fetal red blood cells. Chorionic villous
their quantity is markedly lower in the Rhnull sampling performed during the first trimester of
individuals' cells, which might mean that Rh proteins pregnancy, which is frequently used nowadays, has
form a multimeric complex with these glycoproteins.2 been associated with very severe cases of hemolytic
disease even with hydrops. Amniocentesis causes
ETIOLOGY AND PATHOGENESIS OF fetomaternal hemorrhage in 2 to 3% of the cases.
RH-HR INCOMPABILITY Spontaneous or induced abortion if also associated
with transplacental hemorrhage.
The antigens of the Rh system are located on the
Antigen D has already developed by the 35th -
surface of the erythrocyte, although they are also
45th day of gestation, which explains why 4 to 5%
thought to be part of the trophoblast.3
of post-abortion patients may become sensitized.
Rh system's anti-D antibodies are responsible for
Intravenous drug abuse can also lead to isoimmuni-
the majority of clinically detectable PHD cases. This
zation.
situation is observed in Rh negative mothers whose
When an Rh-negative person receives Rh-positive
husbands are Rh positive, and whose immunization
blood an immunologic response takes place in 50%
occurred during pregnancy, abortion, postpartum or
or more of the cases.
incompatible transfusion.
The primary immunologic response is usually
There are other Rh-Hr system's antibodies that
weak. The initial antibodies are of IgM nature, with
are capable of producing a clinical disease. They are
a high molecular weight and are unlikely to cross
listed below in order of frequency:
the placenta. As a result, they do not produce fetal
Anti-c (hr's), anti-C (rh'), anti-e (hr'') or the hemolysis labely in pregnancy, the IgG antibodies,
combination of any of them with factor D. cross the placenta and produce hemolysis.
In Argentina 13% of couples are Rh incompatible, The IgG antibodies involved in the etiology and
and it is estimated that there is 1 PHD case every pathogenesis of PHD due to Anti D are mainly
150 deliveries. On the other hand, according to subtypes IgG I and IgG III. The former crosses the
different statistics, the immunization rate is between placenta early in pregnancy, and therefore have a
7 and 14%. role in the most severe cases of PHD.
In our experience, the frequency of immunization
RH -SENSITIZATION MECHANISM
in Rh-negative patients during their second
The passage of fetal red blood cells to maternal pregnancy with compatible Rh-positive fetuses is 12
circulation is considered normal during pregnancy. to 15%.
Using the Kleihauer-Betke technique it was ABO incompatibility in an Rh-negative patient
established this the passage of fetal red blood cells provides partial protection against primary anti Rh
is not higher than 0,1 to 0,2 ml. In this case the isoimmunization, but not against a secondary
competent immunological system would not be immunologic response. In the former, the anti-A or
activated; however, the chances of it being stimulated anti-B incompatibility immunized blood cells are
are much higher if transplacental hemorrhage is captured by the liver, which is not an immunologically
greater than the established values. active organ and does not produce anti Rh antibodies.
1022 Textbook of Perinatal Medicine

On the other hand, in a secondary immunologic gene status for unborn babies at risk for hemolytic
response, the spleen receives the blood cell stroma disease of the newborn. The occurrence of D gene
and produces anti Rh antibodies. Therefore, there is variants has led to errors in prenatal typing. The
a higher incidence of Rh hemolytic disease in children effectiveness of using PCR in a clinical setting has
whose parents are HBO compatible. been reported. It verifies the importance of testing
more than one region of the gene and also the need
PATHOGENESIS AND PHYSIOPATHOLOGY OF
for a testing strategy where both maternal and
PERINATAL HEMOLYTIC DISEASE
paternal testing for RHD gene dosages are per-
According to different studies, the rate of active formed. 5
transport of human IgG varies in the course of normal In present time, it is possible to determine the
gestation; before 12 weeks of pregnancy this transfer fetal DNA in maternal serum during the first
is very low; but it has been demonstrated that, in trimester of pregnancy. The advantage of this
severe Rh disease, the direct antiglobulin test on the method is its non-invasive nature.6
fetal (Rh-positive) red cells may be positive as early
as 6-10 weeks. The IgG antibodies rise exponentially FOLLOW UP OF THE RH-NEGATIVE PATIENT
until term. Sometimes, IgG levels in the infants could
The anamnesis will focus on relevant data such as:
be higher than in the mother. The placental transport
number of previous deliveries, history of anti-D
of IgG1 and IgG3 in women with RH (D) immu-
prophylaxis, history of perinatal morbidity and
nizations is not diminished compared with normal
mortality attributable to hemolysis, history of
pregnancy. The placental transport of IgG3 is
significantly higher in pregnancies at risk of hemolytic previous transfusions, and history of neonatal
disease of the newborn with IgG3 concentrations in exchange transfusions or luminotherapy in previous
normal pregnancy.4 deliveries.
The pathogenesis of PHD lies in the hemolysis of If an indirect Coombs test does not detect anti-
fetal erythrocytes caused by maternal antibodies. D antibodies, it should be repeated every 4 weeks
Hemolysis then results in fetal anemia. until immediate puerperium.
According to the severity of hemolysis, PHD will If the test is positive we will proceed as follows:
be anemic, icteroanemic, or hydropic. In hydropic • Study of husband's zygosity. If he is heterozygous,
PHD the hepatic parenchyma is replaced partially the fetus might not be Rh-positive.
with secondary erythropoiesis tissue, which causes • Serial titration of anti-D antibodies every 3 weeks
a portal and umbilical venous hypertension with the purpose of drawing a curve.
syndrome, as well as alterations in the metabolism • Serial ultrasonographic follow up to evaluate fetal
of proteins, and decreased albumin. Both clinical growth or detect characteristic signs of the
conditions cause edema and ascitis, which are disease: polihydramnios, hepatomegalia, ascitis,
characteristic of hydrops. soft tissue edema.
Frequently, fetal cardiac failure secondary to • MCA peak systolic velocity provides a non-
severe anemia is observed. Both other forms of PHD, invasive modality for determining moderate to
anemic and icteroanemic, are the result of a less severe fetal anemia. This technique does not
severe hemolysis that does not compromise either differentiate between mild fetal anemia and no
the cardiocirculatory system or the protein anemia. The sensitivity of an increased peak
metabolism. systolic velocity in the MCA for prediction of
moderate to severe fetal anemia is 100% either in
EARLY FETAL GENE DIAGNOSIS
the presence or the absence of hydrops fetalis and
The use of polymerase chain reaction (PCR) for the false positive is 12%. 7,8 On the contrary,
detection of the RHD gene can measure the RHD amniotic fluid is more direct to predict the fetal
 Perinatal Rh Hemolytic Disease and Other Alloimmunizations 1023
status and it constitutes an intermediate step for The purpose of all the procedures described below
cordocentesis when it is difficult to implement is to allow the fetus to reach viability.
it.9 The timing of the initial amniocentesis depends
on the patient's history and antibody titer. If the Intrauterine Fetal Transfusion
patient's antibody titer is just at the critical level Intraperitoneal Route
and the patient has not had a baby with EBF, the
initial amniocentesis can be done at 28 to 29 weeks' It is estimated that the total amount of blood
gestation. If the titer or the history suggests that transfused into the peritoneal cavity flows into fetal
the EBF may be more severe, then amniocentesis bloodstream within 7 to 10 days after being injected.
can be performed earlier. In this way, a fetus that This technique relies on the absorption capability
needs an intrauterine transfusion can be of the fetal peritoneum and subdiaphragmatic
identified. lymphatic, and it is not usually indicated before the
Many methods have been used to evaluate AF by 24th week gestation. Ultrasound plays an essential
detecting fetal hemolysis. Liley plotted curves of role in this procedure: it locates the fetal abdomen
AF ∆OD450 values based on gestational age and and shows the precise point of entry.
derived three zones of severity of fetal disease. The inferior portion of the peritoneal cavity is
Therefore, using the Liley curves, fetal condition then accessed, considering the bladder as a reference
can be predicted based on the AF ∆ OD450 point to prevent injury to the liver or spleen.
value. 10,11 Type O, Rh-negative blood-compatible with
• Amniotic fluid spectrophotometry, in accordance maternal blood- with a hematocrit concentration not
with previous history of Rh disease and levels of less than 75% should be transfused. Blood should
anti-D antibodies in relation to the patient's have been recently extracted (not more than 48 hours
gestational age. before the procedure).
• Cordocentesis for the prediction of the severity Ascites, if present, should be evacuated before
of fetal anemia through the analysis of fetal blood the procedure, although in this case the intravascular
is used since the development of high-resolution route is always preferred.
US. It is indicated in cases either requiring The use of uterine inhibitors is recommended, and
assessment of fetal anemia <26 weeks' gestation the administration of antibiotics in order to prevent
(anti-D titers >1/128) or showing amniotic fluid possible infections is controversial.
spectrophotometric analysis in the Upper Zone B The procedure should be repeated, according to
or Zone C of Liley's chart, anterior placenta and the patient's evolution, every 14 days or more, until
a poor obstetric history.12 fetal viability is achieved.
• Antenatal fetal monitoring as soon as it is reliable The amount of blood to be transfused should be
to assess fetal vitality and specially sinusoid estimated as follows: gestational age in weeks minus
patterns. 20, multiplied by 10. For example, in a 28 weeks'
pregnancy, (28-20) × 10 = 80, a total of 80 ml of
TREATMENT OF SEVERE MATERNAL- erythrocytes should be transfused.
FETAL RH-INCOMPATIBILITY
Intravascular Fetal Transfusion
In 1963 Liley described intrauterine transfusion as
the only possible way to prevent intrauterine fetal Indications to use this approach are: especially in case
death of severely affected Rh-positive fetuses. When of fetal hydrops or very severe fetal anemia. This
pregnancy interruption is indicated, fetal prematurity technique, which may be used as from 18 weeks of
becomes an aggravating factor which conspires pregnancy, involves access to an umbilical vessel near
against successful results. its placental insertion, in the intrahepatic portion of
1024 Textbook of Perinatal Medicine

the umbilical vein, or in the fetal heart (fetal rescue diseases both in children and adults and recurrent
operation). intrauterine fetal loss has been frequently reported
Nowadays this procedure is superior to the former in the literature with varying degrees of effective-
because it allows the immediate reversal of fetal ness.
anemia as it is possible to obtain a sample of fetal Although the mechanisms of action of IVIG remain
blood and determine its hematocrit and hemoglobin unclear, several explanations have been proposed
values. Also, a faster remission of fetal hydrops is during pregnancy: feedback inhibition of antibody
observed in most of the cases. synthesis, competition for macrophage or Fc
The amount of blood to be transfused depends receptors of target cells, and blockade of Fc-mediated
on the patient's gestational age, and blood donor's antibody placental transport. We have used IVIG
and fetal blood's hematocrit. The procedure should therapy in a prospective study in order to analyze
be repeated according to post-transfusion hematocrit its effectiveness in the antenatal treatment of severe
values, until fetal extraction is indicated. Rh-hemolytic disease.
If no complications occur, this technique allows The only immunoglobulin which is transferred
the lengthening of intrauterine fetal life until the fetus into the fetal circulation is IgG; the other classes of
is viable, which results in a marked decrease in maternal immunoglobulins are either not transferred
perinatal mortality rates. or only cross the placenta in small quantities. The
mechanisms involved in the active transfer of IgG
High-Dose Intravenous IgG for the Treatment across the human placenta are not yet known.
of Severe Rhesus Alloimmunization Brambell et al.'s studies in rabbits suggest that the
Intrauterine fetal transfusion, either by the intra- transport of IgG molecules across the placenta is
peritoneal or intravascular routes, has shown to be mediated through a receptor for the Fc part of the
an effective treatment of Rh-hemolytic disease. molecule. Further studies have clarified the role of
However, some fetuses are already severely Fc as a placental Fc receptor for IgG. This receptor
compromised at an early stage when it is technically has been demonstrated on the surface of the
impossible to indicate the procedure. trophoblast at 10 weeks and at term.
In agreement with other authors, we have found The mechanisms of placenta transfer of exogenous
that repeated invasive techniques result in an IgG infused into the mother are still to be elucidated.
important increase in anti-D titers owing to the It must be emphasized that transplacental IgG
variable amounts of fetomaternal bleeding inevitably transfer is a slow process and requires an intact Fc
caused by the procedure itself. As a result of this, a portion of the IgG molecule. Gitlin et al.'s studies
moderate Rh disease in a present pregnancy can often demonstrated that when labeled IgG was injected
become a severe one in the subsequent gestation. into pregnant women at various intervals before
It has been reported that transfusional therapy delivery, even after 12 days, the concentration in the
before 32 weeks gestation is associated to a higher infant's serum was only about 40% of that in the
fetal mortality rate.13 The early treatment in the first mother. Studies performed by Contractor al about
weeks of pregnancy would reduce the severity of IgG transport in perfused placentas suggest that the
fetal anemia, decreasing the fetal morbidity and trophoblast absorbs a substantial amount of human
mortality. That is why we started a protocol of IgG and all bovine IgG, both broken down in small
treatment with high doses of gammaglobulin.14 fractions by a mechanism of nonspecific endocytosis,
The use of high doses of intravenous immuno- and transmits these fragments to the fetal circulation.
globulin (IVIG) in the treatment of immunologic A small amount of human IgG, however, would
 Perinatal Rh Hemolytic Disease and Other Alloimmunizations 1025
escape this process of lysosomal destruction by Six of the 9 neonates in group 3 were depressed at
diverse protective mechanisms, and would be birth (1-min Apgar below 7). However, at 5 min only
released intact on the fetal side. 1 newborn showed an Apgar below 7. Mean birth
There are very few cases in the literature weight was over 2,500 g in all the cases. Neonatal
reporting the treatment of severe Rh-hemolytic hematological condition in group 2 (50% of the babies
disease with high doses of IVIG and the findings are required only phototherapy) was better than in the
too dissimilar to allow for conclusive generalizations. other two groups (transfusional therapy).
Rewald and Berlin et al obtained satisfactory results The decrease in pre- versus post-treatment anti-
with the combined use of plasmapheresis and IVIG D antibody quantification, the reduction in
in 4 cases of severe Rh-hemolytic disease. De la intrauterine hemolysis, and the strongly positive
Cámara et al reported the successful treatment of direct antiglobulin test in all neonates may indicate
two cases with repeated doses of IVIG throughout that the mode of action of high doses of IVIG in Rh-
gestation. Scott et al, on the other hand, used a hemolytic disease is (1) feedback inhibition of
combined protocol of IVIG and repeated intrauterine antibody synthesis, and (2) partial blockade of Fc-
transfusions in one case of hemolytic disease. mediated antibody transport across the placenta. No
We have administered IVIG as the only treatment adverse effects from the drug were observed in the
in 24 severely Rh-sensitized patients with a previous mother or neonate.
history of affected fetuses and/or neonates, with Our findings show that IVIG treatment was
elevated anti-D titers, and a high degree of effective in both groups 1 and 2, where IVIG was
intrauterine hemolysis. Patients in group 1 (< 20 administered before the 28th week of gestation and
weeks, n = 8) fulfilled the first two of these inclusion the fetuses were not hydropic at the onset of therapy.
criteria, whereas in groups 2 (20-28 weeks, n = 7) In group 3, however, where fetal anemia was already
and 3 (> 28 weeks, n = 9), IVIG treatment was advanced at the time of treatment, intrauterine
indicated on the basis of intrauterine hemolysis. transfusions and prompt fetal extraction should have
IVIG was infused at a daily dose of 0,4 g/kg been the treatment of choice.
maternal body weight for 4-5 consecutive days, and The analysis of the series including only the 13
repeated every 21 days until delivery. most severely affected cases as judged by their
Group 3 also included those patients who history of fetal/neonatal death, demonstrated again
attended the antenatal clinic very late in pregnancy; the effectiveness of IVIG treatment. It can be inferred
as a consequence of this delay, the fetuses in these from the results in this particular group of patients
cases were highly compromised because of the that: 1) after 28 weeks' gestation the administration
advanced stage of the hemolytic disease, and they of IVIG does not elicit significant reductions in anti-
evidenced major neonatal depression and severe fetal D titers and intrauterine hemolysis, thus intrauterine
anemia at birth, requiring -in almost all cases- transfusion is the therapy of choice, and 2) IVIG
exchange transfusions. treatment is not indicated in case of hydrops fetalis.
Initial mean anti-D level was significantly higher Excepting these two indications, it is in this series
in group 1 (25.9 ± 12.9 IU/ml) than in the other two with the poorest history, the highest antibody level,
groups, whose values were, however, higher than and failure of transfusional therapy in previous
10 IU/ml. Amniotic fluid total bilirubin levels before gestations, where we find the most encouraging
the onset of therapy were pathologic and in 55% of therapeutical results of IVIG treatment.
the cases they coincided with zone 3 of Liley's chart. The high cost of IVIG therapy is immediately
Hydrops fetalis at the onset of treatment accounted outweighed by the highly satisfactory perinatal
for the only 3 fetal deaths in groups 1 and 2. None results obtained in our population of extremely
of the fetuses developed hydrops during treatment. severe Rh-sensitized patients. Moreover, babies born
1026 Textbook of Perinatal Medicine

after treatment with intrauterine transfusions, as well hematocrit at first IUT and at birth. However, the
as those prematurely delivered because of their percentage of severely anemic fetuses was higher in
severe disease, require a prolonged stay in the the IUT group. Fetal mortality rate was 36% less in
neonatal intensive care unit (a mean of 60 days in the Gamma group.
the latter case), the cost of which greatly exceeds In summary, considering that in very severe cases
that of IVIG therapy. of Rh-isoimmunization:
To conclude, the results of our study, which to a. the development of fetal hemolysis in the first 20
the best of our knowledge is the largest reported in weeks of gestation increases the risk of fetal death;
the literature, show the value of high doses of IVIG b. the early onset of invasive fetal therapy is only
in the treatment of severe Rh incompatibility when partially effective and potentially harmful; and
administered repeatedly before 28 weeks' gestation c. according to the present study, those patients
and in the absence of hydrops fetalis. who received high-dose intravenous gammaglo-
bulin in the first 20 weeks of pregnancy, seem to
High-Dose Gammaglobulin (IVIG) Followed by have a better fetal outcome.
Intrauterine Transfusions (IUTs): A New Our results show that high-dose gammaglobulin
Alternative for the Treatment of Severe Fetal therapy followed by IUTs improves fetal survival in
Hemolytic Disease these severe cases.15 Conventional treatment has also
Intrauterine fetal transfusion is currently the therapy been modified by the administration of immune
of choice in cases of severe anti-D isoimmunization. globulin to the neonate.16
However, its efficacy is reduced in patients with early
Neonatal Treatment
severe hydrops fetalis due to the technical difficulties
in performing this procedure before 20 weeks' Our studies suggest that the frequency of neonatal
gestation and because the fetuses are alredy anemic transfusion therapy can be reduced by a combination
at that term. of conventional phototherapy with HDIVIG. Further
The purpose of this study was to determine studies are needed to determine the optimum timing
whether early onset of high-dose gammaglobulin and dosage of HDIVIG therapy.17
therapy followed by intrauterine transfusions (IUTs) Other studies show that intravenous immuno-
is more effective than IUTs alone in the treatment of globulin is effective in decreasing the maximum
very severe isoimmunized fetuses. bilirubin levels and the need for repeated exchange
The population studied in this retrospective transfusions in Rh hemolytic disease of the newborn.
clinical research was assigned to one of the following There is, however, an increased need for blood
two groups: 1) Gamma group: 30 patients receiving transfusions for late anemia in the babies treated with
gammaglobulin therapy before 21 weeks' gestation IVIG.18
and IUTs after 20 weeks; or 2) IUT group: 39 patients
receiving IUT treatment starting at a gestational age Other Alloimmunizations
of 20-25 weeks. Routine antibody screening of Rh (D)-positive
Both groups were statistically similar regarding women is probably not warranted from a clinical cost-
history of perinatal deaths and anti-D antibody titers. benefit perspective.19
The number of hydropic fetuses at the first IUT and Anti c isoimmunization follow up is similar to that
of fetal deaths were significantly higher in the IUT of anti D and, together with anti E they are the next
than in the Gamma group. No significant differences in order of frequency as a cause of perinatal allo-
were observed between the groups in fetal immunization.20
 Perinatal Rh Hemolytic Disease and Other Alloimmunizations 1027
The treatment for anti E sensitization is similar SUMMARY: STEPS TO FOLLOW
to that of anti D. Amniotic fluid is a weak indicator
Rh-Isoimmunization: Patients with no Maternal and/
of the result, that is why the management of the or Perinatal History of the Disease
disease remains questionable. It is not clear yet if With Positive Indirect Coombs Test

the presence of anti E implies the accummulation of

a hemolytic effect with other antibodies.
Repeat the test at
24 weeks

Anti-D titers Anti-D titers Anti-D titers

< 1/32 1/64 - 1/128 > 1/256

Pregnancy Follow-up in Anti-Kell Alloimmunization US at

18, 28, 32 weeks
US at
18, 22, 26 weeks
US at
18, 22 weeks

Fetal heart rate monitoring Amniocentesis * + US at Amniocentesis * + US at

It is identified by the presence of anti-Kell antibodies 36 weeks to term 28 weeks 24 weeks

in maternal serum or previous fetal anemia. The Delivery at term:

No more than 40 weeks
LILEY'S
GRAPHIC
LILEY'S
GRAPHIC

search for hemolysis in amniotic fluid through *And/or MCA peak systolic velocity and conventional ultrasound
bilirubin concentration is not useful as the patho-
Rh-Isoimmunization: Patients with no Maternal and/
genesis responds to fetal anemia due to the inhibition
or Perinatal History of the Disease
of erythroid progenitor and not to the destruction
of the Kell-positive erythroid by the antibodies. LILEY'S
GRAPHIC

Therefore, cordocentesis should be chosen to Zon e A o r I Zon e B lo w o r IIa Zon e B h igh or IIb Zon e C or III

obtain fetal blood and, in this way, be able to detect Amnioc entesis
at 2 8 weeks *
Amnioc entesis
every 14 - 21 day s *
Amnioc entesis
every 7 - 14 day s *
Co nfirm valu es

fetal anemia and make the Kell-serotyping by Co nfirm valu es If r ema in in the If r ema in in the Immature Matu re
same zone same zone fetu s fetu s

studying the fetal DNA when the father is K1 Ter m del ive ry De livery De livery afte r IUT Immed iate

heterozygous.
at 3 7 - 40 weeks feta l lung del ive ry
matu rity

De livery afte r

Other studies show that fetal anemia due to anti- lun g maturi ty

Kell isoimmunization might be due in part to *And/or MCA peak systolic velocity and conventional ultrasound
erythropoietic suppression, but it is still largely a
Rh-Isoimmunization: Patients with Maternal and/or
hemolytic process. The methods based on a hemolytic
Perinatal History of the Disease
process, including use of a critical maternal serum
titer of 1:32, serial amniotic fluid analyses when the Any Anti-D titers

titer was exceed and liberal use of funipuncture were History of early hidrops or US at 18 weeks

successful in identifying severely affected fetuses.21

IU fetal death

Natural and monoclonal anti-Kell antibodies

< 20 weeks: IVIG Amniocentesis * + US
> 20 weeks: IUT at 24 weeks

inhibit the growth in the Kell-positive erythroid LILEY'S Graphi cs

progenitor.
Zone A or BIIa Zone BIIb

Fetal Hematology Follow-up with

Amniocentesis *
Before
28 weeks
After
28 weeks

It shows just a few reticulocytosis and normoblasts IUT + IVIG IUT

compared to fetuses affected by anti D, what suggests Delivery when Delivery when

that erythroid suppression would be the mechanism

fetus is mature fetus is mature

responsible for fetal anemia, mechanism that has been * And/or MCA peak systolic velocity and conventional ultrasound
proved by Vaughan's studies.22
The treatment is similar to that of the anti D. PROPHYLAXIS
Needless to say, an ultrasound follow-up is very In 40 to 50 % of pregnancies the passage of fetal red
important. blood cells to maternal circulation usually takes place
1028 Textbook of Perinatal Medicine

during the last trimester. In the majority of the cases • Kleihauer Betke is, if carried out correctly, a very
the amount of blood transferred is less than 0.1 ml.23 sensitive and specific method, but it is subject to
In 1977 there were 110 cases of stillbirths or laboratory and technological errors.
postnatal deaths due to anti-D hemolytic disease in • Flow cytometry is also a very sensitive method,
the U.K. In 1992, the figure decreased to only 9 cases. but difficult to perform and to expensive.
This decrease came as a result of the introduction of • The Rosette method is easy to carry out and very
anti-D gamma-globulin prophylaxis since 1969 but it sensitive, but has low specificity and its results
is also subject to the application of public health must be confirmed by Kleihauer or flow
policies for perinatal care, especially in developing cytometry.
countries.24 • A gel technology method has been reported for
In 1969 the prophylaxis protocol consisted of anti- the assessment of fetomaternal hemorrhage and
D gamma-globulin administration only after the birth determination of minimum necessary dose of
of an Rh-positive child, or after certain pregnancy RhIG. This technique works well in determining
events such as antepartum hemorrhage. Most of the the appropriate dose of anti-D required to treat
deaths resulted from maternal sensitization between D-patients with D+ newborns. There are potential
28 and 40 weeks of the first pregnancy (third cost savings in decreased use of RhIG, less direct
trimester) and during post partum. technical time required and more rapid
Further studies have determined that the availability of results.26
percentage of sensitization decreases from 1.2% to Anti-D gammaglobilin has very few adverse
0.28% if antenatal prophylaxis is carried out. effects. Some fetuses yield with a slightly positive
In practice, the combination of antenatal and Direct Coombs Test at birth after antenatal adminis-
postnatal prophylaxis will prevent immunization in tration. The presence of anemia or hyperbilirrubi-
96% of the high risk cases. The remaining 4% nemia is very rare. All plasma involved in the
corresponds to the absence or inappropriate production of anti-D immunoglobulin is carefully
administration of immunoglobulin administration checked for infectious diseases.
when it is indicated. There have not been any HIV cases due to
Due to the fact that isoimmunization during contaminated plasma.
pregnancy is caused by transplacental hemorrhage25, The American College of Obstetricians and
the risk of immunization increases after the following Gynecologists recommends both typifying the
procedures: pregnant patient and looking for antibodies in her
1. Spontaneous or induced abortion first visit, and again at 24-28 weeks, offering anti-D
2. Amniocentesis gammaglobulin to all Rh-negative, non-sensitized
3. Chorion villous sampling patients.
4. Cordocentesis It has been found that transplacental hemorrhage
5. Ectopic Pregnancy occurs in 3%, 12% and 45% of the cases during the
6. Fetal manipulation: external version first, second, and third trimesters, respectively.
7. Antepartum hemorrhage The capacity of an antibody to eliminate D-red
8. Antepartum fetal death cells in vivo depends both on its avidity, and to a
9. Positive blood transfusion. lesser degree, on its affinity for the D-antigen.
The standard postpartum dose of 300 mg contains Absorption is also a limiting factor.
enough anti-D to neutralize at least 15 ml. of fetal Even though antepartum gammaglobulin
red blood cells. administration offers many additional benefits, some
There are different methods to detect excessive authors argue that, as the incidence of isoimmuni-
fetomaternal hemorrhage: zation is relatively small, it makes medication 16
 Perinatal Rh Hemolytic Disease and Other Alloimmunizations 1029
times less cost- effective than postpartum prevention fluid at 450 nm (∆OD 450) are useful in the diagnosis
programs. The Cochrane Review states that anti-D, and management of fetal anemia.30
given within 72 hours after childbirth reduces the
risk of RhD alloimmunization in Rhesus negative REFERENCES
women who have given birth to a Rhesus positive 1. Margulies M, Voto LS, Mathet E, Margulies M. High-
infant. However, the evidence on the optimal dose Dose Intravenous IgG for the Treatment of Severe
is limited.27 Alloimmunization. Department of Maternal-Fetal
Medicine, Juan A. Fernández Hospital, University of
Buenos Aires School of Medicine. Buenos Aires,
Unit Equivalents Argentina. Vox Sang 1991;61:181-189.
2. Carton JP. Defining the Rh blood group antigens.
• 50 ug 250 I.U. Biochemistry and molecular genetics. Blood Rev
• 100 ug 500 I.U. 1994;8:199-212.
• 300 ug 1,500 I.U. 3. Hohlfeld P,Wirthner D,Tissot JA. Perinatal hemolytic
• 225 ug 1,250 I.U. disease: physiopathology. J Ginecol Obstet Biol Reprod.
1998;27(2):135-43.
4. Palfi M, Hilden JO, Gottvall T, Selbing A. Placental
Route of Administration transport of maternal immunoglobulin G in pregnancies
at risk of Rh (D) hemolytic disease of the newborn.
Intramuscular route, deltoides muscle. In the gluteal Department of Transfusion Medicine and Clinical
area, it only penetrates to subcutaneous tissue, thus Immunology, University Hospital, Linkoping, Sweden.
absorption is prolonged. National Library of Medicine. Medline. Am J Reprod
Immunol 1998 May;39(5):323-8.
5. Chan FY, Cowley NM, Wolter L, Stone M, Carmody F,
Anti-D Igg Use Recommendations
Saul A, Hyland CA. Prenatal RHD gene determination
• Dose: 500 I.U. or 100 ug every 4 ml of fetal red and dosage analysis by PCR: clinical evaluation.
Department of Maternal-Fetal Medicine, Mater Mother's
blood cells in maternal circulation. Hospital, South Brisbane, Australia. National Library of
• Indications: Medicine. Prenat Diagn 2001 Apr;21(4):321-6.
– Postpartum, within the first 72 hours = 300 mg 6. Costa JM, Giovangrandi Y, Ernault P, Lohmann L, Nataf
– Prenatal: V, El Halali N, Gautier E. Fetal RHD genotyping in
maternal serum during the first trimester of pregnancy.
– A) First trimester: abortion, ectopic pregnancy, Centre de Diagnostic Prenatal, American Hospital of
chorion villous sampling or amniocentesis. Paris, Neuilly, France. Br J Haematol 2002 Oct;119(1):255-
– B) Second trimester: suspected fetomaternal 60.
7. Mari G, Deter RL, Carpenter RL, et al. Noninvasive
hemorrhage, invasive procedures
diagnosis by Doppler ultrasonography of fetal anemia
– C) Third trimester: prophylactic: 500 I.U. at due to maternal red-cell alloimmunization. Colla-
28 and 34 weeks or only one dose of 300 ug borative Group for Doppler Assessment of the Blood
between above-mentioned weeks. 28 Velocity in Anemia Fetuses. N Engl J Med 2000; 342:9-
14.
8. Queenan JT. Rh isoimmunization. Georgetown
GENERAL AND FUTURE MANAGEMENT OF
University School of Medicine, Washington DC, USA.
RHD ISOIMMUNIZATION Contemporary OB/GYN Archive. Apr. 15, 2002.
9. Nishie EN, Brizot ML, Liao AW, Carvalho MH, Toma
Future therapy will involve selective modulation of O, Zugaib M. A comparison between middle cerebral
the maternal immune system turning the need for artery peak velocity and amniotic fluid optical density
intrauterine transfusions into a rarity.29 at 450 nm in the prediction of fetal anemia. Department
When RhD sensitization occurs, careful follow- of Obstetrics, Hospital das Clinicas, Sao Paulo University
Medical School, Sao Paulo, Brazil. Am J Obstet Gynecol
up of these mothers and judicious intervention can 2003 Jan;188(1):214-9.
result in good outcomes for most pregnancies. Both 10. Liley AW. Liquor amnii analysis in the management of
Doppler assessment of middle cerebral artery peak the pregnancy complicated by rhesus sensitization. Am
systolic velocity and spectral analysis of amniotic J Obstet Gynecol. 1961; 82:1359.
1030 Textbook of Perinatal Medicine

11. Liley AW. Errors in the assessment of haemolytic complicated by anti c isoimmunization. Department of
disease from amniotic fluid. Am J Obstet Gynecol. 1969; Obstetrics and Gynecology, The Ohio State University,
86:485. College of Medicine and Public Health, Columbus, Ohio,
12. Voto LS. Ultrasonography in Rh hemolytic disease. USA.
Head, Maternal-Fetal Medicine Department, Juan A. 21. McKenna DS, Nagaraja HN, O'Shaughnessy R.
Fernández Hospital, University of Buenos Aires, School Management of pregnancies complicated by anti-Kell
of Medicine, Buenos Aires, Argentina. isoimmunization. Department of Obstetrics and
13. Klumper FJ, van Kamp IL, Vandenbussche FP, Meerman Gynecology, The Ohio State University, College of
RH, Oepkes D, Scherjon SA, Eilers PH, Kanhai HH. Medicine, Columbus, Ohio, USA.
Benefits and risks of fetal red-cell transfusion after 32 22. Vaughan JI, Warwick R, Letsky E, Nicolini U, Rodeck
weeks gestation. Department of Obstetrics and Fetal CH, Fisk NM. Erythropoietic suppression in fetal
Medicine, Leiden University Medical Center, Leiden, anemia because of Kell alloimmunization. Am J Obstet
The Netherlands. Eur J Obstet Gynecol Reprod Biol 2000 Gynecol 1994;171:247-52.
Sep;92(1):91-6. 23. Jorgensen J. Fetal-maternal bleeding during pregnancy
14. Margulies M, Voto LS, Mathet E, Margulies M. High- and delivery. Acta Obstet Gynecol Scand 1977;56:487-
Dose Intravenous IgG for the Treatment of Severe 90.
Alloimmunization. Department of Maternal-Fetal 24. Joseph KS, Kramer MS. The decline in Rh hemolytic
Medicine, Juan A. Fernández Hospital, University of disease: should Rh prophylaxis get all the credit? Mc Gill
Buenos Aires School of Medicine. Buenos Aires, University -Montreal Children's Hospital Research
Argentina. Vox Sang 1991;61:181-189. Institute, Quebec, Canada. Am J Public Health 1998
15. Voto LS, Mathet ER, Zapaterio JL, Orti J, Lede RL, Feb;88(2):209-15.
Margulies M. High-dose gammaglobulin (IVIG) 25. Quartier P, Floch C, Meier F, Fruchart MF, Brossard Y,
followed by intrauterine transfusions (IUTs): a new Lejeune C. Massive fetomaternal hemorrhage and
alternative for the treatment of severe fetal hemolytic prevention of fetomaternal Rhesus incompatibility. The
disease. Maternal-Fetal Department, Juan A Fernández failure of our present system of prevention. Service de
Hospital, University of Buenos Aires, Buenos Aires, Neonatologie, Hopital Louis-Mourier, Colombres. J
Argentina. J Perinat Med 25 (1997) 85-88. Gynecol Obstet Biol Reprod (Paris) 1993;22(5):517-9.
16. Porter TF, Silver RM, Jackson GM, Branch DW, Scott 26. Fernandes JR, Chan R, Coovadia As, Reis MD,
JR. Intravenous immune globulin in the management
Pinkerton PH. A gel technology system to determine
of severe RhD hemolytic disease. Obstet Gynecol Surv
postpartum RhIG dosage. Department of Laboratory
1997 Mar;52(3):193-7.
Medicine and Pathobiology, University of Toronto.
17. Voto LS, Sexer H, Ferreiro G, Tavosnanska J, Orti J,
Immunohematol 2000 Sep;16(3):115-9.
Mathet ER, Margulies M, Margulies M. Neonatal
27. Crowther C, Middleton P. Anti-D administration after
administration of high-dose intravenous immuno-
childbirth for preventing Rhesus alloimmunization.
globulin in rhesus hemolytic disease. Division of
Cochrane Review. The Cochrane Library, Issue 4, 2004.
Obstetrics and Unit of Neonatology, Juan A. Fernández
Chichester, UK: John Wiley & Sons, Ltd.
Hospital, University of Buenos Aires, Argentina. J
28. Hartwell EA. Use of Rh immune globulin: ASCP practice
Perinat Med 23 (1995) 443-451.
parameter. American Society of Clinical Pathologists.
18. Mukhopadhyay K, Murki S, Narang A, Dutta S. Intra-
venouse immunoglobulins in rhesus hemolytic disease. Department of Pathology and Laboratory Medicine,
Neonatal Unit, Department of Pediatrics, Postgraduate University of Texas Health Science Center, Houston,
Institute of Medical Education and Research, USA. Am J Clin Pathol 1998 Sep;110(3):281-92.
Chandigarh, India. Indian J Pediatr 2003 Sep;70(9):697- 29. Moise KJ Jr. Management of rhesus alloimmunization
9. in pregnancy. Division of Maternal-Fetal Medicine,
19. Lurie S, Eliezer E, Piper I, Woliovitch I. Is antibody University of North Carolina, School of Medicine,
screening in Rh (D)-positive pregnant women Chapel Hill, USA. Obstet Gynecol 2002 Sep;100 (4):833.
necessary? Women's Health Center, Netka, Tel Aviv, 30. Harkness UF, Spinnato JA. Prevention and management
Israel. J Matern Fetal Neonatal Med 2003 Dec;14(6):404- of RhD isoimmunization. Division of Maternal Fetal
6. Medicine, Department of Obstetrics and Gynecology,
20. Hackney DN, Knudtson EJ, Rossi KQ, Krugh D, University of Cincinnati, Cincinnati, OH, USA. Clin
O'Shaughnessy RW. Management of pregnancies Perinatol 2004 Dec;31(4):721-42.
 77
Preinatal Therapy of Endocrine
and Metabolic Disorders

Guy Rosner, Shay Ben Shachar, Yuval Yaron, Mark I Evans

INTRODUCTION adrenal cortex, causing adrenal hyperplasia. The most

common abnormality, responsible for > 90% of
Our understanding of molecular and genetic basis
patients with CAH is caused by a deficiency of the
of disease is ever-incresing. This has resulted in more
21-hydroxylase (21-OH) enzyme. Other, less
and better ways for primary prevention. This is often
common causes for CAH, include deficiencies in 11β-
achieved by prenatal diagnosis and termination of
affected pregnancies and more recently, preimplan- hydroxylase, 17α-hydroxylase, and 3βhydro-
tation genetic diagnosis. Some metabolic and xysteroid-dehydrogenase. Decreased 21-OH activity
endocrine disorders however, such as congenital results in accumulation of 17-hydroxyprogesterone
adrenal hyperplasia and cardiac arrhythmias are (17-OHP) which is converted via androstenedione
amenable to pharmacological interventions.1,2 This to androgens, the levels of which increase by as much
chapter describes different modes of intrauterine as several hundred-fold (Fig. 77.1). The excess
pharmacological therapy in the fetus with an androgens cause virilization of the undifferentiated
endocrine or metabolic disorder. The use of folic acid female external genitalia. The degree of virilization
supplementation for the prevention of neural tube may vary from mild clitoral hypertrophy to complete
defects will also be discussed. formation of a phallus and scrotum. In contrast,
genital development in males is normal. The excess
ENDOCRINE DISORDERS androgens cause postnatal virilization in both genders
and may manifest in precocious puberty.
Adrenal Disorders
The “classical” form of CAH involves a severe
Congenital Adrenal Hyperplasia enzyme deficiency or even a complete block of
Treatment of congenital adrenal hyperplasia (CAH) enzymatic activity, which is associated in more than
in the fetus is an excellent example of pharmacological half of the cases with a life threatening salt-lossing
therapy during pregnancy. CAH is a group of form. The classical form is easy to recognize in female
autosomal recessive metabolic disorders charac- newborns but may be overlooked in males, who may
terized by an enzymatic defect in the steroidogenetic present at a later stage with severe dehydration and
pathway. As a result of the enzymatic deficiency, even demise. The “non-classical” attenuated form of
there is a compensatory increase in ACTH secretion 21-OH deficiency results in partial blockade of
in order to maintain cortisol production. This leads enzymatic activity and results in simple virilization
to overproduction of the steroid precursors in the in women only later in life. It is estimated to
1032 Textbook of Perinatal Medicine

CHOLESTEROL

20,22 Desmolase ACTH

MINERALCOCORTICOIDS GLUCOCORTICOIDS SEX STEROIDS
17-OH 17,20 DESMOLASE
PREGNENOLONE 17αOH PREGNENOLONE DHEA

3β-OHD 3β-OHD 3β-OHD

PROGESTERONE 17αOH PROGESTERONE

17α ANDROSTENEDIONE

21-OH 21-OH

11 DESOXYCORTISOL
11-DOC TESTOSTERONE
(COMPOUND S)
11-βOH 11-βOH
CORITISOL (F) ESTROGENS
COTICOSTERONE (B)
18-OH

18-OH COTICOSTERONE

ALDOSTERONE
Fig. 77.1: Steroidogenic pathway: Androgen production in 21-Hydroxylase deficiency (Congenital adrenal hyperplasia)

occur in ~ 3.5% in Ashkenazi jews and ~ 2% in weeks of gestation.6 Serial maternal estriol and
Hispanics.3 cortisol levels indicated that adrenal gland
The gene for 21-OH is in close linkage to the HLA suppression had been achieved. The female fetus was
major histocompatability complex on the short arm born at 39 weeks gestation with normal external
of chromosome 6.4 The gene for 21-OH (CYP21B) genitalia. Forrest and David then employed a similar
has now been mapped, allowing direct mutation protocol beginning at 9 weeks gestation to treat
analysis in informative families.5 several fetuses at risk for CAH.7 Female fetuses
In the past, diagnosis of CAH was made by the subsequently confirmed to be affected with severe
finding of elevated levels of 17-OHP in the amniotic CAH were spared masculinization of the external
fluid. With the development of chorionic villus genitalia. Several hundred pregnant women and their
sampling (CVS) in the 80’s, linkage based molecular fetuses have since been treated with prevention of
diagnosis in the first trimester became available. masculinization in more than 85% of affected females.8
Since discovery and mapping of the gene, direct The differentiation of the external genitalia begins
DNA mutation analysis has become the routine at about 7 weeks of gestation. Thus, diagnosis by
approach. amniocentesis or even CVS is too late to prevent
The fetal adrenal gland can be pharmacologically masculinization. Therefore for carrier parents,
suppressed by maternal administration of dexa- pharmacological therapy has to be initiated prior to
methasone. 6 The suppression can prevent mascu- prenatal diagnosis: Therapy is administered to all
linization of affected female fetuses in carriers patients at risk, despite the fact that the chance of an
couples. In the first attempt to prevent female genital affected female fetus for carrier parents is only 1 in
birth defects in 1982, Evans et al. administered 8 (i.e. 1/4 affected x 1/2 female). Following molecular
dexamethasone to a carrier mother beginning at 10 diagnosis, by CVS, in 7 out of 8 of patients, therapy
 Prenatal Therapy of Endocrine and Metabolic Disorders 1033
is discontinued if the diagnosis of a male is made or estimated prevalence of 1:30,000-1:50,000 live-
if CAH is ruled out. However, if the fetus is an births.11 Fetal goiterous hypothyroidism is caused
affected female, therapy is continued throughout in most instances by maternal exposure to thyrostatic
gestation. Stress-dose corticosteroids should be given agents used to treat maternal hyperthyroidism. 12
to the mother during labor and tapered gradually These drugs include propylthiouracil (PTU), the
post-partum. inadvertent use of radioactive 131I in the pregnant
No consistent untoward effects on fetuses have women or iodide exposure. Maternal ingestion of
been reported. Greater weight gain, edema and amiodarone (antiarrhythmic drug) or lithium (drug
striae were noticed in treated mothers but no for people with mood disorders may also cause
increased risk of hypertension or gestational diabetes hypothyroidism in the fetus. Finally, fetal hypo-
was noted. 8 thyroidism may result from transplacental passage
Inclusion criteria of the European Society for of maternal blocking antibodies (known as TBIAb
Paediatric Endocrinology and Wilkins Pediatric or TBII) or rarely due to rare defects in fetal thyroid
endocrine society 9 for prenatal treatment of CAH hormone biosynthesis.11
include: 1) a previously affected sibling or first-degree Fetal goiterous hypothyroidism may lead to
relative with known mutation causing classical CAH severe fetal and neonatal consequences. An enlarged
proven by DNA analysis. 2) reasonable expectation goiter may cause esophageal obstruction which may
that the father is the same as the proband’s. 3) lead to polyhydramnios, which may result in preterm
availability of rapid and quality genetic analysis. 4) delivery or premature rupture of membranes. Rarely,
Therapy started less than 9 weeks following the last a goiter may even lead to high-output heart failure
menstrual period. 5) Lack of intent for therapeutic due to high vascular flow in the goiter.13 A large
abortion. 6) Reasonable expectation of patient’s fetal goiter can cause extension of the fetal neck
compliance. leading to dystocia in labor. The effects of the fetal
There is an agreement that the treatment requires hypothyroidism itself may be devastating. Without
a professional team that includes an expert high risk treatment, postnatal growth delay and severe mental
obstetrician, a pediatric endocrinologist, genetic retardation may ensue. Even with immediate
counselor and a molecular genetic laboratory. diagnosis and treatment at birth, long term follow
up of children with congenital hypothyroidism has
Thyroid Disorders demonstrated that they have lower scores on
perceptual-motor, visuospatial, and language tests.14
Hypothyroidism
In suspicious cases, an extensive maternal and
Congenital hypothyroidism affects about 1:3000 to family history should be obtained. In patients with
1:4000 infants.10 About 85% of the cases are the result a positive history, maternal thyroid hormone levels,
of thyroid dysgenesis, a heterogeneous group of as well as blocking immunoglobulin levels should be
developmental defects characterized by inadequate measured. In addition, all women with a history of
amount of thyroid tissue. Congenital hypothyroidism any thyroid disease (both hypothyroidism and
is only rarely associated with errors of thyroid hyperthyroidism) are advised to have monthly fetal
hormone synthesis, TSH (thyroid-stimulating ultrasound scans to screen for fetal goiter,
hormone) insensitivity, or absence of the pituitary polyhydramnios, or fetal tachycardia.15
gland. Fetal hypothyroidism may not necessarily Occasionally, fetal goiterous hypothyroidism may
manifest in a goiter before birth since maternal be identified by a ultrasound performed due
thyroid hormones may cross the placenta. Congenital increased uterine size caused by polyhydramnios
hypothyroidism presenting with a goiter can be secondary to esophageal obstruction and impaired
found in only about 10-15% of cases, with an swallowing. Sometimes, a fetal goiter may
1034 Textbook of Perinatal Medicine

incidentally be discovered on a routine scan. Before graphy. Others may be discovered in patients
the advent of cordocentesis, amniotic fluid levels of referred for scan because of polyhydramnios. Beside
TSH and FT4 (free thyroxine) were used as potential the risks related to the goiter itself, untreated fetal
indicators of fetal thyroid function. However, these hyperthyroidism may be associated with a mortality
proved to be inconsistent.16 With cordocentesis, fetal rate of 12-25% due to high-output cardiac failure.21
thyroid status can be directly and accurately Once a fetal goiter is identified, biochemical
evaluated; fetal response to therapy can therefore evaluation is indicated. Historically, amniotic fluid
be reliably measured using available appropriate levels of TSH and FT4 were used as potential
nomograms for fetal serum levels of FT4, total T4 indicators of fetal thyroid function. These however,
(thyroxine), free T3 (triiodothyronine), total T3, and proved inconsistent in that amniotic fluid levels of
TSH.15,17 In utero treatment was initially suggested these hormones do not always correlate with their
by Van Herle et al. using intramuscular injection of serum levels. Some controversy still exists regarding
levothyroxine sodium. 18 Subsequent studies their use, however, they may be of some benefit in
however, have indicated that intra-amniotic centers that do not have available cordocentesis.16
administration of thyroxine may be superior and can As previously stated, cordocentesis allows reliable
lead to resolution of the polyhydramnios as well. assessment of fetal thyroid status TSH, 15,17 and
The dose of the injected drug may be refined using treatment can be planned accordingly.
the fetal thyroid profile in the amniotic fluid and the Once the diagnosis of fetal hyperthyroidism is
thyroid size. 19 The doses commonly used for confirmed, fetal treatment should be initiated.
treatment range from 200-500 mg intra-amniotic Authors have attempted treating fetal hyper-
every week. With this regimen, fetal goiters have thyroidism with maternally administered antithyroid
been shown to regress, the hyperextension of the drugs. Porreco has reported maternal treatment of
fetal head have been shown to resolve and fetal and fetal thyrotoxicosis with the antithyroid drug
newborn TSH levels have normalized.19 propylthiouracil (PTU), which lead to a good
outcome.22 The initial dose used was 100mg PO three
Hyperthyroidism
times a day, which was later decreased to 50 mg PO
Neonatal hyperthyroidism is rare with an incidence three times a day. Wenstrom et al. described a
of 1:4,000 to 1:40,000/live births.10 Fetal thyrotoxic favorable outcome using maternal methimazole to
goiter is usually secondary to maternal autoimmune treat fetal hyperthyroidism in a patient who could
disease, principally Graves’ disease or Hashimoto’s not tolerate PTU.21 Hatjis also treated fetal goiterous
thyroiditis. As many as 12% of infants of mothers hyperthyroidism with a maternal dose of 300 mg
with a known history of Graves’ disease are affected PTU. This patient however, required supplemental
with neonatal thyrotoxicosis, which may occur even synthroid to remain euthyroid. There was good fetal
if the mother is euthyroid.20 As with hypothyroidism, outcome in this case as well.23
inherent to the underlying mechanism is the
transplacental passage of maternal IgG antibodies. INBORN ERRORS OF METABOLISM
In this case the antibodies, known as TSAb or (TSI),
Methylmalonic Acidemia
are predominantly directed against the TSH receptor.
Usually, the investigation of fetal hyper- The methylmalonic acidemias (MMA) are a group of
thyroidism begins only after the discovery of fetal enzyme-deficiency diseases inherited in an
goiter. Often, the goiter is diagnosed on ultrasound autosomal recessive manner resulting from one of
in patients referred due to elevated thyroid several genetically distinct etiologies. Some cases are
stimulating antibodies. In some cases, fetal goiters caused by mutations in the gene encoding methyl-
are realized serendipitously on routine ultrasono- malonyl-coenzyme A mutase while others are due
 Prenatal Therapy of Endocrine and Metabolic Disorders 1035
to a defect that reduces the biosynthesis of the mother in divided doses. The treatment only
adenosylcobalamin from vitamin B12. The disease is marginally altered the maternal serum B12 level.
characterized by wide clinical spectrum ranging from However, there was a slight reduction of maternal
a benign condition to a fatal neonatal disease. In the urinary methylmalonic acid excretion that remained
severe form, MMA is characterized by severe several fold above normal. At approximately 34
metabolic acidosis, developmental delay and weeks gestation, 5 mg of cyanocobalamin per day
biochemical abnormalities that include methylmalonic was administered intramuscularly. The maternal
aciduria, long chain ketonuria, and intermittent serum B12, level then rose gradually to more than six
hyperglycinemia. Patients with defects in adeno- fold above normal and was accompanied by a
sylcobalamin biosynthesis may respond to progressive decrease in urinary methylmalonic acid
administration of large doses of vitamin B12, which excretion. Maternal urinary methylmalonate was
may enhance the amount of active holoenzyme only slightly above the normal range when delivery
(mutase apoenzyme plus adenosylcobalamin). A occurred at 41 weeks. Amniotic fluid methylmalonic
proposed mechanism for the neurological acid concentrations were three times the normal
abnormalities observed in methylmalonic acidemia mean at 19 menstrual weeks and four times the
was suggested by a group of Brazilian investigators normal mean at term, despite prenatal treatment.
who administered methylmalonic acid to rats during Postnatally, the diagnosis of methylmalonic acidemia
the first month of their life.24 A significant diminution was confirmed. The infant suffered no acute neonatal
of myelin content and of ganglioside N-acetyl- complications and had an extremely high serum B12
neuraminic acid were noted in the cerebrum. level. Long-term postnatal management involved
More than 20 years ago, Ampola and colleagues protein restriction; however, no continuous B 12
were the first to attempt prenatal diagnosis and treatment was required. In this instance prenatal
treatment of a B 12 -responsive variant of MMA.25 treatment certainly improved the fetal and,
They followed the pregnancy of a patient who had secondarily, the maternal biochemistry. Whether
previously suffered the loss of a child to severe there was any significant clinical benefit to the fetus
acidosis and dehydration at the age of 3 months. by in utero treatment cannot be assessed adequately.
The diagnosis of MMA was made posthumously by It seems likely that reducing the fetal burden of
chemical analysis of blood and urine. In the methylmalonic acid should have some beneficial effect
subsequent pregnancy, amniocentesis at 19 weeks on fetal development and could reduce the risks in
revealed elevated methylmalonic acid in the amniotic the neonatal period.
fluid. Cultured amniocytes also demonstrated Andersson et al. 26 followed a cohort of eight
defective propionate oxidation and undetectable children with MMA for an average of 5.7 years.
levels of adenosylcobalamin. When adenosyl- Congenital malformations were described,
cobalamin was added, normal succinate oxidation reinforcing the deleterious effects of prenatally
and methylmalonyl-coenzyme A mutase activity were abnormal cyanocobalamin metabolism. Growth was
noted. These studies established that the fetus also significantly improved in most cases after initiation
suffered from MMA apparently due to deficient of therapy postnatally and in one case microcephaly
synthesis of adenosylcobalamin. It was already been resolved. However, developmental delay of variable
known that fetal MMA is associated with increased severity was always present regardless of treatment
methylmalonic acid excretion in the maternal urine. onset. These data suggest that prenatal therapy of
Indeed, Ampola et al 25 documented increased MMA may be effective and perhaps ameliorate some
methylmalonic acidemia in maternal urine at 23 and of the prenatal effects. Evans et al, have documented
25 weeks gestation. Late in the pregnancy, cyano- the changing dose requirements necessary over the
cobalamin (10 mg/day) was orally administered to course of pregnancy to maintain adequate levels of
1036 Textbook of Perinatal Medicine

B12. They sequentially followed maternal plasma and approximately 100 during biotin administration.
urine levels in a prenatal treated pregnancy.27 Data Non-identical twins were subsequently delivered at
such as these suggest that modulation of maternal- term. Cord blood and urinary organic acid profiles
fetal pharmacological interchange of therapeutic were normal, and cord blood biotin concentrations
drugs will be difficult to precisely control. were four to seven times greater than normal. The
neonatal course for both twins was unremarkable.
Multiple Carboxylase Deficiency Subsequent study of the cultured fibroblasts of both
Biotin-responsive multiple carboxylase deficiency is twins indicated that the cells of twin B (but not of
an inborn error of metabolism caused by diminished twin A) had virtually complete deficiency of all three
activity of the mitochondrial biotin-dependent carboxylase activities. Genetic complementation
enzymes (pyruvate carboxylase, propionyl-coenzyme studies confirmed that despite the normal clinical
A carboxylase and a-methylcrotonyl-coenzyme A presentation during the newborn period, twin B was
carboxylase). The condition may arise from homozygous for the disease mutation. Packman and
mutations in the holocarboxilase synthetase (HCS) colleagues have also reported prenatal diagnosis and
gene on chromosome 21q22.1 or the biotinidase gene treatment of biotin-responsive multiple carboxylase
localized to chromosome 3p25.28-32 Affected patients deficiency for a mother who had previously given
present as newborns or in early childhood with birth to a male with the neonatal-onset form of this
dermatitis, severe metabolic acidosis, and a disease.35 In the subsequent pregnancy, maternal
characteristic pattern of organic acid excretion. It has urine organic acid profiles were normal. Carboxylases
been demonstrated that metabolism in patients or in activities were assayed in cultured amniotic fluid cells
their cultured cells can be restored toward normal obtained by amniocentesis at 17 menstrual weeks.
levels by biotin supplementation. Prenatal diagnosis In biotin-restricted medium, the amniotic cells
can be made by demonstration of elevated levels of demonstrated the characteristic severe reduction in
typical organic acids (3-hydroxyisovalerate, carboxylase activities. Since these initial reports of
methylcitrate) in the amniotic fluid or in the chorionic prenatal administration of biotin to fetuses affected
villi. However, the existence of a mild form of HCS with this disorder, other cases have been publi-
deficiency can complicate prenatal diagnosis as shed,33,36,37 further provided compelling evidence
organic acids level in amniotic fluid might be that biotin administration antenatally is effectively
normal.33 Therefore, prenatal diagnosis must be taken up by the fetus and prevents functional
performed by enzyme assay in cultured fetal cells in deficiency of the carboxylases in an affected newborn.
biotin-restricted medium. No toxicity from treatment was observed. However,
Roth and colleagues treated a fetus without the because experience with this treatment is confined
benefit of prenatal diagnosis in a case in which two to a small number of cases, it is reasonably to carry
previous siblings had died of multiple carboxylase out prenatal diagnosis and only then to initiate
deficiency.34 The first had died within 3 days of birth treatment with biotin in any affected fetus.
and in the second, the diagnosis of biotin-responsive
Smith-Lemli-Optiz Syndrome (SLOS)
carboxylase deficiency was made posthumously.
Since the mother was first seen at 34 weeks gestation, Smith-Lemli-Optiz syndrome (SLOS) is a dysmor-
prenatal diagnosis was not attempted. Because of phological syndrome first reported in 1964. 38
severe neonatal manifestations in previous offspring Features include characteristic facies, growth and
and due to the probable harmlessness of biotin - oral mental retardation, and anomalies of the heart,
administration was begun at a dose of 10 mg/day. kidneys, central nervous system, and limbs. Cleft
There were no apparent untoward effects; maternal palate, postaxial polydactyly, 2-3 syndactyly of the
urinary biotin excretion increased by a factor of toes and cataracts are often seen in affected patients.
 Prenatal Therapy of Endocrine and Metabolic Disorders 1037
The 2-3 syndactyly of the toes is very specific for Since identification of the cholesterol metabolic
this disorder and is seen in > 90% of affected patients. defect in SLOS, a treatment protocol has been
Affected patients typically present with a narrow attempted providing exogenous cholesterol. This
forehead, ptosis, anteverted nares, low-set ears, and form of therapy has now been provided to many
micrognathia. patients with SLOS for the past several years in many
Males may present with ambiguous genitalia. In centers in the United States and internationally,48-50
contrast with CAH, patients with SLOS are deficient with the goal of raising cholesterol levels and
in cholesterol and therefore lack steroid precursors. decrease the precursors, 7-DHC and 8-DHC. It has
This leads to lack of androgens that results in under- been shown that dietary cholesterol supplementation
masculinization of the male genitalia. Patients with can restore a normal growth pattern in children and
adolescents with SLOS, alleviate behavioral
the severe form of the syndrome present not only
abnormalities and improve general health.48-50
with these dysmorphological findings but also with
Fetal therapy strategies may theoretically include
a high rate of neonatal mortality.39 The incidence of
providing cholesterol to the mother or to the fetus.
SLOS is estimated to be 1:20,000 - 1: 40,000 live
The former however, is not possible because
births, 40 and it appears to be most common in
cholesterol does not cross the placenta well in the
Caucasians population of North European origin, second trimester and there is lack of evidence that
with an estimated carrier frequency of 1:70.41 In 1993, it crosses the placenta in the third trimester.
the etiology of SLOS was discovered to be an inborn Moreover, cholesterol is available only in a crystalline
error of cholesterol biosynthesis due to a deficiency form, which cannot be given intravenously or
of the enzyme 7-dehydrocholesterol-DD 7 intramuscularly. Furthermore, it is impractical to
reductase.38,41-44 The gene for 7-dehydrocholesterol- inject cholesterol into the amniotic fluid because it
DD7 reductase has been localized to chromosome would precipitate. However, cholesterol can be given
11q12-13. 44 to the fetus by giving fresh frozen plasma in the form
As a result of this enzymatic defect, there is a of LDL-cholesterol. The group at Tufts University
characteristic biochemical pattern of reduced has attempted treatment antenatally in several
cholesterol levels and elevated 7 and 8 dehydro- affected fetuses. In cases where treatment was
cholesterol levels (7-DHC and 8-DHC respectively) started late in pregnancy, the results were incon-
in all body fluids and tissues including red blood clusive. Although few descriptions of fetal therapy
cells, fibroblasts, amniotic fluid and chorionic villi. for
SLOS exist, the latest report of antenatal treat-
The values observed in affected patients may be
ment comes from that same group of investi-gators.51
extremely variable. The diagnosis is made primarily
Therapy was begun at 34 weeks of gestation and
by the presence of the cholesterol precursor, 7-DHC,
resulted in increased fetal cholesterol levels and red
and not by the deficiency of cholesterol. Unaffected
blood cell mean corpuscular volume with subtle
individuals have levels of 7-DHC and 8-DHC of less
improvement in fetal growth, as assessed by conse-
than 1 mg/dl whereas patients with SLOS usually quent fetal weight plots. However, no significant
have levels of 7 to 20 or greater. Clinical mani- change in 7-DHC and 8-DHC levels was observed,
festations correlate with cholesterol levels. Severely further emphasizing the inconclusiveness of that
affected patients have very low levels of total treatment. However, the main point is that since
cholesterol (usually < 10- 15mg/dl), while those with significant development of the central nervous system
more mild manifestations may present with levels and myelination occurs prior to birth it is a reasonably
of 40-70 mg/dl. Prenatal diagnosis of SLOS has been to assume that providing cholesterol to the fetus, as
available since 1994 by either amniocentesis or early as possible would result in the most clinical
chorionic villus sampling.45-47 benefit.
1038 Textbook of Perinatal Medicine

Galactosemia Exposure to a high-galactose diet has been

considered to represent an animal model for human
Galactosemia is an inborn error of metabolism caused
galactosemia. Chen and colleagues have observed a
by diminished activity of the enzyme galactose-1-
phosphate uridyltransferase (GALT). This causes a reduction in the oocyte content of rat ovaries after
defective metabolism of the sugar galactose which is prenatal exposure to a 50% galactose diet. 53 No
the constituent of lactose, the main carbohydrate of analogous alterations in the testes were observed in
milk, fresulting in accumulation of galactose in the prenatally treated males. Experiments in rats suggest
bloodstream. It is inherited in an autosomal recessive that toxicity to the female gonads from galactose or
manner and results in cataracts, mental deficiency, its metabolites is most obvious during the premeiotic
growth deficiency, and ovarian failure. Clinical stages of ovarian development. Recently, impaired
symptoms appear in the neonatal period and can be germ cell migration leading to the development of
largely ameliorated by elimination of galactose from gonads with deficient initial pools of germ cells was
the diet. Cellular damage in galactosemia is thought proposed as the causal link between galactosemia
to be mediated by accumulation of galactose-l- and premature ovarian failure.54
phosphate intracellularly and of galactitol in the lens. These observations in animals and human beings
The GALT gene, localized to chromosome 9p13, is have led to speculation that galactose restriction
the only known gene to be associated with galacto- during pregnancy may be desirable if the fetus is
semia. Several disease-causing mutations are affected with galactosemia. In the human female,
commonly encountered in classical galactosemia, the ovarian meiosis begins at 12 and is complete by 28
most frequently observed is the Q188R classical menstrual weeks. Thus, ovarian damage, and
mutation. Mutational analysis is available usefully perhaps neurological or lens abnormalities, might
for the six classical galactosemia alleles (Q188R, occur prior to the usual time when prenatal diagnosis
S135L, K285N, L195P, Y209C, F171S) and for the by amniocentesis can be accomplished. Thus,
N314D Durate variant mutation.52 In cases in which anticipatory treatment in pregnancies at risk for
disease causing mutation are not identified (as having a galactosemic fetus might best be initiated
observed in 10-29% of classic galactosemia), GALT very early in gestation or even preconceptually.
sequence analysis may be performed to detect private Despite these experiments and speculations, we
mutations. Galactosemia can be diagnosed prenatally are unaware of studies that adequately assess the
by study of cultured amniocytes and chorionic villi. impact of prenatal administration of a low-galactose
There are suggestions that even the early diet to galactosemic fetuses. However such data,
postnatal treatment of galactosemic individuals with especially controlled, will be difficult to obtain.
a low galactose diet may not be sufficient to ensure Nevertheless, prenatal galactose restriction is
normal development. Some have speculated that probably desirable in galactosemia and should be
prenatal damage to galactosemic fetuses could harmless. There is little reason to suppose that galac-
contribute to subsequent abnormal neurological tose restriction would have adverse consequences,
development and to lens cataract formation. since galactosemic and normal fetuses are both
Furthermore, it has been recognized that female capable of some endogenous galactose synthesis.
galactosemics, even when treated from birth with
galactose deprivation, have a high frequency of MULTIFACTORIAL DISORDERS
primary or secondary amenorrhea because of ovarian
Neural Tube Defects
failure. This is because oocytes have already been
damaged irreversibly long before birth. There also Neural tube defects (NTDs) are malformations
may be some subtle abnormalities of male gonadal secondary to abnormal neural tube closure between
function. the third and fourth weeks of gestational age. The
 Prenatal Therapy of Endocrine and Metabolic Disorders 1039
etiology is complex and imperfectly understood with mandatory fortification.64 It was found that the birth
both genetic and environmental factors involved. prevalence of NTDs reported decreased by 19% . It
Animal studies suggest that NTDs can arise from a is important to note that the continuing decline in
variety of vitamin or mineral deficiencies. There are NTDs rates are estimated to be due to the intro-
historical data in humans suggesting increased NTD duction and increased utilization of prenatal
frequencies in subjects with poor dietary histories diagnosis, recommendations for multivitamin use in
or with intestinal bypasses. Biochemical evidence of women of childbearing age, and the population-wide
suboptimal nutrition is present in some women increases in blood folate levels since food fortification
bearing infants with NTDs. Analysis of recurrence was mandated.65
patterns within families and of twin-twin concordance Folate plays a central part in embryonic and fetal
data provides evidence of a genetic influence in non- development because of its role in nucleic acid
syndromal cases, although factors such as synthesis mandatory for the widespread cell division
socioeconomic status, geographic area, occupational that takes place during embryogenesis. Folate
exposure and maternal use of antiepileptic drugs are deficiency can occur because of low dietary folate
also associated with variations in the incidence of intake or because of increased metabolic requirement
NTDs.55 In 1980, Smithells et al suggested that as seen in particular genetic alterations such as the
vitamin supplementation containing 0.36 mg folate polymorphism of the thermolabile enzyme methyl-
can reduce the frequency of NTD recurrence by tetrahydrofolate reductase (MTHFR). A metabolic
sevenfold in women with one or more prior affected effect of folate deficiency is homocysteine elevation
children.56,57 For almost a decade, there has been a in blood. As mentioned, the thermolabile variant of
great deal of controversy regarding the benefit of MTHFR 677TT, is a known risk factor for NTDs.
folate supplementation for the prevention of NTDs.58- However, evidence regarding a second polymor-
61
Finally, in 1991, a randomized double-blinded trial phism in the same gene, 1298AàÐC, does not support
designed by the Medical Research Council Vitamin it’s role in NTDs.66 Additionally, numerous studies
Study Research Group demonstrated that analyzing MTHFR variants have resulted in positive
preconceptual folate reduces the risk of recurrence associations with increased NTD risk only in certain
in high risk patients.62 Subsequently, it was shown populations, suggesting that these variants are not
that preparations containing folate and other vitamins large contributors to the etiology of NTDs. 67
also reduce the occurrence of first time NTDs.63 In Therefore, it seems less likely to advise parents
response to these findings, guidelines were issued prospectively to test for MTHFR variants. Rein-
calling for consumption of 4.0 mg/day folic acid by forcement to the assumption that additional
women with a prior child affected with a NTD, for candidate genes other than MTHFR may be responsi-
at least 1 month prior to conception through the first ble for an increase risk to NTDs comes from the NTD
3 months of pregnancy. In addition, 0.4 mg/day folic collaborative group of Duke University. 68 175
acid is recommended to all women planning a American Caucasians NTD patients and their families
pregnancy to be taken preconceptually. The data on were examined for the thermolabile variant of
NTD recurrence prevention is now very well MTHFR. Although a significant association has been
established, and became routine for high risk cases. found comparing patients and controls, no such
As of January, 1998, the United States Food and Drug association was found in patients’ parents. Two other
Administration has mandated that breads and grains key enzymes in the metabolic pathway of
be supplemented with folic acid. The impact of food homocysteine are methionine synthase (MTR) and
fortification with folic acid on NTDs birth prevalence methionine synthase reductase (MTRR). Recently
during the years 1990-1999 was evaluated by reported, MTR and a specific (A66G) MTRR poly-
assessing birth certificate reports before and after morphisms have been found to be associated with
1040 Textbook of Perinatal Medicine

increased risk for NTDs. Interestingly, the NTDs risk deficiency, thereby averting the characteristic
was not influenced by maternal preconception folic neonatal acidosis. In theory, it would be desirable
acid intake at doses of 0.4 mg / day. However, due to minimize copper accumulation in Wilson disease
to limited sample size further studies are needed in as early as possible. If and when reliable prenatal
order to draw meaningful inferences. 69 Other diagnosis of Wilson disease is possible, cautious
candidate genes suggested as risk factor for NTDs administration of penicillamine prenatally might be
(mainly spina bifida), are polymorphisms in the considered. This would be a double-edged sword,
mitochondrial membrane transporter gene UCP2.70 however, as the teratogenic potential of penicillamine
Despite previous studies suggesting zinc deficiency would demand careful evaluation. Batshaw and
to play a role in the etiology of NTDs,71,72 further colleagues76 have treated certain urea cycle defects
studies found this observation inconclusive.73,74 by administering arginine and benzoate. Since
Methionine deficiency might be involved in NTDs hyperammonemia in some of these entities develops
as 30%-55% reduction in the risk of having NTD very acutely after birth, it might be desirable to
associated pregnancy was reported when methionine consider pretreating the fetus with these compounds
intake was greater then the lowest quartile of intake, just prior to or during labor to minimize postnatal
with further reduction in risk with greater hyperammonemia.76 Conversely, it may be desirable
methionine intake. 75 In conclusion, preconception to consider drug avoidance as an approach to fetal
intake of folic acid alone or as multivitamin treatment. For example, fetuses with glucose-6-
supplementation reduces the risk of recurrence and phosphate dehydrogenase deficiency are sensitive
first time NTDs. Additionally, folic acid-multivitamin to a variety of drugs that induce hemolysis. It would
supplementation reduces the occurrence of other probably be appropriate to avoid administering such
congenital anomalies such as seen in the urinary tract agents to women carrying or known to be at risk for
(e.g vesicorenal reflux, horshoe kidney and othres),in carrying fetuses deficient in glucose-6-phosphate
the cardiovascular system (e.g conotruncal heart dehydrogenase.
defects), and anomalies involving the limbs and face Umbilical cord catheterization under ultrasound
(orofacial clefting). guidance may lead to the development of other types
of fetal treatment.77 Systems such as gene replacement
PHARMACOLOGIC APPROACHES are being developed for certain lysosomal storage
It might be appropriate to consider suppressing disorders. Progress is being made in postnatal
excessive cholesterol production prenatally in severe experimental models on administration of thymic
hypercholesterolemia when a safe and effective agent cells for certain immune deficiency states, bone
for accomplishing this becomes available (although marrow transplantation for a variety of genetic
there is no clear evidence for hypercholesterolemic disorders, and gene transfer. The development of
prenatal damage). If cysteamine or related agents better and earlier techniques for prenatal treatment
were to prove an effective treatment for lethal will be complex, especially with regard to gene
variants of cystinosis, prenatal therapy might be transfer; but progress will be made, and access to
considered, because excessive and possibly harmful the fetal vasculature may be required for these
cystine accumulation is evident even in cystinotic methods to have a chance for success.
fetuses. Cysteamine levels have been detected in Bone marrow transplantation or thymic cell
chorionic villi, and significant elevations even at 10 infusion is actually only a specialized example of
weeks gestation have been hypothesized. Inhibitors organ transplantation. In the future, fetal organ
of gamma-glutamyl transpeptidase, if safe, would transplantation may become possible and may open
elevate intracellular glutathione levels and inhibit many prospects for surgical treatment of certain
oxoproline production in glutathione synthase biochemical genetic disorders.
 Prenatal Therapy of Endocrine and Metabolic Disorders 1041
One can also speculate about the therapeutic 7. Forest M, David M. Prenatal treatment of congenital
adrenal hyperplasia due to 21-hydroxylase deficiency.
possibilities involving compounds administered
7th International Congress of Endocrinology, Abstract
directly into the amniotic fluid or into the fetal y11, Quebec, Canada, 1984.
intestinal tract. It might be possible, for example, to 8. New MI, Carlson A, Obeid J et al. Prenatal diagnosis
administer thyroid hormone in this fashion or to for congenital adrenal hyperplasia in 532 pregnancies.
Clin Endocrinol Metab 2001; 86:5651-7.
prevent meconium ileus in cystic fibrosis by instilling
9. Clayton PE, Miller WL, Oberfield SE, Ritzen EM, Sippell
not yet determined enzymes into the fetal intestinal WG, Speiser PW; ESPE/ LWPES CAH Working Group.
tract. Consensus statement on 21-hydroxylase deficiency from
the European Society for Paediatric Endocrinology and
CONCLUSION the Lawson Wilkins Pediatric Endocrine Society. Horm
Res 2002;58:188-95.
While a multitude of metabolic disorders exist, 10. Fisher DA, Neonatal thyroid disease of women with
prenatal treatment for most has never been autoimmune thyroid disease. -Thyroid Today 1986;9:1-
7.
attempted or considered. The discovery of new
11. Fisher DA, Klein AH. Thyroid development and
disease associated genes and prenatal carrier testing disorders of thyroid function in the newborn. N Engl J
may in the future allow preconceptual carrier Med 1981;304:702-12.
detection, without the tragedy of first having an 12. Volumenie JL, Polak M, Guibourdenche J, et al.
Management of fetal thyroid goitres: a report of 11 cases
affected child. This may provide targeted therapy in
in a single perinatal unit. Prenat Diagn 2000;20:799-806.
families who chose to continue the pregnancy and 13. Morine M, Takeda T, Minekawa R, et al. Antenatal
offer the prospect of improved outcome by diagnosis and treatment of a case of fetal goitrous
ameliorating at least some of the prenatal deleterious hypothyroidism associated with high-output cardiac
effects of the metabolic disease. failure. Ultrasound Obstet Gynecol 2002; 19:506-9.
14. Rovet J, Ehrlich R, Sorbara D, Intellectual outcome in
children with fetal hypothyroidism. J Pediatr 1987;
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young rats. Braz J Med Biol Res 2001;34:227-31. male pseudohermaphroditism and frequent early
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therapy of a patient with vitamin B responsive 40. Opitz JM. RSH-SLO (“Smith-Lemli-Opitz”) syndrome:
methylmalonic acidemia. N Engl J Med 1975;293:313. historical, genetic, and development considerations. Am
26. Andersson HC, Marble M, Shapira E. Long term J Med Genet 1994; 50:344-6.
outcome in treated combined methylmalonic acidemia 41. Kelley RI. Diagnosis of Smith-Lemli-Opitz syndrome by
and homocysteinemia. Genet Med 1999;1:146-50. gas chromatography/mass spectrometry of 7-
27. Evans MI, Duquette DA, Rinaldo P,et al. Modulation of dehydrocholesterol in plasma, amniotic fluid and
B12 dosage and response in fetal treatment of cultured skin fibroblasts. Clin Chim Acta 1995; 236: 45-
methylmalonic aciduria (MMA); Titration of treatment 58.
dose to serum and urine MMA. Fet Diag and Ther 42. Kelley RI. A new face for an old syndrome. Am J Med
1997;12:21-23. Genet 1997; 65: 251-6.
28. Leon Del Rio A, Leclerc D, Gravel RA. Isolation of a 43. Tint GS, Irons M, Elias E, et al. Defective cholesterol
cDNA encoding human holocarboxylase synthetase by biosynthesis associated with the Smith-Lemli-Opitz
functional complementation of a biotinauxotroph of syndrome. N Engl J Med 1994; 330: 107-13.
E.coli. Proc. Natl. Acad. Sci. USA 1995; 92: 4626-30. 44. Waterham HR, Wijburg FA, Hennekam RCM, et al.
29. Suzuki Y, Akoi Y, Ishida Y, et al. Isolation and Smith-Lemli-Opitz is caused by mutations in the 7-
characterization of mutations in the holocarboxylase dehydrocholesterol reductase gene. Am J Hum Genet
synthetase cDNA. Nature Genet. 1994; 8: 122-8. 1998; 63: 329-38.
30. Akoi Y, Suzuki Y, Sakamoto O, et al. Molecular analysis 45. Gelman-Kohan Z, Nisani R, Chemke J, Appelman Z,
of holocarboxylase synthetase deficiency: a missense
Rappaport S, Hegesh E. Prenatal detection of recurrent
mutation and a single base deletion are predominant in
SLOS type 2. Am J Hum Genet 1990; 47: A57.
Japanese patients. Biochim. Biophys. Acta 1995; 1272:
46. Hobbins JC, Jones OW, Gottesfeld MD, Persutte W.
168-74.
Transvaginal ultrasonography and transabdominal
31. Dupuis L, Leon-Del-Rio A, Leclerc D, et al. Clustering
embryoscopy in the first-trimester diagnosis of Smith-
of mutations in the biotin-binding region of holo-
Lemli-Opitz syndrome, type II. Am J Obstet Gynecol
carboxilase synthetase in biotin responsive multiple
1994; 171: 546-9.
carboxylase deficiency. Hum Mol Genet 1996; 5: 1011-6.
47. Sharp P, Haan E, Fletcher JM, Khong TY, Carey WF.
32. Popmponio RJ, Hymes J, Reynolds TR, et al. Mutation
First trimester diagnosis of Smith-Lemli-Opitz
in the human biotinidase gene that cause profound
biothinidase deficiency in symptomatic children: syndrome. Prenatal Diagnosis 1997; 17:4: 355-61.
molecular, biochemical, and clinical analysis. Pediatr Res 48. Irons M, Elias E, Tint GS, et al. Abnormal cholesterol
1997; 42: 840-8. metabolism in the Smith-Lemli-Opitz syndrome: Report
33. Suormala T, Fowler B, Jakobs C, et al. Late onset of clinical and biochemical findings in 4 patients and
holocarboxylase synthetase deficiency: pre- and post- treatment in 1 patient. Am J Med Genet 1994; 50: 347-
natal diagnosis and evaluation of effectiveness of 52.
antenatal biotin therapy. Eur J Pediatr 1998; 157: 570-5. 49. Irons M, Elias ER, Abuelo D, et al. Treatment of Smith-
34. Roth KS, Yang W, Allen L, et al. Prenatal administration Lemli-Opitz syndrome: Results of a multicenter trial.
of biotin: biotin responsive multiple carboxylase Am J Med Genet 1997; 68: 311-4.
deficiency. Pediatr Res 1982;16:126-9. 50. Elias ER, Irons MB, Hurley AD, Tint GS, Salen G. Clinical
35. Packman S, Cowan Mj, Golbus MS, et al. Prenatal effects of cholesterol supplementation in six patients with
treatment of biotin responsive multiple carboxylase the Smith-Lemli-Opitz syndrome (SLOS). Am J Med
deficiency. Lancet 1982;1:1435-8. Genet 1997; 68: 305-10.
36. Thuy LP, Belmont J, Nyhan W. Prenatal diagnosis and 51. Irons MR, Nores J, Stewart TL, et al. Antenatal therapy
treatment of holocarboxylase synthetase deficiency. of Smith-Lemli-Opitz syndrome. Fetal Diagn Ther 1999;
Prenat. Diagn. 1999;19:108-12. 14: 133-7.
37. Thuy LP, Jurecki E, Nemzer L, et al. Prenatal diagnosis 52. Elsas LJ. Prenatal diagnosis of galactos-1-phosphate
of holocarboxylase synthetase deficiency by assay of uridyltransferase (GALT) deficient galactosemia. Prenat
the enzyme in chorionic villus material followed by diagn 2001; 21: 302-3.
 Prenatal Therapy of Endocrine and Metabolic Disorders 1043
53. Chen YT, Mattis’on DR, Feigenbaum L, et al. Reduction 66. Parle-McDermott A, Mills JL, Kirke PN, et al. Analysis
in oocyte number following prenatal exposure to a high of MTHFR 1298AàÐC and 677 CàÐT polymorphisms
galactose diet. Science 1981;314:1145-7. as risk factor neural tube defects. J Hum Genet. 2003;
54. Bandyopadhyay S, Chakrabarti J, Banerjee S, et al. 48: 190-3.
Prenatal exposure to high galactose adversely affects 67. Finnell RH, Shaw GM, Lammer EJ, Volcik KA. Does
initial gonadal pool of germ cells in rats. Hum Reprod prenatal screening for 5,10-methylenetetrahydrofolate
2003;18:276-82. reductase (MTHFR) mutations in high-risk neural tube
55. Frey L, Hauser WA. Epidemiology of neural tube defect pregnancies make sense? Genet Test 2002;6: 47-
defects. Epilepsia 2003; 44 (Suppl 3): 4-13. 52.
56. Smithells RW, Nevin NC, Seller MJ, et al. Further 68. Rampersaud E, Melvin EC, Siegel D, et al. Updated
experience of vitamin supplementation for prevention investigations of the role of methylenetetrahydrofolate
of neural tube defect recurrences. Lancet 1983;1:1027- reductase in human neural tube defects. Clin Genet.
2003; 63: 210-4.
31.
69. Zhu H, Wicker NJ, Shaw GM, et al. Homocysteine
57. Smithells RW, Sheppard S, Schorah CJ et al. Possible
remethylation enzyme polymorphisms and increased
prevention of neural tube defects by preconceptual
risks for neural tube defects. Mol Genet Metab. 2003;
vitamin supplementation. Lancet 1980;1:339-40.
78: 216-21.
58. Younis JS, Granat M. Insufficient transplacental digoxin
70. Volocik KA, Shaw GM, Zhu H, et al. Risk factors for
transfer in severe hydrops fetalis. Am J Obstet Gynecol neural tube defects: associations between uncoupling
1987;157:1268-9. protein 2 polymorphisms and spina bifida. Birth Defects
59. Mills JL, Rhoads GG, Simpson JL, et al. The absence of Res Part A Clin Mol Teratol. 2003 ; 67: 158-61.
a relation between the periconceptional use of vitamins 71. Sever LE. Zinc deficiency in man. Lancet 1973;I:887.
and neural-tube defects. N Engl J Med 1989;321:430-5. 72. McMichael AJ, Dreosti IE, Gibson GT. A prospective
60. Mulinare J, Cordero JF, Erickson JD, Berry RJ. study of serial maternal serum zinc levels and pregnancy
Periconceptional use of multivitamins and the outcome. Early Hum Dev 1982; 7: 59-69.
occurrence of neural tube defects. JAMA 1988;260:3141- 73. Stoll C, Dott B, Alembik Y, Koehl C. Maternal trace
5. elements, vitamin B12, vitamin A, folic acid, and fetal
61. Schulman JD. Treatment of the embryo and the fetus malformations. Rep Toxicol 1999; 13: 53-57.
in the first trimester: current status and future prospects. 74. Hambidge M, Hackshaw A, Wald N. Neural tube
Am J Med Genet 1990;35:197-200. defects and serum zinc. Br J Obstet Gynaecol 1993; 100:
62. MRC Vitamin Study Research Group. Prevention of 746-9.
neural tube defects: results of the MRC vitamin study. 75. Shoob HD, Sargent RG, Thompson SJ, et al. Dietary
Lancet 1991;338:132-7. methionine is involved in the etiology of neural defect-
63. Czeizel AE, Dudas I. Prevention of the first occurrence affected pregnancies in humans. J Nutr 2001; 131: 2653-
of neural-tube defects by preconceptional vitamin 8.
supplementation. N Engl J Med 1992;327:1832-5. 76. Batshaw M, Brusilow S, Waber L, et al. Treatment of
inborn errors of urea synthesis: activation of alternative
64. Honein MA, Paulozzi LJ, Mathews TJ, Erickaon JD,
pathways of waste nitrogen synthesis and excretion. N
Wong LY. Impact of folic acid fortification of the US food
Engl J Med 1982;306:1387-92.
supply on the occurrence of neural tube defects. JAMA
77. Nicolaides KH, Thorpe-Beeston JG, Noble P.
2001; 285: 2981-6. Cordocentesis. In: Eden RD, Boehm H, eds. Assessment
65. Olney RS, Mulinare J. Trends in neural tube defect and care of the fetus: physiological, clinical and
prevalence, folic acid fortification, and vitamin medicolegal principles, Nor-walk, Appleton and Lange,
supplement use. Semin Perinatol 2002; 26: 277-85. 1990:291.
1044 Textbook of Perinatal Medicine

78
Fetal Surgical Interventions

Michael R Harrison, Mark I Evans

INTRODUCTION LUTO, although other etiologies such as stenosis of

Over the last two decades, fetal therapy has evolved the urethral meatus, anterior urethral valves, ectopic
into four major areas: open surgical approaches, insertion of a ureter and tumors of the bladder have
“closed” endoscopic surgical approaches, pharma- been observed. LUTO can result in massive distention
cologic therapy, and stem cell/gene therapy. of the bladder with compensatory hypertrophy and
Advances in the field have been characterized by hyperplasia of the smooth muscle within the bladder
dramatic successes, but also intense frustration at wall, leading to a loss of compliance and elasticity,
technical challenges and moving targets as ancillary and poor postnatal function generally requiring
therapies change risk/reward equations.1 surgical reconstruction. 3 Elevated intravesicular
If something can be treated safely postnatally, pressures prevent urine inflow from the ureters and
then there is no justification for prenatal intervention. eventual distortion of the ureterovesicle angles
However, for the conditions discussed below, contribute to reflux hydronephrosis. Progressive
profound and irreparable damage occurs before pyelectasis and calyectasis compress the delicate renal
birth, making fetal intervention the best or sometimes parenchyma within the encasing serosal capsule,
only way to ameliorate the damage. Some procedures leading to functional abnormalities within the
have been quite rare. Others are more common, but medullary and eventually the cortical regions. Focal
the expectation is that with improvements and compressive hypoxia likely contributes to the
increasing utilization of prenatal diagnosis, that more progressive fibrosis and perturbations in tubular
women will chose consider the opportunities to treat function resulting in urinary hypertonicity which is
fetuses before birth.2 observed. Obstructive processes can eventually
lead to type IV cystic dysplasia and renal insuffi-
SURGICAL THERAPY ciency.4-7
The affects extend beyond the GU tract.
In Utero “Closed” Fetal Surgery
Progressive oligo/anhydramnios leads to com-
The most efficacious percutaneous in utero fetal pressive deformations as seen in Potter sequence,
surgery has been for the evaluation and treatment including extremity contractures and facial
of obstructive uropathy. Lower urinary tract obstruc- dysmorphology. Absence of normal amniotic fluid
tion (LUTO) is a heterogeneous entity that affects volume also interferes with pulmonary growth and
1:5000-8000 newborn males. Posterior urethral valves development. Constant compressive pressure on the
or urethral atresias are the most common causes for fetal thorax leads to restriction of expansion of the
 Fetal Surgical Interventions 1045
chest through normal physiologic “breathing reliable results within five days during which the
movements”. Babies born with LUTO generally die remainder of the prenatal evaluation is underway.
secondary to pulmonary complications and not renal Fluorencence in situ hybriduzation (FISH) can be used
failure. to get rapid status of chromosomes 13, 18, 21, X and
The prenatal sonographic diagnosis of LUTO Y. 8
includes dilated and thickened walls of the bladder, Essential to the prenatal workup is the evaluation
hydronephrosis, and oligohydramnios (Fig. 78.1). of underlying renal status in the fetus. Over the past
Urethral strictures or atresia, urethral agenesis, 15 years, we have developed a multicomponent
megalourethra, ureteral reflux, and cloacal anomalies approach for the analysis of fetal urine that evaluates
may be present and have a very similar appearance proximal tubular and possible glomerular status using
on ultrasound. The typical “keyhole sign” of proximal sodium, chloride, osmolality, calcium, beta-2 micro-
urethral dilation is secondary to urethral obstruction globulin, albumin, and total protein concentrations.5
Predictive reliability has been shown to be signi-
present in PUV or atresia. However, the precise
ficantly improved by sequential samplings at 48-72
diagnosis can only be made after birth.7
hour intervals. 6 Using such an approach, one can
The prenatal evaluation and management of
directly correlate the degree of impaired renal
fetuses with the sonographic findings of LUTO are
function and damage with the extent of urinary
complex.4-6 Ruling out other congenital anomalies
hypertonicity and proteinuria. As such, the ability
such as cardiac and neural tube defects is necessary
to counsel patients about the renal status of their
before intervention can be considered.
fetus and the long term prognosis has been
Karyotyping is needed to confirm a normal male
dramatically improved.
chromosomal status, as cases of LUTO have an Vesicoamniotic catheter shunts bypass the urethral
increased incidence of aneuploidy. Female fetuses obstruction diverting the urine into the amniotic
almost always have more complex syndromes of space to allow appropriate drainage of the upper
cloacal malformations which do not benefit from in urinary tract and prevention of pulmonary
utero shunt therapy. Because of the presence of oligo/ hypoplasia and physical deformations (Fig. 78.2). In
anhydramnios, we commonly obtain karyotypes by fetuses with isolated LUTO, a normal male karyo-
transabdominal chorionic villus sampling which gives type, and progressively improving urinary profile

Fig. 78.1: Oligohydramnios and dilated bladder in a Fig. 78.2: Vesicoamniotic shunt with the proximal portion lying within
fetus at 17 weeks with good electrolytes the fetal bladder while the distal portion lies within the amniotic fluid
space allowing diversionary draining of urine into the appropriate
space.
1046 Textbook of Perinatal Medicine

that meet threshold parameters (Table 78.1), essential. The Paris group has found that about 25%
intervention has been very successful in salvaging of children had serious, long term renal impairments
fetuses using percutaneous vesicoamniotic shunt and about 15% actually developed end stage renal
therapy. disease requiring transplant.9
Experience in humans has been widely variable Although vesicoamniotic shunting has clearly
and appears to be related to the extent of prenatal improved survival and renal function in cases of early
evaluation prior to shunt placement, as well as the obstructive uropathy, complications of this procedure
etiology of obstruction. Freedman, et al., confirmed remain unacceptably high. We found in the 80’s and
that Prune Belly infants, without complete urethral 90’s that in 40% of our cases, the shunts became
obstructions have very good renal outcomes physically displaced into the amniotic or intra-
following vesicoamniotic shunt therapy.7 They have peritoneal space, or have become obstructive with
also found significant improvement in survival and loss of drainage function necessitating replacement.
renal function in infants with posterior urethral On balance, intervention for LUTO has saved fetuses
valves treated by shunting, however, many have who would otherwise have surely died. Many have
mild to moderate renal insufficiency at birth and normal to moderately impaired renal function. A
several of these have progressed to renal failure, carefully balanced approach in counseling is required
dialysis, and transplantation. The worst group of for patients to determine what is right for them.
infants appears to be those with urethral atresia.
However, there have been survivors with urethral Other Shunts
atresia following early shunt intervention. These In the late 1970’s, shunting was attempted for
findings support animal studies, which indicated that obstructive hydrocephalus.10 Attempts in the late
early onset, complete obstructions resulted in more 1970’s and early 80’s at in utero ventriculoperitoneal
severe renal damage than later onset or partial shunting were nearly uniformly disastrous.
obstructions. Such data emphasize the necessity for However, in retrospect, most operated patients were,
early diagnosis, evaluation and intervention in such in fact, very poor candidates for intervention. Many
cases. had multisystem syndromic disorders, including
More recently, data from our experience over the aneuploidy, and hopeless congenital anomalies such
past 15 years suggests that patients having bladder as holoprosencephaly.
shunts had a 91% survival, but that long-term renal Accordingly, ventriculoamniotic shunts were
function was not guaranteed. Just under half had abandoned since the early 80’s. With a better
“normal renal function”, and about a quarter had understanding of the poor natural history of the
mild impairments. The experience depended highly anomaly, and better, more accurate diagnostic
on the exact etiology of the disorder with posterior techniques, we have speculated that there may
urethral value having the best outcomes and urethral eventually be limited applications for prenatal
atresia the worst. The experience suggests that close neurologic shunting in cases of early onset, isolated,
pediatric urologic/renal function assessment is progressive obstructive hydrocephaly.
Table 78.1: Upper threshold values for selecting
The other use of percutaneously placed shunts
fetuses that might benefit from prenatal intervention has been for thoracic abnormalities.11,12 The macro-
Sodium < 100 mg/dl
cystic form of congenital cystic adenomatous malfor-
Chloride < 90 mg/dl mation can present with a very large intrathoracic
Osmolality < 190 mOsm/L mass with a, dominant macrocyst which causes
Calcium < 8 mg/dl cardiac and mediastinal shift and comes with its
b-2 microglobulin < 6 mg/L
Total protein < 40 mg/dl potential hemodynamic changes, as well as
pulmonary compression and risk of lung hypoplasia.
 Fetal Surgical Interventions 1047
Such dominant cysts can be approached using the clinical necessity to improve the safety of open
pleuroamniotic shunts to chronically drain these fetal surgery for both the fetus and the mother.
structures, reducing their volume, and diminishing
their space occupying effects within the thoracic Congenital Diaphragmatic Hernia (CDH)
cavity. The fetal approach to CDH has undergone continuous
Isolated pleural effusions can also accumulate to evolution since the first attempted CDH repair in
the point of causing hemodynamic changes and onset 1986 and the first success in 1989.13-16 Definitive repair
of generalized hydrops as well as pulmonary of CDH by reduction of viscera from the chest,
compression which interferes with normal lung diaphragmatic patch placement, and abdominal silo
development increasing the risk of hypoplasia. Small, construction (to reduce intraabdominal pressure) had
unilateral effusions generally do not warrant unacceptable mortality, particularly after a clinical
intervention, but must be followed closely as they trial showed open fetal repair was no better than
have the potential for rapid progression and postnatal repair, when the liver was herniated into
development of generalized hydrops.12 the chest. 17,18 The definitive repair was abandoned
As with all fetal interventions, prenatal evalua- as an option for CDH; in utero tracheal occlusion
tion prior to intervention is critical for appropriate took its place.18-25 (Fig. 78.3) Tracheal occlusion leads
case selection. Seemingly isolated effusions may be to an increase in lung size through accumulation of
the first sign of a cardiac malformation, aneuploidy, pulmonary secretions, which reduces the herniated
anemia, or an infectious process. Thoracoamniotic viscera from the chest and decreases the risk for lung
shunting is effective in carefully evaluated cases when hypoplasia. The technique of achieving reliable,
the risk of pulmonary hypoplasia from large effusions complete and reversible trachael occlusion has
early in gestation is present, or early signs of evolved. Initially, it could only be accomplished by
progressive hydrops (unilateral - bilateral effusion, open fetal surgery and fetal neck dissection (taking
skin or scalp edema, ascites, pericardial effusion) care to avoid the recurrent laryngeal nerves) and
appear. Fetal anemia, per se, is not an indication for placement of occlusive hemoclips. Next, a fetoscopic
thoracoamniotic effusion shunting, as hydropic technique was developed to accomplish the same neck
changes will usually resolve with timely fetal dissection and tracheal clip (the Fetendo Clip
transfusion therapy. Also, if one waits to intervene Procedure).22-23 While successful, it proved difficult,
until the fetus develops significant ascites, the
prognosis even with successful shunt intervention,
diminishes considerably.12 However, several cases
with suddenly progressive pleural effusions and onset
of generalized hydrops (skin/scalp edema,
pericardial effusion, and moderate ascites) have been
treated with complete resolution of all hydropic
complications and normal postnatal infants.

Open Surgical Approaches

For a limited number of indications open fetal surgery
has been performed for about 20 years.2 Appropriate
concerns for maternal risk, rigorous selection criteria,
and somewhat frustrating results have limited its use.
Fig. 78.3: Surgical isolation of the fetal trachea prior to placement of
There has been continuing innovation and develop- hemoclips in a tracheal occlusion procedure for congenital
ment of instruments and techniques, motivated by diaphragmatic hernia
1048 Textbook of Perinatal Medicine

with a significant learning curve. Attempts to simplify return to the heart. When fetuses with CCAM develop
the procedure by developing an appropriate polymer hydrops, the fetal mortality approaches 100%26-28 (Fig.
to use as a tracheal plug inserted through the fetal 78.4). Fetal resection of CCAM reverses hydrops and
mouth were unsuccessful. Experience quickly showed has improved survival dramatically.26-28 The fetal
that unless there was complete occlusion, the operation is performed by exposure of the arm and
pulmonary secretions would leak, thereby defeating chest wall on the side of the lesion through the
the purpose of the plug. Finally, a relatively simple maternal hysterotomy. A large muscle sparing
technique was developed in which a fetoscope passed thoracotomy is performed through the midthorax
through a single port is advanced into the fetal of the fetus and the lobe containing the CCAM is
trachea (fetal bronchoscopy) and a detachable silicone isolated. The attachments of the lobe to adjacent lung
balloon is inflated to occlude the trachea. tissue are bluntly divided and the lobar hilum is
CDH has been a classic example of rapid changes divided by use of a TIA stapler or a bulk ligature.
in technology clouding any simple attempts to During the remainder of the pregnancy, the
understand the role for fetal surgery. With increasing remaining normal lung shows compensatory growth
sophistication of the surgical approach as well as the fill the space left showing mass removal.
concomitant improvements in neonatal care using
extracorporeal membrane oxygenation (ECMO), it Sacrococcygeal Teratoma (SCT)
was impossible to accurately determine the relative Fetal SCT arises from the presacral space which may
benefits of each approach without a prospective, grow to massive proportions and in some fetuses
randomized comparison that held all other details induce high output failure from tumor vascular steal.
constant. Thus, after much debate, a randomized trial Fetal SCT with high output physiology with
of surgery for CDH versus optimal postnatal care associated placentomegaly or hydrops uniformly
was funded by NICHD.18 The principle component result in fetal demise 29,30 (Fig. 78.5). The patho-
of the trial was that patients in the postnatal care physiologic rationale for fetal surgery is to ligate the
(control) arm would receive the same neonatal care vascular connections to the tumor, remove the
by the same center as the surgical arm. vascular “sin”, and reverse the high output
It was originally expected that patients having physiology. The fetal operation is performed by
the surgery would have a survival rate of about 70%
as compared to the best data on controls expecting
about 35%. The surgically treated patients achieved
expected survival. However, the trial was stopped
prematurely, when by having the controls cared for
at the same tertiary specialty centers as the surgical
group, survival in the controls was essentially the
same as the surgical group. Such data show
conclusively the principle of “the moving target” and
how our use of technology must continually adapt
to changing conditions.25

Congenital Cystic Adenomatoid

Malformation (CCAM)
CCAM is a space occupying congenital cystic lesion
of the lung which may grow and induce hydrops by Fig. 78.4: Microcystic congenital cystic adenomatous
causing mediastinal shift and compromise venous malformation (microcystic) with beginnings of hydrops .
 Fetal Surgical Interventions 1049
of the low resistance tumor circuit, the fetal
hemodynamic status must be monitored by fetal
echocardiography during and in the immediate
period following the ligation.

The EXIT Procedure

The EXIT procedure is a modified cesarean delivery
and may be applied to deliver fetuses after fetal
surgical procedures such as tracheal ligation, or for
fetuses with difficult airway problems such as
massive cervical teratomas or cystic hygromas.31,32
The most important component of the EXIT procedure
is maintenance of uteroplacental perfusion until the
fetal airway is secured and ventilation is established.
In direct contrast to cesarean section where uterine
contraction for hemostasis is encouraged, uterine
relaxation is maintained by deep general anesthesia.
The fetal manipulations are then performed with
maternal support via the placenta. Clips can be
removed, chest masses removed, bronchoscopy
performed, and stable airway access established in
otherwise very difficult circumstances with this
Fig. 78.5: Saccrococcygeal teratoma in a fetus approach. Once the fetus is ready for transport to
exteriorization of the fetal buttocks with attached the nursery or adjacent operating suite following
tumor.29 Every attempt is made to keep the head, these preliminary steps, the cord is clamped and cut
torso, and lower extremities of the fetus in the uterus. and the cesarean delivery completed.
Since the tumor can sometimes be larger than the
Meningomyelocele
fetus, significant loss of uterine volume occurs, and
the uterus may contract increasing the risk for Babies with myelingomyloceles have impaired lower
placental abruption, placental dysfunction because motor function, loss of bowel and bladder control.
of compression, or post-operative preterm labor. A significant percentage develop obstructive
Once exteriorized, the anus is identified and the fetal hydrocephalus which requires ventriculoperitoneal
skin incised posterior to the anorectal sphincter shunting. 33 Experience from the 1970’s and 80’s
complex to avoid injury to the continence mechanism. showed that babies with meningomyelocele delivered
A tourniquet is then applied to the base of the tumor atraumatically by cesarean section had a better level
and brought down gradually as the tumor is finger of motor function for the given level of anatomic
fractured down to it’s vascular pedicle. The vascular defect, than those babies delivered through the
pedicle is then ligated with suture ligatures or TIA vaginal canal.34 Such data suggest that compression
device stapled depending upon the width of the and trauma to the cord in the delivery process can
pedicle. The entire fetal procedure can be performed have permanent long term sequelae to motor
in less than 15 minutes with minimal blood loss. function. It therefore follows that trauma to the
Because of the increase in afterload following ligation spinal cord in utero, either from banging into the
1050 Textbook of Perinatal Medicine

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uropathy: Specific outcomes diagnosis. J Urology
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controversy surrounding the data.33 A randomized, FISH for prenatal diagnosis of common aneuploidies.
Methods Mol Biol. 204:219-41, 2002.
prospective trial comparing fetal to postnatal 9. Dommergues M. Mueller F. Experience of 100
neurosurgical closure began in 2003 but will take Obstructive Uropathies. International Fetal Medicine
several years to be completed. A major milestone of and Surgery Society 2003, (unpublished).
10. Drugan A, Krause B, Canady A, Zador IE, Sacks AJ,
this trial has been the agreement among the
Evans MI. The natural history of prenatally diagnosed
participating centers not to perform any cases outside ventriculomegaly. JAMA 261:1785-1788, 1989.
the trial, and other centers around the country have 11. Ahmad FK, Sherman SJ, Hagglund KH, Johnson MP,
agreed not to start programs until the trial is Krivehcnia EL. Isolated unilateral pleural effusion: The
role of sonographic surveillance and in utero therapy .
completed. Fetal Diagn and Ther 11:383-89, 1996.
12. Nicolaides KH, Azar GB. Thoracoamniotic shunting.
CONCLUSION Fetal Diagn and Ther 5:153-164, 1990.
13. Adzick N, Harrison M, Flake A, Glick P, Bottles K.
There are an increasing number of congenital and Automatic uterine stapling devices in fetal surgery:
genetic abnormalities for which in utero treatment Experience in a primate model. Surgical Forum 1985;
XXXVI:479-81.
is possible, and in some cases, now relatively routine.
14. Jennings RW, Adzick NS, Longaker MT, Lorenz HP,
Advances in therapies have progressed at different Estes JM, Harrison MR. New techniques in fetal surgery.
paces for different disorders, but there is great hope Journal of Pediatric Surgery 1992;27:1329-33.
and enthusiasm that progress will continue to expand 15. Jennings RW, Adzick NS, Longaker MT, Lorenz HP,
Harrison MR. Radiotelemetric fetal monitoring during
the number of disorders for which therapy can be and after open fetal operation. Surgery, Gynecologic
effective. and Obstetrics 1993;176:59-64.
 Fetal Surgical Interventions 1051
16. Harrison MR, Longaker MT, Adzick NS, Goldberg JD, 28. Crombleholme TM, Coleman BG, Howell LJ et al.
Rosen MA, Filly RA, Evans MI, Golbus MS. Successful Elevated Cystic Adenomatoid Malformation Volume
repair in utero of a fetal diaphragmatic hernia after (CVR) Outcome in Prenatal Diagnosis of Cystic
removal of herniated viscera from the left thorax. NEJM Adenomatoid Malformation of the Lung. J Pediatr Surg
1990;322:1582-1584. 37:331-338, 2002.
17. Harrison MR, Adzick NS, Flake AW, et al. Correction 29. Hotterman AX, Filiatrault D, Lallier M, et al: The Natural
of congenital diaphragmatic hernia in utero: VI. Hard- History of Sacrococcygeal Teratomas diagnosed through
learned lessons. J of Ped Surg 1993;28:1141-7; discussion Routine Obstetric Sonogram: A single institution
1417-8. experience. J Pediatr Surg 37:331-338, 2002.
18. Harrison MR, Keller RL, Hawgood SB, Kitterman JA, 30. Paek B. Vaezy S, Fujimoto V, et al: Tissue Ablation Using
Sandberg PL, Farmer DL, Lee H, Filly RA, Farrell JA,
High-intensity Focused Ultrasound. Potential for Fetal
Albanese CT. A Randomized Trial of et al Endoscopic
Treatment. Am J Obstet Gynecol 1875-77, 2003.
Tracheal Occlusion for Severe Fetal Congenital
31. Liechty KW, Crombleholme TM, Flake AW, et al:
Diaphragmatic Hernia. N Engl J Med. 349:1916-24, 2003.
19. Harrison MR, Sydorak RM, Farrell JA, Kitterman JA, Intrapartum Airway Management for giant neck
Filly RA, Albanese CT. Fetoscopic Temporary Tracheal masses. The EXIT (ex utero Intrapartum Treatorus
Occlusion for Congenital Diagphragmatic Hernia: procedure. Am J Obstet Gynecol 177:870-874, 1997.
Prelude to a Randomized, Controlled Trial. J Pediatr 32. Hedrick HL: Ex Utero Intrapartum Therapy. Seminars
Surg. ;38(7):1012-20, 2003. in Perinatology 12:190-195, 2003.
20. Heerema AE, Rabban JT, Sydorak RM, Jarrison MR, 33. Meningomyelocele: Prenatal Diagnosis, Pathophysiology
Jones KD. Lung Pathology in Patients with Congenital and Management Seminars in Perinatology 12:168-174,
Diaphragmatic Hernia Treated with Fetal Surgical 2003.
Intervention, Including Tracheal Occlusion. Pediatr Dev 34. Lemire RJ. Neural tube defects. JAMA 259:558-562, 1988.
Pathol., 2003. 35. Meuli M, Meuli-Simmen C, Hutchins GM, Yingling CD,
21. Sydorak RM, Harrison MR. Congenital Diaphragmatic McBiles-Hoffman K, Harrison MR, Adzick NS. In utero
Hernia: Advances in Prenatal Therapy. Clin Perinatol. surgery rescues neurological function at birth in sheep
30(3):465-79, 2003. with spina bifida. Nature Med 1(4):342-346, 1995.
22. Danzer E, Sydora RM, Harrison MR, Albanese CT. 36. Bruner JP, Tulipan N, Paschall RL, Boehm FH, Walsh
Minimal Access Fetal Surgery. Eur J Obstet Gynecol WF, Silva SR, Hernanz-Schulman M, Lowe LH, Reed
Reprod Biol. 1;108(1):3-13, 2003. GW. Fetal Surgery For Myelomeningocele and the
23. Evans MI, Harrison MR, Flake AW, Johnson MP. Fetal Incidence of Shunt-Dependent hydrocephalus. JAMA
Therapy. Best Pract Res Clin Obstet Gynaecol 16(5):671-
282(19):1819-25, 1999.
83, 2002.
37. Sutton LN, Adzick NS, Bilaniuk LT, Johnson MP,
24. Paek BW, Coakley FV, Lu Y, Filly RA, Lopoo JB,
Crombleholme TM, Flake AW. Improvement in Hind-
Qayyum A, Harrison MR, Albanese CT. Congenital
brain
Diaphragmatic Hernia: Prenatal Evaluation with MR
Lung Volumetry – Preliminary Experience. 220(1):63-7, 38. Tulipan N, Hermanz-Schulman M, Bruner JP: Reduced
2000. Hirdbrain Hermination After Intrauterine Myelo-
25. Wenstrom KD. Fetal Surgery for Congenital Diaphrag- mingocele repair. A Report of Four Cases. Pediatr
matic Hernia. N Engl J Med 13;349(20):1887-8, 2003. Neurosurgery 29:274-278, 1998.
26. Adzick NS, Kitano Y: Fetal Surgery for Lung Lesions, 39. Bruner JP, Tulipan N, Paschall RL, et al. Intrauterine
Congenital Diaphragmatic Hernia, and Saccrococcygeal Repair of Myelomingocele, “Hirdbrain Hermination”,
Teratoma. Seminars in Pediatric Surgery 12:154-167, and the Incidence of Shunt Dependent Hydrocephalus.
2003. JAMA 282:1819-1825, 1999.
27. Adzick NS, Harrison MR, Crombleholme TM et al: Fetal 40. Johnson MP, Adzick WS, Rintoul N, et al Fetal Menyo-
Lung: Management and Outcome. Am J Obstet Gynecol ngocele Repair: Short Term Outcomes. Am J Obstet
179:884-889, 1998. Gynecol. 189:482-487, 2003.
 SECTION 9
Screening and Risk Assessment
G Monni, S Chasen
1054 Textbook of Perinatal Medicine
 First-Trimester Ultrasound Screening for Fetal Malformations 1055

79
First-Trimester Ultrasound
Screening for Fetal Malformations
Stephen T Chasen

INTRODUCTION well. The cavum septum pellucidum and structures

in the posterior fossa cannot be reliably evaluated in
The most significant advance in first-trimester
many cases, though visualization becomes more likely
ultrasound screening has been the recognition of
nuchal translucency (NT) as a potent marker for fetal by 14 weeks.
aneuploidy.1 Abnormal NT in a euploid fetus is also
Fetal Face
associated with structural fetal abnormalities that can
be diagnosed in the second-trimester. 2 Thus, The profile is well imaged in most fetuses from 11-
measurement of NT can lead to earlier and targeted 14 weeks, and this has led to the use of nasal bone
screening in the second trimester. evaluation in Down syndrome screening.5 The orbits
While abnormal NT can suggest the possibility of can be identified as well. While the lips can be seen
a structural abnormality, advances in ultrasound at these gestational ages in some fetuses, they cannot
imaging have made the direct diagnosis of some be reliably evaluated in a significant proportion of
anomalies possible.3,4 Evaluation of other anatomic cases.
structures in the first trimester can diagnose
anomalies or identify useful markers for anomalies Fetal Spine
that may be diagnosed later in pregnancy. As more The cervical and cervical spines can be evaluated in
women will be presenting for NT measurement at the first-trimester. Unfortunately, the lumbar and
11-14 weeks’ gestation, it is important to consider sacral spines, in which spina bifida are much more
other anatomic structures amenable to evaluation at likely to occur, are often not well imaged prior to
this time. the second trimester.

EVALUATION OF FIRST-TRIMESTER ANATOMY Fetal Heart

Fetal Head Aside from cardiac axis, the structure of the fetal
Structures that can be well visualized in the first- heart is generally not well evaluated at 14 weeks’
trimester include the calvarium and portions of the gestation or earlier. Four-chamber view, outflow
developing brain. Midline structures, including a falx tracts, ductus arteriosus, and the aortic arch cannot
cerebri and thalamic bodies, are easily visualized. be evaluated in many cases at these gestational
Choroid-filled lateral ventricles can be identified as ages.6
1056 Textbook of Perinatal Medicine

Abdomen
An intact diaphragm and stomach bubble are visible
at 11-14 weeks in most cases. The umbilical cord
insertion in the ventral wall and the urinary bladder
just below the site of cord insertion can be seen in
the vast majority of fetuses as well. The kidneys can
usually be identified, though this is not possible in
a small proportion of cases.

Extremities
By 11 weeks, high-resolution ultrasound can
document the presence of all long bones in the
extremities in most fetuses. Reference ranges for limb
Fig. 79.1: Acrania at 11 weeks’ gestation. No bony structures are
measurements early in pregnancy have been
seen above the level of the orbits. Brain tissue can be seen. This
published.7The hands and feet are usually easily would not be visualized in the case of anencephaly.
identified. Evaluation of the fingers is possible,
though this may be limited prior to the second in future pregnancies to prevent open neural tube
trimester. defects.

DIAGNOSIS OF FETAL ANOMALIES Holoprosencephaly

AT 11-14 WEEKS
This condition is due to the failure of the forebrain
While we can identify many structures by the end of to cleave into hemispheres early in gestation. Alobar
the first-trimester, sonographic diagnosis of holoprosencephaly, in which no midline structures
abnormalities in these structures is limited. Although are noted and only a single ventricle is present, is
first-trimester sonographic diagnosis has been the most severe variant. This condition should be
reported for a wide variety of anomalies, 4,8-10 strongly suspected when two separate choroid
relatively few can be reliably diagnosed or excluded plexuses are not seen in a transverse view through
with confidence. The following anomalies can be the fetal brain. Alobar holoprosencephaly can be
reliably diagnosed or excluded sonographically in diagnosed or excluded after 10 weeks’ gestation.12
most cases at the 11-14 week scan. (Fig. 79.2) Semilobar and lobar holoprosencephaly,
in which some form of midline division has occurred,
Anencephaly/Acrania
cannot always be detected prior to the second
Anencephaly and acrania are characterized by the trimester.
absence of a cranial vault. Both conditions are easily While not lethal in all cases, alobar holo-
identified or excluded after 10 weeks’ gestation.11 prosencephaly is associated with virtual absence of
While anencephaly is characterized by absence of the cognitive function. Cytogenetic studies are indicated,
cranial vault and the cerebral cortex, the latter as this abnormality is associated with Trisomy 13 as
structure can be seen in acrania (Fig. 79.1). Both well as other less common forms of aneuploidy. As
conditions are uniformly lethal. While there is some holoprosencephaly has been described to have
controversy as to whether acrania is due to failed autosomal recessive inheritance in some families,13
closure of the rostral portion of the neural tube (as recurrence can be excluded with identification of
is anencephaly), women should be counseled to take normal midline structures by the end of the first-
high doses of folic acid starting prior to conception triemster.
 First-Trimester Ultrasound Screening for Fetal Malformations 1057

Fig. 79.2: Alobar holoprosencephaly at 12 weeks’ gestation. A single, Fig. 79.3: Encephalocele at 12 weeks’ gestation. In this profile view, a
small cresecent-shaped holoventricle is seen anteriorly. The thalami midline skull defect is seen above the level of the occiput.
are large, and not divided by a third ventricle. Separate choroid plexuses
are not seen. It is important not to confuse physiologic midgut
herniation, which occurs prior to 11-12 weeks’
Cephalocele
gestation, with omphalocele. 15 After 12 weeks’
Cephalocele is characterized by a defect in the skull, gestation, omphalocele, particularly if a large defect
with protrusion of the meninges. In most cases, there is present, is easily identified (Fig. 79.4). Omphalocele
will be brain tissue in the meningeal sac (encepha- is frequently associated with Trisomy 18 or Trisomy
locele). Most midline cephaloceles are open neural 13.
tube defects, though they are much less common than
either anencephaly or spina bifida. When a non- Skeletal Defects
midline cephalocele is detected, amniotic band
Though fetal long bones can be identified and
syndrome may be present.
measured late in the first-trimester, most skeletal
Ultrasound can detect cephalocele at 11-14 weeks
dysplasias that are characterized by abnormal limb
(Fig. 79.3). Large cephaloceles are easily identified,
though smaller ones may not be seen early in
pregnancy. In patients with a prior fetus with Meckel-
Gruber syndrome, which is characterized by
cephalocele, multicystic kidneys, and polydactyly,
first-trimester ultrasound can be used to detect early
signs of recurrence of this autosomal recessive
condition.14

Omphalocele
Omphalocele is a midline ventral wall defect. All
layers of the abdominal wall are absent at the site of
the umbilical cord insertion, and a sac can be seen
protruding from this site. The sac usually contains
bowel and stomach. In larger lesions, liver may be
present. The umbilical cord can be seen inserting into Fig. 79.4: Omphalocele at 13 weeks’ gestation. A large
the sac. sac containing bowel and liver is seen
1058 Textbook of Perinatal Medicine

growth cannot be reliably detected or excluded early high risk of having a fetus with malformations
in pregnancy.16 Limb reduction defects, which occur detectable in the first-trimester.
sporadically, are characterized by absence of all or Studies evaluating the detection rates for
a large part of an extremity can be identified at the anomalies in the first-trimester suggest that the
11-14 week scan. majority of major structural anomalies can be
identified or suspected.4,8,9 As these studies have
Megacystis been done in large perinatal centers, however, it is
In this condition, the fetal urinary bladder is not clear that similar outcomes can be achieved
markedly enlarged. (Fig. 79.5) A longitudinal outside this setting. The experience of the examiner
diameter of >7mm has been suggested to establish is important, as a learning curve for prenatal
the diagnosis. 17 While the presence of megacystis diagnosis in the first-trimester has been demons-
does not indicate a specific diagnosis, high rates of trated. 9
fetal aneuploidy (especially when NT is abnormal) While evaluation of anatomy at 11-14 weeks is
and obstructive uropathy have been reported.18 The recommended when NT is measured, this exami-
presence of megacystis is an indication to evaluate nation cannot replace routine second-trimester
the genitourinary tract for obstructive uropathy early ultrasound. Comparison of detection rates of fetal
in the second trimester. anomalies demonstrates higher sensitivity at 16-20
weeks.9 This is particularly true for cardiac abnor-
APPROACH TO SCREENING malities, the most common category of malfor-
mations.
In patients who present for ultrasound late in the
first-trimester, evaluation of fetal anatomy can CONCLUSION
provide valuable information. This information can
be obtained in a relatively short amount of time in With the emergence of first-trimester risk assessment
most patients.4,6 While certain findings (such as for aneuploidy, many patients will be undergoing
nuchal edema or megacystis) are not diagnostic and ultrasound late in the first-trimester. If the sole
require second-trimester follow-up, some conditions objective of this examination is to measure NT, the
can be diagnosed or excluded at this stage in opportunity to assess fetal anatomy will be lost. With
pregnancy. This may be especially useful to those at experience, examination of the fetus at 11-14 weeks’
gestation can be accomplished in a short amount of
time, and patients will have the benefit of early
diagnosis of certain anomalies.

REFERENCES
1. Nicolaides KH. Nuchal translucency and other first-
trimester sonographic markers of chromosomal
abnormalities. Am J Obstet Gynecol 2004;191:45-67.
2. Hyett JA. Increased nuchal translucency in fetuses with
a normal karyotype. Prenat Diagn 2002;22:864-8.
3. Whitlow BJ, Chatzipapas IK, Lazanakis ML, Kadir RA,
Economides DL. The value of sonography in early
pregnancy for the detection of fetal abnormalities in an
unselected population. Br J Obstet Gynaecol 1999;
106:929-36.
4. Souka AP, Nicolaides KH. Diagnosis of fetal abnor-
Fig. 79.5: Megacystis at 11 weeks’ gestation. A cystic
malities at the 10-14-week scan. Ultrasound Obstet
midline mass is seen in the pelvis. Gynecol 1997;10:429-42.
 First-Trimester Ultrasound Screening for Fetal Malformations 1059
5. Cicero S, Curcio P, Papageorghiou A, Sonek J, weeks of gestation. Ultrasound Obstet Gynecol 1997;
Nicolaides K. Absence of nasal bone in fetuses with 9:14-6.
trisomy 21 at 11-14 weeks of gestation: an observational 12. Sepulveda W, Dezerega V, Be C. First-trimester sono-
study. Lancet 2001;358:1665-7. graphic diagnosis of holoprosencephaly: value of the
6. Timor-Tritsch IE, Bashiri A, Monteagudo A, Arslan AA. “butterfly” sign. J Ultrasound Med 2004;23:761-5.
Qualified and trained sonographers in the US can 13. Barr M Jr, Cohen MM Jr. Autosomal recessive alobar
perform early fetal anatomy scans between 11 and 14 holoprosencephaly with essentially normal faces. Am J
weeks. Am J Obstet Gynecol. 2004;191:1247-52. Med Genet 2002;112:28-30.
7. Zorzoli A, Kustermann A, Caravelli E, Corso FE, 14. Tanriverdi HA, Hendrik HJ, Ertan K, Schmidt W. Meckel
Fogliani R, Aimi G, Nicolini U. Measurements of fetal Gruber syndrome: a first trimester diagnosis of a
limb bones in early pregnancy. Ultrasound Obstet recurrent case. Eur J Ultrasound 2002;15:69-72.
Gynecol 1994;4:29-33. 15. van Zalen-Sprock RM, Vugt JM, van Geijn HP. First-
trimester sonography of physiological midgut
8. Chen M, Lam YH, Lee CP, Tang MH. Ultrasound
herniation and early diagnosis of omphalocele. Prenat
screening of fetal structural abnormalities at 12 to 14
Diagn 1997;17:511-8.
weeks in Hong Kong. Prenat Diagn 2004;24:92-7.
16. Gabrielli S, Falco P, Pilu G, Perolo A, Milano V, Bovicelli
9. Taipale P, Ammala M, Salonen R, Hiilesmaa V. Learning
L. Can transvaginal fetal biometry be considered a useful
curve in ultrasonographic screening for selected fetal
tool for early detection of skeletal dysplasias in high-
structural anomalies in early pregnancy. Obstet risk patients? Ultrasound Obstet Gynecol 1999;13:107-
Gynecol. 2003;101:273-8. 11.
10. Dugoff L. Ultrasound diagnosis of structural abnor- 17. Sebire NJ, Von Kaisenberg C, Rubio C, Snijders RJ,
malities in the first trimester. Prenat Diagn. 2002;22:316- Nicolaides KH. Fetal megacystis at 10-14 weeks of
20. gestation. Ultrasound Obstet Gynecol 1996;8:387-90.
11. Johnson SP, Sebire NJ, Snijders RJ, Tunkel S, Nicolaides 18. Sepulveda W. Megacystis in the first trimester. Prenat
KH. Ultrasound screening for anencephaly at 10-14 Diagn 2004;24:144-9.
1060 Textbook of Perinatal Medicine

80
Fetal Nasal Bone in Screening
for Down’s Syndrome
Simona Cicero, Jiri D Sonek,
Georgios Rembouskos, Kypros H Nicolaides

INTRODUCTION patient-specific risk of chromosomal defects, it is

necessary to take into account the background risk
The major cause of perinatal death and childhood
(which depends on maternal age and gestational age)
disabilities are chromosomal abnormalities. Prenatal
and multiply this by a series of factors, which depend
diagnosis of chromosomal defects necessitates
on the results of a series of screening tests carried
invasive testing, by chorionic villous sampling,
out during the course of the pregnancy. Every time
amniocentesis or cordocentesis, which is associated
a test is carried out the background risk is multiplied by
with a risk of miscarriage of about 1%. For this reason,
the test factor to calculate a new risk, which then
these techniques are reserved for pregnancies
becomes the background risk for the next test. This
considered to be at high risk for chromosomal defects.
process is called sequential screening1.
The methods of screening to identify the high-risk
group are described in Table 80.1. Screening using BACKGROUND
ultrasound is based on the fact that most fetuses with
chromosomal abnormalities have structural defects The physical characteristic of the individuals affected
that can be detected by sonographic examination, by trisomy 21, were described for the first time in
both in the first and the second trimesters of 1866 by the physician Langdon Down2. He reported
pregnancy. In order to calculate the individual that the skin is too large for their body, their face is
flat and the nose is small2. In recent years it has
Table 80.1: The screening performance of the various become possible to observe these features by
tests is compared by examining the detection rate (DR)
ultrasound examination during the third month of
for a fixed screen positive rate of 5%
intrauterine life. Extensive studies over the last
Screening test DR
decade have demonstrated that the most effective
MA ( ≥ 37 years) 30% sonographic marker of trisomy 21, and other
Maternal serum biochemistry at 16 weeks
(AFP and β-hCG and uE3) 65%
chromosomal abnormalities, is increased nuchal
NT at 12 weeks 80% translucency (NT) at 11-13 +6 weeks’ gestation.
NT and β-hCG and P-APPA at 12 weeks 90% Another promising marker for trisomy 21, which it
NT and NB and β-hCG and P-APPA at 12 weeks 96% has been extensively studied over the past four years,
MA: maternal age; AFP: α-fetoprotein; β-hCG: free β-human is the absence of the fetal nasal bones (NB), both in
chorionic gonadotropin; uE3: unconjugated estriol; NT: the first and in the second trimesters of pregnancy.
nuchal translucency; PAPP-A: pregnancy-associated plasma
This chapter reviews the association between
protein-A; NB: nasal bone.
absence or hypoplasia of the fetal NB and Down’s
 Fetal Nasal Bone in Screening for Down’s Syndrome 1061
syndrome in the first and second trimester of gestation age, and a crown-rump length (CRL)
pregnancy, and examine the value of incorporating ranging from 33 to 225 mm. Radiographically, the
this novel marker in screening policies. first appearance of the NB was documented in a
specimen with a CRL of 50 mm.8
DEVELOPMENT OF THE NASAL BONES Keeling et al 10 , investigated the abnormal
During the fourth week of gestation, collections of development of the NB in aborted Down syndrome
neural crest cells undergo proliferation, forming the fetuses. They examined the development of the axial
nasal placodes. In the sixth week, the nasal placodes skeleton in 31 human trisomy 21 aborted fetuses at
of the frontonasal prominence invaginate to form the 12-24 weeks’ gestation and found a 60% incidence of
nasal pits and the lateral and medial processes. The either NB absence (26%) or NB hypoplasia (34%).10
medial nasal processes will fuse with the nasofrontal Stempfle et al11, conducted a radiological study and
found that the NB was absent in 23% of the 60
process to form the nasal septum, which in turn will
Down’s syndrome aborted fetuses between 15 and
grow toward the forming palate, defining the left
40 weeks’ gestation. The authors also observed that,
and right nasal cavities. While this is occurring, the
when present, the NB in the Down syndrome fetuses
cartilaginous frame of the nose is developing. During
were short.11
the eighth week, initial centres of ossification of the
NB will appear in the membrane covering the SONOGRAPHIC, RADIOLOGICAL AND
cartilaginous nasal capsule.3-7 HISTOLOGICAL CORRELATION
In 1994 Sandikcioglu et al 8, established normal
prenatal development standards for the NB. This Tuxen et al12 conducted a post-mortem radiological
study showed that the two bilateral NB appear as a study to investigate the presence of the NB in 33
thin bony contour ventral to the cartilaginous nasal aborted Down’s syndrome fetuses at 14-25 weeks’
septum in the sagittal plane, and changes gradually gestation. They found that 30% (10 of 33) of fetuses
during growth to a wedge-shaped bone. The initial had either bilateral or unilateral absence of NB. They
appearance of the NB occurred at different also performed a histological evaluation of the
developmental stages in normal fetuses. The smallest specimens, which confirmed a complete NB absence
in 7 of 10 fetuses. Histological evaluation was not
crown-rump length at which NB was observed
performed in the remaining 3, including the 2 that
histologically was 42 mm corresponding to approxi-
had unilateral absence of the NB. Presence of a NB
mately 10.9 weeks’ gestation. Furthermore, the NB
was confirmed in all 23 fetuses that had a radiological
increased in length with advancing gestation and
evidence of NB formation.12
their appearance changed morphologically, being
Minderer and his colleagues13 compared prenatal
wider and more pointed at the anterior tip in the
sonographic findings on the NB in 17 Down’s
most mature specimens.8
syndrome fetuses between 11 and 14 weeks’
gestation, to those obtained by histological study
ANTHROPOMETRICS AND
performed after termination of pregnancy. In this
RADIOLOGICAL STUDIES
report, the NB could not be examined sonographi-
An anthropometric study in 105 patients with Down’s cally in 1 of the 17 cases, due to fetal position, and
syndrome at 7 months to 36 years of age reported in the remaining 16 cases the NB was either absent
that the nasal root depth was abnormally short in or hypoplastic. By contrast, the histological evalu-
about 50% of cases.9 ation of the NB area showed evidence of NB
Sandikciolglu et al8 demonstrated the feasibility formation in 16 of the 17 cases. Armed with the
of post-mortem radiological evaluation the NB in 62 knowledge of the results of the histological
chromosomally normal aborted fetuses at 9-24 weeks’ evaluation, the investigators reviewed the ultrasound
1062 Textbook of Perinatal Medicine

images of the fetuses originally classified as having SONOGRAPHIC STUDIES

an absent NB. They claimed that they were able to
The observation that in fetuses affected by trisomy
now detect evidence of a NB albeit “smaller, less
21 sonographic examination may reveal absence of
distinct, and less echogenic”.13
the NB was only made at the beginning of 2001. In
A study by Larose et al14 compared sonographic
the initial description15 , three Down’s syndrome
and radiological findings on the NB in 21 aborted
fetuses were evaluated in the second trimester. Two
fetuses with trisomy 21. The ultrasonographic
of them had no identifiable NB and one had a
evaluations were done between 11+3 and 13+5 weeks’
hypoplastic NB. A review of the videotaped exam
gestation. The subsequent radiological studies on the
from the first trimester examination of one of the
aborted fetuses were performed between 13 and 25+5
fetuses at the time of the NT evaluation revealed
weeks’ gestation. Interestingly, the incidence of NB
that the NB could not be identified at that point in
absence on ultrasound was very similar to the one
pregnancy 15 . Armed with this information,
noted on X-ray. However, the ultrasound and X-ray
findings were discordant in 9 of the 21 cases (43%). observational studies were undertaken to investigate
Four of the cases where the NB was present on the role of NB examination in screening for Down
ultrasound showed no evidence of a NB on X-ray, syndrome.
indicating a possible wrong assessment of the fetal
First Trimester: the 11-13+6 Week Scan
profile by ultrasound. In the other 5 cases where the
NB was noted to be absent on ultrasound, this Several studies have demonstrated that the fetal NB
resulted to be present on X-ray. However, can be visualized by sonography in the first trimester
radiological examinations were performed at a later of pregnancy, and that there is a high association
gestational age than that of the ultrasound between absent NB at 11-13+6 weeks and trisomy
examination, suggesting that the NB could have 21, as well as other chromosomal abnormalities.16-25
developed in the period of time occurred between Cicero et al16 reported for the first time on the
the two examinations14. absence of the NB in trisomy 21 fetuses in the first
The apparent discrepancies in the NB identi- trimester of pregnancy. In this observational study
fication among the three modalities (ultrasound, ultrasound examination of the fetal profile, for
radiology and histology) have a number of possible evaluation of absence or presence of the NB, was
explanations. It is likely that small areas of performed in 701 fetuses at 11-13+6 weeks’ gestation
calcification can be seen on histological evaluation
following screening test by maternal age and NT,
even if those cannot be detected on either
and immediately before chorionic villous sampling.
ultrasonography or X-ray. The likelihood of picking
In this series, the NB was absent in 73% (43 of 59)
these up will depend on the number of sections done.
of Down’s syndrome fetuses and in only 0.5% (3 of
Different types of staining were used in the two
603) of chromosomally normal fetuses. In this initial
studies mentioned above possibly contributing to the
contradictory results. In the study by Larose et al14, study, presence or absence of the NB was found to
the ultrasounds and the X-rays were done at very be independent of other fetal and maternal variables.
different gestational ages (11 +3 -13 +5 weeks for It became clear that incorporation of the examination
ultrasound and 13-25+5 weeks for X-ray). Since the of the NB into the screening for trisomy 21 by
prevalence of NB absence changes with gestational maternal age and NT could increase the sensitivity
age, they are not truly comparable. Just as is the case of the test and reduce, at the same time, the false
with the ultrasound examination, controlling for the positive rate.16
gestational age and standardization of the technique In an extended series18 of 5,818 fetuses under-
for both the radiological and the histological going prenatal diagnosis by chorionic villous
examinations is crucial. sampling at 11-13+6 weeks, the fetal profile was
 Fetal Nasal Bone in Screening for Down’s Syndrome 1063
successfully examined in 5,851 (98.9%) cases. study, the fetal nose could be examined in only 75.9%
Furthermore, the NB was absent in 129 of 5,223 (2.5%) of the cases and the NB was reported as being
chromosomally normal fetuses, in 229 of 333 (68.8%) present in all nine of the trisomy 21 fetuses. Issues
fetuses with trisomy 21 and in 95 of the 295 (32%) regarding adequacy of training in this study remain
with other chromosomal defects. An important to be elucidated. Furthermore, images published by
finding of this study was that the incidence of absent the lead authors of this study suggest that their
NB is higher in fetuses of Afro-Caribbean origin than technique may not be consistent with that used by
in Caucasians, it decreases with fetal CRL and others.28 Similarly, De Biasio and Venturini29, who
increases with fetal NT. Consequently, in the examined retrospectively the photographs obtained
calculation of an individual patient-specific risk for for measurement of NT, reported that the NB was
trisomy 21 it is necessary to take into account these present in all five fetuses with trisomy 21. However,
demographic and ultrasound findings.18 the five images that they published were
The fact that ethnic origin of the mother may play inappropriate both for the measurement of NT and
a role on the evaluation of the fetal NB, was also for examination of the NB, because they were either
suggested by Prefumo et al.26 The authors conducted too small or the fetus was too vertical or too oblique.
a prospective study in 4492 fetuses. Due to Preliminary data of a prospective study conducted
chromosomal abnormalities or an unsatisfactory by the Fetal Medicine Foundation on a series of
examination 500 cases were excluded from the 18,636 fetuses 30, who underwent screening by
analysis. In the remaining 3992 fetuses, the failure to maternal age, NT, maternal serum free b-human
visualise the fetal NB was significantly higher in chorionic gonadotropin (β-hCG) and pregnancy-
women of African but not Asian origin, compared associated plasma protein-A (PAPP-A) at 11-13+6
to the Caucasian origin. In this study, it was weeks, the fetal profile was successfully examined
demonstrated that having a mother of African origin in 18,405 (98.8%) cases. The NB was absent in 101 of
is significantly associated with an increased 18,388 (0.5%) chromosomally normal fetuses, in 85
likelihood of absent fetal NB compared with of 138 (61.6%) fetuses with trisomy 21 and in 34 of
Caucasians, even after correcting for maternal age, the 103 (33%) with other chromosomal defects.30
parity and crown-rump length. The authors Based on the available data (Table 80.2), it can be
suggested that corrections for maternal ethnicity concluded that at 11-13+6 weeks the fetal profile can
might be required to ensure equity of fetal NB be successfully examined in about 95% of cases, and
screening in multiracial populations.26 that the NB is absent in about 65% of trisomy 21
There are seven additional studies 19-25 that fetuses and in about 1% of chromosomally normal
support the high association between trisomy 21 and fetuses. Consequently, absence of the NB is an
absent NB at 11-13+6 weeks. In their combined data important marker of trisomy 21. However,
on 12,315 fetuses the fetal profile was successfully appropriate adjustments need to be made on the basis
examined in 11,973 (97.2%) cases. The NB was absent of maternal ethnic origin, fetal crown-rump length
in 56 of 9,825 (0.6%) chromosomally normal fetuses and NT when calculation of individual patient-specific
and in 53 of 79 (67.1%) fetuses with trisomy 21 (Table risk for trisomy 21 is performed.
80.2).
Malone et al 27, reported that they were able to Second Trimester: 15-24 Week Scan
examine the fetal nose in only 4,796 of 6,316 (75.9%) Absence or hypoplasia of the NB represents a new
fetuses scanned at 10-14 weeks and that the NB was ultrasound marker also in the second trimester of
apparently present in all nine of their trisomy 21 pregnancy, and it is likely to have a major impact on
fetuses. Their results contrast significantly with the screening for trisomy 21 during the 16-24 week scan.
above published studies in a number of ways. In this Its role has now been confirmed in large trials.
1064 Textbook of Perinatal Medicine

Table 80.2: Summary of studies reporting on the incidence of absent nasal bone in first-trimester trisomy 21 fetuses

Author Study Successful examination Absent nasal bone

(n (%)) Normal (n (%)) Trisomy 21 (n (%))
Cicero et al 200116* Pre-CVS 701/701 (100%) 3/603 (0.5%) 43/59 (72.9%)
Otano et al 200219 Pre-CVS 183/194 (94.3%) 1/175 (0.6%) 3/5 (60.0%)
Zoppi et al 200320 Screening 5,525/ 5,532 (99.8%) 7/3,463 (0.2%) 19/27 (70.0%)
Orlandi et al 200321 Screening 1,027/1,089 (94.3%) 10/1,000 (1.0%) 10/15 (66.7%)
Viora et al 200322 Screening 1,752/1,906 (91.9%) 24/1,733 (1.4%) 8/10 (80.0%)
Senat et al 200323 Retrospective 956/1,040 (91.9%) 4/944 (0.4%) 3/4 (75%)
Wong et al 200324 Pre-CVS 119/143 (83.2%) 1/114 (0.9%) 2/3 (66.7%)
Cicero et al 200317* Pre-CVS 3,788/3,829 (98.9%) 93/3,358 (2.8%) 162/242 (67%)
Cicero et al 200418 Pre-CVS 5,851/5,818 (98.9%) 129/5,223 (2.5%) 229/333 (68.8%)
Orlandi et al 200525 Screening 2,411/2,411 (100%) 9/2,396 (0.4%) 8/15 (53%)
FMF30 Screening 18,405/18,636 (98.8%) 101/18,388 (0.5%) 85/138 (61.6%)
Total 36,229/36,769 (95.5%) 286/33,436 (0.9%) 367/550 (66.7%)
* included in Cicero et al 200418

Bromley et al31, assessed the NB using ultrasound profile in 1046 singleton pregnancies undergoing
in 239 fetuses between 15 and 20 weeks’ gestation. amniocentesis for fetal karyotyping at 15 to 22 weeks.
Six (37%) of the 16 Down’s syndrome fetuses had no The NB was absent or hypoplastic (<2.5mm) in 21 of
detectable NB. Among the fetuses with a normal the 34 (61.8%) fetuses with Down syndrome, in 12
karyotype, absence of the NB had a prevalence of of 982 (1.2%) chromosomally normal fetuses, and in
0.5%. In this study, absence of the NB was associated 1 of the 30 (3.3%) with other chromosomal defects.
with a likelihood ratio for Down’s syndrome of 83. It was noted that the prevalence of NB hypoplasia
Interestingly, in 2 of the 16 (13%) Down’s syndrome was higher in the euploid Afro-Caribean population
fetuses, NB absence was the only abnormal finding. (8.8%) in comparison to the Caucasian population
In addition, the NB length was found to play an (0.5%), suggesting for the first time that adjustments
important role. Biparietal diameter (BPD) to NB based on ethnicity may need to be made when using
length (NBL) ratio was generated to control for the the NB for screening. Furthermore, the overall
gestational age and the size of the fetus. This ratio likelihood ratio for trisomy 21 for hypoplastic NB
increases as the NB becomes shorter. Using the BPD/ was 50.5 (95% CI 27.1–92.7) and for present NB it
NBL ratio of 10 or grater as a cut off in screening for was 0.38 (95% CI 0.24–0.56).32
Down syndrome gives this test sensitivity of 81% Bunduki et al 33 looked at the utility of NB
with a false positive rate of 11%. This study measurement in the second trimester (16-24 weeks’
confirmed that NB length increases linearly with gestation) in 1631 patients. The association between
gestation in chromosomally normal fetuses. hypoplasia of the NB and Down’s syndrome was
However, the NB length in Down syndrome fetuses also demonstrated. Using the 5th percentile of the
was found to be remarkably uniform over the normal curves generated in the same study as a cut
gestational age investigated (3.5mm +/-.47) off for screening for trisomy 21, a sensitivity of 59%
suggesting the possibility that a single cut-off value was achieved.33
for NB length may be appropriate in Down syndrome Vintzileos et al34 looked retrospectively at profiles
screening in the first half of the second trimester.31 of 29 Down’s syndrome fetuses between 17.7 and
Such approach was used in another study32 20.7 weeks’ gestation. The nasal bone was absent in
looking at the utility of NB evaluation in the second 12 of the 29 (41%) fetuses with trisomy 21 and in
trimester (15-22). The authors examined the fetal none of the 102 chromosomally normal fetuses.34
 Fetal Nasal Bone in Screening for Down’s Syndrome 1065
A prospective study involving ultrasound With a few minor exceptions, the method of NB
evaluation of the fetal NB between 19 and 22 weeks’ evaluation is very similar in both the first and second
gestation35 also looked at the utility of NB length trimesters of pregnancy. The NB should be seen as
and its presence or absence in screening for Down’s an echogenic line within the nasal bridge, i.e.
syndrome. The normal NB ranges were based on underneath the nasal skin. This is usually not a
examinations of 1913 fetuses. All of the five Down’s difficult task in the second trimester.
syndrome fetuses in the study had either an absent 1. The gestation should be 11-13+6 weeks and the
NB or a NB length below the 2.5th percentile. None fetal crown–rump length should be 45-84 mm.
of the fetuses with other chromosomal abnormalities There is no value on examining the fetal NB before
had a short or absent NB. 35 this gestational age, as the NB first appear at a
It is premature to speculate on the precise crown-rump length of 42 mm and increase linearly
detection rates that could be achieved in the second with gestation.8
trimester by a combination of maternal age, serum 2. The image should be magnified so that the head
biochemistry and ultrasound examination for the and the upper thorax only are included in the
fetal NB and other sonographic markers. screen (Figs 80.1 and 80.2).
Nevertheless, on the basis of currently available data, 3. A mid-sagittal view of the fetal profile should be
nasal hypoplasia is likely to be the single most obtained with the ultrasound transducer held in
sensitive and specific second trimester marker of parallel to the direction of the nose (i.e. ultrasound
trisomy 21. beam perpendicular to longitudinal axis of the
NB). The ultrasound transducer should then be
ULTRASOUND EXAMINATION OF gently tilted from side to side to ensure that the
THE NASAL BONE: TECHNIQUE NB is seen separate from the nasal skin. The fetus
should be facing the transducer.
Ultrasound evaluation of the NB requires strictly
4. When the correct view is obtained, three distinct
adherence to standard criteria and it is essential that
lines will be visualized: the first two lines, which
the operators performing this examination undergo
are proximal to the forehead, are horizontal and
adequate training and gain extensive experience.36,37 parallel to each other and resemble an “equal sign”
The need for adequate training is highlighted by (Fig. 80.1). The top line represents the skin and
a study published in 2003 37, which looked at the bottom one, which is usually thicker and more
extent of training needed for 15 sonographers echogenic than the overlying skin, represents the
experienced in measuring fetal NT, to become NB. A third line, distal to the forehead, and
competent in examining the fetal NB at 11+0-13+6 almost in continuity with the skin, but at a higher
weeks’ gestation. The study demonstrated that the level, represents the tip of the nose. Therefore, is
number of supervised scans required to achieve the absence of the bottom line of the equals sign
proficiency is on average 80 with a range of 40 to that represents the absence of the fetal NB (Fig.
120. However, evaluation of the NB does not appear 80.2).
to significantly impact the length of the ultrasound 5. If the bottom line of the “equal sign” is absent,
examination.38 the diagnosis of nasal bone absence is fairly
This was confirmed in a study of 501 consecutively straightforward. Occasionally, a line that is
scanned fetuses by experienced sonographers. The thinner and less echogenic than the skin line is
authors reported that the fetal NB could be noted within the nasal bridge. This may either
successfully examined and measured in all cases represent a nasal bone that is not yet ossified or
without extending the length of time required for an unusually prominent cartilage. Either way, this
scanning.39 finding should also be classified as nasal bone
1066 Textbook of Perinatal Medicine

Fig. 80.1: Fetal profile at 12 weeks of gestation in a Fig. 80.2: Fetal profile at 12 weeks of gestation in a
normal fetus showing the nasal bone trisomy 21 fetus showing absence of the nasal bone

absence. Similarly, the presence of a tiny echo- is extremely important. The best angle of insonation
genic dot that can occasionally be seen in the area used to simply differentiate between the presence
of the nasal bone should not be interpreted as and the absence of the NB is 90 degrees to the
nasal bone presence. longitudinal axis of the NB (i.e. the beam of the
Two techniques for calliper placement have been ultrasound perpendicular to the longitudinal axis of
employed to measure the NB in the first trimester of the NB) (Fig. 80.3). Evaluation of the NB should not
pregnancy: including the central hyperechogenic be attempted with either a 0 or 180-degree angle of
region only or including the entire length of the insonation (i.e. with the ultrasound beam parallel to
echogenic line.21,40 the longitudinal axis of the NB) (Fig. 80.3). At this
The angle of insonation used to evaluate the NB angle, the NB is insonated at its thinnest dimension

Figs 80.3: The best angle of insonation to assess the nasal bone in the first trimester is 90 degrees to the longitudinal axis of the nasal bone
(i.e. the beam of the ultrasound perpendicular to the longitudinal axis of the nasal bone) (left). Evaluation of the nasal bone should not be
attempted with either a 0 or 180-degree angle of insonation (i.e. with the ultrasound beam parallel to the longitudinal axis of the nasal bone)
(right).
 Fetal Nasal Bone in Screening for Down’s Syndrome 1067
and the lateral resolution of the ultrasound equipment
available today is not sufficient to reliably detect the
NB in this view. When the transducer is adjusted to
an angle of insonation approaching 45 or 135 degrees,
the lateral scatter at the ends of the NB is reduced
rendering the NB ends as more sharply delineated
(Fig. 80.4). This is helpful in the second trimester to
improve the accuracy of NB length measurement.
Figs 80.5 to 80.7 show absence, hypoplasia and
presence of NB in the mid-second trimester.
Several factors make the ultrasound examination
challenging; the foremost of these are maternal
habitus and an unfavorable fetal position, such as
hyperextension or vertical position. Others factors, Fig. 80.5: Fetal profile at 20 weeks of gestation in a
such as large uterine fibroids or, early in pregnancy, trisomy 21 fetus showing absence of the nasal bone
retroflection of the uterus can also make the
examination difficult. Fetal small parts, especially the which can give the incorrect impression that the NB
hand, often lie in a close proximity to the fetal face, is present if the correct technique is not followed.
especially early in gestation. This can lead to These structures include the medial aspect of the orbis
erroneous results in two ways. If the digits are oculi and the maxilla. Being able to demonstrate either
actually resting on the fetal face they can mimic the the presence or the absence of the NB from several
NB. Small parts in front of the fetal face, but not different angles will make the correct diagnosis more
actually resting on it, can produce an obscuring effect certain
and may create an erroneous impression of NB Occasionally, the addition of transvaginal sono-
absence. Finally, fetal face contains other echogenic graphy can be a helpful adjunct. However, the
structures, which are located laterally to the NB, directions and angles with which the fetus can be

Fig. 80.4: Diagrammatic representation of the bony structures of the

fetal face with angles of insonation. (Reprinted and adopted with
permission from O’Brien W, Cefalo R. Simpson J, editors. Obstetrics:
normal and problem pregnancies. 3rd ed. New York: Churchill Livingstone; Fig. 80.6: Fetal profile at 20 weeks of gestation in a trisomy 21
1996. p. 393) fetus showing nasal bone hypoplasia
1068 Textbook of Perinatal Medicine

to obtain both a perfect midsagittal section and a

perfect angle. However, in the first study published
on 3D assessment of the NB in the first trimester of
pregnancy, Rembouskos et al 41, found that the
visualisation of the fetal NB in a perfect reconstructed
view of the nasal bridge by 3D multiplanar imaging,
is entirely dependent on the initial 2D section. In
this study, the authors demonstrated that in order
to obtain a good quality volume, the initial section
should be taken with a sagittal view of the fetal
profile facing upwards, and that the angle between
the fetal profile and the ultrasound beam should be
in a range of 30° to 60°, with maximum quality at
45°. In volumes obtained in any other initial 2D view,
the visualisation of the fetal NB was poor at this
Fig. 80.7: Fetal profile at 20 weeks of gestation in a gestation, and could lead to an erroneous diagnosis
normal fetus showing presence of the nasal bone
of absent NB. Consequently, the inability to examine
viewed using this approach are limited. Rarely, the the NB by 2D scanning because of the fetal position
patient may need to be asked to return for a follow- cannot be overcome by 3D ultrasound.41
up if the initial examination is not satisfactory. In correctly acquired volumes, 3D multiplanar
mode permits further assessment of both NB. Peralta
THREE-DIMENSIONAL ASSESSMENT et al 42 , used this technique to examine the gap
OF THE NASAL BONES between the two NB at 11-13+6 weeks of gestation,
and compared the 3D findings to those obtained
The role of three-dimensional (3D) sonography and
following 2D examination. The authors found that a
its potential benefit in the assessment of the fetal
gap between the NB is present in about 20% of the
NB, has been investigated in the last two years in
fetuses examined by 3D. When the gap measured
the first, second and third trimesters of pregnancy.
0.6 mm or more (40% of cases), it was possible to
The published studies have focused on trying to
obtain a perfect mid-sagittal plane where the NB
overcome the technical difficulties encountered
could erroneously be considered absent. By contrast,
during routine two-dimensional (2D) sonography, in all cases in which the gap was less than 0.6 mm,
and on further investigating aspects of the NB the NB was visualized in the perfect mid-sagittal
development, by using different techniques such as plane. These findings can be explained by the limit
multiplanar imaging and 3D rendering of the facial of the lateral resolution of the ultrasound equipment.
bones. However, none of the cases with a gap was associated
with a diagnosis of absent NB when the examination
First Trimester of Pregnancy
was performed with the 2D scan, and therefore the
The two major technical problems in the assessment false positive rate would not increase. Furthermore,
of the fetal NB during the 11-13+6 weeks scan are the the authors observed that, when using the
need to obtain a mid-sagittal view of the fetal profile multiplanar mode, unilateral or bilateral absence of
and the need for the angle between the ultrasound the NB could be demonstrated in about 1% of the
beam and the fetal profile to be about 45° (i.e. chromosomally normal fetuses, and in 61% of the
ultrasound beam perpendicular to the NB). In the fetuses with trisomy 21. In about 10% of trisomy 21
acquired 3D volume, multiplanar imaging permits fetuses only one of the two NB was absent.
 Fetal Nasal Bone in Screening for Down’s Syndrome 1069
However, all the cases with unilateral absence al 41 found in the first trimester, in all Down’s
demonstrated with the 3D scan, were classified as syndrome fetuses with unilateral absent NB, the two
‘absent’ NB during the 2D ultrasound examination, dimensional assessment of the nasal bridge had
and therefore the sensitivity of the test, when diagnosed ‘absent’ NB45
performed by 2D sonography, would not decrease.42 In conclusion, 3D ultrasound evaluation in those
In the original description of the technique for cases with suspicious findings of hypoplastic/absent
examination of the fetal NB by 2D ultrasound16, it NB may improve the accuracy of the test. However
was suggested that, once obtained the mid-sagittal the extend to which 3D ultrasound could be
section of the fetus, the transducer should be gently demonstrated essential in effective screening using
tilted from one side of the fetal profile to the other, the NB at 11 to 13 +6 weeks needs to be further
in order to adequately examine the NB. Therefore, investigated.
by using this technique, it is extremely unlikely that
the presence of a gap can lead to a false positive INTEGRATED FIRST-TRIMESTER
diagnosis of absent NB when 2D sonographic SONOGRAPHIC AND BIOCHEMICAL
assessment of the NB is undertaken.16 SCREENING
A retrospective case-control study46 comprising of
Second and Third Trimesters of Pregnancy
100 trisomy 21 and 400 chromosomally normal
The role of multiplanar imaging and 3D rendering singleton pregnancies at 11-13+6 weeks of gestation,
of the NB have also been evaluated in the second and a subsequent study which extended the previous
and third trimester of pregnancy. It has been series of data47, examined the potential performance
suggested that 3D ultrasonography allows a better of screening for trisomy 21 by a combination of
description of normal, absent, hypoplastic and sonography for measurement of fetal NT and
unilaterally absent NB.43-45 assessment of the presence or absence of the fetal
Lee et al43, used the multiplanar mode to evaluate NB, and measurement of maternal serum free β-hCG
the NB of 20 fetuses with Down syndrome and 20 and PAPP-A. It was concluded that, as no relationship
fetuses with normal karyotype, between 16 and 30 between an absent fetal NB and the levels of maternal
weeks’ gestation. Two examiners independently serum PAPP-A or free b-hCG in trisomy 21 fetuses
evaluated the same images. The incidence of absent was demonstrated, for a false positive rate of 5%,
NB in the fetuses with Down’s syndrome was 40% the detection rate of trisomy 21 would be 96% .46,47
(8 of 12) and 45% (9 of11) by examiner #1 and
examiner #2 respectively. These results were similar NASAL BONE REFERENCE RANGES
to those observed by 2D sonography. However, the BY ULTRASOUND
prevalence of absent NB in the normal population First Trimester
was 20% (4 of 16) and 10% (2 of 18) by examiner #1
and examiner #2 respectively. These prevalences are Cicero et al40, reported that in the chromosomally
much higher than those reported using 2D normal group the fetal NB length increases
sonography during this gestational time period significantly with crown-rump length (CRL) from a
(<1.3%). These data suggest that routine application mean of 1.3 mm at a CRL of 45 mm to 2.1 mm at CRL
of 3D assessment of the NB in screening for trisomy of 84 mm. In the fetuses with Down’s syndrome in
21 could increase the false positive rate.43 which the NB was present, even though these were
Benoit and Chaoui 45 assessed the unilateral found to be shorter than in chromosomally normal
absence of NB by using 3D rendering of the facial fetuses, the difference in the NB lengths was not
bones. In their study, similarly to what Peralta et sufficiently great to be of clinical utility.40
1070 Textbook of Perinatal Medicine

Second Trimester with fetal NT. Therefore, when calculating an

individual patient-specific risk for trisomy 21, it is
Guis et al 48 published reference ranges for NB
necessary to take into account these demographic
lengths, based on 376 cases, between 14-34 weeks’
and ultrasound findings. The likelihood ratio for
gestation. Sonek et al49 , provided reference range
trisomy 21 with absent NB is considerably higher in
based on a larger number of patients (3547) and for
Caucasians than in those of Afro-Caribbean origin,
a wider gestational range (11-40 weeks) using the
it is lower at 11 than at 13 weeks and it is higher for
ultrasound technique described above was published
low than high NT. The relationship between absent
in 2003.
NB and ethnic group, fetal CRL and fetal NT are
shown in Tables 80.3 to 80.5.
IMPACT OF THE NASAL BONE IN SCREENING
It has been estimated that if examination of the
FOR TRISOMY 21 IN THE FIRST TRIMESTER OF
fetal profile for the absence / presence of the NB is
PREGNANCY
incorporated in first trimester screening for trisomy
In this chapter, we have already reported on the 21 by fetal NT thickness or NT and maternal serum
prospective study of 5,918 fetuses 18, in which free β-hCG and PAPP-A the detection rates for
assessment of the fetal profile for absence or presence trisomy 21 would increase substantially and the false
of the NB was performed during the routine positive rate would decrease.16-18,46,47
ultrasound examination at 11-13+6 weeks, carried out Very recently, the potential role of the NB in
before chorionic villus sampling for fetal karyo- screening fro trisomy 21 in the first trimester of
typing. In all cases there was prior screening for pregnancy, has been further investigated in a large
chromosomal defects by a combination of maternal series by Nicolaides et al.51 The authors proposed a
age and fetal NT49 and after counselling the parents new policy for first-trimester screening, based on
elected to have invasive testing. The NB was absent two-stage individual risk. After having evaluated the
in 129 of 5,223 (2.5%) chromosomally normal fetuses performance of first-trimester screening for trisomy
and in 229 of 333 (68.8%) fetuses with trisomy 21. 21 by a combination of maternal age, fetal NT and
Logistic regression analysis was used to examine the maternal serum free â-hCG and PAPP-A (Combined
effect of maternal ethnic origin, fetal CRL and NT test) in prospective study of 75,821 singleton
on the incidence of absent NB in the chromosomally pregnancies, they examined the potential impact of
normal and trisomy 21 fetuses. This study a new individual risk orientated two-stage approach
demonstrated that the incidence of absent NB is to first-trimester screening (Fig. 80.8), based on the
higher in fetuses of Afro-Caribbean origin than in additional examination of the fetal NB in the group
Caucasians, it decreases with fetal CRL and increases of women who fell in an intermediate risk following

Table 80.3: Incidence of absent nasal bone (NB) in chromosomally normal and trisomy 21
fetuses and likelihood ratio (LR) according to ethnic group (from Cicero et al18)
Ethnic group Trisomy 21 Normal karyotype LR (95% Cl) for Trisomy 21
(n (%)) (n (%)) NB absent NB present
Total (n = 5851 ) 229/333 (68.8) 129/5223 (2.5) 27.8 (23.1-33.5) 0.32 (0.27-0.37)
Caucasian (n = 5384) 207/303 (68.3) 105/4811 (2.2) 31.3 (25.5-38.4) 0.32 (0.27-0.38)
Afro-Caribbean (n = 170) 11/14 (78.6) 13/145 (9.0) 8.8 (4.7-15.5) 0.24 (0.08-0.52)
Asian* (n = 201) 10/14 (71.4) 9/179 (5.0) 14.2 (6.8-28.4) 0.30 (0.12-0.58)
Chinese/Japanese (n = 69) 1/2 (50.0) 2/61 (3.3) 15.3 (2.1-73.4) 0.52 (0.10-0.94)
Mixed (n = 27) – 0/27 ( – ) – –
*People originating from India, Pakistan, Bangladesh, Sri Lanka and Philippines
 Fetal Nasal Bone in Screening for Down’s Syndrome 1071
Table 80.4: Incidence of absent nasal bone (NB) in chromosomally normal and trisomy 21 fetuses and
likelihood ratio (LR) according to crown-rump length (CRL) (from Cicero et al18)
CRL (mm) Trisomy 21 Normal karyotype LR (95% Cl) for Trisomy 21
(n (%)) (n (%)) NB absent NB present
Total (n=5851) 229/333 (68.8) 129/5223 (2.5) 27.8 (23.1-33.5) 0.32 (0.27-0.37)
45-54 41/49 (83.7) 32/675 (4.7) 17.6 (12.3-25.2) 0.17 (0.09-0.30)
55-64 78/118 (66.1) 63/1850 (3.4) 19.4 (14.7-25.5) 0.35 (0.27-0.44)
65-74 85/118 (72.0) 25/1805 (1.4) 52.0 (34.8-77.8) 0.28 (0.21-0.37)
75-84 25/48 (52.1) 9/893 (1.0) 51.8 (25.8-102.8) 0.48 (0.35-0.62)

the initial screening test. The detection and false- first-trimester combined screening for trisomy 21 is
positive rates were calculated for different risk cut- associated with a detection rate of about 90% for a
offs and the screened population was then classified false-positive rate of 5% 52-54 and concluded that
in three groups: a high risk group, which included individual risk-orientated two-stage screening for
patients with a risk estimate of 1 in 100 or more; a trisomy 21 can potentially identify, in the first
low risk group, which included those with a risk trimester of pregnancy, more than 90% of affected
estimate of less than 1 in 1000; and the intermediate- fetuses for a false-positive rate of about 2%.
risk category, with a risk estimate of between 1 in
101 and 1 in 1000. The authors proposed that patients CONCLUSIONS
in the high-risk category are offered karyotyping by Trisomy 21 is the most common chromosomal
chorionic villus sampling (CVS), and those in the low abnormality found at birth, with an incidence of
risk category are reassured that their fetus is unlikely about 1:600. However, the sonographic appearance
to be chromosomally abnormal. Those in the of individuals with Down’s syndrome, is often quite
intermediate-risk category have further assessment similar to those with normal karyotype, making
of risk by first-trimester ultrasound examination to screening for Down syndrome more difficult
determine absence / presence of the NB, and CVS is compared to that of other chromosomal abnor-
offered if their adjusted risk becomes 1 in 100 or malities. Hence the importance of a continued search
more.51 for markers, that would accurately discriminate
Following the combined screening test, for a false between affected and unaffected fetuses.
positive rate of 2% the detection rate was 80%. When The sonographic appearance of increased nuchal
the nasal bone examination is performed into the two- translucency and absent/hypoplastic nasal bone
stage screening, for a risk cut-off of 1 in 100 the total could be due to connective tissue abnormalities.55-57
false-positive rate would be 2.1%, and the detection The increased thickness of subcutaneous tissues in
rate would be 92.0%. The authors confirmed that association with Down syndrome has lead to the

Table 80.5: Incidence of absent nasal bone (NB) in chromosomally normal and trisomy 21 fetuses and
likelihood ratio (LR) according to nuchal translucency thickness (NT) (from Cicero et al18)
NT (mm) Trisomy 21 Normal karyotype LR (95% Cl) for Trisomy 21
(n (%)) (n (%)) NB absent NB present
Total (n=5851) 229/333 (68.8) 129/5223 (2.5) 27.8 (23.1-33.5) 0.32 (0.27-0.37)
<95th 23/38 (60.5) 53/3245 (1.6) 37.1 (25.0-52.5) 0.40 (0.26-0.56)
>95th-3.4 48/83 (57.8) 40/1500 (2.7) 25.1 (16.7-37.4) 0.45 (0.34-0.56)
3.5-4.4 49/67 (73.1) 16/294 (5.4) 13.4 (8.2-22.1) 0.28 (0.19-0.41)
4.5-5.4 26/41 (63.4) 5/84 (6.0) 10.7 (4.6-25.3) 0.39 (0.25-0.55)
=5.5 83/104 (79.8) 15/100 (15.0) 5.3 (3.4-8.7) 0.24 (0.16-0.34)
1072 Textbook of Perinatal Medicine

Fig. 80.8: New individual risk orientated two-stage approach to first-trimester screening, (Nicolaides et al50 ). Screening by maternal age,
fetal nuchal translucency and maternal serum free â-human chorionic gonadotropin and pregnancy-associated plasma protein-A

development of the NT measurement between 11 If the individual risk-orientated two-stage

and 13 +6 weeks of gestation, which is the most screening for trisomy 21 51 , which includes
sensitive and specific ultrasound marker for this examination of the fatal NB in those women with a
condition.58 individual risk between 1:101 to 1:1000, is to be
Several studies have demonstrated that the best introduced in the routine clinical practice, the
screening test for trisomy 21 is given by the detection rate could be potentially be increased to
combination, in the first trimester of pregnancy, of more that 90%, and the false positive rate could be
maternal age, fetal NT thickness and maternal serum decreased to about 2%. This aspect is extremely
free â-hCG and PAPP-A. This test allows a detection important for three main reasons: firstly, such a
rate of 90% for a false positive rate of 5%.51-54 By screening test would reduce the economic costs due
adding the ultrasonographic evaluation of the NB, a to unnecessary invasive testing; secondly, it would
sensitivity of over 90% could be achieved for a false reduce the number of miscarriage of chromosomally
positive rate of about 2%.46,47,51 normal fetuses due to the invasive testing59,60; thirdly
Although extensive studies have demonstrated would provide an early reassurance to pregnant
that absence of the NB is highly sensitive and specific women, and at the same time, would allow them to
marker of trisomy 21, its accurate examination have an early termination of pregnancy should they
requires highly skilled operators and at present it is wish so in case their baby is found to be affected.
unlikely that this assessment will be incorporated However, in order to reproduce the same results,
into the routine first-trimester scan. Nevertheless, it is imperative that sonographers receive appropriate
this sonographic marker could be used in specialist training and adhere to a standard technique for the
centres to re-evaluate the risk, in patients with measurement of NT and the assessment of the NB.
intermediate risk after screening by fetal NT and Furthermore, the success of a screening program
maternal serum biochemistry.51 necessitates the presence of a system for regular audit
 Fetal Nasal Bone in Screening for Down’s Syndrome 1073
of results and continuous assessment of the quality syndrome: A radiologic postmortem study. Pediatr
Radiol 1999;29:682-8.
of images. The Fetal Medicine Foundation, which is
12. Tuxen A, Keeling JW, Reintoft I, Fischer Hansen B,
a UK registered charity, has established a process of Nolting D, Kjaer I.A histological and radiological
training and quality assurance for the appropriate investigation of the nasal bone in fetuses with Down
introduction of NT screening into clinical practice.61 syndrome. Ultrasound Obstet Gynecol 2003;22:22-6.
13. Minderer S, Gloning KP, Henrich W, Stoger H. The nasal
In conclusion, improvements in ultrasound bone in fetuses with trisomy 21: sonographic versus
resolution have allowed us to evaluate and measure pathomorphological findings. Ultrasound Obstet
very minute fetal structures with a concomitant Gynecol 2003;22:16-21.
decrease in the room for error. If they are to be 14. Larose C, Massoc P, Hillion Y, Bernard JP, Ville
Y.Comparison of fetal nasal bone assessment by
included in prenatal screening protocols, their ultrasound at 11-14 weeks and by postmortem X-ray
evaluation must be done with a high degree of in trisomy 21: a prospective observational study.
precision and accuracy. This can be accomplished only Ultrasound Obstet Gynecol 2003;22:27-30.
15. Sonek J, Nicolaides K. Prenatal ultrasonographic
through strict standardization of the fetal image and
diagnosis of nasal bone abnormalities in three fetuses
with appropriate training and an ongoing quality with Down syndrome. Am J Obstet Gynecol 2002;
assurance. Just like the NT measurements, it is only 186:139-141.
by strictly adhering to these principles that the 16. Cicero S, Curcio P, Papageorghiou A, Sonek J,
Nicolaides K. Absence of nasal bone in fetuses with
evaluation of the NB can be incorporated into any trisomy 21 at 11-14 weeks of gestation: an observational
screening protocol using prenatal sonography. study. Lancet 2001; 358:1665-67.
17. Cicero S, Longo D, Rembouskos G, Sacchini C,
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HM, Tripp T, D’Alton ME; FASTER Research Consor- Johnson A, Huang R, Romero R. Nasal bone evaluation
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29. De Biasio P, Venturini PL. Absence of nasal bone and R. Phenotypic characteristics of absent and hypoplastic
detection of trisomy 21. Lancet 2002;13:1344. nasal bones in fetuses with Down syndrome: description
30. Fetal Medicine Foundation. Screening study on absent by 3-dimensional ultrasonography and clinical
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results. In press. 45. Benoit B, Chaoui R. Three-dimensional ultrasound with
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32. Cicero S, Sonek J, McKenna D, Croom C, Johnson L,
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33. Bunduki V, Ruano J, Miguelez J, Yoshizaki C, Kahhale
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34. Vintzileos A, Walters C, Yeo L. Absent nasal bone in Maternal serum biochemistry at 11-14 weeks in relation
the prenatal detection of fetuses with trisomy 21 in a to the presence or absence of the fetal nasal bone on
high-risk population. Obstet Gynecol 2003;101:905-8. ultrasonography in chromosomally abnormal fetuses:
35. Gamez F, Ferreiro P, Salmean JM. Ultrasonographic an updated analysis of integrated ultrasound and
measurement of fetal nasal bone in a low risk popu- biochemical screening. Prenat Diagn In press.
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Down’s screening News 2003;10:33-34. 1995;5:304-307.
37. Sonek JD, Cicero S. Ultrasound evaluation of the fetal 49. Sonek J, McKenna D, Webb D, Croom C, Nicolaides K.
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KH. Learning curve for sonographic examination of the 50. Snijders RMJ, Noble P, Sebire N, Souka A, Nicolaides
fetal nasal bone at 11-14 weeks. Ultrasound Obstet KH. UK multicentre project on assessment of risk of
Gynecol 2003;22:135-7. trisomy 21 by maternal age and fetal nuchal trans-
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Examination of fetal nasal bone and repeatability of 1998;351:343-46.
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Nicolaides K. Fetal nasal bone length in chromosomally of the potential impact of individual risk-orientated two-
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 Fetal Nasal Bone in Screening for Down’s Syndrome 1075
52. Spencer K, Souter V, Tul N, Snijders R, Nicolaides KH. in the skin of trisomy 21 fetuses. Obstet Gynecol
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human chorionic gonadotropin and pregnancy- Nicolaides KH, Brand-Saberi B. Hyaluran in the nuchal
associated plasma protein-A. Ultrasound Obstet Gynecol skin of chromosomally abnormal fetuses. Human
1999;13:231–237. Reprod 2000; (5) 15: 1155-1158.
53. Bindra R, Heath V, Liao A, Spencer K, Nicolaides KH. 58. Nicolaides KH. Nuchal translucency and other first-
One stop clinic for assessment of risk for trisomy 21 at trimester sonographic markers of chromosomal
11–14 weeks: a prospective study of 15 030 pregnancies. abnormalities. Am J Obstet Gynecol 2004;191:45-67.
Ultrasound Obstet Gynecol 2002;20:219–225. 59. Tabor A, Philip J, Madsen M, Bang J, Obel EB, Norgaard-
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KH. Screening for chromosomal abnormalities in the
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1076 Textbook of Perinatal Medicine

81
Second Trimester Ultrasound
Screening of Fetal Anomalies

Lami Yeo, Anthony M Vintzileos

INTRODUCTION of routine ultrasound screening in low-risk pregnant

patients are not as clear.
It is an unfortunate fact that birth defects sometimes
This chapter focuses on the components of a
occur in human development.
normal fetal anatomic survey, second trimester
In fact, they are the single most common cause of
sonographic markers for aneuploidy, and describes
perinatal mortality in many countries. It is important
the value of sonographic second trimester screening.
to detect fetal congenital anomalies prior to birth
for various reasons, such as delivering at a tertiary
SECOND TRIMESTER FETAL ANATOMIC
care center, offering prenatal surgical correction,
SURVEY AND ITS CONTENTS
giving the option of invasive testing, and to
appropriately and accurately counsel parents. Because ultrasonography utilizes sound waves to
While there are varying modalities that currently provide imaging capability, it has rapidly become
exist to screen for fetal anomalies (such as magnetic the most commonly used method for imaging during
resonance imaging and fetoscopic examination), the pregnancy. Its major advantages include lack of
most accepted method is ultrasonographic imaging. adverse fetal effects,1 ability to view the fetus in real-
The concept of prenatal ultrasonography as a time (with capabilities of observing and studying fetal
screening tool has received widespread acceptance behavior/movements), and most recently the ability
among both physicians and patients. Unlike to acquire a volume of data to generate 3-
biochemistry screening, ultrasound is a very tangible dimensional imaging. With the introduction of
and realistic tool that provides a visible assessment two-dimensional static scanning in the early 1970s,
for patients. Accordingly, the second trimester is physicians were allowed to view the fetus for the
often utilized because fetal anatomic structures are first time. Subsequently in the late 1970s and early
readily assessed at this time of pregnancy. Once 1980s, real-time B-mode imaging became widespread
sonographic screening in the second trimester reveals as a clinical tool. However, despite its many
the presence of abnormalities, further diagnostic technological advancements over the years, many in
testing may be offered to the patient such as the United States still believe that the appropriate
amniocentesis or percutaneous umbilical blood use of fetal sonography should be limited to only
sampling. Although the advantage of performing when there is an indication. This is despite the fact
sonography in patients at high-risk for fetal structural that detailed examination of the fetus for both
anomalies is clear, the benefits and cost-effectiveness aneuploidy markers and structural abnormalities has
 Second Trimester Ultrasound Screening of Fetal Anomalies 1077
become a true reality. In contrast, many European Published guidelines exist that describe the
countries perform ultrasound examinations routinely components of a complete obstetrical ultrasound. This
during pregnancy. involves both biometric measurements which reflect
In order to screen for fetal abnormalities on a gestational age, growth or size, and evaluation of
second trimester ultrasound, the sonographer must specific organ structures for the absence/presence
be able to recognize normal fetal anatomy first. of anomalies. In 1994, the American Institute of
Accordingly, we will describe the features of a Ultrasound in Medicine published standards for the
targeted, complete fetal anatomic survey on performance of obstetrical ultrasound.4 In the first
ultrasound. There are many possible indications to trimester, the requirements include evaluation of the
undergo an obstetrical exam, such as estimating uterus, adnexa, cul-de-sac, gestational sac, crown-
gestational age and/or growth, vaginal bleeding, rump length, fetal number, and presence/absence of
multiple gestation, history or prior congenital cardiac activity. In the second and third trimesters,
anomaly or syndrome, placental localization, adjunct the requirements include fetal life/number/
to interventional or invasive procedures, biophysical presentation/activity (with multiple gestations
profile, and evaluation of amniotic fluid quantity. In requiring additional documentation), amniotic fluid,
most cases, ultrasonography will provide placental location/appearance/relationship to the
reassurance of a normal and healthy fetus. Because internal os, fetal biparietal diameter (BPD) or head
most anomalies are sporadic and often occur in circumference (HC), limb measurement, estimated
otherwise low-risk women, we believe that all fetal weight (requires abdominal diameter or
patients regardless of risk should have uniform circumference), uterus, cervix, adnexa, cerebral
access to obstetrical sonography in the second ventricles, posterior fossa, 4 chamber view of the
trimester. Most importantly, this should be performed heart and position, spine, stomach, kidneys, bladder,
with a high level of expertise, since both false- abdominal cord insertion site, and umbilical cord.
positive and false-negative information can have a However, in order to increase the diagnostic
detrimental impact. A systematic fetal anatomic sensitivity for fetal anomalies, a more comprehensive
survey is able to detect the majority of fetal exam above and beyond what is required by the
malformations,2 and can also evaluate fetal growth, American Institute of Ultrasound in Medicine should
amniotic fluid, placenta, and cervix. To be effective, be performed. Table 81.1 depicts the components of
the sonographic exam should be performed a second trimester fetal anatomic survey that we
systematically, and with complete thoroughness. routinely perform via ultrasonography. Of course,
Recently, we examined the value (from the to carry out this task, other criteria should also be
patient’s perspective) of a targeted ultrasound met. For instance, proper sonographic equipment and
performed after an abnormal karyotype was transducers with the highest frequency probe should
discovered. 3 All patients valued the ultrasound be utilized to maximize fetal anatomic resolution. The
because it provided visualization of anomalies, and sonographers should be adequately and appro-
this additional information influenced pregnancy priately trained to ensure that these detailed exams
management. Interestingly, all patients thought that are performed at the highest level. To properly
the impact of sonography was superior to chromo- recognize fetal anomalies, one must have familiarity
somal diagnosis alone, and all believed that with normal fetal anatomy, normal variants, and the
sonography should be utilized in patients facing various sonographic landmarks.
likewise clinical situations. These patients found Factors that can limit the ability to adequately
sonography invaluable because it provided more examine the fetus sonographically in the second
information and helped them to accept the diagnosis trimester include: sonographer expertise, quality of
of fetal aneuploidy. ultrasound equipment, length of time spent scanning,
1078 Textbook of Perinatal Medicine

Table 81.1: Components of second trimester incompletely filled or overfilled maternal bladder,
sonographic fetal anatomic survey (at Robert maternal habitus, depth of penetration, tissue density,
Wood Johnson Medical School)
and other scanning characteristics, fibroids, early or
Anatomic Structures
advancing gestational age, ossification of fetal bony
Head
Cranial shape, degree of mineralization
structures (later in the second trimester), fetal
Cerebral hemispheres, cavum septum pellucidum, position, and amniotic fluid abnormalities (increased
thalami, cerebral peduncles, lateral ventricles, choroid or decreased). Techniques that can improve fetal
plexus, third and fourth ventricles, cerebellum and
vermis, cisterna magna
visualization include using various probes (including
Face / Neck transvaginal scanning for instance, in the obese
Orbits, nasal bone, lips/palate, profile, nuchal fold, ear patient) and changing maternal position (which
length
Thoracic Cavity
effectively changes the fetal position).
Lungs The timing of scans in the second trimester may
Configuration of bony thorax, including ribs and clavicles vary, depending on the scanning center, indication
Heart
for the exam (amniocentesis), or physician
Four-chamber views (apical and subcostal), both outflow
tracts, aortic and ductal arches, inferior and superior vena preference. Later scans (for example, 23-24 weeks)
cava, valves, atria and ventricular septums can improve visualization of certain fetal anatomic
Abdominal structures such as the heart and improve overall
Situs
Stomach sensitivity. However, scanning later in the second
Liver, gallbladder, spleen trimester of pregnancy may limit the window of
Umbilical vein, portal vein opportunity for patients who desire termination of
Bowel
Wall/cord insertion site pregnancy for various reasons. On the other hand,
Genitourinary system patients who desire amniocentesis testing may choose
Kidneys to undergo a sonographic survey earlier, such as 16-
Bladder
Genitalia 17 weeks of gestation. Some patients who have had
Spine a previous child affected with structural anomalies
Extremities or genetic syndromes may choose to undergo an
Upper (including bilateral hands)
Lower (including bilateral feet) initial early scan for some reassurance, and then a
Umbilical cord more detailed repeat exam later in the pregnancy.
Number of umbilical arteries At our own center, we schedule fetal anatomy
Placental insertion site
Biometry measurements
surveys around 18-21 weeks in order to optimize
Biparietal Diameter anatomy assessment, and yet still provide patients
Head Circumference the opportunity for amniocentesis if necessary. Some
Atria of lateral ventricles, cisterna magna, nuchal fold
(when applicable)
studies suggest that among low-risk women, second
Cerebellum trimester ultrasound screening is easier to perform
Thoracic Circumference (when applicable) and less likely to require an additional scan at 20-22
Abdominal Circumference
Femur lengths, humerus lengths, radius and ulna lengths
weeks than at 18 weeks.5 Fetal echocardiograms are
tibia and fibula lengths best performed between 22-24 weeks when cardiac
Foot length structures are large enough, and better visualization
Nasal bone length
and assessment are possible.
Orbital diameters
Other With multiple gestations, not only should the fetal
Estimation of dates or evaluation of growth anatomy be evaluated, but the number, position of
Number of fetuses, position fetuses, and type of dividing membrane should be
Placenta
Amniotic fluid delineated. In addition, when screening for fetal
Cervix/lower uterine segment anomalies sonographically, the placenta and amniotic
 Second Trimester Ultrasound Screening of Fetal Anomalies 1079
fluid volume must also always be assessed. Placental The transthalamic view is an axial view through
appearance, thickness, echogenicity, location, and the cranium at the level of the thalami. At this level,
characteristics should be examined, along with the biparietal diameter (BPD) and head circumference
amniotic fluid volume, to rule out polyhydramnios, (HC) are obtained. Because of excessive variation in
oligohydramnios, or anhydramnios. These structures the BPD shape which can occur, when the head is
can provide clues to a potential anomalous fetus. For either brachycephalic or dolicocephalic, the HC is the
instance, polyhydramnios is associated with preferred measurement. The BPD is obtained with
esophageal atresia, anyhydramnios is associated with the cranial bones perpendicular to the ultrasound
renal agenesis, and a thickened placenta can be seen beam, and is measured from the outer margin of the
with fetal hydrops. near calvarium to the inner margin of the far
At the beginning of the examination, the entire calvarium. The HC is measured circumferentially at
uterus should be imaged both transversely and the outer margin of the calvarium. Other anatomic
longitudinally to assess fetal position, amniotic fluid
structures that should be assessed in the
volume, and placental location. Determining the right
transthalamic view are the cavum septum pellucidum
and left sides of the fetus is crucial. Situs solitus is
(fluid-filled midline structure anterior to the thalami
the term used when there is the usual arrangement
and between the lateral ventricles), midline falx, third
of organs and vessels within the fetal body. Finally,
ventricle (located between the thalami), and frontal
examination of the lower uterine segment and cervix
horns of the lateral ventricles. Visualization of the
is important.
cavum septum pellucidum implies proper formation
The examination of the fetal intracranial anatomy
of midline intracranial structures. Its absence can be
is extremely important since the presence of central
a sign of agenesis of the corpus callosum,
nervous system abnormalities can have a major and
holoprosencephaly, or other brain anomalies.
devastating impact on perinatal morbidity and
The transventricular view is found just superior
mortality. From the late first trimester until delivery,
the calvarium can be identified. Thus, the biparietal to the transthalamic view, and is marked by the
diameter and head circumference can be readily lateral ventricles, which contain sonolucent cere-
measured. The calvarium should not be hypo- brospinal fluid. Within this system is the echogenic
mineralized (which can indicate a skeletal dysplasia), choroid plexus, which normally fills the body of the
and should be elliptical in shape. Reverberation lateral ventricle extending into the atrium. The
artifact from properly mineralized bone will usually frontal horns are seen as prominent sonolucent
obscure the proximal hemisphere. “Strawberry” or anterior components of the lateral ventricles.
“lemon” shaped heads can indicate the presence of Through an axial plane of the atrium, the cerebral
trisomy 18 or neural tube defects, respectively. ventricle is measured. To rule out ventriculomegaly/
Brachycephaly (anteroposterior shortening) can also hydrocephalus, normally it should be < 10 mm.
be a sign of fetal trisomy 21 or trisomy 18 The transcerebellar view contains the biconvex
(“strawberry” head). Dolicocephaly (elongation of cerebellar hemispheres and midline vermis, cisterna
the anteroposterior length) can be a normal variant, magna (between the dorsum of cerebellar
or secondary to decreased amniotic fluid and hemispheres and inner calvarium), and nuchal fold.
compression of the fetal head. Tangential imaging Importantly, the transcerebellar diameter can also
through the fetal calvarium may identify cranial be measured and utilized as a one-point estimate of
sutures (hypoechoic spaces between bones), which gestational age. The transcerebellar view is obtained
are best visualized early in gestation since ossification by angling the scan plane down posteriorly from the
progresses with time. In certain syndromes (such as transthalamic view. This area is of vital importance
craniosynostosis and skeletal dysplasias), premature in ruling out open spina bifida, since obliteration of
closure of the sutures can be seen. the cisterna magna and a “banana” shape of the
1080 Textbook of Perinatal Medicine

cerebellum may be seen with this disorder. Other fetuses). Multiple studies have found sonographically
anomalies that can be ruled out in this view include absent or short fetal nasal bone in both the first and
Dandy-Walker malformation/variant, cerebellar second trimesters to be sensitive for the detection of
agenesis/hypoplasia, and occipital encephaloceles. Down syndrome.8-10 Structures in the anterior neck
The cisterna magna normally ranges from 3-9 cm.6 that may have to be examined on occasion include
On occasion, this measurement may be increased, the fetal thyroid, and the fluid-filled trachea and
but is a usually normal finding if the transcerebellar hypopharynx.
diameter is normal for gestational age and the vermis Examination of the fetal spine should be
is well seen and intact. An incorrect scan plane can performed in three planes: sagittal, transverse, and
lead to a false positive appearance of Dandy-Walker coronal. Each vertebral segment is composed of three
variant or to an abnormally large measurement of echogenic ossification centers (two posteriorly, and
the cisterna magna.7 An increased nuchal fold (greater one anteriorly which is the vertebral body), which
than 6 mm) may be secondary to fetal aneuploidy are positioned in a symmetric triangular shaped
(especially Down syndrome) or may be falsely configuration in the transverse plane. In this plane,
thickened due to breech presentation. In certain the posterior processes are also oriented towards
clinical scenarios, the intracranial major vessels (such the midline like the roof of a house. When these
as middle cerebral artery) can be identified with color processes appeared splayed, a neural tube defect must
and/or power Doppler imaging. This information be ruled out. Transverse imaging of the spine is
may be quite useful in assessing for anemia (Rh perhaps the most sensitive method of examining for
isoimmunization, Parvovirus infection) or intra- a spinal defect, since it allows a simultaneous
uterine fetal growth restriction. On occasion, the fetal examination of posterior ossification centers and
head may be low in the pelvis that it prohibits an overlying soft tissue. Sagittal imaging of the fetal
adequate examination of the intracranial anatomy; spine should show two rows of approximately
transvaginal scanning may be quite useful and solve parallel ossification centers with overlying intact skin.
this dilemma. Both sagittal and coronal views are useful to observe
Although examination of the fetal face is not this “lining up” of the ossification centers, and should
required, we believe it should be examined routinely be able to rule out scoliosis or hemivertebrae (which
because it can add tremendous information when can cause disorganization or absence of ossification
discriminating between genetic disorders/ centers). The sacrum normally should curve slightly
syndromes, including aneuploidy, and it completes upwards. The overlying skin and soft tissues should
the full examination of the fetus. Three distinct planes also be examined carefully to rule out masses/tumors,
can be examined: axial, coronal, and sagittal (profile) or open spina bifida.
although a combination of these planes is the most In examining the fetal thorax, the scapulae,
optimal. In evaluating for cleft lip/palate (anterior clavicles, and ribs should be assessed, especially when
palate), both axial and coronal images towards the ruling out certain types of skeletal dysplasias.
anterior surface of the nose/upper lips provide the Abnormal lung tissue and echogenicity (such as
best visualization. The posterior or hard palate cannot bronchopulmonary sequestration, cystic adeno-
be imaged sonographically, since it is obscured by matoid malformations), diaphragm, pleural effusions,
overlying osseous structures. Other anatomic and thoracic circumference (to rule out pulmonary
structures that should be evaluated include the chin hypoplasia) should all be examined.
(to rule out micrognathia), nasal bone, nose, lower Performing an adequate and detailed fetal cardiac
lips, tongue, orbits (and diameters if necessary, to examination on ultrasound can be one of the most
exclude hyper/hypotelorism), and ear length (which difficult and challenging tasks, since it is dynamic,
can be shortened in both aneuploid and nonaneuploid complex, and can depend significantly on fetal
 Second Trimester Ultrasound Screening of Fetal Anomalies 1081
position. First, the situs should be established along abdominal circumference (AC) is taken at the
with the presence of a normal cardiac rate and transverse level where stomach and spine are
rhythm. In a transverse image of the fetal chest, the visualized, and the umbilical vein joins the right
heart should occupy about one-third of the fetal portal venous system, which should curve away from
thorax, and its normal axis and position should be the stomach. If, however, the curve is towards the
verified (apex points to the left, bulk of the heart stomach, persistence of the right umbilical vein should
occupies left side of chest, 45 ± 20 degree angle of be suspected. The AC has its greatest value in
the heart relative to the midline). Any alterations in evaluating fetal growth later in pregnancy, and also
position, axis, or both can suggest intrinsic mal- comprises a parameter used for fetal dating. This is
position or an intrathoracic mass. In order to because AC deviations are a result of changes in both
sufficiently rule out cardiac defects, multiple planes liver size and subcutaneous fat. The stomach should
and views (in addition to the 4-chamber view) should always be located below the diaphragm as a fluid-
be examined in real-time imaging. A single static 4- filled structure in the left upper quadrant. An absent
chamber view is no longer acceptable or adequate to or small stomach in the usual location despite
completely examine the heart. Both outflow tracts prolonged scanning to allow for filling, can be
should be evaluated to increase the sensitivity for indicative of esophageal atresia with or without
cardiac defects, such as tetralogy of Fallot, tracheoesophageal fistula, or diaphragmatic hernia
transposition of the great vessels, truncus arteriosus, (stomach located within the chest). The rest of the
etc. In screening second trimester fetuses, we abdomen is filled with bowel, with the appearance
advocate visualization of the 4 chamber apical and changing with advancing gestational age. In the
subcostal views, both outflow tracts, longitudinal second trimester, the fetal bowel appears as midlevel
parasternal arches (aortic and ductal), inferior/ to increased echogenicity filling the abdominal
superior vena cava, valves, and the atria/ventricular cavity; when using higher frequency transducers, it
septa. All chambers should have approximately equal often appears mildly echogenic when compared to
sizes, the great vessels should cross each other, the the liver. 13 True hyperechoic bowel is diagnosed
pulmonary veins should be seen entering the left when its echogenicity is similar to that of bone. It
atrium, and there should be no pericardial effusion. can be can be a normal variant, or associated with
Depending on the indication or clinical scenario, aneuploidy, infection, cystic fibrosis, fetus swallow-
color, M-mode, or pulsed Doppler sonography can ing blood, intrauterine growth restriction, and bowel
also be performed of the fetal heart and its great malformations/atresias. To exclude ventral wall
vessels. In about 3-4% of normal second trimester defects such as omphalocele or gastroschisis, the
fetuses,11 an echogenic intracardiac focus can be seen, umbilical cord insertion site into the abdominal wall
usually located in the left ventricle. It is caused by must be evaluated to confirm the cord penetrating
specular reflection from the papillary muscle and the abdomen, with the adjacent abdominal wall
chordae tendinae. However, some studies have also intact. No fetal ascites or hydrops should be seen
confirmed an association between this and fetal under normal circumstances.
Down syndrome in high-risk populations.12 The fetal genitourinary tract is a common site for
Fetal abdominal organs that can be identified on fetal anomalies. The kidneys appear as bilateral,
second trimester ultrasonography include liver hypoechoic, paraspinal structures that contain the
(majority of the upper abdomen), gallbladder (right urine-filled renal pelvis and can sometimes be difficult
upper quadrant at inferior edge of the liver and “tear- to visualize. Dilation of the renal pelvis/calyx or
drop” shaped), spleen (solid organ posterior to ureter, renal masses, hyperechogenicity, parenchymal
stomach), stomach, bowel, umbilical vein, and cord cysts, or enlargement/absence of the kidneys may
insertion site/adjacent anterior abdominal wall. The reflect anomalies. To delineate the renal arteries,
1082 Textbook of Perinatal Medicine

color or power Doppler imaging is frequently used. actual length. Also, only the ossified portions of the
The fetal adrenals can be seen cephalad to their bone should be measured, with the hypoechoic
kidneys. While the right adrenal lies immediately cartilaginous epiphyses excluded. Both lower
posterior to the inferior vena cava, the left adrenal extremities should not be clubbed, nor the plantar
lies lateral to the aorta. The fetal bladder is sono- surface appear “rocker-bottom.” Five toes should be
lucent (contains urine) and located in the midline, present, and they should not appear dysplastic. Foot
anteriorly, and low in the pelvis. Absence of the length is also another biometric parameter than can
bladder may be secondary to recent voiding or be obtained.
bladder/cloacal exstrophy, while a very enlarged Normally, the umbilical cord is comprised of three
bladder may be a sign of lower obstructive uropathy. vessels: two smaller umbilical arteries and one larger
Male genitalia is confirmed only if penis and scrotum umbilical vein; this can be confirmed by directly
are seen. Occasionally, the hypoechoic umbilical cord imaging the cord or by observing the umbilical
lying between the thighs can be mistaken for the solid arteries coursing around the fetal bladder. Depending
penis. Also, a prominent clitoris seen during the early on the clinical situation, an umbilical artery Doppler
second trimester can also sometimes be confused for waveform can be obtained. Its flow is a reflection
a penis. The echogenic testicles usually do not mainly of the placental resistance, and to a certain
descend into the scrotum until the seventh month. extent, of the fetal systemic circulation. Once the
Female genitalia are identified by the presence of umbilical vein enters the fetal abdomen, it turns
several parallel linear echoes, which represent the superiorly, enters the liver, and communicates with
margins of the labia, and not by the observed absence the portal vein. The umbilical vein also continues into
of penis/scrotum. One should never forget that the ductus venosus, and then the inferior vena cava
ambiguous genitalia may also be present. and right atrium.
Although routine evaluation of all fetal upper and
lower extremities is not a part of routine obstetrical SONOGRAPHIC ANEUPLOIDY MARKERS IN
sonographic guidelines, it is our opinion that a THE SECOND TRIMESTER
complete survey of all extremities (including hands/ Aneuploid fetuses account for approximately 6-11%
feet) may provide important diagnostic information of all stillbirths and neonatal deaths. 15 Prenatal
and can screen for abnormalities. Both of the hands ultrasonography can often detect many abnormalities
should contain five fingers, should be open (full in fetuses with aneuploidy. These can include major
extension of all fingers in the same plane as the structural defects or other “soft” sonographic
metacarpals), have normal movement and tone, and markers of aneuploidy. Aneuploidy “soft” markers
the middle phalanx of the 5th digit must be visualized. are usually nonspecific, most commonly seen in
The presence of clenched hands with overlapping normal fetuses, are often transient (such as choroid
digits is a highly sensitive (95%) sonographic marker plexus cysts), and may not be significantly linked to
of trisomy 18.14 All the long bones (femur, humerus, perinatal outcome. The aneuploidy markers that we
radius, ulna, tibia, fibula) should be present and there use in our institution include shortened long bones,
should not be demineralized, shortened, fractured, pyelectasis, increased nuchal fold thickening,
contracted, or bowed bones. The ulna normally hyperechoic bowel, choroid plexus cysts, hypoplastic
extends farther into the elbow, and the tibia extends middle phalanx of the fifth digit, clinodactyly, sandal
farther into the patella. Routinely on our second gap (wide space between first and second toes), two-
trimester surveys, we measure all long bone lengths. vessel cord, echogenic intracardiac focus, short ear
These measurements should be obtained with the length, and absent nasal bone. Each marker alone,
long bone located horizontally within the image, has only low to moderate sensitivity for detecting
since vertical measurements can falsely “shorten” the fetal Down syndrome (DS). Many of these
 Second Trimester Ultrasound Screening of Fetal Anomalies 1083
sonographic findings when found in isolation in low- sonogram is used to generate an adjusted (lower)
risk patients do not necessarily increase the risk for DS risk to guide a high-risk woman’s decision on
aneuploidy. However, when found in the context of genetic amniocentesis. Thus far, many studies have
multiple other sonographic abnormalities or markers been published that examine the accuracy of genetic
(in low-risk patients), or when isolated markers are sonography for detecting DS in high-risk popu-
seen in high-risk patients, the risk for fetal lations.17 By defining as abnormal the ultrasound with
aneuploidy may increase. In general, as the number at least 1 abnormal marker, the overall sensitivity is
of markers present increases, the risk for 77% (50-93%) and the false-positive rate is 13% (7-
chromosomal abnormality also increases directly. 17%).17 In 1998, a large multi-center collaborative
The presence of most fetal congenital abnorma- study involving 11 centers (including our own)
lities will increase the risk for underlying aneuploidy examined the sensitivity of sonography in detecting
except for some disorders felt to be “acquired” fetal DS.18 They found that 85% of DS fetuses (n=241)
(rather than inherent) from tissue or vascular had at least one abnormal finding on ultrasound. In
disruption. Such disorders include hydranencephaly, 2003, an eight center study (including our own)
gastroschisis, tumors, amniotic band syndrome, limb- evaluated the utility of second trimester genetic
body wall complex, etc. Examples of specific sonography among high-risk pregnancies, including
structural anomalies that can be associated with fetal 176 DS fetuses. 19 The sensitivity for DS was 72%,
aneuploidy are: cerebral ventriculomegaly, with a range from 64-80% at the various sites. Of
holoprosencephaly, agenesis of the corpus callosum, significance, about half (47%) of DS fetuses had a
Dandy-Walker malformation/cerebellar hypoplasia, thickened nuchal fold of 5 mm or more, making this
spina bifida, cleft lip/palate, ocular abnormalities, marker the one with the highest sensitivity.
craniofacial anomalies, cystic hygroma, nonimmune Nuchal fold thickening is the single most sensitive
hydrops, cardiac abnormalities, diaphragmatic and specific marker for fetal DS (sensitivity 40% and
hernia, duodenal atresia, omphalocele, genitourinary false-positive rate of 0.1%),20 although absent nasal
anomalies, clubfeet, and extremity malformations. bone has also recently been shown by us to have a
The most common autosomal trisomy in liveborn 41% sensitivity and 100% specificity for fetal DS. 8
infants is Down syndrome. Because only 25% of DS Short femur length (measured to expected length
fetuses in the second trimester have a sonographically < 0.91) has been found in 24% of DS fetuses,21 while
detectable major anomaly (unlike trisomies 18 and a short humerus (measured to expected length < 0.90)
13 where the majority will have anomalies identified 50% of DS fetuses, with a false-positive
visualized), several investigators have been searching rate of 6.25%.22 Unfortunately, there tends to be a
to find aneuploidy ultrasonographic markers in order large overlap in bone measurements between
to increase the sensitivity for fetal Down syn- affected and normal fetuses. The sensitivity for
drome. 16 Genetic sonography is performed in the pyelectasis (antero-posterior diameter renal pelvis >
second trimester, ideally between 18-20 weeks. It is 4 mm in second trimester) for DS is 25%.22 Echogenic
a specific, targeted exam for fetal aneuploidy (most bowel has a reported sensitivity of 7-12.5%, while
specifically for trisomy 21) where the examiner echogenic intracardiac focus has a sensitivity of
evaluates for abnormal fetal biometry, fetal structural 18%.22 Recently, we examined the sensitivity for fetal
anomalies, and other markers of aneuploidy. By DS by sonographic ear length.23 We found that of 51
combining multiple aneuploidy markers, the sensiti- DS fetuses, 41% (n=21) had ear length < 10 th
vity for DS can be increased to >80%, with false- percentile. However, short ear length was not as
positive rates of 10-15% (by defining as abnormal sensitive a marker for DS as it was for trisomies 18
ultrasound exam with at least 1 abnormal marker (96%) and 13 (100%). Although an association
present). Information derived from a normal genetic between choroid plexus cysts and trisomy 18 has
1084 Textbook of Perinatal Medicine

been established,24 the association with fetal DS has risk for fetal anomalies is clear, the benefits and cost-
been controversial, especially when isolated. When effectiveness of routine sonographic screening in
the choroid plexus cyst(s) are isolated, obstetrical pregnancy are not as obvious. In the United States,
management should not be altered in the absence of approximately 60-70% of all pregnant women
any other high-risk factors.25 Single umbilical artery undergo an ultrasound at various times in the
has been found to be associated with aneuploidy and gestation. 27 However, the efficacy of routine
congenital malformations. The risk for fetal sonographic screening for fetal abnormalities varies
aneuploidy depends on the presence of associated widely. One of the first studies to determine the
anomalies; the greater the number of anomalies, the diagnostic accuracy of ultrasonography in high-risk
greater the chances for aneuploidy. In a low-risk pregnancies was performed during the late 1970s and
patient, an isolated single umbilical artery on early 1980s in the United Kingdom.28 It was around
ultrasound is probably not an indication for fetal this time that real-time imaging became widespread
karyotyping, provided that a search for additional as a clinical tool. This study found that 95% of
malformations is negative. malformations were correctly diagnosed.28 Other
In 1996, our group was the first to publish data published sensitivities have ranged broadly anywhere
on using second-trimester genetic sonography to from 13.3% to 82.4%,29 with the average collaborative
guide clinical management of women at high-risk for world experience being 50%.30 After reviewing these
fetal Down syndrome. 26 Subsequently, once we extremely wide and different detection rates, it
analyzed our 1999 data, in the presence of a normal becomes apparent why the reliability and utility of
genetic ultrasound, we counseled patients that the sonographic screening for fetal abnormalities has
likelihood for fetal DS was reduced by at least 80% become very controversial in some countries. Even
from the a-priori risk (triple or quadruple screen, or for those who already advocate routine sonographic
screening, when to perform scans and the number
if unavailable, maternal age).17 Over almost a ten year
period (since November 1992), we have evaluated of sonographic exams are debatable and inconsistent.
Since 75% of patients with abnormal fetuses will be
5,299 fetuses by genetic sonography; the over-
“low-risk,” it is reasonable to review data in the
whelming majority (85%) had no markers seen
literature that assesses the impact of routine screening
(normal scan), 12% had one abnormal marker
sonography.29
present, and 3% had 2 or more markers present.
Diagnosing fetal anomalies prior to birth can
When one or more abnormal sonographic markers
provide many advantages. Prenatal sonographic
were present, the sensitivity, specificity, positive and
diagnosis can lead to further diagnostic testing (such
negative predictive values for DS were 87% (52/60),
as amniocentesis), prepare parents for an adverse
91% (4395/4831), 11% (52/488) and 99.8% (4395/
pregnancy outcome, alert the clinician to the
4403), respectively. Approximately two-thirds of DS
possibility of other abnormalities, and can determine
fetuses had 2 ore more abnormal sonographic
appropriate management choices (such as
markers seen.
intrauterine therapy, early delivery, delivery at a
SECOND TRIMESTER ULTRASOUND tertiary care center, or termination of pregnancy).
However all these advantages are achieved only if
SCREENING FOR FETAL ABNORMALITIES
the ultrasound exam is performed by qualified,
While there are numerous acceptable indications for knowledgeable individuals who possess expertise
performing a second trimester sonographic exam performing ultrasonographic exams. Sonographic
during pregnancy, perhaps one of the most common screening done by individuals who are inexperienced
indications is to rule out the presence of fetal and unqualified may not only increase the costs of
abnormalities. While the advantages of performing health care, but can create high false-negative and
a screening ultrasound in the pregnancies at high- false-positive results with significant consequences.
 Second Trimester Ultrasound Screening of Fetal Anomalies 1085
There are a multitude of biases and problems that the higher the rate of anomaly detection. Levi found
can account for the sensitivity variation across various that the average sensitivity from studies including
studies.29 Fetal abnormalities that resolve, technical scans performed once before 20 weeks was 45%;
factors (obesity, fetal positioning), quality of when scanning was done several times during the
sonographic equipment, and undetectability of pregnancy, the sensitivity rose to 60%. 29 The
certain anomalies comprise some of the reasons. In prevalence of specific malformations within a given
addition, each center has differing criteria and population may also have a significant impact on the
interpretations as to what exactly constitutes a overall sensitivity of ultrasound. A low frequency
detailed sonographic exam. There is no doubt that of anomalies in a certain population can introduce
the less detailed the exam, the higher the chances bias in diagnostic accuracy. Studies which exclude
are for having a lower diagnostic accuracy. Selection certain anomalies because they are felt to be “minor”
bias can also play an important role in affecting or undetectable may have dramatically different
diagnostic accuracy, depending on whether the sensitivities than when all fetal anomalies are
patient source is a hospital, or office practice-based. included. In 1996, one study found that the sensitivity
Perhaps the most important bias is the variation in of sonography for diagnosing both minor/major
sonographic skills, capability, and experience of anomalies was only 8.7%; however, if only major
individuals performing the ultrasound examination. anomalies detectable by ultrasound were included,
In the Helsinki study that incorporated patient the sensitivity was increased up to 75%.30 Finally,
populations from two hospitals, the ultrasonographic other factors that can affect the reported fetal
sensitivity for detecting anomalies was more than abnormality detection rates in sonographic screening
two-fold higher in the university hospital than in the may be related to ascertainment biases, such as lack
city hospital (77% vs. 36%). 31 A study in Vienna of autopsies (considered the “gold standard”),
examined the influence of the experience of the suboptimal or incomplete neonatal evaluation at birth,
investigator on the rate of sonographic diagnosis of and insufficient length of neonatal follow-up since
fetal malformations. 32 Of 323 cases of fetal some abnormalities may not express themselves
malformations, obstetricians in private offices immediately after birth and can take time to
detected 22%, hospital examiners detected 40%, and manifest.29
examiners in the prenatal diagnosis and therapy In the United States, the RADIUS (Routine Ante-
center detected 90% of all fetal malformations.32 The natal Diagnostic Imaging with Ultrasound) study was
selection of pregnant women is also significant. the first randomized clinical trial of second trimester
Screening high-risk women is likely to be much more ultrasound.33 This trial was performed to determine
effective. In this scenario, the chances of discovering the benefits, if any, of routine sonograms among
an anomaly is higher, and the sonographers may be pregnant women at low risk. It compared routinely
more attentively focused. For instance, in one study scanned pregnant women to those having ultra-
they found that the average sensitivity in low-risk sounds only when indicated. An additional ultr-
populations is 55%, while in high-risk populations it asound exam was performed in the early third
is 92%.29 trimester in the study group. Although the identi-
The gestational age at the time of ultrasound fication rate of anomalies was found to be three times
screening also impacts sensitivity, since various better with routine ultrasound vs. indicated
anomalies are manifested at differing gestational ultrasound (35% vs. 11%, respectively), the sensitivity
weeks or may be easier to visualize/detect, and some in detecting anomalies by ultrasound performed
anomalies may present only later in gestation between 15-22 weeks was extremely low (17%). A
(duodenal atresia). In general, the more sonographic possible source of bias was that practice-based
exams a patient undergoes during the pregnancy, patients were utilized, which may have created an
1086 Textbook of Perinatal Medicine

inadvertent selection bias (rather than a community it was less satisfactory in detecting cardiac and
or hospital-based population). This study reported gastrointestinal tract anomalies. 36 The Belgian
a relative detection rate of 2.7 (95% CI 1.3-5.8) in Multicentric Study found that of 381 structurally
tertiary vs. nontertiary ultrasound units.33 Within a abnormal fetuses, 154 were correctly detected by
subgroup evaluated at tertiary care centers, the ultrasound (sensitivity 40%). 37 The specificity,
detection rate of anomalous fetuses was 35% vs. 13% positive, and negative predictive values were 99.9%,
in nontertiary centers. This trial found that 95%, and 98.6%, respectively.
sonographic screening did not significantly influence In 2002, we examined the value of our
the management or outcome of pregnancies aforementioned complete anatomic sonographic
complicated by congenital malformations. A 1998 survey in detecting fetal abnormalities, and
study at a tertiary care center found that the correlated our sonographic findings with perinatal
sensitivity of anomaly detection in women at risk autopsy results.38 Autopsy findings were considered
for anomalies was very high (89.7%). 34 In the the “gold standard.” Of 88 abnormal autopsies, 85
screening group, or lower-risk population, although fetuses had 1 or more abnormal structural sono-
the sensitivity was less (47.6%), it was still sufficient graphic findings, for a sensitivity of 97% (for ano-
to ensure cost-effectiveness for their patients.34 malous fetuses). From autopsy, a total of 372 separate
In 1999, the Eurofetus study was designed to abnormalities were found; of the 299 major and 73
evaluate the sensitivity of routine sonographic minor abnormalities, prenatal ultrasonography
screening for fetal malformations.35 In the largest detected 75% and 18%, respectively. Thus, we found
among screening studies, ultrasound screening was that the sensitivity for detecting minor abnormalities
applied to almost 200,000 pregnant women in 60 was poor, even when utilizing a complete sono-
hospital laboratories and 14 European countries. They graphic survey. We found either complete agreement
found a sensitivity rate of 64% (2363/3685), which at or only minor differences between sonographic and
first glance, was much higher compared to the autopsy findings in 65% of the cases.38
RADIUS study. However, for various reasons these In examining the literature, it is evident that there
two studies may not be exactly comparable. For is a wide range in sensitivity of ultrasonography to
example, patients studied in the RADIUS trial were detect fetal anomalies, and it depends highly on the
low-risk (and probably not relevant to the average clinical setting in which the exam is performed, along
population), since very strict exclusion criteria had with the varying skills, expertise, and experience of
been applied prior to patient recruitment. The criteria those performing the sonographic exam. Therefore,
used to designate major fetal anomalies (gold there appears to be insufficient evidence to comment
standard) was also very liberal, and both of these on a single estimate of the sensitivity of routine
facts could have lowered the sensitivity. On the other ultrasound in screening for fetal anomalies. However,
hand, in the Eurofetus study, all patients were in many studies, the specificity of a fetal anatomic
studied regardless of their risk status, and only survey has been found to exceed 99%.33,39-41 This fact
“truly” major abnormalities were considered as indicates that in the low-risk population, sonography
endpoints. This could have artificially raised the may be helpful in ruling out abnormalities and
sensitivity of the sonographic screening. detecting the normal, but may not be equally reliable
The Helsinki trial had patients undergo one in detecting abnormalities. It is expected that with
ultrasound screening exam within the second time, the sensitivity of sonographic screening
trimester; 40% of major fetal anomalies were programs should improve. This can be partly
detected. 36 Although screening did detect most attributable to improvements in equipment quality,
anomalies of the central nervous system, genito- training, and experience of sonographers, along with
urinary system, and cases with multiple anomalies, the emergence of new technological advances such
 Second Trimester Ultrasound Screening of Fetal Anomalies 1087
as 3 and 4-dimensional sonography. It is thought that determination of gestational age, multiple gestations,
uniform and detailed training for practitioners is the and placental abnormalities, thus theoretically
best guarantee for an efficient screening program.29 improving perinatal risk. Three trials have examined
In addition, standardization of the scanning process perinatal morbidity and mortality in patients
for each and every scan should also improve overall undergoing routine ultrasonography. In both the
sensitivity. In a 1996 review article, Seeds argues that RADIUS and Stockholm trials, perinatal mortality
the diagnostic sensitivity of the screening obstetrical rates were similar between the routine sonography
ultrasound examination appears to be highest in high- and control groups.27,43 However, the Helsinki trial
risk patients examined by highly specialized and found the perinatal mortality rate was significantly
experienced personnel. 42 However, diagnostic improved in the routine ultrasound group (4.6/1000
sensitivity may be quite good even in low-risk vs. 9.0/1000); this 49.2% reduction was mainly
patients with a basic or routine examination if attributable to improved early detection of major
recognized guidelines for content are followed and malformations which led to termination of
referral to experienced referral resources for unclear pregnancy.31 In all three trials, no differences were
or suspicious images is liberally practiced.42 found between the study and control groups in terms
A common and often touted benefit of the prenatal of perinatal morbidity.27,31,43 Perinatal morbidity was
detection of fetal abnormalities, especially those that defined as admission to the neonatal unit, 31,43
are life-threatening, is the delivery of these infants
moderate morbidity (neonatal sepsis, grade I or II
in tertiary care centers that are capable of providing
intraventricular hemorrhage, stay of > 5 days in
immediate and appropriate care. A valid and
neonatal unit), or severe morbidity (ventilation > 48
legitimate question often asked is whether routine
hours, stay of > 30 days in neonatal unit).27 In terms
sonography improves the survival rates of anomalous
of birth weight and number of low birth weight (<
neonates. Ten years ago, the RADIUS study examined
2500 grams) infants, the RADIUS and Helsinki trials
this question.33 Screening ultrasound was not found
found a similar birth weight distribution between
to have any impact on the detection, management
the routine ultrasound and control groups. 27,31
and outcome of fetuses with anomalies. Although
However, the Stockholm trial found fewer births of
survival rates for fetuses with anomalies were not
< 2500 grams (2.5% vs. 4%) in the routine ultrasound
affected by sonographic screening, in an analysis of
group.43 Finally, this same trial found that for women
infants with life-threatening anomalies, 75% (21/28)
smokers, there was a higher mean birth weight (3413
in the routinely screened group survived, vs. 52%
(11/21) in the routine-care group. 33 While this vs. 3354 grams) in the routine ultrasound group, and
difference did not reach statistical significance, this the authors surmised that this improvement could
may be attributed in part to the small sample sizes. be attributed to healthier maternal behaviors after
At the current time, there is insufficient evidence to women visualized their fetuses on ultrasound.43 The
either refute or support the benefit of routine RADIUS trial investigators concluded that adopting
sonography in reducing mortality of those neonates sonographic screening in the United States would
with life-threatening anomalies, although this may increase health care costs without either improving
not be intuitively apparent to those families affected perinatal outcome or providing any measurable
with these problems. It is clear that further studies benefit from early detection of fetal anomalies. By
are required to address this issue. contrast, however, another group found that routine
A significant question regarding routine abnormality screening improves perinatal outcome
ultrasonography is whether this improves overall by leading to termination of pregnancies for certain
perinatal morbidity and mortality. It is known that anomalies, and selected delivery at tertiary care
routine diagnostic sonography can lead to accurate centers for life-threatening malformations. 34
1088 Textbook of Perinatal Medicine

An important issue to examine is the cost-benefit ultrasonography may reduce perinatal mortality
analysis of routine second trimester sonography. Our because of induced abortions following the detection
group recently performed a cost-benefit analysis of fetal abnormalities. In the United States, the
based on the RADIUS results, and compared a policy current standard of care remains at performing
of routine second trimester sonography in low-risk ultrasound only for specific indications. However,
pregnant women vs. not offering such screening.44 some would argue that every obstetrical patient
We concluded that routine second trimester should have an ultrasound examination only if it is
sonographic screening is associated with net benefits competently performed, properly recorded, and if
only if the ultrasound was performed in tertiary care the patient is aware of appropriate goals and
centers. Another tertiary center also assessed the limitations.42
cost-effectiveness of anomaly screening in their Although ultrasonographic screening for fetal
patient population, and found that routine screening abnormalities may have widely varying sensitivities
appeared cost-effective. 34 Leivo and associates depending on the particular unit, in our opinion it
demonstrated that a one-stage second trimester still offers great value to both patients and physicians
screening ultrasound was cost-effective, and was that may not be quantifiable. Psychological
associated with fewer perinatal deaths. 45 In the reassurance, referrals, genetic counseling, antepartum
United Kingdom, a prospective study was performed management, and preparation of families and health
to evaluate the cost-benefit of changing from selective care providers are just some examples of the possible
to routine ultrasound screening for fetal anomaly.46 advantages. Overall, these reasons may outweigh the
They found that routine sonography was the sole “risks” of ultrasound, such as false-positive dia-
method of detection for 11 major and 18 less severe gnoses. If patients are given the choice and counseled
congenital abnormalities found in low-risk regarding the diagnostic capabilities of present day
pregnancies, which would not previously have sonography, most would choose to undergo fetal
qualified for selective ultrasound. They felt that anomaly screening. It is important to remember that
routine fetal anomaly ultrasound would seen to be pregnant women often do not perceive ultra-
economically justifiable.46 In 2002, Roberts reviewed sonography as a “test,” but rather utilize it as a tool
evidence from the literature and found a need for to evaluate their fetus as a patient. We concur with
more data on the costs and cost effectiveness of this philosophy, and would also argue that examining
routine sonographic screening for fetal anomalies.47 the fetus as a patient via ultrasound should be
All published trials have shown that more twin offered routinely, as in all other aspects of adult
pregnancies are diagnosed earlier with routine medicine.
ultrasound. The Helsinki trial found that with the
routine ultrasound group, 100% of twins were CONCLUSIONS
detected prior to 21 weeks, compared with 76% in Second trimester sonographic screening for fetal
the control group.31 In addition, they found that the anomalies and prenatal diagnosis is performed for
perinatal mortality for the twins was 27.8/1000 vs. many reasons. It can provide useful information and
65.8/1000, respectively. The RADIUS trial also knowledge for patients, may give them reassurance
performed subgroup analyses for small for regarding their pregnancy and the health of their
gestational age infants and neonates born at ³ 42 fetus, provides the opportunity for further diagnostic
weeks. 27 The data did not show improvement in testing such as amniocentesis, provides counseling
overall outcome for these conditions when routing regarding prognosis, and can modify management
sonography was performed. (such as location and method of delivery, termination,
In conclusion, examination of the available fetal surgery). Some patients will utilize this
evidence shows that in low-risk pregnancies, routine information to prepare ahead of the delivery date
 Second Trimester Ultrasound Screening of Fetal Anomalies 1089
by consulting genetics, pediatric surgeons, 10. Bromley B, Liberman E, Shipp TD, Benacerraf BR. Fetal
nose bone length; a marker for Down syndrome in the
neonatologists, and other specialists. In addition, for
second trimester. J Ultrasound Med 2002; 21:1387-1394.
the physician, information regarding specific 11. Levy DW, Mintz MC. The left ventricular echogenic
abnormalities or aneuploidy can optimize pregnancy focus: a normal finding. Am J Roentgenol 1988; 150(1):
management, along with the labor and delivery 85-86.
12. Sepulveda W, Cullen S, Nicolaidis P, Hollingsworth J,
process. Importantly, knowledge of anomalies can Fisk NM. Echogenic foci in the fetal heart: a marker of
raise the possibility of genetic syndromes, can impact chromosomal abnormality. Br J Obstet Gynaecol 1995;
future pregnancies, and can influence counseling 102(6):490-492.
regarding genetics and prognosis. Therefore, because 13. Vincoff NS, Callen PW, Smith-Bindman R, Goldstein RB.
Effect of ultrasound transducer frequency on the
of its many advantages, it is our opinion that all appearance of the fetal bowel. J Ultrasound Med 1999;
patients should have access to sonographic screening 18(12):799-803.
within the second trimester of pregnancy, and a 14. Yeo L, Guzman ER, Day-Salvatore D, Walters C, Chavez
D, Vintzileos AM. Prenatal detection of fetal trisomy 18
complete, targeted, and thorough exam should be
through abnormal sonographic features. J Ultrasound
performed to increase sensitivity. Med 2003; 22:581-590.
15. Alberman ED, Creasy MR. Frequency of chromosomal
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Ultrasound Obstet Gynecol 1999;14(2):92-97. shortening in the detection of Down syndrome: is
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fossa: false appearance of mega-cisterna magna and 23. Yeo L, Guzman ER, Ananth CV, et al. Prenatal detection
Dandy-Walker variant. Radiology 1994; 192:247-251. of fetal aneuploidy by sonographic ear length. J
8. Vintzileos A, Walters C, Yeo L. Absent nasal bone in Ultrasound Med 2003; 22:565-576.
the prenatal detection of fetuses with trisomy 21 in a 24. Gross SJ, Shulman LP, Tolley EA, et al. Isolated fetal
high-risk population. Obstet Gynecol 2003; 101:905-908. choroid plexus cysts and trisomy 18: a review and meta-
9. Cicero S, Bindra R, Rembouskos G, Tripsanas C, analysis. Am J Obstet Gynecol 1995; 172:83-87.
Nicolaides KH. Fetal nasal bone length in 25. Chitty LS, Chudleigh P, Wright E, Campbell S, Pembrey
chromosomally normal and abnormal fetuses at 11-14 M. The significance of choroid plexus cysts in an
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26. Vintzileos AM, Campbell WA, Rodis JF, et al. The use ultrasound screening trial. A report from the Helsinki
of second-trimester genetic sonogram in guiding clinical Ultrasound Trial. J Perinat Med 1994; 22:279-289.
management of patients at increased risk for fetal 37. Levi S, Hyjazi Y, Schaapst JP. Sensitivity and specificity
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27. Ewigman BG, Crane JP, Frigoletto FD, LeFevre ML, Bain by ultrasound: the Belgian Multicentric Study. Ultra-
RP, McNellis D. Effect of prenatal ultrasound screening sound Obstet Gynecol 1991; 1:102-110.
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Med 1993; 329:821-827. Vintzileos AM. Value of a complete sonographic survey
28. Campbell S, Pearce JM. The prenatal diagnosis of fetal in detecting fetal abnormalities: correlation with
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1983a; 10:475-506. 39. Chitty LS, Hunt GH, Moore J, Lobb MO. Effectiveness
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radiographer screening for fetal abnormalities by
31. Saari-Kemppainen A, Karjalainen O, Ylostalo P,
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32. Bernaschek G, Stuempflen I, Deutinger J. The influence 43. Waldenstrom U, Axelsson O, Nilsson S, Eklund G, Fall
of the experience of the investigator on the rate of O, Lindeberg S, Sjodin Y. Effects of routine one-stage
sonographic diagnosis of fetal malformations in Vienna. ultrasound screening in pregnancy: a randomized
Prenat Diagn. 1996; 16:807-811. controlled trial. Lancet 1988; 2:585-588.
33. Crane JP, LeFevre ML, Winborn RC, Evans JK, 44. Vintzileos AM, Ananth CV, Smulian JC, Beazoglou T,
Ewigman BG, Bain RP, Frigoletto FD, McNellis D. A Knuppel RA. Routine second-trimester ultrasonography
randomized trial of prenatal ultrasonographic screening: in the United States: a cost benefit analysis. Am J Obstet
impact on the detection, management, and outcome of Gynecol 2000; 182:655-660.
anomalous fetuses. The RADIUS Study Group. Am J 45. Leivo T, Tuominen R, Saari-Kemppainen A, Ylostalo P,
Obstet Gynecol 1994; 171:392-399. Karjalainen O, Heinonen OP. Cost-effectiveness of one-
34. VanDorsten JP, Hulsey TC, Newman RB, Menard MK. stage ultrasound screening in pregnancy: a report from
Fetal anomaly detection by second-trimester ultra- the Helsinki ultrasound trial. Ultrasound Obstet Gynecol
sonography in a tertiary center. Am J Obstet Gynecol 1996;7:309-314.
1998; 178:742-749. 46. Long G, Sprigg A. A comparative study of routine versus
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team. The performance of routine ultrasonographic Screen 1998;5:6-10.
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Heinonen OP. Fetal anomalies in a controlled one-stage cost effectiveness. BJOG 2002; 109:44-56.
 82
First Trimester Maternal Serum
Markers of Fetal Anomalies

David A Krantz, Terrence W Hallahan, James N Macri

INTRODUCTION nuchal translucency. This protocol has been studied

extensively, and the first trimester risk estimates
Historically, prenatal screening for Down syndrome
have been validated.17
and other chromosomal abnormalities had been
conducted in the second trimester of pregnancy with
FREE BETA HCG
results available between 16 and 18 weeks of
pregnancy. Such screening can detect 60-70% of Down During normal pregnancy free beta hCG rises to peak
syndrome cases with a false positive rate of 5%. 1 levels at 8-9 weeks of pregnancy and then steadily
Now, first trimester Down syndrome screening has declines to about 20 weeks when concentrations
become an important option for prospective parents begin to level off. In second trimester Down
providing risk information as early as 11 to 12 weeks syndrome pregnancies free beta hCG is significantly
of pregnancy and detecting up to 90% of Down elevated with a median MoM of 2.64.18 By contrast,
syndrome cases at the same 5% false positive free alpha hCG has been observed to be unchanged
rate. 2-16 (median MoM=0.99) 19 or marginally elevated
The advantages of first trimester screening are (median MoM=1.31)20 in cases of Down syndrome.
that most patients (95%) receive very early reassu- This proportionally higher increase observed in the
rance that they are at low risk, the test provides a beta subunit relative to the alpha subunit observed
significantly higher detection efficiency compared to at the protein level is reflected at the mRNA level.
most second trimester screening methods, patients Indeed, Eldar-Geva et al. demonstrated that the beta
have more time and more diagnostic options to subunit MRNA content was proportionally increased
consider, and in cases where patients choose to compared to the alpha subunit in cultured second
terminate an affected pregnancy safer procedures are trimester trophoblasts. 21 This suggests that the
available in the first trimester. Further, pregnancies increase of the beta subunit in maternal serum may
that may have ended in an unexplained fetal loss be due in part to increased synthesis. More recently,
may now have karyotype information available. beta subunit MRNA has been detected in maternal
First trimester Down syndrome and Trisomy 18 serum and has also been demonstrated to be elevated
screening includes the biochemical analysis of free in cases of Down syndrome.22
beta human chorionic gonadotropin (free beta hCG) In the first trimester, free beta hCG is significantly
and Pregnancy Associated Plasma Protein A (PAPP- elevated in Down syndrome pregnancies and is the
A) combined with the ultrasound evaluation of only Down syndrome marker that is effective in both
1092 Textbook of Perinatal Medicine

first and second trimester screening. In two recent COMBINING FREE BETA HCG AND PAPP-A
studies the median free beta hCG multiples of the
The levels of both free beta hCG and PAPP-A in Down
median (MoM) in Down syndrome increased with
syndrome affected pregnancies tend to increase with
increasing gestational age from about 1.5 MoM at 9
increasing gestational age. As a result, with
weeks gestation to 2.1 MoM at 13 weeks 6 days
increasing gestational age free beta hCG is becoming
gestation.23,24 In the SURUSS case-control study the
more effective while PAPP-A is becoming less
median MoM of free beta hCG in Down syndrome
effective. These two trends tend to offset each other,
cases increased from 1.6 MoM at 10 weeks gestation
such that the combination is effective in screening
to 2.6 MoM at 13 weeks 6 days.25 Therefore, free
for Down syndrome between 9 weeks and 13 weeks
Beta hCG becomes more effective with increasing
6 days. However, the combined performance of free
gestational age. In trisomy 18 affected pregnancies,
beta hCG and PAPP-A is optimized in the earlier
a study of 28 cases showed the Median free beta
gestations. For example, at a 5% false positive rate,
hCG MoM to be 0.18 in the first trimester representing
the detection rate is 69% if the blood is drawn at 10
an 80% reduction from normal pregnancies7.
weeks while it is 63% if the blood is drawn at 13
weeks.26 These detection rates are as good as or
PREGNANCY ASSOCIATED PLASMA
better than those seen with second trimester triple
PROTEIN-A (PAPP-A)
test.
Pregnancy associated plasma protein-A (PAPP-A) is
a 750 kDa zinc metalloproteinase. It is produced by DRIED BLOOD COLLECTION
the trophoblast and exists in maternal circulation as
Maternal serum screening has largely involved
a disulfide bridged dimeric glycoprotein and as a
venepuncture collection of whole blood into red-top
2:2 complex with the proform of eosinophil major
tubes. Recently, whole blood sample collection using
basic protein (proMBP). Circulating levels are
finger-stick lancets and filter paper has become more
detectable as early as 4 weeks in pregnancy and
common. The ease of collection and transport of
double approximately every 6 days throughout the
dried blood specimens allows for greater flexibility
first trimester. PAPP-A concentrations rise expo-
in screening logistics. Since no phlebotomist is
nentially in the second trimester to reach
required, the simple finger-stick procedure can easily
approximately 50mg/L in the third trimester.
take place in the physician’s office, ultrasound lab or
In the first trimester PAPP-A is significantly
ultimately in the patient’s home. Quantitative analysis
decreased in Down syndrome pregnancies. The
of prenatal screening markers in dried blood samples
discrimination between unaffected and Down
is highly correlated with liquid serum samples.27 In
syndrome pregnancy is greatest earlier in pregnancy.
addition, dried blood technology stabilizes serum
Our own data on 163 cases of Down syndrome
proteins and therefore provides better overall analyte
showed a median MoM of 0.3 at 9 weeks and 0.8
precision leading to both higher detection rates and
Mom at 13 weeks 6 days.23 Spencer et al.24 showed
lower false positive rates.
a median MoM of 0.37 at 9 weeks and 0.70 at 13
weeks 6 days while the SURUSS study showed a COMBINED BIOCHEMISTRY AND
median MoM of 0.29 at 9 weeks and 0.62 at 13 weeks ULTRASOUND SCREENING
6 days.25 Therefore, PAPP-A becomes less effective
with increasing gestational age and by the second In addition to maternal serum markers, the
trimester is no longer a marker for Down syndrome. evaluation of fetal nuchal translucency in ultrasound
In trisomy 18 pregnancies, the median first trimester has been demonstrated to be a highly effective
level of PAPP-A is 0.33 representing a 2/3 reduction marker for Down syndrome.28 As a result, for the
from normal levels.7 first time, biochemical and biophysical markers are
 First Trimester Maternal Serum Markers of Fetal Anomalies 1093
combined in a single screening protocol for the Table 82.1: Impact of training and quality review of
detection of Down syndrome. The challenge has nuchal translucency measurements on first trimester
Down syndrome screening detection rates
been to introduce nuchal translucency assessment in
a standardized, quality-controlled fashion to allow Study Snidjers et al 199828 Haddow et al 199829
for efficient population screening. Laboratories Training and Yes No
perform a significant number of quality control Quality Review
Centers 22 11
procedures prior to releasing the results of Patients 96,127 3,991
biochemical tests to the clinician. Nuchal False Positive Rate 5% 5%
translucency, as a quantitative marker in the screening Detection rate 77% 31%
process must meet similar standards of quality Note: Results based on nuchal translucency only without
control as biochemical markers. Therefore, biochemistry.
sonographers must be specifically trained to perform
nuchal translucency measurement using a and PAPP-A with the ultrasound evaluation of nuchal
standardized methodology and their results audited translucency. A summary of 15 studies encompassing
on a regular basis. The improved effectiveness of over 80,000 patients using the free beta hCG, PAPP-
nuchal translucency screening when a quality control A and nuchal translucency protocol demonstrates a
program is in place is dramatic (Table 82.1). In the 88% detection rate for Down syndrome at a 5% false
study of Snidjers et al. 28, in which sonographers positive rate (Table 82.2). 2-16
underwent training and quality review, nuchal Combined biochemical and biophysical screening
translucency detected 77% of Down syndrome cases significantly improves the detection and false positive
while in the study of Haddow et al29, in which there rates for Down syndrome compared to either mode
was no specific training or quality control, the alone. The study by Krantz et al 7, for example,
detection was only 31%. showed the additional detection rate attributable to
Currently, the standard first trimester Down each marker in the protocol. In that study, free beta
syndrome and Trisomy 18 screening protocol hCG added 10 %, PAPP-A added 11% and nuchal
combines the biochemical analysis of free beta hCG translucency added 28% detection beyond that

Table 82.2: Summary of first trimester down syndrome screening studies using
free beta hCG, PAPP-A and nuchal translucency
Down syndrome cases
Number Detection
Study N FPR detected Total rate
Orlandi 19972 744 5.0 6 7 86%
Biagiotti 19983 232 5.0 24 32 75%
De Biasio 19994 1467 3.3 11 13 85%
De Graaf 19995 300 5.0 31 37 84%
Spencer 19996 1156 5.0 187 210 89%
Krantz 20007 5718 5.0 30 33 91%
Niemimaa 20018 1602 5.4 4 5 80%
Schucter 20029 4939 5.0 12 14 86%
Von Kaisenberg 200210 3864 6.6 16 19 84%
Bindra 200211 15030 5.0 74 82 90%
Wapner 200312 8514 5.0 48 61 79%
Spencer 200313 10458 5.0 23 25 92%
Sheffield 200314 18140 5.0 60 64 94%
Borrell 200415 2780 3.3 7 8 88%
Stenhouse 200416 5084 5.9 14 15 93%
Total 80028 5.0 547 625 88%
1094 Textbook of Perinatal Medicine

achieved by the corresponding other two markers Krantz et al31 found that PAPP-A values less than
alone (Table 82.3). Therefore to reach the optimal the 1st percentile were associated with a 5.4 fold
detection rate it is necessary to include all of these increase in the odds of intrauterine growth restriction
markers in the analysis. with a positive predictive value of 24.1%. Krantz et
Combined screening is also highly effective in al31 also found that free beta hCG values less than
detecting trisomy 18 and other chromosomal the 1st percentile were associated with a 2.7 fold
abnormalities. Using an independent algorithm for increase in the odds of intrauterine growth restriction
the calculation of patient specific trisomy 18 risk with a positive predictive value of 14.3% while other
detects 97% of trisomy 18 cases with only an studies that evaluated less extreme cut-offs for free
additional 1.2% false positive rate.7 In the BUN study, beta hCG or treated free beta hCG as a continuous
all 11 cases of trisomy 18 and 16 of 29 (55%) cases of variable did not find an association with intrauterine
other chromosomal abnormalities were detected.12 growth restriction.32-33,36-39 Goetzl et al40 have found
Spencer et al have shown that triploidy is associated that low levels of both free beta hCG and PAPP-A
with abnormal combined screening results with are associated with increased risk of spontaneous
triploidy types I and II having different patterns of abortion. Free beta hCG levels below the 1st
marker levels.30 Type I triploidy, in which the addi- percentile were associated with an 8.5 fold increase
tional chromosome is of paternal origin is associated in the odds of spontaneous abortion while levels
with extremely high free beta hCG , mildly decreased below the 5th percentile were associated with a 4.3
PAPP-A and increased nuchal translucency. Type II fold increase in the odds ratio. PAPP-A levels below
triploidy, in which the additional chromosome is of the first percentile were associated with a 5.4 fold
maternal origin is associated with extremely low free increase, while PAPP-A levels below the 5th
beta hCG, extremely low PAPP-A and normal nuchal percentile were associated with a 2.4 fold increase in
translucency. the odds of spontaneous abortion. Most importantly,
patients with normal free beta hCG, PAPP-A and
OTHER PERINATAL RISKS
nuchal translucency (i.e. those with levels between
Abnormal free beta hCG and PAPP-A are both the 5th and 95th percentiles) had a very low risk of
associated with increased perinatal risk. Low levels fetal loss before 20 weeks (0.36%). Yaron et al34,38
of PAPP-A are associated with increased risk of found a similar association between free beta hCG
intrauterine growth restriction.31-37 For example, and PAPP-A with fetal loss.

Table 82.3: Relative contribution of biochemistry and nuchal translucency in first-trimester

down syndrome screening at a 5% false positive rate
Initial protocol PAPP-A+NT Free beta hCG Free beta hCG NT
+ NT +PAPP-A
A. % detected 81% 80% 63% 74%
B. % undetected 19% 20% 37% 26%
Additional marker(s) Free beta hCG PAPP-A NT Free beta hCG + PAPP-A
C. Combined detection (%) 91% 91% 91% 91%
D. Extra detection with inclusion of
additional marker(s) = (C-A) 10% 11% 28% 17%
E. % of remaining undetected cases
detected with inclusion of
additional marker(s) = (D ÷ B) 53% 55% 76% 65%
Reprinted from: Krantz DA, Hallahan TW, Orlandi F, Buchanan P, Larsen JW Jr, Macri JN. First-trimester Down syndrome
screening using dried blood biochemistry and nuchal translucency. Obstet Gynecol. 2000 Aug;96(2):207-13.7
 First Trimester Maternal Serum Markers of Fetal Anomalies 1095
MATERNAL FACTORS expected to be similar to that observed in singleton
pregnancies. However, 67% of naturally conceived
As with second trimester screening, maternal factors
and 93% of assisted reproduction twin conceptions
play a role in first trimester Down syndrome
are dizygotic, and therefore the majority of Down
screening. Several studies have shown that patients
syndrome affected twin pregnancies can be expected
with increased maternal weight tend to have lower
to be discordant. In such cases, since the observed
free beta hCG and PAPP-A levels.41-43 Spencer et al42
maternal serum marker levels are the sum
showed that there can be a 2-fold difference in Down
contribution from each fetus, not only is it impossible
syndrome risk estimates if maternal weight is not
to determine which fetus is contributing abnormal
accounted for. The effect on trisomy 18 risk can be
analyte levels but the detection efficiency will be
even greater since heavier patients would have lower
decreased due to a dilution effect from the
levels of both free beta hCG and PAPP-A which
contribution of the normal fetus. Indeed the detection
would increase the trisomy 18 risk based on both
of Down syndrome in twins by second trimester
markers.
maternal serum screening is estimated at about 50%,
Ethnic differences in biochemical results have also
significantly lower than that expected in singletons
been observed.43 After weight adjustment, free beta
at a 5% FPR.47
hCG levels are higher for African Americans (15%)
In first trimester screening, nuchal translucency,
and Asians (6%) but lower for Hispanics (11%)
a biophysical marker, is fetus specific. Fetus-specific
compared to Caucasians. For PAPP-A, African
risks can be calculated based on nuchal translucency
Americans have 30% higher levels than Caucasians
and the detection rate should be similar to that
after weight adjustment.
observed in singleton pregnancy. However, each
The effect of assisted reproduction techniques on
fetus will carry an approximate 5% false positive rate
first trimester combined ultrasound and biochemical
and therefore the false positive rate per twin
Down syndrome screening is minimal. Orlandi et al44
pregnancy based on nuchal translucency only is
found that the false positive rate for ICSI (5.2%) and
significantly greater than in singleton pregnancy. For
IVF pregnancies (4.2%) was only slightly higher than
example, in a study by Sebire et al48, 7.3% of fetuses
the false positive rate in naturally conceived
had an increased nuchal translucency. However,
pregnancies (3.3%). Similarly, Liao et al45 found that
among pregnancies, 11.6% had at least 1 twin with
the false positive rate increased by only 1.2 percentage an increased nuchal translucency.
points in IVF pregnancies. Wojdemann et al46 found Incorporating biochemistry into the first trimester
no significant difference in the false positive rates protocol along with nuchal translucency can reduce
among a group of naturally conceived pregnancies the false positive rate. In our own data on a group
(4.9%), IVF pregnancies (4.7%) and ovulation of 212 twin pregnancies the false positive rate was
induction pregnancies (5.1%). reduced from 13.2% using maternal age and nuchal
translucency to 6.6% by also including the bio-
SCREENING IN TWIN PREGNANCY
chemistry.49 Detection efficiency in twin pregnancy
First trimester screening of twin pregnancies offers is difficult to document because Down syndrome
a distinct advantage over second trimester screening affected twin pregnancies are rare. However,
in that it can be used to evaluate the risk of each modeling indicates that combining free beta hCG and
individual fetus. In second trimester screening, which PAPP-A with nuchal translucency can result in 80%
is based on biochemical markers alone, the risk is detection rate for a 7% false positive rate in twin
pregnancy specific. For monozygotic twins, in which pregnancy.49 Therefore it is feasible to screen twin
either both are affected or both are unaffected, pregnancies for Down syndrome in the first
second trimester detection efficiencies can be trimester. However until larger datasets of affected
1096 Textbook of Perinatal Medicine

twin pregnancy are available a caution that risk

estimates in twin pregnancy are less precise than in
singleton pregnancy should be indicated on patient
reports.

FREE BETA HCG VS. INTACT HCG

HCG is a non-covalently bound heterodimeric
glycoprotein consisting of an alpha and beta subunit.
It exists in maternal circulation predominantly as the
biologically active intact dimer. It is also found in
the unbound state as both the free-alpha and free
beta subunits (Fig. 82.1). The genes for the alpha and
beta subunits of hCG are separate and distinct with
the alpha subunit located on chromosome 6 and the Fig. 82.2: Schematic representation of assay commonly
used to measure intact hCG
beta subunit located on chromosome 19. 50 The
separate synthesis and unbalanced secretion of the concentration of intact hCG. During pregnancy
subunits provides the rationale for monitoring levels intact hCG is measurable as early as 5 weeks in
of hCG subunits in obstetricical and gynecological pregnancy making it an excellent indicator of preg-
disorders. Thus, assays for free beta hCG and intact nancy. An immediate and steep increase is observed
hCG measure distinct proteins in the maternal blood. with hCG levels peaking at about 120 IU/ml at 9
Assays used to measure intact hCG are commonly weeks followed by a steady decline to about 20
called “Total Beta” or simply “beta hCG” assays. weeks when concentrations level off at 10-20 IU/ml.
These assays use a capture antibody directed to the Free beta hCG exists in maternal blood at a level
beta subunit of hCG and a detecting antibody of about 1/200th that of intact hCG. Assays that
directed to another epitopic site on the beta subunit measure free beta hCG utilize an epitopic site that is
(Fig. 82.2). As a consequence, these assays detect both located at the interface with the alpha subunit such
intact hCG and free beta hCG. However, since the that it is covered in the intact hCG molecule (Fig.
intact molecule is present in a 200 fold molar excess 82.3). As a result, antibodies directed toward this
relative to the free beta subunit, these assays reflect

Fig. 82.1: Schematic representation of hCG and its free subunits Fig. 82.3: Schematic representation of free beta hCG assay
 First Trimester Maternal Serum Markers of Fetal Anomalies 1097
site capture free beta hCG but not intact hCG which Table 82.5: Median first trimester free beta
is washed away in the assay procedure. hCG MoM in down syndrome cases
Prior to the prospective evaluation of the first Study N Median down
trimester combined screening protocol free beta hCG syndrome MoM
and intact hCG were evaluated in a number of Spencer ‘9267 13 1.85
Aitken ‘9357 16 1.96
studies.29,51-76 Overall, it was seen that intact hCG
Macri ‘9368 38 2.20
was not an effective marker in the first trimester of Brambati ‘9469 13 1.13
pregnancy with a median MoM in 463 cases of Down MacIntosh ‘9458 21 2.10
syndrome of just 1.30 while free beta hCG was an Biagiotti ‘9559 41 2.00
Brizot ‘9560 41 2.00
effective marker with a median MoM of 2.0 based Noble ‘9570 102 2.13
on 858 cases of Down syndrome (Tables 82.4 and Forest ‘9561 12 1.60
82.5). Hallahan et al64, summarized 7 case-control Krantz ‘9671 22 2.09
studies57-60,64-66 in which both intact hCG and free Scott ‘9672 8 2.00
Wald ‘9664 77 1.79
beta hCG were measured in the same samples and Jauniaux ‘9665 17 1.46
showed that free beta hCG detected nearly twice as Berry 9773 47 1.99
many cases of Down syndrome as intact hCG (Table Spencer ‘9774 22 1.72
Haddow ‘9829 48 2.08
82.6). On the basis of these results prospective first
Wheeler ‘9875 17 2.06
trimester screening studies using the combined Spencer ‘9976 210 2.15
protocol have all included free beta hCG. Hallahan ‘0066 63 1.89
Recently, Spencer et. al24,26 have suggested, that Overall 828 2.00
the evaluation of all the Down syndrome markers
should be conducted on a week by week basis since were 7%-11% better than the combination of intact
the performance of the markers varies by gestational hCG and PAPP-A at each gestational week from 10-
age. Spencer et al, showed that the combination of 13 weeks at a corresponding 5% false positive rate
free beta hCG and PAPP-A had detection rates that (Table 82.7).
In a case control study, Wald et al25 modeled the
Table 82.4: Median first trimester intact hCG Multiples of performance of free beta hCG and PAPP-A in
the Median (MoM) values in Down syndrome cases
combination with nuchal translucency. The model
Study Cases Median down
syndrome MoM
indicated that free beta hCG significantly
outperformed intact hCG within the combined
Cuckle ‘8851 22 1.10
Bogart ‘8952 6 1.14 protocol at 10 and 11 weeks gestation but that at 12
Brock ‘9053 21 1.43 weeks the two markers had similar performance and
Johnson ‘9154 11 0.91 that at 13 weeks intact hCG performed better.
Kratzer ‘9155 17 1.23
Van Lith ‘9256 24 1.19
However, Krantz et al77 determined that a more
Aitken ‘9357 16 0.97 appropriate analysis would show that free beta hCG
MacIntosh ‘9458 20 1.45 was better than intact hCG at 10, 11 and 12 weeks
Biagiotti ‘9559 41 1.12 and that the two markers only appear similar in the
Brizot ‘9560 41 1.50
Forest ‘9561 12 1.83 model at 13 weeks. In response, Wald et al 78
Cassals ‘9662 19 1.35 concluded that their data at 13 weeks were probably
Aitken ‘9663 8 1.05 due to chance and that there was an advantage to
Wald ‘9664 77 1.23
using free beta hCG compared to intact hCG in the
Jauniaux ‘9665 17 0.96
Haddow ‘9829 48 1.54 first trimester. An analysis79 combining the results
Hallahan ‘0066 63 1.37 from Spencer et al72 and Wald et al23 demonstrated
Overall 463 1.30 that using free beta hCG was better than intact hCG
1098 Textbook of Perinatal Medicine

Table 82.6: Meta–analysis of intact hCG vs. free beta hCG in case control studies in
which both analytes were measured in the same sample set
Intact hCG Free beta hCG
N Unaffected DS cases Unaffected DS cases
%DS A %DS A
Study Unaff DS Median SD Median SD >95th Median SD Median SD >95th
%tile %tile
Aitken et al., 199357 320 16 1.0 0.2190 0.97 0.3150 11.8% 1.0 0.2580 1.96 0.2560 30.3%
Macintosh et al., 199458 258 21 1.0 ——- 1.45 0.4512 ——- 1.0 ——- 2.10 0.4280 ——-
Biagiotti et al., 199559 246 41 1.01 0.2458 1.12 0.2555 8.2% 1.0 0.2208 2.00 0.2294 39.3%
Brizot et al., 199560 394 41 1.0 0.2054 1.50 0.1939 20.2% 1.0 0.2911 2.00 0.3168 28.7%
Wald et al., 1996B 64 383 77 1.0 ——- 1.23 0.1957 13.0% 1.0 0.2833 1.79 0.2870 22.9%
Jauniaux et al., 199665 51 17 1.0 0.2375 0.96 0.1347 0.0% 1.0 0.3474 1.46 0.1673 0.1%
Hallahan et al., 200066 400 63 1.0 0.1697 1.37 0.2158 25.5% 1.0 0.2157 1.89 0.2322 36.8%
Overall 2052 276 1.0 0.2083 1.27 0.2421 16.2% 1.0 0.2545 1.89 0.2782 30.4%
A
Based on normal distribution parameters.
B
Author provided observed %DS cases > 95th percentile for intact hCG
—— indicates data was not available.
Reprinted from: Hallahan T, Krantz D, Orlandi F, Rossi C, Curcio P, Macri S, Larsen J, Buchanan P, Macri J. First Trimester
Biochemical Screening for Down Syndrome: Free beta hCG versus Intact hCG. Prenat Diagn 2000;20:785-89.66

in a protocol that includes PAPP-A and nuchal specimen is collected and forwarded to the laboratory
translucency at 10-13 weeks. When false positive rates along with the ultrasound information. The
were evaluated the difference between the two biochemical analytes are analyzed in the laboratory
markers was even more apparent. For example at 10 and risk results based on free beta hCG, PAPP-A
weeks, the false positive rate with free beta hCG and nuchal translucency are available usually within
was half that of intact hCG (Table 82.8). a few days.

SCREENING STRATEGIES ONE STOP CLINIC FOR THE ASSESSMENT

OF RISK (OSCAR)
First trimester screening is usually conducted
between 11 weeks 1 day and 13 week 6 days The OSCAR approach represents a procedural
gestation. In general, the patient comes in for an variation of first trimester screening in which the
ultrasound exam, CRL is measured for accurate blood sample is collected and analyzed on a rapid
gestational dating and a nuchal translucency value is Table 82.8: Free beta hCG vs. Intact hCG within a Down
obtained. At the time of the ultrasound exam a blood syndrome protocol including PAPP-A and nuchal
translucency and maternal age
Table 82.7: Comparison of the performance of free beta
Detection rate at False positive rate
hCG vs Intact hCG in combination with PAPP-A and
a 5% false positive at a fixed 85%
maternal age in first trimester screening using an
rate detection rate
overall 5% false positive rate
Gestational Age Intact Free Intact Free
Intact hCG Free beta hCG hCG beat hCG beta
+ PAPP-A + PAPP-A hCG hCG
Gestational Age FP DR FP DR
10 84% 88% 6.0% 3.1%
10 4.7 58 4.7 69 11 83 86 6.7 4.1
11 4.9 56 4.8 67 12 82 86 6.9 4.3
12 5.1 56 5.0 65 13 85 85 5.1 4.7
13 5.2 56 5.3 63
Analysis79 performed using results from Spencer et al 24,26 and
Data from Spencer et al26 Wald et al25.
 First Trimester Maternal Serum Markers of Fetal Anomalies 1099
assay instrument during the patient’s ultrasound tricuspid valve regurgitation for those specific
appointment. The advantage of this modality is that patients that have a borderline risk.
the biochemical result is ready during the patient’s
visit allowing her to have her combined risk result INDEPENDENT SEQUENTIAL SCREENING
immediately with the option of having CVS the same The first trimester combined screening test with free
day. This screening strategy is currently practiced beta hCG, PAPP-A and nuchal translucency can
very effectively in many European clinics.11,13 The detect approximately 90% of Down Syndrome
disadvantage is that in order to analyze the pregnancies with a 5% false positive rate. In
biochemistry specialized equipment and personnel sequential testing both first trimester screening and
are required at the ultrasound center. Therefore, this second trimester multiple marker screening are
strategy is best suited for settings with high volume performed independently. In this case, the false
in order for the biochemical screening to be cost positive rate in first trimester is additive with the
effective. The rapid assays needed to provide a blood false positive rate in second trimester. For example
result in under a half hour have not yet been in the BUN study, a group that contained about 50%
approved by the FDA and are therefore not currently advanced maternal age patients, 9.9% of patients had
available in the United States. Even with the rapid increased risk results in the first trimester and
assays the total time required to interview the patient, another 9.0% had increased risk results in the second
draw a blood specimen, allow time for clotting and trimester.80 Thus the overall false positive rate for
centrifugation, perform the biochemical assays and the screening program using data in both trimesters
conduct the ultrasound examination could easily last was nearly doubled.
more than one hour. Further the burdens of data
entry, quality control and risk assessment in this MODIFIED SEQUENTIAL SCREENING
modality are all the responsibility of the ultrasound
Alternatively, the Down syndrome risk can be
clinic.
calculated based on both the first and second
FINGER STICK BLOOD COLLECTION WITH trimester markers. Such an approach can reduce the
INSTANT RISK ASSESSMENT (IRA) increase in the false positive rate compared to the
independent sequential approach described above.
IRA is a variation of the OSCAR approach that takes However, sophisticated software is required to
advantage of the simplified blood collection and ensure that the patient’s results in the second
transport of dried blood. In this approach, patients trimester are appropriately matched with those from
draw their own blood at home about 1 week before the first trimester.
their ultrasound appointment using a sterile lancet The modified sequential screening approach
and a dried blood collection card. The sample is requires 95% of the population to return for second
mailed to the laboratory and the biochemical results trimester multiple marker screening. A refinement
are ready in time for the ultrasound exam. Like the to this approach could be to offer second trimester
OSCAR approach the risk results are available screening only to those patients with a borderline
immediately at the conclusion of the ultrasound exam result.81 For example, those patients with very high
but with IRA the ultrasound center has no need for risks (e.g. greater than 1 in 100) in the first trimester
specialized equipment and personnel. Additional can be immediately offered CVS. Those patients with
time is not required for drawing blood and waiting low risk (e.g. less than 1 in 1500) can be reassured
for a biochemical result. That time may be better that no further screening is necessary. Patients with
spent performing more detailed ultrasound borderline first trimester risks (e.g. between 1 in 100
evaluations such as ductus venosus, nasal bone and and 1 in 1500) could be offered second trimester
1100 Textbook of Perinatal Medicine

multiple marker screening and have their final risk CONCLUSION

calculated based on the marker results in both the
One of the first questions that expectant parents ask
first and second trimester. This so-called “contin-
after discovering they are pregnant is “Will my baby
gency” screening approach has the advantage of be normal?”. Although there are no guarantees that
reducing by as much as 75% the number of second a baby will be healthy, screening can reassure the
trimester screening tests that are performed, vast majority of couples that they are not likely to
reducing the overall cost of the screening program have a baby with a major birth defect. Along with
and minimizing the number of added false positives the benefits of early reassurance and diagnosis, first
generated by second trimester testing.81 trimester screening with free beta hCG, PAPP-A and
The sequential screening approaches outlined nuchal translucency has raised the standards in terms
above have been described with respect to multiple of detection efficiency. As a result, the ability to
marker serum screening in the second trimester. screen for Down syndrome and trisomy 18 in the
Nyberg et al82 and Bromley et al83 have determined first trimester of pregnancy represents the most
likelihood ratios for second trimester ultrasound significant advancement in prenatal screening in the
markers. Any of the sequential screening metho- past 10 years.
dologies described above could be conducted by
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chorionic gonadotrophin and pregnancy associated KH. First-trimester screening for trisomy 21 in singleton
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Complications. Br J Obstet Gynecol 2000;107:1265-1270. Reprod. 2001;16:1501-4.
33. Tul N, Pusenjak S, Osredkar J, Spencer K, Novak-Antolic 46. Wojdemann KR, Larsen SO, Shalmi A, Sundberg K,
Z. Predicting Complications of Pregnancy with First- Christiansen M, Tabor A. First trimester screening for
Trimester Maternal Serum free beta hCG, PAPP-A and Down syndrome and assisted reproduction: no basis for
Inhibin A. Prenat Diagn 2003;23:990-996. concern. Prenat Diagn. 2001;21:563-5.
34. Yaron Y, Heifetz S, Ochshorn Y, Lehavi O, Orr-Urteger 47. Spencer K, Salonen R, Muller F. Down’s syndrome
A. Decreased First Trimester PAPP-A is a Predictor of screening in multiple pregnancies using alpha-feto-
Adverse Pregnancy Outcome. Prenat Diagn 2002;22:778- protein and free beta hCG. Prenat Diagn. 1994;14:537-
782. 42.
35. Pedersen JF, Sorensen S, Ruge S. Human Placental 48. Sebire NJ, Snijders RJ, Hughes K, Sepulveda W,
Lactogen and Pregnancy-Associated Plasma Protein A Nicolaides KH. Screening for trisomy 21 in twin
in First Trimester and Subsequent Fetal Growth. Acta pregnancies by maternal age and fetal nuchal trans-
Obstet Gynecol Scand 1995;74:505-508. lucency thickness at 10-14 weeks of gestation. Br J Obstet
36. Smith GCS, Stenhouse EJ, Crossley JA, Aitken DA, Gynaecol. 1996;103:999-1003.
Cameron AD, Connor JM. Early Pregnancy Origins of 49. Orlandi F, Krantz DA, Hallahan TW, Buchanan PD,
Low Birth Weight. Nature 2002;417:916. Larsen JW. First-Trimester Down syndrome screening
37. Smith GCS, Stenhouse EJ, Crossley JA, Aitken DA, in twins. Am J Hum Genet 2000;67 (Suppl): Abstact 155.
Cameron AD, Connor JM. Early Pregnancy Levels of 50. Naylor SL, Chin WW, Goodman HM, Lalley PA,
Pregnancy-Associated Plasma Protein A and the Risk Grzeschik KH, Sakaguchi AY. Chromosome assignment
of Intrauterine Growth Restriction, Premature Birth, of genes encoding the alpha and beta subunits of
Preeclampsia, and Stillbirth. J Clin Endocrinol Metab glycoprotein hormones in man and mouse. Somatic Cell
2002;87:1762-1767. Genet. 1983;9:757-70.
38. Yaron Y, Ochshorn Y, Heifetz S, Lehavi O, Sapir Y, Orr- 51. Cuckle HS, Wald NJ, Barkai G, Fuhrmann W, Altland
Urtreger A. First trimester maternal serum free human K, Brambati B, Knight G, Palomaki G, Haddow JE,
chorionic gonadotropin as a predictor of adverse Canick J. First-Trimester Biochemical Screening for
pregnancy outcome. Fetal Diag Ther 2002;17:352–6. Down syndrome. Lancet 1988;2:851-852.
39. Morssink LP, Kornman LH, Hallahan TW, Kloosterman 52. Bogart MH, Golbus MS, Sorg ND, Jones OW. Human
MD, Beekhuis JR, de Wolf BTHM, Mantingh A. Maternal Chorionic Gonadotropin Levels in Pregnancies with
serum levels of Free beta hCG and PAPP-A in the First Aneuploid Fetuses. Prenat Diagn 1989;9:379-384.
Trimester of Pregnancy are not Associated with 53. Brock DJ, Barron L, Holloway S, Liston WA, Hillier SG,
Subsequent Fetal Growth Retardation or Preterm Seppala M. First-trimester maternal serum biochemical
Delivery. Prenat Diagn. 1998;18:147-152. indicators in Down syndrome. Prenat Diagn 1990;10:245-
40. Goetzl L, Krantz D, Simpson JL, Silver RK, Zachary JM, 251.
Pergament E, Platt LD, Mahoney MJ, Wapner RJ. 54. Johnson A, Cowchock FS, Darby M, Wapner R, Jackson
Pregnancy-associated plasma protein A, free beta-hCG, LG. First-Trimester Maternal Serum Alpha-Fetoprotein
 First Trimester Maternal Serum Markers of Fetal Anomalies 1103
and Chorionic Gonadotropin in Aneuploid Pregnancies. 67. Spencer K, Macri JN, Aitken DA, Connor JM. Free beta-
Prenat Diagn 1991;11:443-450. hCG as First-Trimester Marker for Fetal Trisomy.
55. Kratzer PG, Golbus MS, Monroe SE, Finkelstein DE, Lancet 1992;339:1480.
Taylor RN. First-Trimester Aneuploidy Screening Using 68. Macri JN, Spencer K, Aitken DA, Garver K, Buchanan
Serum Human Chorionic Gonadotropin (hCG), free PD, Muller F, Boue A. First-Trimester Free beta (hCG)
ahCG and progesterone. Prenat Diagn 1991;11:751-763. Screening for Down Syndrome. Prenat Diagn 1993;
56. Van Lith JMM. First-Trimester maternal serum human 13:557-562.
chorionic gonadotrophin as a marker for fetal 69. Brambati B, Tului L, Bonacchi I, Shrimaker K, Suzuki Y,
chromosomal disorders. The Dutch Working Party on Grudzinskas JG. Serum PAPP-A and free beta hCG are
Prenatal Diagnosis. Prenat Diagn 1992;12:495-504. first trimester screening markers for Down syndrome.
57. Aitken DA, MCCAW G, Crossley JA, Berry E, Connor Prenat Diagn 1994;14:1043-47.
JM, Spencer K, Macri JN. First-Trimester Biochemical 70. Noble PL, Abraha HD, Snijders RJ, Sherwood R,
Screening for Fetal Chromosome Abnormalities and Nicolaides KH. Screening for fetal trisomy 21 in the first
trimester of pregnancy: maternal serum free beta-hCG
Neural Tube Defects. Prenat Diagn 1993;13:681-689.
and fetal nuchal translucency thickness. Ultrasound
58. Macintosh MCM, Iles R, Teisner B, Sharma K, Chard T,
Obstet Gynecol 1995;6:390-95.
Grudzinskas JG, Ward RHT, Muller F. maternal serum
71. Krantz DA, Larsen JW, Buchanan PD, Macri JN. First-
human chorionic gonadotrophin and pregnancy
Trimester Down syndrome screening: Free beta-human
associated plasma protein A, markers for fetal Down chorionic Gonadotropin and pregnancy-associated
syndrome at 8-14 weeks. Prenat Diagn 1994;14:203-208. plasma protein A. Am J Obstet Gynecol 1996;174:612-
59. Biagiotti R, Cariati E, Brizzi L, Dagata A. Maternal serum 616.
screening for Down’s syndrome in the first trimester 72. Scott F, Wheeler D, Sinosich M, Boogert A, Anderson J,
of pregnancy. Br J Obstet Gynecol 1995;102:660-662. Edelman D. First Trimester Aneuploidy Screening Using
60. Brizot ML, Snijders RJ, Butler J, Bersinger NA, Nicolaides Nuchal Translucency, Free beta Human Chorionic
KH. Maternal serum hCG and fetal nuchal translucency Gonadotropihin and Maternal Age. Aust NZ J Obstet
thickness for the prediction of fetal trisomies in the first Gynaecol 1996;36:381384.
trimester of pregnancy. Br J Obstet Gynaecol 1995; 73. Berry E, Aitken DA, Crossley JA, Macri JN, Connor JM.
102:127-132. Screening for Down’s syndrome: Changes in Marker
61. Forest JC, Masse J, Rousseau F, Moutquin JM, Brideau Levels and Detection rates between First and Second
NA, Belanger M. Screening for Down syndrome During Trimester. Br J Obstet Gynaecol 1997;104:811-817.
the First and Second Trimesters: Impact of Risk Esti- 74. Spencer K, Noble PL, Snijders RJM, Nicolaides KH.
mation Parameters. Clin Biochem 1995;28:443-449. First-Trimester Urine Free beta hCG, Beta Core, and
62. Casals E, Fortunoy A, Grudzinskas JG, Suzuki Y, Teisner Total Oestriol in Pregnancies affected by Down’s
B, Comas C, Sanllehy C, Ojuel J, Borrel A, Soler A, syndrome: Implications for First-Trimester Screening
Ballesta Am. First-Trimester biochemical screening for with Nuchal Translucency and Serum Free beta hCG.
Down syndrome with the use of PAPP-A, AFP, and Prenat Diagn 1997;17:525-538.
75. Wheeler DM, Sinosich MJ. Prenatal Screening in the first
beta-hCG. Prenat Diagn 1996;16:405-410.
trimester of Pregnancy. Prenat Diagn 1998;18:537-543.
63. Aitken DA, Wallace EM, Crossley JA, Swanston IA, Van
76. Spencer K, Souter V, Tul N, Snijders R, Nicolaides KH.
Pareren Y, Maarle MV, Groome NP, Macri JN, Connor
A screening program for trisomy 21 at 10-14 weeks
JM. Dimeric Inhibin A as a Marker for Down’s Syndrome using fetal nuchal translucency, maternal serum free
in Early Pregnancy. N Engl J Med 1996;334:1231-36. beta human chorionic gonadotropin and pregnancy
64. Wald NJ, George L, Smith D, Densem JW, Petterson K. associated plasma protein-A. Ultrasound Obstet Gynecol
Serum screening for Down’s syndrome between 8 and 1999;13:231-237.
14 weeks of pregnancy. International Prenatal Screening 77. Krantz DA, Hallahan TW, James Macri V, Macri JN.
Research Group. Br J Obstet Gynaecol. 1996 May;103(5): Statistical flaw in SURUSS model. Prenat Diagn.
407-12. 2004;24:753-4 (Letter).
65. Jauniaux E, Nicolaides KH, Nagy AM, Brizot M, Meuris 78. Wald N, Rodeck C, Hackshaw A, Rudnicka A.
S. Total Amount of Circulating Human Chorionic Correlations between nuchal translucency and serum
Gonadotrophin Alpha and Beta Subunits in First markers in SURUSS. Prenat Diagn 2004;24:835-836
Trimester Trisomies 21 and 18. Journal of Endocrinology (Letter).
1996;148:27-31. 79. Bloom P (Ed). Free beta or Intact hCG. DS News
66. Hallahan T, Krantz D, Orlandi F, Rossi C, Curcio P, 2004;11:37.
Macri S, Larsen J, Buchanan P, Macri J. First Trimester 80. Platt LD, Greene N, Johnson A, Zachary J, Thom E,
Biochemical Screening for Down Syndrome: Free beta Krantz D, Simpson JL, Silver RK, Snijders RJ, Goetzl L,
hCG versus Intact hCG. Prenat Diagn 2000;20:785-89. Pergament E, Filkins K, Mahoney MJ, Hogge WA,
1104 Textbook of Perinatal Medicine

Wilson RD, Mohide P, Hershey D, MacGregor S, Bahado- 86. Orlandi F, Bilardo CM, Campogrande M, Krantz D,
Singh R, Jackson LG, Wapner R; First Trimester Hallahan T, Rossi C, Viora E. Measurement of Nasal
Maternal Serum Biochemistry and Fetal Nuchal Bone Length at 11-14 Weeks of Pregnancy and Its
Translucency Screening (BUN) Study Group. Sequential Potential Role in Down Syndrome Risk Assessment.
pathways of testing after first-trimester screening for Ultrasound Obstet Gynecol 2003;36-39.
trisomy 21. Obstet Gynecol. 2004;104:661-6. 87. Otano L, Aiello H, Igarzabal L, Matayoshi T, Gadow EC.
81. Wright D, Bradbury I, Benn P, Cuckle H, Ritchie K. Association Between First Trimester Absence of Fetal
Contingent screening for Down syndrome is an efficient Nasal Bone on Ultrasound and Down syndrome. Prenat
alternative to non-disclosure sequential screening. Diagn 2002;22:930-932.
Prenat Diagn. 2004;24:762-6. 88. Viora E, Masturzo B, Errante G, Sciarrone A, Bastonero
S, Campogrande M. Ultrasound Evaluation of Fetal
82. Nyberg DA, Souter VL, El-Bastawissi A, Young S,
Nasal Bone at 11 to 14 Weeks in a Consecutive Series
Luthhardt F, Luthy DA. Isolated sonographic markers
of 1906 Fetuses. Prenat Diagn 2003; 784-787.
for detection of fetal Down syndrome in the second
89. Zoppi MA, Ibba RM, Axianna C, Floris M, Manca F,
trimester of pregnancy. J Ultrasound Med. 2001;20:1053- Monni G. Absense of Fetal Nasal Bone and Aneuploidies
63. at First-Trimester Nuchal Translucency Screening in
83. Bromley B, Lieberman E, Shipp TD, Benacerraf BR. The Unselected Pregnancies. Prenat Diagn 2003;23:496-500.
genetic sonogram: a method of risk assessment for 90. Cicero S, Bindra R, Rembouskas G, Spencer K,
Down syndrome in the second trimester. J Ultrasound Nicolaides KH. Integrated Ultrasound and Biochemical
Med. 2002;21:1087-96. Screening for Trisomy 21 using Fetal Nuchal
84. Cicero S, Curcio P, Papageorghiou A, Sonek J, Nico- Translucency, Absent Fetal Nasal Bone, free beta hCG
laides K. Absense of Nasal Bone in Fetuses with Trisomy and PAPP-A at 11-14 weeks. Prenat Diagn 2003;23:306-
21 at 11-14 Weeks of gestation: an Observational Study. 310.
Lancet 2001;358:1665-1667. 91. Malone FD, Ball RH, Nyberg DA, Comstock CH, Saade
85. Cicero S, Rembouskos G, Vandecruys H, Hogg M, G, Berkowitz RL, Dugoff L, Craigo SD, Carr SR, Wolfe
Nicolaides KH. Likelihood Ratio for Trisomy 21 in HM, Tripp T, D’Alton ME. First-trimester nasal bone
Fetuses with Absent Nasal Bone at the 11-14 Week Scan. evaluation for aneuploidy in the general population.
Ultrasound Obstet Gynecol 2004;23:218:223. Obstet Gynecol. 2004;104:1222-8.
 83
Influence of Ethnicity on
Prenatal Screening

Farah Sethna , Basky Thilaganathan

INTRODUCTION Prenatal screening allows women to make

informed decisions about their reproductive choices.
With each passing day the western world becomes
The vast majority of structural and chromosomal
increasingly multicultural, multiethnic and multi-
abnormalities arise in pregnancies without any risk
lingual. Statistics from the last census (2001) to be
factors. Therefore aneuploidy and anomaly screening
carried out in the UK revealed that 7.9% of the
is offered to all women. However, certain genetic
population (4.6 million people) were from a minority
disorders occur with an increased frequency, or are
background, with the majority being from the Indian
confined to certain ethnic groups, and in these cases
subcontinent or Africa and the Caribbean. 1 In
screening will be targeted at these individuals. It is
comparison, in the United States, approximately 28%
important to ensure that prenatal screening is
of the population at the present time are from a
available and accessible equally to all women
minority background (African Americans, Hispanics,
regardless of their background. This chapter will be
Asians, Pacific Islanders, Native Americans and
examining the influence of ethnicity on screening
Alaskan Natives representing the majority).
methods within the field of prenatal diagnosis,
It is anticipated that immigrants and their
targeted screening in ethnic groups and finally at
descendents will continue to shape and alter the
the effect of ethnicity on uptake of screening.
demographic landscape for several years to come.
Consequently, it can be predicted that women from EFFECTS OF ETHNICITY ON
the ethnic minorities will form a growing proportion SCREENING METHODS
of the obstetric populations of many health districts.
As clinicians assume responsibility for caring for an Down Syndrome
increasingly diverse population, genetic and ethnic Down syndrome is the commonest congenital cause
connections to disease will become clearer. All health of severe mental retardation.2 In developed countries,
professionals must be prepared to meet the challenges there are approximately 100,000 deliveries per year,
such diversity will pose, if a uniform standard of per 10,000,000 of the population. The birth incidence
healthcare is to be provided for all patients. It is of trisomy 21 is about 1 in 500, and therefore in such
important to be aware of the variations in need a population the total number of affected neonates
between individuals within similar communities, and is about 200.3 The incidence of Down syndrome rises
not just across the population as a whole. sharply with increasing maternal age4, however, as
1106 Textbook of Perinatal Medicine

the majority of children are born to women in their between the different ethnic groups in both studies.
twenties and early thirties, 75% of babies with Down The magnitude of the differences was small, ranging
syndrome are born to women in this age group. from 0.08mm to 0.22mm. However, when compared
Screening women of all ages for Down syndrome is to reported nuchal translucency intra-observer and
now common practise in the West. inter-observer variability’s of 0.54mm and 0.62mm
There is substantial variation in screening services respectively 11, the differences are clinically
for Down syndrome throughout the world. Options insignificant. No correction for ethnic origin is
for screening include nuchal translucency measure- therefore required when first trimester nuchal
ment (alone, in combination with first/second translucency screening for Down syndrome is
trimester biochemistry, fetal nasal bone assessment performed in multiethnic populations.
or ductus venous Doppler measurement), maternal
serum screening in the second trimester, or Ductus Venosus
ultrasound for the detection of fetal defects and
There is a clear association between abnormal
markers at 16-23 weeks. The influence of ethic origin
Doppler flow in the ductus venosus (absence/
on screening efficacy by each of these modalities will
reversed) and fetal aneuploidy. The use of ductus
now be examined in turn.
venosus Doppler velocimetry in combination with
nuchal translucency is better than either test alone,
Nuchal Translucency
since it increases the sensitivity in the detection of
Babies born with Down syndrome show a distinct Down syndrome to 94% and decreases the likelihood
set of physical characteristics. Langdon Down first ratio of a negative test to 0.08.12 Although, the effect
reported in 1866 that the skin of individuals with of ethnicity on ductus venosus Doppler indices are
trisomy 21 appeared to be too large for their bodies.5 unknown, this screening method is so technically
This excess skin, in the form of nuchal translucency demanding that it is only likely to be performed on
thickness, has formed the basis of one of the main selected high-risk populations.
non-invasive prenatal tests for this disorder since
the early 1990’s. Since this time, the association Nasal Bone
between increased nuchal translucency at 11-14
In 2001 Cicero and colleagues demonstrated the
weeks gestation and chromosomal abnormality has
been well established and documented (6-8). For an possibility of using absence of the nasal bone at 11-
invasive testing rate of 5%, about 75% of trisomic 14 weeks as a marker for Down syndrome. They
pregnancies can be identified using this method of examined 701 routine ultrasound scans performed
screening alone. Two studies have shown that nuchal on women about to undergo prenatal diagnosis
translucency screening can be effectively and because of positive results on nuchal translucency
equitably delivered to a multiethnic population. screening.13 The same group subsequently reported
Thilaganathan et al performed an observational study that nasal bones were absent in about 3% of
in a district general hospital with a large multiethnic chromosomally normal fetuses, in two-thirds of those
population serving African, Asian, Caribbean and with trisomy 21 and in about one third of babies
Caucasian women. 9 In comparison, Chen et al with other chromosomal defects.14 The estimated
examined the effect of ethnic origin on nuchal likelihood ratio for trisomy 21 in the latter study
translucency in a multiethnic Asian population was over 120 when the nasal bone cannot be seen.
comprised of Chinese, Indian, Pakistani, Nepalese Given the significance of this ratio, and before nasal
and Filipino women.10 Significant differences in the bone assessment is integrated into routine screening
nuchal translucency measurement were obtained programs, knowledge about how to correct for
 Influence of Ethnicity on Prenatal Screening 1107
ethnicity is required if this test is to be used equitably absence of the nasal bones. However, as both parents
in multiethnic populations. contribute to a baby’s phenotypic appearance, it
It is known that morphometry of the splanchno- remains to be determined whether any correction is
cranium, and of nasal bones in particular, differs also required for the father’s ethnic origin.
between adults of various ethnic origins.15 Likewise,
ethnicity is known influence whether the nasal bones Second Trimester Maternal Serum Screening
are seen in second trimester fetuses. It has been shown In 1984, a major advance in screening for
that second-trimester nasal bone hypoplasia is chromosomal defects was made by Merkatz et al who
commoner in fetuses of Afro-Caribbean mothers than reported low levels of maternal serum alpha-
in Caucasian mothers.16 More recently, studies have fetoprotein (AFP) in trisomy 21 pregnancies.19 Since
demonstrated a similar significant difference in the this time, prenatal screening for trisomy 21 based on
rate of visualisation of the fetal nasal bones in the the analysis of biochemical markers in maternal
first trimester in chromosomally normal fetuses in
serum between 15 and 22 weeks of pregnancy has
mothers of different ethnic origins. 17
become an established part of obstetric practice. The
In 2004 Cicero et al. produced data to update the
principal markers found to be of value are AFP, total
likelihood ratio for trisomy 21 in fetuses with absent
human chorionic gonadotrophin (hCG) (or it’s
nasal bone at the 11-14 week scan. They examined
individual subunits: free β-hCG and free α-hCG),
5918 pregnancies undergoing first trimester
unconjugated estriol (uE3) and dimeric inhibin A. On
karyotyping and found that the incidence of absent
average, in Down syndrome affected pregnancies,
nasal bone was higher in fetuses of Afro-Caribbean
the AFP and uE3 levels are about three-quarters that
and Asian origin than in Caucasians, it decreased
of an unaffected pregnancy (MoM < 0.84), whereas
with increasing fetal CRL and increased with
inhibin A and free β-hCG levels are about double
increased fetal NT.18 The authors provided data on
(MoM > 1.3 and >1.6 respectively). Most screening
the incidence of absent nasal bone in chromosomally
programmes use multiple markers in combination
normal and trisomy 21 fetuses and likelihood ratios
with maternal age to generate a risk. Performance is
according to ethnic group (see Table 83.1).
known to vary according to the choice of markers
Table 83.1: The prevalence of absent nasal bones (NB) in used and whether ultrasound has been used to
normal and aneuploid pregnancies and their associated
determine the gestational age. When the latter is used
likelihood ratios (LR) for trisomy 21
in combination with maternal age, the detection rate
Caucasian Afro-Caribbean Asian
for a 5% false-positive rate is estimated to be 59%
Number 5284 170 201 for the double test (AFP and either total hCG or free
Absent NB in 68.3% 78.6% 71.4%
β-hCG), 69% for the triple test (AFP, total hCG, uE3)
aneuploid
fetuses and 76% for the quadruple test (AFP, hCG, uE 3,
Absent NB in 2.2% 9.0% 5.0% inhibin A).
normal fetuses The results of second trimester maternal serum
LR for trisomy 31.3 8.8 14.2
21 with absent biochemistry are expressed as multiple of the median
NB (MoM) values for gestation. MoM values normalise
LR for trisomy 0.32 0.24 0.3 results for gestation to provide an equivalent
21 with NB
measure between laboratories. The majority of
(Table adapted from Cicero et al. 2004) published population data used to derive median
values for the individual markers relate to European
This data suggest that appropriate corrections and American Caucasian populations. The degree of
may be applied for maternal ethnic origin and the risk to an individual pregnant woman relies on
1108 Textbook of Perinatal Medicine

combining the results with maternal age in a complex Correcting for ethnic origin has a small overall
mathematical algorithm using commercially available effect on screening performance. The detection rate
software programs. The test is interpreted as positive increases by about 0.5 % for a false positive rate of
or negative according to whether or not risk exceeds 5%22. Having said that, the adjustment is worthwhile
a fixed cut-off point. It is known that smoking, because it does not require resources and because of
maternal weight, parity, previous pregnancy results, it’s established value in screening for open neural
multiple pregnancy, and insulin dependent diabetes tube defects using serum AFP, where the false
can influence the concentration of the markers. It has positive rate is higher in Asian and Black women
been proposed that adjusting the risk algorithm, by compared to white women for a fixed AFP cut off
taking into account these factors, can lead to an level. In fact, The American College of Medical
improvement in detection efficiency, although to Genetics recommends that a correction be made
what extent is not clear.
when also screening for NTD.23 If Down screening
Another factor known to have an impact on the
is being carried out in isolation and no risk for NTD
biochemical marker levels is ethnic origin. Gilbert et
is being provided to the mother it could be argued
al20 raised the issue that racial differences existed in
that an adjustment for ethnicity need not be made
both age ranges for Down syndrome and in the
because of the counterbalancing effect that of the
medians for biochemical markers. They proposed
different analytes used in combination. For example,
that outcome data on serum screening should be
collected by ethnic groups, so that validated risk a Hispanic patient screened at 16 weeks with median
estimations could be formed, thereby making serum values (1.00 MoM) of AFP, hCG and uE3 when
screening in ethnic groups more effective. interpreted against a Hispanic patient derived
There have been several publications documenting dataset. If a primary white population dataset had
differences in the marker levels in Afro-Caribbean, been used her AFP value would have remained the
South Asian, Oriental and Hispanic women compared same, hCG would have been 1.06 MoM and the uE3
to White women. Maternal serum AFP and hCG value 1.12 MoM. Although the higher hCG MoM
levels have been shown to be approximately 10-15% would increase the Down risk, the higher uE3 MoM
higher in black women compared to Caucasian value would counteract to reduce the risk.
women. In contrast, uE3 levels hardly differ, and
dimeric inhibin-A levels are about 8% lower in First Trimester Maternal Serum Screening
pregnancies in African Women. One of the largest All the serum markers used or considered in the
published study’s21 evaluated data from more than second trimester have been assessed in Down
21000 pregnancies to determine the extent of race-
syndrome and unaffected pregnancies during the
specific differences in median concentrations of
first trimester. Only two serum markers have stood
analytes used in the triple test. This study found that
out as being useful in screening at 11-14 weeks,
at most gestational ages, median AFP, hCG and uE3
namely, pregnancy-associated plasma protein-A
values for White, Black, Hispanic and other patients
(PAPP-A) and free β-hCG. Maternal serum PAPP-A
were all significantly different. Further, these
levels are lower in pregnancies affected by trisomy
differences remained significant even after the data
21, with the difference in PAPP-A levels between
was corrected for patient weight. For the individual
trisomy 21 and normal pregnancies decreasing with
analytes the extent of the variation was not the same
at different gestational ages. It is important that increasing gestational age. In comparison, the
screening laboratories follow the literature to keep maternal serum free β-hCG level is higher in trisomy
abreast of new findings to ensure that they continue 21 pregnancies, and the difference in levels between
to provide the best possible screening service for unaffected and affected pregnancies increases with
women from minority backgrounds. advancing gestation.24
 Influence of Ethnicity on Prenatal Screening 1109
The consensus estimate of screening performance robust methods of correcting for ethnic origin and
by using PAPP-A and free β-hCG in combination with to assess the biological significance of such marker
maternal age is a 60% detection rate with a 5% false production between various ethnic groups.
positive rate. This is similar to the screening
performance of second trimester double markers, but 16-23 Week Ultrasound Scan
not as good as the screening performance of second If the mid-trimester 16-23 week scan demonstrates
trimester triple or quadruple markers. However, major structural defects it is advisable to offer fetal
there is a significant improvement in screening karyotyping, even if these defects are isolated. The
efficiency when biochemistry analysis is combined prevalence of these defects is low and therefore the
with ultrasound in the first trimester. This form of financial cost implications are relatively small. Even
screening can be provided in the setting of a one- if the defect is potentially correctable by surgery,
stop clinic for assessment of risk (OSCAR), and is such as exomphalos, it would seem appropriate to
associated with a detection rate of about 90%, when exclude an underlying chromosomal abnormality.
the fetal nuchal translucency is also measured. The management policy for major fetal structural
In 2000, Spencer et al. examined the influence of abnormality is unlikely to require changing on an
ethnic origin on first trimester biochemical markers ethnic basis. The same does not follow for the so-
of chromosomal abnormalities. It was seen that the called ‘minor’ markers of chromosomal abnormality.
median maternal serum marker MoMs for free β- Minor defects or markers are common and they
hCG and PAPP-A were 19% and 48% higher in Afro- are not usually associated with any handicap, unless
Caribbean women, and 19% and 35% higher in Asian there is an associated chromosomal abnormality.
women compared to Caucasian women. Correcting Most practitioners adopt an individualized approach
for maternal weight made very little difference to to the assessment of risk depending on the marker
the Afro-Caribbeans (21% and 57% higher after identified either using the appropriate likelihood
weight correction), but reduced the effect in Asians ratio or a genetic sonogram score. 3 In high-risk
(4% and 17% higher after weight correction). populations as defined by advanced maternal age or
Correcting first-trimester biochemical markers for positive maternal serum biochemistry, this approach
maternal ethnicity and weight has little impact at the has been shown to maintain a high sensitivity for
population level for detection rates (an increase in fetal aneuploidy without significantly increasing the
the overall detection rate by a mere 1.4%). However, invasive prenatal testing rate.
the effect on the individual patient-specific risk can However, routine karyotyping of all low-risk
be substantial (up to a two fold increase), and can pregnancies with these markers would have major
certainly make a difference to the patient’s decision implications, both in terms of miscarriage and
on whether to have an invasive test. For example, in financial costs. As a general concern, this process of
a 67Kg, 25-year old Afro-Caribbean, with an sequential screening assumes the unproven
uncorrected free β-hCG of 2.10 MoM, and a PAPP- independence between the findings of different
A of 0.65 MOM, the risk for trisomy 21 without screening results. For example, second trimester
correction for weight and ethnicity would be 1 in intracardiac echogenic foci are known to increase in
540. After correction the free β-hCG MoM would be prevalence when first trimester nuchal translucency
1.73, whilst the PAPP-A MoM would be 0.41, with measurements are elevated in fetuses of normal
a corrected screening risk of 1:260. 25 karyotype. 26 Hence, prior screening test results
It would appear that ethnic origin has a greater should be followed until data evaluating the
impact on first trimester biochemical markers than interdependence of such markers become available.
second trimester biochemical markers. However, Additionally, only a few have attempted to
further larger data sets are required to develop evaluate ethnic variation in such minor markers for
1110 Textbook of Perinatal Medicine

fetal aneuploidy. Despite this, they have all invariably frequently than in the general population. Small
established significant ethnic variations in prevalence genetic differences are known to exist between
of the markers such as nasal bone, intracardiac individuals from different ethnic groups. Certain
echogenic foci, humeral, and femoral length. 27-33 ethnic groups have a higher risk of certain genetic
Hence, if these markers are to be used for modulating conditions, especially autosomal recessive disorders,
the risk of fetal chromosomal abnormality, the ethnic than the general population. Prenatal diagnosis is
influence of the exact markers used need to be available for many genetic conditions, and a growing
evaluated. In the long-term, it would seem more number of women are seeking advice regarding
reliable to use first trimester nuchal translucency and prenatal testing for a present or planned pregnancy.
maternal serum biochemistry, where corrections are Knowledge of a patient’s ethnicity can therefore help
not required or are easily made. make a diagnosis, or help to identify individuals or
couples at an increased risk of having a child with a
Neural Tube Defects
specific genetic condition. The American College of
Neural tube defects (NTDs) have a complex aetiology Obstetricians and Gynecologists (ACOG) recom-
in which both genetic and environmental factors mends genetic counselling for couples at increased
appear to be involved. Analysis of recurrence risk for birth defects. Counselling enables the couple
patterns within families and of twin-concordance data to become more informed about the disorders
provides evidence of a genetic influence in sporadic involved, the current availability of prenatal and
cases, but factors such as socioeconomic status and postnatal testing, the accuracy and limitations of such
geographic area (independent of race or ethnicity) testing, and their reproductive options.36
are also associated with variations in the incidence
of NTDs. Furthermore, exposure in pregnancy to “Jewish” Genetic Disorders
various drugs, most commonly antiepileptics, are
associated with increased risk for NTDs. Recently, The “Jewish” genetic disorders are a group of
Rothenberg et al. demonstrated the increased disorders that occur at a higher frequency among
prevalence of autoantibodies against folate receptors Jews compared to the general population, yet are
in serum of women with a current or previous not exclusive to the Jewish population. There is no
pregnancy complicated by a fetal NTD.34-35 It remains official list of conditions, however it is known that
to be established whether there is a causative Mendelian disorders, and diseases associated with
relationship between the presence of these antibodies predisposition genes occur at a higher incidence in
and the development of NTDs. an individual of Ashkenazi or Sephardic ancestry.
Screening by mid-trimester ultrasound appears As different Jewish groups are at risk for different
to be superior to maternal serum AFP assessment, disorders, it is important to establish not only a
but the latter modality is still widely used as a prior patient’s religion, but also of their ethnicity and
screening modality before detailed ultrasound ancestral countries of origin.
assessment. The ethnic variation in AFP levels are Ancestors of the Ashkenazi Jews lived in Central
well established and corrective formulae may be and Eastern Europe (Germany, Poland, Lithuania and
applied to produce accurate risks for NTDs in various Russia). Approximately 95% of Jews living in North
ethnic groups as recommended by the American America are Ashkenazi. This population are more
College of Medical Genetics guidelines for the likely to carry genes for: Tay-Sachs disease, Canavan
screening of neural tube defects.23 disease, familial dysautonomia, Niemann-Pick (type
A) disease, Fanconi anemia (group C), Bloom
TARGETED SCREENING IN ETHNIC GROUPS syndrome, Gaucher disease (the non-neuronopathic
In every ethnic, demographic, or racial group, there type), mucolipidosis type IV, and cystic fibrosis (see
are certain inherited disorders that occur more table). As these conditions can be severely
 Influence of Ethnicity on Prenatal Screening 1111
incapacitating, tragically debilitating, or lead to death thalassaemia screening to all women as an integral
in infancy or early childhood, some orthodox part of early antenatal care.
communities encourage the use of premarital carrier The population of Cyprus (both Greek and
screening to discourage the marriage of two carriers. Turkish) has one of the highest rates of beta-
Disease Carrier frequency thalassaemia carriers in the world, and in the past
one of every 158 infants was born with the condition.
Tay-Sachs Disease 1 in 26
Canavan Disease 1 in 38
Today in Cyprus, antenatal screening for thalassaemia
Familial Dysautonomia 1 in 30 has been almost totally superseded by premarital
Niemann-Pick Disease (type A) 1 in 70 screening. The religious authorities had ethical
Fanconi Anemia (group C) 1 in 89 objections to screening during pregnancy, on the
Bloom Syndrome 1 in 110
Gaucher Disease 1 in 10 grounds that it excluded most options other than
Mucolipidosis IV 1 in 100 termination of affected pregnancies. The church in
Cystic Fibrosis 1 in 25 Cyprus therefore insists on testing as a formal
prerequisite to church weddings. The certificate
In comparison, the Sephardic Jews ancestry can
required states merely that the partners have been
be traced to Spain, Portugal, North Africa (Morocco
tested and appropriately advised. In this way the
and Tunisia), and the Middle East. This Jewish
confidentiality of the test result is preserved and the
population are more likely to be carriers for Beta-
couple can exercise an informed choice about
thalassemia, Familial Mediterranean Fever, Glucose-
reproduction. This societal approach to inherited
6-phosphate dehydrogenase deficiency and Type III
genetic disorders is to be applauded and is would
glycogen storage disease.
be a suitable model for other communities to adapt.
The Ashkenazi Jewish community is a unique and
ideal population in which to provide multiple diseases
Cystic Fibrosis
screening because detection rates are high (> 95%)
by testing a limited number of mutations. The Cystic fibrosis (CF) is a common inherited condition
American College of Obstetricians and Gynecologists that affects many systems in the body, most often
(ACOG) recommends screening couples with resulting in chronic, progressive lung disease,
European-Jewish ancestry at a minimum for Tay- problems with digestion, and subsequent malnutri-
Sachs disease, Canavan disease, and cystic fibrosis tion. CF is the most commonly inherited disease in
(37/38). No standards of care have been set for the Caucasians affecting approximately 1:2500 indivi-
Sephardic population. duals, but it has been identified in people of all races
and ethnicities around the world. The incidence in
Haemoglobinopathies other ethnic groups varies from 1:15,000 for African
Haemoglobinopathies are the commonest single gene Americans to 1:90,000 in Asians. In 2001, the
recessive disorders in the world. They occur as a American College of Obstetricians and Gynecologists
result of mutations in the globin gene and are and the American College of Medical Genetics 38
primarily seen in populations whose ancestors are recommended that CF carrier screening be offered
from Africa, the Middle East, the Caribbean, the to all Caucasian couples that are pregnant, or are
Mediterranean, Asia and the Far East. These considering pregnancy. These groups additionally
disorders have appeared in the West due to global recommended that carrier screening be made
migration. In the UK, the NHS Sickle Cell and available to other ethnic populations with the
Thalassaemia Screening Programme are working understanding that the likelihood of being a CF
towards a policy of universal antenatal screening carrier may be much lower in non-Caucasian
which will allow the offer of sickle cell and populations (see carrier risks table).39
1112 Textbook of Perinatal Medicine

Ethnicity Detection Before After deficiency also occasionally occurs in Caucasians.

rate test -ve test Antenatal screening is available for at risk patients.
Ashkenazi Jewish 97% 1/29 1/934
Caucasian (Northern 90% 1/25 1/241 EFFECTS OF SCREENING ON ETHNICITY
European)
Caucasian (Southern 70% 1/25 1/81 Knowledge
European)
African American 69% 1/65 1/207
The uptake of any screening test is influenced by
Hispanic Americana 57% 1/46 1/105 knowledge of the condition being screened for.
Asian 30%b 1/90 1/128b Parents need appropriate knowledge of Down
This is a pooled set of data based on ∆F508deletion and syndrome; what it is, and how it affects the child
requires additional information to accurately predict risk for and adult, both mentally and physically. They also
specific Hispanic populations. Residual carrier risk after a need appropriate knowledge of the screening test,
negative test is further modified by the presence of a
positive family history of CF and/or by mixed ethnicity. together with the limitations of the test, so they can
Data adapted from Laboratory Standards and Guidelines for
decide whether they wish to be screened. A study
Population-based Cystic Fibrosis Carrier Screening. Genetics by Chilaka et al40 at Leicester General Hospital in
in Medicine 2001;3:149-154. the UK looked at the knowledge of Down syndrome
amongst pregnant women from different ethnic
Although there have been over 1000 mutations groups. The study showed that racial groups other
identified that cause CF, only 25 have been than Caucasian had a poorer understanding of Down
recommended for carrier screening as additional syndrome. Fifty one per cent of Caucasians in the
mutations are rare, not well understood, and have study had a good knowledge of Down syndrome
minimal impact on the overall probability of affecting compared to 8% of Asians born outside the UK. The
a child. Mutations of the CF also vary with ethnicity. factors affecting knowledge included the quality of
The ÄF508 mutation accounts for 70% of the CF spoken English, knowing an affected child, parity
mutations in Caucasians of Northern European and religion. Only 5 women in the study could not
descents but only 30% of CF mutations in individuals speak English; however none of these women had
of Ashkenazi Jewish descent. A different mutation, any reasonable knowledge of Down syndrome
W1282X, is more common in the Ashkenazi Jews. compared to those who could speak English. The
importance of the study results are highlighted by
Glucose-6-Phosphate it’s main finding that knowledge of the condition
Dehydrogenase Deficiency was the most influential factor in the decision making
Glucose-6-Phosphate Dehydrogenase(G6PD) process about accepting or declining a Down
deficiency is the most common human enzyme syndrome screening test. In addition, information
deficiency. G6PD deficiency can result in the rapid retention about prenatal screening also varies
destruction of blood cells in the presence of infection significantly by ethnicity and level of education.41
or certain drugs. Different populations have different
Access and Equity
types of mutations, but within a specific population,
common mutations are usually shared. There are a Women from ethnic minorities can experience
wide variety of normal genetic variants of the financial, linguistic, and cultural barriers to access
enzyme G6PD. The main races affected are in West health care services, limiting utilisation of genetic and
Africa, the Mediterranean, the Middle East and other maternal child health services. Genetic
South East Asia. The degree of deficiency varies, conditions may go undetected with deleterious
often being mild in Black Africans, more severe in impact during prenatal, perinatal, and newborn
Orientals and most severe in Mediterranean’s. Severe periods. Society has an ethical obligation to ensure
 Influence of Ethnicity on Prenatal Screening 1113
equitable access to health care for all, yet there conditions, as it may have profound cultural
remains a persistence of health disparities across race, implications such as impacting on marriage prospects
income and ethnicity. for themselves or their close family.
The extent and quality of prenatal care is In many cultures the concept of having to go
important for the health of women and their babies. outside the family for health education or infant care
Early prenatal care can encourage healthy habits is an alien concept, and would indicate an
during pregnancy, help to identify potential medical unacceptable lack of respect for the older women in
problems, facilitate screening and involvement with the family who traditionally are an important part
parenting support, nutrition, and other educational of the child care system, and who expect to instruct
resources. Women from ethnic groups have been the young mother in the care of her baby. To be
shown to use antenatal services less intensely with obliged to seek such education from members of
a high proportion booking too late for screening to another culture whose values and beliefs are different
be useful. Although the percentage of women from one’s own is almost bizarre. However, if the
receiving prenatal care during the first three months concept of instruction in parentcraft by a midwife is
of pregnancy has increased over the past two accepted, the actual attendance at parentcraft may
decades for white, black, Asian and Hispanic women, present considerable difficulties. The ‘usual’
white women are still the most likely to receive inhibitions to attendance experienced by young
prenatal care in their first trimester. Sadly a significant women e.g. child care, the need to take time off work,
proportion of women from the ethnic minorities still may be further complicated by the need for a young
receive no care until the third trimester. woman to be escorted (particularly in the evenings),
In some countries in the world, a substantial or by difficulties with communication or socio-
barrier to health care access for some people is the economic issues.
lack of either public or private health insurance. Despite these constraints, with an ethnically-
Another difficulty in accessing health services is sensitive strategy, it is still possible to provide equal
problems of communication and language barriers. access to prenatal screening. For example, in a
The difficulties for the patient if English is not the previous study on ethnic differences in nuchal
first language with respect to screening can be translucency measurement, it was noted that the
divided into problems of recruitment into a screening ethnic balance of the population accepting and
program, of giving the patients enough information declining prenatal Down syndrome screening was
not significantly different in an obstetric population
to allow informed consent, and of problems arising
from one of the most socially deprived regions of
if detailed information needs to be provided in
the UK, where over 15% of the women did not speak
follow up. To counter language difficulties inter-
English. 42
preters may be used and information leaflets can be
produced in different languages. Interpreting skills
Culture and Religion
continue to be a scare resource in any health service.
One way round this problem has been the setting up Understanding and valuing cultural diversity is
of a language service which enables remote critical to ensure the best possible care. For example,
interpreting via a shared telephone line. Another is a woman is likely to decline prenatal screening and
via asking relatives to act as interpreters. However, diagnosis because of fears that she may be divorced
this can however be problematic as it is often assumed by her partner or shunned by her in-laws in the event
that they are knowledgeable in all aspects of both that a fetal abnormality is diagnosed. The difficulties
languages, and this may place them under a great such attitudes create are further amplified by the fact
deal of stress. Also, patients may feel uncomfortable that such women may well have a poorer
with even close relatives knowing about their medical understanding of the local language, be financially
1114 Textbook of Perinatal Medicine

insecure and be reliant on her partner for right of Counselors (NSGC) in America who developed
residency in the country. This maternal perception, guidelines providing recommendations on
often unbeknown to the clinician, may be interpreted counselling and screening for consanguineous couples
by health care workers as denial or lack of defined as being second cousins or closer.44
knowledge. Most of the genetic fall-out of consanguinity is in
It is also important not to make the assumption the form of autosomal recessive disorders, which in
that all women from a particular community follow fact adversely affect only a minority of such families.
the same customs and religion. For example attitudes The more closely two people are related, the more
to termination vary even within the Muslim genes they share, and the more likely that both will
community. Some Muslim parents do not see termi- carry a copy for the same recessive mutation, thereby
nation as ‘halal’ (permitted) but as ‘haram’ (not increasing their chances of having a child affected
permitted). They know their child is diseased but by that disorder. Although it is not possible to come
they choose to keep it believing that God will up with one number for all populations of consan-
(inshaallah) created that child and they expect to get guineous couples, the risk is not as high as was
their rewards in heaven. Even when termination of previously envisaged. It is estimated that the
pregnancy is acceptable, there are different additional risk for significant birth defects, including
interpretations of the gestation up to which such a mental retardation or genetic disorders; above the
procedure may be carried out.43 general population risk is about 1.7 to 2.8% for first
Clinicians therefore need to develop an cousin unions. The consensus from the NSGC is that
appreciation and respect for cultures and religions beyond a thorough medical family history, with
that differ hugely from their own. This may be often follow-up of significant findings, no additional
impossible to attain unless members of the local ethnic preconception screening is recommended for
and religious communities are co-opted into health consanguineous couples. Consanguineous couples
service delivery as health care workers of aides.
should be offered similar genetic screening as
Consanguinity suggested for any couple of their ethnic group.

In the West our knowledge and understanding of CONCLUSIONS

consanguinity is limited. Whilst marriages between
Ethnic differences in the delivery of health care are
close biological kin are preferential in many parts of
the world, such unions are not commonplace in the prevalent across various domains of health, including
West. First cousin marriages are legal in countries mortality, morbidity, behavior, and utilization of
such as the U.K. and Australia, but are against the health services. This chapter highlights some areas
law in others. The 1981 marriage law of the People’s of ethnic differences and potential inequalities in
Republic of China prohibits marriage between access to prenatal testing. The elimination of health
couples related as first cousins or closer, and in the inequality will firstly require a reliable assessment
USA, consanguineous unions are prohibited in 30 of the disparity in care provision as well as a clear
States. Irrespective of prevailing legislation, a future understanding of differences across populations
decline in the prevalence of consanguineous unions identified in terms of race/ethnicity. Further research
can be predicted, accompanying the expected is required to improve our understanding of why
reduction in family sizes. Regardless, it is important testing may not be offered, the reasons for failure to
that health care providers have an understanding of take up testing when offered, and to identify whether
the potential genetic consequences of such unions. there are other social inequalities in access to prenatal
This was recognized by National Society of Genetic testing.
 Influence of Ethnicity on Prenatal Screening 1115
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 84
Screening for Fetal Heart Defects and
Associated Chromosomal Anomalies

R Chaoui

INTRODUCTION Real-time Gray-scale Ultrasound and

Two-dimensional Echocardiography
Congenital heart defects are one of the most common
anomalies in human fetuses (5/1000 livebirths) and Gray scale two-dimensional ultrasound is still the
are the leading cause of death due to malformations gold standard for the structural evaluation of the
in the first year of life. Heart abnormalities and soft fetal heart. Resolution has continuously increased
markers are present in a substantial amount in fetuses over the last two decades in step with the huge
with chromosomal aberrations and fetal echo- progress in the development of computer technology
cardiography is thus intrinsic part of the genetic and fast processors. In most sophisticated (and
scan.1 expensive) ultrasound machines there is an ideal
A prenatal diagnosis can be reliably achieved by setting for fetal heart examination which is based on
means of ultrasound during pregnancy and the a high image resolution (using scan heads with 250-
accurate prenatal diagnosis improves in many 1012 acoustic lines), a high frame rate and good
conditions fetal outcome by delivering the baby at penetration. Visualisation of very tiny structures like
a specialized tertiary centre. In this chapter the the coronary arteries using real-time ultrasound has
examination of the fetal heart is reviewed, focusing become possible as well as of other structures such
on the role of screening and how to imply the heart as the fetal thymus that has not been seen before.
into the genetic scan. The increased resolution using 5-7-MHz transducers
has also led to the identification of new details like
EXAMINATION TECHNIQUES OF THE the echogenic intracardiac focus with the discussion
FETAL HEART whether or not it is associated with chromosomal or
other anomalies (see below).
No organ in the fetus can be examined with as many Two main features, however, have facilitated
diagnostical techniques as the heart. Detailed enormously the fetal heart examination and are now
information on structure, function and time-related standard even on mid- to low-range machines: the
events has become available thanks to the cine-loop and the zoom functions. The magnification
development of sophisticated tools.1 However this of the image allows better assessment of the
has not been accompanied by a significant increase structures of interest and visualisation of the different
in prenatal detection rate of anomalies, but rather in cardiac cycle phases image-by-image facilitates
increasing reliability in precise diagnosis. assessment of the structures during systole and
1118 Textbook of Perinatal Medicine

diastole. In the recent years image resolution in gray We described few years ago how most congenital
scale was increased by completing the native image heart anomalies could be detected in only three
with harmonic and/or compound imaging. planes using color Doppler: the four-chamber view,
the five chamber view and the three-vessel-trachea
Time Motion or M-Mode view.4 The exact examination in gray scale completed
Time motion application in the fetus was not possible by the expected typical flow in color Doppler became
until simultaneous real-time visualisation became the basis of diagnosis of fetal CHD.
available. Cardiac biometry first performed with
M-Mode was very soon abandoned since such Three Dimensional Fetal Echocardiography
measurements became easier using cine-loop As soon as the first three-dimensional (3D) ultra-
technique to image selectively diastole and systole.2,3 sound equipment became available an attempt to
Two main fields of interest are still in the domain of examine the fetal heart was undertaken. It was
M-Mode: one is the classification of fetal arrhythmia hoped that 3D information of the fetal heart could
and the other is the calculation of indices used in facilitate understanding of orientation especially the
cardiology to assess contractility e.g. shortening assessment of the great vessels’ anatomy which is
fraction, ejection fraction, etc... difficult for many examiners. However, since the heart
is beating the main challenge is still the gating of the
Spectral Doppler Flow Velocity Waveform
signals and the acquisition of information during
Doppler ultrasound enables a non-invasive systole or diastole.5 The advent of STIC technology
quantification of perfusion across different fetal few years ago allowed a reliable acquisition of a 3D
cardiac valves and vessels. Peak velocities can be with systole and diastole as off-line 4D fetal echo.6
assessed and indices calculated. By measuring the STIC can be used in gray scale6 or in combination
area of a valve the perfusion can then be calculated with color or power Doppler mode. 7 A detailed
either as stroke volume or involving the heart description of 3D of heart and vessels is described
frequency as cardiac output. The advent of color elsewhere in this book and I refer to the reader to
Doppler enabled a more reliable use over of spectral this chapter. The technique is however too young to
Doppler across the known valves, but also the be evaluated for its role in screening for fetal heart
evaluation of more difficult otherwise not assessable defects or in genetic scan.
regions, as pulmonary arteries and veins, ductus
arteriosus, foramen ovale and even coronary vessels. SCREENING OF THE FETAL HEART OR
TARGETED EXAMINATION BASED ON
Color Doppler
INDICATIONS ?
In addition to the gray-scale examination of the fetal
heart, color Doppler is now considered as the second CHD have a multifactorial etiology and therefore
part of a complete cardiac evaluation. The method prenatal detection cannot be achieved solely by
allows rapid orientation within the fetal heart and concentrating on the high-risk population defined
completes the evaluation supplied by gray-scale by patient history. Therefore seeking for heart
information. Once abnormal flow is suspected abnormalities should be part of the midtrimester
quantification becomes mandatory using spectral ultrasound screening. In many countries such a
Doppler. The advent of color Doppler did not general screening is not established (no insurance or
contribute to a huge increase in detection rate of mother care coverage), but is often performed either
CHD but increased the reliability of screening on risk indication or by the willingness of the patient.
when routinely applied and in the detailed fetal Signs of cardiac disease are often subtle, necessi-
echocardiography in suspected heart diseases. tating careful targeted examination. In the 1980s, the
 Screening for Fetal Heart Defects and Associated Chromosomal Anomalies 1119
four-chamber view was proposed as the most are not detectable in the simple “four-chamber-
important plane for screening, allowing a greater screening” and their detection has been
detection rate for anomalies. Recently, however, demonstrated to improve children outcome in
incorporation of views of the great vessels has been various CHD. Whereas the four-chamber-view can
recommended as part of the routine screening be examined in a single plane, the great vessels can
examination. be only assessed by a dynamic scan, i.e. by tilting
Many studies in the last 10 years have emphasized and moving the transducer. 9 The checklist for
the importance of cardiac screening, but they have assessing the great vessels will include the list as
achieved widely divergent results, with reported presented in table 2.
detection rates varying from 5% to 92%.8 However, Targeted fetal echocardiography should be performed
it should be noted that these studies employed by those familiar with the prenatal diagnosis of CHD
different approaches and are therefore not directly and the wide spectrum of possible anomalies. In such
comparable (see for details 8). a chapter I cannot recommend whether the examiner
There is a list of indications, generally accepted should be an obstetrician or a pediatric cardiologist,
as referral reason for fetal echocardiography, and since this may be decided by the local specificities of
were presented in another chapter. The percentage the country. I recommend however a close
of detection of heart anomalies within single groups cooperation between both groups, especially during
(the yield) differs between 3-5% (i.e. diabetes, drugs, counselling a pregnant woman with a suspected heart
genetic ultrasound) to more than 50% (i.e. suspicious anomaly in the fetus.
four-chamber-view). In some indications fetal Often the expectations are bigger and therefore
echocardiography are performed rather to calm the the time, equipment, and expertise needed for an
pregnant woman (low recurrence risk in positive examination are larger. In these conditions the use
family history) whereas in other conditions to of color and pulsed Doppler techniques increase the
seriously rule out a heart anomaly (non immune accuracy of the examination. In cases of arrhythmia
hydrops, extracardiac malformations). M-Mode or pulsed Doppler should be used to
demonstrate the relationship between atrial and
FETAL CARDIAC EXAMINATION IN A ventricular contractions.
LOW-RISK POPULATION AND TARGETED The checklist in these conditions is longer and
FETAL ECHOCARDIOGRAPHY IN A the dynamic examination of the heart in different
HIGH-RISK POPULATION planes9 is mandatory as shown in Tables 1 and 2.
It is generally agreed that the “four-chamber- view”
should be part of every routine ultrasound in FETAL ECHOCARDIOGRAPHY AND THE
pregnancy. However there are different reasons why DETECTION OF A CONGENITAL
this plane was not successful in improving the HEART DEFECT
detection rate of CHD in the recent past. In order to There are two steps in the detection of a fetal heart
achieve an accurate assessment of this plane we defect, namely first: the suspicion of an abnormality
recommend to follow a step-by-step checklist on and second: the detailed precise description and
every single cardiac examination, including the list classification of the heart defect. Generally the first
in table 1. is easily achieved when the examiner is able to get
It is furthermore agreed that the assessment of the four-chamber-view and the great vessels in nearly
the great vessels belongs rather to an extended fetal all patients as described in Tables 1 and 2 and he/
cardiac examination. We expect however that in she knows the typical hints for an abnormal heart in
future this will be part of a basic cardiac examination these planes. The second step can be solved chiefly
as well, since many anomalies of the great vessels by getting experience in many CHD and knowing
1120 Textbook of Perinatal Medicine

the spectrum of the different diseases. In many

countries the latter examination is either achieved
together with a pediatric cardiologist or by referring
the pregnant to a pediatric cardiologist specialized
in fetal echo examination.
It is important to know the most common
“abnormalities” detected during fetal cardiac scan
and leading to a referral. In my experience the most
common signs detected in the four-chamber-view
and the great vessel planes are summarized in table
3. The differential diagnosis of most common
Fig. 84.1: Fetuses with atrioventricular septal defect during diastole
suspicions of referrals are summarized in table 4. (left) and systole (right). In the left image the gap in the crux of the
heart is easily recognized. On the right side on one hand both AV
FETAL ECHOCARDIOGRAPHY IN valves are linear and on the other the measurement of atrial to
ventricular length will reveal a ratio >0.6 suspicious for an AVSD.
GENETIC SCAN
Fetal examination allows to detect fetuses at high- We proposed recently a new simple cardiac
risk for chromosomal aberrations owing to measurement the AVL-Ratio11, in order to increase
malformations or signs called soft markers.10 The the detection rate for AVSD on routine scan. After
latter increases the risk to a specific malformation, a standardized four-chamber-view, the ratio of the
without being obligatory per se a structural atrial length to the length of the ventricle in the
malformation. The fetal heart belongs to the organs midline is measured. Where as the normal AVL Ratio
often evaluated carefully when seeking for a during second trimester is constant around 0.5,
chromosomal anomaly, either the common numerical almost all fetuses with AVSD had a ratio exceeding
aberrations as trisomy 21,18,13 or monosomy X or 0.6.11
more specific deletions as the microdeletion 22q11 Other anomalies which are found in association
involving often the heart. In numerical aberrations with Trisomy 21 are the VSD and the Tetralogy of
except Down´s syndrome, the other anomalies have Fallot. Typical anomalies for Trisomy 18 are besides
many extracardiac signs leading to a invasive the VSD and AVSD, the overriding of the aorta (Fig.
procedure independent from the heart finding. 84.2) with or without the pulmonary stenosis, a
double outlet right ventricle and occasionally a left
Structural Heart Anomaly outflow tract obstruction. Trisomy 13 cardiac
anomalies are besides the VSD, left outflow tract
Atrioventricular septal defect (AVSD) (Fig. 84.1) is
obstructions as aortic coarctation of the aorta and
the most common heart anomaly associated with a
occasionally a hypoplastic left heart syndrome
chromosomal aberration mainly Trisomy 21 and 18.
(HLHS). Turner syndrome has in almost all cases
The diagnosis can be achieved by detecting the gap
detected prenatally generally in combination with a
in the crux of the heart (the combination of defects
cystic hygroma also the left ventricular outflow tract
within the interventricular and interatrial septa). The
obstruction typically the aortic coarctation and also
association with trisomy 21 or 18 is between 50-80%;
occasionally the HLHS.
however, when in AVSD the left ventricle is small as
in combination with aortic coarctation the rate of Cardiac Soft Markers
aneuploidy is lower (10% or less) and if there are
Intracardiac Echogenic Focus
signs of isomerism (i.e. stomach on the right side)
there is no association with chromosomal aberrations. The debate on this unspecific sign will not be
 Screening for Fetal Heart Defects and Associated Chromosomal Anomalies 1121
increase significantly the risk for chromosomal
anomalies. The isolated EF in the left ventricle was
accepted in the last years as increasing the
background risk of a factor of 1.5 or even only 1.
This led recently to a debate whether the finding of
an echogenic focus should be told to younger women
or not.12,13
In an observation of a series with CHD we found
that 11% of all cardiac defects were associated with
an EF14 some with malformations not detectable in
the four-chamber plane as the Tetralogy of Fallot or
a TGA. 50% of all the cases were however not
isolated left ventricular EF. Therefore not only
chromosomal anomalies but also cardiac defects
should be ruled out in fetuses with a detected EF.
Since the use of nuchal translucency in the risk
assessment for chromosomal anomalies, the
importance of second trimester soft markers is
Fig. 84.2: This is an overriding of the aorta over a VSD (*), which can reduced, especially the EF.
be detected in the visualization of the five-chamber-view. This is a
sign and its differential diagnosis is listed in Table 4.
Discrepant LV/RV width
continued in this chapter. There are controversial Devore15 described an increased risk for Trisomy 21
data in the literature supporting the EF as a sign for in early second trimester fetuses with a narrow left
Down-Syndrome10 as well as a benign sign with no ventricle compared with the right ventricle, without
relationship to chromosomal anomalies. the additional signs of an aortic coarctation.
Since most cases (around 90%) are found as
isolated EF in the left ventricle (Fig. 84.3), it is to be Tricuspid Regurgitation
emphasized that EF in the right ventricle or two EF Isolated tricuspid regurgitation detected by the
either in the left (Fig. 84.3), right or in both ventricles routine use of color Doppler is present in ca. 4% of
all normal fetuses at 20-22 weeks scan.16 Tricuspid
regurgitation was however also discussed as
associated with Down´s syndrome when detected
at 16-18 weeks15 or at the 11-14 weeks scan.17

Pericardial Effusion
An isolated pericardial effusion was described to
increase the risk of association with Down´s
syndrome (Fig. 84.4).18 It is not known whether in
these cases, the effusion is the remaining of early
hydrops with a thickened nuchal translucency in
Fig. 84.3: Two fetuses with echogenic foci. On the left the echogenic early pregnancy. This sign was unfortunately not
focus is present in the left ventricle and is the most common condition
found. In the right figure two echogenic foci are present in the left evaluated in the recent years in the age of NT
ventricle. This fetus had a heart defect associated with a del.22q11. measurement.
1122 Textbook of Perinatal Medicine

trachea and is thus detectable with color Doppler in

the three-vessels-trachea view (Fig. 84.5).20
In few pediatric cardiology studies it was
described that an ARSA (also called lusorian artery)
is found in 1% of the normal population but as high
as 35% in persons with Down´s syndrome with or
without heart defects.
We were the first to describe this sign in fetuses
with Down´s syndrome in a paper published
recently 20, where we found that 5/14 (36%) of
consecutive fetuses with Down´s syndrome had this
aberrant vessel, we detected prenatally. Only one
had it as an isolated sign, three in association with
an echogenic focus in addition to extracardiac signs,
and in only one case it was associated with an AVSD.
Personal experience and communication from
pathologists support that this sign is also common in
trisomy 13,18 and recent reports emphasized the
Fig. 84.4: In this fetus with Down Syndrome there is occurrence in Turner-syndrome and in microdeletion
a pericardial effusion at 20 weeks 22q11.
Further observations from other groups are
Linear Insertion of the AV Valves necessary to confirm our new finding.

This is an interesting new sign presented by a French

group few years ago. Fredouille and co-workers19
found on autopsy specimens of hearts from fetuses
with Down-Syndrome that in some cases, even with
the absence of structural heart anomalies both
atrioventricular valves inserted at the same level and
not the tricuspid valve inserting lower in the right
ventricle as under normal conditions. This is a very
subtle and interesting subtle sign, used also in the
detection of AV-septal defect, but should be
evaluated by other groups.

Aberrant Right Subclavian Artery (ARSA): The

New Cardiac Sign for Down-Syndrome
The normal right subclavian artery arises as a first
vessel from the brachiocephalic artery and courses
ventral of the trachea. An aberrant right subclavian
artery arises separately from the aortic arch in the Fig. 84.5: In this fetus with Down’s syndrome at 20 weeks, an aberrant
right subclavian artery is present. It is demonstrated in the three-
region of the junction of the aortic arch and the ductus
vessel-tracheal view as a vessel with a course behind the trachea
arteriosus. It courses to the right arm behind the toward the right arm.
 Screening for Fetal Heart Defects and Associated Chromosomal Anomalies 1123
Cardiac Signs for Microdeletion 22q11 being in the group with conotruncal anomaly. 9 of
the 10 fetuses with microdeletion had an abnormal
The del.22q11 is reported to have a frequency of 1:4000
thymus detected prenatally (sensitivity 90%,
livebirths and is considered to be after trisomy 21
specificity 98.5%). In our experience the examination
the second most common chromosomal anomaly in
of the thymus region helps in defining a group at
liveborn children with a CHD. The earlier used and
high risk for del.22q11 21 (Fig. 84.6).
now abandoned acronym CATCH-22 summarizes the
According to other studies additional signs were
combination of finding in these patients: C=cardiac
described to increase the risk of 22q11 (in predefined
anomaly, A=abnormal facies, T=Thymus hypo- or high-risk groups) and some of these are: increased
aplasia, C=cleft palate, H= Hypercalcemia, 22 for NT in early pregnancy, intrauterine growth retar-
del.22q11. Prenatally the clinical features of an dation, polyhydramnios, renal or facial abnormality,
abnormal facies are generally very subtle and we right aortic arch, aberrant right subclavian artery,
can mainly rely on the heart anomaly and as we aberrant pulmonary artery etc.22,23
showed few years ago also on the thymus sign.
Among the heart anomalies, conotruncal and REFERENCES
aortic arch malformations are the leading defects
1. Chaoui R. Fetal echocardiography: state of the art of
permitting a concrete suspicion of a del.22q11. The the state of the heart. Ultrasound Obstet Gynecol 2001;
occurrence of this deletion is present in ca. 50% of all 17:277-284.
cases with interrupted aortic arch, 40% of absent 2. Sharland GK, Allan LD. Normal fetal cardiac measure-
ments derived by cross- sectional echocardiography.
pulmonary valve syndrome, 30% of Truncus Ultrasound Obstet Gynecol 1992;2:175-181.
arteriosus communis, 20% of pulmonary atresia with 3. Chaoui R, Heling KS, Bollmann R. Ultrasound
VSD, 15% with Tetralogy of Fallot, and in around measurements of the fetal heart in the 4-chamber image
5% in other anomalies as complex transpositions, plane. Geburtsh. u. Frauenheilk. 1994;54:92-97.
4. Chaoui R, McEwing R. Three cross-sectional planes for
double outlet right ventricle and others.21 fetal color Doppler echocardiography. Ultrasound
Few years ago we examined a group of 147 fetuses Obstet Gynecol 2003;21:81-93.
with CHD including 76 with conotruncal defects. In 5. Chaoui R, Kalache KD, Hartung J. Application of three-
dimensional power Doppler ultrasound in prenatal
this study we examined the role of analysing the diagnosis. Ultrasound Obstet Gynecol 2001; 17:22-29.
absence or hypoplasia of the thymus in predicting a 6. DeVore GR, Falkensammer P, Sklansky MS, Platt LD.
del.22q11. Ten of the 147 cases had a del.22q11, all Spatio-temporal image correlation (STIC): new
technology for evaluation of the fetal heart. Ultrasound
Obstet Gynecol 2003; 22:380-387.
7. Chaoui R, Hoffmann J, Heling KS. Three-dimensional
(3D) and 4D color Doppler fetal echocardiography using
spatio-temporal image correlation (STIC). Ultrasound
Obstet Gynecol 2004; 23:535-545.
8. Chaoui, R: The four-chamber-view: four reasons why
it seems to fail in screening for cardiac abnormalities
and suggestions to improve detection rate. Ultrasound
Obstet.Gynecol. 2003;22:3-10.
9. Chaoui R. The examination of the normal fetal heart
using two-dimensional echocardiography. In: Yagel S,
Silvermann N, Gembruch U, editors. London New York:
Martin Dunitz, 2003: 141-149.
Fig. 84.6: Thymus sign in predicting fetuses with del.22q11. In the left 10. Bromley B, Lieberman E, Shipp TD, Benacerraf BR. The
figure the thymus is recognized (arrows) as a slightly echogenic
genetic sonogram - A method of risk assessment for
structure in front of the three-vessels and behind the sternum. In the
right figure the fetus had a absent pulmonary valve syndrome with
Down syndrome in the second trimester. J Ultrasound
gross dilated pulmonary arteries. No thymus was visualized between Med 2002; 21:1087-1096.
the vessels and sternum (?) and FISH technique revealed the 11. Machlitt A, Heling KS, Chaoui R. Increased cardiac atrial-
suspected del.22q11 to-ventricular length ratio in the fetal four-chamber
1124 Textbook of Perinatal Medicine

view: a new marker for atrioventricular septal defects. 19. Fredouille C, Piercecchi-Marti MD, Liprandi A, Duyme
Ultrasound Obstet Gynecol. 2004 24:618-622. M, Gonzales M, Bigi N, Rouault F, Pellissier JF. Linear
12. Filly RA, Benacerraf BR, Nyberg DA, Hobbins JC. insertion of atrioventricular valves without septal defect:
Choroid plexus cyst and echogenic intracardiac focus in a new anatomical landmark for Down’s syndrome?
women at low risk for chromosomal anomalies. J Fetal Diagn Ther. 2002 ;17:188-192.
Ultrasound Med. 2004;23:447-449. 20. Chaoui R, Heling KS, Sarioglu N, Schwabe M, Dankof
13. Doubilet PM, Copel JA, Benson CB, Bahado-Singh RO,
A, Bollmann R: Aberrant right subclavian artery
Platt LD. Choroid plexus cyst and echogenic intracardiac
(lusorian artery) as a new cardiac sign in second and
focus in women at low risk for chromosomal anomalies:
third trimester fetuses with Down syndrome, Am.J.
the obligation to inform the mother. J Ultrasound Med.
2004 Jul;23:883-885. Obstet.Gynecol. 2005 (in press).
14. Chaoui R , Bierlich A: Intracardiac echogenic focus and 21. Chaoui R, Kalache KD, Heling KS, Tennstedt C,
fetal heart defects Ultrasound Obstet Gynecol 2000 16:13- Bommer C, Korner H. Absent or hypoplastic thymus
14 (abstract). on ultrasound: a marker for deletion 22q11.2 in fetal
15. Devore GR. The role of fetal echocardiography in cardiac defects. Ultrasound Obstet Gynecol 2002; 20:546-
genetic sonography. Sem Perinatol 2003; 27:160-172. 552.
16. Respondek ML, Kammermeier M, Ludomirsky A, Weil 22. Boudjemline Y, Fermont L, Le Bidois J, Lyonnet S, Sidi
SR, Huhta JC. The prevalence and clinical significance D, Bonnet D.Prevalence of 22q11 deletion in fetuses with
of fetal tricuspid valve regurgitation with normal heart conotruncal cardiac defects: a 6-year prospective study.
anatomy. Am J Obstet Gynecol 1994; 171:1265-1270. J Pediatr. 2001;138:520-524.
17. Huggon IC, DeFigueiredo DB, Allan LD.Tricuspid 23. Volpe P, Marasini M, Caruso G, Marzullo A, Buona-
regurgitation in the diagnosis of chromosomal ano-
donna AL, Arciprete P, Di Paolo S, Volpe G, Gentile M.
malies in the fetus at 11-14 weeks of gestation.
22q11 deletions in fetuses with malformations of the
Heart. 2003;89:1071-1073.
18. Sharland G, Lockhart S. Isolated pericardial effusion: an outflow tracts or interruption of the aortic arch: impact
indication for fetal karyotyping? Ultrasound Obstet of additional ultrasound signs. Prenat Diagn. 2003;23:752-
Gynecol 1995; 6:29-32. 757.
 85 Ultrasound Screening of
Chromosomopathies by
Nuchal Translucency
Maria Angelica Zoppi, Giovanni Monni

INTRODUCTION In physiological condition these tissues can

accumulate more or less fluids and as a result the
Nuchal translucency (NT) is the term that has been
thickness of the NT is expected to individually differ
used for 10 years to describe the echo-free space
among normal fetuses.
behind the fetal neck visible by ultrasound in almost
Moreover, during the 11-14 weeks period, the
all fetuses at 10- 14 weeks 1 (Fig. 85.1). Before this
thickness of the NT increases with the crown-rump
gestational age the NT is not clearly evident in all
length and with the age of the fetus. Tables of
cases and after 14 weeks the NT reduces, becoming
reference for NT thickness in normal fetuses have
less transonic and turning into the nuchal fold space
been generated by cross-sectional studies. Some
visible in the second trimester.
studies have calculated the ranges by using linear
The NT is in fact the ultrasound image of some
regression formulas, however, quadratic regression
soft tissues that cover the occipital bone and cervical
approach seems to better fit the trend of the nuchal
spine (muscles, connective tissue, limphatic vessels,
thickness.2-5
subcutaneous tissues, cutis).
Other studies have shown that longitudinal
assessments of NT in the same fetus showed a
tendency toward a growth of the thickness to reach
a peak that is achieved individually and differently
by each fetus, mostly around 12 weeks and then it
show a decrease.6
It is evident that some subtle differences can be
achieved among different centers that perform the
measurement of the NT, due to local contingent
conditions (operators, machines, approach to the
ultrasound technique, ethnicity). Therefore it has been
suggested to favour local reference ranges for normal
NT, to assess the thickness, whenever it is possible.7
At 10 weeks, essentially, the NT thickness in
normal fetuses most frequently measures around 1-
Fig. 85.1: Nuchal translucency 1.2 mm, and at 13-14 weeks around 1.7-1.9 mm.
1126 Textbook of Perinatal Medicine

The visualisation and measurement of the NT is some difficulty in the drainage of the normal quantity
not included among the main identified objectives of fluid present in the neck.
for first trimester ultrasound as recommended in most Regardless the underlying cause of the accumu-
guidelines issued by ultrasound scientific societies. lation of fluids, what is apparent on the ultrasound
The presence of the gestational sac in the uterine is the increased thickness of the echo-free space
cavity, the number of fetuses and the visualisation behind the fetal neck, that has been labelled
of embryonic or fetal heart beat, the datation of "enlarged nuchal translucency".12 This space can be
pregnancy are the most frequent goals of the first absolutely transonic or faintly echogenic, and can be
trimester scan.8-10 limited to the neck or extended at the whole length
Therefore, during the first trimester ultrasound of the fetus, as a "space suit"13 (Fig. 85.3).
examination, only if it is specifically requested, a When the thickness of a NT is very enlarged at
normal NT is then visualised and measured. Because 10- 14 weeks, it could easily be visualised during the
of the implications that the measurement of the NT scan without especially looking for it. This is a
can carry for the pregnancy (reducing or increasing situation comparable with that occurs with some soft
the risk for chromosomal abnormalities, opening a markers for chromosomopathies in the second
scenario for invasive prenatal diagnosis), it is trimester (hyperechogenic focus, hyperechogenic
advisable to perform the measurement of the NT bowel, dilated renal pelvis etc.)14, where these signs
only in the right setting (after a conscious request could be obviously evident, without looking for them.
While these signs are not malformations, and they
for screening by the informed patient and measure-
could be visible during an ultrasound examination
ment performed by a skilled operators and in a
which has not be performed with the finality of
certificated screening program).11
chromosomopathies screening, the guidelines of
THE ENLARGED NUCHAL TRANSLUCENCY some Scientific Society that have faced this problem,
recommend to disclose the presence of evident soft
Sometimes a surplus accumulation of fluid in the markers to the patient, in order to offer the opportu-
nuchal tissues can occur (Fig. 85.2). The accumulation nity of an adequate genetic counselling.8
of nuchal fluid can be caused by either an increased It has been noticed since the early '90's that fetuses
amount of fluid directed in the nuchal region or by with trisomy 21 can show an enlarged NT at first
trimester examination15 (Fig. 85.4).
When an ultrasound scan is performed with the
specific intention to measure the NT it is essential to
correctly visualise the fetus and to perform the NT

Fig. 85.2: Enlarged NT Fig. 85.3: "Space suit" nuchal tranlucency

 Ultrasound Screening of Chromosomopathies by Nuchal Translucency 1127

Fig. 85.4: Trisomy 21 fetus with enlarged nuchal translucency Fig. 85.5: Trisomy 18 with enlarged NT

measurement in the adequate way in order to In fetuses with Turner syndrome the evolution
compare the actual measurement with the reference of first trimester enlarged NT is frequently described
values. The range of NT thickness varies with CRL, into a cystic hygroma (cystic malformation of the
so that the 95th centile for a CRL of 45 mm is quite lymphatic system) in the second trimester19 (Fig.
different than for 82 mm of CRL, and it was evident 85.8).
that a fixed- cut- off for NT measurement could not
be used with efficiency to assess the enlargment of PATHOPHYSIOLOGY OF ENLARGED NT
a NT. 16 The term of enlarged NT in the first trimester that
It has been noted that the majority of fetuses with is used in ultrasound practice may indicate many
Trisomy 21 show a NT greater than the 95th centile different background conditions.
of ranges obtained for normal fetuses with a An accumulation of fluids in the neck is presumed
standard technique of NT measurement. Fetuses with to come from either an abnormal local composition
chromosomal abnormalities other than trisomy 21
(trisomy 18, trisomy 13, Turner syndrome, Klinefelter
syndrome and Triploidy) can have an enlarged NT16
(Figs 85.5 to 85.7).
In fetuses with normal and abnormal chromo-
somes the enlarged NT is frequently a transient sign.
In an early study of trisomies 21, at the beginning of
the second trimester, a re-absorption of the nuchal
edema has been longitudinally described in 6 cases.17
A study of the evolution of enlarged NT during the
1st trimester, described a decrease in the thickness
that occurred in both chromosomally normal and
abnormal fetuses. At second measurement per-
formed in the same fetus, the frequency of decreasing
NT was greater in the normal than in the abnormal
karyotype fetuses.18 Fig. 85.6: Trisomy 13 with NT
1128 Textbook of Perinatal Medicine

trimester fetus is evident only in the nuchal region.23-

24
An extra- accumulation of fluid that overcome the
normal capacity of mechanism deputate to the
drainage may be the cause of enlarged NT in trisomy
21 fetuses.26
In Turner syndrome the accumulation of fluid in
the nuchal region seems to be related to a failure in
the drainage by the lymphatic system, because of an
abnormal structure, that involves either the minor
lymphatic vessels in the skin, and the greater vessel,
with a lack of definitive connections between the
jugular lymphatic sacs and jugular veins system, as
Fig. 85.7: Turner syndrome with enlarged NT an expression of a failure in the development of the
lymphatic system, due to the underlying karyotype
of the tissues that tend to capture more fluids, or anomaly 22,26 (Fig. 85.9). In fetuses with Turner
from a situation of hampered re-absorption of a syndrome, the first trimester translucencies are
normal quantity of fluids regularly passed from the tipically large, bilateral and septated, occupying the
vessel to the interstitial spaces, or to a condition of lateral and posterior regions of the neck of the fetus.
increased passage of fluids from the vessel to the In Turner syndrome the first trimester NT is in fact
connective, due to an abnormal hydrostatic pressure often not transient, with a tendency to evolve into
as consequence of impairment of the arterial or a second trimester "cystic hygroma colli".26
venous circulation.20-26 A different mechanism related to a temporary
In trisomy 21, some alteration in the composition lymphatic failure due to a delay in the connection
of the skin, with an increased expression of type VI with the venous system has been considered in
collagen and a raise in the quantity of hyaluronic trisomy 21 and normal fetuses. In these cases, the
acid could justify an increased entrapment of liquids, evolution towards a-re-absorption in the second
that for reasons not yet explained, in the first trimester is frequent.26
Pathological studies carried out on fetuses with
enlarged NT with normal karyotype and trisomies
21 and 18, have in fact shown in the posterior side
of the neck of the fetus, exactly where of the NT is

Fig. 85.8: Turner syndrome fetus at 16 weeks Fig. 85.9: Turner syndrome fetus at 12 weeks
 Ultrasound Screening of Chromosomopathies by Nuchal Translucency 1129
visualised by ultrasound, the presence of some
cavities, negative for immunohistochemical markers
for lymphatic vessel endothelium and arteries. These
cavities seem to be the result of coalescence of
edematous mesenchymal spaces (due to an edematous
mesenchymal). In these cases, a lymphatic distension
of jugular lymphatic sacs in the lateral side of the
neck, has been shown to occur prior to the
manifestation of the nuchal edema (Figs 85.10 and
85.11). The hypothesis was that the first occurrence
would be the delay in the lymphatic drainage, which
may then cause the accumulation of mesenchymal
fluid and nuchal edema. At 14 weeks, when jugular
lymphatic sacs complete their development, making
definitive connections with the venous system, both
findings (nuchal edema and dilatation of lymphatic
sacs) finally resolve.26-27
In trisomy 21 another mechanism has been
postulated to cause the accumulation of fluids and Fig. 85.11: Three- dimensional surface rendering of a trisomy 21
fetus with enlarged jugular lymphatic sacs
enlargement of the NT, due to an increase of the
perfusion of the vessel direct to the neck and the An accumulation of extravascular liquids, as it is
upper part of the fetus. In pathology studies, a present in adults with an impairment of cardiac
narrowing of the isthmus of the aorta, associated function can also be present in fetuses with
with a dilatation of the supravalvular portion of the chromosomal abnormalities or normal katyotype
vessel has been described. An increased passage of fetuses, with structural heart abnormality. The
fluids into the connective tissue for hydrostatic subcutaneous edema depends on an impaired re-
pressure factors could be involved in the enlargement absorption of fluids due to an increased of the
of the NT.28 hydrostatic pressure in the venous system. A wide
spectrum of heart defects has been described to be
present in chromosomal abnormalities and normal
fetuses with enlarged NT, but a clear connection
between specific cardiac diseases and the
development of the enlarged NT in the first trimester
of pregnancy has not been demonstrated28-29 (Figs
85.12 to 85.15).
A relationship between an impaired diastolic
function and enlarged NT has been hypothesized on
the grounds of some alterations signs on the
velocimetry of the ductus venosus in fetuses with
abnormal karyotype, cardiac defects and NT
thickness. 30-31 The ductus venosus is a vessel that
connects the umbilical circulation with the right
Fig. 85.10: Multiplanar view of a trisomy 21 fetus with atrium. In the first trimester of pregnancy the pulsed
enlarged jugular lymphatic sacs Doppler waveform of this vessel is characterised by
1130 Textbook of Perinatal Medicine

Fig. 85.12: Heart defect in a first trimester fetus with Fig. 85.14: First trimester tachycardia in a first trimester
normal karyotype and enlarged NT feutus with normal karyptype and enlarged NT

a forward flow with a peak during systole, a second altered (70-90%), with an atrial contraction velocity
peak in diastole and a forward velocity during atrial absent or inverted.
contraction (Fig. 85.16). In cases when the pressure Another parameter that has been used to evaluate
in the atrium at the end of diastolic phase is increased the alteration of the velocimetry in the ductus
(that could be a sign of cardiac dysfunction due to venosus is the pulsatility of the wave form, that in
a great number of factors, including some heart chromosomal abnormalities appears increased.32 If
structural malformations), the velocity during the there is a single cause that determines at the same
atrial contraction in the ductus venosus decreases, it time two parallel consequences as the altered ductus
can be zero or inverted (Figs 85.17 to 85.18). In fetuses venousus flow and the enlarged nuchal thickness, or
with chromosomal abnormalities, that are suspected if there is a consequential connection between the
to have a greater occurrence of cardiac abnormalities, two findings, and which of these findings happen
and that show frequently an enlarged NT, the first, needs to be demonstrate.
velocimetry of the ductus venosus is frequently

Fig. 85.13: Heart defect in a first trimester fetus with Fig. 85.15: First trimester 2nd degree heart block in a
trisomy 21 and enlarged NT normal karyotype fetus with enlarged NT
 Ultrasound Screening of Chromosomopathies by Nuchal Translucency 1131

Fig. 85.16: Normal velocity flow in the ductus Fig. 85.18: Inverted velocity during atrial contraction
venosus in a first trimester fetus in the ductus venosus

An impairment in the diastolic function has been A mechanism of increased hydrostatic pressure
shown in fetuses with enlarged NT in the first in the thorax has been postulated to be involved in
trimester and normal karyotype, that persist in the cases of first trimester enlarged NT and venous
second trimester, and this is demonstrated by an congestion as in cases of diaphragmatic hernia and
alteration of the velocimetry of the atrium- skeletal dyspalsias.21
ventricular valves.33
In fetuses with enlarged NT, no impairment in ENLARGED NT FOR TRISOMY 21 SCREENING
the ventricular systolic function has been described.
Amniocentesis or chorionic villus sampling are
In fact, no difference of umbilical Pulsatilily Index in
invasive prenatal diagnosis techniques for fetal
the first trimester, has been shown in normal
karyotype analysis, that carry a procedure-related
karyotype fetuses with normal and enlarged NT, and
risk of abortion of about 1%. Since the introduction
in trisomy 21 fetuses with enlarged NT.34
of invasive prenatal diagnosis, medical and financial
reasons have pushed to offer karyotype analysis only
to high risk cases, and the maternal age-related risk
Down's syndrome was the older and most commonly
used approach to prenatal screening. The aim of the
screening is to select those women that are at high
enough risk for Down's syndrome to justify a
invasive prenatal diagnosis procedure.35
In the last 20 years, prenatal ultrasound
examination has been able to identify some of the
malformations of trisomy 21 fetuses and other
aneuploidies, and some of the anatomical features
that slightly differ from normal fetuses. The
ultrasound approach has been proposed for
identification of cases at a higher risk.14 In the middle
Fig. 85.17: Absent velocity during atrial contraction '80's the first finding of trisomy 21 that has been
in the ductus venosus identified by ultrasound as a marker for trisomy 21
1132 Textbook of Perinatal Medicine

was the increased nuchal fold thickness in the second performed according to a defined technique, with
trimester fetuses.36 Later, in the middle '90's, the adequate training of operators and constant audit of
association between first trimester increased nuchal the results.39 Using this approach, in a multi-centric
translucency thickness and trisomy 21 and other study (22 centers involved), performed over 100,000
chromosomal abnormalities was described.1 cases, with an average maternal age of 28 years, for
For NT an algorythm for the calculation of a risk greater than or equal to 1 in 300, the sensitivity
individualised risk and a specific quality control for for trisomy 21 has been estimated to be 82%, with
the test has been proposed since its introduction, 8% false positive rate.40 With this performance results
while for serum markers for trisomy 21 this is a the NT test was considered to be the most effective
consolidated approach, for ultrasound in prenatal prenatal screening to identify cases at risk for trisomy
diagnosis was relatively new.2 21. Comparable results were obtained by other
Frequencies of Trisomy 21 cases and normal centers where guidelines for NT screening were
fetuses were compared for the deviation of the observed. 5
measured NT from the normal expected values, in Fetuses at higher risk for trisomy 21 because of
order to calculate likelihood ratios.2 Two principal enlarged NT were at the same time found to be at
methods have been used to calculate the deviation higher risk for other chromosomopathies as trisomies
from the normality: the Delta value and MoM 18 and 13, triploidy and sex aneuploidies.40
approach. 2,37 The Delta value approach is now
considered more correct.38 Delta value in millimeters CLINICAL IMPORTANCE OF NT SCREENING
indicates the difference from the measured NT and The availability of an accurate screening test in the
the expected median of NT calculated for normal first trimester, such as nuchal translucency, is useful
fetuses given a determined CRL. An estimate of the to recognise cases at a higher risk for trisomy 21 at
risk for trisomy 21 was calculated by multiplying the an early stage, in order to offer an early invasive
maternal age related risk for trisomy 21 by the prenatal diagnosis that could be performed
likelihood ratios obtained from the NT thickness, preferably by chorionic villus sampling. It is true that
giving a new, individual numerical risk.16 The risk when the performance of NT test is considered, the
estimate for trisomy 21 based on the ultrasound spontaneous intrauterine lethality of affected fetuses,
measurement of nuchal translucency is based on few from first trimester to term has to be taken into
but important principles. First of all the maternal account. A number of those fetuses identified to be
background risk is the essential factor of the at high risk on the first trimester, and on which an
screening test for trisomy 21, and each time it needs invasive prenatal diagnosis procedure is performed,
to be considered in the calculation. Second, the results would be spontaneously demised in uterus before
is given not as "test positive" or "test negative" on birth, without all the troubles and anxieties that the
the ground of an arbitrarily chosen cut- off, but the prenatal screening procedure can carry. In numbers:
woman is faced with a numerical result, on which about 30% of trisomy 21 fetuses that are detected by
she can base her thoughts according to her wishes first trimester NT screening are destined to die
and anxieties. Third, a quality control method has during the pregnancy. This percentage is about an
been applied to ultrasound measurement (this is new extra 10% than the lethality of fetuses detected by a
for this field of medicine, while it has been used for second trimester screening test, that is about 20% to
decades for, i.e. laboratory serum markers). There term.41
is evidence that the nuchal translucency test is However, there is evidence that for pregnant
reliable, because the inter-operators and inter-centers women there are some particular aspects of prenatal
variability can be reduced and comparable results screening that are of value. A test that give the result
are obtained, in cases when the measurement is early in pregnancy, that obviously has at the same
 Ultrasound Screening of Chromosomopathies by Nuchal Translucency 1133
time a low rate of false negatives and false positives, NT screening can be used for chromosomal
with a reduced number of invasive procedures and abnormalities screening with the same accuracy on
fetal demises because of procedure- related risk, is twin and multiple pregnancies.45-46
considered to be better.42-43 Enlarged first trimester
NT could identify, at the same time, fetuses at higher RECENT DEVELOPMENT OF NT SCREENING
risk for abnormalities other than chromosomopathies. At its introduction in clinical practice, NT screening
Cardiac defects, some structural abnormalities and test has been proposed to be performed from 10
genetic syndromes can occur more frequently in weeks plus 3 days (from a 38 mm of CRL). After
fetuses with enlarged NT than in the general evidence that around 12 week a better evaluation of
population.29 fetal anatomy could be in most cases achieved, it was
Women at high risk for trisomy 21 because of suggested to perform the screening after 45 mm of
advanced age can have some advantage to have the CRL, so that at the same time, an early detection of
NT test offered. In fact a more precise estimate of structural abnormalities can be obtained.47
individual risk for trisomy 21 can be made, and In order to decrease the false negatives and the
therefore the opportunity to decide about prenatal rate of invasive testing, the risk obtained by maternal
diagnosis with more autonomy is given. Reduction age and NT has been combined with other markers,
of request for invasive prenatal diagnosis in women which occur more frequently in trisomy 21 cases than
aged 35 years or over and earlier detection of cases in normal fetuses, but are not related to the increase
at risk by first trimester chorionic villus sampling of the thickness of first trimester NT. First trimester
has been underlined when NT screening test is maternal serum markers, PAPP-A and free beta-hCG,
performed in a contest where invasive prenatal combined with nuchal translucency test, increase the
diagnosis because of maternal age is offered. 44 sensitivity to 90% and decrease the false positive rate
(Tables 85.1 and 85.2). to about 3%.48

Table 85.1: Acceptance of invasive prenatal diagnosis

1600

1400

1200
patients with age >/=35 years

1000

invasive prenatal diagnosis declined

800
invasive prenatal diagnosis requested

600

400

200

0
1 2
(1) in 1995 genetic counselling w ithout NT screening
(2) in 1999 genetic counselling after NT scr eening
in Cagliari center (44)
1134 Textbook of Perinatal Medicine

Table 85.2: Procedure used for prenatal diagnosis of chromosomopathies

25

20
No. of chromosomopathie

15

Prenatal diagnosis by chorionic villus sampling

Prenatal diagnosis by amniocentesis

10

0
1 2
(1) in 1995 genetic counse lling w ithout NT scree ning
(2) in 1999 ge netic counselling after NT scre ening
in Cagliari center (44)

The combination of NT test with the sign of absent national health care systems is the purchaser, it can
nasal bone in the first trimester is still under offer a politicy of screening that is more cost-effective
assessment. 49-50 The integration of the nuchal after a rigorous cost-benefit analysis.
translucency test with maternal screening markers When a screening program regards a disease for
of the first and second trimester has been shown to which the definitive diagnosis exposes an human
improve the accuracy of the test, but it requires to being to a potential lethal risk, and, in case of
wait until the second trimester to disclose the result ascertained disease, there is no cure as is for trisomy
and eventually to offer the diagnosis.51 21 at prenatal diagnosis, many ethical problems come
Having the possibility to combine and integrate into light and they put doctors and patients in front
different tests, a new scenario for trisomy 21 prenatal of great dilemmas.
screening for trisomy 21 is now appearing. Different In this specific case of screening, the principle of
tests can be performed at different time (one stop, self determination for the patient, that for decades
two step, one step), the results can be disclosed after has been applied to the field of invasive prenatal
every single test or integrated, the successive test diagnosis, should be the fundamental issue of the
can be performed only in established cases, for entire process, and should be the goal to be achie-
example only in borderline cases (contingent test), ved.52 From the start, all the steps of the screening
and each test could obtain different performance.35 procedure should be accurately considered, leaving
Some test s carry a greater sensitivity, others a nothing to chance, as for example, the first apparently
greater specificity. There are many options to screen innocent question on how old she is, that everyone
for trisomy 21, but the choice on which direction to asks, on the path to motherhood, to a completely
move is delicate. If the screening test for trisomy 21 unaware (about prenatal screening troubles)
is performed on an financial ground basis, and the prospective mother.
 Ultrasound Screening of Chromosomopathies by Nuchal Translucency 1135
REFERENCES 16. Nicolaides KH, Subire NJ, Snijders RJM, Souka AP. The
11-14 week's scan book. London, UK: Pathenon
1. Nicolaides KH, Azar G, Byrne D, Mansur C, Marks K. Publishing, 2001.
Fetal nuchal translucency screening for chromosomal 17. Pandya PP, Snijders RJM, Johnson S, Nicolaides K.
defects in first trimester of pregnancy. Br Med J 1992; Natural history of trisomy 21 fetuses with increased
304: 867-9. nuchal translucency thickness. Ultrasound Obstet
2. Pandya PP, Snijders RJM, Johnson SP, Brizot ML, Gynecol 1995; 5: 381-383.
Nicolaides KH. Screening for fetal trisomies by maternal 18. Zoppi MA, Ibba RM, Floris M, Axiana C, Manca F,
age and fetal nuchal translucency thickness at 10 to 14 Monni G. Changes in nuchal translucency thickness in
weeks of gestation. Br J Obstet Gynaecol 1995; 102: 957- normal and abnormal karyotype fetuses. Br J Obstet
962. Gynaecol 2003;110: 584-8.
3. Snijders RJM, Nicolaides K. Ultrasound markers 19. Fukada Y, Yasumizu T, Takizawa M, Amemiya A, Hoshi
for chromosomal defects. London, UK: Pathenon K. The prognosis of fetuses with transient nuchal
Publishing, 1996. translucency in the first and early second trimester. Acta
4. Braithwaite JM, Morris RW, Economides DL. Nuchal Obstet Gynecol Scand 1997; 76: 913- 916.
translucency measurements: frequency distribution and 20. Moscoso G. Fetal nuchal translucency: a need to
understand the physiological basis. Ultrasound Obstet
changes with gestation in a general population. Br J
Gynecol 1995; 5: 6-8.
Obstet Gynaecol. 1996 Dec;103(12):1201-4.
21. Von Kaisenberg CS, Brand- Saberi B, Jonat W,
5. Zoppi MA, Ibba RM, Floris M, Monni G. Fetal nuchal
Nicolaides KH. Pathophysiology of increased nuchal
translucency screening in 12,495 pregnancies in Sardinia.
translucency in chromosomally abnormal fetuses.
Ultrasound Obstet Gynecol 2001; 18: 649-51. Prenat Neonat Med 1999; 4: 431-440.
6. Pajkrt E, De Graaf IM, Mol BWJ, van Lith JMM, Bleker 22. von Kaisenberg CS, Krenn V, Ludwig M, Nicolaides KH,
OP, Bilardo CM. Weekly nuchal translucency measure- Brand Saberi B. Morphological classifiation of nuchal
ments in normal fetuses. Obstet Gynecol 1998; 91: 208- skin in human fetuses with trisomy 21, 18, and 13 at 12-
211 18 weeks and in a trisomy 16 mouse. Anat Embryol
7. Logghe H, Cuckle H, Sehmi I. Centre-specific ultra- 1998; 197:105-24.
sound nuchal translucency medians needed for Down 23. von Kaisenberg CS, Brand-Saberi B, Christ B, Vallian S,
syndrome screening. Prenat Diagn 2003; 23:389-392. Farzaneh F, Nicolaides KH. Collagen type VI gene
8. Linee Guida SIEOG (Società Italiana Ecografia Ostetrica expression in the skin of trisomy 21 fetuses. Obstet
e Ginecologica); Cento (FE), Italy: Editeam Publishing, Gynecol 1998; 91: 319-23.
2002. 24. Bohlandt S, von Kaisenberg CS, Wewetzler K, Christ B,
9. Antenatal care routine care for the healthy pregnant Nicolaides KH, Brand- Saberi B. Hyaluronan in the
woman. Clinical Guideline. National Collaborating nuchal skin of chromosomally abnormal fetuses. Hum
Centre for Women's and Children's Health. London UK, Rep 2000; 15: 1155-8.
RCOG press, 2003. 25. Haak MC, van Vugt JMG. Pathophysiology of incresed
10. Practice guidelines for the Performance of an Ante- nuchal translucency: a review of the literature. Hum
partum Obstetric Ultrasound Examination. AIUM Reprod Update 2003;2:175-184.
(American Institute of Ultrasound in Medicine). 2003. 26. Haak MC, Bartelings MM, Jackson DG, Webb S, van
11. Chasen ST, Skupsi DW, McCullogh LB, Chervenak FA. Vugt JM, Gittenberger-de Groot AC. Increased nuchal
Prenatal informed consent for sonogram: the time for translucency is associated with jugular lymphatic
first trimester nuchal translucency has come. J Ultra- distension. Hum Reprod. 2002;17:1086-92.
sound Med 2001; 20: 1147-52. 27. Castelli E, Todros T, Mattutino G, Torre C, Panattoni G.
12. Nicolaides KH. The 11-14 weeks scan. Fetal Medicine Light and scanning electron microscope study of nuchal
translucency in a normal fetus. Ultrasound Obstet
Foundation, London 2004.
Gynecol. 2003; 21:514-6.
13. Shulman LP, Phillips OP, Emerson DS, Felker RE,
28. Hyett J, Moscoso G, Nicolaides K. Abnormalities of the
Tharapel AT. Fetal 'space-suit' hydrops in the first
heart and great arteries in first trimester chromosomally
trimester: differentiating risk for chromosome abnor-
abnormal fetuses. Am J Med Genet 1997; 17: 207-216.
malities by delineating characteristics of nuchal 29. Hyett J, Perdu M, Sharland G, Snijders R, Nicolaides KH.
translucency. Prenat Diagn. 2000 Jan;20(1):30-2. Using fetal nuchal translucency to screen for major
14. Benacerraf BR. The second- trimester fetus with Down congenital cardiac defects at 10-14 weeks of gestation:
syndrome: detection using sonographic features. population based cohort study. Br Med J. 1999; 318: 70-
Ultrasound Obstet Gynecol 1996;7:147-55. 71.
15. Szabo J, Gellen J. Nuchal fluid accumulation in trisomy- 30. Matias A, Montenegro N. Ductus venosus blood flow
21 detected by vaginosonography in first trimester. in chromosomally abnormal fetuses at 11 to 14 weeks
Lancet. 1990 Nov 3;336(8723):1133. of gestation. Semin Perinatol 2001; 25: 32-7.
1136 Textbook of Perinatal Medicine

31. Zoppi MA, Putzolu M, Ibba RM, Floris M, Monni G. 42. Monni G, Ibba RM, Zoppi MA. Antenatal screening for
First trimester ductus venosus velocimetry in relation Down's syndrome. Lancet 1998;352:1631-2.
to nuchal translucency thickness and fetal karyotype. 43. Mulvey S, Zachariah R, McIlwaine K, Wallace EM. Do
Fetal Diagn Ther 2002;17:52-7. women prefer to have screening tests for Down syn-
32. Antolin E, Comas C, Torrents M, Munoz A, Figueras F, drome that have the lowest screen-positive rate or the
Echevarria M, Cararach M, Carrera JM. The role of highest detection rate? Prenat Diagn. 2003 Oct;23(10):828-
ductus venosus blood flow assessment in screening for
32.
chromosomal abnormalities at 10-16 weeks of gestation.
44. Zoppi MA, Ibba RM, Putzolu M, Floris M, Monni G.
Ultrasound Obstet Gynecol. 2001;17: 295- 300.
33. Rizzo G, Muscatello A, Angelini E, Capponi A. Abnor- Nuchal translucency and the acceptance of invasive
mal cardiac function in fetuses with increased nuchal prenatal chromosomal diagnosis in women aged 35 and
translucency. Ultrasound Obstet Gynecol. 2003 older. Obstet Gynecol 2001; 97: 916-20.
Jun;21(6):539-42. 45. Sebire NJ, Snijders RJ, Hughes K, Sepulveda W,
34. Zoppi MA, Ibba RM, Putzolu M, Floris M, Monni G. Nicolaides KH. Screening for trisomy 21 in twin
First trimester umbilical artery pulsatility index in fetuses pregnancies by maternal age and fetal nuchal trans-
presenting enlarged nuchal translucency. Prenat Diagn. lucency thickness at 10-14 weeks of gestation. Br J Obstet
2000; 20: 701-4. Gynaecol. 1996;103: 999- 1003.
35. Cuckle HS. Growing complexity in the choice of Down's 46. Monni G, Zoppi MA, Ibba RM, Putzolu M, Floris M.
syndrome screening policy. Ultrasound Obstet Gynecol. Nuchal translucency in multiple pregnancies. Croat Med
2002;19: 323-6. J. 2000; 41: 266-9.
36. Benacerraf BR. Barss VA, Laboda LA. A sonographic sign 47. Souka AP, Krampl E, Bakalis S, Heath V, Nicolaides KH.
for the detection in the second trimester of the fetus Outcome of pregnancy in chromosomally normal
with Down's syndrome. Am J Obstet Gynecol 1985; 151: fetuses with increased nuchal translucency in the first
1078-9.
trimester. Ultrasound Obstet Gynecol. 2001; 18: 5-8.
37. Biagiotti R, Periti E, Brizzi L, Vanzi E, Cariati E. Com-
48. Spencer K, Souter V, Tul N, Snijders R, Nicolaides A
parison between two methods of standardization for
gestational age differences in fetal nuchal translucency screening program for trisomy 21 at 10-14 weeks using
measurement in first-trimester screening for trisomy 21. fetal nuchal translucency, maternal serum free beta-
Ultrasound Obstet Gynecol. 1997 Apr;9(4):248-52. human chorionic gonadotropin and pregnancy-
38. Spencer K, Bindra R, Nix AB, Heath V, Nicolaides KH. associated plasma protein-A. Ultrasound Obstet Gynecol.
Delta-NT or NT MoM: which is the most appropriate 1999; 13: 231-7.
method for calculating accurate patient-specific risks for 49. Cicero S, Curcio P, Papageorghiou A, Sonek J,
trisomy 21 in the first trimester? Ultrasound Obstet Nicolaides KH. Absence of nasal bone in fetuses with
Gynecol. 2003 Aug;22(2):142-8. trisomy 21 at 11-14 weeks of gestation: an observational
39. Monni G, Zoppi MA, Ibba RM, Floris M. Fetal nuchal study. Lancet 2001; 358: 1665-7.
translucency test for Down's syndrome. Lancet 1997; 50. Monni G, Zoppi MA, Ibba RM Absence of nasal bone
350:1631. and detection of trisomy 21. Lancet 2002; 359: 1343.
40. Snijders RJM, Noble P, Sebire N, Souka A, Nicolaides 51. Wald NJ, Watt HC, Hackshaw AK. Integrated screening
KH. UK multicentre project on assessment of risk of for Down's syndrome on the basis of test performed
trisomy 21 by maternal age and fetal nuchal- trans-
during the first and second trimesters. N Engl J Med
lucency thickness at 10-14 weeks of gestation. Lancet
1999; 12: 461-7.
1998; 352: 343-6.
52. Chasen ST, Skupski DW, McCullough LB, Chervenak
41. Snijders RJM, Sundberg K, Holzgreve W, Henry G,
FA. Prenatal informed consent for sonogram: the time
Nicolaides KH. Maternal age and gestation- specific risk
for trisomy 21. Ultrasound Obstet Gynecol 1999; 13: 167- for first-trimester nuchal translucency has come. J
70. Ultrasound Med. 2001;20(11): 1147-52.
 86
First Trimester Ultrasound Screening
for Down Syndrome in Multiples

Giovanni Monni, Maria Angelica Zoppi

INTRODUCTION depending mostly on the number of needle

insertions.9-10 Prenatal diagnosis of a chromosomal
In the last decades, the older maternal age at
abnormality in multizygotic multiples, allows an
conception and the more frequent use of assisted
informed decision about the management of the
reproductive techniques, have moved to a constant
pregnancy. Therefore an accurate estimate of
increased rate of multiple pregnancies. Some specific
individual fetal risk for chromosomal abnormality is
prenatal and perinatal problems make these
advisable in multiple pregnancies.
pregnancies at higher risk.1-4 Neonatal mortality and
Ultrasound screening for trisomy 21 by first
morbidity is higher in multiple pregnancies, and
trimester nuchal translucency (NT) measurement is
maternal complications are more frequent.
correctly applicable in twin and multiples.11-13 The
Moreover, mostly because of the advanced
test gives an individual risk for each fetus and it is
maternal age, multiple pregnancies are at higher risk
for chromosomal defects. At the same time, as these comparable in the accuracy to the screening test for
pregnancies (frequently obtained after years of trisomy 21 in singleton pregnancies.14-17
infertility) are especially precious to the prospective
TYPE OF MULTIPLES
parents, there is no unanimous acceptance of the need
of invasive prenatal diagnosis procedures, which are Zygosity depends on the type of conception.
more difficult to perform than in singleton preg- Monozygotic pregnancies originate from the
nancies.5,6 division of a single zygote, and account about 30%
Non-invasive screening test for chromosomal of twin pregnancies. The frequency of monozygotic
abnormalities in multiple pregnancies are more pregnancy is stable in the world and among different
acceptable. Maternal serum biochemistry for trisomy populations at around 1 case on 250 deliveries. The
21 in multiple pregnancies has been proposed. 7-8 origin of monozygotic pregnancy is unknown. Next
However it may be difficult to interpretate because to the theory of an accidental event, a delay in the
of the interference between the serum marker implantation of the zygote, with a reduction of
concentrations and assisted reproductive therapies, oxigen transport, has been hypothesized. 18
and a great concern is the identification of which of Multizygotic pregnancies originate from the
the fetuses is positive at the biochemical test. fertilization of two or more oocytes by two or more
For invasive prenatal diagnosis, the risk of spermatozoa (Fig. 86.1). Dizygotic pregnancies
miscarriage related to the procedure is increased, account for about 70% of the total twin pregnancies.
1138 Textbook of Perinatal Medicine

Fig. 86.1: A dichorionic diamniotic twin pregnancy at 9 weeks Fig. 85.2: A dychorionic triamniotic triplet pregnancy
obtained by in vitro fertilization

The frequency of dizygotic pregnancy varies among monozygotic pregnancies), the placenta will be single
population, and the origin appears to be multi- with two amniotic cavities (mono-chorionic,
factorial. High levels of FSH, advanced maternal age, diamniotic pregnancy). If the division occurs between
high grade of parity, tall maternal stature and 9th and 13th day from fertilisation (it happens in less
proportionate maternal weight (reflecting a good than 1% of monozygotic pregnancies), the placenta
nutritional maternal status and probably higher and the amniotic cavity will be only one (mono-
levels of FSH), ethnical and familiar inherited factors, chorionic, monoamniotic pregnancy). In very rare
seasonality (peak of those kind of conceptions in cases, the division occurs by 14th to 16th days from
summer), the application of technologies of assisted conception, and the result is the conjoined twins.
reproduction and the use of drugs for the induction
of ovulation, support an increased frequency of
multiple conceptions.1,2 The in vitro manipulation of
embryos in techniques of assisted reproduction and
the use of special culture mediums, seem to induce
a greater frequency of iatrogenic monozygotic
pregnancies19 (Fig. 86.2).
The chorionicity depends on the type of
placentation. Dizygotic and multizygotic pregnancies
are always dichorionic and multichorionic (Fig. 86.3).
Monozygotic pregnancies can be dichorionic or
monochorionic and the chorionicity and it depends
on the time of the division of the conceptus (Fig.
86.4).
If the division occurs by the 3rd day from ferti-
lization (and this happen in about 30% of monozygotic
pregnancies), two placentas are generated. If the
division occurs between the 4th and the 8th day from
fertilisation (and this happens in about 70% of Fig. 86.3: A multizygotic pregnancy (9 fetuses)
 First Trimester Ultrasound Screening for Down Syndrome in Multiples 1139

Fig. 86.4: 3D rendering Monochorionic diamniotic Fig. 86.5: First trimester lambda sign in a dichorionic pregnancy
pregnancy at 9 weeks

Monozygotic twins are at higher risk for in the second trimester is not sufficient to exclude
structural anomalies than multizygotic because of the presence of two placentas. In triplet trichorionic
higher potential errors in the division of the zygote pregnancies, the junction of interfetal membranes is
and pre-embryo.1 called “ipsilon zone” (Fig. 86.8).21
The accurate identification of chorionicity is one
PRENATAL ULTRASOUND DETERMINATION of most important goal of obstetrics ultrasound in
OF CHORIONICITY multiple gestations, and in all cases it should be
Prenatal diagnosis of chorionicity can be made easier ideally performed by first trimester, so that the risk
by ultrasound in the first trimester. By transvaginal of each individual pregnancy can be assessed.
ultrasound, gestational sacs can be seen at 5 weeks
gestation (from 4 weeks plus 2 or 3 days), and the
number of sacs indicates the number of placentas
(monochorionic, dichorionic, trichorionic, etc.). As
the gestation proceeds, the septum between the sacs
become thinner, and only a triangular structure, the
“lambda sign” or “twin- peak sign”, remains from
10 to 14 weeks (Fig. 86.5). In monochorionic
pregnancy there is no chorionic tissue between the
two-amniotic sacs, and the joint of membranes to
the chorionic sac is called “T sign” (Fig. 86.6). In
dichorionic pregnancies, later in pregnancy, the
“lambda sign” is difficult to visualise in all case, and
it can completely disappear around 20 weeks (Fig.
86.7).20
The visualisation of the “lambda sign” is an Fig. 86.6: Absence of lambda sign (T sign) in a
unequivocal sign of dichorionicity, while the absence monochorionic twin pregnancy
1140 Textbook of Perinatal Medicine

RISK OF CHROMOSOMAL ABNORMALITIES

IN MULTIPLES
To calculate the risk of chromosomal abnormalities
in multiple pregnancies, it is fundamental to estimate
the zygosity.
For monozygotic pregnancies, if cases with mitotic
nondisjuction are excluded that determine “hetero-
karyotypia”, the karyotype in both fetuses would
be the same. 23 Fetuses can be discordant for
anomalies that are generated by the splitting
phenomenon, but are concordant for anomalies
genetically- determined. Both fetuses have the same
Fig. 86.7: Second trimester dichorionic pregnancy: karyotype either normal or abnormal.
the lambda sign is disappeared For multiple pregnancies derived from multi-
zygotic conception, discordant karyotypes are
Monochorionic pregnancies are at higher risk than expected. Therefore prenatal sonographic estimation
dichorionic pregnancies of prenatal and perinatal of zygosity is fundamental in the process of risk
problems, as they are monozygotic, and because of calculation. 9,24 In prenatal life, ultrasonographic
the occurrence of specific problems due to trans- evaluation of the placentas can give information in
placental circulation imbalance, which is the twin- this direction. DNA analysis of the fetal or neonatal
to-twin transfusion syndrome. This complication sampling allows a definitive diagnosis of zygosity.
occurs in about 20% of monochorionic pregnancies When a monochorionic pregnancy is diagnosed
and frequently manifests itself at 16th–22nd weeks, by prenatal ultrasound (whether monoamniotic or
by polyhydramnios in one sac and olygo- diamniotic), monozygosity can be supposed, and an
anhydramnios in the other sac. If untreated, the equal risk for trisomy 21 for both fetuses, similar to
mortality is about 90%. Amniodrainage or laser the maternal age- related risk, can be calculated.
coagulation of artero-venous connections in the When dichorionic or multiple placentas are eviden-
placenta are the therapies proposed in the second
tiated, a little probability of monozygotic pregnancy
trimester, allowing a survival of about 50% of
cannot be excluded, but the most frequent condition
cases.22
is multizygotic pregnancy. If the assessment is made
in a period where it is possible to define by ultra-
sound the fetal gender, and the placentas are
multiple, in cases with discordant sex, the probability
of multizygosity is validated. The risk for the
pregnancy of having one fetus with trisomy 21 is
calculated by the sum of the risk for each fetus. For
example, in a triplet trizygotic pregnancy, if the
maternal trisomy 21 background risk is 1 in 150, the
final risk for the entire pregnancy is: 1 in 150 + 1 in
150 + 1 in 150. For calculations, risks can be expressed
as odds (that is 1:149 + 1: 149+ 1:149), that is about
3: 149, or 1:47, for a final risk for the pregnancy to
Fig. 86.8: The ipsilon sign in a trichorionic pregnancy have one fetus with trisomy 21 of 1 in 48. In
 First Trimester Ultrasound Screening for Down Syndrome in Multiples 1141
multichorionic pregnancies, the risk for all fetuses to SELECTIVE FETOCIDE AND MULTIFETAL
have trisomy 21 is very rare, this being calculated by EMBRYOREDUCTION
multiplying the maternal age risk for one fetus for
The diagnosis of a single affected twin after a
the risk of the other. For example, in a dichorionic
and “hypothetical” dizygotic pregnancy, where the procedure of invasive prenatal diagnosis, can
maternal age risk for trisomy 21 is 1 in 150, the consents to plan a selective termination of the affected
background risk of the entire pregnancy is calculated fetus and to continue the pregnancy of the normal
by multiplying 1: 149 X 1: 149, then 1: 22,201, that is fetus.
a risk of 1 in 22,202. Multifetal embryoreduction is an option that
A sort of uncertainty is originated by the presence could be considered for therapeutical options in cases
of those cases of monozygotic dichorionic preg- of high order multiple pregnancies. Maternal and
nancies that are unrecognised in prenatal life, where fetal risk (related to high prematurity) are increased
the background risk of the pregnancy would be the in these pregnancies. The neonatal and pregnancy
same as the age- related risk for trisomy 21 of the outcome has been shown to improve in cases of four
pregnant woman. o higher multiples reduced to twin, because a
significant increase of the gestational age at delivery,
INVASIVE PRENATAL DIAGNOSIS PROCEDURES and a better maternal outcome. At present time, the
FOR KARYOTYPE ANALYSIS IN MULTIPLES role of embryoreduction for the management of
When a multiple pregnancy is discovered, extra- triplet pregnancies is under discussion.25,26
counselling is due regarding procreative risks, Embryoreduction is usually performed in the first
pregnancy- related risk for the mother, prenatal trimester, because it carries fewer complications than
management of the pregnancy, screening and in the second, by intrathoracic or intracardiac
prenatal diagnosis of fetal anomalies and chromo- injection of potassium chloride at 11- 13 weeks, under
somal abnormalities is advisable.9,10 ultrasounographic continuous guidance. When the
When an invasive procedure for prenatal number of fetuses is high, it is preferable to perform
diagnosis is planned, whatever is the approach the reduction by steps.
considered (chorionic villus sampling, amniocentesis, At the beginning when performing this proce-
fetal blood sampling), some fundamental conditions dure, the choice as to which fetus to reduce was based
should be fulfilled. fundamentally on technical considerations (the fetus
The knowledge of the type of placentation is nearest to the uterine surface or the one easier to
imperative (mono or multichorionic placenta). Each
reduce for the operator). The likelihood to reduce a
sample obtained from a distinct twin should be
normal fetus while maintaining some abnormal cases
defined (or checked by biological tests that analyse
(affected by structural anomalies or chromo-
the fetal phenotype or genotype); each fetus should
somopathies) was considered. Therefore it was
be mapped carefully by ultrasound during the
procedure to later allow the precise identification proposed to offer in invasive prenatal diagnosis for
when the result from diagnosis becomes available. karyotype by chorionic villus sampling in all cases
We should consider the increased risk of procedure- before performing embryoreduction.27 Because of the
related abortions, of invasive diagnosis in multiples, difficulties and costs of such invasive prenatal
compared to singles, which depends among others diagnosis in multiples, and the greater risk of
factors, mostly on multiple needle entrances through miscarriage related to the numerous procedures
the uterus. carried out, this approach has not be universally
When the operators are faced with invasive approved and performed.
procedures in multiple pregnancies, a specific To avoid a non-selective reduction and to decrease
experience and skill in this particular field of prenatal the use of invasive procedures, it has been considered
diagnosis is required. to offer the nuchal translucency screening before
1142 Textbook of Perinatal Medicine

embryo reduction. In fact the finding of an enlarged enlarged nuchal translucency than in spontaneous
nuchal translucency, allowing the possibility to multichorionic pregnancies, and the sensitivity was
calculate the individual risk for trisomy in each fetus, the same.17
can identify cases at higher risk for chromosomal The increased accumulation of fluid in the fetal
abnormalities and for structural malformation in nuchal, leading to the ultrasound finding of an
multiple pregnancies.28 enlarged nuchal translucency, can be determined by
several different mechanisms: cardiac failure,
NT IN MULTIPLES abnormal or delayed development of the lymphatic
The ultrasound measurement of the soft tissues vessels, altered composition of the connective tissue
behind the fetal neck (nuchal translucency thickness of the skin or venous congestion due to an increased
or NT) (Fig. 86.9), and the combination of the pressure in the fetal thorax.29,30
likelihood ratios obtained with the maternal The presence of an enlarged NT is associated with
background risk for trisomy 21, is a valid test of an increased rate of chromosomal abnormalities, but
screening to identify fetuses with chromosomal moreover the risk for structural malformations and
abnormalities. mostly cardiac defects in fetuses with normal
In multiple pregnancies an individual risk for karyotype is increased.31,32
trisomy 21 can be calculated for each fetus, and, as It has to be considered that a higher frequency of
for the background risk due to maternal age, the fetal malformation per pregnancy is expected in
risk for the entire pregnancy can be considered. multifetal pregnancies than in singleton pregnancies,
In twin and multiple pregnancies, screening for and in a dizygotic twin pregnancy there is a slight
chromosomal abnormalities by nuchal translucency chance of a double risk per pregnancy for fetal
can be performed and it is as accurate as in singleton malformations (because of the independent
pregnancies.14-17 probability that is carried by each fetus).
In a large collaborative study on 448 twin In multiple pregnancies, the absence of nasal bone
pregnancies, Sebire et al. have found an enlarged visualization, which is another accurate soft marker
nuchal translucency in 7.3% of all cases and in 7 out for trisomy 21 in the first trimester, can be used with
of 8 cases of trisomy 21.15 the same efficiency as in singleton pregnancies (Fig.
NT measurement can be used in high order 86.10). About 70% of trisomies 21 and an important
multiple pregnancies, and in those cases obtained by percentage of other chromosomal abnormalities as
assisted reproductive technologies, because no trisomy 18 and 13, 45, X0, can manifest the sign of
evident difference has been found in the rate of

Fig. 86.9: Nuchal translucency Fig. 86.10: Absent nasal bone in a trisomy 21 fetus
 First Trimester Ultrasound Screening for Down Syndrome in Multiples 1143

Fig. 86.11: Dichorionic pregnancy with a normal fetus Fig. 86.13: Dichorionic pregnancy: the fetus with normal
and a fetus with trisomy 21 karyotype with normal NT and present nasal bone

the absent nasal bone at ultrasound examination A higher rate of enlarged nuchal translucency has
performed at 11-14 weeks33,34 (Figs 86.11 to 86.13). been described in monochorionic pregnancies. The
enlarged NT has been described in both fetuses or
THE CASE OF ENLARGED NT IN in one. The enlarged NT in monochorionic preg-
MONOCHORIONIC PREGNANCIES nancies can indicate fetuses at higher risk for
In monozygotic pregnancies the rate of mendelian chromosomal abnormalities, or structural defects or
disorders and chromosomal abnormalities are can be a possible early manifestation of heart failure
identical to those of singleton pregnancies, while due to twin-to twin transfusion.35
there is an increased risk of structural malformations. When in a monochorionic pregnancy, the enlarged
Malformations due to disruption mechanisms, as NT is discordant between fetuses, a consideration
midline facial, heart, abdomen anomalies are more should be made (Figs 86.14 to 86.18). Excluding the
frequent. extremely rare case of heterokaryotypia, due to a

Fig. 86.12: Dichorionic pregnancy: the fetus with trisomy 21 Fig. 86.14: Discordant NT in a monochorionic
with enlarged NT and absent nasal bone diamniotic twin pregnancy
1144 Textbook of Perinatal Medicine

Fig. 86.15: The fetus with enlarged NT in a monochorionic Fig. 86.17: The fetus with normal NT in a monochorionic
diamniotic twin pregnancy with discordant NT diamniotic twin pregnancy with discordant NT

mitotic non-disjunction, where a normal karyotype one of the monozygotic fetuses. Concordance for the
can co-exists with a 45, X0 or a trisomy fetus, it should most common structural abnormalities that occur in
be considered that the two fetuses should have the monochorionic – monozygotic twins is rare.
same karyotype. In monochorionic diamniotic pregnancy, an
The increased NT in one fetus may indicate a enlarged nuchal translucency could be caused by
chromosomal abnormality in both fetuses. However, placental circulation problems, rather than chromo-
while the presence of a trisomy in both fetuses cannot somal abnormalities. This early imbalance of fluids
be ruled out without kayrotype analysis, this finding between the fetuses can anticipate in the first
can be associated to a normal karyotype in both trimester the inter-twin-to-twin transfusion, that
fetuses. Moreover it should be considered indicative manifest the most important diagnostic sign only after
for a structural anomaly that could be present in only 16 weeks.

Fig. 86.16: The same fetus with enlarged NT in a monochorionic Fig. 86.18: The same fetus with normal NT in a monochorionic
diamniotic twin pregnancy with discordant NT with an enlarged bladder diamniotic twin pregnancy with discordant NT with an enlarged bladder
 First Trimester Ultrasound Screening for Down Syndrome in Multiples 1145
REFERENCES 16. Maymon R, Dreazen E, Tovbin Y, Bukovsky, Weinraub
Z, Herman A. The feasibility of nuchal translucency
1. Snijders RJM, Nicolaides K. Ultrasound markers for measurement in higher order multiple pregnancies
chromosomal defects. London, UK: Parthenon achieved by assisted reproduction. Hum Reprod 1999;
Publishing, 1996. 14: 2102-2105.
2. KH Nicolaides, NJ Sebire, RJM Snijders and AP Souka. 17. Monni G, Zoppi MA, Ibba RM, Putzolu M, Floris M.
The 11- 14 week’s scan book. London, UK: Parthenon Nuchal translucency in multiple pregnancies. Croat Med
Publishing, 2001. J. 2000; 41: 266-9.
3. Dunn A, MacFarlane A. Recent trends in the incidence 18. Keith LG, Papiernik E, Keith DM, Luke B eds. Multiple
of multiple births and associated mortality in England pregnancy, Epidemiology, Gestation and perinatal
and Wales. Arch Dis Child 1996; 75: 10-19. outcome. New York. The Parthenon Publishing Group;
4. Callahan T, Hall J, Ettner S, Christiansen C, Greene M, 1995.
Crowley W. The economic impact of multiple- gestation 19. Wenstrom KD, Syrop CH, Hammitt DG, Van Voorhis
pregnancies and the contribution of assisted-repro- BJ. Increased risk of monochorionic twinning associated
duction techniques to their incidence. N Engl J Med 1994; with assisted reproduction. Fertil Steril. 1993;60: 510-4.
331: 244-249. 20. Sepulveda W, Sebire NJ, Hughes K, Odibo A, Nicolaides
5. Meschede D, Lemcke B, Stussel J, Louwen F, Horst J.
KH. The lambda sign at 10-14 weeks of gestation as a
Strong preference for non- invasive prenatal diagnosis
predictor of chorionicity in twin pregnancies. Ultrasound
in women pregnant through intracytoplasmic sperm
Obstet Gynecol. 1996;7: 421-3.
injection. Prenat Diagn 1998; 18: 700-705.
21. Sepulveda W, Sebire NJ, Odibo A, Psarra A, Nicolaides
6. Monni G., Cau G, Lai R, Demontis G, Usai V. Intra-
KH. Prenatal determination of chorionicity in triplet
cytoplasmic sperm injection and prenatal invasive
pregnancy by ultrasonographic examination of the
diagnosis. Prenat Diagn 1999; 19: 389-390.
ipsilon zone. Obstet Gynecol. 1996; 88: 855-8.
7. Neveux LM, Palomaki GE, Knight GJ, Haddow JE.
22. Senat MV, Deprest J, Boulvain M, Paupe A, Winer N,
Multiple marker screening for Down syndrome in twin
Ville Y. Endoscopic laser surgery versus serial
pregnancies. Prenat Diagn 1996; 16: 29-34.
8. Spencer K.. Screening for trisomy 21 in twin pregnancies amnioreduction for severe twin-to-twin transfusion
in the first trimester using free beta- hCG and PAPP-A, syndrome. N Engl J Med. 2004 8; 351: 136-44.
combined with fetal nuchal translucency thickness. 23. Machin GA. Some causes of genotypic and phenotypic
Prenat Diagn 2000; 20: 91-95. discordance in monozygotic twin pairs. Am J Med Genet
9. Wapner RJ. Genetic Diagnosis in multiple pregnancies. 1996; 61: 216-228.
Sem Perinat 1995; 19: 351-62. 24. Rodis JF, Egan JFX, Craffey A, Ciarleglio L, Greenstein
10. Monni G, Ibba RM. Invasive procedures in multiple RM, Scarza W. Calculated risk of chromosomal
pregnancies. In : Weiner S, Kurjak A, editors. Inter- abnormalities in twin gestations. Obstet Gynecol 1990;
ventional Ultrasound. New York- London: The 76: 1037-1041.
Parthenon Publishing Group; 1999. p 105-115. 25. Evans MI, Berkowitz RL, Wapner RJ, Carpenter RJ,
11. Nicolaides KH, Azar G, Byrne D, Mansur C, Marks K. Golberg JD, Ayoub MA, Horenstein J, Dommerguez M,
Fetal nuchal translucency screening for chromosomal Brambati B, Nicolaides KH, Holzgreve W, Timor Tritsch
defects in first trimester of pregnancy. Br Med J 1992; IE. Improvement in outcomes of multifetal pregnancy
304: 867-869. reduction with increases experience. Am J Obstet
12. Monni G, Zoppi MA, Ibba RM, Floris M. Fetal nuchal Gynecol 2001; 184: 7-103.
translucency test for Down’s syndrome. Lancet 1997; 26. Dodd JM, Crowther CA. Reduction of the number of
350: 1631. fetuses for women with triplet and high order multiple
13. Snijders RJM, Noble P, Sebire N, Souka A, Nicolaides pregnancies (Cochrane Review). In: the Cochrane
KH. UK multicentre project on assessment of risk of Library 2003, Issue 4, Chicester, UK: John Wiley and
trisomy 21 by maternal age and fetal nuchal- trans- Sons, Ltd.
lucency thickness at 10- 14 weeks of gestation. Lancet 27. Eddleman KA, Stone JL, Lynch L, Berkowitz RL.
1998; 352: 343-346. Chorionic villous sampling before multifetal pregnancy
14. Pandya PP, Hilbert F, Snijders RJM, Nicolaides KH. reduction. Am J Obstet Gynecol 2000; 183: 1078-81.
Nuchal translucency thickness and crown- rump length 28. Monni G, Zoppi MA, Cau G, Lai R, Baldi M. Importance
in twin pregnancies with chromosomally abnormal of nuchal translucency in multifetal pregnancy
fetuses. J Ultrasound Med 1995; 14: 565-568. reduction. Ultrasound Obstet Gynecol 1999; 13, 377-378.
15. Sebire NJ, Snijders RJM, Hughes K, Sepulveda W, 29. Moscoso G. Fetal nuchal translucency: a need to
Nicolaides KH. Screening for trisomy 21 in twin understand the physiological basis. Ultrasound Obstet
pregnancies by maternal age and fetal nuchal Gynecol 1995; 5: 6-8.
translucency thickness at 10- 14 weeks of gestation. Br 30. Von Kaisenberg CS, Brand-Saberi B, Jonat W, Nicolaides
J Obstet Gynaecol 1996; 103: 999-1003. KH. Pathophysiology of increased nuchal translucency
1146 Textbook of Perinatal Medicine

in chromosomally abnormal fetuses. Prenat Neonat 33. Cicero S, Curcio P, Papageorghiou A, Sonek J, Nico-
Med 1999; 4: 431-440. laides KH. Absence of nasal bone in fetuses with trisomy
31. Souka AP, Snijders RJ, Novakov A, Soares W, Nicolaides 21 at 11-14 weeks of gestation: an observational study.
KH. Defects and syndromes in chromosomally normal Lancet 2001; 358: 1665-7.
fetuses with increased nuchal translucency thickness at 34. Monni G, Zoppi MA, Ibba RM Absence of nasal bone
10- 14 weeks of gestation. Ultrasound Obstet Gynecol and detection of trisomy 21. Lancet 2002; 359: 1343.
1998; 11: 391-400. 35. Sebire NJ, D’Ercole C, Hughes K, Carvalho M, Nico-
32. Hyett J, Perdu M, Sharland G, Snijders R, Nicolaides KH. laides KH. Increased nuchal translucency thickness at
Using fetal nuchal translucency to screen for major 10-14 weeks of gestation as a predictor of severe twin-
congenital cardiac defects at 10-14 weeks of gestation: to-twin transfusion syndrome. Ultrasound Obstet
population based cohort study. Br Med J 1999;318:81-
Gynecol. 1997;10: 86-9.
85.
 SECTION 10
Fetal and Maternal Physiology
B Arabin, DW Skupski
1148 Textbook of Perinatal Medicine
 Maternal Hemodynamic Changes in Pregnancy 1149

87
Maternal Hemodynamic
Changes in Pregnancy

Jacky Nizard

INTRODUCTION CARDIOVASCULAR SYSTEM

Adaptation to pregnancy begins rapidly after Blood Volume
conception. Most probably, all described modi-
Plasma volume increase starts as early as 6 weeks
fications of maternal hemodynamics are triggered and reaches a maximum volume by the end of the
early every menstrual cycle, before conception, but third trimester of 5200 mL, which represents an
are too small to be detected. These modifications increase of 1200-1600 mL or 45% from non pregnant
are reversible, either at the end of the cycle with values.1,2 Although absolute volume values vary
menstruations, or within the first weeks or months from individual to individual, and among studies,
after delivery. Physiological modifications are only the overall percentage of increase is constant,
detectable when the amplitude of changes is between 45 and 50%.3 It is not clear whether the
sufficient, thus most of the time at the end of the importance of plasma volume is constant for an
first trimester of pregnancy. Functional as well as individual2,3 or depends on parity.4,5 Interestingly,
anatomical changes are observed in most systems, plasma volume increases throughout pregnancy, even
of which the cardiovascular and volume homeostasis when indexed to weight.2
systems are among the most important. The plasma volume increase is greater in multiple
These changes in maternal physiology are gestations and the increase is proportional to the
asymptomatic in normal pregnant women, resulting number of fetuses.6-8 More fetuses also means more
from an adapted process. They are nevertheless placental volume. It is probable that the amplitude
important to know for their implications in pathology of these changes is proportional to placenta volume
and its treatment. Most data we have are from time since the plasma volume increase is greater, on
radioactive molecules and cells, or dye techniques average, in cases of molar pregnancy.9 In the study
that were used in pregnant women. Modern non from Pritchard on hemodilution in patients with
invasive techniques do not provide the same possible molar pregnancies, after accounting for blood loss
measurements. If echocardiography, for instance, can associated with the pathology, he describes in 5 out
replace invasive measurements of cardiac output, we of 8 patients anaemia associated with significant
still lack non invasive techniques for such parameters hypervolemia.9 The increase in blood volume ranged
as plasma volume. from 25 to 51% at 9 to 24 weeks when compared
1150 Textbook of Perinatal Medicine

with non pregnant values in the same patients. This • Placental circulation: The placenta acts like a low
is consistent with the increase in cases of multiple pressure maternal arterio-venous shunt, affecting
pregnancy or increased fetal weight where placenta arterial blood pressure and cardiac output.
volume is proportionally increased. Placental circulation could thus explain part of the
On the other hand, in cases where placenta plasma expansion by induced hyperaldo-
volume is likely to be decreased, such as preeclampsia steronism.
and intra uterine growth restriction, plasma expan-
sion is reduced.10-12 Red Blood Cells
What happens at the very end of the third Total red blood cell mass increases by 20 to 40% by
trimester of pregnancy is largely debated in the term, which represents an absolute increase of 250
literature. Contradictory data on whether maternal to 450 mL. The rise is the consequence of greater
plasma volume declines in the last month of production of red blood cells, not longer lifetime,
pregnancy seem related to maternal positioning. The since iron supplementation increases even more the
increase in plasma volume seems to continue even in red blood cell mass.1 The increase in total red blood
the last month of pregnancy when mothers are in cell volume is proportional to weight gain in
the left lateral position, at least in twin pregnancies. singleton pregnancies as opposed to plasma volume
According to some authors plasma volume reaches which increases more than the weight gain. 2 The
a plateau at around 32 weeks in singleton preg- lesser increase in total red blood cell volume than
nancies, but continues to increase in twin preg- the physiologic plasma volume expansion is responsi-
nancies.6 This peculiarity explains the increased risks ble for pseudo anemia (Fig. 87.1). Biologically,
of pulmonary oedema in twin pregnancies when women have a haemoglobin at 1 standard deviation
using beta-mimetics or plasma expansion in the third (SD) below the mean, but the value should always
trimester be above 10.5g/dl.16 Hematocrit can physiologically
Why does plasma volume expand? go as low as 33%.17 The increase in red blood cell
There are several theories to explain why plasma mass starts, or is detectable, later than plasma
volume expands during pregnancy: volume, by the end of the first trimester. Twin preg-
• Hyperaldosteronism: Physiologic hyperaldostero- nancy is responsible for an increase in total red blood
nism during pregnancy can be responsible for cell mass but is not as proportional to weight gain as
plasma increase. Primary hyperaldosteronism is in singleton pregnancy. This increase in erythro-
responsible for hypervolemia in non-pregnant poiesis is probably influenced by placental secretion
patients, with an increase in plasma volume in of placental chorionic somatomammotropin,
the two cases described by Briglier and Forsham progesterone, or prolactin.18 This increase in erythro-
of 48 and 76%, with no changes in total red blood poiesis increases maternal needs for iron by about
cell volume.13 500 mg.18 Moreover, maternal haemoglobin , by an
• Influence of estrogens: Estrogens affect plasma increase in 2.3-diphosphoglycerate concentrations in
volume in many circumstances. Plasma volume red blood cells, has less affinity for oxygen to facilitate
expansion has been described in women using oral dissociation across the placenta to the fetus.19
contraception or hormonal replacement therapy This hemodilution, as a result of a greater increase
(i.e., estrogens in postmenopausal women).14,15 in plasma volume than total red blood cell mass, has
Estrogens are responsible for an increase in renin beneficial effects:
levels, which are responsible for an increase in • It limits haemoglobin loss in cases of prepartum
aldosterone level. or postpartum haemorrhage,
• Placental growth hormones implications are • It facilitates heart function by limiting the blood
uncertain. viscosity,
 Maternal Hemodynamic Changes in Pregnancy 1151
60%

50%

40%

Plasma volume
30%
Total red blood cell volume
Heart Rate
20%
stroke volume
cardiac output
10%
Mean arterial blood pressure

0%

-10%

-20%
Prior 8 weeks 16 weeks 24 weeks 32 weeks 40 weeks
Fig. 87.1: Evolution of different parameters throughout pregnancy, adapted from Ayala et al 40,
Capeless and Clapp 36, Robson et al 33, Thomsen et al 8, and pitkin17

• It facilitates placental microcirculation by limiting detectable only in the second trimester 21, and
blood viscosity, although the changes are not detected at the same
• It facilitates venous circulation to limit throm- moment, they are part of a continuum.
boembolic events16,20,
• It limits impaired venous return, reduction in Atria
cardiac output, and hypotension in the supine Left atrial diameter increases during pregnancy to
position. reach a plateau at around 30 wks. 24 Left atrial
diameter is related to vascular filling. The increase
Heart Anatomical Changes
in left atrial diameter during pregnancy is in relation
Ventricles with physiologic plasma volume expansion.
End-diastolic ventricular volume and ventricular
Vessels
mass increase throughout pregnancy. These
modifications, which include anatomical modification Changes are observed in large vessels during
of the maternal heart during pregnancy, take place pregnancy. Aortic compliance increases which,
without end-systolic volume or end-diastolic combined with decreasing vascular tone, results in
pressure increasing. 21,22 The combination of lower afterload and enhanced left ventricular
increasing end-diastolic ventricular volume and performance. 25 Venous distensibility increases
stable end-systolic volumes and end-diastolic throughout pregnancy as soon as the first trimester.26
pressure are the consequences of an increased Increasing capacity of the venous system is essential
compliance of the myocardium. It is not clear when to the physiological adaptation to plasma volume
cardiac compliance starts to increase during increase. It allows stability in venous pressure and
pregnancy. protects the right heart from too high preload
Ventricular mass increases as soon as the first pressure. The fall in vascular resistance occurs at the
trimester23 and the end-diastolic volume increase in same time as increasing compliance of large arteries
1152 Textbook of Perinatal Medicine

and veins as early as the 5th week of gestation.27 et al compared stroke volume, heart rate, and cardiac
The causal relation between increased vascular output at three different intervals in pregnancy, 20-
compliance, fall in vascular resistance, physiologic 24 weeks, 28-32 weeks, and 38-40 weeks.39 They
plasma volume expansion, and increasing cardiac performed their measurements in the supine, lateral
output during pregnancy are yet to be determined. decubitus and sitting position. Their main findings
were:
Cardiac Output • In the lateral decubitus, there is a fall in cardiac
Cardiac function was initially studied using invasive output by the end of the third trimester, as a result
techniques. It has even been used in term pregnancies of the fall in stroke volume.
more recently. 28 Echocardiography combined with • In the supine position, cardiac output values at
pulse- or continuous-wave Doppler measurements the very end of pregnancies are lower than non-
of cardiac output was validated against invasive pregnant values, as a result of a major fall in stroke
techniques in non pregnant patients. 29 These volume partly compensated by an increase in heart
techniques were later validated in pregnant rate.
women.30,31 Since then, most available data collected Evolution of cardiac output in late pregnancy was
has used non-invasive techniques. not coherent in the literature. This issue seems settled
Cardiac output depends on heart rate and stroke by the work of Clark et al in1989.28 In a study on 10
volume. Stroke volume increases throughout healthy singleton pregnant patients between 36 and
pregnancy as demonstrated by mid twentieth 38 weeks of gestation, using invasive central hemo-
century invasive procedures and more recent non dynamic assessment, they found a 44% increase in
invasive ultrasound examinations.32-34 The major cardiac output, with a 17% increase in heart rate and
parameters responsible for stroke volume increase 27% increase in stroke volume.28 Cardiac output does
are: not fall in late pregnancy.
• A moderate increase in preload and greater The variations in cardiac output measurements
venous return, in late pregnancy observed in older studies were
• A decreased afterload, increased arterial probably related to maternal positioning during
compliance and fall in vascular resistance measurements.
• An increased cardiac compliance and an intrinsic
myocardial contractility increase that is indepen- Blood Pressure
dent of loading conditions.35
Arterial Blood Pressure
Cardiac output increases by 30 to 50% during
pregnancy.28,30,32-35 The increase in cardiac output is Arterial blood pressure declines from 7th week.36
detectable as early as the 5th week of gestation. Early Using 24-hour mean blood pressure measurements
in pregnancy, the cardiac output increase is mostly in normal pregnancies, Ayala et al found a steady
the result of a stroke volume increase.33,36 Heart rate decrease of systolic blood pressure, diastolic blood
increase occurs later in pregnancy and contributes, pressure and mean arterial pressure up to the 21st
then, to the increase in cardiac output observed in week of gestation, followed by an increase to near
the second half of pregnancy33,37 (Fig. 87.1). non-pregnant values by the end of pregnancy 40 (Fig.
Caval syndrome in pregnancy was described by 87.1). When the circadian variations of blood pressure
Holmes in 1960. 38 Maternal position influences were studied, the lowest pressures were measured
hemodynamics. When in the supine position, the at 4 to 5 hours, and the highest at 12 to 21-hours.41
uterus compresses the inferior vena cava, affecting The magnitude of the difference between highest and
venous return to the right atrium. The reduction in lowest blood pressure within the same circadian
preload affects all hemodynamic parameters. Ueland period is maximal in the second trimester. These
 Maternal Hemodynamic Changes in Pregnancy 1153
modifications in blood pressure are influenced by 5. Pirani BB, Campbell DM, MacGillivray I. Plasma volume
maternal age, but not by parity.42 in normal first pregnancy. J Obstet Gynaecol Br
Commonw 1973; 80:884-7.
6. Rovinsky JJ, Jaffin H. Cardiovascular Hemodynamics
Vascular Systemic Resistance in Pregnancy. I. Blood and Plasma Volumes in Multiple
The total vascular resistance drop early in pregnancy Pregnancy. Am J Obstet Gynecol 1965; 93:1-15.
7. MacGillivray I, Campbell D, Duffus GM. Maternal
is probably due to low resistance placental metabolic response to twin pregnancy in primigravidae.
vascularization. It seems actually to be the first J Obstet Gynaecol Br Commonw 1971; 78:530-4.
parameter to be significantly modified in early 8. Thomsen JK, Fogh-Andersen N, Jaszczak P. Atrial
pregnancy.43 Duvekot et al performed serial weekly natriuretic peptide, blood volume, aldosterone, and
measurements from 5 to 8 weeks of gestation. They sodium excretion during twin pregnancy. Acta Obstet
Gynecol Scand 1994; 73:14-20.
unfortunately did not have non pregnant values and 9. Pritchard JA. Blood Volume Changes in Pregnancy and
compared the results with the 5 weeks’ gestation data. the Puerperium. Iv. Anemia Associated with Hydati-
It is not clear if this drop in total vascular resistance, diform Mole. Am J Obstet Gynecol 1965; 91:621-9.
due to the placental low resistance effect on the 10. Salas SP, Rosso P, Espinoza R, Robert JA, Valdes G,
maternal circulation, is a cause or a consequence of Donoso E. Maternal plasma volume expansion and
hormonal changes in women with idiopathic fetal
plasma expansion and hyperaldosteronism. The only growth retardation. Obstet Gynecol 1993; 81:1029-33.
significant changes observed from the 6th to the 8th 11. Duvekot JJ, Cheriex EC, Pieters FA, Peeters LL. Severely
week of gestation compared to the 5th week were impaired fetal growth is preceded by maternal
a raise in plasma 17β-estradiol and a drop in plasma hemodynamic maladaptation in very early pregnancy.
17-hydroxyprogesterone. Interestingly, Walters and Acta Obstet Gynecol Scand 1995; 74:693-7.
12. Brown MA, Gallery ED. Volume homeostasis in normal
Lim described in 1969 a fall in total vascular resistance pregnancy and pre-eclampsia: physiology and clinical
when estroprogestative contraceptives were given implications. Baillieres Clin Obstet Gynaecol 1994; 8:287-
to women. 15 The total vascular resistance remains 310.
low throughout pregnancy and is still 21% lower than 13. Biglieri EG, Forsham PH. Studies on the expanded
non pregnant values at 36-38 weeks of gestation.28 extracellular fluid and the responses to various stimuli
in primary aldosteronism. Am J Med 1961; 30:564-576.
14. Luotola H, Pyorala T, Lahteenmaki P, Toivanen J.
CONCLUSION Haemodynamic and hormonal effects of short-term
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