Medical Problems in Pregnancy 0025-7125/89 $0.00+ .

20

The Fetus as a Patient

Edward R. Newton, MD*

The obstetrician has a uniquely difficult role to play in the care of

pregnant women with intercurrent medical disease as one treatment plan
will affect two patients, the mother and the fetus. The specter of diethyl-
stilbestrol and thalidomide continue to remind us of the tragedy caused by
disregard for fetal welfare. Unfortunately, incomplete knowledge of normal
and abnormal fetal and maternal physiology hinders the formulation of a
treatment plan. The effects of treatment on fetal status can be measured
only through indirect means: (1) biochemical tests of maternal serum; (2)
percutaneous needle aspirations (amniocentesis, cordocentesis); (3) ultra-
sound; and (4) electronic fetal heart rate monitoring. There is no consensus
on the best indirect measure of fetal status. The issues of disease prevalence
and test efficacy have been applied only recently to fetal testing. Treatment
plans must account for the recognized and unrecognized risks of intervention
based on the low predictive power of these tests.
This article reviews perinatal definitions, causes of perinatal mortality
and morbidity, the efficacy of high-risk identification, and the common meth-
ods of fetal surveillance. The predictive power and complications of fetal
surveillance tests are reviewed.

PERINATAL DEFINITIONS

Perinatal mortality statistics are the crude rulers by which governments,

lawyers, epidemiologists, and clinicians measure the quality of obstetric care.
When pregnancy experience associated with intercurrent medical disease is
reported in nonobstetric literature, pregnancy wastage is often ill-defined.
Clear definitions are necessary in order to accurately define the added con-
tributions of the intercurrent medical disease to pregnancy wastage.
A termination of a pregnancy prior to the 20th week is defined as an
abortion. This definition is confused by European literature which defines
abortion as pregnancy loss up to 28 weeks' gestation, and the legality of
therapeutic abortion up to 24 weeks in the United States. However, from
*Assistant Professor, Department of Obstetrics and Gynecology, University of Texas Health
Science Center at San Antonio, San Antonio, Texas
Medical Clinics of North America-Vo!. 73, No. 3, May 1989
517
518 EDWARD R. NEWTON

a pathophysiologic point of view, a major breakpoint occurs after the first 10

to 13 weeks. The majority of abortions, 25 to 30 per cent of all conceptions,
occur in the first trimester.45 Chromosomal and developmental aberrations
are associated with 50 to 80 per cent of pregnancy wastage in the first
trimester. Such disorders are related to preconceptual and conceptual events.
The relationship between these disorders and intercurrent medical disease
is unknown. After the demonstration of fetal heart activity at 8 to 10 weeks
by real-time ultrasound or 10 to 13 weeks by Doppler ultrasound, the in-
cidence of pregnancy loss falls to 2 to 4 per cent,40 and the majority of the
losses relate to factors common to the losses in the latter part of gestation-
that is, structural abnormalities of the uterus, abnormalities of placentation,
premature rupture of membranes, infection, idiopathic preterm labor, and
maternal diseases (pre-eclampsia). An abnormal maternal environment
caused by an intercurrent medical disease will increase pregnancy loss
through the latter mechanisms.
All jurisdictions in the United States require the certification of a live
birth that results from a pregnancy of more than 20 weeks' duration. Most
jurisdictions have included morphometric criteria as well as gestational age
as additional requirements for the certification of a stillbirth. These criteria
include birth weight greater than or equal to 500 g or a crown-heel length
greater than or equal to 25 cm. These criteria may exclude some fetuses as
normal growth rates do not reach these criteria until 21 to 23 weeks' ges-
tation.
A stillbirth or fetal death is a death prior to birth. The fetal death rate
is calculated per 1000 live births and is 7 to 9 per 1000 live births in the
United States. The fetal death rate has fallen from 17.1 per 1000 live births
in 1955. An intrapartum death is a fetal death that occurs during labor; it
occurs in less than 1 per 1000 live births.
A neonatal death is defined as a death occurring within the first 28 days
of life. The neonatal death rate is calculated per 1000 live births and is
between 6 to 8 per 1000 live births in the United States. The neonatal death
rate in the United States has fallen from 19.1 in 1955. An early neonatal
death is a death occurring within 7 days of life. A postneonatal death occurs
between 28 days and 1 year of life. While these deaths include those caused
by accident, sudden infant death syndrome, or childhood infection, an in-
creasingly larger percentage (5 per cent) of postneonatal deaths result from
perinatal causes postponed as a result of technological support systems. 5
Perinatal mortality is the sum offetal and neonatal deaths. The perinatal
mortality rate is calculated per 1000 total births; it is between 11 to 14 per
1000 births in the United States. Infant mortality is the sum of neonatal and
postneonatal mortality. The infant mortality rate is calculated per 1000 live
births and is between 9 to 11 per 1000 live births in the United States.
Perinatal and infant mortality rates in the United States are often com-
pared to those of other countries. Despite the technological sophistication
of its health care system, the infant mortality of the United States ranks well
behind most other developed countries (14 to 16th). However, this may be
due to the high-risk character of the United States population: more teenage
pregnancies, less prenatal care, and a more heterogeneous population. In
fact, when the data are standardized by birth weight categories, the birth
THE FETUS AS A PATIENT 519

Table 1. Causes of Maternal Mortality USA

PER CENT OF DEATH

1974-1978 17 19838
Embolism 20 26
Hypertensive disease 17 8
Hemorrhage 13 8
Infection 8 8
Cerebrovascular accident 4 10
Anesthesia related 4 5
Abortion 17
Other 17 15
Cardiomyopathy 13

weight specific mortality rates of the United States are near the top of
international rankings. ll Several authors have observed 22 ,46 that despite no
decline in the overall rate of premature birth (6 to 7 per cent), an improve-
ment in perinatal care (70 to 80 per cent) and birth weight distribution (20
to 30 per cent) has been associated with the fall in mortality rates in the
United States.
A maternal death is a death of a pregnant woman or a woman who was
pregnant within 42 days of death. The maternal mortality rate is calculated
per 100,000 live births and is 7 to 11 per 100,000 live births in the United
States. Some jurisdictions will include deaths occurring up to 90 days after
a pregnancy. A direct maternal death is a death arising from an obstetric
complication, for example, a postpartum infection. An indirect maternal
death occurs as a result of pre-existing medical disease aggravated by preg-
nancy, for example, pulmonary hypertension. A nonobstetric death occurs
during pregnancy or within the 42-day window, but is not related to preg-
nancy (such as homicide).
The under-reporting of perinatal and maternal mortality has been the
focus of several recent studies. 7 ,8,23,39 Death certificates are the instrument
used to monitor maternal and perinatal deaths. This instrument will miss
20 to 30 per cent of perinatal deaths and 30 to 60 per cent of maternal deaths.
The improvement in ascertainment has come through linkage of death cer-
tificates and live birth certificates and increased collaboration with state
maternal mortality committees. The failure to ascertain a maternal death
occurs most often after surgical complications (anesthesia or thrombosis) or
when intercurrent medical disease (peripartum cardiomyopathy) is present.
The failure to ascertain perinatal death occurs with misclassification of very
premature infants (20 to 23 weeks' gestation) as abortions and the failure of
undertakers to complete the documentation.

CAUSES OF MORBIDITY AND MORTALITY

Prior to 1980, the largest proportion of maternal deaths was associated

with hypertension, infection, or hemorrhage. Recent reviews (Table 1) of
maternal mortality demonstrate that the complications of surgery are more
likely to cause maternal death. These observations coincide with increased
520 EDWARD R. NEWTON

550 90

500 /
/
/ 80
/
/
450 /
/

,. 70
/
/
/
400
I Percent
I
Perinatal I
I 60 Free of
350 I
Mortality I Short-
I
per 300 I
I
50 Term
I
1000 I
I Morbidity
Births 250 I or

_.
I
I 40
I Neonatal

---
I
200 Death
30

20

- - - -_ _ _~10

o
26-27 28-29 30-31 32-33 34-35
Gestational Age (Weeks)

Figure 1. Perinatal morbidity and mortality by gestational age. PMN = perinatal mor-
tality; free = free of major short-term morbidity or death.

ascertainment of surgically related deaths and an unprecedented increase

in the number of cesarean deliveries. In the early 1970s, the cesarean de-
livery rate was 5 to 7 per cent and in 1985 to 1986 it was 22 to 24 per cent.
While the safety of cesarean section has improved, its morbid and mortal
risks exceed those of vaginal delivery. The risk of death, infection, throm-
bosis, and transfusion is 4- to lO-fold higher after cesarean sections than after
vaginal deliveries. The increasing numbers of surgical complications predict
an increased likelihood of medical consultation for bleeding disorders, an-
esthetic complications, and severe infections.
In the 1960s, there was little likelihood of intact survival of a neonate
born at less than 30 weeks' gestation. Most tertiary case perinatal centers
currently expect better than 90 per cent survival with 80 per cent of survivors
having no major long-term handicaps (Fig. 1, Table 2). The major causes of
perinatal death are prematurity (40 per cent), anoxia (25 per cent), and
congenital abnormalities (18 per cent) (Table 3). Specific maternal compli-
cations are associated with higher or lower perinatal mortality rates (Table
4). Intercurrent medical disease may increase the likelihood of one or more
of these complications, thus considerably increasing the perinatal risk of
pregnancy. For example, chronic hypertension increases the risk of third
trimester bleeding and intrauterine growth retardation. While chronic hy-
pertension without complications has only a modest increase in perinatal
death (6 per cent), the combination with bleeding and intrauterine growth
retardation may increase the risk of perinatal death lO-fold.
THE FETUS AS A PATIENT 521

Table 2. Survival Free of Long-term Handicap

CESTATIOl\ (WEEKS) PER CENT

24 9
26 41
28 67
30 81
32 90
34 9.5
36 97
Data from Goldenberg RL, Nelson KG, Davis RO, et al: Delay in delivery: Influence of
gestational age and duration of delay on perinatal outcome. Ohstet Gynecol 64:480-486, 1984.

While improvement in birth weight specific perinatal mortality and

long-term morbidity has been dramatic, the incidence of short-term mor-
bidity is considerable (Table 5). Figure 1 illustrates the discrepancy between
perinatal mortality and the incidence of survival free of short-term morbidity.
While 85 to 95 per cent of infants survive between 28 to 32 weeks, only 30
per cent have a neonatal hospitalization free of short-term morbidity. Short-
term morbidity includes hyaline membrane disease, assisted ventilation,
bronchopulmonary dysplasia, intraventricular hemorrhage, seizures, hydro-
cephalus, sepsis, necrotizing enterocolitis, neonatal death, or infant death
more than 28 days after birth and prior to discharge. Until recently, perinatal
mortality has been the unit of measure. Today, obstetric judgment is meas-
ured by the incidence of neonatal morbidity in gestations over 28 weeks.
Preterm neonates contribute to 75 to 85 per cent of perinatal mortality,
morbidity, and health care costs. It is estimated that the cost per survivor
of a less than 1000-g birth weight is between $50,000 to $150,000. 2 . 24 The

Table 3. Causes of Perinatal Death

Anoxia 26%
Immaturitv 2.5%
Congenital ahnormality 18%
Respiratory death 17%
Infection 8%
Other 6%
Data from Newton ER, Kennedy JL, Louis F, et al: Obstetric diagnosis and perinatal
mortality. AmJ Perinatol 4:300-304, 1987.

Table 4. Obstetric Diagnosis and Perinatal Death

OBSTETRIC DIAGNOSIS PERI"IATAL DEATH RATE

Intrauterine growth retardation 217

Preterm labor 163
Third trimester bleeding 1.58
Premature rupture of memhranes 72
Hypertension/pre-eclampsia 60
Diabetes 26
Postdates 17
Others (including normal pregnancies) 6
Data from Newton ER, Kennedy JL, Louis F, et al: Obstetric diagnosis and perinatal
mortality. Am J Perinatol 4:300-304, 1987.
522 EDWARD R. NEWTON

Table 5. Incidence of Neonatal Morbidity and Mortality by Gestational

Age 1011/84 to 10/31186*
PER CE'JT BY GESTATIOl\AL AGE

25-26 27-28 29-30 31-32 33-34

CO~IPLICATION 11=53 11= 71 11=84 11 = 154 11 = 180

Hyaline membrane disease 81 61 49 24 22

Intraventrieular hemorrhage 17 24 14 8 3
Seizures 13 7 6 2 0
Sepsis 13 7 6 3 3
Necrotizing enterocolitis 15 10 11 8 2
Neonatal death 13 13 7 2 3
Late neonatal deatht 6
* Data from Newton ER, Kennedy JL n, Kennedy JL Ill, et al. St. Margaret's Hospital
for Women, Boston, MA (unpublished data).
t Death occurring after 28 days and before discharge.

majority of the adverse outcomes relate to the diseases of prematurity such

as respiratory immaturity, intraventricular hemorrhage, and necrotizing en-
terocolitis. Table 6 illustrates the benefits of delaying delivery by 1 week.
A reduction in neonatal mortality does not occur between 30 to 35 weeks;
however, there is a 15 to 30 per cent reduction in short-term morbidity for
each week delay in delivery until 33 to 34 weeks.
On the other hand, most perinatal complications have a risk of utero-
placental insufficiency with subsequent death or long-term neurologic mor-
bidity from the asphyxial insult. This risk may be additive as placental reserve
is irreversibly compromised through thrombosis or infarction. Figure 2 de-
scribes the inverse relationship between the risk of death from prematurity
and gestational age, on one hand, and the positive relationship between
death from anoxia and gestational age, on the other. The obstetrician must
decide the point at which the risks of continued in utero stress (anoxia)
outweigh the risks of prematurity.
The gestational age at which the obstetrician intervenes with delivery
is affected by the reliability and validity of the gestational age estimate, the

Table 6. The Effect of Delaying Delivery by 1 Week

CHANGE IN THE INCIDENCE (PER CENT) WITH DELAY
IN DELIVERY BY 1 WEEK
GESTATIONAL AGE AT Ol\SET
OF CO\IPLICATIONS N eOllatal Death Short-term Morbidity
26 15 o
27 5 10
28 3 8
29 o (-4)
30 5 14
31 o 28
32 o o
33 o 16
34 o 4
Data from Newton ER, Kennedy JL 11, Kennedy JL Ill, et al. St. Margaret's Hospital for
Women, Boston, MA (unpublished data).
THE FETUS AS A PATIENT 523

70 , prematurity"

60

50
Percent
of
40
Perinatal
Mortality 30

20

10

o ~ ____________- L______________L -__________ ~~

24-28 29-32 33-36 ~37

Gestational Age (Weeks)

Figure 2. Causes of perinatal mortality by gestational age. * Death from prematurity

includes those deaths associated with respiratory failure, necrotizing entcrocolitis, intraven·
tricular hemorrhage, or immaturity. Data from Newton ER, Kennedy JL, Louis F, et al:
Obstetric diagnosis and perinatal mortality. Am J Perinatol 4:300-304, 1987.

availability of sophisticated perinatal care, the efficacy and dangers of inter·

ventions to delay delivery, the effects of intercurrent medical disease, and
the ability to monitor the fetus.
The single most important predictor of neonatal morbidity and mortality
is the gestational age. A reliable and documented gestational age estimate
must be obtained in all pregnant women. An estimate of gestational age is
based on the recorded first day of the last menstrual period (LMP). In a
regularly ovulating woman, the LMP is the most reliable predictor of the
estimated date of confinement (EDC). Depending on the population, 20 to
50 per cent of women will have a confused EDC based on their LMP.
Irregular cycle length, abnormal bleeding, and late or no prenatal care cause
the confusion. A urine pregnancy test-that is, a home pregnancy test-has
a sensitivity of 80 per cent and a specificity of 95 per cent and is usually
positive 7 to 10 days after missed period. Urine pregnancy tests performed
in some clinics and hospitals can detect human chorionic gonadotropin at
the time of the expected period. Serum pregnancy tests can detect a preg·
nancy 3 to 7 days prior to expected period. If a positive pregnancy test is
recorded prior to the second missed period in a previously regularly cycling
woman, the EDC should not be changed by later ultrasound findings.
Several other clinical signs and symptoms may confirm that EDC based
on an LMP. These include a first pelvic examination at less than or equal
524 EDWARD R. NEWTON

to 12 weeks, fetal heart tones recognized by Doppler ultrasound at 9 to 12

weeks, fetal heart tones recognized by auscultation by 20 weeks, and/or
maternal perception of fetal movement by 22 weeks. Multigravidas may
know they are pregnant by how they feel and, if these feelings occur prior
to the second missed period, the LMP is confirmed.
Ultrasonographic measurements have been used extensively to predict
gestational age and EDC. The measurements include gestational sac size,
crown-rump length, biparietal diameter, femur length, abdominal circum-
ference, and head circumference. The most widely used are the biparietal
diameter and the femur length and, when measured between 16 to 24 weeks,
they can predict an EDC within 10 days with a 95 per cent accuracy. This
is no better than an EDC determined by a recorded LMP in a woman with
a normal cycle length (26 to 30 days). When LMP is not accurate, two
consistent ultrasound examinations performed at least 4 weeks apart between
16 to 30 weeks adequately predict an EDC. Ultrasonographic measurements
after 30 weeks can predict an EDC only within 21 days with an accuracy of
95 per cent.
Birth weight is a proxy for gestational age in predicting perinatal out-
come. When the LMP is inaccurate and the first ultrasound is obtained after
24 weeks, the obstetrician must rely on estimated fetal weight for estimating
neonatal risks. The mean per cent error of an estimated fetal weight com-
pared to actual birth weight is ± 5 to 7 per cent between actual birth weights
of 1500 to 4000 g. Below 1500 g and above 4000 g, the error is ± 10 to 15
per cent.
High-risk consultation, in utero transportation by regional to perinatal
centers, and specialized neonatal care reduce neonatal morbidity and mor-
tality.1O,16,24,29,36 Maternal transport, as opposed to neonatal transport, in-
creases neonatal survival despite the fact that the neonates of maternal trans-
ports are at higher risk. 29 Not only are short-term morbidities reduced, but
long-term neurologic deficit may be reduced by 50 per cent. IQ
A lack of knowledge about the pathophysiology of preterm labor has
limited obstetricians to a few crude and sometimes dangerous agents to
prevent preterm birth and neonatal morbidity. Advanced labor and other
complications of pregnancy eliminate 80 per cent of potential candidates for
tocolytic therapy. Tocolytic therapy is not used in the presence of fetal
compromise, infection, maternal bleeding, hypertension, or rupture of mem-
branes. In appropriate candidates, a wide variety of agents have been at-
tempted: alcohol, beta-mimetics, prostaglandin synthetase inhibitors, mag-
nesium sulfate, and calcium channel blockers. Most regimens stop labor for
48 hours in 60 to 80 per cent of cases, but term delivery occurs in only 40
to 60 per cent. Despite the large quantity of tocolytics that have been used
in the United States, the incidence of preterm birth remains the same.
In addition, these agents are not without risk and their complications
may be the reason for medical consultation. Ritodrine hydrochloride, a beta-
mimetic, is the only Food and Drug Administration (FDA) approved to-
colytic. Chest pain (10 to 15 per cent), subendocardial ischemia (4 to 6 per
cent), and pulmonary edema (1 to 2 per cent) are major complications. Most
patients will have hyperglycemia (120 to 200 mg per dl) and a 0.6 to 1.0 mg
per dl drop in serum potassium levels. Occasionally, patients will require
THE FETUS AS A PATIE~T 525
an insulin drip to treat the hyperglycemia or potassium therapy when the
serum potassium falls below 2.5 mg per dl.
Magnesium sulfate is another commonly used tocolytic. Therapeutic
levels are 5.0 to 8.0 mEq per L and toxic levels (greater than or equal to
10 mEq per L) are manifest by progressive neuromuscular blockade leading
to respiratory paralysis and cardiac arrest. The antidote is intravenous cal-
cium gluconate or calcium chloride in a 10 per cent solution; 10 ml (1 g) is
injected slowly.
Specific infant-related interventions that are designed to prevent neo-
natal complications are also crude. Most interventions are directed at re-
ducing respiratory morbidity and mortality. Antepartum glucocorticoid and
surfactant are two such interventions. In the last 10 years, many (but not
all) institutions give mothers glucocorticoids to reduce the risk of hyaline
membrane disease. The most common drugs and dosages are betamethasone
12 mg every 12 hours intramuscularly (IM) for two doses, dexamethasone 5
mg every 12 hours IM or intravenously (IV) for four doses, or hydrocortisone
500 mg every 8 hours IV for four doses. The anti-inflammatory and glucose
intolerance associated with glucocorticoids lasts 2 to 3 days. Recently, the
injection of artificial surfactant into the respiratory tree of premature neo-
nates prior to their first breath has been shown to reduce respiratory dis-
tress. 21 While the latter two interventions significantly reduce neonatal res-
piratory morbidity, the premature infant still has significant morbidity
associated with the immaturity of other organ systems.
The malpractice crisis has caused physicians, patients, lawyers, and
governmental agencies to focus on the timing and etiology of perinatal hy-
poxic insult and subsequent long-term neurologic handicap. The legal and
medical community have incorrectly focused on intrapartum events as the
major cause of long-term deficit. Most chronic neurodevelopmental handi-
caps result from injury weeks before birth. Support for this fact is derived
from an understanding of fetal neurodevelopment, the pathophysiology of
perinatal asphyxia, histologic markers of asphyxial injury, and epidemiologic
studies. 33
Gestational age, metabolic activity, and the degree of perfusion deter-
mine the sensitivity of the fetal central nervous system to asphyxia. The
metabolic activity and the degree of perfusion to various parts of the brain
vary with gestational age. A large portion of cortical neurocellular differ-
entiation and innervation occurs in the third trimester.33 The differentiation
and growth require an increased metabolic rate and perfusion; thus, these
areas are most sensitive to hypoxia. At 24 weeks, the subependymal germinal
matrix, brain stem, and periventricular areas are areas of high metabolic rate
and perfusion. On the other hand, the cerebral cortex is less metabolically
active with less perfusion. Although a hypoxic insult may severely damage
the periventricular area and germinal matrix, the cortex is relatively insen-
sitive. Over the next 12 weeks, there is a gradual increase in the activity
and perfusion of the periventricular areas and an increasing activity and
perfusion of the cortex. In the term fetus and the adult, the cerebral cortex
and brain stem have a high metabolic activity and perfusion. The border
areas between arterial trees (watershed zones) are at risk for hypoperfusion
from hypotension, increased intracranial pressure, or both. The major wa-
526 EDWARD R. NEWTON

tershed areas include the periventricular and middle parasagittal areas of

the cortex. Chronic hypoxia, that results in cardiomyopathy and increased
intracranial pressure, places these areas--especially the parasagittal cortical
regions with its higher metabolic rate-at risk for permanent injury. The
relationship between gestational age and tissue sensitivity to asphyxial injury
predicts that cerebral palsy is an injury of the premature brain, and decreased
cortical function may be the effect of preterm or term injury.
Fetal neurosurgery on primate models confirms the latter observation. 33
Rhesus monkey feti underwent controlled cerebral cortical resections at
midge station with functional and anatomic examination after term birth.
These studies demonstrate that, in the Rhesus monkey, thalamocortical in-
nervation of the occipital lobe occurs between 91 to 124 embryonic days (22
to 30 weeks' human gestation). Cortico-cortical and callosal fibers innervate
the cortex between 124 to 150 embryonic days (30 to 36.5 weeks). These
innervations correlate with the increased metabolic activity and perfusion
of the cortex. Removal of the frontal associative cortex between 102 and 119
embryonic days (24.5 to 29 weeks) caused little change on testing offunction
after birth; on the other hand, injury later in gestation produced permanent
functional changes.
An episode of acute asphyxia severe enough to cause permanent brain
damage is followed by a consistent pattern of deficit and recovery whether
the victim is a Rhesus monkey, a human neonate, a child after a near drown-
ing, or an adult after a cardiac arrest. Invariably, there is a period of 6 or
more hours during which the neonate is comatose or deeply stuporus. There
is little spontaneous or elicited movement. Between 12 and 24 hours, there
is an apparent improvement of activity. There is later a variable period of
ob tun dation or hypotonia. Early neonatal seizures usually occur 12 to 36
hours after an insult in 30 to 50 per cent of neonates. However, seizures
can occur at any time in the presence of metabolic disorders, intracranial
trauma, intracranial hemorrhage, or in the presence of scar tissue from
previous antenatal injury.
An acute asphyxial insult severe enough to cause permanent brain dam-
age must necessarily produce damage in other organs. In fact, hypoxic car-
diomyopathy manifested by electronic fetal heart rates monitoring is an
essential component of brain injury. Between 30 to 60 per cent of infants
with 5-minute Apgar scores less than 5 demonstrate significant injury to their
lungs, heart, gastrointestinal tract, or kidneys.33
Most children with cerebral palsy or mental retardation do not have
neonatal signs consistent with acute asphyxial insult. 31 ,33 Sixty-eight per cent
of children with birth weights exceeding 2500 g and cerebral palsy had a 5-
minute Apgar score of 6 or more and no signs of asphyxial insult.
Evidence of prenatal injury can be shown by scar tissue in the brain,
teeth, and/or cartilage. Histologic study of these tissues demonstrates an
increasing incidence of prenatal injury with increasing gestational age. 33 For
example, a study of hypoxic injury to cartilage in 570 stillbirths and neonatal
deaths occurring within 48 hours of birth showed that 60 per cent of children
born at 32 weeks' gestation or less showed evidence of prenatal injury. The
proportion of term infants with prenatal injury was 75 per cent and in over
90 per cent of those delivered at or after 41 weeks.
THE FETUS AS A PATIENT 527
Multiple retrospective and prospective studies have demonstrated the
lack of relationship between intrapartum care at term and long-term neu-
rologic handicap.33 The most reliable data come from the National Collab-
orative Perinatal Project. This was a multicentered, prospective project that
registered 54,000 pregnant women between 1959 and 1966 and followed
them and their offspring until the children were 7 years old. Each mother
and child had standardized ascertainment and testing of information. In
infants born with birth weights greater than or equal to 2500 g, less than 5
per cent of the variance in the incidence of cerebral palsy, nonfebrile sei-
zures, IQ scores, and visual motor performance scores can be explained by
intrapartum complications. Maternal mental retardation, breech presenta-
tion (but not delivery), severe proteinuria, maternal seizures during preg-
nancy, and maternal thyroid disease were the significant risk factors for
cerebral palsy. Socioeconomic class, race, maternal age, maternal education,
and maternal IQ explained 37 per cent of the variance in IQ scores. Prenatal
and antenatal factors, including prior perinatal loss, smoking, hypertension,
anemia, and alcoholism, were associated with only 2 per cent of the variance
in IQ scores. Intrapartum factors and signs of perinatal anoxia explained less
than 1 per cent of the IQ scores.

HIGH-RISK INDEX

The ability to predict the degree at which a fetus is at high risk because
of an intercurrent medical disease or obstetric complication is critical to
obstetric management. If recognized prior to pregnancy, a woman designated
at risk for a complicated pregnancy may not get pregnant. If the pregnancy
is designated as high-risk, it may be more intensively and specifically mon-
itored for signs of compromise. Finally, early high-risk identification allows
for in utero transport rather than more complicated and costly neonatal
transport.
There are several qualities that are important to an effective high-risk
index.
1. The independent and dependent variables must be clearly defined in
clinically applicable terms.
2. The independent variables and their relative strength should be identified
through appropriate statistical techniques. This requires extensive pro-
spective ascertainment of clinical variables in a large heterogeneous pop-
ulation.
3. The index should identify only a small portion of the population as high-
risk, yet capture the majority of the "bad" outcomes. Thus, the index
should have high predictive values of positive and negative tests. Without
these characteristics, an excess number of unnecessary interventions may
be performed. These tests are the basis of receiver operating characteristic
(ROC) analysis. 28
4. The index must be practical and easy to administer so as to promote its
use.
5. The interventions based on a high-risk designation must be evaluated as
to efficacy and risk.
There are several indices currently used. 12 Table 7 depicts the accuracy
528 EDWARD R. NEWTON

Table 7. Efficacy of High-risk Indices

PREDICTIVE
PREVALENCE PER CENT OF VALUE OF
11\ GENERAL POPULATION POSITIVE
DEPENDENT POPULATION DESIGI\ATED AS SEI\SITIVITY SPECIFICITY TEST
VARIABLE (PER CEI\T) HIGH RISK (PER CENT) (PER CENT) (PER CENT)

Perinatal 2 34 75 67 5
mortality
Preterm birth 6 30 56 72 11
«37 weeks)
Low birth weight 8 34 46 68 11
«2500 g)
Low 5-minute 2 15 53 88 8
Apgar (";6)

of a typical index in predicting perinatal mortality, preterm birth, low birth

weight, and low 5-minute Apgar scores. Approximately one third of the
screened population will be defined as high-risk and will encompass 50 to
75 per cent of bad outcomes. The score required to be designated as high-
risk is determined by the proportion of the normal population the investigator
is Willing to classify as high-risk to capture a threshold proportion of bad
outcomes. The maximum proportion of the population designated as high-
risk depends on the cost of intervention in terms of patient or physician
time, material costs, and the number of normal women and fetuses exposed
to the risks of unnecessary intervention. The currently used antepartum
high-risk indices accept an 80 to 90 per cent likelihood of a normal outcome
despite a high-risk score.
Multivariate analysis reveals the independent risk of each factor. Table
8 depicts selected reproductive and medical risk factors for prematurity. 38
The prevalence, logistic odds ratio, and attributable risk are presented.
Attributable risk is the fraction of all cases of disease that are independently
associated with the risk factor. The individual contribution of anyone risk
factor is small (less than 8 per cent). When the relative risk of a factor is
high but the prevalence is low (history of myomectomy), the overall impor-
tance of the risk factor is small. On the other hand, a risk factor of high
prevalence explains a larger proportion of bad outcomes despite a low relative
risk (tobacco abuse). The limitations of multivariate models are discussed in
detail by Guzick et al. I4
Can intervention based on high-risk identification prevent a bad out-
come? While it is clear that high-risk obstetrical consultation, in utero trans-
port, and tertiary neonatal care will improve neonatal mortality and mor-
bidity, the effectiveness of preterm delivery prevention programs is
uncertain. Publications supporting premature delivery prevention programs
are descriptive and report lower than expected incidence of preterm birth
and neonatal morbidity.3,20 However, gestational age at the first prenatal visit
and the frequency and intensity of prenatal visits may be just as important
as other interventions,30 Indeed, Main et al25 have seriously challenged the
efficacy of one preterm delivery prevention program. A population of poor
inner-city women with a high score on the Creasy premature delivery index
THE FETUS AS A PATIENT 529
Table 8. Prevalence, Odds Ratio, and Attributable Risk
of Selected Risk Factors for Preterm Birth
ATIRIBUTABLE
PREVALENCE LOGISTIC RISK
RISK FACTOR (PER CENT) ODDS RATIO (PER CENT)

Reproductive
Previous myomectomy 0.04 22.8 0.9
Incompetent cervix 0.3 12.5 3.3
Multiple gestation 0.6 6.7 3.3
Bleeding ~20 weeks 0.8 5.3 3.3
Bleeding <20 weeks 0.7 4.1 2.1
Previous preterm birth 5.6 2.5 7.2
Habitual abortion 1.3 2.2 1.5
Pre-eclampsia, mild 1.6 1.7 1.1
Medical Disease
Anemia, HCT ~27% 1.0 2.2 1.2
Renal disease 1.4 2.1 1.5
Marijuana abuse 0.1 2.1 0.1
Inpatient surgery 1.1 1.9 1.0
Narcotic abuse 0.5 1.9 0.4
Chronic hypertension 0.8 1.8 0.6
Psychiatric hospitalization 1.1 1.4 0.4
Tobacco abuse 9.5 1.4 3.7
Previous urinary tract infection 11.4 1.1 1.1
Data from Ross MC, Hobel CJ, Bragonier JR, et al: A simplified risk scoring system for
prematurity. Am J Perinatol 3:339-344, 1986.

were randomized between standard high-risk care and a formalized intensive

preterm delivery prevention program. Despite an increased intervention
rate as measured by incidence of tocolytic therapy, cerclage, number of
prenatal visits, and number of pelvic examinations, there was no statistical
difference in the incidence of preterm delivery between the two groups.

THE TECHNOLOGY OF FETAL DIAGNOSIS

Prior to the mid 1960s, few techniques were available to evaluate the
health of the fetus. Since then, there has been an explosion of technology
designed to indirectly or directly diagnose fetal status. The technology has
been directed at the diagnosis of chromosomal or developmental defects,
disorders of fetal growth, uteroplacental insufficiency, fetal infection, Rhesus
disease, or fetal lung maturity. These modalities have been rightfully credited
with reducing morbidity and mortality in many infants. However, fetal di-
agnosis is not without risk. The risks are not just the physical risks of the
procedure, but also include the risks of intervention based on the inaccuracy
of the test.
The use of any test requires the measurement of its validity, reliability,
sensitivity, specificity, the predictive values of positive and negative tests,
practicality, compliance, and cost. The following section will review the
current methods of fetal diagnosis with respect to the latter test qualities.
530 EOWARO R. NEWTON

Maternal Serum Alpha-fetoprotein

Maternal serum alpha-fetoprotein (MSAFP) is a blood test performed
at 15 to 20 weeks' gestation. The value, measured in ng per dl, should be
corrected for weight, presence of maternal diabetes, and race. This value is
compared to the median values for the patient's gestational age. The result
is reported as multiples of the median (MoM). Between laboratories, there
is a 22 per cent variation in results at low concentrations of MSAFP (0.3
Mo M) and a 12 per cent variation at high concentrations (2.5 MoM).19
Patients with elevated MSAFP (more than 2.5 Mo M) on repeat ex-
amination (2 per cent of the total population) are at risk for neural tube
defect. Approximately one half of these patients will have other diagnoses
after an ultrasound (wrong gestational age, anencephaly, fetal death, multiple
gestation, or oligohydramnios). An amniocentesis for amniotic fluid alpha-
fetoprotein and acetylcholinesterase is recommended in the remaining 1 per
cent. Ninety per cent of these patients will have normal amounts of alpha-
fetoprotein in their amniotic fluid. While they do not have an open neural
tube defect, these patients are at greater risk for a complicated pregnancy. 6
The remaining 10 per cent have an open neural tube defect. In total, only
5 per cent of patients with an initial elevated MSAFP will have a neural
tube defect. This low predictive value necessitates the sequence of expensive
and dangerous diagnostic tests in order to reduce the likelihood of performing
a second trimester abortion unnecessarily.
In women 35 years or younger, low values of MSAFP (less than or equal
to 0.5 MoM) have been associated with increased risk of chromosomal ab-
normalities, especially Down's syndrome and trisomy 18. 19 There is an in-
creased risk of Down's syndrome in women older than 35 years but the age-
related risk (1 :270) already dictates the discussion of amniocentesis for
diagnosis of chromosomal abnormalities. If MSAFP screening is performed
on women less than 35 years old, 3.6 per cent will be judged at risk for
chromosomal abnormalities based on MSAFP and age-adjusted risk of a
defect. Forty per cent will have ultrasound findings that will obviate the
need for amniocentesis. Between 1 to 2 per cent of those patients who
undergo amniocentesis will have trisomy 21 or 18.19

Chorionic Villus Sampling

Transcervical and transabdominal sampling of the chorionic villi be-
tween 8 to 12 weeks' gestation is becoming a clinical rather than a research
procedure. 32 The biopsy obtains 15 to 30 mg of living trophoblasts for chro-
mosomal and/or biochemical analysis. One advantage over traditional genetic
amniocentesis is the speed of diagnosis-2 to 3 hours for a direct preparation
to 5 to 7 days for cell culture. Another major advantage is the ability to
perform an abortion at an earlier and safer gestational age, if an abnormality
is found.
The overall pregnancy loss is about 4 per cent once the operator has
performed more than 25 to 30 procedures. This exceeds the expected loss
in the second trimester by 1 to 2 per cent. Ten to 20 per cent of patients
will have light vaginal bleeding and about 4 per cent will have a subchorionic
hematoma demonstrated by ultrasound. The hematoma usually resolves over
THE FETUS AS A PATIENT 531
the next 6 to 10 weeks. Because this area is intimately related to oxyen and
nutritional exchange, this is an unproven concern about long-term effects.
Fetal blood is transfused into the mother as evidenced by an acute rise in
MSAFP after transcervical chorionic villus sampling (CVS) in 50 per cent of
women. 1 Mini-dose RhoGAM is recommended for unsensitized Rh-negative
patients. The risk of clinical infection is less than 1 per cent after CVS.
Cervical cultures for gonorrhea and chlamydia are recommended prior to a
transcervical CVS; the procedure should not, however, be performed in the
presence of a cervicitis or vaginitis.
In any cytogenetic examination, there is concern for the possibility of
discordance between the prenatal cytogenetic diagnosis and the actual fetal
karyotype. Direct preparations and culture of chorionic villi reveal a dis-
cordance (2 to 4 per cent) between the sample karyotype and the fetal
karyotype. In most cases, the discordance results from maternal cell con-
tamination and mosaicism in the CVS.

Amniocentesis

Needle aspiration of amniotic fluid for amniocytes or chemicals has been

a mainstay offetal diagnosis for the last 20 years. Cytogenetic and biochemical
analysis of cultured amniocytes is usually the reason for mid-trimester am-
niocentesis. The list of diagnosable genetic defects is growing; over 350 are
currently diagnosable. 43 However, 80 to 90 per cent of mid-trimester genetic
amniocentesis are performed for advanced maternal age or an abnormal
MSAFP. A repeat amniocentesis is required in 2 to 5 per cent because of
technical errors or confusing cytogenetic results. Errors in diagnosis occur
in less than 1 in 1000, and are mainly due to maternal cell contamination.
Amniotic fluid alpha-fetoprotein is normal in 5 to 10 per cent of patients
with neural tube defects; these are usually closed neural tube defects.
The major indication for amniocentesis in the third trimester is to meas-
ure the concentrations of compounds that predict neonatal respiratory dis-
tress. The most commonly used tests are the lecithin/sphingomyelin (LIS)
ratio and phosphatidylglycerol. In the presence of glucose intolerance,
polyhydramnios, blood, or meconium, the reliability of these tests is de-
creased. However, in their absence, fetal lung maturity tests are very spe-
cific. When the LIS ratio is greater than or equal to 2, the incidence of
respiratory distress syndrome (RDS) is 1 to 2 per cent. On the other hand,
fetal lung maturity studies are not sensitive. With an LIS ratio between 1.5
to 2.0, the incidence of RDS is 20 per cent and, when the ratio is between
1.0 to 1.5, the incidence is only 50 per cent. The sensitivity of the test is
inversely proportional to the gestational age after 32 weeks.
The complications of amniocentesis (Table 9) are similar regardless of
the type of tests to be performed on the fluid. In general, premature delivery
as a result of the procedure occurs in 1 to 2 per cent. Mid-trimester delivery
results in death and third trimester delivery may result in the complications
of prematurity. 32,41 If an abnormal karyotype is found, a subsequent second
trimester abortion has considerable risk. The risk of a major complication is
2 to 3 per cent. These include uterine perforation, hemorrhage, infection,
laparotomy, or anesthetic complications. If the patient is unwilling to have
532 EOWARD R. NEWTON

Table 9. Complications of Amniocentesis

\IID-TRIMESTER THIRD TRIMESTER

Incidence Incidence
Complication (Per Cent) Complication (Per Cent)
Failed attempt 5-10 Failed attempt 5-10
Bloody amniotic fluid 5-10 Bloody amniotic fluid 5-10
Fetal injury 1-5 Fetal injury 1-5
Fetal-maternal bleed 1-5 Fetal-maternal bleed 1-5
Rupture of membranes <1 Rupture of membranes 4-6
Pregnancy loss 1 Preterm labor <1

a second trimester abortion, the risk-benefit ratio for amniocentesis is ad-

versely affected.
Cordocentesis
Cord hematomas and fetal exsanguination have made the obstetrician
reluctant to sample fetal blood directly from the umbilical cord. However,
this caution has been overcome in the last 3 to 5 years. 44 A needle technique
for ultrasound-guided umbilical blood sampling (cordocentesis) is being de-
veloped in many university settings. In experienced hands, the perinatal
loss rate is less than 1 per cent over the elevated background risk of the
fetuses for whom this procedure is appropriate. Cord hematomas are rare
and, although the cord will bleed after a needle injury, the flow will cease
in less than 2 minutes in most cases. The access to both blood cells and
uncontaminated fetal serum opens a wide range of diagnostic possibilities.
The current uses have been the diagnosis and management of hemolytic
disease, and the diagnosis of genetic disease, infectious disease, respiratory
abnormalities, or coagulation disorders.
Ultrasound
Most fetuses in the Western world are exposed to ultrasound radiation
through the use of one or more modalities: Doppler detection of the fetal
heart rate, diagnostic ultrasound, umbilical blood flow determinations, and
external electronic fetal monitoring. A recent governmental report reviews
the indications for, use, and safety of diagnostic ultrasound in pregnancy. 9
Ultrasound is extremely versatile and has largely replaced radiographic di-
agnosis. Widespread clinical experience has supported the safety of ultra-
sound in pregnancy. In addition, the physics and biomedical principles of
ultrasound predict a large margin of safety at the frequency, power, and
duration used in clinical practice. 32
Although the physical and developmental effects of diagnostic ultra-
sound are insignificant, there is considerable risk to obstetric intervention
or lack of intervention based on an inaccurate ultras ono graphic diagnosis.
Table 10 reviews the diagnostic accuracy of ultrasound in selected condi-
tions. 32 While the sensitivity and specificity of ultrasound are good, unless
the population incidence is increased by the selection of patients at higher
risk, there is considerable likelihood of unnecessary intervention. For ex-
ample, if patients with hypertension and lagging fundal height growth are
THE FETUS AS A PATIENT 533

Table 10. The Diagnostic Accuracy of Ultrasound

PREDICTIVE VALVE
INCIDEt-.'CE OF A
CONDITIOt-.' (PER CENT) SENSITIVITY SPECIFICITY POSITIVE TEST

Birth weight <5th percentile 5 90 90 32

Birth weight >95th percentile 5 90 90 32
Placenta previa 0.5 95 95 9
Spina bifida* 5 83 97 60
*After MSAFP greater than 2.5 MoM X 1.

used to evaluate the accuracy of ultrasound in predicting a birth weight less

than the fifth percentile, the predictive value of a positive test increases
from 32 per cent in the general population to 97 per cent in the high-risk
population. In summary, diagnostic ultrasound must be used in conjunction
with the clinical history and examination.
Doppler Measurements of Maternal and Fetal Blood Flow
Recent advances in ultrasound technology have made it possible to study
maternal and fetal blood flow in a non invasive manner. The mean velocity
of red cells in a discrete section of a blood vessel can be calculated from the
Doppler equation. The Doppler equation describes a relationship between
a shift in sound frequency upon reflection of a moving object and the velocity
of the moving object. If one can measure the diameter of the blood vessel
and the sampling (insonation) angle, the flow equals the cross-sectional area
of the vessel multiplied by the mean velocity.
Insonation is performed using a continuous or pulsed system. A con-
tinuous Doppler system sends and receives Doppler signals on a continuous
basis with a power output ofless than 10 mW per cm 2 • This system is most
commonly used as it is the least expensive and its power input is well within
the accepted safety ranges. Its disadvantages are that there can be no si-
multaneous real-time ultrasound. Because the diameter of the vessel and
the angle of insonation cannot be measured, the investigator has to rely on
pattern recognition to display the appropriate flow pattern.
A pulsed Doppler system integrates a brief pulse of higher intensity
(46 m W per cm 2 ) pulse with real-time ultrasound. This system allows precise
measurements of the vessel diameter, the angle of insonation, velocity, and
flow. The system allows range-gating: the reflected signal can be precisely
limited to echoes originating from the study vessel. These qualities avoid
the controversies surrounding the reliability (operator dependency) of pat-
tern recognition as a means of vessel identification. The disadvantages of the
pulsed Doppler system are the expense and that pulsed intensity is higher
than is recommended in pregnancy by the American Institute of Ultrasound
in Medicine.
Both the pulsed and continuous Doppler systems display the measured
Doppler shifts on a real-time spectrum analyzer, with the degree of the
Doppler shift on the y-axis and time on the x-axis. Since the red cells move
at different rates in the vessel, the signal is a heterogeneous one with the
brighter points representing a larger number of cells moving at the same
534 EOWARO R. NEWTON

velocity. The higher the Doppler shift on the y-axis, the greater is the velocity
of the blood and, with a vessel of a constant diameter, the greater is the
flow.
A pulsed Doppler system can measure the critical blood flow of a vessel
and is quite accurate when compared to older systems. The major sources
of error are the measurements of the insonation angle and vessel diameter.
The average errors for these measurements are 5 per cent and 25 per cent,
respectively. Despite these variations, there is considerable agreement be-
tween laboratories concerning normal blood flow within fetal and maternal
vessels.
Doppler determination of blood flow has many potential applications:
these include diagnosis of reduced placental perfusion or uterine blood flow,
or the effects of drugs on maternal or fetal blood flow. The most common
clinical settings are hypertensive disease, intrauterine growth retardation,
and postdates. Technical difficulties and the lack of sensitivity and specificity
of the test limit its use in the general population. Currently, it is an actively
investigated research tool.
Diagnostic Radiography
The use of diagnostic radiography is of special concern to the medical
consultant. The fear of radiation and a lack of understanding about birth
defects have led the public to blame diagnostic radiographs for bad pregnancy
outcome (malpractice litigation). Physicians are therefore often overcautious
in its use and may recommend therapeutic abortion if exposure occurred in
the first trimester. These reactions are not justified when diagnostic radio-
graphs are performed using modern equipment and techniques.
Therapeutic radiation (greater than 100 rads) may cause growth retar-
dation, microcephaly, microphthalmia, mental retardation, genital and skel-
etal malformations, and cataracts. At lower doses (20 to 100 rads) the inci-
dence of defects falls off rapidly. When the dose is 5 to 20 rads in the first
trimester, a large population (thousands) of exposed versus unexposed em-
bryos is required to demonstrate a statistical increase in the incidence of
developmental defects in exposed fetuses. Virtually all diagnostic x-rays will
deliver a fetal absorbed dose of less than 5 rads: barium enema (5 rads),
intravenous pyelogram (1. 75 rads), computerized tomography (CT) of pelvis
(1 rad per plate), lumbar spine (0.54 rads), upper gastrointestinal tract series
(0.29 rads), gallbladder (0.003 rads), chest (0.001 rads), dental x-ray (0.001
rads), or mammogram (0.001 rads).32
When ascertained at 6 years of age, the background incidence of birth
defects is 3 to 5 per cent. This incidence relates to different factors such as
gestational age at exposure, familial history of defects, maternal or paternal
age, and/or concurrent environmental exposure (alcohol, smoking, drugs).
It is likely that if the population of exposed and unexposed fetuses was
controlled for the latter risk factors, no excess incidence of birth defects
would be demonstrated with any diagnostic radiograph.
In summary, diagnostic radiographs should not be withheld during a
pregnancy at any gestation age if the information cannot be obtained by safer
and more reliable means, and, if the new information will significantly change
management. If inadvertent exposure occurs during pregnancy, especially
THE FETUS AS A PATIENT 535
the first trimester, the following minimum information should be recorded
in the chart:
1. Gestational age at exposure.
2. Menstrual history (dating criteria).
3. Previous pregnancy history.
4. Familial genetic on developmental risk.
5. Concurrent environmental risks.
6. Age of mother and father.
7. The type of radiation study, dates, and number of films performed.
8. Calculation of the embryonic dose by an expert.
9. Status of the pregnancy (complications, wanted or unwanted).
10. Documentation of the patient counseling with a statement of background
risk plus the exposure risks, if any, to radiation.
Magnetic Resonance Imaging
Nuclear magnetic resonance imaging (MRI) and spectroscopy (NMR)
are noninvasive techniques that reveal biochemical information reflected by
nuclear magnetic moments in tissue. The technique allows a much better
examination of soft tissue structures, an ability adapted to abnormalities in
the fetus (birth defects) or mother (pelvic structure).
The mechanics of these techniques are discussed by Mattison and Ang-
tuaco. 27 In summary, the procedure is to place the patient into an intense
magnetic field, a field 2500 to 250,000 more intense than the earth's magnetic
field. Radiofrequency energy is then pulsed into the patient at the resonant
frequency (1 H is 42.7 MHZ per Telsa). Perturbing the system with ra-
diofrequency energy at the resonant frequency moves the nuclear magnetic
moments within the patient into positions where they can be measured and
used to form the nuclear magnetic resonance spectrum or magnetic reso-
nance image. The current techniques require a 5- to 20-minute imaging
time.
While the imaging of MRI ·is clearly superior to ultrasound and diag-
nostic radiographs, the effects of the high intensity magnetic energy on the
developing fetus are unknown. In addition, as fetal motion obscures the
image, accurate imaging of fetal soH: tissue requires maternal sedation and/
or fetal paralysis. With these two caveats MRI and NMR must be considered
research tools to be evaluated under strict protocols.
Biochemical Fetal Assessment
In the 1970s, placental hormones were found to reflect placental func-
tion. The concentration of hormones in the maternal blood or urine reflected
the volume of metabolically active placental tissue. Estriol and human pla-
cental lactogen (HPL) were the most commonly used assays. Clinical ex-
perience revealed several weaknesses in these assays as measures of fetal
well-being.
1. The reliability of the tests were poor-for example, estriol assays are
subject to ± 10 to 15 per cent diurnal and 20 to 30 per cent day-to-day
variation. Repeat analysis of the same sample could yield up to 40 per
cent difference in the results.
2. Many substances, such as antibiotics, glucocorticoids, or proteinuria,
were found to interfere with the results.
536 EDWARD R. NEWTON

3. The false positive rates ranged between 20 and 70 per cent.

4. Different clinical settings required different ranges of normal; for ex-
ample, diabetes with its normally increased volume of placenta had a
higher range of normal.
5. Less expensive and more timely methods of fetal surveillance have been
developed.
Maternal Perception of Fetal Movement
Maternal perception of fetal movement has been associated with fetal
health for many years. In the last 10 to 15 years, researchers have evaluated
this simple and inexpensive tool for efficacy. Mothers feel between 70 to 90
per cent of fetal movements recorded mechanically. Obese patients and
patients where the placenta is attached anteriorly will feel fewer movements
than thin women whose placentas are implanted posteriorly. The mean num-
ber of fetal body movements during a 20- to 30-minute observation period
is 17 to 30. Each fetus has his own pattern and frequency, so that the absolute
number of movements is not helpful. A clear reduction over several days is
suspicious. There are several published thresholds of decreased activity that
initiate further testing. They consist of either less than 10 movements in 12
hours or less than 2 to 4 movements per hour for three I-hour periods during
the day.
Clinical experience suggests that fetal motion monitoring is highly spe-
cific (90 to 95 per cent) with only moderate sensitivity of 50 to 70 per cent
in predicting unfavorable perinatal outcome. Given the lack of sensitivity
and the high rate of false positive tests, it is recommended that abnormal
tests must be followed up with further testing: biophysical profile and/or
external electronic fetal monitoring.
External Electronic Fetal Monitoring
For the last 80 years, fetal heart rates have been believed to predict
fetal status. In the last 25 years there has been an explosion of technology
designed to record fetal heart rate over time. Most commonly, Doppler
ultrasound is used to note the motion of the fetal heart. The duration between
heart beats is used to calculate the fetal heart rate. As the fetal heart beats
between one to four times per second, the external monitoring averages
several beats such that the recorder can depict the rate.
The fetal heart rate is a proxy for the balance between parasympathetic
and sympathetic influences on the heart. The parasympathetic develops later
in gestation than the sympathetic control of the fetal heart. The maturation
of the parasympathetic system results in a decrease in mean heart rate,
increased heart rate variability, heart rate accelerations with fetal movement,
and a quick and robust reaction to stimulation of the carotid and/or aortic
arch chemoreceptors and baroreceptors (variable decelerations). As hypoxia
develops (less than 3 to 4 ml per dl O 2 content), a stress response develops
with increased sympathetic tone. This results in a fetal tachycardia (more
than 160 beats per minute), decreased variability, and loss of accelerations.
Moreover, higher cortical centers, which control the parasympathetic sys-
tem, may dysfunction and, ultimately, undergo permanent damage. This
also results in tachycardia, decreased variability, and loss of accelerations.
The effects of permanent damage to the parasympathetic system persist after
TilE FETUS AS A PATIEr-.iT 537

the initial insult and may indeed be associated with the normal fetal blood
gases and pH. In a severe and chronic hypoxia state, there is a primary
depression of the fetal heart rate through a cardiomyopathy (late decelera-
tions).
The nonstress (NST) and contraction stress (eST) tests are records of
the fetal cerebral and cardiac physiology.ls.32 The NST is usually a 20- to 30-
minute recording of the baseline fetal heart rate. A rate of 120 to 160 beats
per minute, a 6 to 10 beat variation in fetal heart rate over a 1O-minute
period, and 2 to 4 fetal heart rate accelerations with fetal movement are
expected in a normal fetus. The eST evaluates the baseline characteristics
and the heart rate response to uterine contraction activated by nipple stim-
ulation or intravenous oxytoxin. eST is positive when late occurring decel-
erations occur after each of three contractions within a 1O-minute window.
The disadvantages of the eST over the NST are the length of time taken to
perform the test (60 versus 20 minutes) and the decreased reliability sec-
ondary to hyperstimulation (10 to 20 per cent).
Reliability is the variation of test results given the same disease state.
The reliability of the NST and eST is overestimated. The weakness in re-
liability results from the mechanics of Doppler ultrasound and variations in
the interpretation of the tests. While the measurement of the heart rate is
reliable between 60 to 200 beats per minute, the variability may be artificially
increased on the external monitor. This occurs when the ultrasound pulses
reflect off different parts of the fetal heart from cycle to cycle; the motion
of the mitral and tricuspid valves occurs at different time points in the cycle
than the motion of the ventricular wall.
M uch of the unreliability results from the variation in the interpretation
of the tests. Interobserver agreement of the NST results is 40 to 50 per
cent. 15 Peck had five obstetricians read 50 positive or negative eSTs.37 Four
of five obstetricians agreed with the positive reading in 18 per cent of positive
tests. In 62 per cent of negative tests, four of five obstetricians agreed with
the negative reading.
Validity is a measure of whether a test reflects true disease. Because
perinatal death due to asphyxia (0.4 per cent) and long-term neurodevel-
opmental handicap (0.3 per cent) are so rare, the NST and eST have been
used to predict low Apgar scores, meconium staining, and/or fetal distress
during lab or as proxies for perinatal asphyxia. The latter outcome variables
occur after the significant stress of labor and may be due to intrapartum
stress (hyperstimulation during oxytocin induction) rather than antepartum
stress. Moreover, each of these variables predicts neonatal death or long-
term sequelae from asphyxia less than 5 per cent of the time.
The other measures of the accuracy are depicted in Table 11. In a
population with a low prevalence of asphyxia, the vast majority (80 to 95 per
cent) of these tests are falsely positive. 32 .42 By high-risk screening, a popu-
lation with a higher prevalence of the disease is identified and the predictive
power of the test increases. Even so, the NST must still be used in con-
junction with other testing. 26
The Biophysical Profile
The advent of real-time ultrasound in the 1970s allowed researchers to
identify fetal activities that correlated with fetal tolerance to labor. These
538 EOWARO R. NEWTO:-l

Table 11. Accuracy of Antepartum Testing in Predicting Fetal Distress

in Labor or as-minute Apgar Score Less than 7
PPV* AT ppv* AT
I PER CENT 10 PER CENT
TEST SENSITIVITY SPECIFICITY PREVALENCE PREVALE!';CE

Nonstress 20 94 3 27
Contraction stress 50 99 20 85
Biophysical profile 70 97 15 72
*PPV = predictive value of a positive test.

activities include fetal tone, fetal breathing, fetal motion, and fetal heart rate
accelerations. It was also recognized that, as the volume of amniotic fluid
reflects fetal urine output, the measurement of amniotic fluid volume pre-
dicts fetal health. Subsequently, these observations were incorporated into
a composite score: the biophysical profile. 4 In simple terms, the biophysical
score is similar to an in utero Apgar score with measures of heart rate
accelerations, breathing, movement, and tone. Amniotic fluid volumes are
also measured. Each of the five parameters is given 0 to 2 points, for a total
score of 0 to 10.
In experienced hands, the biophysical profile adds significantly to the
accuracy of other antepartum testing (see Table 11). When a general pop-
ulation was screened and high-risk patients followed with the biophysical
profile, approximately 88 per cent of infants with bad outcomes were iden-
tified and the corrected perinatal rate of high-risk patients was 2.7 per 1000
births. The likelihood of a perinatal death with a biophysical score of 10 was
0.77 per 1000 births. 4 ,26
The disadvantages of the biophysical profile include (1) operator de-
pendence-no studies of reliability have been performed; (2) as is true of
all antepartum testing, the appropriate frequency of testing is unknown; (3)
there is significant cost associated with biophysical testing; and (4) the true
validity of the test has not been verified.

CONCLUSIONS

With the advent of sophisticated fetal diagnosis, the practice of obstetrics

has shifted from a focus on primarily maternal concerns to maternal-fetal
concerns. The newer techniques of antepartum testing and major advances
in regionalized perinatal care have initiated a dramatic reduction in perinatal
mortality rates. Consequently, obstetric management is being judged by the
incidence of neonatal morbidity rather than neonatal mortality.
Perinatologists and neonatologists recognize that long-term neuro-
developmental injury is related to antepartum rather than intrapartum
events. While high-risk screening indices may identifY a population with
excessive risk for antepartum injury, they cannot pinpoint which, when, or
how a fetus is injured. Many different methods offetal surveillance are being
utilized to identify the compromised infant among the high-risk group. As
basic measures of diagnostic accuracy are applied to these methods, essential
TilE FETUS AS A PATIENT 539

questions of accuracy are being raised. Is there adequate reliability in fetal

heart rate interpretation? Do the NST, eST, and biophysical profile measure
the appropriate outcome variable: prelabor fetal acidosis, fetal death, neo-
natal morbidity or mortality from asphyxia, or long-term neurodevelopmen-
tal handicaps? Finally, any diagnostic test must be evaluated in terms of the
costs of intervention. Unnecessary intervention resulting from an inaccurate
test may lead to serious maternal morbidity from tocolysis or cesarean section
and neonatal morbidity and mortality from iatrogenic preterm delivery.

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Department of Obstetrics and Gynecology

University of Texas Health Science Center at San Antonio
7703 Floyd Curl Drive
San Antonio, TX 78232