The prospects of fetal electrocardiography during pregnancy

and labour
Citation for published version (APA):
Verdurmen, K. M. J. (2017). The prospects of fetal electrocardiography during pregnancy and labour. [Phd
Thesis 1 (Research TU/e / Graduation TU/e), Electrical Engineering]. Technische Universiteit Eindhoven.

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The prospects of fetal electrocardiography
during pregnancy and labour

Kim Verdurmen
Cover design and lay-out by Kleine Kunstjes
Printed by GVO drukkers & vormgevers B.V.
ISBN: 978-94-6332-194-5
A catalogue record is available from the Eindhoven University of Technology Library.

© Copyright 2017, Kim M.J. Verdurmen

All rights reserved. No part of this book may be reproduced in any form by any means, without prior
permission of the author.

Financial support for the publication of this thesis has been kindly provided by Bridea Medical B.V.,
ChipSoft, Gedeon Richter, GrafiMedics B.V., Nemo Healthcare, Memidis Pharma B.V., Vakblad Vroeg,
Noldus Information Technology B.V., Stichting de Wijerhorst.

A part of the research described in this thesis is performed within the IMPULS perinatology
framework.
 The prospects of fetal electrocardiography
during pregnancy and labour

PROEFSCHRIFT

ter verkrijging van de graad van doctor aan de Technische Universiteit

Eindhoven, op gezag van de rector magnificus prof. dr. ir. F.P.T. Baaijens, voor
een commissie aangewezen door het College voor Promoties, in het
openbaar te verdedigen op woensdag 5 juli 2017 om 16:00 uur

door

Kim Margriet Johannes Verdurmen

geboren te Terneuzen
Dit proefschrift is goedgekeurd door de promotor en de copromotores.
De samenstelling van de promotiecommissie is als volgt:

Voorzitter: prof. dr. ir. A.B. Smolders

Promotor: prof. dr. S.G. Oei
1 copromotor:
e
dr. J.O.E.H. van Laar Máxima Medisch Centrum, Veldhoven
2e copromotor: dr. ir. R. Vullings

Leden:
dr. M.C. Haak Leids Universitair Medisch Centrum
prof. dr. J.G. Nijhuis Maastricht Universitair Medisch Centrum
prof. dr. G.H.A. Visser Universitair Medisch Centrum Utrecht
prof. dr. ir. P.F.F. Wijn
prof. dr. ir. J.W.M. Bergmans

Het onderzoek dat in dit proefschrift wordt beschreven is uitgevoerd in overeenstemming met
de TU/e Gedragscode Wetenschapsbeoefening.
 Summary

The prospects of fetal electrocardiography during pregnancy and labour

Fetal electrocardiography (ECG) is a relatively new and still evolving technique in fetal
monitoring. During pregnancy it can be registered non-invasively via electrodes on the
maternal abdomen and during labour it can be obtained via a fetal scalp electrode. In this
thesis, several prospects of fetal ECG are described.

In Part I of this thesis we describe that fetal ECG could be valuable in diagnosing congenital
heart disease (CHD) in fetuses. Since CHD is the most common severe congenital anomaly
worldwide, an adequate and timely diagnosis is important. Nowadays, screening for CHD is
performed during the fetal anomaly scan around 20 weeks of gestation. This ultrasound has a
detection rate of approximately 65-80%. The fetal ECG can be obtained non-invasively from 18
weeks of gestation onwards. It reflects the intimate relation between the conduction system
and the structural morphology of the heart, and it is particularly helpful in detecting the
electrophysiological effects of cardiac anatomical defects (e.g. hypotrophy, hypertrophy and
conduction interruption). Therefore, it seems to be a promising diagnostic tool to comple-
ment ultrasonography in the screening for CHD. However, the normal values and ranges of
amplitudes and segment intervals of the fetal ECG in a healthy fetus should be established
first, before we are able to detect CHD. In this thesis, the study design for a prospective cohort
study that will provide these normal values and ranges is described.

In Part II of this thesis we study the effect of drugs that are administered during threatened
preterm birth on heart rate frequency and variability. Corticosteroids are administered in
order to expedite fetal lung maturation, and are known to decrease neonatal morbidity
and mortality. Tocolytics are administered to attenuate uterine contractions, and therefore
postpone preterm delivery. Since heart rate variability is one of the most important features
when assessing fetal wellbeing, it is important to bear in mind the “side-effects” of adminis-
tered drugs on heart rate variability. As corticosteroids and some tocolytic drugs can cause
a decrease in fetal heart rate variability and in fetal movements, clinicians need to be aware
Summary

of the risk of iatrogenic preterm birth when patients receive these drugs. By analysing the
fetal ECG, we found that the influence of the autonomic nervous system is minor following
administration of betamethasone (a corticosteroid). This indicates that the reduced fetal heart
rate variability is not a sign of fetal distress, but rather a consequence of a reduction in fetal
movements in the first days following corticosteroid administration.

In Part III of this thesis we focus on ST monitoring during labour. In ST monitoring, the fetal
ECG is obtained invasively via a fetal scalp electrode. The T/QRS baseline is measured early
during delivery and serves as a benchmark for successive T/QRS ratios. The amplitude of
the T wave, and therefore the T/QRS ratio, is influenced by hypoxia in the fetal myocard.
T/QRS ratios that exceed the baseline value can cause an ST alarm, hence warning for possible
fetal hypoxia. However, in current ST monitoring false alarms are encountered frequently. We
hypothesised that this might be due to variation in orientation of the fetal electrical heart
axis. We demonstrated that there is major variation in orientation of the electrical heart axis
between fetuses. This variation in orientation yields variation in shape and amplitude of the
ECG, and therefore in height of the T/QRS ratio. We further hypothesised that the orientation
of the electrical heart axis is related to the occurrence of ST alarms. In a retrospective study
we confirmed our hypothesis and found that there was a significant increment in ST alarms
with increasing height of the T/QRS baseline, irrespective of the fetal condition at birth. As a
solution for these false alarms we studied “relative” ST analysis, which analyses the T/QRS rise
as a percentage from baseline. In a small retrospective case-control study we found the same
sensitivity of conventional and relative ST analysis, and a significant increase in specificity of
relative ST analysis. This first explorative study therefore shows that relative ST analysis is a
promising alternative for detecting imminent fetal distress.

The results of the fundamental research reported in this thesis show that fetal ECG has
multiple promising prospects, both during pregnancy and labour. Fetal ECG measurements
can provide additional and objective information, amongst others in detecting congenital
heart disease, measuring fetal heart rate variability, describing autonomic modulation and
detecting fetal distress. Further improvement of the technologies described in this thesis will
aid clinicians in more accurate diagnosis of the fetal condition, and will therefore improve
perinatal outcome in the future.
 Table of Contents

Contents

Chapter 1 General introduction 9

Chapter 2 Physiological background 23
Chapter 3 Technical background 35

Part I: fetal ECG and congenital heart disease

Chapter 4 A systematic review of prenatal screening for congenital heart 53

disease by fetal electrocardiography.
Int J Gynaecol Obstet. 2016;135(2):129-134
Chapter 5 Normal ranges for fetal electrocardiogram values for the healthy 71
fetus of 18-24 weeks of gestation: a prospective cohort study.
BMC Pregnancy Childbirth. 2016;16:227

Part II: fetal ECG in preterm labour

Chapter 6 The influence of corticosteroids on fetal heart rate variability: a 87

systematic review of the literature.
Obstet Gynecol Surv. 2013;68(12):811-824
Chapter 7 Effect of tocolytic drugs on fetal heart rate variability: a systematic 113
review.
J Matern Fetal Neonatal Med. 2016;1-8
Chapter 8 The influence of betamethasone on fetal heart rate variability, 131
obtained by non-invasive fetal electrocardiogram recordings.
Revision pending
Part III: fetal ECG to prevent asphyxia

Chapter 9 Orientation of the electrical heart axis in mid-term pregnancy. 153

Eur J Obstet Gynecol Reprod Biol. 2016;207:243-246
Letter to the Editor – Brief communication
Chapter 10 The electrical heart axis and ST events in fetal monitoring: a 161
post-hoc analysis following a multicentre randomised controlled
trial.
PLoS One. 2017;12(4):e0175823
Chapter 11 Relative versus absolute rises in T/QRS ratio: a case-control study. 175
Submitted for publication

Chapter 12 General discussion 189

Appendices
List of abbreviations 206
List of publications 208
Nederlandse samenvatting 210
Dankwoord 215
Curriculum vitae 220
 Chapter 1
1

General introduction

11
 Chapter 1

Introduction
Pregnancy and delivery are life changing events, and it is the task of obstetric caregivers
to make sure both are completed as safely as possible. The World Health Organisation
reports that of the 130 million babies born worldwide every year, there are over 6.3 million
perinatal deaths1. The description “perinatal mortality” includes deaths that might be related
to obstetric events, such as stillbirths and neonatal deaths in the first week of life. Perinatal
mortality is six times more common in low-income countries, in comparison to high-income
countries1. Despite the relatively low occurrence of perinatal mortality in high-income
countries, the major part of these deaths is preventable. If all high-income countries achieved
stillbirth rates equal to the best performing countries, almost 20.000 stillbirths beyond
28 weeks of gestation could have been avoided in 20152. In the Netherlands, the perinatal
mortality rates are relatively high compared to other European countries3. In 85% of the cases,
perinatal mortality is preceded by at least one of the “Big Four”4:

• Congenital anomalies
• Preterm labour
• Birth asphyxia
• Fetal growth restriction

In addition to perinatal mortality, it is also important to take perinatal morbidity into account.
The “Big Four” mentioned above can also lead to perinatal morbidity, possibly resulting in
major impact on, for instance, neurological and cognitive development. Moreover, there are
associations with chronic diseases such as diabetes, cardiovascular disease and chronic lung
disease5. Therefore, it is important that obstetricians keep seeking for new methods that can
aid in identifying possible threats in pregnancy or during labour.

This thesis is subdivided into three parts, that apply to the first three items of the “Big Four”.
In Part I, we focus on identifying congenital heart disease (CHD) early in gestation. CHD is
the most common congenital anomaly worldwide. Next, in Part II we describe the effects of
medication commonly used in threatened preterm labour on fetal heart rate parameters. By
knowing the exact effect of these drugs, misinterpretation of fetal heart rate tracings and
consequent unnecessary iatrogenic preterm delivery can be prevented. Finally, in Part III we
focus on false alarms in fetal monitoring during labour; a method introduced to warn in case
of fetal hypoxia. We explain and investigate our hypothesis regarding the orientation of the
fetal electrical heart axis and these false alarms. Fetal electrocardiography (ECG) is a promising
and still evolving technique that can be used for multiple purposes during pregnancy and
labour. All studies described in this thesis use fetal ECG to detect possible threats during
pregnancy and labour.

12
 General introduction
1
Fetal ECG; why do we need it?
During pregnancy and labour, we want to have an accurate monitor for fetal wellbeing.
Nowadays, we can use ultrasonography for a biophysical profile and cardiotocography (CTG)
for fetal heart rate recording. CTG is the simultaneous registration of the fetal heart rate and
the uterine activity, and is used worldwide for fetal surveillance. In Figure 1, an example of a
CTG tracing is shown. During pregnancy, it can be obtained by using an external non-invasive
Doppler-ultrasound sensor and tocodynamometer. During labour, it can also be obtained via
a scalp electrode on the fetal head and an intra-uterine pressure catheter. While the sensitivity
of CTG is good, the specificity and positive predictive value of CTG are rather poor6. When
using CTG during labour, the rate of neonatal seizures halves but there is no decrease in
perinatal death or cerebral palsy, while the chances of an instrumental vaginal delivery or
caesarean section are elevated7. In addition, CTG interpretation is based on visual pattern
recognition by the physician. It has been known for a long time that this is characterised by
a high inter- and intra-observer variability, especially in tracings that are not reactive7,8. Up to
date, there is no satisfying solution for this and it is still a topic of debate and concern9.

Figure 1. Example of a cardiotocogram.

Upper line: fetal heart rate. Lower line: uterine activity. Paper speed: 2cm/min.

13
 Chapter 1

During pregnancy, there are no complementary diagnostics like ST analysis or fetal

scalp blood sampling that can be used to objectify fetal wellbeing10. Moreover, these
complementary diagnostics are not applicable in case of prematurity. Therefore, there is
need for a non-invasive method that provides more reliable information concerning the
fetal condition than CTG alone can provide.

The fetal electrocardiogram (ECG) can be measured by direct registration via a scalp electrode
on the fetal head during labour, or antepartum via indirect measurements with skin elec-
trodes on the maternal abdomen. Fetal ECG recordings obtain beat-to-beat heart rate
information and spectral analysis can be performed on these recordings. This gives detailed
information regarding heart rate variability, which is a reliable marker for fetal wellbeing11,12.
Spectral analysis can quantify rather small changes in fetal heart rate variability, that can
remain undetected with visual interpretation of the fetal heart rate tracing13. In addition, the
shape and amplitude of the fetal ECG can be assessed. More details concerning fetal ECG
measurements and spectral analysis can be found in chapter 3 – technical background.

Part I: fetal ECG and congenital heart disease

CHD is the most common severe congenital anomaly worldwide14. It is estimated that CHD
has an incidence of 6-12 per 1000 live births15, of which 4 per 1000 are major forms of CHD
that are lethal or require intervention16. CHD is a major health problem, being six times more
common than chromosomal anomalies and four times more common than neural tube
defects16,17.

CHD is classically diagnosed by echocardiography, which is part of the congenital anomaly

scan offered to all pregnant women around 20 weeks of gestation. However, the detection
rate of CHD with this ultrasound is rather low and varies from 65-81%16,18-20. Specific echocar-
diography has a higher detection rate, with a sensitivity of 90% and a specificity of 98%21. This
specific ultrasound is only performed in fetuses with a risk factor for CHD; amongst others
family history, maternal diabetes, exposure to teratogens and infections, abnormal nuchal
translucency, aneuploidies and other known congenital anomalies. However, up to 90%
of all CHD occur in the low risk population17. About 25% of the neonates with major CHD is
described to be discharged from the hospital undiagnosed22.

It is important to diagnose CHD early in pregnancy for multiple reasons. First, it enables the
identification of associated extracardiac and chromosomal anomalies, that occur in respec-
tively 29% and 26% of the fetus with CHD23. Both influence the fetal and postnatal prognosis,
and should be included in prenatal and genetic counselling that is offered to parents.

14
 General introduction
1
Hereafter, parents can decide to terminate or continue the pregnancy. The termination of
pregnancy rate is higher if the prenatal diagnosis was made at an earlier gestational age (61%
at 19 weeks of gestation, 44% at 24 weeks of gestation)23,24. When the pregnancy is continued,
it is important to develop an adequate treatment plan including intra-uterine therapy, timing,
mode and location of delivery and immediate treatment after birth. For ductus- and foramen
ovale dependent CHDs, survival rates increase and long-term morbidity decreases if the CHD
is diagnosed prenatally24-27.

In neonates, it has already been described over 50 years ago that characteristic ECG patterns
can be found which suggest the presence of a particular heart defect28. Therefore, the
development of reliable non-invasive diagnostic methods that increase the predictive value
for the diagnosis of CHD is of major importance. In Part I of this thesis, the opportunities
of fetal ECG to aid in the diagnosis of CHD is elaborated.

Part II: fetal ECG in preterm labour

Preterm birth is defined as birth before 37 weeks of gestation, and is one of the “Big Four” as
described earlier. The preterm delivery rate is approximately 5-9% in Europe, and even higher
in the USA with rates near 12-13%29. It is described that preterm birth accounts for 75% of
perinatal mortality and more than 50% of long-term morbidity such as neurodevelopmental
impairments, respiratory and gastro-intestinal problems29. Preterm births occur spontaneously
in 65-75% of the cases, due to contractions or preterm premature rupture of the membranes29.
Approximately 25-35% of preterm births are iatrogenic, following both maternal and fetal
indications (for instance severe pre-eclampsia or suspected fetal distress, respectively).

In case of threatened preterm labour between 24 and 34 weeks of gestation, both spontane-
ous or when iatrogenic preterm birth is expected, patients can be treated with corticosteroids
and, if indicated, tocolytics. Antenatal administration of corticosteroids is known to enhance
fetal lung maturation and is associated with an overall reduction in neonatal death, respiratory
distress syndrome, cerebroventricular haemorrhage, necrotising enterocolitis, respiratory
support, intensive care admissions and systemic infections in the first 48 hours of life30. There
are no associated long-term negative effects reported after a single course of antenatal
corticosteroids30-33. Betamethasone is the corticosteroid used most frequently, followed by
dexamethasone30. Betamethasone is administered via two injections, 24 hours apart.

In spontaneous preterm labour, treatment with corticosteroids is often combined with

short-term tocolytic therapy in an attempt to postpone delivery for at least 48 hours. This
will yield time to transfer the patient to a centre with neonatal intensive care facilities and to

15
 Chapter 1

await maximal beneficial effect of corticosteroids. There are multiple tocolytic agents, and the
tocolytic agent of first choice is still a topic of debate and varies considerably in different parts
of the world34. The tocolytics most commonly used in clinical practice nowadays are nife-
dipine, magnesium sulphate, atosiban, indomethacin, fenoterol and ritodrine. Maintaining
tocolytic therapy with nifedipine for more than 48 hours does not improve perinatal outcome,
neither is it effective to prolong pregnancy35,36.

Both corticosteroids and most tocolytics are known to have influence on fetal heart rate
parameters. Since they are administered to a highly vulnerable population, fetuses at risk for
preterm birth, it is of the utmost importance to know the exact effects of these drugs. Only
then, iatrogenic preterm birth due to misinterpretation of fetal heart rate tracing, caused by
therapeutic side-effects, can be avoided. In Part II of this thesis, the effects of corticosteroids
and tocolytics on fetal heart rate tracings are studied.

Part III: fetal ECG to prevent asphyxia

The World Health Organisation estimated that 4 million neonatal deaths occur every year due
to birth asphyxia, representing 38% of deaths of children under 5 years of age37. As described
above, fetal monitoring with CTG alone has some shortcomings and additional information
regarding the fetal condition is often desired during labour. Fetal blood sampling can offer
information regarding the acid-base balance of the fetus. In some parts of the world it is
used frequently in clinical practice, but it can only be performed during labour, when the
membranes are ruptured and there is enough dilation. In addition, the relation between
relative changes of acid-base balance in the various subcutaneous, cerebral and blood
levels during fetal hypoxia are not yet fully understood38. The Cochrane review considering
electronic fetal monitoring reported more instrumental deliveries, but less neonatal acidosis
following fetal blood sampling (p = 0.04 for both) in a subgroup analysis7. However, the access
to fetal blood sampling did not influence the difference in neonatal seizures or any other
outcomes. Although the NICE guideline recommends fetal blood sampling as an additional
test during labour39, this received criticism since fetal blood sampling was never validated and
the scientific evidence for its use is questionable40. It is important to realise that fetal blood
sampling only gives information regarding the fetal condition at the time of blood collection
and sometimes has to be repeated multiple times during labour. There are rare but serious
complications such as leakage of cerebral spinal fluid, haemorrhage and sepsis reported
following fetal blood sampling41. Therefore, advantages and disadvantages should be consid-
ered carefully before performing fetal blood sampling.

16
 General introduction
1
ST analysis is a second source for additional information regarding the fetal condition during
labour. The ST segment of the fetal ECG is analysed, following registration via an invasive
scalp electrode. More technical details considering ST analysis can be found in chapter 3 –
technical background. In combination with CTG, ST analysis was reported to significantly
lower the rates of metabolic acidosis42 and operative delivery42,43. Subsequent multicentre
trials were performed, including the most recent and largest randomised trial in the USA44.
These trials could not reproduce the initial findings and showed no additional benefit for
perinatal outcome, besides a reduction in the need for fetal blood sampling44-47. Conflicting
results regarding the decrease in metabolic acidosis are reported in recent meta-analysis,
indicating the need for more research48-52. In addition, ST analysis gives as many alarms in
cases of proven uncompromised fetal condition as in cases of deteriorating fetal condition53.
The guidelines that apply to ST analysis state that alarms must be ignored when CTG shows
a reassuring pattern. However, taking the high inter-observer variability and low specificity
of CTG into account, one can wonder if this is a proper solution for the false alarms encoun-
tered. Classifying between a reassuring or non-reassuring CTG determines whether or not
to ignore an alarm, making the success of ST monitoring dependent on CTG assessment54.

In term fetuses during labour, the orientation of the fetal electrical heart axis can vary
between +90 and +180 degrees55. Similar inter-person variations in orientation of the elec-
trical heart axis are present in neonates and adults28,56-58. This orientation of the electrical
heart axis influences the shape and amplitude of the ECG. We hypothesise that the alignment
between the scalp lead and the electrical heart axis, a normal variation in human physiology,
can make the difference between ST alarms and no ST alarms. In current ST analysis, this is not
taken into account properly.

In Part III of this thesis, we will discuss the orientation of the fetal electrical heart axis
and its effect on false ST alarms.

17
 Chapter 1

Outline of the thesis

This thesis concerns fetal electrocardiography and its applicability. This thesis aims to
answer the following questions:

1. Is fetal electrocardiography valuable in diagnosing congenital heart disease in fetuses?

2. What is the influence of corticosteroids and tocolytics on fetal heart rate variability?

3. Are the changes in fetal heart rate variability following corticosteroid administration in
the time-domain (obtained by Doppler ultrasound cardiotocography) comparable to the
changes in fetal heart rate variability in the frequency-domain (obtained by non-invasive
fetal electrocardiography recordings)?

4. Is the variation in orientation of the fetal electrical heart axis in premature fetuses
comparable to the variation seen in term fetuses?

5. Is variation in orientation of the electrical heart axis the cause of false ST events in ST
analysis during labour?

6. Can we improve the method of ST analysis for fetal monitoring during labour?

To answer these questions we performed several literature and clinical studies, which are
described below. The results of these studies are described in this thesis.

Chapter 2 provides physiological background information considering the fetal heart.

Chapter 3 provides technical background information considering CTG recordings, non-

invasive transabdominal fetal ECG measurements, calculating fetal heart rate variability by
means of spectral analysis and the reasoning and technology behind ST analysis.

Part I: fetal ECG and congenital heart disease

Chapter 4 reviews the possibilities of fetal ECG as a screening tool for the detection of
CHD in fetuses.

Chapter 5 describes the study protocol of a prospective cohort study, in which the normal
ranges for fetal ECG values for the healthy fetus of 18-24 weeks of gestation are established.

18
 General introduction
1
Part II: fetal ECG in preterm labour
Chapter 6 gives an overview of the literature regarding the influence of the corticosteroids
betamethasone and dexamethasone on fetal heart rate parameters, in particular heart
rate variability, and fetal behaviour.

Chapter 7 gives an overview of the literature regarding the influence of the tocolytics
nifedipine, magnesium sulphate, atosiban, indomethacin, fenoterol and ritodrine on fetal
heart rate parameters, in particular heart rate variability.

Chapter 8 presents the results of a prospective cohort study that describes the influence of
betamethasone on fetal heart rate variability. Measurements were obtained by non-invasive
fetal ECG recordings and spectral analysis was used to calculate fetal heart rate variability.

Part III: fetal ECG to prevent asphyxia

Chapter 9 describes the inter-fetal variation and the main orientation of the electrical heart
axis in premature fetuses. These results are compared with what is known for term fetuses
and adults.

Chapter 10 reveals the results from a post-hoc analysis following the Dutch multicentre
randomised controlled ST analysis trial. This study describes the relation between the fetal
electrical heart axis and the number of ST alarms that were encountered in fetal monitoring.

Chapter 11 presents the results of a case-control study, in which a new method for ST
analysis is proposed; relative ST analysis is compared to regular “absolute” ST analysis
in intrapartum fetal monitoring.

Chapter 12 provides a summary and general discussion considering the data presented in
this thesis. In addition, suggestions for future research are included.

Chapters 4 to 11 are either published or submitted for publication. Therefore, these chapters
are written to be self-contained which causes some overlap between these chapters.

19
 Chapter 1

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 General introduction
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anomalies: the value of routine addition of the aortic root to the four-chamber view. Obstet
Gynecol 1994 Sep;84(3):427-431.
20. Wu Q, Li M, Ju L, Zhang W, Yang X, Yan Y, et al. Application of the 3-vessel view in routine prenatal
sonographic screening for congenital heart disease. J Ultrasound Med 2009 Oct;28(10):1319-1324.
21. Cohen EH, Rein AJ. Antenatal diagnosis of cardiac malformation: a structural study. Fetal Diagn Ther
2000 Jan-Feb;15(1):54-60.
22. Sharland G. Fetal cardiac screening and variation in prenatal detection rates of congenital heart
disease: why bother with screening at all? Future Cardiol 2012 Mar;8(2):189-202.
23. Clur SA, Van Brussel PM, Mathijssen IB, Pajkrt E, Ottenkamp J, Bilardo CM. Audit of 10 years of
referrals for fetal echocardiography. Prenat Diagn 2011 Dec;31(12):1134-1140.
24. Trines J, Fruitman D, Zuo KJ, Smallhorn JF, Hornberger LK, Mackie AS. Effectiveness of prenatal
screening for congenital heart disease: assessment in a jurisdiction with universal access to health
care. Can J Cardiol 2013 Jul;29(7):879-885.
25. Brick DH, Allan LD. Outcome of prenatally diagnosed congenital heart disease: an update. Pediatr
Cardiol 2002 Jul-Aug;23(4):449-453.
26. Hunter LE, Simpson JM. Prenatal screening for structural congenital heart disease. Nat Rev Cardiol
2014 Jun;11(6):323-334.
27. Brown KL, Ridout DA, Hoskote A, Verhulst L, Ricci M, Bull C. Delayed diagnosis of congenital
heart disease worsens preoperative condition and outcome of surgery in neonates. Heart 2006
Sep;92(9):1298-1302.
28. Depasquale NP, Burch GE. The Electrocardiogram, Ventricular Gradient and Spatial Vectorcardio-
gram during the First Week of Life. Am J Cardiol 1963 Oct;12:482-493.
29. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet
2008 Jan 5;371(9606):75-84.
30. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at
risk of preterm birth. Cochrane Database Syst Rev 2006 Jul 19;(3):CD004454.
31. Dalziel SR, Lim VK, Lambert A, McCarthy D, Parag V, Rodgers A, et al. Antenatal exposure to beta-
methasone: psychological functioning and health related quality of life 31 years after inclusion in
randomised controlled trial. BMJ 2005 Sep 24;331(7518):665.
32. Dessens AB, Haas HS, Koppe JG. Twenty-year follow-up of antenatal corticosteroid treatment. Pedi-
atrics 2000 Jun;105(6):E77.

21
 Chapter 1

33. Mariotti V, Marconi AM, Pardi G. Undesired effects of steroids during pregnancy. J Matern Fetal
Neonatal Med 2004 Nov;16 Suppl 2:5-7.
34. Crowther CA, Brown J, McKinlay CJ, Middleton P. Magnesium sulphate for preventing preterm birth
in threatened preterm labour. Cochrane Database Syst Rev 2014 Aug 15;8:CD001060.
35. Roos C, Spaanderman ME, Schuit E, Bloemenkamp KW, Bolte AC, Cornette J, et al. Effect of mainte-
nance tocolysis with nifedipine in threatened preterm labor on perinatal outcomes: a randomized
controlled trial. JAMA 2013 Jan 2;309(1):41-47.
36. Roos C, Vis JY, Scheepers HC, Bloemenkamp KW, Duvekot HJ, van Eyck J, et al. Fetal fibronectin
status and cervical length in women with threatened preterm labor and the effectiveness of main-
tenance tocolysis. J Matern Fetal Neonatal Med 2016;29(10):1556-1561.
37. World Health Organisation. Birth Asphyxia - Summary of the previous meeting and protocol
overview. 2007; Available at: http://www.curoservice.com/health_ professionals/news/pdf/10-09-
2007_birth_asphyxia02.pdf.
38. Amer-Wahlin I, Nord A, Bottalico B, Hansson SR, Ley D, Marsal K, et al. Fetal cerebral energy metab-
olism and electrocardiogram during experimental umbilical cord occlusion and resuscitation. J
Matern Fetal Neonatal Med 2010 Feb;23(2):158-166.
39. National Institute of Clinical Excellence. Intrapartum care: care of healthy women and their babies
during labour. NICE Clinical Guideline. December 2014.
40. Chandraharan E. Should national guidelines continue to recommend fetal scalp blood sampling
during labor? J Matern Fetal Neonatal Med 2016 Feb 24:1-4.
41. Schaap TP, Moormann KA, Becker JH, Westerhuis ME, Evers A, Brouwers HA, et al. Cerebrospinal
fluid leakage, an uncommon complication of fetal blood sampling: a case report and review of the
literature. Obstet Gynecol Surv 2011 Jan;66(1):42-46.
42. Amer-Wahlin I, Hellsten C, Noren H, Hagberg H, Herbst A, Kjellmer I, et al. Cardiotocography only
versus cardiotocography plus ST analysis of fetal electrocardiogram for intrapartum fetal monitor-
ing: a Swedish randomised controlled trial. Lancet 2001 Aug 18;358(9281):534-538.
43. Westgate J, Harris M, Curnow JS, Greene KR. Plymouth randomized trial of cardiotocogram only
versus ST waveform plus cardiotocogram for intrapartum monitoring in 2400 cases. Am J Obstet
Gynecol 1993 Nov;169(5):1151-1160.
44. Belfort MA, Saade GR, Thom E, Blackwell SC, Reddy UM, Thorp JM,Jr, et al. A Randomized Trial of
Intrapartum Fetal ECG ST-Segment Analysis. N Engl J Med 2015 Aug 13;373(7):632-641.
45. Ojala K, Vaarasmaki M, Makikallio K, Valkama M, Tekay A. A comparison of intrapartum automated
fetal electrocardiography and conventional cardiotocography--a randomised controlled study.
BJOG 2006 Apr;113(4):419-423.
46. Vayssiere C, David E, Meyer N, Haberstich R, Sebahoun V, Roth E, et al. A French randomized
controlled trial of ST-segment analysis in a population with abnormal cardiotocograms during
labor. Am J Obstet Gynecol 2007 Sep;197(3):299.e1-299.e6.
47. Westerhuis ME, Visser GH, Moons KG, Zuithoff N, Mol BW, Kwee A. Cardiotocography plus ST
analysis of fetal electrocardiogram compared with cardiotocography only for intrapartum monitor-
ing: a randomized controlled trial. Obstet Gynecol 2011 Feb;117(2 Pt 1):406-407.

22
 General introduction
1
48. Schuit E, Amer-Wahlin I, Ojala K, Vayssiere C, Westerhuis ME, Marsal K, et al. Effectiveness of elec-
tronic fetal monitoring with additional ST analysis in vertex singleton pregnancies at >36 weeks of
gestation: an individual participant data metaanalysis. Am J Obstet Gynecol 2013 Mar;208(3):187.
e1-187.e13.
49. Blix E, Brurberg KG, Reierth E, Reinar LM, Oian P. ST waveform analysis versus cardiotocography
alone for intrapartum fetal monitoring: a systematic review and meta-analysis of randomized trials.
Acta Obstet Gynecol Scand 2016 Jan;95(1):16-27.
50. Neilson JP. Fetal electrocardiogram (ECG) for fetal monitoring during labour. Cochrane Database
Syst Rev 2015 Dec 21;(12):CD000116.
51. Saccone G, Schuit E, Amer-Wahlin I, Xodo S, Berghella V. Electrocardiogram ST Analysis During
Labor: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Obstet Gynecol
2016 Jan;127(1):127-135.
52. Vayssiere C, Ehlinger V, Paret L, Arnaud C. Is STAN monitoring associated with a significant decrease
in metabolic acidosis at birth compared with cardiotocography alone? Review of the three
meta-analyses that included the recent US trial. Acta Obstet Gynecol Scand 2016 Oct;95(10):1190-
1191.
53. Kwee A, Dekkers AH, van Wijk HP, van der Hoorn-van den Beld CW, Visser GH. Occurrence of
ST-changes recorded with the STAN S21-monitor during normal and abnormal fetal heart rate
patterns during labour. Eur J Obstet Gynecol Reprod Biol 2007 Nov;135(1):28-34.
54. Amer-Wahlin I, Arulkumaran S, Hagberg H, Marsal K, Visser GH. Fetal electrocardiogram: ST
waveform analysis in intrapartum surveillance. BJOG 2007 Oct;114(10):1191-1193.
55. Larks SD. Estimation of the Electrical Axis of the Fetal Heart. Am J Obstet Gynecol 1965 Jan 1;91:46-
55.
56. Wagner GS, Strauss DG. Marriott’s Practical Electrocardiography. 12th edition ed. Philadelphia:
Lippincott Williams & Wilkins; 2014.
57. Goodacre S, McLeod K. ABC of clinical electrocardiography: Paediatric electrocardiography. BMJ
2002 Jun 8;324(7350):1382-1385.
58. Schaffer AI, Beinfield WH. The vectorcardiogram of the newborn infant. Am Heart J 1952
Jul;44(1):89-94.

23
24
 Chapter 2

Physiological background

25
 Chapter 2

The fetal heart

The fetal heart is a complex structure. There are shunts and metabolic adaptations present
during intra-uterine life, while major changes occur in the postnatal period. Once one takes
a closer look, the fetal heart is a very flexible, responsive and adaptive structure.

Embryology and circulation of the fetal heart

During the embryologic development, the fetal heart is the first functioning organ1. Initially,
the embryologic body plan is symmetric. One of the first indications of left-right asymmetry is
the rightward looping of the midline heart tube, at day 23 of the human embryology2. Simul-
taneously, the heart starts to beat from day 22 onwards and pumps blood by day 24-251. The
time line of the formation of the fetal heart is depicted in Figure 1. From day 28 onwards,
the remainder of the development consists of remodelling of the chambers, development
of the septa and valves, and formation of the epicardium, coronary vasculature and cardiac
innervation and conduction system1. Once all the cardiac structures have been formed and
organised, the fetal heart will continue to grow in an adaptive interplay with the changing
demands3.

The fetal myocardium can grow due to cell division. In addition, there is an increase
in density of myofibrils. In the second half of pregnancy, there is also improvement in
contractility of the myofibrils. In animal studies, the maximal systolic volume of a fetus is
restricted by preload limitation through the extracardiac constraint (pericardium and chest
wall-lung combination)5. Therefore, the myocardial contractile element is relatively poor
during fetal life, which makes it difficult to change the stroke volume of the fetal heart3,5.
As a consequence, regulation of the cardiac output is mainly dependent on alterations
in fetal heart rate. In the fetus, the systemic circulation is fed from both the left and right
ventricle in parallel, with equal intraventricular pressures6. The median biventricular output
is estimated to be 425ml/min/kg, and is not associated with gestational age7. The cardiac
outflow of the right ventricle is slightly larger (about 60% of total cardiac output) compared
to the left ventricle (about 40% of total cardiac output)3,7. Approximately 55% of the left
ventricular output is delivered directly to the brain via the carotid and vertebral arteries8.

The heartbeat is initiated in the sino-atrial node, the pacemaker of the heart. Electrical
depolarisation triggers the myocardium to contract, and the depolarisation spreads from
cell to cell via conduction pathways. The timing of contraction of the various regions of
the myocardium is thereby influenced, ensuring an efficient contraction in the correct
sequence1. A secondary pacemaker, the atrioventricular node, is formed within the
atrioventricular junction and regulates the conduction of depolarisation from the atria

26
 Physiological background

to the ventricles. From there, the depolarisation is transmitted through both ventricles
via the bundle of His. Following neural input of the sympathetic and parasympathetic
2
branches of the autonomic nervous system, the heart rate can be modified.

In Figure 2, an overview of the fetal blood flow is shown. During fetal life, oxygen-rich
blood enters the fetal body via the umbilical vein. It mixes with a small amount of deoxy-
genated portal blood in the ductus venosus, and enters the inferior vena cava. From there,
it is propelled into the right atrium. Due to hemodynamically distinct blood streams of
the inferior vena cava (with oxygenated blood) and the superior vena cava (with deoxy-
genated blood), there is little mixture in the right atrium1. A part of the oxygenated blood
originating from the inferior vena cava is moved via the foramen ovale to the left side of the
heart, bypassing the fetal lungs. Since the vascular resistance of the collapsed fetal lungs is
very high, there is only a limited amount of blood flow through the pulmonary circulation
entering the left atrium that mixes with the oxygenated blood originating from the right
atrium. Via the left ventricle, the blood is pushed into the aorta and the head, neck and arms
are supplied with oxygenated blood. This blood is therefore slightly higher oxygenated
than the blood in the descending aorta, where a mix with blood originating from the right
side of the heart via the ductus arteriosus takes place. The amount of blood that is shunted
increases exponentially during gestation9. About 46% of the combined cardiac output
is propelled across the ductus arteriosus9. After distribution of blood to the trunk and
lower limbs, the blood returns to the placenta for oxygenation via the umbilical arteries.

Postnatal adaptations
After birth, there is an abrupt dilation of the pulmonary vasculature and cessation of the
umbilical flow. When the alveoli are filled with air, the pulmonary vessels open and pulmonary
resistance drops. It is thought that this is a direct response to oxygen1. Simultaneously,
due to spontaneous constriction or obstetrical clamping, the flow from the placenta is
discontinued. Changes in flow and pressure occur as a consequence.

Due to opening of the pulmonary vasculature and cessation of the umbilical blood flow, the
pressure in the right atrium decreases. The resultant sudden increase in pulmonary venous
return causes a rise in pressure in the left atrium. The mechanical effect of the reversal in
pressure between the left and right atrium causes the flexible and rigid part of the septum
of the foramen ovale to be forced against one another, and thus to functionally close the
foramen ovale. Normally, both parts of the septum are fused three months postpartum.

27
 Chapter 2

Figure 1. Time line of the formation of the fetal heart.

Adapted from: Anatomy & Physiology4.

Figure 2. The fetal blood flow.

Adapted from: the American Heart Association.

28
 Physiological background

The decrease in pressure in the pulmonary trunk resulting from opening of the pulmonary
circulation, is thought to cause a slight reverse flow of oxygenated aortic blood through the
ductus arteriosus1. It is thought that the oxygen tension might locally induce the vascular 2
smooth muscle cells to contract and therefore restrict the blood flow. However, the exact
mechanism for closure of the ductus arteriosus is not clear yet1. At term, constriction of the
ductus arteriosus normally occurs within 72 hours after birth10.

In addition, the ductus venosus closes soon after birth as no blood is flowing through the
umbilical vein anymore1. Hereafter, the portal circulation replaces the hepatic blood flow
from the placenta.

Hypoxia and the fetal heart

Hypoxemia is defined as an abnormally low level of oxygen in the arterial blood. In
case of the human fetus, the natural environment is hypoxemic (but not pathologi-
cally hypoxic)11. The fetus can thrive under these conditions due to several adaptation
mechanisms, amongst others fetal haemoglobin that has a high affinity for oxygen
and allows easy diffusion from the maternal to the fetal circulation, the organisation
of the fetal circulation as described above and the higher rate of tissue perfusion in
the fetus compared to adults. These mechanisms compensate for the lower oxygen
levels in the fetal blood, and make sure that oxygen supply is sufficient at tissue level.

In case of hypoxia, the oxygen supply at tissue level is inadequate and tissue damage can
arise. Even so, the fetus can compensate through variabele mechanisms such as redistri-
bution of blood flow and activation of the anaerobic metabolism. Progressive metabolic
acidosis occurs following hypoxia if these mechanisms are not sufficient in compensating
the oxygen shortage or in case of longlasting activation of the anaerobic metabolism.
When there is acidosis in combination with organ damage, this is referred to as asphyxia.

In the late 1900s, multiple animal studies have been performed regarding the effect of
hypoxia on the fetal heart. As summarised by Widmark et al.12, these studies showed
that when the maternal-placental blood flow is reduced, and therefore an acute hypoxic
event is induced, both the chemo- and baroreceptor reflexes are activated. Initially, the
chemoreceptor reflex increases both sympathetic and parasympathetic tone. In the fetal
heart, parasympathetic influences predominate resulting in fetal heart rate bradycardia.
During this reduced fetal heart rate the end-diastolic filling time is prolonged, which
increases the end-diastolic volume. Therefore, cardiac output and perfusion pressure are
both maintained despite fetal heart rate bradycardia13. Sympathetic activation causes

29
 Chapter 2

peripheral vasoconstriction, realising blood flow redistribution favouring the brain, heart
and adrenals13,14. An increase in mean arterial blood pressure activates the baroreceptor
reflex, and causes a secondary (inhibitory) effect on the fetal heart rate. Once initiated, the
peripheral vasoconstriction is maintained by release of vasoactive agents14. These can
be measured 15 minutes from the onset of acute hypoxia13. In addition, it is thought that
impulse conduction through the atrioventricular node is directly inhibited (parasympa-
thetic activation, baroreceptor reflexes) or directly facilitated (sympathetic activation)12.

After reoxygenation, there is a baroreceptor reflex-enhanced parasympathetic tone that

causes a negative chronotropic effect. This might exert a protective effect on the cardi-
ovascular system, as this is still affected by an enhanced sympathetic tone due to circulat-
ing humoral agents12. Therefore, late decelerations may be interpreted as an adaptive
mechanism to excessive sympathetic influence after a hypoxic event12. Because of the
increased levels of catecholamines and other constrictor agents in the fetal circulation, the
peripheral vasoconstrictor response and redistribution of blood flow is maintained longer13.

A previous study by Amer-Wåhlin et al.15 showed that cardiac effects following hypoxia
(changes in the electrocardiogram) precede cerebral damage, and can therefore
been seen as a marker for fetal distress. In the fetal heart, a high amount of glycogen
is stored in case anaerobic metabolism needs to set in when oxygen supply is inade-
quate16. As described by Rosén and Isaksson16, in the initial less severe states of hypoxia
both liver and cerebral glycogen stores are well maintained and the fetus maintains
a normal cardiac rhythm. When hypoxia becomes more severe, cerebral glycogen is
still unaffected while there is depletion of liver glycogen stores. In 50% of these cases,
fetal heart rate bradycardia was present. In case of severe hypoxia, both brain and
liver glycogen stores were depleted and all cases showed fetal heart rate bradycardia.
In addition, a correlation between changes in the ST segment of the electrocardio-
gram and depletion of glycogen in the fetal heart was found in animal experiments16.

Fetal heart rate variability & the autonomic nervous system

Variability in the fetal heart rate is a resultant from the counteracting autonomic influences
of the sympathetic and parasympathetic nervous system17,18. These systems do not simply
interact as a “push-pull” system, but complex interactions exist between them18. Amongst
others, intrinsic variability of the heart, the baroreceptor reflex, humoral agents (for instance
circulating catecholamines), respiration and thermoregulation have their influence on heart
rate variability18,19.

30
 Physiological background

When fetal heart rate variability is normal, this is a reliable indicator of fetal wellbeing, irre-
spective of the fetal heart rate pattern20. Decreased fetal heart rate variability is associated
with fetal acidosis, low Apgar score and perinatal death20. Therefore, fetal heart rate varia- 2
bility is one of the most important factors to assess in fetal monitoring. Specific heart rate
variability parameters that are mentioned below (for instance high-frequency (HF)-energy
and low-frequency (LF)-energy) are described in detail in chapter 3 – technical background.

Multiple confounding factors can influence fetal heart rate variability. Several drugs that
are commonly used in obstetric care may alter the fetal heart rate, heart rate variability, or
the central nervous system. Two categories of these drugs will be described in this thesis in
chapter 6 (betamethasone, a corticosteroid) and chapter 7 (various tocolytic drugs). Another
confounder is birthweight; a study by Siira et al.21 revealed that HF-power is negatively related
to birthweight in case of fetal growth restriction. In addition, in cases where pregnancy is
complicated by pregnancy induced hypertension or pre-eclampsia higher absolute LF- and
HF-power was found in comparison to a control group, and greater instability of the fetal
heart rate was seen in this group22. Changes in fetal behavioural states and diurnal rhythm
can also influence fetal heart rate variability23,24. Below, the influences of gestational age and
oxygen depletion on fetal heart rate variability are described in more detail.

When gestational age advances, there is evolution towards a more stable and mature
autonomic nervous system25. By means of spectral analysis of fetal heart rate variability, the
functional state of the autonomic nervous system can be assessed. This is described in more
detail in chapter 3 – technical background. Prior research has shown there is an increase in
absolute LF- and HF-power with increase in gestational age26-28. The sympathetic nervous
system is effective from mid-gestation onwards, while the parasympathetic nervous system
matures later18,29. The typical parasympathetic reflex responses are first seen during term
gestation and reach adult levels after birth29. As gestational age progresses the parasym-
pathetic modulation seems to increase, while the sympathetic modulation decreases30.

As described previously in this chapter, the autonomic nervous system is activated in case of
oxygen shortage. Subsequently, the beat-to-beat heart rate is modulated17. Initially, in case of
mild fetal distress, there is a rise in fetal heart rate variability (total power, LF- and HF-power,
LF/HF ratio)21,31,32. This is a reflection of increased sympathetic activity. Thereafter, in case of
fetal hypoxia or acidemia, there is a decrease in fetal heart rate variability. More specifically,
the absolute LF-power seems to be decreased33. In prior research, normalised LF-power was
found to be negatively associated with fetal pH, while normalised HF-power was positively

31
 Chapter 2

associated with fetal pH34,35. This can be explained by increased sympathetic and decreased
parasympathetic cardiac modulation, as the internal pH value decreases. This is in line with
the increased LF/HF ratio that is found in acidotic fetuses, which indicates a shift towards
sympathetic predominance21. It is suggested that both circulating catecholamines and
sympathetic neural activity cause the decreased heart rate variability that is seen in case of
severe fetal distress35. Eventually, in case of major fetal compromise, loss of central autonomic
cardiovascular control and cardiovascular decompensation is likely21,33.

In adult cardiology, heart rate variability already plays a role in determining prognosis and
guiding therapy36. Almost 25 years ago, it was suggested that analysis of fetal heart rate
variability might be able to improve the diagnosis of pathological conditions25. Since then,
advances have been made regarding defining, monitoring and interpreting fetal heart rate
variability.

32
 Physiological background

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35. van Laar JO, Peters CH, Vullings R, Houterman S, Bergmans JW, Oei SG. Fetal autonomic response to
severe acidaemia during labour. BJOG 2010 Mar;117(4):429-437.
36. Rosenstock EG, Cassuto Y, Zmora E. Heart rate variability in the neonate and infant: analytical 2
methods, physiological and clinical observations. Acta Paediatr 1999 May;88(5):477-482.

35
36
 Chapter 3

Technical background

37
 Chapter 3

Introduction
In this thesis, various studies considering fetal monitoring are described in which multiple
technologies were used. In this chapter, the technological background regarding these
techniques will be explained. First, the cardiotocogram (CTG) will be discussed. This
technique is mainly used in prior studies regarding fetal heart rate parameters, as described
in chapters 6 and 7. The fetal electrocardiogram (ECG) is a technique that is still developing.
In chapter 5 and chapter 9, fetal ECG measurements are used to establish the normal fetal
ECG in mid-term pregnancy and to calculate the orientation of the electrical heart axis in
premature fetuses. Once fetal ECG recordings have been performed, these can be used to
apply spectral analysis and hence give more reliable estimates considering fetal heart rate
variability, as described in chapter 8. During labour, fetal ECG measurements are required
to be able to perform ST analysis. Chapters 10 and 11 relate to ST analysis.

The cardiotocogram
External cardiotocography (CTG) is a Doppler ultrasound-based system, detecting heartbeats
as a reflection from all moving parts of the fetal heart. Simultaneously, uterine contractions
are recorded by means of tocodynamometry. External registration of the fetal heart rate is
prone to signal loss, inadvertent maternal heart rate monitoring, signal artefacts such as
double-counting or half-counting and it might not record fetal arrhythmias accurately1. In
addition, this technology is not able to provide beat-to-beat interval registration, since some
of these irradiated ultrasound waves are reflected by the valves instead of the walls of the
heart, causing inaccuracies. Moreover, the autocorrelation techniques used cause averaging
of two to three subsequent cardiac cycles. Therefore, it cannot follow fast changes in fetal
heart rate signal. This has a significant influence on the values of some variability indices;
mainly on the indices that describe parasympathetic activity. As studied by Jezewski et al.2,
this introduces an average error in the RR-intervals of 0.42 ms, compared to the fetal ECG. For
visual interpretation of fetal heart rate variability this has little influence, given the limited
resolution of the human eye. However, in automated analysis this can have a significant effect
on values of variability indices2. Therefore, CTG is an imprecise method for acquiring varia-
bility of the fetal heart rate. By means of fetal ECG measurements, QRS complex detection
enables precise registration of fetal beat-to-beat heart rate variability. This technique
considers the full shape of the analysed signal; an example is shown in Figure 1. Definitions
for quantitative evaluation of fetal heart rate variability (long- and short-term variability) were
originally proposed for the direct fetal ECG signal2. However, they have been applied for ultra-
sound-based registration without any adaptation.

38
 Technical background

Besides the shortcomings of CTG as listed above, the specificity and positive predictive value
of CTG are rather poor as previously described in chapter 1 – introduction1. This indicates the
need for a technology that enables more accurate and reliable monitoring of fetal wellbeing.

The fetal electrocardiogram 3

The fetal ECG during pregnancy can be obtained via non-invasive electrodes placed on the
maternal abdomen. During labour, the fetal ECG can also be obtained via direct recordings
through a scalp electrode on the fetal head.

Figure 1. Electrocardiography complex of one heartbeat.

The electrocardiography complex of one heartbeat, including the different segments and intervals
referred to in this thesis.

Fetal ECG extraction through the maternal abdomen was first described by Cremer et al.3
in 1906. In comparison to other fetal monitoring techniques, development of the fetal ECG
lagged behind, because there were multiple technical challenges to overcome. At 20 weeks
of gestation, the fetal heart is about 1/10th the size of an adult heart causing low voltage
of the fetal ECG (1/50th of the maternal ECG)4. Therefore, there is a low signal-to-noise ratio
when recording a fetal ECG. In addition, fetal signals are masked by the maternal ECG and
high background noises caused by the abdominal and uterine electromyogram. Amniotic
fluid and maternal tissues surrounding the fetus further enlarge the distance from the
fetal heart to the electrodes on the maternal abdomen. Between 30 and 34 weeks of
gestation, the fetus is surrounded by the vernix caseosa that results in an electrical isolation

39
 Chapter 3

which diminishes the signal amplitude further, and which is the main cause of the poor
signal-to-noise ratio in this period5,6. Furthermore, the complex three-dimensional
shape of the fetal ECG alters with changes in the fetal position with reference to the
electrodes that are placed in a fixed configuration on the maternal abdomen. Despite
these challenges, fetal ECG technique improved and it has previously been demonstrated
that fetal heart rate recordings obtained by non-invasive fetal ECG measurements correlate
very well with fetal ECG signals obtained directly via a scalp electrode7.

Apart from the technical difficulties encountered when performing a fetal ECG, the inter-
pretation is also challenging. This is mainly caused by the marked differences in prenatal
and postnatal circulation, which are elaborated in chapter 2 – physiological background.

In our studies, non-invasive fetal ECG recordings are performed using eight self-adhesive elec-
trodes of which six are fetal ECG channel electrodes, one reference and one ground electrode.
Other studies have used fewer electrodes8 or more electrodes9. Before placing the electrodes,
the maternal skin is prepared by gentle excoriation of surface skin cells and cleaning of the
skin in order to reduce the electrode-skin impedance. The electrodes are placed in a fixed
configuration on the maternal abdomen, as illustrated in Figure 2. For each of the six fetal ECG
electrodes, the voltage difference between a recording electrode and the reference electrode
is calculated. By using multi-lead recordings we can combine different leads in order to
increase the signal quality and to allow recombination of leads to reconstruct the standard
Einthoven leads. The chances of recording good quality fetal ECG signals in at least one of
the electrodes is maximised by spreading the electrodes over the uterus. Electrode leads
are shielded and a ground electrode is used to reduce the effect of power line interference.

For the measurements performed in the context of this thesis, two systems were used to
obtain and store the fetal ECG recordings; the Porti amplifier system (Twente Medical Systems
International B.V., Oldenzaal, the Netherlands) and the Nemo system (Nemo Healthcare,
Veldhoven, the Netherlands). Both systems are approved by the Medical Technical
Department of the Máxima Medical Centre.

In order to obtain fetal ECG recordings, several filters are applied to suppress high-frequency
noise, baseline drift and power line interference. Thereafter, the maternal ECG is removed
by weighted averaging of maternal ECG segments10. This is illustrated in Figure 3. By
spatially combining the signals of the six fetal ECG channels, the signal-to-noise ratio is
enhanced. Following detection of the R peaks in the fetal ECG, a beat-to-beat fetal heart
rate signal is created.

40
 Technical background

Figure 2. Configuration of the electrodes on the maternal abdomen in order to acquire a

non-invasive fetal electrocardiogram.

REF = reference electrode

GND = ground electrode

Fetal heart rate analysis

The aim of fetal heart rate analysis is to describe changes in heart rate objectively. Heart
rate variability is depicted as a function of the fluctuation of the R-R interval (length
between two successive R waves)11. By means of analysis of fetal heart rate variability, the
functional state of the autonomic nervous system can be assessed. It is important that the
fetal heart rate is acquired on a beat-to-beat basis. In addition, most heart rate analysis
methods require equidistant data. Therefore, R-R intervals are resampled at 4 Hz (at least
twice the frequency of the highest frequency of interest; 1.5 Hz). There are two distinct
approaches in heart rate analysis; analysis in the time-domain or the frequency-domain.

Examples of time-domain indices are short-term variability (STV) and long-term variabil-
ity (LTV). STV is sensitive to changes in successive heartbeats, and LTV gives a measure for
the overall variability in the heart rate. Over the years, multiple definitions have been
proposed12. In general, STV is calculated based on the difference between successive
inter-beat intervals12,13. If no beat-to-beat information is available (e.g. in CTG monitoring),

41
 Chapter 3

STV can be estimated as the epoch-to-epoch variation in 3.75 second epochs14. LTV is
generally defined based on the overall variation within one minute and can be calculated as
the difference between the maximum and minimum inter-beat interval.

With spectral analysis in the frequency-domain, the energy in specific frequency compo-
nents of heart rate variability is determined. This reveals the underlying system that
controls the heart rate; the autonomic nervous system. Fluctuations in fetal heart rate, and
therefore spectral estimates, reflect the influences of the autonomic nervous system. The
autonomic nervous system and its influence on fetal heart rate and variability are explained
in more detail in chapter 2 – physiological background. With spectral analysis, the signal is
decomposed into sinusoids of different frequencies and amplitudes. The magnitude of
heart rate variability (power) present at different frequency ranges, is reflected in the power
spectrum13. The power spectrum can be calculated with one of the following algorithms.

Figure 3. The obtained electrocardiography signal.

A
Amplitude

Time [s]
= Fetal complex
= Maternal complex

B
Amplitude

Time [s]

A: Filtered abdominal electrocardiogram recording, containing both fetal and maternal electrocardiogram
complexes. B: Fetal electrocardiogram, after subtraction of the maternal electrocardiogram.

42
 Technical background

The Fourier transform describes the relationship between a signal in the time-domain and
its representation in the frequency-domain15, and decomposes the R-R interval signal into
its various frequency components as a function of their relative power11.

A second algorithm that can be used, is the continuous wavelet transformation. Wavelets
are used as analytical functions and allow multi-resolution analysis in the time-frequency 3
domain16. In this thesis, we used the symlet 5 wavelet.

Impulses from the parasympathetic part of the autonomic nervous system are
conducted much faster than impulses from the sympathetic part. Hence, sympathetic
modulation causes slow fetal heart rate oscillations, while parasympathetic modulation
also causes fast oscillations19,20. Therefore, the sympathetic system is solely present in
the low-frequency (LF) band20,21. The LF peak is attributed to the baroreceptor reflex,
and is the result of changes in blood pressure11,13. Parasympathetic modulation is
present in both the LF and high-frequency (HF) band20,21. Following neonatal and adult
studies, a HF spectral peak appears at the respiratory frequency, and is the result of
respiratory sinus arrhythmia11,13. The very low-frequency (VLF) band is described to be
related to peripheral vascular resistance fluctuations caused by thermoregulation and
humoral systems11, but seems to have less clinical significance than LF and HF since
changes in the VLF band only appear after a delay of almost 6 minutes23.

In adult cardiology, the LF band is defined to range from 0.04 – 0.15 Hz and the HF band
from 0.15 – 0.4 Hz22. In newborns, the parasympathetic nervous system is shown to act in a
higher frequency range. Therefore, the HF band is defined to range from 0.4 – 1.5 Hz in both
newborns and fetuses. The VLF band is defined to range below 0.4 Hz22. Accordingly, these
definitions have been used in previous studies24-27. HF and LF spectral power are suggested
to be clinically similar to STV and LTV in the time-domain, respectively13.

When absolute units are used, changes in total power influence both LF- and HF-power
in the same direction. Normalised LF- and HF-power can be calculated by dividing LF- or
HF-power by total power, respectively. By this normalisation, relative changes in LF- and
HF-power are not masked by changes in total power and one can distinguish between
both branches of the autonomic nervous system22. In addition, the LF/HF ratio is a
reflection of the sympathicovagal balance22.

Results are depicted as power spectral density (PSD), which is the squared amplitude
calculated for each frequency. Analysis of the power spectrum can be performed by
quantifying the area under the spectrum in various bands of frequency11. A characteristic

43
 Chapter 3

spectrum with a high- and low-frequency band can be distinguished following spectral
analysis of heart rate variability, as depicted in Figure 4.

Figure 4. Example of a power spectrum of heart rate variability for human adults.

Adapted from: J.O.E.H. van Laar, Thesis: Fetal autonomic cardiac response during pregnancy and labour15.
Abbreviations: HF = high-frequency, LF = low-frequency, PSD = power spectral density.

ST analysis
ST analysis is performed using a STAN® monitor (several types available, Neoventa Medical,
Mölndal, Sweden). In clinical practice, interpretation of the CTG is combined with automatic
analysis of the ST segment of the fetal ECG. The ST waveform is a representation of the repo-
larisation phase of the myocardium, which is an energy demanding process28. The energy
metabolism in the myocardium (aerobic or anaerobic) will influence this repolarisation
process, and will therefore change the ST waveform. The fetal ECG is recorded with a scalp
electrode, which provides a unipolar ECG lead configuration. The monitor detects the R peak
of each heartbeat, measures and processes the beat-to-beat R-R intervals.

Before introduction of ST analysis in the labour wards, extensive (animal) studies have been
performed. During hypoxia, the heart is one of the organs that is favoured to receive oxygen
by autoregulation (as well as the brain and adrenal glands). It is suggested that cardiac signs
precede other central organ failure in case of asphyxia, and thus the heart can be used as an
indirect indicator of the condition of the fetal brain during labour28. The fetal heart compen-
sates by an increase in myocardial blood flow during the initial phase of hypoxia. Eventually,

44
 Technical background

sustained deprivation of oxygen is followed by enhanced β-adrenoreceptor activity and an

adrenalin surge, to switch from an aerobic to an anaerobic cardiac metabolism with glycog-
enolysis29,30. This is accompanied by an increase of potassium ions in the myocard31, which
mainly affects the relaxation phase of the cardiac cycle and leads to an increase in T wave
amplitude of the fetal ECG32. The oxygen content can fall more than 50% before the anaerobic
metabolism is activated, and ST waveform changes occur30. A direct correlation between the 3
increase in ST waveform and the rate of myocardial glycogenolysis (lactate production) is seen
in fetal lambs29, as well as a direct correlation between the T/QRS ratio and adrenalin levels30.
In acidotic fetuses, the increase in T/QRS ratio coincides with the increase in LF-power33.

In ST analysis, the hypoxia-related rise in T wave amplitude is analysed via a three-step protocol;

1. Of 30 heart cycles, an average ECG signal is rendered. The amplitude of the T wave is
normalised against the amplitude of the QRS complex, yielding a T/QRS value.

2. A baseline T/QRS value is determined; this is the median value of at least 20 T/QRS values
within a time frame of 20 minutes at the start of the recording. This baseline needs to be
determined when there is a normal CTG (normal variability, accelerations) or the fetal
status should be verified by fetal blood sampling. The baseline resets if it becomes lower
or after three hours of recording.

3. New T/QRS values are compared to this baseline value.

An increase in T/QRS ratio is known to correlate with a surge in catecholamines, activation

of β-adrenoreceptors, myocardial glycogenolysis and metabolic acidosis34. The STAN®
monitor gives an alarm (“event”) in case any of the three following changes occur; a rise
in baseline T/QRS (during >10 minutes), an episodic rise in T/QRS (during <10 minutes)
or a biphasic ST segment. However, there is limited evidence regarding the cut-offs,
specificity and sensitivity of these individual items35. In addition, dynamic changes in the
ST waveform have been reported during repeated brief hypoxic insults34.

Biphasic ST segments can occur when there is acute hypoxic stress in the fetal heart with
no time to respond to the hypoxia, or in case of chronic stress with a reduced capacity to
respond in case of lack of resources or already used resources34,36. A biphasic ST segment
is also associated with disturbances in the function of the heart muscle, infection or
congenital malformations36. A recent study suggested that biphasic ST events have no
additional value in detecting hypoxia35. ST depression can occur in case of myocardial
ischemia, accompanied by severe fetal acidosis and hypotension34. It is possible that the

45
 Chapter 3

ischemic-type ST waveforms develop earlier in growth-restricted fetuses due to their

limited glycogen reserves and possibly blunted sympathetic responses34. In this thesis, we
will not discuss biphasic ST evens or ST depression; we will only focus on the T/QRS ratio.

When ST changes occur, the STAN® monitor provides an automatic warning called “ST
event”. The relevance of such an event is depending on the visual assessment of the CTG.
The CTG is classified as normal, suspicious or pathological. Although the FIGO (International
Federation of Gynecology and Obstetrics) published an updated CTG classification system1,
the STAN® clinical guidelines are based on a former version of this classification system.
Therefore, this former version is included in Table 1. The T/QRS changes that can occur are
displayed in Table 2 (biphasic events are not shown). If the T/QRS change is smaller than
the alarm threshold, this can be due to normal beat-to-beat fluctuation in the behaviour of
the fetal heart, which is unrelated to the fetal condition, and is hence ignored. In case the
CTG is classified as normal, any ST event given by the STAN® monitor can be ignored36,37. In
case of a (pre)terminal CTG, immediate intervention is advised irrespective of ST events36,37.
When the CTG is suspicious or pathological, the STAN® clinical guidelines indicate if an
intervention is advised in relation to the ST event. These guidelines indicate ST changes that
prompt a clinical intervention, such as expedite delivery, fetal blood sampling and alleviate
possible causes of fetal distress (such as uterine hypertonus and maternal hypotension).

Table 1. Cardiotocography classification38.

Abbreviations: bpm = beats per minute, CTG= cardiotocography, min = minutes, sec =seconds.

46
 Technical background

Table 2. STAN® clinical guidelines38.

Abbreviations: CTG = cardiotocography, min = minutes.

3

47
 Chapter 3

References
1. Ayres-de-Campos D, Spong CY, Chandraharan E, FIGO Intrapartum Fetal Monitoring Expert
Consensus Panel. FIGO consensus guidelines on intrapartum fetal monitoring: Cardiotocography.
Int J Gynaecol Obstet 2015 Oct;131(1):13-24.
2. Jezewski J, Wrobel J, Horoba K. Comparison of doppler ultrasound and direct electrocardiography
acquisition techniques for quantification of fetal heart rate variability. IEEE Trans Biomed Eng 2006
May;53(5):855-864.
3. Cremer M. Über die direkte Ableitung der Aktionsströme des menschlichen Herzens vom Oesopha-
gus und über das Elektrokardiogramm des Fötus. Münch Med Wschr 1906;53:811-813.
4. Kimura Y, Sato N, Sugawara J, Velayo C, Hoshiai T, Nagase S, et al. Recent Advances in Fetal Electro-
cardiography. The Open Medical Devices Journal 2012;4:7-12.
5. van Laar JO, Warmerdam GJ, Verdurmen KM, Vullings R, Peters CH, Houterman S, et al. Fetal heart
rate variability during pregnancy, obtained from non-invasive electrocardiogram recordings. Acta
Obstet Gynecol Scand 2014 Jan;93(1):93-101.
6. Oostendorp TF, van Oosterom A, Jongsma HW. The fetal ECG throughout the second half of
gestation. Clin Phys Physiol Meas 1989 May;10(2):147-160.
7. Vullings R, Peters C, Andriessen P, Oei S, Wijn P. Monitoring the Fetal Heart Rate and Fetal Electro-
cardiogram: Abdominal Recordings Are As Good As Direct Ecg Measurements. Pediatric Research
2005;58(2):242.
8. Reinhard J, Hayes-Gill BR, Schiermeier S, Hatzmann H, Heinrich TM, Louwen F. Intrapartum heart
rate ambiguity: a comparison of cardiotocogram and abdominal fetal electrocardiogram with
maternal electrocardiogram. Gynecol Obstet Invest 2013;75(2):101-108.
9. Clifford G, Sameni R, Ward J, Robinson J, Wolfberg AJ. Clinically accurate fetal ECG parameters
acquired from maternal abdominal sensors. Am J Obstet Gynecol 2011 Jul;205(1):47.e1-47.e5.
10. Vullings R. Non-invasive fetal electrocardiogram: analysis and interpretation, PhD thesis. Eindhoven:
Eindhoven University of Technology; 2010.
11. Rosenstock EG, Cassuto Y, Zmora E. Heart rate variability in the neonate and infant: analytical
methods, physiological and clinical observations. Acta Paediatr 1999 May;88(5):477-482.
12. Cesarelli M, Romano M, Bifulco P. Comparison of short term variability indexes in cardiotocographic
foetal monitoring. Comput Biol Med 2009 Feb;39(2):106-118.
13. Van Ravenswaaij-Arts C, Kollee L, Hopman J, Stoelinga G, van Geijn H. Heart rate variabilitiy. Ann
Intern Med 1993;118:436-447.
14. Dawes GS, Lobb M, Moulden M, Redman CW, Wheeler T. Antenatal cardiotocogram quality and
interpretation using computers. BJOG 2014 Dec;121 Suppl 7:2-8.
15. van Laar JO. Fetal autonomic cardiac response during pregnancy and labour; PhD thesis.
Eindhoven: Eindhoven University of Technology; 2012.
16. Warmerdam GJ, Vullings R, Bergmans JW, Oei SG. Reliability of spectral analysis of fetal heart rate
variability. Conf Proc IEEE Eng Med Biol Soc 2014;2014:2817-2820.

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17. Peters CH, ten Broeke ED, Andriessen P, Vermeulen B, Berendsen RC, Wijn PF, et al. Beat-to-beat
detection of fetal heart rate: Doppler ultrasound cardiotocography compared to direct ECG cardiot-
ocography in time and frequency domain. Physiol Meas 2004 Apr;25(2):585-593.
18. Peters C, Vullings R, Bergmans J, Oei G, Wijn P. The effect of artifact correction on spectral estimates
of heart rate variability. Conf Proc IEEE Eng Med Biol Soc 2008;2008:2669-2672.
3
19. van Laar JO, Peters CH, Vullings R, Houterman S, Bergmans JW, Oei SG. Fetal autonomic response to
severe acidaemia during labour. BJOG 2010 Mar;117(4):429-437.
20. Akselrod S, Gordon D, Ubel FA, Shannon DC, Berger AC, Cohen RJ. Power spectrum analysis of
heart rate fluctuation: a quantitative probe of beat-to-beat cardiovascular control. Science 1981 Jul
10;213(4504):220-222.
21. Dalton KJ, Dawes GS, Patrick JE. The autonomic nervous system and fetal heart rate variability. Am J
Obstet Gynecol 1983 Jun 15;146(4):456-462.
22. Task Force of the European Society of Cardiology and the North American Society of Pacing and
Electrophysiology. Heart rate variability: standards of measurement, physiological interpretation
and clinical use. Circulation 1996 Mar 1;93(5):1043-1065.
23. Van Laar JO, Porath MM, Peters CH, Oei SG. Spectral analysis of fetal heart rate variability for fetal
surveillance: review of the literature. Acta Obstet Gynecol Scand 2008;87(3):300-306.
24. van Laar JO, Peters CH, Houterman S, Wijn PF, Kwee A, Oei SG. Normalized spectral power of fetal
heart rate variability is associated with fetal scalp blood pH. Early Hum Dev 2011 Apr;87(4):259-263.
25. van Laar JO, Peters CH, Vullings R, Houterman S, Oei SG. Power spectrum analysis of fetal heart rate
variability at near term and post term gestation during active sleep and quiet sleep. Early Hum Dev
2009 Dec;85(12):795-798.
26. De Beer N, Andriessen P, Berendsen R, Oei S, Wijn P, Bambang Oetomo S. Customized spectral band
analysis compared with conventional Fourier analysis of herat rate variability in neonates. Physiol
Meas. 2004;25:1385-1395.
27. Min SW, Ko H, Kim CS. Power spectral analysis of heart rate variability during acute hypoxia in fetal
lambs. Acta Obstet Gynecol Scand 2002 Nov;81(11):1001-1005.
28. Amer-Wahlin I, Nord A, Bottalico B, Hansson SR, Ley D, Marsal K, et al. Fetal cerebral energy metab-
olism and electrocardiogram during experimental umbilical cord occlusion and resuscitation. J
Matern Fetal Neonatal Med 2010 Feb;23(2):158-166.
29. Greene KR, Dawes GS, Lilja H, Rosen KG. Changes in the ST waveform of the fetal lamb electrocardi-
ogram with hypoxemia. Am J Obstet Gynecol 1982 Dec 15;144(8):950-958.
30. Rosen KG, Dagbjartsson A, Henriksson BA, Lagercrantz H, Kjellmer I. The relationship between
circulating catecholamines and ST waveform in the fetal lamb electrocardiogram during hypoxia.
Am J Obstet Gynecol 1984 May 15;149(2):190-195.
31. Fenn W. The deposition of potassium and phosphate with glycogen in rat livers. J Biol Chem
1939;128:297-308.

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32. Rosén K, Isaksson O. Alterations in Fetal Heart Rate and ECG Correlated to Glycogen, Creatine
Phosphate and ATP Levels during Graded Hypoxia. Biol Neonate 1976;30:17-24.
33. Siira SM, Ojala TH, Vahlberg TJ, Jalonen JO, Valimaki IA, Rosen KG, et al. Marked fetal acidosis and
specific changes in power spectrum analysis of fetal heart rate variability recorded during the last
hour of labour. BJOG 2005 Apr;112(4):418-423.
34. Westgate JA, Bennet L, Brabyn C, Williams CE, Gunn AJ. ST waveform changes during repeated
umbilical cord occlusions in near-term fetal sheep. Am J Obstet Gynecol 2001 Mar;184(4):743-751.
35. Becker JH, Krikhaar A, Schuit E, Martendal A, Marsal K, Kwee A, et al. The added predictive value of
biphasic events in ST analysis of the fetal electrocardiogram for intrapartum fetal monitoring. Acta
Obstet Gynecol Scand 2015 Feb;94(2):175-182.
36. Amer-Wahlin I, Kwee A. Combined cardiotocographic and ST event analysis: A review. Best Pract
Res Clin Obstet Gynaecol 2016 Jan;30:48-61.
37. Visser GH, Ayres-de-Campos D, FIGO Intrapartum Fetal Monitoring Expert Consensus Panel. FIGO
consensus guidelines on intrapartum fetal monitoring: Adjunctive technologies. Int J Gynaecol
Obstet 2015 Oct;131(1):25-29.
38. Amer-Wahlin I, Arulkumaran S, Hagberg H, Marsal K, Visser GH. Fetal electrocardiogram: ST
waveform analysis in intrapartum surveillance. BJOG 2007 Oct;114(10):1191-1193.

50
Technical background

51
 Part I

Fetal ECG and congenital heart disease

54
 Chapter 4

A systematic review of prenatal screening

for congenital heart disease by fetal
electrocardiography

Kim M.J. Verdurmen, Noortje B. Eijsvoogel, Carlijn Lempersz, Rik

Vullings, Christian Schroer, Judith O.E.H. van Laar, S. Guid Oei

Published: International Journal of Gynecology and Obstetrics.

2016;135(2):129-134

55
 Chapter 4

Abstract
Background
Congenital heart disease is the most common severe congenital anomaly worldwide.
Diagnosing early in pregnancy is important, but the detection rate by two-dimensional
ultrasonography is only 65%-81%.

Objectives
To evaluate existing data on congenital heart disease and non-invasive abdominal fetal
electrocardiography.

Search strategy
A systematic review was performed through a search of the Cochrane Library, PubMed
and Embase for studies published up to April 2016 using the terms “congenital heart
disease”, “fetal electrocardiogram”, and other similar keywords.

Selection criteria
Primary articles that described changes in fetal electrocardiography among fetuses with
congenital heart disease published in English were included.

Data collection and analysis

Outcomes of interest were changes in fetal electrocardiography parameters observed
for fetuses with congenital heart disease. Findings were reported descriptively.

Main results
Only five studies described changes observed in the fetal electrocardiogram for fetuses
with congenital heart disease, including heart rate, heart rate variability, and PR, QRS
and QT intervals. Fetal electrocardiography reflects the intimate relation between the
cardiac nerve conduction system and the structural morphology of the heart. It seems
particularly helpful in detecting the electrophysiological effects of cardiac anatomical
defects (e.g. hypotrophy, hypertrophy, and conduction interruption).

Conclusions
Fetal electrocardiography might be a promising clinical tool to complement ultrasonography
in the screening programme for congenital heart disease.

56
 Review: screening for congenital heart disease with fetal ECG

Introduction
Congenital heart disease (CHD) is the most common severe congenital anomaly worldwide1.
CHD is defined as “a gross structural abnormality of the heart or intra-thoracic large vessels,
that is actually or potentially of functional significance”2. Major CHD is usually defined as a
form of CHD that is lethal or requires intervention in the first year of life. The incidence of
CHD is estimated at 6-12 per 1000 live births (4 cases of major CHD per 1000 live births),
which makes this disorder six times more common than chromosomal anomalies and four
times more common than neural tube defects3-5. In Europe, the overall rate of mortality
due to CHD (both perinatal deaths and termination of pregnancy) was 0.7 per 1000 births 4
in 2000-20056. Of the fetuses affected by CHD, 4.5% die in utero and 21.1% die after birth7.

Diagnosing CHD early in pregnancy enables the identification of associated extracardiac

anomalies (present in 29% of cases) and chromosomal anomalies (26% of cases) that have
an effect on fetal and postnatal prognosis8. Prenatal and genetic counselling by experts
can be offered to parents. Thereafter, parents can decide to terminate or continue with the
pregnancy. Studies have shown that the frequency of pregnancy termination is higher if
prenatal diagnosis is made at an earlier gestational age (61% and 44% at 19 and 24 weeks
of pregnancy, respectively)8,9. If pregnancy is continued, an adequate plan of management
can be developed, including intra-uterine therapy, timing, mode and location of delivery,
and immediate treatment after birth. It has been demonstrated that prenatal diagnosis of
CHD increases survival rates and decreases long-term morbidity in both ductus-dependent
and foramen ovale-dependent CHD9-12. As Yates et al.13 has pointed out, however, prenatally
diagnosed CHD often has a worse prognosis because it is more likely to be severe (i.e. easier
to detect by ultrasonography) or associated with extracardiac or chromosomal anomalies.

Fetal cardiac screening during the second trimester was standardised in 200614. The
detection rate of CHD varies widely, from 65% to 81%15-18. The challenges encoun-
tered include the complex anatomy of the fetal heart, its motion, and small size.
Specific echocardiography is performed for fetuses with risk factors for CHD, and this
technique has a higher detection rate (sensitivity 90%, specificity 98%)19. However, up
to 90% of all cases of CHD occur in the low-risk population, indicating the necessity of
an effective screening procedure that is available to all pregnant women3,4,20-22.

Therefore, there is need for a reliable non-invasive diagnostic method with improved predic-
tive value for the diagnosis of CHD. Non-invasive transabdominal fetal electrocardiography
(ECG) is a new field that is being investigated. This technique can be used early in
pregnancy (from 18 gestational weeks), is safe to use, and easy to apply23. A big advantage

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 Chapter 4

is that fetal ECG is a potentially non-expensive long-term diagnostic tool, and raw data
can be forwarded for evaluation elsewhere.

Extraction of fetal ECG data was first described in 1906 by Cremer et al.24, and the approach
was first reviewed in 1986 by Pardi et al.25. Despite this early documentation, the develop-
ment of fetal ECG has lagged behind other techniques for fetal monitoring, partly because
of technical challenges. The fetal signal has low amplitude (2-50 microvolts, 1/50th of the
maternal ECG), and is masked by both the maternal ECG and background noises (maternal
electromyogram), resulting in a low signal-to-noise ratio25,26. The fetus is surrounded by
amniotic fluid and maternal tissues, which enlarge the distance to the electrodes and cause
a non-homogenous tissue conduction that interferes with signal quality. Additionally, the
vernix caseosa is electrically isolating and a main cause of the poor signal-to-noise ratio from
30 to 34 gestational weeks23,27. Other challenging factors are the complex three dimensional
form of the fetal ECG and the movements of the fetus, which makes it difficult to evaluate the
heart from one direction. Furthermore, at 20 gestational weeks, the fetal heart is approximate-
ly one-tenth of the size of an adult heart and the fetal heart rate is two to three times faster
than the adult heart rate28. With improvements in technology and knowledge of information
theory, however, fetal ECG is becoming more and more attractive.

In addition to the challenges in the conduction of fetal ECG, it is also difficult to interpret
the data. By contrast with postnatal life, the systemic circulation in the fetus is fed from the
left and right ventricle in parallel with equal intraventricular pressure29. The right ventricular
outflow is slightly larger than the left ventricular outflow. The ductus arteriosus propels 40%
of the combined cardiac output during the second trimester. Right-sided obstructive lesions
(e.g. tetralogy of Fallot or pulmonary stenosis) with a dominance of the right ventricle are
difficult to diagnose in utero; however, they are often accompanied by septal defects or by
left-side obstructive lesions (e.g. aortic stenosis or coarctation of the aorta), which can be
detected more easily. Owing to the fetal circulation in utero, fetuses affected by CHD do not
always show overt signs of cardiac failure, because one side of the heart can compensate
for an abnormality on the other side. At present, the changes in the fetal ECG amplitudes,
segment intervals, and heart axis that are characteristic of CHD are not known. Although
the changes due to CHD seen on neonatal ECG are documented, these data are not likely
to correspond with those of fetal ECG because the circulation changes markedly directly
after birth. The aim of the present review was to evaluate the existing data on CHD and
non-invasive abdominal fetal ECG.

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 Review: screening for congenital heart disease with fetal ECG

Materials and Methods

As part of a systematic review, the Cochrane Library (2016, Issue 4), PubMed and Embase elec-
tronic databases were searched to identify all studies published on fetal ECG and CHD up to
April 30, 2016. The following keywords were used: “congenital heart disease”, “congenital heart
defects”, “fetal electrocardiogram”, “fetal electrocardiography”, and “fetal ECG”. The outcomes
of interest were changes seen in fetal ECG parameters, such as ECG intervals, ECG segments,
and the electrical heart axis among fetuses with CHD.

Primary articles that described the changes in fetal ECG among fetuses with CHD were 4
selected. The reference lists of the selected articles were also searched. The study language
was restricted to English. Review articles and studies describing diagnostic tools other than
non-invasive abdominal fetal ECG were excluded. Articles that solely described fetal arrhyth-
mia were excluded because only few arrhythmias are associated with CHD.

The search and selection of articles were performed independently by two authors (K.M.J.V.
and N.B.E.). The guidelines and quality assessment forms of the Dutch Cochrane Centre were
used to evaluate the quality of the studies. The findings were reported descriptively and no
statistical analysis was performed.

Results
The search and selection of articles is summarised in Figure 1. In total, five articles met the
inclusion criteria and were reviewed, including case reports by Hamilton et al.30 and Brambati
and Bonsignore31. Three articles by Siddiqui et al.32, Velayo et al.33, and Yilmaz et al.34 were
prospective cohort studies, including normal fetuses and cases of CHD. The five studies were
published between 1977 and 2016.

Owing to the low number of fetuses, the variation in outcome measures described, and the
differences in signal processing techniques used in the five studies, it was not possible to
directly compare or pool the results. The basic characteristics and a quality assessment of the
two case reports are given in Table 1, whereas the basic characteristics and a quality assess-
ment of the prospective studies are given in Tables 2 and 3. Table 4 presents an overview of
the fetal ECG parameters of the fetuses with CHD included in this review.

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 Chapter 4

Figure 1. Flowchart depicting the search and selection of articles.

Initial search: 30
-PubMed 18
-EMBASE 12

Duplicates: 10

Screened: 20

Excluded: 15
-Review 5
-Doppler ultrasonography 3
-Magnetocardiography 1
-Cardioversion 1
-Arrhythmia 1
-Risk factor assessment for CHD 1
-Fetal ECG in diabetic mothers 1
-Intrapartum ST monitoring 1
-Signal transmission 1

Included: 5

Abbreviations: CHD = congenital heart disease, ECG = electrocardiography.

Table 1. Characteristics and quality assessment of the two case reports on fetal ECG.

Abbreviation: ECG = electrocardiography.

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 Review: screening for congenital heart disease with fetal ECG

Table 2. Characteristics and quality assessment of the study by Velayo et al.33

Abbreviations: ECG = electrocardiography, MRI = magnetic resonance imaging.

Table 3. Characteristics and quality assessment of the studies by Yilmaz et al.34 and
Siddiqui et al.32

Abbreviations: ECG = electrocardiography, HLHS = hypoplastic left heart syndrome, TGA = transposition
of the great arteries, TOF = tetralogy of Fallot.

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 Chapter 4

Hamilton et al.30 described a case of complex CHD, in which a complete heart block was
seen in 1977. They used a cardiotocograph with the capacity to process fetal phonocar-
diographic and abdominal fetal ECG signals. The bizarre QRS complexes found on fetal
ECG (not otherwise specified) suggest that the pacemaker was distal to the bundle of His,
with a fetal heart rate of 50 beats per minute. After delivery, cardiac catheterisation and
angiocardiography were performed to confirm the existence of complex CHD (Table 4).

Seven years later, Brambati et al.31 described a case of an atrioventricular septal defect
in which cardiac arrhythmia was seen. The signal processing method is not extensively
described, but data extraction was mainly performed manually and a median fetal ECG
constituting 50 heartbeats was generated. Extrasystoles without a preceding P wave were
found, suggestive of ventricular origin. Additionally, a prolonged QRS time was found,
which was stated to be suspicious of cardiac enlargement and/or cardiac anomaly. After
delivery, ventricular extrasystoles, left axis deviation and right ventricular hypertrophy
were found on ECG. The neonate was diagnosed with an atrioventricular septal defect.

Velayo et al.33 performed a prospective cohort study using simultaneous fetal ECG and
cardiotocography (Doppler ultrasonography) recordings. The fetal heart rate information
derived from Doppler ultrasonography was used to filter the fetal ECG35. Overall, 179
women were prospectively screened from a low-risk population. Twelve (7%) showed an
abnormal fetal ECG; of these, 8 (4%) were excluded from further analysis because the fetus
had no underlying structural heart defects, whereas 4 (2%) were confirmed to have CHD
by an ultrasonography examination performed after inclusion in the study. The remaining
167 women (93%) with normal fetal ECG and no CHD or other anomalies on ultrasonogra-
phy evaluation were used for standardisation of normal parameters. The fetal ECG was
found to have a sensitivity of 100%, specificity of 95%, positive predictive value of 33%,
and negative predictive value of 100% for the detection of CHD in a low-risk population.

Velayo et al.33 described the four cases of CHD that they found in their study population in
detail (Table 4). They stated that premature ventricular contractions, as seen in cases one and
three, might be caused by a primary developmental anomaly of the conduction system in the
presence of endocardial cushion defects or an underlying genetic defect affecting intrinsic
myocardial cell physiology. Prolongation of the QT interval, as seen in cases two and four,
might be explained by repolarisation dysfunction (alterations in action potential duration),
caused by ventricular aberrations33. This is also seen in cases of cardiac remodelling due to
disease progression. In case four, the various prolonged intervals might have been late signs
of the critical condition of the fetus, supported by the cardiomegaly with signs of heart failure.

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 Review: screening for congenital heart disease with fetal ECG

Yilmaz et al.34 and Siddiqui et al.32 both performed a prospective cohort study of the same
set of 92 participants: 41 healthy controls and 51 fetuses with CHD, confirmed by fetal
echocardiography. The Monica AN24 fetal electrocardiographic monitor was used to perform
measurements at three gestational ages (19-27, 28-33 and 34-38 gestational weeks). Tracing
quality was analysed in both studies.

Yilmaz et al.34 calculated the PR, QRS, and QT intervals during gestation. They showed that
the PR and QRS intervals both lengthen as gestational age increases among normal fetuses.
Among fetuses with CHD, this lengthening during gestation was not seen, but longer PR
and QRS intervals were seen at all gestational ages as compared with normal values (Table
4
4). T waves seemed to be difficult to detect, and were therefore not included in the analysis.

Siddiqui et al.32 calculated fetal heart rate and fetal heart rate variability during gestation.
Among the control fetuses, heart rate decreased during gestation, whereas heart rate
variability increased. Fetuses with CHD generally had a lower fetal heart rate than healthy
fetuses, but no differences in heart rate variability at 34-38 weeks were observed between the
controls and cases, except for fetuses with hypoplastic left heart syndrome (which showed
significantly lower heart rate variability during the active fetal state).

Discussion
Overall, the present systematic review revealed that little research has been published
regarding the changes seen in fetal ECG parameters observed for fetuses with CHD. The
methods of conducting the fetal ECG measurements were different in most studies and
evolved with time. Additionally, the fetal ECG parameters described in the studies varied. All
the studies included show that fetal ECG can be a valuable tool to diagnose CHD early in utero.
However, data on the fetal ECG changes observed among fetuses with CHD remain limited.

Both the case reports by Brambati et al.31 and Hamilton et al.30 are from another era, and
are therefore not comparable with the signal processing techniques in current use. It is
not likely that the two pregnancies described received prenatal ultrasonography screening
to detect CHD. Nevertheless, both studies do indicate the potential of fetal ECG in
diagnosing CHD and fetal arrhythmias.

Velayo et al.33 reported a promising sensitivity and specificity of 100% and 95%, respectively;
however, the positive predictive value of fetal ECG was only 33%. The low positive predictive
value can be explained by the low probability that fetuses in the general population will have
CHD. The eight cases with an abnormal ECG that were excluded had other abnormalities,

63
64
Table 4. Overview of the fetal ECG parameters of the included fetuses with congenital heart disease. Chapter 4
 a
In the studies of Yilmaz et al.34 and Siddiqui et al.32, the number of fetuses included varied by gestational age; therefore, the minimum and maximum
number of fetuses per group is indicated.
b
Common atrium, complete atrioventricular canal, double outlet right ventricle, pulmonic stenosis, aneurysmal right aortic arch with mirror-image
branching, interrupted left-sided vena cava with azygous continuation.
c
Total anomalous pulmonary venous connection, pulmonic stenosis, systemic right ventricular dysfunction, common atrioventricular valve, bilateral
superior vena cava, pulmonary venous return anomaly.
d
Tetralogy of Fallot, ventricular septal defect, pulmonic stenosis, double outlet right ventricle, transposition of the great arteries, multi-aortopulmo-
nary collateral arteries.
e
Dilated cardiomyopathy, ventricular septal defect, congestive heart failure.

Abbreviations: bpm = beats per minute, CHD = congenital heart disease, ECG = electrocardiography, GA = gestational age, HR = heart rate, ms =
millisecond, No. = number of included patients, SD = standard deviation of heart rate during active fetal state (i.e. heart rate variability), QTc = fetal QT
interval corrected for heart rate (QT divided by the square root of RR).
Review: screening for congenital heart disease with fetal ECG

65
4
 Chapter 4

including non-immune hydrops fetalis, hypoxemia, or arrhythmia (not otherwise specified).

Although CHD was not detected in this group, it is nonetheless important to identify this
subset of fetuses that are possibly at risk of fetal distress36.

Yilmaz et al.34 and Siddiqui et al.32 describe the largest case series of fetal ECG measurements
among fetuses with CHD published so far. However, only three types of CHD – which were
commonly diagnosed and with “distinct anatomical and physiological features that could
potentially impact ECG intervals”34 – were included in those studies. As a result, there is a high
risk of selection bias in both studies. Additionally, identification of the P, QRS and T waves is
not extensively described by Yilmaz et al.34. Siddiqui et al.32 calculated heart rate variability in
three different ways: interquartile range of the fetal heart rate, standard deviation of the fetal
heart rate, and root mean square of the standard deviation of the heart rate. Unfortunately,
exact values are not given for each type of CHD separately for either fetal heart rate or varia-
bility. A new trial with a greater sample population and the inclusion of more types of CHD is
needed.

The fetal ECG reflects the intimate relationship between the cardiac nerve conduction
system and the structural morphology of the heart33. In accordance with Yilmaz et al.34,
other studies also found that the duration of the P wave, QRS complex, and PR interval
increases progressively from 18 gestational weeks until term for fetuses with normal
cardiac structures34,37. This reflects the anatomical development of the atria and ventri-
cles during pregnancy, with gain in the weight and mass of the fetal heart. The increase
in PR interval indicates the development of the atrioventricular conducting tissue38.

Yilmaz et al.34 showed that, among fetuses with CHD, the normal lengthening in PR and QRS
intervals during pregnancy is absent. Additionally, most CHDs are associated with an
increased or decreased ventricular mass or cardiac arrhythmias25,30,31,33. In case of a severe
endocardial cushion defect (atrioventricular septum defect), the abnormal atrioventricular
connection affects the conduction system, and this is reflected in a longer PR interval
and left axis deviation25,31,33,39.

The aim of Siddiqui et al.32 was to characterise autonomic regulation in fetuses with CHD, and
to study whether autonomic development is altered in comparison with healthy controls.
Although it was not the aim, the study seems to indicate that heart rate variability might not
be a good screening tool to detect CHD because heart rate variability was lower only among
fetuses with hypoplastic left heart syndrome and only in the measurement at 34-38 gesta-
tional weeks. Moreover, there were only minor differences in fetal heart rate between controls
and fetuses with CHD.

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 Review: screening for congenital heart disease with fetal ECG

The rate of prenatal detection by two-dimensional ultrasonography is mainly influenced by

the experience of the sonographer. It is relatively difficult to interpret the anatomy of the
fetal heart correctly because it is a dynamic, constantly moving structure that rhythmically
beats approximately more than twice per second. In addition, some diagnoses (e.g.
coarctation of the aorta and CHDs that develop/progress during pregnancy such as
pulmonary stenosis, aortic stenosis, ventricular hypoplasia, and cardiomyopathy) remain
challenging to diagnose even in experienced centres. Given the fetal circulation, it is
difficult to define lesion severity in the presence of the unique fetal shunts that permit
redistribution of ventricular preload and output to the contralateral ventricle or great artery3.
4
Computerised evaluation of the fetal ECG might eliminate some of the abovementioned
problems. First, performer variability – as occurs in the case of ultrasonography – would
be absent because the data are analysed by computerised algorithms. Second, the
equipment is cheaper and smaller by comparison with ultrasonography equipment.
Third, application of the fetal ECG system involves minimum training. Last, at the time of
the fetal anomaly scan, CHDs that evolve during gestation might present no anomalies
by ultrasonography, but might show fetal ECG characteristics.

The present review has some limitations. Because little research has been published, the
amount of ECG recordings that was available per type of CHD was limited. Only two case
reports and three prospective trials were found. The methods of conduction the fetal ECG
measurements were different in the five studies and evolved during time. Additionally, the
fetal ECG parameters that were described varied in every study. Nevertheless, all the studies
included show that fetal ECG can be a valuable tool for diagnosing CHD early in utero.

In conclusion, fetal ECG is a promising clinical tool that complements ultrasonography in the
screening programme for CHD. It is particularly suitable for the detection of secondary effects
due to CHD (i.e. hypotrophy, hypertrophy, and conduction interruption). However, more
research establishing normal fetal ECG values and studies concerning the true incidence of
fetal ECG anomalies in CHD are needed.

Acknowledgements
The research was performed within the IMPULS Perinatology framework (Netherlands).

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 Chapter 4

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8. Clur SA, Van Brussel PM, Mathijssen IB, Pajkrt E, Ottenkamp J, Bilardo CM. Audit of 10 years of
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14. International Society of Ultrasound in Obstetrics & Gynecology. Cardiac screening examination of
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15. Carvalho JS, Mavrides E, Shinebourne EA, Campbell S, Thilaganathan B. Improving the effectiveness
of routine prenatal screening for major congenital heart defects. Heart 2002 Oct;88(4):387-391.
16. Kirk JS, Riggs TW, Comstock CH, Lee W, Yang SS, Weinhouse E. Prenatal screening for cardiac
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17. Ogge G, Gaglioti P, Maccanti S, Faggiano F, Todros T. Prenatal screening for congenital heart disease
with four-chamber and outflow-tract views: a multicenter study. Ultrasound Obstet Gynecol 2006
Nov;28(6):779-784.
18. Wu Q, Li M, Ju L, Zhang W, Yang X, Yan Y, et al. Application of the 3-vessel view in routine prenatal
sonographic screening for congenital heart disease. J Ultrasound Med 2009 Oct;28(10):1319-1324.
19. Cohen EH, Rein AJ. Antenatal diagnosis of cardiac malformation: a structural study. Fetal Diagn Ther
2000 Jan-Feb;15(1):54-60.
20. Galindo A, Herraiz I, Escribano D, Lora D, Melchor JC, de la Cruz J. Prenatal detection of congenital
heart defects: a survey on clinical practice in Spain. Fetal Diagn Ther 2011;29(4):287-295. 4
21. Rocha LA, Araujo Junior E, Nardozza LM, Moron AF. Screening of fetal congenital heart disease: the
challenge continues. Rev Bras Cir Cardiovasc 2013 Jul-Sep;28(3):V-VII.
22. Achiron R, Glaser J, Gelernter I, Hegesh J, Yagel S. Extended fetal echocardiographic examination
for detecting cardiac malformations in low risk pregnancies. BMJ 1992 Mar 14;304(6828):671-674.
23. van Laar JO, Warmerdam GJ, Verdurmen KM, Vullings R, Peters CH, Houterman S, et al. Fetal heart
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24. Cremer M. Über die direkte Ableitung der Aktionsströme des menschlichen Herzens vom Oesopha-
gus und über das Elektrokardiogramm des Fötus. Münch Med Wschr 1906;53:811-813.
25. Pardi G, Ferrazzi E, Cetin I, Rampello S, Baselli G, Cerutti S, et al. The clinical relevance of the
abdominal fetal electrocardiogram. J Perinat Med 1986;14(6):371-377.
26. Kimura Y, Sato N, Sugawara J, Velayo C, Hoshiai T, Nagase S, et al. Recent Advances in Fetal Electro-
cardiography. The Open Medical Devices Journal 2012;4:7-12.
27. Oostendorp TF, van Oosterom A, Jongsma HW. The fetal ECG throughout the second half of
gestation. Clin Phys Physiol Meas 1989 May;10(2):147-160.
28. Van Mieghem T, DeKoninck P, Steenhaut P, Deprest J. Methods for prenatal assessment of fetal
cardiac function. Prenat Diagn 2009 Dec;29(13):1193-1203.
29. Kiserud T, Acharya G. The fetal circulation. Prenat Diagn 2004 Dec 30;24(13):1049-1059.
30. Hamilton LA,Jr, Fisher E, Horn C, DuBrow I, Vidyasagar D. A new prenatal cardiac diagnostic device
for congenital heart disease. Obstet Gynecol 1977 Oct;50(4):491-494.
31. Brambati B, Bonsignore L. The significance of indirect electrocardiography in fetal cardiac arrhyth-
mias. Eur J Obstet Gynecol Reprod Biol 1983 Mar;14(6):371-373.
32. Siddiqui S, Wilpers A, Myers M, Nugent JD, Fifer WP, Williams IA. Autonomic regulation in fetuses
with congenital heart disease. Early Hum Dev 2015 Mar;91(3):195-198.
33. Velayo C, Sato N, Ito T, Chisaka H, Yaegashi N, Okamura K, et al. Understanding congenital heart
defects through abdominal fetal electrocardiography: case reports and clinical implications. J
Obstet Gynaecol Res 2011 May;37(5):428-435.
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35. Sato M, Kimura Y, Chida S, Ito T, Katayama N, Okamura K, et al. A novel extraction method of fetal
electrocardiogram from the composite abdominal signal. IEEE Trans Biomed Eng 2007 Jan;54(1):49-
58.
36. Sato N, Hoshiai T, Ito T, Owada K, Chisaka H, Aoyagi A, et al. Successful detection of the fetal
electrocardiogram waveform changes during various states of singletons. Tohoku J Exp Med
2011;225(2):89-94.
37. Chia EL, Ho TF, Rauff M, Yip WC. Cardiac time intervals of normal fetuses using noninvasive fetal
electrocardiography. Prenat Diagn 2005 Jul;25(7):546-552.
38. Pardi G, Marconi A, Ferrazzi E. The intraventricular conduction time of fetal heart in pregnancies
with suspected fetal growth retardation. Br J Obstet Gynaecol 1986 Mar;93(3):250-254.
39. Barnes N, Archer N. Understanding congenital heart disease. Current Paediatrics 2005(15):421-428.

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 Chapter 5

5
Normal ranges for fetal electrocardiogram
values for the healthy fetus of 18-24 weeks of
gestation: a prospective cohort study

Kim M.J. Verdurmen, Carlijn Lempersz, Rik Vullings, Christian Schroer,

Tammo Delhaas, Judith O.E.H. van Laar, S. Guid Oei

Published: BMC Pregnancy and Childbirth. 2016;16:227

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Abstract
Background
The fetal anomaly ultrasound only detects 65-81% of the patients with congenital heart
disease, making it the most common structural fetal anomaly of which a significant part is
missed during prenatal life. Therefore, we need a reliable non-invasive diagnostic method
which improves the predictive value for congenital heart diseases early in pregnancy. Fetal
electrocardiography could be this desired diagnostic method. There are multiple technical
challenges to overcome in the conduction of the fetal electrocardiogram. In addition,
interpretation is difficult due to the organisation of the fetal circulation in utero. We want to
establish the normal ranges and values of the fetal electrocardiogram parameters in healthy
fetuses of 18 to 24 weeks of gestation.

Methods/Design
Women with an uneventful singleton pregnancy between 18 and 24 weeks of gestation are
asked to participate in this prospective cohort study. A certified and experienced sonogra-
phist performs the fetal anomaly scan. Subsequently, a fetal electrocardiogram recording is
performed using dedicated signal processing methods. Measurements are performed at two
institutes. We will include 300 participants to determine the normal values and 95% confi-
dence intervals of the fetal electrocardiogram parameters in a healthy fetus. We will evaluate
the fetal heart rate, segment intervals, normalised amplitude and the fetal heart axis. Three
months postpartum, we will evaluate if a newborn is healthy through a questionnaire.

Discussion
Fetal electrocardiography could be a promising tool in the screening programme for congen-
ital heart diseases. The electrocardiogram is a depiction of the intimate relationship between
the cardiac nerve conduction pathways and the structural morphology of the fetal heart, and
therefore particularly suitable for the detection of secondary effects due to a congenital heart
disease (hypotrophy, hypertrophy and conduction interruption).

74
 Normal fetal ECG ranges: design of a prospective cohort study

Background
During pregnancy, the condition of the fetus is assessed with different techniques. One of
these techniques is ultrasound examination. Between week 18 and 22 of gestation the fetal
anomaly ultrasound is performed. During this examination, the fetus is screened for all kind
of possible congenital anomalies, including congenital heart disease (CHD). CHD is defined
as a “gross structural abnormality of the heart or intra-thoracic large vessels, (possibly) with
functional significance”1. CHD is the most common severe congenital anomaly worldwide2;
the incidence is estimated at 6-12 per 1000 live births3-5. CHD is six times more common than
chromosomal anomalies and four times more common than neural tube defects4,6.

The fetal anomaly ultrasound, including planes of the ventricular outflow tracts and the
three-vessel view, only detects 65-81% of the patients with CHD6-9. That makes CHD the most
common structural fetal abnormality of which a significant part is missed during prenatal life.
5
Therefore, we need a reliable non-invasive diagnostic method which improves the predictive
value for the diagnosis CHD. This diagnostic technique should be able to diagnose CHD
early in pregnancy for multiple reasons. First, we get the opportunity to identify associated
extracardiac and chromosomal anomalies that affect fetal and postnatal prognosis. Second,
parents get the chance to opt for termination of pregnancy in case of a severe CHD. Third, one
can develop an adequate treatment plan including intra-uterine therapy, timing, mode and
location of delivery and planning of immediate treatment after birth. In ductus- and foramen
ovale dependent CHDs, it is demonstrated that prenatal diagnosis increases the survival rates
and decreases long term morbidity10-13.

The currently used two-dimensional ultrasonography provides multiple anatomic planes,

relying on the sonographists mental reconstruction of these planes to define the fetal cardiac
anatomy. The antenatal diagnostic value is therefore to a great extent depending on the
experience of the performer. As stated by Gardiner5; “you only see what you look for and
identify what you already know”. Three- and four-dimensional ultrasonography gives a more
fluid and representative image of the fetal cardiac structures, and therefore aids in this mental
reconstruction14. Spatio-temporal image correlation (STIC) is a new modality using automated
volume acquisition of the fetal heart with one sweep of the probe, further facilitating the
examination of the fetal heart. Disadvantages of these ultrasound modalities are that they are
extremely expensive and only applicable in centres with experienced personnel.

The non-invasive fetal electrocardiogram (ECG) could be a valuable tool for the detection
of CHD early in pregnancy. In 1906, Cremer and colleagues15 were the first to describe fetal
ECG extraction through the maternal abdomen and 80 years later, Pardi and colleagues16

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 Chapter 5

were the first to write a review considering fetal ECG and, amongst others, CHD. Compared to
other techniques for fetal monitoring, the development of the fetal ECG lagged behind. This
is mainly because there are multiple technical challenges to overcome. First, at a gestational
age of 20 weeks, the fetal heart is about 1/10th of the size of an adult heart. Due to the low
voltage of the fetal ECG (1/50th of the maternal ECG), there is a low signal-to-noise ratio. In
addition, identifying the fetal signals is challenging due to masking by the maternal ECG and
high background noises caused by the maternal electromyogram. The amniotic fluid and
maternal tissues that surround the fetus enlarge the distance to the electrodes, and cause a
non-homogenous tissue conduction that interferes with signal quality. In addition, the vernix
caseosa causes electrical isolation and further diminishes the signal amplitude17. This is the
main cause of the poor signal-to-noise ratio from 30 to 34 weeks of gestation18,19. Second, the
fetal ECG has a complex three-dimensional shape, alternating with changes in fetal presenta-
tion. Following fetal movements, the electrical signal from each electrode changes frequently.
Another challenging factor is the speed of the fetal heart rate, which is two to three times
faster compared to the adult heart rate20.

Besides the technical difficulties encountered when conducting a fetal ECG, it is also chal-
lenging to interpret the fetal ECG. In contrast with postnatal life, the systemic circulation in
the fetus is fed from both the left and right ventricle in parallel, with equal intraventricular
pressures21. The outflow in the right ventricle is slightly larger compared to the outflow in the
left ventricle, and increases during gestation; 53% vs 47% at 20 weeks of gestation, 57% vs
43% at 30 weeks of gestation and 60% vs 40% at 38 weeks of gestation21. In utero, the O2-rich
blood flows from the umbilical vein to the right atrium. There, the formen ovale propels a
major part of the O2-rich blood to the left side of the heart and into the systemic circulation,
bypassing the fetal lungs. In addition, in the second trimester the ductus arteriosus propels
40% of the combined cardiac output. Because of these major differences between the
systemic circulation in utero and postpartum, it is difficult to predict what a normal fetal ECG
looks like. Furthermore, due to this organisation of the fetal circulation in utero, in case of a
CHD one side of the heart can compensate for an abnormality on the other site, and fetuses
affected by a CHD do not always show signs of cardiac failure.

However, before we are able to detect CHD with the fetal ECG, we need to establish the
normal range and values of amplitudes and segment intervals of the fetal ECG in a healthy
fetus.

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 Normal fetal ECG ranges: design of a prospective cohort study

Methods/Design
Aim
The aim of this study is to establish the normal ranges and values (mean with 95% confidence
intervals) of fetal ECG parameters in a healthy fetus of 18 to 24 weeks of gestation.

Study design
We will perform a prospective cohort study. The study protocol is approved by the
medical ethical committee of the Máxima Medical Centre, Veldhoven, the Netherlands
(NL48535.015.14).

Setting
Measurements are performed at the Máxima Medical Centre, Veldhoven, the Netherlands
and “Diagnostiek voor U” (DvU), Eindhoven, the Netherlands. The Máxima Medical Centre is
5
a tertiary care teaching hospital for obstetrics. DvU is a diagnostic centre which, amongst
others, performs blood tests and ultrasounds. Measurements are performed directly before
or after the sonographist performed the fetal anomaly scan. The fetal anomaly ultrasound is
performed by a certified and experienced sonographist.

Participants
Patients with an uneventful pregnancy, carrying a singleton fetus with a gestational age
between 18 and 24 weeks, are included in the study after written informed consent. At the
Máxima Medical Centre, this will be patients who visit the outpatient clinic for an appoint-
ment. At DvU, this will be patients who visit the centre for their fetal anomaly ultrasound.
These patients are generally seen by a midwife or by a doctor at the Máxima Medical Centre
for their obstetrical care. Pregnant women must be aged older than 18 years. If any of the
fetuses turn out to have a form of CHD, they are excluded from the cohort. Other exclusion
criteria are multiple pregnancies, insufficient understanding of the Dutch language, and any
known fetal congenital anomalies.

Three months postpartum we will evaluate if the newborn is healthy, which is defined as
absence of CHD, through a questionnaire. If the neonate turns out to have a CHD, which was
missed at the time of the structural anomaly ultrasound, we will exclude the patient from the
cohort.

Procedures
The fetal ECG is a non-invasive, transabdominal research method. The pregnant women is
lying down in a semi-recumbent position to prevent aortocaval compression. The fetal ECG

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 Chapter 5

is conducted with eight electrodes on the maternal abdomen, placed in a fixed configuration
(Figure 1). Before applying the electrodes on the abdomen, the skin is cleaned and prepared
by scrubbing the skin areas with abrasive paper to optimise the skin-electrode impedance.
The impedance is measured after the skin is prepared and before the fetal ECG recording is
started. A ground and reference electrode are placed near the belly button. The six recording
electrodes give bipolar signals that, among others signals, contain the fetal ECG. The
placement of the electrodes is chosen in order to assess the fetal heart with as much accuracy
as possible. With the fetus able to move freely in the uterus, at least some of the six electrodes
will be close to the fetal heart and thus will give a usable bipolar signal. We will record the
fetal ECG for 30 minutes. During this recording, the fetal position is determined four times by
ultrasound assessment. Good signal quality is verified via the real-time bedside monitoring
system (Figure 2).

Figure 1. Configuration of the electrodes on the maternal abdomen.

The fetal electrocardiogram is recorded with eight electrodes on the maternal abdomen, placed in a
fixed configuration. A ground and reference electrode are placed near the belly button. The electrodes
are connected to our fetal ECG system, which is connected to a computer. This system records 6 channels
of fetal ECG data.

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 Normal fetal ECG ranges: design of a prospective cohort study

Figure 2. Real-time bedside monitoring system.

1 2 3

4 4

4 4

4 5

4 5

6
Good signal quality can be verified via the real-time bedside monitoring system. Depicted in the screen
are; 1. maternal heart rate, 2. uterine activity, 3. fetal heart rate, 4. output from the six abdominal electro-
des, 5. computation of the fetal signal, after subtraction of the maternal signal, 6. estimate of the signal
quality. The user interface can be switched to a different screen in which the cardiotocogram is depicted.

The fetal ECG signals are digitised and stored by a prototype fetal ECG system (Nemo
Healthcare BV, the Netherlands). This prototype system comprises of a six-channel amplifier
that is dedicated for electrophysiological recordings during pregnancy. After digitisation,
the acquired signals are processed by PC-based dedicated signal processing techniques as
previously described by Vullings et al.22,23 to suppress interferences such as maternal ECG,
powerline, and electromyographic signals from within the maternal body, and retrieve the
fetal ECG. Following, we can calculate the fetal ECG for each of the six electrodes. However,
before we can compare ECG values between patients we need to normalise the ECG for
different orientations of the fetus within the uterus. A specific electrode would record a
different ECG waveform for a fetus in cephalic position versus for a fetus in breech position,
also yielding differences in some of the ECG parameters mentioned below.

To normalise for fetal orientation, we calculate the vectorcardiogram (VCG) of the fetus24.
This VCG entails a three-dimensional representation of the fetal electrical cardiac activity.
As described by Frank et al.25, in adult electrocardiography the VCG can be used to calculate
standardised ECG leads such as Einthoven 1-3, aVF, aVL, and aVR. By mathematically rotating

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 Chapter 5

the fetal VCG prior to calculating the ECG, we can create standardised fetal ECG leads. The
amount of rotation required is determined based on a simultaneously performed ultrasound
assessment of the fetal presentation. Via these mathematical rotations, we are also capable
of detecting and correcting for fetal movements in between the ultrasound assessments,
as described previously by Vullings et al.26. The four ultrasound assessments during the
measurements are used to correct for cumulative errors in this correction method and to
determine the initial orientation of the fetus. To enhance the signal quality of the measure-
ments, the fetal ECG is filtered further (amongst others by averaging of the ECG waveforms).
The detection of segments and intervals is performed semi-automatically. The detection of
fetal ECG complexes is computerised, while marking of the fetal ECG intervals (P top, QRS
complex, T top) is performed manually by two independent researchers following a protocol
that is verified by an experienced paediatric cardiologist. We will calculate the inter-observer
variability between the two researchers.

Normal heart rhythm is assumed to show variations in heartbeat intervals smaller than 20%
between consecutive beats. In case these variations are larger, this is assumed to be the result
of either fetal arrhythmia or erroneous detection of the heartbeat interval, e.g. because of
poor signal quality. Assessment of erroneous detection is based on energy of the ECG signal
and correlations between consecutive ECG waveforms. The ECG is a quasi-periodic signal,
meaning that consecutive ECG waveforms have a similar appearance and similar amplitude/
energy. In case of poor ECG signal quality, the energy of the ECG signals is expected to
differ from the energy during good quality recordings. Present artefacts or noise cause the
energy of the ECG to increase beyond physiologically plausible ranges. Likewise, correlations
between consecutive ECG waveforms are reduced in the presence of poor signal quality.

It has to be noted here, that fetal arrhythmia can also cause poor correlation between ECG
waveforms. Some arrhythmias are hence expected to be incorrectly classified as poor signal
quality. This misclassification affects the detection of fetal arrhythmia, but will not have any
impact on other study parameters as these are determined only during normal rhythm and
good signal quality. The recording must contain a minimum of 200 ECG complexes that were
assessed to have good signal quality and that were corrected for fetal movement26.

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 Normal fetal ECG ranges: design of a prospective cohort study

Study parameters
Multiple outcome values are evaluated:
• Fetal heart rate; mean, standard deviation, 95% confidence intervals and heart rate
arrhythmia

• Segment intervals (PQ, QRS, ST etc.); mean, standard deviation and 95% confidence
intervals

• Normalised amplitudes (P, QRS, T); mean, standard deviation and 95% confidence
intervals

• Fetal electrical heart axis

• % of total patients in which the recording contains the required amount of data to
perform the analysis
5
Heart rate arrhythmia is defined based on heuristic rules that dictate that during normal
rhythm subsequent heartbeat intervals cannot differ more than 20%. Any rhythm not
complying with this rule, and assessed to not be caused by erroneous detection of heart-
beats, e.g. as a result of poor signal quality, is labelled as a fetal arrhythmia.

Sample size
There are previously published studies (see Discussion for more details) that describe fetal
ECG parameters. However, these studies use different methods for obtaining the fetal signal
and do not correct for the fetal position in the uterus. Therefore they are not able to calculate
the fetal electrical heart axis. Moreover, all studies describe another parameter of the fetal
ECG. Statistical experts calculated that we need a study population of 200 pregnant patients
in order to determine normal values and 95% confidence intervals of a healthy fetus27. Antic-
ipating on loss to follow-up and insufficient data quality, we will include 300 patients in the
initial cohort.

Statistical analysis
The collected data is analysed through SPSS. With the collected data, we perform several
analyses. We calculate the normal values and ranges of the fetal heart rate, segment intervals
(PQ, QRS, ST etc.), normalised amplitudes (P, QRS and T) and the fetal heart axis. Initially, we
will calculate the values and ranges for all included patients as one group (18 to 24 weeks
of gestational age). Thereafter, we will perform a subanalysis for every group per week of
gestational age.

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Discussion
Previous studies have been published regarding the normal values and ranges of the fetal
ECG. In their review, Pardi et al.16 summarised the normal evolution of the cardiac cycle during
gestation. From the 17th week of gestation up to term, the duration of the P wave increases
progressively. This reflects the anatomical development of the atria during pregnancy. Similar,
the duration of the QRS complex increases progressively, parallel with the weight gain of the
fetal heart and in particular with the gain in ventricular mass. In fetal life, the intraventricular
conduction is delayed compared to adult values, most likely due to anatomical differences of
the ventricular conduction tissue. There is a slight increase in PR interval during pregnancy,
indicating development of the atrioventricular conduction tissue.

Recently, longitudinal studies followed pregnancies from 14 to 41 weeks of pregnancy and

performed fetal ECG measurements during different stages of gestation18,28,29. In the 1960s,
Larks and colleagues30-33 described the orientation of the electrical fetal heart axis. All
mentioned studies performed fetal ECG recordings with different conduction and analysis
techniques. The amount of electrodes on the maternal abdomen varied from three to sixteen.
Average fetal ECG complexes were generated from segments of 60 seconds up to 2.5 minutes.
Analyses were performed manually or by computerised signal processing programs. These
studies did not take the fetal position in the uterus into account.

In a group around 20 weeks of gestation, the following mean values were found by Chia
and Taylor28,29, respectively: P wave length 43.9 ms, PR interval 102.1/91.7 ms, QRS duration
47.2/40.7 ms, QT interval 224.0/242.3 ms and T wave duration 123.8 ms. Larks33 found a
normal range of the fetal heart axis between +100 and +160 degrees, with a mean value
of +134 degrees in term fetuses during labour. Due to the lack of correcting for the fetal
position in utero, fetuses in breech position showed a negative electrical heart axis (-180 to
0 degrees)32. In fact, due to the lack of correcting for fetal position, also findings for fetuses in
vertex position were unreliable. In their analysis, Larks implicitly assumed that every fetus was
facing the frontal plane. In cases where this assumption was incorrect, the measured heart
axis must have been incorrect as a consequence. For example, a fetus with an electrical heart
axis at +135 degrees will indeed be measured as +135 degrees when facing the frontal plane.
When this same fetus, still in vertex position, rotates to face the sagittal plane, the measured
heart axis will be +90 degrees. When opposing the frontal plane, the measured heart axis will
be +45 degrees.

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 Normal fetal ECG ranges: design of a prospective cohort study

Up to our knowledge our study is the first to calculate the fetal electrical heart axis, taken the
fetal position into account. A reliable calculation of the electrical heart axis is important in
interpreting the fetal ECG. In addition, changes in the orientation of the fetal electrical heart
axis might be able to aid in the diagnosis of CHD in the future.

The fetal ECG can be used from early gestation, it is non-invasive, easy to apply and safe to
use18. One of the big advantages of the fetal ECG is that it potentially is a non-expensive
diagnostic test in the long term. In addition, it creates the opportunity to perform meas-
urements anywhere in the world and transmit the raw ECG data to be evaluated elsewhere.
The equipment is smaller in comparison to ultrasound machines. Moreover, the fetal ECG is
evaluated by semi-computerised algorithms, taking away some of the performer-dependent
5
variability in diagnostic value. The fetal ECG system takes minimum training to be applied.

The fetal ECG could be a promising clinical tool in the screening programme for CHD. It is
a depiction of the intimate relationship between the cardiac nerve conduction pathways
and the structural morphology of the fetal heart8,34. The fetal ECG is likely to be particularly
suitable for the detection of secondary effects due to a CHD; hypotrophy, hypertrophy and
conduction interruption.

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 Chapter 5

References
1. Mitchell SC, Korones SB, Berendes HW. Congenital heart disease in 56,109 births. Incidence and
natural history. Circulation 1971 Mar;43(3):323-332.
2. van der Linde D, Konings EE, Slager MA, Witsenburg M, Helbing WA, Takkenberg JJ, et al. Birth
prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll
Cardiol 2011 Nov 15;58(21):2241-2247.
3. Donofrio MT, Moon-Grady AJ, Hornberger LK, Copel JA, Sklansky MS, Abuhamad A, et al. Diagnosis
and treatment of fetal cardiac disease: a scientific statement from the American Heart Association.
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4. Simpson LL. Screening for congenital heart disease. Obstet Gynecol Clin North Am 2004
Mar;31(1):51-59.
5. Gardiner HM. Keeping abreast of advances in fetal cardiology. Early Hum Dev 2006 Jun;82(6):415-
419.
6. Carvalho JS, Mavrides E, Shinebourne EA, Campbell S, Thilaganathan B. Improving the effectiveness
of routine prenatal screening for major congenital heart defects. Heart 2002 Oct;88(4):387-391.
7. Kirk JS, Riggs TW, Comstock CH, Lee W, Yang SS, Weinhouse E. Prenatal screening for cardiac
anomalies: the value of routine addition of the aortic root to the four-chamber view. Obstet
Gynecol 1994 Sep;84(3):427-431.
8. Ogge G, Gaglioti P, Maccanti S, Faggiano F, Todros T. Prenatal screening for congenital heart disease
with four-chamber and outflow-tract views: a multicenter study. Ultrasound Obstet Gynecol 2006
Nov;28(6):779-784.
9. Wu Q, Li M, Ju L, Zhang W, Yang X, Yan Y, et al. Application of the 3-vessel view in routine prenatal
sonographic screening for congenital heart disease. J Ultrasound Med 2009 Oct;28(10):1319-1324.
10. Brick DH, Allan LD. Outcome of prenatally diagnosed congenital heart disease: an update. Pediatr
Cardiol 2002 Jul-Aug;23(4):449-453.
11. Hunter LE, Simpson JM. Prenatal screening for structural congenital heart disease. Nat Rev Cardiol
2014 Jun;11(6):323-334.
12. Brown KL, Ridout DA, Hoskote A, Verhulst L, Ricci M, Bull C. Delayed diagnosis of congenital
heart disease worsens preoperative condition and outcome of surgery in neonates. Heart 2006
Sep;92(9):1298-1302.
13. Trines J, Fruitman D, Zuo KJ, Smallhorn JF, Hornberger LK, Mackie AS. Effectiveness of prenatal
screening for congenital heart disease: assessment in a jurisdiction with universal access to health
care. Can J Cardiol 2013 Jul;29(7):879-885.
14. Rogers L, Li J, Liu L, Balluz R, Rychik J, Ge S. Advances in fetal echocardiography: early imaging,
three/four dimensional imaging, and role of fetal echocardiography in guiding early postnatal
management of congenital heart disease. Echocardiography 2013 Apr;30(4):428-438.
15. Cremer M. Über die direkte Ableitung der Aktionsströme des menschlichen Herzens vom Oesopha-
gus und über das Elektrokardiogramm des Fötus. Münch Med Wschr 1906;53:811-813.
16. Pardi G, Ferrazzi E, Cetin I, Rampello S, Baselli G, Cerutti S, et al. The clinical relevance of the
abdominal fetal electrocardiogram. J Perinat Med 1986;14(6):371-377.

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17. Kimura Y, Sato N, Sugawara J, Velayo C, Hoshiai T, Nagase S, et al. Recent Advances in Fetal Electro-
cardiography. The Open Medical Devices Journal 2012;4:7-12.
18. van Laar JO, Warmerdam GJ, Verdurmen KM, Vullings R, Peters CH, Houterman S, et al. Fetal heart
rate variability during pregnancy, obtained from non-invasive electrocardiogram recordings. Acta
Obstet Gynecol Scand 2014 Jan;93(1):93-101.
19. Oostendorp TF, van Oosterom A, Jongsma HW. The fetal ECG throughout the second half of
gestation. Clin Phys Physiol Meas 1989 May;10(2):147-160.
20. Van Mieghem T, DeKoninck P, Steenhaut P, Deprest J. Methods for prenatal assessment of fetal
cardiac function. Prenat Diagn 2009 Dec;29(13):1193-1203.
21. Kiserud T, Acharya G. The fetal circulation. Prenat Diagn 2004 Dec 30;24(13):1049-1059.
22. Vullings R, Peters CH, Sluijter RJ, Mischi M, Oei SG, Bergmans JW. Dynamic segmentation and
linear prediction for maternal ECG removal in antenatal abdominal recordings. Physiol Meas 2009
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Mar;30(3):291-307.
23. Vullings R, de Vries B, Bergmans JW. An adaptive Kalman filter for ECG signal enhancement. IEEE
Trans Biomed Eng 2011 Apr;58(4):1094-1103.
24. Vullings R, Peters CH, Mossavat I, Oei SG, Bergmans JW. Bayesian approach to patient-tailored
vectorcardiography. IEEE Trans Biomed Eng 2010 Mar;57(3):586-595.
25. Frank E. General theory of heat-vector projection. Circ Res 1954 May;2(3):258-270.
26. Vullings R, Mischi M, Oei SG, Bergmans JW. Novel Bayesian vectorcardiographic loop alignment
for improved monitoring of ECG and fetal movement. IEEE Trans Biomed Eng 2013 Jun;60(6):1580-
1588.
27. Altman DG. Practical Statistics for Medical Research. London: Chapman&Hall/CRC; 1990.
28. Chia EL, Ho TF, Rauff M, Yip WC. Cardiac time intervals of normal fetuses using noninvasive fetal
electrocardiography. Prenat Diagn 2005 Jul;25(7):546-552.
29. Taylor MJ, Smith MJ, Thomas M, Green AR, Cheng F, Oseku-Afful S, et al. Non-invasive fetal electro-
cardiography in singleton and multiple pregnancies. BJOG 2003 Jul;110(7):668-678.
30. Larks SD, Larks GG. Components of the fetal electrocardiogram and intrauterine electrical axis:
quantitative data. Biol Neonat 1966;10(3):140-152.
31. Larks SD, Larks GG. Comparative aspects of the fetal and newborn electrocardiograms. Evidence
for the validity of the method for calculation of the electrical axis of the fetal heart. Am J Obstet
Gynecol 1966 Oct 15;96(4):553-555.
32. Larks SD. Estimation of the Electrical Axis of the Fetal Heart. Am J Obstet Gynecol 1965 Jan 1;91:46-
55.
33. Larks SD, Larks GG. The electrical axis of the fetal heart: a new criterion for fetal well-being or
distress. Am J Obstet Gynecol 1965 Dec 1;93(7):975-983.
34. Velayo C, Sato N, Ito T, Chisaka H, Yaegashi N, Okamura K, et al. Understanding congenital heart
defects through abdominal fetal electrocardiography: case reports and clinical implications. J
Obstet Gynaecol Res 2011 May;37(5):428-435.

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 Part II

Fetal ECG in preterm labour

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 Chapter 6

The influence of corticosteroids on

fetal heart rate variability: a systematic review
of the literature 6

Kim M.J. Verdurmen, Joris Renckens, Judith O.E.H. van Laar,

S. Guid Oei

Published: Obstetrical and Gynecological Survey. 2013; 68(12):811-824

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 Chapter 6

Abstract
Corticosteroids play an important role in the clinical management of threatened preterm
delivery between 24 and 34 weeks of gestational age. It is known that corticosteroids have a
direct, transient effect on fetal heart rate parameters. Fetal heart rate variability is a reflection
of autonomic nervous system activity and a useful marker for fetal wellbeing. Therefore, it is
important to interpret the changes that occur in fetal heart rate parameters during cortico-
steroid treatment correctly, to avoid unnecessary iatrogenic preterm delivery. We performed
a systematic review of the literature in CENTRAL, PubMed, and EMBASE, including 15 articles.
In this review, we discuss the influence of corticosteroids on fetal heart rate parameters, in
particular fetal heart rate variability, and fetal behaviour. Furthermore, we explain possible
mechanisms of action and confounding factors.

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 Review: corticosteroids and fetal heart rate variability

Background
Antenatal corticosteroids are administered to enhance fetal lung maturation in cases of
threatened preterm delivery between 24 and 34 weeks’ gestational age (GA)1-3. In 1972,
Liggins and Howie4 first described this breakthrough in obstetric care. A significant reduction
in neonatal mortality and morbidity, due to a reduction in respiratory distress syndrome,
respiratory support/intensive care admissions, cerebroventricular hemorrhage and necrotis-
ing enterocolitis, has been demonstrated in the 2006 Cochrane review by Roberts and
Dalziel5.

As elucidated by van Runnard Heimel et al.6, endogenous corticosteroids are converted into
their inactive metabolites by the 11β-hydroxysteroid dehydrogenase (HSD) enzyme. This
enzyme limits the fetal exposure to prednisone and methylprednisolone, making them ideal
for maternal treatment (e.g. treatment of preterm HELLP [hemolysis, elevated liver enzymes,
and low platelet count] syndrome). In contrast, betamethasone and dexamethasone are not
converted into inactive metabolites by the 11β-HSD enzyme and can therefore easily cross
the placenta in active form6-8. This makes them specifically useful for fetal treatment in case 6
of threatened preterm delivery. Confirming this, Blanford and Murphy9 demonstrated that
cortisol and prednisolone were significantly converted into their inactive metabolites in an
in vitro study, whereas the conversion of betamethasone and dexamethasone into inactive
metabolites was low or negligible.

After administration of a single course of antenatal corticosteroids, no associated long-term

negative effects have been reported10-12. However, it is known that corticosteroids have a
direct, transient, effect on fetal heart rate (HR) and fetal heart rate variability (HRV)13.

In cases of threatened preterm delivery, objective information concerning the fetal condition
is important for clinical decision making. During hypoxia, the autonomic nervous system
(ANS) is activated and modulates the beat-to-beat fetal HR14. A fetus is not able to adapt its
single stroke volume because of the small size of the fetal heart. Therefore, fetal HR is the
primary variable for controlling cardiac stability and is primarily regulated by the ANS15.
It is known that fetal HRV is a reliable marker of fetal wellbeing16,17. In 1963, Hon and Lee18
observed that, in cases of fetal distress, changes in beat-to-beat heart rate interval occur
before changes in heart rate itself. Assessing the variability of the fetal HR is therefore useful
in fetal monitoring and determining fetal wellbeing.

Autonomic modulation and therefore fetal HRV are influenced by several medications
commonly used in obstetric care19. With regard to corticosteroids, it is known that a transient

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but significant decrease in fetal HRV occurs20. It is important to understand and appreciate the
exact effects of corticosteroids on fetal HR parameters so that these changes are not misinter-
preted as non-reassuring fetal status, with iatrogenic preterm delivery as a consequence.

In this review, we will focus on literature describing the effect on fetal HRV of corticosteroids
administered in the setting of potential preterm delivery. We will describe the changes in fetal
HR parameters and discuss the proposed mechanisms of action.

Material and Methods

Inclusion and exclusion criteria
Published studies that describe the influence of corticosteroids (betamethasone and dexa-
methasone) on fetal HRV, assessed by computerised analysis, were included in this review.
Review articles were excluded. Participants of interest were human fetuses at risk for preterm
delivery, receiving corticosteroids.

Search
We performed a systematic search in the electronic databases CENTRAL (the Cochrane
Library; 2013, Issue 3), PubMed, and EMBASE through June 2013. The study language
was restricted to English. The following keywords were used: fetal HRV, fetal HR variation,
betamethasone, dexamethasone and corticosteroid. In addition, references of selected and
related articles were searched.

Two authors (K.M.J.V. and J.R.) independently abstracted the data. There were no discrepan-
cies regarding inclusion or data extraction of the reviewed articles. Included studies were
critically assessed using the review guidelines for cohort studies and randomised trials from
the Dutch Cochrane Centre.

A quality assessment of the included cohort studies was performed. The risk of selection bias
was determined taking into account the study type, description of inclusion and exclusion
criteria, and the methods for recruitment of the study population and is described as “high”
or “low”. The duration of follow-up was scored as “adequate” when follow-up lasted at least 4
days after the first dose of the corticosteroid, to assess for both short- and longer-term direct
effects on fetal HR parameters. Important confounders included administration of other
drugs, intra-uterine growth restriction (IUGR), GA, and the influence of diurnal rhythm. In the
column “confounding variables described”, the number of confounding factors addressed in
the study is given.

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 Review: corticosteroids and fetal heart rate variability

A quality assessment of the included randomised trials was also performed. We described
blinding of randomisation and compared the description of baseline characteristics of the
different treatment groups. Baseline characteristics included demographic characteristics,
reason for hospitalisation and fetal HR parameters at baseline. Comparability was described
as the combination of co-interventions, contamination, and compliance. This was scored as
“yes”, “partially” or “no”, with the number of factors described in parentheses. The final conclu-
sion concerning the overall quality of the included studies was based on internal validity
and clinical applicability of the study. The internal validity was a summary of the previously
assessed factors.

The outcome measures of interest were fetal HR and variability of the fetal HR, assessed by
computerised analysis. Mean fetal HR (mfHR) is expressed in beats per minute. Long-term
variation (LTV) is calculated as the average of 1-minute pulse-interval differences, while short-
term variation (STV) is calculated as the average of sequential 1/16th minute (3.75 seconds)
pulse-interval differences in all studies.
6
Results
Our search in the Cochrane Database revealed no reports applicable for this review. In Pub-
Med, we found 35 reports. Of these, 20 articles were excluded because they did not meet our
inclusion criteria. Among the remainder, seven articles described other effects rather than fetal
HRV, three articles described effects of other drugs rather than corticosteroids, two articles as-
sessed only fetal HRV in fetuses at term or in newborns who were previously treated with cor-
ticosteroids, and two articles described visual analysis of fetal HRV. In EMBASE, two additional
articles were found that were not present in PubMed. Both of these articles did not meet our
inclusion criteria; one article was a conference abstract, and one article described the effect
of a congenital heart block on fetal HR patterns. Eventually, 15 articles were included in this
review. A quality assessment of the included studies is shown in Tables 1 and 2. Characteristics
and basic fetal HR parameters of the included studies are shown in Table 3.

In all studies, day 0 is defined as the “control day”, before administration of the first dose of
corticosteroids. Subsequently, day 1 is defined as the next day after the first dose of cortico-
steroids (approximately 24 hours later), day 2 is the second day (approximately 48 hours later),
and so on. All values are compared with the baseline value, measured on day 0.

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Table 1. Quality assessment of the included cohort studies. Chapter 6
 Table 2. Quality assessment of the included randomised trials. Review: corticosteroids and fetal heart rate variability

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Chapter 6

Table 3. Characteristics and basic fetal heart rate parameters of the included studies.

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↓ ↑ ↑
↑ ↓ ↓

↓ ↓

In several studies, patients were allowed to participate multiple times in the study protocol. This is indicated in the column “No. patients” as “repeat”;
in case of Derks et al.13, 31 patients were included, of whom 5 participated multiple times in the study protocol, resulting in a total of 38 sets of
observations.

* Significant



Abbreviations: CTG = cardiotocogram, DM= diabetes mellitus, fHR = fetal heart rate, fHRV = fetal heart rate variability, fMCG = fetal magnetocardio-
graphy, h = hour, HT = hypertension, IUGR = intra-uterine growth restriction, LTV = long-term variation, mfHR= mean fetal heart rate, No. = number of,
PE= pre-eclampsia, PROM = preterm rupture of membranes, STV = short-term variation, TPL = threatened preterm labour, VBL = vaginal blood loss,
wGA= weeks of gestational age.
Review: corticosteroids and fetal heart rate variability

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6
 Chapter 6

In several studies, patients were allowed to participate multiple times in the study protocol if
corticosteroids were administered again after a 10- to 14-day interval. This is indicated in the
column “number of patients” in Table 3 as “repeat”. In the study by Derks et al.13, 31 patients
were included, of whom 5 participated multiple times in the study protocol, resulting in a
total of 38 sets of observations. All included studies were published between 1994 and 2010.
A total of 538 fetuses (range; 8-105) were described.

Betamethasone
As shown in Table 3, a decrease in mfHR was found after betamethasone administration
on day 1 in eight of the included studies15,21-27, of which seven showed a significant result.
However, this effect was relatively small, with a 3-5% decrease in mfHR21,27. On days 2 and 3,
a trend was seen towards an increase in mfHR in multiple studies20,24,27. This trend was signifi-
cant only in fetuses younger than 27.5 weeks’ GA25. Other studies showed no effect on mfHR
after corticosteroid administration during the study period13,28-31.

All studies observing the effects of corticosteroids on fetal HRV during day 1 showed an
increase in both LTV and STV (Table 3)1,21,22,24,27,28. In addition, nearly all studies showed a
decrease in both LTV and STV during days 2 to 31,13,15,20-25,27,29-31. Both Mulder et al.23 and Ville
et al.31 demonstrated a similar overall response in twin pregnancies compared with singleton
pregnancies. There were no significant intertwin differences reported. In IUGR fetuses with
redistribution of blood flow (cerebral vasodilation), these modifications were even more
profound30. In the study reported by Lunshof et al.21 fetal HRV was decreased by 10% during
day 2. The decrease in fetal HRV was also present in more than 80% of the fetuses studied by
Mulder et al.27. Likewise, Senat et al.1 demonstrated a significant decrease in both LTV and STV
when comparing measurements during days 1 to 2 with measurements during days 4 to 7.
Fetal HRV fell below the normal range (30 milliseconds at 30 weeks’ GA) in 46% of the cases;
however, no fetal HR decelerations occurred20.

Mulder et al.20,27 also studied movement patterns of the included fetuses with ultrasound, with
activity expressed as a percentage of total observation time. All medians were compared with
the fetal HR recording during day 0. Body movements were significantly reduced during days
1 and 2 (p <0.01). After both doses of betamethasone, the incidence of body movements was
about 50% of the incidence during day 0 (p <0.01). Breathing movements were decreased by
90% during days 2 and 3 (p <0.01); the incidence of hiccups did not change. The total fetal
activity (the sum of body- and breathing movements and hiccups) showed a trend with a
minimum during day 2 (median incidence falls from 47.7% during day 0 to 8.3% during day
2). A decrease in body- and breathing movements was demonstrated in 88.5% of all fetuses.

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For all parameters measured, there were no significant differences between the subgroups
(fetuses with IUGR, preterm onset of labour, pre-eclampsia, placenta praevia, and a miscel-
laneous group) in all of the included studies. All values returned to baseline during day 420,24.

Dexamethasone
Dexamethasone is less well-studied in comparison with betamethasone. Most studies found
the same effect of dexamethasone on fetal HR parameters as with betamethasone22,24,27,29.
Both Senat et al.1 and Multon et al.26 concluded no significant changes were present
after administration of dexamethasone. Concerning mfHR, Dawes et al.28 described no
significant changes, whereas Mulder et al.27 found a trend towards decreasing mfHR on day
1 in more than 50% of fetuses following two doses of dexamethasone. STV was increased
significantly during day 1 in the reports of both Dawes et al.28 and Mulder et al.27, and this
increase was present in more than 80% of the fetuses. In addition, Rotmensch et al.29 found
a reduction in fetal HRV during day 2. However, the magnitude of this reduction was less
after exposure to dexamethasone as compared with betamethasone. In addition, fetuses
exposed to betamethasone had a significantly slower return to baseline LTV as compared
6
with the dexamethasone group (p <0.001). In contrast to reports of betamethasone, no
significant differences in fetal movement patterns were observed after the administration of
dexamethasone27.

Discussion
Quality assessment of the included studies
A summary of the quality of the included studies can be found in Tables 1 and 2. In the
included cohort studies, a high risk for selection bias was found. This can be attributed to an
unclear definition of inclusion and exclusion criteria, the retrospective nature of some studies,
and the selection procedure of participants. In the three retrospective studies, only complete
data sets were selected for analysis, resulting in a risk for selection bias23,26,28. This risk for
selection bias is not clearly reported by most authors. However, the consequences of this
possible bias are limited, because every fetus is regarded as its own control in these studies.

Most included patients were at high risk for preterm delivery, and in most studies, it takes
up to five days to complete the study protocol. Therefore, a considerable loss of participants
can be expected, mainly caused by preterm delivery or discharge before completing the final
measurements. Unfortunately, this is not described properly in some of the included studies.
It is not clear how, or if, this might impact the results of these studies.

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Multon et al.27 used both betamethasone and dexamethasone for fetal lung maturation in
fetuses with IUGR; however, this was not in a randomised fashion. Fetuses received 1-7 (mean;
2.2) successive weekly courses of corticosteroids, and six fetuses received both drugs alterna-
tively at weekly intervals. Therefore, this study is different in study design from other included
studies.

Randomisation was blinded in all randomised trials, whereas observer blinding was
performed in three of five studies. In this type of research, observer blinding is less important
because of computerised analysis of the data. In general, the description of baseline
characteristics of the study population and fetal HR parameters was sufficient. None of the
studies conducted an intention-to-treat analysis, because there was no contamination
between betamethasone and dexamethasone in clinical practice. Co-interventions were not
clearly described in all studies, except for the study by Magee et al.22. The most important
co-intervention is the administration of other drugs in addition to corticosteroids.

A point of concern is the small population size in all included studies. Magee et al.22
performed a power analysis but failed to include enough patients in their final analysis. Subtil
et al.24 used the same values to calculate power and included just enough patients to fulfill
their power criteria. A likely challenge to recruitment is that these studies were conducted
in tertiary care hospitals, where a substantial number of the preterm patients are transferred
from other care settings. In most cases, tocolysis and corticosteroid administration are started
before transport, which makes it impossible to conduct a baseline measurement prior to the
first dose of corticosteroids.

Another point to consider is the difference in nature and duration of corticosteroid admin-
istration in the various studies. Because of the heterogeneous dosing regimens, a direct
comparison by pooling the study results is impossible.

A major drawback of all but one of the included studies is that the recordings used for analysis
of fetal HRV were all derived from a Doppler ultrasound-based computerised cardiotocogram
(CTG), making it impossible to achieve true beat-to-beat interval registration. With a known
beat-to-beat interval, fetal HRV can be calculated more accurately. In addition, spectral energy
in the high- and low-frequency bands can be calculated, reflecting both branches of the ANS.
Schneider et al.15 used fetal magnetocardiography to obtain beat-to-beat fetal HR parameters
non-invasively. Unfortunately, this reliable method is not applicable in daily clinical practice.
Direct fetal electrocardiogram (ECG) measurements could be a valuable tool to overcome this
problem. Therefore, we suggest further studies on the influence of commonly used medicines
in obstetric care on fetal HRV, to focus on electrophysiology of the fetal HR tracings. The

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 Review: corticosteroids and fetal heart rate variability

fetal ECG can be recorded non-invasively from the maternal abdomen, using self-adhesive
electrodes32. Accordingly, the effects of medicines on fetal HRV can be quantified by means of
spectral analysis (frequency analysis) objectively33-35.

In conclusion, most of the included studies are of low to medium quality. This is partly due to
high loss to follow-up, which is inherent to the study population. However, a proper descrip-
tion of the inclusion and exclusion criteria, risk of selection bias, and loss to follow-up should
ideally be provided by the authors.

Effects of betamethasone versus dexamethasone

As summarised in Table 3, nearly all studies showed a biphasic change in fetal HR parameters
after maternal administration of corticosteroids. Mean fetal HR decreases during the first day
of corticosteroid administration, whereas there was an increase during days 2 to 3. Fetal HRV,
both STV and LTV, showed an increase during the first day of corticosteroid administration,
and a decrease during days 2 to 3.
6
Betamethasone and dexamethasone are stereoisomers, with the C-16 methyl group in the β-
or α-position, respectively. Compared to the maternal plasma concentration, the fetal plasma
concentration after administration of either betamethasone or dexamethasone is approxi-
mately 33%7,36. Betamethasone is the corticosteroid best studied in relation to fetal HR param-
eters and has a more pronounced suppressive effect on most variables concerning fetal HRV
in comparison to dexamethasone29. Maximal effects were seen during day 2, which coincides
with the highest biological activity of corticosteroids37. In general, all synthetic corticosteroids
have a greater affinity for the glucocorticoid receptor than endogenous cortisol: dexametha-
sone 7.1- and betamethasone 5.4-fold higher38. Betamethasone has a longer plasma half-life
compared with dexamethasone, whereas dexamethasone seems to have a higher add-back
effect; the subsequent decrease in variability might therefore be attenuated. Subtil et al.24 did
not find any differences in fetal HR parameters between different corticosteroid formulations.
Whereas betamethasone causes fetal breathing movements to disappear almost completely,
this was not seen following dexamethasone administration27.

In twin pregnancies, a similar fetal response to betamethasone administration to that

described in singleton pregnancies is seen23,31. This response appears to be irrespective of
modifying effects such as poor fetal growth, chorionicity, Doppler abnormalities, or placental
vascular anastomoses. Although placental insufficiency was suspected in some of the twin
pairs, this did not seem to affect the transplacental passage of betamethasone.

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Proposed mechanisms of action

The exact mechanism of alteration of fetal HRV and fetal behaviour by corticosteroids is
unknown. One hypothesis involves the high affinity of corticosteroids for the gonadotropin
receptor. Gonadotropin receptors are widely expressed in the central nervous system,
including in the brain stem nuclei. They show high affinity to synthetic corticosteroids and
suppress neuronal activity when occupied, thus reducing physical activity39. Corticosteroids
enter the brain slowly and involve cytosolic gonadotropin receptors, accounting for the
prolonged range of action from hours to days40.

The decrease in fetal HR is most likely associated with an increase in fetal systemic blood
pressure. Corticosteroids can cause hypertension via augmentation of vascular tone by
potentiating the actions of vasoconstrictor hormones and by direct actions on vascular
smooth muscle cells40. This yields a vagally-mediated baroreceptor response, which triggers a
reflex inhibition of the sympathetic branch and activation of the parasympathetic branch and
results in a decreased fetal HR.

The increase in fetal HRV can be explained in part by the known inverse relationship between
basal fetal HR and its variation. According to Nijhuis et al.41, about 50% of the differences
in fetal HRV can be explained by differences in fetal HR. Furthermore, Bennet et al.42 found
a positive correlation between sympathetic tone and short-term heart rate variation, which
is attributed to transiently increased local levels of catecholamines (cardiac or neural), and/
or to an increased sensitivity to normal circulating levels of catecholamines. ANS regulation
of fetal HRV proves to be complex, because both vagal and sympathetic activation seems
to cause an increase in fetal HRV. Accordingly, Frasch et al.43 described that sympathetic and
vagal influences might be superimposed nonlinearly on fetal HRV and can act synergistically.

The transient decrease in fetal HRV during days 2 to 4 cannot solely be explained by an
increase in fetal HR, and is likely to be related to the reduction in fetal body- and breathing
movements20,27. This may be caused by occupation of the gonadotropin receptors of
the responsible fetal brain areas. The raphe nuclei and locus coeruleus are, among
others, thought to control motor activity in the third trimester. Neurons of the nucleus
of the solitary tract in the medulla are known to direct respiratory activity. Thus, one
can hypothesise that complete gonadotropin receptor occupancy of these fetal brain
areas after corticosteroid administration reduces both body- and breathing movements.

The reduction in fetal movements and fetal HRV, both of which are associated with fetal
wellbeing, can be misinterpreted as deterioration of fetal status and can therefore potentially
lead to unnecessary iatrogenic preterm delivery13,24. The suppression in fetal HR parameters

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 Review: corticosteroids and fetal heart rate variability

is not only visible with computerised analysis, but also detected by visual analysis of CTG
tracings by clinicians44. In Figures 1 and 2, the decrease in fetal HRV after corticosteroid
administration is illustrated in the case of a 29-week fetus before and 2 days after betametha-
sone administration.

Shenhav et al.45 demonstrated that if women delivered within 48 hours after betamethasone
administration, the reduced fetal HRV was not related to the fetal acid-base balance at birth.
Moreover, no changes have been observed in Doppler flow velocity waveforms of uterine
and umbilical arteries - brain-sparing was absent, and no decelerations or reduction in fetal
eye movements have occurred after corticosteroid administration13,46. Furthermore, there are
no signs of any association of steroids with uterine contractions1,24,27. In animal studies, no
signs of fetal asphyxia were observed following maternal corticosteroid administration42. In
addition, all parameters returned to normal during day 4. These findings all indicate no fetal
deterioration during the course of the study period.

Figure 1. Cardiotocogram, one day before betamethasone administration.

6

Fetal age: 29 weeks + 2 days of gestation. Paper speed: 2cm/minute.

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Figure 2. Cardiotocogram during day 2 after betamethasone administration.

Fetal age: 29 weeks + 5 days of gestation. Paper speed: 2cm/minute.

It seems that the effect of re-administration of corticosteroids is comparable to the primary

effect on fetal HR parameters. In several studies, fetuses were exposed to multiple courses of
corticosteroids, with a similar response after re-administration20,31.

In Figure 3, an overview of the effects of synthetic corticosteroids on fetal HR and fetal HRV
and the proposed mechanisms of action is illustrated.

Confounding factors
In assessing the impact of corticosteroids on fetal HR, it is important to account for possible
confounding factors that might also affect fetal HR and fetal HRV. We assessed other drugs
administered, GA, diurnal rhythm and IUGR as major potential confounders. In Figure 4, an
overview of the hypothesised effects of the different confounders is presented. One can
correct for these variables by measuring at fixed times during the day and by performing
subgroup analyses. Below, we will shortly discuss each of these potential confounders.

To understand some of the underlying confounding mechanisms, it is important to review

the 11β-HSD enzyme. This enzyme is an important regulator of fetal glucocorticoid exposure
and consists of two distinct iso-enzymes, namely 11β-HSD type 1 and 26. 11β-HSD type 1 acts
as a reductase, converting cortisone (inactive metabolite) into cortisol (active metabolite).

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 Review: corticosteroids and fetal heart rate variability

This enzyme is located mainly in the liver, but is also present in the decidua, chorion and the
endothelium of placental villous tissue, where it modulates the effect of cortisol on other
placental pathways (including prostaglandin biosynthesis and metabolism, resulting in an
increase in prostaglandin synthesis, which is involved in parturition)47. In contrast, 11β-HSD
type 2 acts as an oxidising enzyme, converting cortisol to cortisone. 11β-HSD type 2 activity
is located mainly in the kidney, but is also found in the placental syncytiotrophoblast during
pregnancy, where it functions to limit fetal exposure to maternal corticosteroids.

Figure 3. Overview of the effects of corticosteroids on fetal heart rate and fetal heart rate
variability and the proposed mechanisms of action.

↑
↓

6
↓

The changes in fetal heart rate and fetal heart rate variability are relative changes, compared with the
baseline values on day 0. Therefore, no y-axis is shown. As illustrated, fetal heart rate decreases during
day 1 and increases during days 2 to 3, whereas fetal heart rate variability increases during day 1 and
decreases during days 2 to 3. All values returned to baseline during day 4.

Indicates the inverse relation between fetal heart rate and fetal heart rate variability.

Abbreviations: CNS = central nervous system, fHR = fetal heart rate, fHRV = fetal heart rate variability,
GR = glucocorticoid receptor.

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Figure 4. The complex interactions between confounding factors and fetal heart rate and/or
fetal heart rate variability.

If arrows attach to the horizontal line above “fHR” and “fHRV”, this indicates that the confounding factor
has an effect on both fetal HR and fetal HRV. The dashed vertical lines next to “fHR” and “fHRV” indicate an
effect solely on fetal HR (left dashed line) or fetal HRV (right dashed line).

Indicates the inverse relation between fetal heart rate and fetal heart rate variability.
+ Indicates a positive correlation, - indicates a negative correlation.

Tocolytic and antihypertensive drugs: the effect of other administered drugs remains unclear, since these
are mainly co-administered with corticosteroids. Therefore, we illustrated this as a question mark in
the figure. Gestational age: during gestation, fetal HRV increases and fetal HR decreases. This might be
caused by a gradual increase in the parasympathetic-to-sympathetic ratio. Besides, there is an increase
in 11β-HSD type 2 activity during gestation, yielding to a lower fetal corticosteroid plasma concentra-
tion. Intra-uterine growth restriction: in IUGR fetuses, fetal HR was generally higher and fetal HRV was
lower compared to a control group. This might be due to a decrease in placental transfer of corticos-
teroids, premature reduction in 11β-HSD type 2 activity, and maternal/fetal stress. Alternatively, chronic
hypoxemia can cause an increased cortisol concentration. Fetal diurnal rhythm: following corticosteroid
administration, fetal diurnal rhythm abolishes. However, the exact effects on fetal HR and fetal HRV
depend on the time of day. Therefore, it is not possible to indicate this effect as “positive” or “negative”.
The abolishment of fetal diurnal rhythm might be caused by a direct effect on the suprachiasmatic nuclei
(indicated as +/-, since it is not described whether this is an activation or suppression), a temporary
suppression of the fetal HPA-axis and/or by simultaneous abolishment of the maternal diurnal rhythm.

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 Review: corticosteroids and fetal heart rate variability

Abbreviations: 11β-HSD = 11β-hydroxysteroid dehydrogenase, CNS = central nervous system,

CRH = corticotrophin-releasing hormone, fHR = fetal heart rate, fHRV = fetal heart rate variability,
GA = gestational age, GR = glucocorticoid receptor, HPA-axis = hypothalamic-pituitary-adrenal axis,
IUGR = intra-uterine growth restriction, parasymp:symp = parasympathetic:sympathetic ratio.

Influence of other drugs

A significant potential confounder is the use of other medications that might influence fetal
HRV. When administering corticosteroids in threatened preterm labour, tocolytic drugs are
commonly co-administered in order to suppress uterine activity. These tocolytic drugs may
have an effect on fetal HRV, although de Heus et al.48 did not report additional changes in fetal
HR parameters after administration of atosiban or nifedipine, on top of the changes caused by
corticosteroids. However, there are indications that nifedipine might cause fetal tachycardia49.
Because the combined administration of corticosteroids and tocolytic drugs is common
clinical practice and because of the small sample sizes encountered in the described studies,
it is not feasible to design a study in which only effects of one of these drugs on fetal HRV
could be studied. Consequently, the isolated effect of tocolytic drugs on fetal HRV remains
unclear. 6
Antihypertensive agents are also commonly co-administered with corticosteroids in cases of
pre-eclampsia or pregnancy induced hypertension. In a review performed by Waterman et
al.50, it is stated that the available data is inadequate to draw any conclusions concerning the
effect on fetal HRV parameters.

In multiple studies, it is stated that the fetal response to maternal corticosteroid administra-
tion was not significantly related to the type of pregnancy complication20,21,23,27. Therefore, it
is unlikely that the observed changes were only due to concomitant factors such as tocolytic
or antihypertensive drugs. Nevertheless, a comprehensive analysis of the effects on fetal HR
parameters of commonly used medicines in obstetric care, other than corticosteroids, goes
beyond the scope of this review.

Influence of gestational age

In healthy fetuses, both LTV and STV increase during gestation, whereas fetal HR decreases41.
Both Mulder et al.25 and Lunshof et al.21 found that older fetuses (29-34 weeks’ gestation)
show a significant decrease in fetal HR and body- and breathing activity during day 1.
These changes were not statistically significant in younger fetuses (26-28 weeks’ gestation).
However, the relative reduction in fetal HRV during days 2 and 3 was similar in younger and
older fetuses, and not related to changes in basal fetal HR23. This is suggestive of an immature
cardiovascular control mechanism and/or non-functional gonadotropin receptors in the fetal

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brain, heart, or vessels at younger ages. In sheep studies, it is demonstrated that the sympa-
thetic branch of the ANS develops and becomes functional earlier in fetal life than the para-
sympathetic branch51,52. However, the parasympathetic system is capable of exerting a strong
action on the fetal cardiovascular system when stimulated; this capability increases with GA52.

The activity of the placental 11β-HSD type 2 enzyme increases during pregnancy, with a
decrease in activity from 38-40 weeks’ gestation47. In addition, there is an increase in 11β-HSD
type 1 expression at term. These changes result in a rise of cortisol concentrations at term,
regulating the reduction in fetal growth rate and the promotion of fetal organ maturation
towards term and activating pathways associated with labour.

Diurnal rhythm
From the second half of pregnancy onwards, there is a fetal diurnal rhythm present with a
rise in STV and fetal movements and a decrease in fetal HR in the afternoon and evening
compared with the morning53. A part of the increase in fetal HRV during the day can be
explained by a decrease in fetal HR, because correction for fetal HR resulted in absence of any
effect of time of the day on LTV and STV41. However, the effect of corticosteroid administration
is considerably larger than the observed diurnal variations20.

De Heus et al.53 performed daily CTG recordings in both the morning and afternoon, before
and 4 days after betamethasone administration. They found a reduction in fetal HRV and
fetal movements during day 2 in the afternoon and evening, but not in the early morning.
This suggests a transient suppression of the normal fetal diurnal rhythm, induced by cortico-
steroids. The diurnal rhythm returned to normal during days 3 and 454.

The mechanisms by which corticosteroids temporarily influence the fetal diurnal rhythm are
still uncertain. They may exert a direct effect on the suprachiasmatic nuclei in the hypothala-
mus; the same nuclei that regulate the adult biological clock55. Or, corticosteroids may tempo-
rarily suppress the fetal hypothalamic-pituitary-adrenal (HPA) axis with cortisol functioning as
a major “Zeitgeber”56. Another hypothesis is the simultaneous abolishment of the maternal
diurnal cortisol rhythm57. Most likely, there is a combination of direct, reversible effects on the
fetal cardiovascular system and diurnal rhythms.

Intra-uterine growth restriction (IUGR)

Nijhuis et al.41 stated that in IUGR fetuses, fetal HR was generally higher and fetal HRV was
lower compared with a control group. In addition, Frusca et al.30 found an even more
pronounced decrease in STV on day 3 after betamethasone administration in fetuses with
cerebral vasodilation. This may be explained as a sign of a compromised fetal condition or by

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 Review: corticosteroids and fetal heart rate variability

a higher concentration of steroids in the fetal brain due to an increased cerebral blood flow. In
IUGR fetuses, it is possible that the placental transfer of corticosteroids is decreased because
of a diminution in uteroplacental blood flow. 11β-HSD type 2 is a key factor in determining
fetal growth, with a positive correlation between 11β-HSD type 2 activity and birth weight. In
addition, IUGR is probably associated with a premature reduction in 11β-HSD type 2 activity,
thus increasing the glucocorticoid transfer from mother to fetus6,58. In addition, maternal and/
or fetal stress stimulates the placental secretion of corticotrophin-releasing hormone, stimu-
lating the HPA axis to secrete glucocorticoids. Alternatively, an increased plasma concentra-
tion of cortisol has been found in human fetuses with chronic hypoxemia, possibly protecting
some IUGR fetuses from the suppressive effects of synthetic steroids59. However, IUGR fetuses
show a similar trend in response to corticosteroids as do appropriately grown fetuses30.

Conclusions
This review indicates that following maternal corticosteroid administration for threatened
preterm delivery, fetal HR and fetal HRV show a biphasic course. During day 1, fetal HR
decreases and fetal HRV increases, followed by increasing fetal HR and decreasing fetal HRV 6
during days 2 to 3. All parameters typically return to baseline by day 4. This decrease in fetal
HRV, combined with a decrease in fetal body- and breathing movements, can be misinterpret-
ed as non-reassuring fetal status. Therefore, the physician should be aware of unnecessary
iatrogenic delivery of premature infants because of these pharmacological changes in fetal
HR parameters following corticosteroid administration. In future studies, beat-to-beat fetal
HR should be obtained, to calculate fetal HRV more accurately and to interpret these findings
in conjunction with the ANS. Direct fetal ECG measurements could be a valuable tool to
overcome this problem.

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rate and behavior in twin pregnancy. Pediatr Res 2004 Jul;56(1):35-39.
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of antenatal corticosteroids on fetal heart rate: a randomized trial that compares betamethasone
acetate and phosphate, betamethasone phosphate, and dexamethasone. Am J Obstet Gynecol
2003 Feb;188(2):524-531.
25. Mulder EJ, Koenen SV, Blom I, Visser GH. The effects of antenatal betamethasone administration
on fetal heart rate and behaviour depend on gestational age. Early Hum Dev 2004 Jan;76(1):65-77.
26. Multon O, Senat MV, Minoui S, Hue MV, Frydman R, Ville Y. Effect of antenatal betamethasone and
dexamethasone administration on fetal heart rate variability in growth-retarded fetuses. Fetal
Diagn Ther 1997 May-Jun;12(3):170-177.
27. Mulder EJ, Derks JB, Visser GH. Antenatal corticosteroid therapy and fetal behaviour: a randomised
study of the effects of betamethasone and dexamethasone. Br J Obstet Gynaecol 1997
Nov;104(11):1239-1247.
28. Dawes GS, Serra-Serra V, Moulden M, Redman CW. Dexamethasone and fetal heart rate variation. Br
J Obstet Gynaecol 1994 Aug;101(8):675-679.
29. Rotmensch S, Liberati M, Vishne TH, Celentano C, Ben-Rafael Z, Bellati U. The effect of
betamethasone and dexamethasone on fetal heart rate patterns and biophysical activities. A
prospective randomized trial. Acta Obstet Gynecol Scand 1999 Jul;78(6):493-500.
30. Frusca T, Soregaroli M, Valcamonico A, Scalvi L, Bonera R, Bianchi U. Effect of betamethasone on
computerized cardiotocographic parameters in preterm growth-restricted fetuses with and
without cerebral vasodilation. Gynecol Obstet Invest 2001;52(3):194-197.

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31. Ville Y, Vincent Y, Tordjman N, Hue MV, Fernandez H, Frydman R. Effect of betamethasone on the
fetal heart rate pattern assessed by computerized cardiotocography in normal twin pregnancies.
Fetal Diagn Ther 1995 Sep-Oct;10(5):301-306.
32. Vullings R, Peters C, Andriessen P, Oei S, Wijn P. Monitoring the Fetal Heart Rate and Fetal Electro-
cardiogram: Abdominal Recordings Are As Good As Direct Ecg Measurements. Pediatric Research
2005;58(2):242.
33. Siira SM, Ojala TH, Vahlberg TJ, Jalonen JO, Valimaki IA, Rosen KG, et al. Marked fetal acidosis and
specific changes in power spectrum analysis of fetal heart rate variability recorded during the last
hour of labour. BJOG 2005 Apr;112(4):418-423.
34. Van Laar JO, Porath MM, Peters CH, Oei SG. Spectral analysis of fetal heart rate variability for fetal
surveillance: review of the literature. Acta Obstet Gynecol Scand 2008;87(3):300-306.
35. van Laar JO, Peters CH, Houterman S, Wijn PF, Kwee A, Oei SG. Normalized spectral power of fetal
heart rate variability is associated with fetal scalp blood pH. Early Hum Dev 2011 Apr;87(4):259-263.
36. Kream J, Mulay S, Fukushima DK, Solomon S. Determination of plasma dexamethasone in the
mother and the newborn after administration of the hormone in a clinical trial. J Clin Endocrinol
Metab 1983 Jan;56(1):127-133.
37. Haynes RC. Adrenocorticotropic hormone, adrenocortical steroids and their synthetic analogs,
inhibitors of adrenal steroids biosynthesis. In: Goodman Gilman A, Rall TW, Nies AS, Taylor P, editors.
The Pharmacological Basis of Therapeutics. 8th ed.: Pergamon Press, New York; 1990. p. 1431-1462.
38. Ballard PL, Ballard RA. Scientific basis and therapeutic regimens for use of antenatal glucocorti-
coids. Am J Obstet Gynecol 1995 Jul;173(1):254-262.
39. de Kloet ER, Reul JM, Sutanto W. Corticosteroids and the brain. J Steroid Biochem Mol Biol 1990 Nov
20;37(3):387-394.
40. Ullian ME. The role of corticosteriods in the regulation of vascular tone. Cardiovasc Res 1999
Jan;41(1):55-64.
41. Nijhuis IJ, ten Hof J, Mulder EJ, Nijhuis JG, Narayan H, Taylor DJ, et al. Fetal heart rate in relation
to its variation in normal and growth retarded fetuses. Eur J Obstet Gynecol Reprod Biol 2000
Mar;89(1):27-33.
42. Bennet L, Kozuma S, McGarrigle HH, Hanson MA. Temporal changes in fetal cardiovascular,
behavioural, metabolic and endocrine responses to maternally administered dexamethasone in
the late gestation fetal sheep. Br J Obstet Gynaecol 1999 Apr;106(4):331-339.
43. Frasch MG, Muller T, Hoyer D, Weiss C, Schubert H, Schwab M. Nonlinear properties of vagal and
sympathetic modulations of heart rate variability in ovine fetus near term. Am J Physiol Regul
Integr Comp Physiol 2009 Mar;296(3):R702-7.
44. Rotmensch S, Lev S, Kovo M, Efrat Z, Zahavi Z, Lev N, et al. Effect of betamethasone administration
on fetal heart rate tracing: a blinded longitudinal study. Fetal Diagn Ther 2005 Sep-Oct;20(5):371-
376.
45. Shenhav S, Volodarsky M, Anteby EY, Gemer O. Fetal acid-base balance after betamethasone
administration: relation to fetal heart rate variability. Arch Gynecol Obstet 2008 Oct;278(4):333-336.

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46. Cohlen BJ, Stigter RH, Derks JB, Mulder EJ, Visser GH. Absence of significant hemodynamic changes
in the fetus following maternal betamethasone administration. Ultrasound Obstet Gynecol 1996
Oct;8(4):252-255.
47. Murphy VE, Clifton VL. Alterations in human placental 11beta-hydroxysteroid dehydrogenase type
1 and 2 with gestational age and labour. Placenta 2003 Aug;24(7):739-744.
48. De Heus R, Mulder E, Derks J, Visser G. The effects of the tocolytics atosiban and nifedipine on
fetal movements, heart rate and blood flow. The Journal of Maternal-Fetal and Neonatal Medicine
2009;22(6):485-490.
49. Chan LW, Sahota DS, Yeung SY, Leung TY, Fung TY, Lau TK, et al. Side-effect and vital sign profile of
nifedipine as a tocolytic for preterm labour. Hong Kong Med J 2008 Aug;14(4):267-272.
50. Waterman E, Magee L, Lim K, Skoll A, Rurak D, Phil D, et al. Do Commonly Used Oral Antihyper-
tensives Alter Fetal or Neonatal Heart Rate Characteristics? A Systematic Review. Hypertension in
pregnancy 2004;23(2):155-169.
51. Assali NS, Brinkman CR,3rd, Woods JR,Jr, Dandavino A, Nuwayhid B. Development of neurohumoral
control of fetal, neonatal, and adult cardiovascular functions. Am J Obstet Gynecol 1977 Dec
1;129(7):748-759.
52. Nuwayhid B, Brinkman CR,3rd, Su C, Bevan JA, Assali NS. Development of autonomic control of fetal
circulation. Am J Physiol 1975 Feb;228(2):337-344.
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53. de Heus R, Mulder EJ, Derks JB, Koenen SV, Visser GH. Differential effects of betamethasone
on the fetus between morning and afternoon recordings. J Matern Fetal Neonatal Med 2008
Aug;21(8):549-554.
54. Koenen SV, Mulder EJ, Wijnberger LD, Visser GH. Transient loss of the diurnal rhythms of fetal
movements, heart rate, and its variation after maternal betamethasone administration. Pediatr Res
2005 May;57(5 Pt 1):662-666.
55. Rietveld WJ. The central control and ontogeny of circadian rhythmicity. Eur J Morphol 1990;28(2-
4):301-307.
56. Dickmeis T, Lahiri K, Nica G, Vallone D, Santoriello C, Neumann CJ, et al. Glucocorticoids play a key
role in circadian cell cycle rhythms. PLoS Biol 2007 Apr;5(4):e78.
57. Helal KJ, Gordon MC, Lightner CR, Barth WH,Jr. Adrenal suppression induced by betamethasone in
women at risk for premature delivery. Obstet Gynecol 2000 Aug;96(2):287-290.
58. Edwards CR, Benediktsson R, Lindsay RS, Seckl JR. 11 beta-Hydroxysteroid dehydrogenases: key
enzymes in determining tissue-specific glucocorticoid effects. Steroids 1996 Apr;61(4):263-269.
59. Economides DL, Nicolaides KH, Linton EA, Perry LA, Chard T. Plasma cortisol and adrenocorticotro-
pin in appropriate and small for gestational age fetuses. Fetal Ther 1988;3(3):158-164.

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Effect of tocolytic drugs on fetal heart rate

variability: a systematic review

Kim M.J. Verdurmen, Alexandra D.J. Hulsenboom,

Judith O.E.H. van Laar, S. Guid Oei
7

Published: The Journal of Maternal-Fetal & Neonatal Medicine. 2016:1-8

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Abstract
Introduction
Tocolytics may cause changes in fetal heart rate pattern, while fetal heart rate variability is an
important marker of fetal wellbeing. We aim to systematically review the literature on how
tocolytic drugs affect fetal heart rate variability.

Material and Methods

We searched CENTRAL, PubMed, and EMBASE up to June 2016. Studies published in English,
using computerised or visual analysis to describe the effect of tocolytics on heart rate varia-
bility in human fetuses were included. Studies describing tocolytics during labour, external
cephalic version, pre-eclampsia and infection were excluded. Eventually, we included six
studies, describing 169 pregnant women.

Results
Nifedipine, atosiban and indomethacin administration show no clinically important effect
on fetal heart rate variability. Following administration of magnesium sulphate, decreased
variability and cases of bradycardia are described. Fenoterol administration results in a
slight increase in fetal heart rate with no changes in variability. After ritodrine administration
increased fetal heart rate and decreased variability is seen. The effect of co-administration of
corticosteroids should be taken into account.

Conclusion
In order to prevent iatrogenic preterm labour, the effects of tocolytic drugs on fetal heart rate
variability should be taken into account when monitoring these fetuses.

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Introduction
In case of threatened preterm delivery between 24 and 34 weeks of gestation, short-term
tocolytic therapy is commonly used in combination with corticosteroids. The aim is to
postpone delivery for at least 48 hours, in order to gain time for transferring women to a
centre with neonatal intensive care facilities and administering and awaiting maximal bene-
ficial effect of corticosteroids. The tocolytic agent of first choice is still a topic of debate and
varies considerably in different parts of the world. The most commonly used tocolytic drugs
in clinical practice nowadays are nifedipine, magnesium sulphate (MgSO4), atosiban, indo-
methacin, fenoterol and ritodrine. Table 1 summarises the most important properties of these
tocolytics.

Table 1. Overview of the most important tocolytic drugs and their properties.

Abbreviations: a.o. = amongst others, F/M ratio = fetal/maternal ratio, h = hours, min = minutes.

In 1989, the American College of Obstetricians and Gynecologists acknowledged that fetal
heart rate variability (HRV) is a reliable marker for fetal wellbeing10. In accordance with
other studies, Williams and Galerneau11 concluded that minimal or absent variability is the
most significant intrapartum fetal heart rate (HR) parameter to predict acidemia. Since the
fetus is unable to adapt its single stroke volume due to the small size of the heart, the fetal
HR is the primary variable to control the cardiac stability and is the major regulative of the
autonomic nervous system12. Therefore, we should be aware of the influence of commonly
used medicines in obstetric care on fetal HRV. For example, corticosteroids are known to
cause a decrease in fetal HRV that can be interpreted as deterioration of the fetal condition13.
As with corticosteroids, tocolytics may also cause changes in fetal HR pattern, which can be

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erroneously interpreted as a sign of fetal distress. This could lead to iatrogenic preterm
delivery. In this review, we will focus on the influence of tocolytic drugs on fetal HRV in human
fetuses.

Material and Methods

We performed a systematic search in the electronic databases CENTRAL (the Cochrane
Library, 2016, Issue 6), PubMed, and EMBASE up to June 2016. The search strategy is attached
in the Appendix.

All published studies that describe the influence of tocolytic drugs on HRV of the human
fetus, assessed by computerised or visual analysis, were included in this review. The outcome
measure of interest was variability of the fetal HR. There were no restrictions on publication
dates. We excluded review studies, studies that described pre-eclamptic women or women
with an intra-uterine infection and studies that performed measurements during labour or
during external cephalic version. The study language was restricted to English.

Two reviewers (KV and AH) independently performed the search and abstracted the data.
Any discrepancies were resolved by discussion. Articles were initially screened by title
and abstract, when appropriate a full-text evaluation was performed. Qualitative analysis,
including description of the women enrolled, description of the intervention and outcomes,
and possible risks of bias, were based on the review guidelines of the Dutch Cochrane Centre.

Results
The screening and inclusion process is depicted in Figure 1. Eventually, six out of 72 articles
were included in this review (169 women). Study characteristics and basic fetal HR parameters
are shown in Table 2.1 (computerised analysis of fetal HR parameters) and Table 2.2 (visual
analysis of fetal HR parameters). Three of the included studies are randomised controlled
trials, two are case reports and one is a prospective cohort study. Table 3 includes the quality
assessment of the included randomised trials. We considered the trials by de Heus et al.14 and
Neri et al.15 as medium quality evidence, as blinding was not appropriate or not described.
The trial by Hallak et al.16 was considered high-quality evidence. Table 4 includes the quality
assessment of the included prospective cohort study by Wright et al.17. This study was consid-
ered low-quality evidence since there was no description of exclusion criteria and there was a
high risk of selection bias: the tocolytic agent used was the choice of the individual physician
and co-administration of corticosteroids was not described.

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Figure 1. Flowchart of the included and excluded articles.

Identification

Potentially relevant articles: 73

-CENTRAL 8
-PubMed 45
-EMBASE 20

Duplicates removed: 22
Screening

Articles screened by title and abstract: 51

Excluded after screening: 37

-Animal subjects 6
-During labour 2
-External cephalic version 2
-Hypothyroidism 1
-Infection 1
-Language 4
-No fetal HRV 1
-No tocolysis 12
-Pre-ecplampsia 2
Eligibility

-Pre-ecpampsia + during labour 5

Full-text articles assessed for eligibility: 14 -Review 1

Excluded after full-text assessment:

-No fetal HRV
8
3 7
-No tocolysis 1
-Pre-eclampsia 1
-Pre-eclampsia + during labour 3
Included

Included articles: 6

Abbreviation: HRV = heart rate variability.

Calcium channel blocker: nifedipine and magnesium sulphate

Fourteen women were randomised to receive nifedipine in the study by de Heus et al.14. On
days 1 and 2, a significant decrease in fetal HR (-7 bpm) and a significant increase in both
short- and long-term fetal HRV on days 1 and 2 (+2 ms and +12 ms, respectively) were seen.
This effect was observed in both the atosiban and nifedipine groups, there was no difference
between these tocolytic agents. During days 3 and 4, all values (basal fetal HR, short- and
long-term variability) returned to normal (pre-medication values). The authors found no
significant changes in fetal body- and breathing movements or uteroplacental blood flow
during the 5-days study period. Fetuses below 29 weeks of gestation showed higher basal
fetal HR and lower fetal HRV in comparison to older fetuses. However, the initial increase of
fetal HRV and return to baseline were independent of gestational age.

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Table 2.1 Characteristics and basic fetal heart rate parameters of included studies concerning
administration of tocolytic drugs, assessed by computerised analysis.

↓ ↑

↑ ↓

Long-term variation (0.08-0.2 Hz), short-term variation (0.4-1.7 Hz).

Symbol: *, significant; =, no significant difference.
Abbreviations: HR = heart rate, i.v. = intravenous, No. = number of.

Hallak et al.16 included 34 women with an uneventful pregnancy in their randomised trial;
16 in the control group (receiving NaCl-infusion) and 18 in the MgSO4-group. Following
three hours of MgSO4-infusion, they observed a significant decrease in both baseline fetal
HR (136 vs 132 bpm) and fetal HRV (2.82 vs 2.67 bpm). They also observed a trend towards
less accelerations after three hours (11 vs 7.4 per hour). Wright et al.17 found a significant
decrease in both fetal HR (140.8 vs 137.3 bpm) and fetal HRV (“decreased” in 2/48 vs 12/48)
after the MgSO4 loading dose in their prospective cohort group. “Decreased” variability was
defined as a band width ≤5 bpm. They found a trend towards less accelerations after MgSO4
was initiated. Cardosi et al.18 described a case in which fetal bradycardia (100-110 bpm, initial
baseline 140-150 bpm), decreased maternal temperature (-3.1°C) and decreased fetal HRV
followed when serum MgSO4 levels increased. After discontinuing MgSO4, all values returned

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 Table 2.2 Characteristics and basic fetal heart rate parameters of included studies concerning administration of tocolytic drugs,
assessed by visual analysis.

↓ ↓
↓ ↓ ↓
↓ ↓

Symbol: *, significant; =, no significant difference.

Abbreviations: HR = heart rate, i.v. = intravenously, MgSO4 = magnesium sulphate, n = number, No. = number of.
Review: tocolytic drugs and fetal heart rate variability

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Table 3. Quality assessment of the included randomised trials.

Abbreviation: HR = heart rate.

Table 4. Quality assessment of the included cohort study.

Abbreviation: HR = heart rate.

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to pre-MgSO4 levels within 24 hours. Hamersley et al.19 also described a case of fetal brady-
cardia where baseline dropped from 140 bpm to 110 bpm following 30 minutes of MgSO4
infusion and to 100-105 bpm following 90 minutes. The fetal HRV remained good in this case.
After discontinuing MgSO4-infusion on the third day, fetal HR baseline returned to 140 bpm.

Oxytocin receptor antagonist: atosiban

A total of 46 included women with threatened preterm delivery received atosiban in combi-
nation with betamethasone. De Heus et al.14 randomised 17 women to the atosiban group
and found no difference in changes between the atosiban and the nifedipine group: on days
1 and 2, both short- and long-term fetal HRV increased significantly, and returned to premed-
ication values on days 3 and 4. Fetal HR showed a transient significant decrease during days 1
and 2, that returned to premedication values on days 3 and 4.

Neri et al.15 performed their measurements at least twelve hours after the last corticosteroid
administration. They found no significant differences between the atosiban group (n=29) and
the ritodrine group considering fetal HR (148.5 vs 152.5 bpm), long-term variability (18.3 vs
18.9), and short-term variability (5 vs 5.1).

Prostaglandin synthesis inhibitor: indomethacin

We did not find any studies describing the effect of indomethacin on fetal HRV that matched
7
our inclusion criteria.

Selective β2-adrengergic agent: fenoterol and ritodrine

We did not find any studies describing the effect of fenoterol on fetal HRV that matched our
inclusion criteria.
Neri et al.15 observed no differences between 25 women who received ritodrine and those
who received atosiban. Subgroup analysis showed that fetuses before 30 weeks of gestation
treated with ritodrine had a significant higher fetal HR (154 vs 148 bpm), lower long-term fetal
HRV (15.7 vs 21.6 ms) and lower low-frequency/high-frequency ratio (18.5 vs 29.9) than those
treated with atosiban.

Discussion
General Comments
First of all, our search revealed that little research has been published regarding the influence
of tocolytic drugs on fetal HRV. Tocolysis is nearly always combined with corticosteroids that
are known to have transient but considerable effects on fetal HRV13. This makes the interpre-
tation of the sole effect of tocolytics difficult. However, the combination of these medicines

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is daily clinical practice and therefore we chose to include studies that describe the effect of
tocolytics, regardless of the co-administration of corticosteroids. We chose to include studies
that used visual interpretation of fetal HR tracings, despite the well-known inter- and intra-
observer variations in visual fetal HR tracing interpretation. Those study results are valuable,
since visual analysis is common clinical practice and computerised analysis is only used for
research so far.

All included studies used Doppler ultrasound-based cardiotocogram recordings for fetal HRV
analysis (visual or computerised). To perform spectral analysis and obtain more complete
and reliable information on fetal HRV, the fetal HR must be acquired on a beat-to-beat basis.
Standard Doppler recordings cannot derive the fetal HR on a beat-to-beat basis, but produce
an average fetal HR. It is feasible to use Doppler ultrasound for beat-to-beat fetal HR meas-
urements, although this is technically challenging and requires special algorithms20. These are
not described in the included studies. We recommend future studies to focus on beat-to-beat
analysis, to calculate fetal HRV more accurately and to interpret the findings in conjunction
with the autonomic nervous system.

We excluded women during labour, since the stress of labour is known to influence fetal HRV
(the sympathicovagal balance)21 and a woman is likely to receive other pharmacologic agents
in addition to tocolytics which can interfere with the fetal HR. In addition, we did not include
women with pre-eclampsia. This pathological state with abnormal placental-fetal circulation
and hemodynamical fetal stress is known to influence fetal HR tracings due to changes in
cardiovascular regulation22. Women with (suspicion of ) intra-uterine infection were excluded
as well, since it is demonstrated in fetuses that reduced HRV and transient decelerations are
an important physiomarker and can precede clinical signs of sepsis23,24. We also chose to
exclude studies that performed measurements during or after external cephalic version, since
the effect of the version may interfere with the observed fetal HR parameters25-27.

Calcium channel blocker: nifedipine and magnesium sulphate

Nifedipine crosses the placenta easily and contradictory results have been reported
regarding changes in uteroplacental blood flow. In the study by de Heus et al.14, the number
of participants steadily decreased during the study period due to preterm delivery. On day
4, 77% (24/31 women) remained available for analysis. Due to this small amount of women,
study results were depicted as the influence of both atosiban and nifedipine together. A
subanalysis showed no differences in fetal parameters between the two tocolytics, but details
are not shown. The decrease in fetal HR and increase in short- and long-term fetal HRV on
days 1 and 2 were attributed to the known effect of corticosteroids by the authors. However,
our review considering the effects of corticosteroids on fetal HRV showed a decrease in fetal

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HR and increase in fetal HRV during day 1, and an increase in fetal HR and decrease in fetal
HRV during days 2 and 313. This difference might be attributable to the low number of women
included in the study by de Heus et al.14. The nifedipine administration was “progressively
decreased” after 48 hours. However, the authors did not exactly describe in what time course
or dosages this was performed.

In summary, it seems that nifedipine has no clinically important effect on fetal HRV.

MgSO4 crosses the placenta rapidly, and reaches an equilibrium after two hours of admin-
istration between maternal and fetal plasma levels4. Moreover, fetal levels seem to increase
proportionally with maternal levels16,28. It is assumed that MgSO4 crosses the fetal blood-brain
barrier, as it does in the mother. It suppresses the central nervous system and inhibits cardio-
accelerating pathways via the cerebral cortex, hypothalamus and the cardioaccelerator center
in the medulla oblongata29.

Hallak et al.16 studied healthy pregnant women, without any indication for treatment with
MgSO4 in their randomised trial. Therefore, their measurements were not influenced by
conditions like pre-eclampsia, premature contractions or co-administration of corticosteroids.
Besides decreased fetal HR and fetal HRV, they found that the positive correlation between
gestational age and the number of accelerations observed in the control group (treated with 7
NaCl) was missing in women treated with MgSO4. An animal study confirmed a significant
decrease in both baseline fetal HR as well as long- and short-term variability four hours after
MgSO4 administration, compared to the control group (5% glucose infusion)29. The included
prospective study by Wright et al.17 found similar results regarding fetal HR and fetal HRV.
They also state that a lower gestational age increases the likelihood of decreased variability
(odds ratio 0.75, p = 0.03). Cardosi and Hamersley both described a case report with fetal
bradycardia following MgSO4-infusion in a preterm fetus. Cardosi et al.18 state that the effect
on fetal HR might indirectly be related to the hypothermic effect of MgSO4. Hamersley et al.19
suggested a pharmacological depression of the central nervous system. The decrease in fetal
HRV can be interpreted as a sign of compromised fetal condition and expedite iatrogenic
preterm delivery, while Duffy et al.30 showed that the decreased variability is associated with
exposure to MgSO4, since they excluded adverse fetal outcomes. This indicates a transient
medication effect (central nervous system depression) rather than a marker of deteriorating
fetal condition, as confirmed by other studies31,32.

In summary, decreased fetal HRV and cases of fetal bradycardia are described after MgSO4
administration.

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Oxytocin receptor antagonist: atosiban

Atosiban is known to be highly specific for the oxytocin receptors in the uterus, with low
placental passage and few maternal and fetal side effects. Both de Heus et al.14 and Neri et al.15
found no other changes than the changes known to be caused by corticosteroids.

Neri et al.15 performed one measurement, at least 12 hours after the last corticosteroid
administration. They state this would avoid the adverse effects on fetal behaviour following
corticosteroid administration. However, it can take up to 96 hours for fetal HR parameters to
return to baseline values following corticosteroid administration13. Therefore, the effect of
corticosteroids is still likely to overwhelm the effect of atosiban and ritodrine. No baseline
(premedication) measurements were performed, but two medication groups were compared
at one moment. A direct comparison between two drugs was performed, instead of compar-
ison with a placebo or pre-medication group. Thus, potential changes in fetal HR parameters
could be overlooked and it is difficult to conclude if atosiban or ritodrine have any effect on
fetal HRV, based on this study.

A sheep study demonstrated that atosiban does not influence fetal or maternal cardiovas-
cular parameters33. These findings also agree with the study by Valenzuela et al.5, who found
no differences in arterial umbilical cord blood gases in women who did or did not receive
atosiban intravenously before elective caesarean section.

In summary, it seems that atosiban has no clinically important effect on fetal HRV.

Prostaglandin antagonist: indomethacin

We did not find any studies describing the effect of indomethacin on fetal HRV that matched
our inclusion criteria. In a sheep study, there were no significant changes in maternal and fetal
HR or blood pressure following administration of indomethacin34. In summary, animal studies
show no effect on fetal HRV.

Selective β2-adrenergic agent: fenoterol and ritodrine

β-adrenergic receptors are divided in three subtypes; β1-receptors cause positive chrono-
tropic, dromotropic and inotropic effects. β2-receptors cause smooth muscle relaxation and
β3-receptors cause relaxation of the detrusor muscle in the bladder. In fetuses, the density of
β-adrenoreceptors is low compared to adult values, resulting in a less powerful response. The
higher the affinity for the β2-adrenergic receptor, the less cardiac effects are seen.

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Fenoterol is a selective β2-adrenergic receptor agonist, which causes receptor desensiti-

sation in the myometrium resulting in relaxation35. It has negligible α-adrenergic activity
and minimal β1-adrenergic activity36. We did not find any studies that describe the effect of
fenoterol on fetal HRV that matched our inclusion criteria. Based on visual cardiotocography,
a slight increase in fetal HR (up to 10 bpm) with no changes in fetal HRV was found37. In
accordance, Kast and Hermer38 found an increase in fetal HR of approximately 10% (maximum
20%) following fenoterol administration in their review. This can be explained by the low
affinity for the β1-adrenergic receptor, as well as by the low placental transfer of fenoterol
(fetal-maternal ratio 0.40). Overall, little research is published so far concerning the effect of
fenoterol on fetal HRV.

In summary, the abovementioned studies show a slight increase in fetal HR, with no changes
in fetal HRV.

Ritodrine is a potent β2-adrenergic receptor agonist which causes direct relaxation of the
myometrium. The β2-specificity of ritodrine is dose-related39. At higher dosages, other
β-sympathicomimetic effects occur including cardiac stimulation and vasodilation. Fetal
tachycardia, in combination with reduced fetal HRV, was observed by Neri et al.15 in fetuses
below 30 weeks of gestational age. These fetuses were considered in a subgroup analysis, as
baseline fetal HR decreases and parasympathetic activity increases in the second and third 7
trimester. In other studies ritodrine was associated with persistent fetal tachycardia40, which
tended to persist in the newborn for several days after delivery10. Moreover, a concentration-
dependent relation between ritodrine and the fetal HR rise was found, although there was a
clear inter-patient variation41. It is hypothesised that the immaturity of the nervous system
induces an exaggerated response through heart receptor stimulation15. Another explanation
could be that the sympathetic branch of the autonomic nervous system matures earlier
than the parasympathetic branch, resulting in an exaggerated sympathetic reflex with little
parasympathetic suppression42. In addition, ritodrine can freely pass the placenta and there is
even accumulation of ritodrine in the fetal blood (fetal-maternal ratio 1.17). This can explain
the more pronounced fetal tachycardia following ritodrine administration compared to
fenoterol.

In summary, ritodrine seems to cause an increase in fetal HR and a decrease in fetal HRV.

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Conclusions
Our search revealed that little research has been published regarding the influence of
tocolytic drugs on fetal HRV. The limited available evidence indicates that both nifedipine and
atosiban have no clinically important effect on fetal HRV. A decrease in fetal HRV and cases
of fetal bradycardia are described following MgSO4 administration. Animal studies show
no effect on fetal HR parameters after indomethacin administration. Studies considering
fenoterol show a slight increase in fetal HR, with no changes in fetal HRV. Ritodrine seems
to cause an increase in fetal HR and a decrease in fetal HRV. Since most women treated with
tocolytics also receive corticosteroids, the known profound effects of corticosteroids on fetal
HR parameters should be taken into account and could overwhelm the effect of tocolytics
in clinical practice. As with corticosteroids, the changes caused by several tocolytics can be
erroneously interpreted as a sign of fetal distress. Therefore, physicians should be aware of
these effects.

Acknowledgements
This research was performed within the framework of IMPULS Perinatology.

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 Review: tocolytic drugs and fetal heart rate variability

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14. de Heus R, Mulder EJ, Derks JB, Visser GH. The effects of the tocolytics atosiban and nifedipine on
fetal movements, heart rate and blood flow. J Matern Fetal Neonatal Med 2009 Jun;22(6):485-490.
15. Neri I, Monari F, Valensise H, Vasapollo B, Facchinetti F, Volpe A. Computerized evaluation of fetal
heart rate during tocolytic treatment: comparison between atosiban and ritodrine. Am J Perinatol
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16. Hallak M, Martinez-Poyer J, Kruger ML, Hassan S, Blackwell SC, Sorokin Y. The effect of magnesium
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17. Wright JW, Ridgway LE, Wright BD, Covington DL, Bobitt JR. Effect of MgSO4 on heart rate monitor-
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18. Cardosi RJ, Chez RA. Magnesium sulfate, maternal hypothermia, and fetal bradycardia with loss of
heart rate variability. Obstet Gynecol 1998 Oct;92(4 Pt 2):691-693.
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23. Salafia CM, Ghidini A, Sherer DM, Pezzullo JC. Abnormalities of the fetal heart rate in preterm
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24. Moorman JR, Lake DE, Griffin MP. Heart rate characteristics monitoring for neonatal sepsis. IEEE
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version under tocolysis near term. Int J Gynaecol Obstet 1987 Aug;25(4):277-281.
26. Phelan JP, Stine LE, Mueller E, McCart D, Yeh S. Observations of fetal heart rate characteristics
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27. Lau TK, Leung TY, Lo KW, Fok WY, Rogers MS. Effect of external cephalic version at term on fetal
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28. Hallak M, Berry SM, Madincea F, Romero R, Evans MI, Cotton DB. Fetal serum and amniotic fluid
magnesium concentrations with maternal treatment. Obstet Gynecol 1993 Feb;81(2):185-188.
29. Sameshima H, Ikenoue T, Kamitomo M, Sakamoto H. Effects of 4 hours magnesium sulfate infusion
on fetal heart rate variability and reactivity in a goat model. Am J Perinatol 1998;15(9):535-538.
30. Duffy CR, Odibo AO, Roehl KA, Macones GA, Cahill AG. Effect of magnesium sulfate on fetal heart
rate patterns in the second stage of labor. Obstet Gynecol 2012 Jun;119(6):1129-1136.
31. Lin CC, Pielet BW, Poon E, Sun G. Effect of magnesium sulfate on fetal heart rate variability in
preeclamptic patients during labor. Am J Perinatol 1988 Jul;5(3):208-213.
32. Babaknia A, Niebyl JR. The effect of magnesium sulfate on fetal heart rate baseline variability.
Obstet Gynecol 1978 Jan;51(1 Suppl):2s-4s.
33. Greig PC, Massmann GA, Demarest KT, Weglein RC, Holland ML, Figueroa JP. Maternal and fetal
cardiovascular effects and placental transfer of the oxytocin antagonist atosiban in late-gestation
pregnant sheep. Am J Obstet Gynecol 1993 Oct;169(4):897-902.
34. Skarsgard ED, VanderWall KJ, Morris JA, Roman C, Heymann MA, Harrison MR. Effects of
nitroglycerin and indomethacin on fetal-maternal circulation and on fetal cerebral blood flow and
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35. Engelhardt S, Zieger W, Kassubek J, Michel MC, Lohse MJ, Brodde OE. Tocolytic therapy with
fenoterol induces selective down-regulation of beta-adrenergic receptors in human myometrium. J
Clin Endocrinol Metab 1997 Apr;82(4):1235-1242.
36. Kundig H. Preliminary pharmacological and toxicological studies in the baboon (papis ursinus) on a
new beta2-adrenergic stimulant, fenoterol (Berotec). Med Proceed 1972;18(9).
37. Oddoy A, Joschko K. Effects of fenoterol on blood pressure, heart rate, and cardiotocogram of
hypertensive and normotensive women in advanced pregnancy (author’s transl). Zentralbl Gynakol
1982;104(7):415-421.
38. Kast A, Hermer M. Beta-adrenoceptor tocolysis and effects on the heart of fetus and neonate. A
review. J Perinat Med 1993;21(2):97-106.
39. Renaud R, Irrmann M, Gandar R, Flynn MJ. The use of ritodrine in the treatment of premature
labour. J Obstet Gynaecol Br Commonw 1974 Mar;81(3):182-186.
40. Moutquin JM, Sherman D, Cohen H, Mohide PT, Hochner-Celnikier D, Fejgin M, et al. Double-blind,
randomized, controlled trial of atosiban and ritodrine in the treatment of preterm labor: a multi-
center effectiveness and safety study. Am J Obstet Gynecol 2000 May;182(5):1191-1199.
41. Caritis SN, Lin LS, Toig G, Wong LK. Pharmacodynamics of ritodrine in pregnant women during
preterm labor. Am J Obstet Gynecol 1983 Dec 1;147(7):752-759.
42. van Laar JO, Warmerdam GJ, Verdurmen KM, Vullings R, Peters CH, Houterman S, et al. Fetal heart
rate variability during pregnancy, obtained from non-invasive electrocardiogram recordings. Acta
Obstet Gynecol Scand 2014 Jan;93(1):93-101.
7

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 Chapter 8

The influence of betamethasone on fetal heart

rate variability, obtained by non-invasive fetal
electrocardiogram recordings

Kim M.J. Verdurmen, Guy J.J. Warmerdam, Carlijn Lempersz,

Alexandra D.J. Hulsenboom, Joris Renckens, Jeanne P. Dieleman,
Rik Vullings, Judith O.E.H. van Laar, S. Guid Oei

8
Revision pending

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Abstract
Introduction
Betamethasone is widely used to enhance fetal lung maturation in case of threatened preterm
labour. Fetal heart rate variability is one of the most important parameters to assess in fetal
monitoring, since it is a reliable indicator for fetal distress. Spectral analysis of fetal heart rate
variability can quantify the modulation of the autonomic nervous system. High-frequency
power is parasympathetically mediated, while low-frequency power is both sympathetically
and parasympathetically mediated. In this study, we examined the influence of betametha-
sone on spectral values.

Materials & Methods

We performed a prospective cohort study in a tertiary care teaching hospital. Inclusion:
patients with a gestational age from 24 weeks onwards who required betamethasone.
Exclusion: maternal age <18 years, fetal congenital malformation and fetal growth restriction.
We performed daily non-invasive fetal electrocardiogram measurements, from hospitalisation
until delivery, discharge or day 5. Recordings were analysed offline and spectral analysis was
performed on extracted fetal heart rates using a continuous wavelet transform. Measure-
ments during days 1, 2 and 3 were compared to a reference measurement (the median of day
0, and/or day 4, and/or day 5).

Results
Following 68 inclusions, 12 patients remained with complete series of measurements and
sufficient data quality. Due to the low number of patients remaining, we mainly used descrip-
tive statistics. During day 1, an increase in absolute fetal heart rate variability values (low- and
high-frequency power, short- and long-term variability) was seen. During day 2, a non-signifi-
cant decrease in these values was seen. All trends indicate to return to pre-medication values
on day 3. Normalised high- and low-frequency power show little changes during the study
period. During days 1 and 2 the number of segments in quiet state increased.

Conclusions
The changes in fetal heart rate variability following betamethasone administration show the
same pattern when calculated by spectral analysis of the fetal electrocardiogram, as when
calculated by cardiotocography. The change in absolute spectral values is likely to correspond
to the change in quiet and active state of the fetus. Since normalised spectral values show
little changes, the influence of autonomic modulation is minor.

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 Betamethasone and fetal heart rate variability, assessed by fetal ECG

Introduction
Cardiotocography (CTG) is used for fetal monitoring worldwide. One of the most important
parameters to assess in CTG monitoring is fetal heart rate variability (HRV). Normal fetal HRV
is a reliable indicator of fetal wellbeing, while decreased fetal HRV is associated with poor
neonatal outcome (acidosis, low Apgar score and death)1. The fetal heart rate (HR), and thus
HRV, is regulated by a complex interplay of the sympathetic and parasympathetic branches
of the autonomic nervous system2. Spectral analysis (frequency analysis) of fetal HRV can be
used to quantify these changes in autonomic regulation3-8. The low-frequency (LF)-compo-
nent reflects baroreceptor reflex activity, and is both sympathetically and parasympathetical-
ly mediated9. The high-frequency (HF)-component is associated with fetal respiration, and is
solely parasympathetically mediated9.

Antenatal betamethasone administration plays an important role in the clinical management

of threatened preterm delivery between 24 and 34 weeks of gestation (wG). It enhances
fetal lung maturation and results in a significant reduction in, amongst others, neonatal
mortality and respiratory distress syndrome10. However, betamethasone can easily cross the
placenta and influence fetal autonomic modulation and thus fetal HRV11. Since fetal HRV is
an important marker for fetal distress, knowledge on the influence of betamethasone on
autonomic regulation is needed to avoid misinterpretation of changes in fetal HRV following
betamethasone administration, and therefore prevent unnecessary iatrogenic preterm
delivery.

Results of previous studies describing the effect of betamethasone on fetal HRV indicate 8
that fetal HRV increases during the first day, followed by a decrease during days 2-312. Values
returned to baseline during day 4. However, these studies were performed using CTG and
measured the fetal HR by Doppler-ultrasound. With CTG, the fetal HR is averaged over several
heartbeats and therefore beat-to-beat information is lacking. As a consequence, it is not
possible to perform reliable spectral analysis.

The aim of this study is to quantify the effects of maternally administered betamethasone
on spectral values of fetal HRV. To perform a reliable calculation of LF- and HF-power, we
extracted beat-to-beat fetal HR information from non-invasive abdominal fetal ECG record-
ings.

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Materials and Methods

We performed a prospective, longitudinal cohort study at the Máxima Medical Centre,
Veldhoven, the Netherlands. This is a tertiary care teaching hospital for obstetrics. The study
protocol was approved by the Medical Ethical Committee of the Máxima Medical Centre.
Participants were included after written informed consent.

Study population
As described in our study protocol, we aimed for at least 50 inclusions and expected to end
with 10-20 complete sets of measurements due to the anticipated loss to follow-up in this
study group. From March 2013 until July 2016, women with a singleton pregnancy, at risk
for preterm delivery and admitted to the Obstetric High Care unit were asked to participate
in this study. All women requiring betamethasone (Celestone Chrondose®, Schering AG,
Berlin, Germany; 2 doses of 12mg intramuscularly, 24 hours apart) as part of standard
clinical management were eligible to participate. In case of threatened preterm labour,
co-administration of tocolytic drugs was allowed. Nifedipine was used to attenuate uterine
contractions, occasionally complemented by indomethacin in case of continuous uterine
contractions when betamethasone administration was not yet completed. In case of preterm
prelabour rupture of membranes, patients also received antibiotics (erythromycin 250mg 4
times daily during 10 days) as part of the standard treatment protocol. Women were excluded
in case of maternal age <18 years, multiple pregnancy, fetuses with a known congenital
malformation or fetal growth restriction (defined as the estimated weight of the fetus below
the 5th percentile for gestational age).

The following data was gathered prospectively: maternal gravidity and parity, indication for
betamethasone administration, obstetrical and general medical history, gestational age at
inclusion and administered medication during the study period. Follow-up measurements
of study participants lasted from the date of informed consent until five days after the first
measurement, discharge or delivery, whichever occurred first. Postpartum, neonatal charts
were checked for any indications of congenital anomalies that might have influenced the
measurements and for missed cases of growth restriction defined as birth weight below the
5th percentile (corrected for gestational age, parity and sex of the neonate).

Outcome measures
The primary outcome was fetal HRV, which was quantified using both time-domain features
(short-term variability [STV] and long-term variability [LTV]) and frequency-domain features
(LF- and HF-power). As secondary outcomes, we calculated the fetal HR (in beats per minute,
bpm). In addition, based on the HR variance, segments were classified into periods of

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 Betamethasone and fetal heart rate variability, assessed by fetal ECG

quiet state (fetal HR variance <15 bpm2) and periods of active state (fetal HR variance >30
bpm2)4,13,14.

Measurements
We performed series of measurements as visualised in Figure 1. Recordings were obtained
while the patient was lying in a semi-recumbent position, to prevent supine hypotension
syndrome. The duration of a measurement was approximately 30 minutes in pregnancies <34
wG and 45 minutes in pregnancies ≥34 wG, to account for the influence of fetal behavioural
states4. The total measurement was divided in segments of 60 seconds, and per segment HRV
parameters were calculated. The median value of all available segments was used for statisti-
cal analysis.

To reduce the influence of diurnal variations, the timing of measurements within a series was
fixed for each patient (between 20 and 28 hours after the previous measurement). In order
to respect the patient’s night rest, no measurements were performed between 24.00h and
7.00h.

Complete series were defined as series including a reference measurement, and measure-
ments during at least days 1, 2, and 3. In case one or more of these measurements was
missing, the patient was excluded.

8
Figure 1. Flowchart of patient inclusion and timing of measurements.

Patient presenting with threatened preterm delivery

Day 0

Administration of
Administration of
betamethasone, transport from
betamethasone in tertiary care
secondary to tertiary care
hospital
hospital

Day 1: Betamethasone 1st dose + 24h

Day 2: Betamethasone 1st dose + 48h
Day 3: Betamethasone 1st dose + 72h
Day 4: Betamethasone 1st dose + 96h
Day 5: Betamethasone 1st dose + 120h

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 Chapter 8

Reference measurement
Most patients were transferred from secondary care hospitals in the region. Since for these
patients betamethasone treatment was initiated prior to transport, they had no baseline
measurement (0-measurement, on day 0). Former research showed that all changes in fetal
HR and HRV returned to baseline values from day 4 onwards (96 hours after the first dose
of betamethasone)12. Therefore, we included transferred patients if we were able to conduct
a measurement during day 4 or 5 following the first dose of betamethasone. We used the
median value of the measurements during day 0, and/or day 4, and/or day 5 as the “reference
measurement”. By means of a full range plot, we verified whether our reference measurement
was comparable with the real 0-measurement in a separate subset of patients. Included cases
with good quality measurements on day 0, and day 4, and/or day 5 were selected.

Data acquisition and signal processing

The fetal ECG was recorded on six channels, using a fixed configuration on the maternal
abdomen as illustrated in Figure 2. The abdominal signals were recorded by two non-inva-
sive electrophysiological monitoring devices; the Nemo fetal monitor (Nemo Healthcare
BV, Eindhoven, the Netherlands) and the Porti system (TMSi, Enschede, the Netherlands),
operating at sampling rates of 500 Hz and 512 Hz, respectively. Both devices were approved
by the Medical Technical Service Department of the Máxima Medical Centre.

The recordings were analysed offline. Recordings were first pre-processed to suppress the
maternal ECG using a dynamic template subtraction technique15. The signals remaining after
maternal ECG suppression were spatially combined to enhance the signal-to-noise ratio
of the fetal ECG with respect to remaining electrophysiological interferences (e.g. muscle
activity)16,17. Finally, a wavelet-based R peak detection was performed to obtain a beat-to-beat
fetal HR18. In case no R peaks were detected using all six channels, channels with good quality
fetal ECG were selected manually to avoid negative effects on the spatial combination of
those channels that were dominated by interferences.

Prior to HRV analysis, the obtained heart rates were automatically analysed for incorrect R-R
intervals. R-R intervals shorter than 0.3 seconds or longer than 1.2 seconds (<50 or >200
bpm) were assumed to be incorrect18. Furthermore, if an R-R interval deviated more than 12%
from a running average R-R interval, it was also assumed to be incorrect19. The incorrect R-R
intervals were replaced by linear interpolation. To ensure reliable spectral analysis, only heart
rate segments of 60 seconds were included with less than 20% interpolation and less than
five seconds of consecutive interpolation19. We only included measurements with at least
three segments that met the quality criteria.

138
 Betamethasone and fetal heart rate variability, assessed by fetal ECG

Figure 2. The fetal electrocardiogram.

The six channel fetal electrocardiogram is recorded with electrodes on the maternal abdomen, placed
in a fixed configuration. The ground (GND) and reference (REF) electrode are placed near the belly
button. The electrodes are connected to a battery operated data acquisition system (Nemo Healthcare
BV), which filters, amplifies, and digitises the data for further processing. This system is connected to a
computer.

Heart rate variability analysis

Since spectral analysis requires signals that are equidistantly distributed in time, the obtained 8
heart rates are resampled at 4 Hz by linear interpolation. Spectral analysis is performed using
a continuous wavelet transform20. Based on previous studies, the following frequency bands
were selected: total frequency 0.04 - 1.5 Hz, LF 0.04 - 0.15 Hz and HF 0.4 - 1.5 Hz4,6,9,21,22. LF- and
HF-power was expressed in absolute units (ms2) and normalised units (LFn = LF-power/total
power, HFn = HF-power/total power).

In addition to spectral powers, STV and LTV were calculated to compare our results to prior
research performed with CTG measurements. LTV was calculated as the difference between
the maximum and minimum R-R interval in every 60 seconds segment23,24. STV was calculated
as the mean of absolute differences between consecutive R-R intervals in every 60 seconds
segment24. Note that in CTG (ultrasound) monitoring, STV is defined based on epochs (e.g.
1/16th of a minute) because fetal HR is not acquired beat-to-beat. However, since the gold
standard for STV is beat-to-beat variation23, we used the aforementioned ECG-based STV
calculation.

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 Chapter 8

Statistical analysis
Descriptive statistics were used to describe the study population. Statistical analysis was
performed using SPSS software version 23 (IBM Corp., Armonk, NY, USA). For each fetus
a different number of segments were available during the study period, mainly due to
variations in ECG signal quality. Median values and interquartile ranges were calculated for
HR, LTV, STV and the different spectral values (LF, HF, LFn, HFn). The results were plotted over
the four day measurement period. The result on each day was compared to the reference
measurement. Statistical analysis was performed using the Wilcoxon signed-rank test.
Statistical significance was assumed at the two-sided p-value of <0.05.

Results
Initially, 68 women were included in this study. The inclusion process is depicted in Figure
3. Three patients requested withdrawal from the study because of poor prognosis for an
extreme premature child (1), technical issues (1) and inconvenient timing of measurements
for the patient (1). In one patient unexpected intra-uterine fetal death occurred during the
study period. Extensive evaluation revealed no evident cause. In 28 patients we were able
to obtain a complete set of measurements, of which 16 were excluded due to insufficient
data quality (fewer than three good quality segments per measurement) in one or more of
the measurements. Eventually, 12 patients with a complete set of sufficient data quality were
included for analysis. Table 1 shows the patient characteristics of the 12 included cases.

Reference measurement
Measurements during day 0, and/or day 4, and/or day 5 were compared in five patients. In
Figure 4, absolute LF, HF, LFn and HFn are displayed. As expected, the absolute fetal HRV
values showed some inter- and intra-patient variation, which can mainly be explained by
variation in the segments that were recorded during active and quiet states and by variation
in gestational age of the fetuses. LFn and HFn showed rather good comparability during day
0, 4, and 5.

Primary outcome
Our primary outcome was fetal HRV. Figure 5 shows the changes in LTV, STV, absolute LF and
HF and normalised LFn and HFn. Only the increase in HF-power during day 1, compared to
the reference measurement (day 0) was statistically significant (p = 0.025). All other trends
were not statistically significant.

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 Betamethasone and fetal heart rate variability, assessed by fetal ECG

Figure 3. Overview of the inclusion process.

Exclusions: 19
-Congenital anomaly 4
-Cardiac arrhythmia 1
68 inclusions -Fetal growth restriction 1
-Measurements* 7
-No betamethasone administration 6

Drop-out: 21
-Preterm labour 10
-Discharged 7
-Withdrawal 3
-Stillbirth 1

28 complete series of
16 series with insufficient data quality
measurements

12 series with sufficient data quality

* Patients were excluded if the measurements were not performed within the time window (between 20
and 28 hours after the previous measurement), had one or more missing measurement in the series, or
were insufficient in data quality.
8
Figure 4. Verification of the reference measurement.

Median value and full range plot of low-frequency (LF)-power, high-frequency (HF)-power, normalised
LF-power (LFn) and normalised HF-power (HFn) on days 0, and/or day 4, and/or day 5 for five patients.

141
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Chapter 8

Table 1. Patient characteristics and pregnancy outcome.

Birth weight percentile: percentiles are corrected for parity, gestational age at delivery and sex, and apply to the Dutch population. Source: Perined.

Abbreviations: LEEP = loop electrosurgical excision procedure of the cervix, LMWH = low molecular weight heparin, NICU = neonatal intensive
care unit, PE = pre-eclampsia, PPROM = premature prelabour rupture of membranes, TPL = threatened preterm labour, VBL = vaginal blood loss,
wG = weeks of gestation.
 Betamethasone and fetal heart rate variability, assessed by fetal ECG

Figure 5. Changes in fetal heart rate variability parameters during the study period.

The x-axis shows the number of days after the first administration of betamethasone. Day 0 is the median
value of the measurements during day 0, and/or day 4, and/or day 5. The outcomes are depicted as
median values with interquartile ranges.
* ; statistically significant result.

Abbreviations: LF = low-frequency power, LFn = normalised low-frequency power, LTV = long-term varia-
bility, HF = high-frequency power, HFn = normalised high-frequency power, STV = short-term variability.
8
Secondary outcomes
Figure 6 shows the changes in mean fetal HR during the study period. There was a statistical
significant decrease in fetal HR during both day 1 (p = 0.007) and day 3 (p = 0.040), compared
to the reference measurement.

The changes in the number of segments measured during quiet state (fetal HR variance <15
bpm2) and active state (fetal HR variance >30 bpm2) during the study period are displayed
in Figure 7. During days 1 and 2, the number of segments in quiet state increased, while the
number of segments in active state decreased. The number of segments in quiet and active
state seemed to return to pre-medication values again from day 4.

Segments available for analysis

The amount of segments that was available for analysis is displayed in Table 2.

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 Chapter 8

Figure 6. Changes in fetal heart rate during the study period.

* *

The x-axis shows the number of days after the first administration of betamethasone. Day 0 is the median
value of the measurements during day 0, and/or day 4, and/or day 5. Data are shown as median values
with interquartile ranges.
* ; statistically significant result.
Abbreviations: HR = heart rate, BPM = beats per minute.

Figure 7. Changes in periods of quiet and active state.

Percentage of all retrieved
segments

Overview of the changes in periods of quiet state (fetal heart rate variance <15 bpm2) and active state
(fetal heart rate variance >30 bpm2). Results are displayed as a percentage of the total number of
analysed good-quality segments.

Discussion
General discussion
Up to our knowledge, this is the first study to report on the influence of betamethasone on
spectral estimates of fetal HRV measured by non-invasive fetal ECG recordings. As we antic-
ipated, over 80% of our inclusions could not be used in the final analysis. This was mainly
due to loss to follow-up and insufficient data quality. Therefore, our study results should be
interpreted with appropriate caution, since only a limited number of series (12) could be used
for data analysis.

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 Betamethasone and fetal heart rate variability, assessed by fetal ECG

Table 2. Amount of segments available for analysis.

a
Day 0: measurements performed in 3 out of 12 patients.
b
Day 5: measurements performed in 9 out of 12 patients.
On the other study days, measurements were performed in all 12 patients.

Primary outcome measures

We found a similar trend in LTV and STV with fetal ECG analysis as compared to previous
studies that used CTG analysis12. No significant differences were found between the succes-
sive study days. This might be due to the small number of analysed series. A more accurate
way to evaluate autonomic modulation is spectral analysis of the beat-to-beat fetal HR.
LF- and HF-power are absolute spectral estimates, that relate to LTV and STV. As expected,
the same trends are seen during the study period for these parameters. Only the increase in
HF-power on day 1 was statistically significant. No significant changes were seen in LFn and
HFn. Due to normalisation, relative changes in LF- and HF-power are not masked by changes 8
in total power. Both LFn and HFn show little changes during the study period. This indicates
that the influence of autonomic modulation is minor.

Secondary outcome measures

The significant changes seen in fetal HR are unlikely to resemble a clinically important effect,
since the median HR was 144 bpm on the reference day, 138 bpm on day 1, and 142 bpm
on day 3. In prior studies with CTG monitoring, the significant decrease on day 1 was also
observed12.

Figure 7 shows an increase in the number of segments in quiet state, while the number of
segments in active state decreases. As described in a previous study, LF- and HF-power are
significantly lower in the quiet state, compared to the active state25. This can explain the
changes seen in absolute spectral values in our study. In addition, it corresponds with the
reduced fetal motility that patients report during betamethasone treatment26-29. However,
one should take into account that in Figure 7, the amount of available segments is limited and
varies between the study days.
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 Chapter 8

Segments available for analysis

As shown in Table 2, the mean available amount of segments per day was always more
than 50%. One has to bear in mind that this is in selected series with sufficient quality of the
performed measurements. There are no obvious differences between the measurement days;
the amount of available segments is steady between 52% and 57%. Only the measurements
performed on day 0 show a higher percentage of available segments. However, only 3 out of
12 patients were eligible for a measurement during day 0.

Considerations
We defined the reference measurement as the median value of the measurements during day
0, and/or day 4, and/or day 5. Although good comparability was seen for fetal HRV values,
this remains second best with regard to a true baseline measurement. The high number of
measurements that had to be excluded due to poor signal quality, can mainly be explained
by presence of vernix caseosa. This fatty layer surrounds the fetus and results in an electrical
isolation, which diminishes the signal amplitude of the fetal ECG. Especially between 30 and
34 wG, this layer causes a poor signal-to-noise ratio25,30.

By including patients receiving other pregnancy-related drugs rather than betamethasone,

we aimed to obtain information that is applicable in daily clinical practice. Nifedipine and
indomethacin seem to have no clinically important effect on fetal HRV, while magnesium
sulphate can cause decreased fetal HRV and cases of bradycardia have been described31. In
one case, magnesium sulphate was administered during days 1, 2 and 3 of the study period.
Since magnesium sulphate was not administered during the reference measurement, this
might have had some influence on the study results. In one case labetalol was administered
to the patient; this was already started prior to the measurements and no changes in dosage
occurred during the study period. Therefore, it is not likely that this had major influence on
the study results. It is unlikely for augmentin, low-molecular weight heparin, methyldopa
and progesterone to have any influence on fetal HRV parameters due to their mechanism of
action.

Apart from pathological conditions, two major factors that one should consider when
assessing fetal HR patterns are gestational age and fetal behavioural states32. Previous studies
show that gestational age significantly affects the fetal HRV power spectrum, with a gradual
increase in LF- and HF-power during gestation13,25,33. In this study, the included fetuses had a
gestational age varying from 24 to 33 wG. Since we studied fetuses on successive days and
were interested in relative changes in fetal HRV parameters, the influence of the increase in
LF- and HF-power during gestation is likely to be minor. This study demonstrated an increase

146
 Betamethasone and fetal heart rate variability, assessed by fetal ECG

in time spent in the quiet state following betamethasone administration. This might be
caused by disturbance of the maternal glucose metabolism34, which is a known side effect of
corticosteroids.

Fetal HRV and fetal movements are two parameters associated with fetal wellbeing. The
reduction in both, due to betamethasone administration, can be misinterpreted as fetal
deterioration and can therefore possibly lead to unnecessary iatrogenic preterm delivery35,36.
No other signs of fetal hypoxia, like decelerations or abnormalities in Doppler flow velocity
waveforms, have occurred after corticosteroid administration29,35-38. In addition, Shenhav et
al.39 demonstrated that reduced fetal HRV was not related to the fetal acid-base balance at
birth when delivery occurred <48 hours following betamethasone administration. This study
confirms these results, since the influence of autonomic modulation was found to be minor
(reflected as no evident changes in normalised spectral powers during the study period).
Therefore, administration of betamethasone is not related to fetal distress. However, in fetal
monitoring it is important to be aware of the side-effects, such as reduced fetal HRV and fetal
movements.

Conclusion
The changes in fetal HRV following betamethasone administration show the same pattern
when calculated by spectral analysis of the fetal ECG, as when calculated by Doppler-ultra-
sound CTG. The change in absolute spectral values is likely to correspond to the change in
quiet and active state of the fetus. Since normalised spectral values show little changes, the
influence of autonomic modulation is minor.
8

Acknowledgements
This research was performed within the framework of IMPULS perinatology. We would like to
acknowledge Davide Aben, Jasmijn Drinkwaard, Noortje Eijsvoogel, Beatrijs van der Hout-van
der Jagt, Carlijn van den Oord, Marlot Sengers, Kirsten Thijssen and Mariëlle van Wierst for
their contributions in performing the measurements.

147
 Chapter 8

References
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2. Van Ravenswaaij-Arts C, Kollee L, Hopman J, Stoelinga G, van Geijn H. Heart rate variabilitiy. Ann
Intern Med 1993;118:436-447.
3. Dawes GS, Moulden M, Redman CW. Improvements in computerized fetal heart rate analysis
antepartum. J Perinat Med 1996;24(1):25-36.
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variability at near term and post term gestation during active sleep and quiet sleep. Early Hum Dev
2009 Dec;85(12):795-798.
5. van Laar JO, Peters CH, Vullings R, Houterman S, Bergmans JW, Oei SG. Fetal autonomic response to
severe acidaemia during labour. BJOG 2010 Mar;117(4):429-437.
6. van Laar JO, Peters CH, Houterman S, Wijn PF, Kwee A, Oei SG. Normalized spectral power of fetal
heart rate variability is associated with fetal scalp blood pH. Early Hum Dev 2011 Apr;87(4):259-263.
7. Vullings R, Peters C, Andriessen P, Oei S, Wijn P. Monitoring the Fetal Heart Rate and Fetal Electro-
cardiogram: Abdominal Recordings Are As Good As Direct Ecg Measurements. Pediatric Research
2005;58(2):242.
8. Siira SM, Ojala TH, Vahlberg TJ, Jalonen JO, Valimaki IA, Rosen KG, et al. Marked fetal acidosis and
specific changes in power spectrum analysis of fetal heart rate variability recorded during the last
hour of labour. BJOG 2005 Apr;112(4):418-423.
9. Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task
Force of the European Society of Cardiology and the North American Society of Pacing and Electro-
physiology. Circulation 1996 Mar 1;93(5):1043-1065.
10. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at
risk of preterm birth. Cochrane Database Syst Rev 2006 Jul 19;(3):CD004454.
11. Petersen MC, Nation RL, Ashley JJ, McBride WG. The placental transfer of betamethasone. Eur J Clin
Pharmacol 1980 Oct;18(3):245-247.
12. Verdurmen KM, Renckens J, van Laar JO, Oei SG. The influence of corticosteroids on fetal heart rate
variability: a systematic review of the literature. Obstet Gynecol Surv 2013 Dec;68(12):811-824.
13. Karin J, Hirsch M, Akselrod S. An estimate of fetal autonomic state by spectral analysis of fetal heart
rate fluctuations. Pediatr Res 1993 Aug;34(2):134-138.
14. Nijhuis JG, Prechtl HF, Martin CB,Jr, Bots RS. Are there behavioural states in the human fetus? Early
Hum Dev 1982 Apr;6(2):177-195.
15. Vullings R, Peters CH, Sluijter RJ, Mischi M, Oei SG, Bergmans JW. Dynamic segmentation and
linear prediction for maternal ECG removal in antenatal abdominal recordings. Physiol Meas 2009
Mar;30(3):291-307.
16. Vullings R, Peters C, Hermans M, Wijn P, Oei S, Bergmans J. A robust physiology-based source sepa-
ration method for QRS detection in low amplitude fetal ECG recordings. Physiol Meas 2010;31:935-
951.

148
 Betamethasone and fetal heart rate variability, assessed by fetal ECG

17. Warmerdam G, Vullings R, Van Pul C, Andriessen P, Oei SG, Wijn P. QRS classification and spatial
combination for robust heart rate detection in low-quality fetal ECG recordings. Conf Proc IEEE Eng
Med Biol Soc 2013;2013:2004-2007.
18. Rooijakkers MJ, Rabotti C, Oei SG, Mischi M. Low-complexity R-peak detection for ambulatory fetal
monitoring. Physiol Meas 2012 Jul;33(7):1135-1150.
19. Peters C, Vullings R, Bergmans J, Oei G, Wijn P. The effect of artifact correction on spectral estimates
of heart rate variability. Conf Proc IEEE Eng Med Biol Soc 2008;2008:2669-2672.
20. Peters CH, Vullings R, Rooijakkers MJ, Bergmans JW, Oei SG, Wijn PF. A continuous wavelet trans-
form-based method for time-frequency analysis of artefact-corrected heart rate variability data.
Physiol Meas 2011 Oct;32(10):1517-1527.
21. De Beer N, Andriessen P, Berendsen R, Oei S, Wijn P, Bambang Oetomo S. Customized spectral band
analysis compared with conventional Fourier analysis of heart rate variability in neonates. Physiol
Meas. 2004;25:1385-1395.
22. Min SW, Ko H, Kim CS. Power spectral analysis of heart rate variability during acute hypoxia in fetal
lambs. Acta Obstet Gynecol Scand 2002 Nov;81(11):1001-1005.
23. Pardey J, Moulden M, Redman CW. A computer system for the numerical analysis of nonstress tests.
Am J Obstet Gynecol 2002 May;186(5):1095-1103.
24. Magenes G, Signorini MG, Arduini D. Classification of cardiotocographic records by neural networks.
Proc IEEE -INNS-ENNS International Joint Conference on Neural Networks IJCNN 2000;3:637-641.
25. van Laar JO, Warmerdam GJ, Verdurmen KM, Vullings R, Peters CH, Houterman S, et al. Fetal heart
rate variability during pregnancy, obtained from non-invasive electrocardiogram recordings. Acta
Obstet Gynecol Scand 2014 Jan;93(1):93-101.
26. Koenen SV, Mulder EJ, Wijnberger LD, Visser GH. Transient loss of the diurnal rhythms of fetal 8
movements, heart rate, and its variation after maternal betamethasone administration. Pediatr Res
2005 May;57(5 Pt 1):662-666.
27. Rotmensch S, Liberati M, Vishne TH, Celentano C, Ben-Rafael Z, Bellati U. The effect of
betamethasone and dexamethasone on fetal heart rate patterns and biophysical activities. A
prospective randomized trial. Acta Obstet Gynecol Scand 1999 Jul;78(6):493-500.
28. Mulder EJ, Derks JB, Zonneveld MF, Bruinse HW, Visser GH. Transient reduction in fetal activity
and heart rate variation after maternal betamethasone administration. Early Hum Dev 1994
Jan;36(1):49-60.
29. Mulder EJ, Derks JB, Visser GH. Antenatal corticosteroid therapy and fetal behaviour: a randomised
study of the effects of betamethasone and dexamethasone. Br J Obstet Gynaecol 1997
Nov;104(11):1239-1247.
30. Oostendorp TF, van Oosterom A, Jongsma HW. The fetal ECG throughout the second half of
gestation. Clin Phys Physiol Meas 1989 May;10(2):147-160.
31. Verdurmen KM, Hulsenboom AD, van Laar JO, Oei SG. Effect of tocolytic drugs on fetal heart rate
variability: a systematic review. J Matern Fetal Neonatal Med 2016 Nov 8:1-8.

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32. Schneider U, Schleussner E, Fiedler A, Jaekel S, Liehr M, Haueisen J, et al. Fetal heart rate variability
reveals differential dynamics in the intrauterine development of the sympathetic and parasympa-
thetic branches of the autonomic nervous system. Physiol Meas 2009 Feb;30(2):215-226.
33. David M, Hirsch M, Karin J, Toledo E, Akselrod S. An estimate of fetal autonomic state by time-
frequency analysis of fetal heart rate variability. J Appl Physiol (1985) 2007 Mar;102(3):1057-1064.
34. Michaan N, Baruch Y, Topilsky M, Amzalag S, Iaskov I, Many A, et al. The effect of glucose
administration on perceived fetal movements in women with decreased fetal movement, a double-
blinded placebo-controlled trial. J Perinatol 2016 Aug;36(8):598-600.
35. Derks JB, Mulder EJ, Visser GH. The effects of maternal betamethasone administration on the fetus.
Br J Obstet Gynaecol 1995 Jan;102(1):40-46.
36. Subtil D, Tiberghien P, Devos P, Therby D, Leclerc G, Vaast P, et al. Immediate and delayed effects
of antenatal corticosteroids on fetal heart rate: a randomized trial that compares betamethasone
acetate and phosphate, betamethasone phosphate, and dexamethasone. Am J Obstet Gynecol
2003 Feb;188(2):524-531.
37. Cohlen BJ, Stigter RH, Derks JB, Mulder EJ, Visser GH. Absence of significant hemodynamic changes
in the fetus following maternal betamethasone administration. Ultrasound Obstet Gynecol 1996
Oct;8(4):252-255.
38. Senat MV, Minoui S, Multon O, Fernandez H, Frydman R, Ville Y. Effect of dexamethasone and
betamethasone on fetal heart rate variability in preterm labour: a randomised study. Br J Obstet
Gynaecol 1998 Jul;105(7):749-755.
39. Shenhav S, Volodarsky M, Anteby EY, Gemer O. Fetal acid-base balance after betamethasone
administration: relation to fetal heart rate variability. Arch Gynecol Obstet 2008 Oct;278(4):333-336.

150
Betamethasone and fetal heart rate variability, assessed by fetal ECG

151
 Part III

Fetal ECG to prevent asphyxia

154
 Chapter 9

Orientation of the electrical heart axis in

mid-term pregnancy

Kim M.J. Verdurmen, Alexandra D.J. Hulsenboom, Judith O.E.H.

van Laar, Pieter F.F. Wijn, Rik Vullings, S. Guid Oei

Published: European Journal of Obstetrics & Gynecology

and Reproductive Biology. 2016;207:243-246
Letter to the Editor – Brief communication

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 Chapter 9

Introduction
The unique fetal shunting system causes an increased cardiac muscle mass in the right
ventricle1. Cardiac currents initiating each contraction are measured from the outside as the
electrocardiogram (ECG), the main direction of propagation is referred to as the electrical
heart axis. Ventricular depolarisation involves the largest cell mass, yielding the largest ECG
signal. Therefore, the QRS segment amplitude mainly defines the electrical heart axis. Due to
the increased right ventricular mass in fetuses, the electrical heart axis is expected to point
towards the right. This has been confirmed in term fetuses during labour and in neonates
directly postpartum2,3. In contrast, the electrical heart axis of adults points towards the left4.
However, it is well-known that in both adults and newborns the orientation of the electrical
heart axis can vary widely from person to person2.

For term fetuses during labour, the orientation of the electrical heart axis has been described
by Larks et al.3 in the 1960s. Their recording techniques are outdated, and they did not take
the fetal orientation into account. Despite these shortcomings, they already acknowledged
the possibilities of the electrical heart axis to contribute in distinguishing between normal
intra-uterine development, congenital heart disease and fetal distress.

The orientation of the fetal electrical heart axis during gestation has never been described.
The relevance of the electrical heart axis increased, since fetal ECG is used to study fetal
wellbeing more often. The aim of this study is to determine the direction of the fetal electrical
heart axis in mid-term pregnancy.

Materials and Methods

We performed a post-hoc analysis on data of two (prospective) studies, both approved by the
ethical committee of the Máxima Medical Centre5. Informed consent was obtained in both
studies. Women between 18 and 29 weeks of pregnancy, carrying a singleton fetus were
included. Exclusion criteria were maternal age <18 years, multiple pregnancy, any known
fetal congenital anomaly, fetal growth restriction (birth weight <p10 for gestational age) and
women receiving medication known to have any cardiac side effects. The absence of severe
cardiac malformations was confirmed after birth by review of medical charts.

We conducted a single fetal ECG recording of approximately 30 minutes with eight adhesive
electrodes on the maternal abdomen, placed in a fixed configuration (Figure 1). Recordings
were performed using a fetal ECG data acquisition system (Nemo Healthcare BV, the Nether-
lands), operating at a sampling frequency of 1 kHz. The fetal ECG was obtained and analysed
from the abdominal recordings to yield a vectorcardiogram that is normalised for the fetal

156
 Orientation of the electrical heart axis in mid-term pregnancy

Figure 1. Configuration of the electrodes orientation via a series of signal processing

on the maternal abdomen. methods, as depicted in Figure 2 and previously
described in other studies6-10.

From this normalised fetal vectorcardiogram we

obtained the orientation of the electrical heart
axis expressed as degrees ranging from -180
to +180, as the direction in which the vector-
cardiogram has its maximum amplitude. This
direction was defined as the average direction
of dominant vectors in the QRS complex. These
dominant vectors were selected from the
point where the R wave exceeded 70% of its
maximum value for the first time until the point
where the R wave fell below the 70% again11.
Per fetus, a mean value of the orientation of
the electrical heart axis was calculated from
the time period of 50 seconds prior to and 50
seconds following the ultrasound localisation of
the fetus in case of good signal quality (at least
80 fetal ECG complexes).

To enable statistical analysis of our results, we categorised the orientations of the electrical
heart axis. Both in the frontal and left-sagittal plane we defined 12 categories of possible
orientations, the first ranging from 0-30°, the second from 30-60°, and so on. The mean orien-
tation of the electrical heart axis per fetus is displayed in a histogram. Matlab (The Mathworks, 9
Natick, MA) was used to perform the statistical analysis. Kolmogorov-Smirnov test was used to
test whether the distribution of scores was significantly different from a normal distribution. A
p-value ≤0.05 was considered to be statistically significant.

Results
We included a total of 25 pregnant women between 18+1 and 28+1 weeks of gestation.
Patient characteristics and neonatal outcome are summarised in Table 1. There were no cases
of asphyxia or perinatal death. Three pregnancies ended in very preterm labour. Two, at 27+2
and 28+6 weeks respectively, because of vaginal blood loss due to placenta praevia, and
one at 31+3 weeks due to spontaneous preterm labour. The interval between the fetal ECG
recording and the preterm birth was more than three weeks in all cases.

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 Chapter 9

Figure 2. Signal processing steps.

1 2 3
Filtering Enhancement

Multi-channel ECG

Orientation
correction
Electrical
VCG calculation
heart axis 5 4

Ultrasound
information

From top left, via a clockwise rotation to bottom left;

1. The signal is recorded by the electrodes on the maternal abdomen. Note that the large peaks
are maternal QRS complexes, the small peaks that occur approximately twice as frequent as the
maternal QRS are the fetal QRS complexes.

2. The signal obtained after filtering the maternal ECG and other interferences. First, interferences
such as powerline and (uterine) muscle activity were suppressed by bandpass filtering the
recorded signals between 1 and 70 Hz and applying a notch filter that was centered around the
powerline frequency. Second, the maternal ECG was suppressed using a technique that dynami-
cally generates a template of the maternal ECG8 and subsequently subtracts this template from the
recorded data. Third, we detected the individual fetal ECG complexes by firstly spatially combining
the various recorded channels9 and subsequently detecting the fetal QRS complexes using a
low-complexity R peak detection method7.

3. The fetal ECG is enhanced by averaging the ECG across multiple heartbeats, where the number
of heartbeats is dynamically varied by an adaptive Kalman filter and depends on the quality and
stationarity of the ECG signal6. For every electrode an average ECG signal is determined.

4. Using knowledge on the placement of the electrodes, we calculated the fetal vectorcardiogram by
spatial combination of multi-channel fetal ECGs10. In case the fetus would change its orientation in
the uterus, the vectorcardiogram would rotate with the fetus.

5. Rotated version of the fetal vectorcardiogram. To determine the vectorcardiogram in the fetal frame
of reference, similarly as an adult vectorcardiogram would be determined, we performed an ultra-
sound examination to determine the fetal orientation simultaneously with the ECG measurements.
The rotated fetal vectorcardiogram represents a standardised view of the fetal vectorcardiogram
(i.e. as if it were recorded with electrodes placed directly on the fetal body). From the standardised
view, the fetal electrical heart axis is calculated.

Abbreviations: ECG = electrocardiogram, VCG = vectorcardiogram.

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 Orientation of the electrical heart axis in mid-term pregnancy

Table 1. Characteristics of the study population.

Data is presented as mean with standard deviation (±), median with interquartile range (Q1-Q3), or
number with percentage (%).

Abbreviations: BMI = Body Mass Index, GA = Gestational Age, n = number.

Figure 3 presents the observed orientation of the fetal electrical heart axis, which shows a
considerable amount of variation. In the frontal view, the heart axis points towards the right
in most cases. In the left-sagittal view, the heart axis points towards the back in most cases.
The orientation of the electrical heart axis in the frontal view varied significantly from a
normal distribution; p = 0.016, Kolmogorov-Smirnov test. In the sagittal view, the orientation
of the electrical heart axis did not differ significantly from a normal distribution (p = 0.22,
Kolmogorov-Smirnov test). 9
Comment
Although our study population is relatively small, the results are in line with our hypothesis
that the fetal heart axis points towards the right due to the increased mass of the right
ventricle. In term fetuses during labour, the main direction of the fetal heart axis is to the
right (between +100° and +160°)12. In neonates directly postpartum, the QRS axis in the
frontal view varies between +60° and +160° and the vectorcardiogram points mainly to the
right-inferior-anterior direction2,13,14. As the mass of the left ventricle increases with age, the
orientation of the electrical heart axis gradually deviates toward the left. At the age of one
year, the electrical heart axis points to the left (between +10° and +100°)13. Normal values
in adults vary between -30° and +90°4. This all indicates that there is a shifting continuum
between the orientation of the electrical heart axis in fetal, neonatal and adult life.

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 Chapter 9

Figure 3. Histograms of the orientation of the electrical heart axis in 25 healthy fetuses.

For every fetus, the orientation of the electrical heart axis was determined in both the frontal plane
(left histogram) and left-sagittal plane (right histogram). This orientation was subsequently scored in
the corresponding histogram, which were defined by dividing all possible orientations, which range
between -180° and +180°, in 12 bins of each 30° width. The number of counts per bin are displayed by
means of the grey areas in the histogram plots.

In addition, the distribution of orientations of the electrical heart axis in Figure 3 shows that
during mid-term pregnancy, this orientation varies as much as it does in newborns and in
adults. Because the electrical heart axis determines the fetal ECG waveform, it is extremely
important for fetal ECG interpretation that the electrical heart axis is taken into account. Alter-
native direction of the main fetal electrical heart axis has direct consequences for the fetal
ECG.

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 Orientation of the electrical heart axis in mid-term pregnancy

References
1. Kiserud T, Acharya G. The fetal circulation. Prenat Diagn 2004 Dec 30;24(13):1049-1059.
2. Depasquale NP, Burch GE. The Electrocardiogram, Ventricular Gradient and Spatial Vectorcardio-
gram during the First Week of Life. Am J Cardiol 1963 Oct;12:482-493.
3. Larks SD. Estimation of the Electrical Axis of the Fetal Heart. Am J Obstet Gynecol 1965 Jan 1;91:46-
55.
4. Wagner GS, Strauss DG. Marriott’s Practical Electrocardiography. 12th edition ed. Philadelphia:
Lippincott Williams & Wilkins; 2014.
5. van Laar JO, Warmerdam GJ, Verdurmen KM, Vullings R, Peters CH, Houterman S, et al. Fetal heart
rate variability during pregnancy, obtained from non-invasive electrocardiogram recordings. Acta
Obstet Gynecol Scand 2014 Jan;93(1):93-101.
6. Vullings R, de Vries B, Bergmans JW. An adaptive Kalman filter for ECG signal enhancement. IEEE
Trans Biomed Eng 2011 Apr;58(4):1094-1103.
7. Rooijakkers MJ, Rabotti C, Oei SG, Mischi M. Low-complexity R-peak detection for ambulatory fetal
monitoring. Physiol Meas 2012 Jul;33(7):1135-1150.
8. Vullings R, Peters CH, Sluijter RJ, Mischi M, Oei SG, Bergmans JW. Dynamic segmentation and
linear prediction for maternal ECG removal in antenatal abdominal recordings. Physiol Meas 2009
Mar;30(3):291-307.
9. Vullings R, Peters C, Hermans M, Wijn P, Oei S, Bergmans J. A robust physiology-based source sepa-
ration method for QRS detection in low amplitude fetal ECG recordings. Physiol Meas 2010;31:935-
951.
10. Vullings R, Peters CH, Mossavat I, Oei SG, Bergmans JW. Bayesian approach to patient-tailored
vectorcardiography. IEEE Trans Biomed Eng 2010 Mar;57(3):586-595.
11. Lipponen J,A., Gladwell VF, Kinnunen H, Karjalainen PA, Tarvainen MP. The correlation of vector-
cardiographic changes to blood lactate concentration during an exercise test. Biomedical Signal
Processing and Control 2013;8(6):491-499.
12. Larks SD, Larks GG. The electrical axis of the fetal heart: a new criterion for fetal well-being or 9
distress. Am J Obstet Gynecol 1965 Dec 1;93(7):975-983.
13. Goodacre S, McLeod K. ABC of clinical electrocardiography: Paediatric electrocardiography. BMJ
2002 Jun 8;324(7350):1382-1385.
14. Schaffer AI, Beinfield WH. The vectorcardiogram of the newborn infant. Am Heart J 1952
Jul;44(1):89-94.

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 Chapter 10

The electrical heart axis and ST events in

fetal monitoring: a post-hoc analysis following
a multicentre randomised controlled trial

Rik Vullings, Kim M.J. Verdurmen, Alexandra D.J. Hulsenboom,

Stephanie Scheffer, Hinke de Lau, Anneke Kwee, Pieter F.F. Wijn,
Isis Amer-Wåhlin, Judith O.E.H. van Laar, S. Guid Oei

Published: PLoS One. 2017;12(4):e0175823

10

163
 Chapter 10

Abstract
Objective
Reducing perinatal morbidity and mortality is one of the major challenges in modern health
care. Analysing the ST segment of the fetal electrocardiogram was thought to be the break-
through in fetal monitoring during labour. However, its implementation in clinical practice
yields many false alarms and ST monitoring is highly dependent on cardiotocogram assess-
ment, limiting its value for the prediction of fetal distress during labour. This study aims to
evaluate the relation between physiological variations in the orientation of the fetal electrical
heart axis and the occurrence of ST events.

Methods
A post-hoc analysis was performed following a multicentre randomised controlled trial,
including 1097 patients from two participating centres. All women were monitored with ST
analysis during labour. Cases of fetal metabolic acidosis, poor signal quality, missing blood
gas analysis, and congenital heart disease were excluded. The orientation of the fetal electri-
cal heart axis affects the height of the initial T/QRS baseline, and therefore the incidence of
ST events. We grouped tracings with the same initial baseline T/QRS value. We depicted the
number of ST events as a function of the initial baseline T/QRS value with a linear regression
model.

Results
A significant increment of ST events was observed with increasing height of the initial T/QRS
baseline, irrespective of the fetal condition; correlation coefficient 0.63, p <0.001. The most
frequent T/QRS baseline is 0.12.

Conclusion
The orientation of the fetal electrical heart axis and accordingly the height of the initial T/QRS
baseline should be taken into account in fetal monitoring with ST analysis.

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 The electrical heart axis and ST events

Introduction
Fetal asphyxia is associated with severe perinatal morbidity and mortality. The cardioto-
cogram, a simultaneous recording of the fetal heart rate and uterine contractions, is used
worldwide for fetal surveillance. However, the poor specificity of this method has resulted in
increased rates of operative deliveries without a decrease in perinatal mortality or cerebral
palsy1. ST analysis (STAN®, Neoventa Medical AB, Mölndal, Sweden) was introduced in 1992
as a promising technique that analyses the ST segment of the fetal electrocardiogram (ECG),
acquired using an invasive scalp electrode2. ST analysis combined with cardiotocography was
reported to significantly lower the rates of metabolic acidosis3 and operative delivery in two
randomised controlled trials3,4. However, subsequent multicentre trials, including the recently
published large American ST analysis trial, could not reproduce these initial findings5-9. Recent
meta-analyses show conflicting results regarding the decrease in metabolic acidosis, which
indicates the need for more research8,10-13. Meanwhile, Kwee et al.14 reported that the STAN®
monitor gives as many ST events in cases of proven uncompromised fetal condition as in
situations with deteriorating fetal condition. This is countered by the STAN® guidelines that
state that ST events must be ignored when cardiotocography shows a reassuring pattern.
However, the high inter-observer variability in cardiotocogram interpretation makes this
a highly unsatisfying strategy15. The correct interpretation of a method as subjective as the
cardiotocogram determines whether or not to ignore the ST event or to act upon the alarm,
making the success of ST monitoring dependent on cardiotocogram assessment.

Background information and hypothesis

Prior to the introduction of ST analysis, the diagnostic value of the fetal ST segment was clearly
demonstrated in animal studies16-18. Sustained deprivation of oxygen is followed by a surge of
adrenalin to induce glycogenolysis, which is accompanied by an increase of potassium ions in
the myocardial cells19. These potassium ions mainly affect the relaxation phase of the cardiac
cycle and lead to an increase in the T wave amplitude of the fetal ECG20.

STAN® uses this hypoxia-related rise in T wave amplitude in a three-step protocol; 10

1. The T wave amplitude is normalised against the amplitude of the QRS complex (mean of
30 ECG complexes), yielding a T/QRS value.

2. A baseline T/QRS value is determined (median of at least 20 T/QRS values within 20

minutes) to gauge future T/QRS values.

3. New T/QRS values are compared to the baseline.

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In case a T/QRS value exceeds the baseline by 0.05, a baseline ST event is reported. Smaller
exceedings of the baseline can be due to normal beat-to-beat fluctuation in the behaviour of
the heart, which is unrelated to the fetal condition. With regard to the detection of rises in T
wave amplitude due to oxygen deprivation, this alarm protocol seems plausible.

The ECG recorded from the fetal scalp electrode is a one-dimensional presentation of the
electrical activity of the heart. However, the propagation of electrical currents over the
cardiac muscle occurs in all three spatial dimensions. The main direction of this propagation
is referred to as the electrical axis of the heart. The orientation of the electrical heart axis with
respect to the fetal scalp electrode hence affects the shape and amplitude of the recorded
ECG. Similarly, (adult) ECG signals recorded at different locations yield different shapes and
amplitudes, as already demonstrated many years ago21.

It is known that the orientation of the fetal electrical heart axis can vary between +100° and
+160° in mid-term fetuses22 and between +90° and +180° in term fetuses during labour23.
Similar inter-person variation in the orientation of the electrical heart axis is present in
neonates and adults24-27. The STAN® monitor attempts to correct for the orientation of the
electrical heart axis with the first step in its protocol (normalisation). However, the propa-
gation of the electrical currents during the contraction (QRS) phase of the cardiac cycle has
a different orientation than during the relaxation (T) phase. Consequently, normalisation
cannot fully compensate for inter-patient differences in the orientation of the electrical heart
axis. As a result, fetuses for whom the scalp lead is almost perpendicular to the direction of
propagation in the relaxation phase have a very small T wave amplitude, and typically also
low T/QRS values and T/QRS baseline. Similarly, fetuses for whom the electrical heart axis is
oriented in a manner creating a propagation during relaxation almost aligned with the scalp
lead, typically have a high T/QRS value and T/QRS baseline.

When the hypoxia-induced release of potassium ions affects the electrical current in the
relaxation phase in the fetuses with a low T/QRS baseline value, the absolute effect in T wave
amplitude will only be marginal as we look at it from an almost perpendicular direction. In
fetuses with high T/QRS values, the rise in T wave amplitude will be relatively large. Based
on this, we hypothesise that normal fluctuations in the electrophysiological behaviour of
the heart can stay below the 0.05 threshold, in case the scalp lead is oriented more perpen-
dicular to the relaxation currents. Similarly, the hypoxia-related fluctuations in the electrical
behaviour can more easily exceed the 0.05 threshold, when the alignment between the elec-
trical heart axis and scalp lead is axial. We explain this phenomenon in Figure 1. Previously,
Becker et al.28 described that the initial T/QRS baseline is not related to the fetal condition.
The incidence of ST events was stated to be related to the fetal condition3, and therefore not

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 The electrical heart axis and ST events

related to the baseline. This is in contrast with our hypothesis that the STAN® monitor will
raise fewer ST events for fetuses with a low baseline, and more ST events for fetuses with a
high T/QRS baseline.

This paper aims to explain how false ST events can occur, based on normal variations in
human physiology. Based on this explanation, clinicians might be able to make a better
informed decision whether or not to act upon a ST event in case of inconclusive cardiotoco-
gram assessment.

Figure 1. The fetal vectorcardiogram for different orientations of the electrical heart axis.

In the top panels, the electrical currents within the heart during a cardiac cycle are depicted in terms of 10
their vectorcardiogram; ventricular contraction (QRS complex = large loop), relaxation phase (T waves
= small loop). From left to right, the entire vectorcardiogram has been rotated over 10° to simulate a
different orientation of the electrical heart axis. Note that these vectorcardiograms are 3-dimensional
images and the 10° rotation was performed in 3-dimensional space. In the bottom panels, the fetal scalp
electrocardiogram has been calculated by projecting the vectorcardiograms onto the scalp lead. Before
rotation, the baseline T/QRS is 0.05 and the T/QRS rise resulting from hypoxia is 0.04, yielding no ST event.
After rotation, the baseline T/QRS is 0.09 and the T/QRS rise resulting from the same level of hypoxia is
0.06, yielding a ST event.

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Materials and Methods

We performed a post-hoc analysis with data derived from a large multicentre randomised
controlled trial, the Dutch ST analysis trial7. The initial study was approved by the Institutional
Review Board of the University Medical Centre Utrecht and was performed between January
2006 and July 2008. After written informed consent, women were randomised to the index
group with ST monitoring (STAN® S21 or S31 monitor) or to the control group, using a conven-
tional fetal heart rate monitor (cardiotocography). The randomisation was performed on a
1:1 basis, web-based with stratification for centre and parity. Since the trial was pragmatic
in nature, there was no blinding of patients or caregivers. All gynaecologists, residents and
midwives in the participating centres were trained and certified as STAN®-users, and decisions
were made following the STAN® clinical guidelines. Fetal blood sampling was allowed, yet
restricted to specific scenarios in the index group. Inclusion criteria were maternal age over
18 years, singleton pregnancy, cephalic presentation, gestational age beyond 36 weeks and
an indication for internal electronic fetal monitoring. The included women were assigned
to a “high-risk pregnancy” group, since they all received secondary care. In the Netherlands,
“low-risk pregnancies” are monitored by midwives or general practitioners (primary care).
In both groups, the umbilical cord was double clamped immediately after birth, in order to
sample both arterial and venous cord blood.

For this post-hoc analysis, we included data from two tertiary hospitals: the University
Medical Centre Utrecht and the Máxima Medical Centre Veldhoven, both participating in the
multicentre randomised controlled trial. Anonymised information from the initial database
was used for this analysis. Following consultation of the Medical Ethical Department in the
Máxima Medical Centre, no separate ethical approval was warranted for this study. We only
included patients from the index group (with ST monitoring). We excluded patients in whom
no STAN® registration was performed or no T/QRS baseline value could be determined, cases
of metabolic acidosis, cases in which no blood gas analysis was performed postpartum and
registrations performed in fetuses with congenital heart disease. Metabolic acidosis was
defined as umbilical cord artery blood pH <7.05 and base deficit of the extracellular fluid
compartment >12 mmol/l in two blood samples with a minimal pH difference of 0.03. In cases
of only one blood sample or smaller differences between samples, metabolic acidosis was set
as cord blood pH <7.10 and base deficit of extracellular fluid >12 mmol/l.

The initial baseline T/QRS value was determined the same way as done in the STAN®
monitor; as the median of all T/QRS values recorded within the first 20-minute window of
the recording, that contained a minimum of 20 T/QRS values. We counted the incidence of ST
events throughout the entire registration. Patients were excluded in case a STAN® registration

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 The electrical heart axis and ST events

was temporarily stopped and more than one STAN® file was stored for the patient. For each
initial baseline T/QRS value encountered in our data set, we counted the number of patients
with that particular baseline. We grouped women with the same initial baseline T/QRS value.
Hereafter, we calculated the relative incidence of ST events (defined as the number of ST
events per 1000 T/QRS values) as a function of the initial baseline value.

Additionally, we calculated the mean pH and mean base deficit of the extracellular fluid
for all women with the same initial baseline T/QRS value. Even though our dataset entails a
subset of the data used by Becker et al.28, it needs to be confirmed that the conclusions from
this study, that the height of the initial baseline is not related to fetal outcome, apply to our
dataset as well.

Matlab (The Mathworks, Natick, MA) was used to perform the statistical analysis. For analysis
of the baseline characteristics, mean, median, standard deviation and interquartile ranges
were calculated using IBM SPSS statistics 22.0 for Mac (IBM corp. Armonk, NY, USA). A linear
regression model was used to calculate the correlation coefficient for the relation between
the number of ST events and the baseline T/QRS value.

Results and Discussion

Initially, 1401 patients were screened; in 273 cases ST information was missing, more than
one STAN® file was available for the same patient, or no T/QRS baseline value had been deter-
mined due to short duration of the measurement or poor quality of the data. These cases were
therefore excluded. In addition, we excluded 11 cases of fetal metabolic acidosis. Further, no
blood sample was available in 12 patients, whom were therefore excluded. In addition, six
women gave birth to neonates with congenital heart disease, one labouring woman younger
than 18 years and one prior to 36 weeks of gestation during labour were excluded. Eventually,
we analysed the number of ST events in 1097 women. In this group, a total of 1.027.054 T/QRS
ratios and 2066 ST events were reported. 10
The baseline characteristics of the included women are summarised in Table 1.

Figure 2 shows the distribution of patients across the various initial baseline T/QRS ratios. In
Figure 3, we present the number of ST events as a function of the initial baseline T/QRS value.
The results show an average increment of 1.42 ST events per 1000 T/QRS values for a rise of
0.1 of the initial baseline T/QRS. The correlation coefficient between data points and fit was
0.63 (p <0.001), as calculated with the linear regression model.

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Table 1. Baseline characteristics of the included patients.

Abbreviations: IQR = interquartile range, MMC = Máxima Medical Centre, SD = standard deviation, UMCU
= University Medical Centre Utrecht.

In Figure 4, we present the pH of the arterial cord blood and base deficit of the extracellu-
lar fluid as a function of the initial baseline T/QRS value. The results show no dependency
between pH and base deficit on the one hand, and height of the initial baseline on the other
hand. The non-significant correlation coefficient between pH and initial baseline height and
between base deficit and baseline height was -0.04 (p = 0.14) and 0.03 (p = 0.34), respectively.
These results are in line with the results of Becker et al.28.

This study suggests that variations in the orientation of the fetal electrical heart axis affect the
height of the initial T/QRS baseline and that the height of this baseline determines the occur-
rence of ST events. This finding could explain for the false ST events that are experienced in
everyday clinical practice.

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 The electrical heart axis and ST events

Figure 2. Distribution of patients across the baseline T/QRS values.

For each initial baseline T/QRS value encountered in our data set, we counted the number of patients
with that particular baseline, showing a non-symmetric distribution with the most frequent encountered
baseline T/QRS ratio at 0.12.

Our aim was to demonstrate that ST events can occur due to normal variations in human
physiology; due to variation in electrical fetal heart axis. Therefore, we chose to exclude all
cases of metabolic acidosis in this post-hoc analysis. The ST events included in our study were
therefore not related to fetal distress.

The distribution of initial T/QRS baseline values in Figure 2 shows that relatively high baselines
are encountered more often than low baselines. Since high baselines are hypothesised to
lead to false positive ST events (i.e. alarms while good fetal condition) and low baselines
are hypothesised to lead to false negative ST events (i.e. no alarms while compromised fetal
condition), this distribution of baseline values can explain why more false positive than false 10
negative ST events are encountered in clinical practice. Since higher baselines do not relate to
higher incidences of fetal distress (see Figure 4 and Becker et al.28) and considering the large
patient population we analysed, we conclude that the presented results support our hypoth-
esis. In other words, some fetuses have a relatively high probability of getting ST events and
some fetuses have a relatively low probability, irrespective of their condition. Whether the
relatively low probability of getting ST events in case of low initial T/QRS baseline indeed
leads to more false negative ST events needs to be confirmed on a dataset including more
cases of metabolic acidosis.

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Figure 3. The number of ST events per 1000 T/QRS values as a function of the initial baseline
T/QRS value.

Cases with the same initial baseline T/QRS were grouped. The intensity of the black colour of the data
points relates to the total number of T/QRS ratios that occurred in the group (right column in the graph).
The red line represents a linear fit through the data points. There is an average increment of 1.42 ST events
per 1000 T/QRS values for a rise of 0.1 of the initial baseline T/QRS. The correlation coefficient between
data points and fit was 0.63 (p <0.001), as calculated with the linear regression model.

Figure 4. The pH of arterial cord blood and base deficit of the extracellular fluid as a function
of the initial baseline T/QRS value.

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 The electrical heart axis and ST events

Cases with the same initial baseline T/QRS value were grouped. The intensity of the black colour of the
data points relates to the total number of patients that were represented in the group (right column in
the graph). The red line represents a linear fit through the data points. The fit suggests a reduction in the
pH of 0.0009 and an increase in the base deficit of 0.03 for a rise in 0.1 of the initial baseline T/QRS. The
respective correlation coefficients between data points and fit are -0.04 (p = 0.14) and 0.03 (p = 0.34), as
calculated with the linear regression model.

Abbreviations: BDecf = base deficit in the extracellular fluid, pHart = pH of the arterial cord blood.

In addition, we propose that ST events are unreliable in case of high or low baseline T/QRS
values. In case of an average T/QRS baseline value, the incidence of false ST events will be
lower. When using the STAN® monitor in clinical practice, clinicians should be aware of this
limitation. In case of inconclusive cardiotocogram assessment in combination with a high
or low baseline T/QRS, fetal blood sampling can be used for complementary diagnostic
information. However, the additional value of fetal blood sampling is uncertain and repeated
fetal blood sampling is an independent risk factor for caesarean delivery29. In case of average
baseline T/QRS, ST events can be considered more reliable and could be considered as
complementary diagnostic information. ST analysis based on relative elevations of the T/QRS
ratio with respect to the baseline or standardised non-invasive fetal ECG recordings30 might
be feasible solutions that warrant further research. In addition, the relation between signal
quality and T/QRS reliability needs to be explored in future research, including analysis of the
effects of signal quality of small variations in the ECG that are caused by e.g. rotation of the
fetal head at the end of labour.

Conclusions
This study showed a significant increment of ST events with increasing height of the initial
T/QRS baseline; correlation coefficient 0.63, p <0.001. The orientation of the fetal electrical
heart axis affects the height of the T/QRS baseline, and therefore the incidence of ST events.
This should be taken into account in fetal monitoring with ST analysis.
10
Acknowledgements
We would like to thank Professor K.G. Rosén for his valuable input.

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References
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4. Westgate J, Harris M, Curnow JS, Greene KR. Plymouth randomized trial of cardiotocogram only
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5. Ojala K, Vaarasmaki M, Makikallio K, Valkama M, Tekay A. A comparison of intrapartum automated
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6. Vayssiere C, David E, Meyer N, Haberstich R, Sebahoun V, Roth E, et al. A French randomized
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8. Schuit E, Amer-Wahlin I, Ojala K, Vayssiere C, Westerhuis ME, Marsal K, et al. Effectiveness of elec-
tronic fetal monitoring with additional ST analysis in vertex singleton pregnancies at >36 weeks of
gestation: an individual participant data metaanalysis. Am J Obstet Gynecol 2013 Mar;208(3):187.
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9. Belfort MA, Saade GR, Thom E, Blackwell SC, Reddy UM, Thorp JM,Jr, et al. A Randomized Trial of
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10. Blix E, Brurberg KG, Reierth E, Reinar LM, Oian P. ST waveform analysis versus cardiotocography
alone for intrapartum fetal monitoring: a systematic review and meta-analysis of randomized trials.
Acta Obstet Gynecol Scand 2016 Jan;95(1):16-27.
11. Neilson JP. Fetal electrocardiogram (ECG) for fetal monitoring during labour. Cochrane Database
Syst Rev 2015 Dec 21;(12):CD000116.
12. Saccone G, Schuit E, Amer-Wahlin I, Xodo S, Berghella V. Electrocardiogram ST Analysis During
Labor: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Obstet Gynecol
2016 Jan;127(1):127-135.
13. Vayssiere C, Ehlinger V, Paret L, Arnaud C. Is STAN monitoring associated with a significant decrease
in metabolic acidosis at birth compared with cardiotocography alone? Review of the three
meta-analyses that included the recent US trial. Acta Obstet Gynecol Scand 2016 Oct;95(10):1190-
1191.
14. Kwee A, Dekkers AH, van Wijk HP, van der Hoorn-van den Beld CW, Visser GH. Occurrence of
ST-changes recorded with the STAN S21-monitor during normal and abnormal fetal heart rate
patterns during labour. Eur J Obstet Gynecol Reprod Biol 2007 Nov;135(1):28-34.
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15. Westerhuis ME, van Horen E, Kwee A, van der Tweel I, Visser GH, Moons KG. Inter- and intra-observer
agreement of intrapartum ST analysis of the fetal electrocardiogram in women monitored by STAN.
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18. Westgate JA, Bennet L, Brabyn C, Williams CE, Gunn AJ. ST waveform changes during repeated
umbilical cord occlusions in near-term fetal sheep. Am J Obstet Gynecol 2001 Mar;184(4):743-751.
19. Fenn W. The deposition of potassium and phosphate with glycogen in rat livers. J Biol Chem
1939;128:297-308.
20. Rosén K, Isaksson O. Alterations in Fetal Heart Rate and ECG Correlated to Glycogen, Creatine
Phosphate and ATP Levels during Graded Hypoxia. Biol Neonate 1976;30:17-24.
21. Einthoven W, Fahr G, De Waart A. On the direction and manifest size of the variations of potential in
the human heart and on the influence of the position of the heart on the form of the electrocardio-
gram. Am Heart J 1950 Aug;40(2):163-211.
22. Verdurmen KMJ, Hulsenboom ADJ, van Laar JOEH, Wijn PFF, Vullings R, Oei SG. Orientation of the
electrical heart axis in mid-term pregnancy. Eur J Obstet Gynecol Reprod Biol 2016.
23. Larks SD. Estimation of the Electrical Axis of the Fetal Heart. Am J Obstet Gynecol 1965 Jan 1;91:46-
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24. Wagner GS, Strauss DG. Marriott’s Practical Electrocardiography. 12th edition ed. Philadelphia:
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25. Goodacre S, McLeod K. ABC of clinical electrocardiography: Paediatric electrocardiography. BMJ
2002 Jun 8;324(7350):1382-1385.
26. Depasquale NP, Burch GE. The Electrocardiogram, Ventricular Gradient and Spatial Vectorcardio-
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28. Becker JH, Kuipers LJ, Schuit E, Visser GH, Van Den Akker ES, Van Beek E, et al. Predictive value of the 10
baseline T-QRS ratio of the fetal electrocardiogram in intrapartum fetal monitoring: a prospective
cohort study. Acta Obstet Gynecol Scand 2012 Feb;91(2):189-197.
29. Holzmann M, Wretler S, Cnattingius S, Nordstrom L. Neonatal outcome and delivery mode in labors
with repetitive fetal scalp blood sampling. Eur J Obstet Gynecol Reprod Biol 2015 Jan;184:97-102.
30. van Laar JO, Warmerdam GJ, Verdurmen KM, Vullings R, Peters CH, Houterman S, et al. Fetal heart
rate variability during pregnancy, obtained from non-invasive electrocardiogram recordings. Acta
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Relative versus absolute rises in T/QRS ratio:

a case-control study

Alexandra D.J. Hulsenboom, Kim M.J. Verdurmen, Rik Vullings,

M. Beatrijs van der Hout – van der Jagt, Anneke Kwee,
Judith O.E.H. van Laar, S. Guid Oei

Submitted for publication

11

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Abstract
Introduction
Conflicting results have been reported regarding the additional value of ST analysis during
labour. In ST analysis, a T/QRS baseline value is calculated from the fetal electrocardiogram
and successive T/QRS ratios are compared to this baseline. Variation in the orientation of the
electrical heart axis between fetuses yields different T/QRS baseline values. In case of a higher
T/QRS baseline value more ST events are encountered, irrespective of perinatal outcome. We
hypothesised that we can partly correct for this effect by analysing T/QRS rises as a percent-
age from baseline (relative ST analysis). This study aims to explore whether relative ST analysis
improves the diagnostic characteristics of ST analysis to detect metabolic acidosis.

Material and Methods

A case-control study was performed in 20 term human fetuses during labour; 10 cases (cord
artery pH <7.05) and 10 controls (cord artery pH >7.20) were included. The fetal electrocardi-
ogram was recorded using a STAN® monitor. We extracted all baseline and episodic ST alarms,
T/QRS values, and calculated the relative T/QRS changes. The cut-off for relative ST alarms was
determined in a receiver operator characteristic (ROC) curve at optimal specificity. Parameters
of interest were area under the curve of the ROC curve for relative ST alarms and test charac-
teristics of both conventional and relative ST analysis.

Results
Relative ST analysis showed an area under the curve of 0.99 (95% confidence interval 0.96-
1.00). The optimal cut-off value for relative T/QRS rise was determined at 0.70. Relative vs
conventional ST analysis showed a specificity of 100% vs 40% (p = 0.031); sensitivity 90% vs
90%; positive likelihood ratio infinity vs 1.5; negative likelihood ratio 0.10 vs 0.25, respectively.

Conclusion
In this study relative ST analysis provides a good distinctive value for metabolic acidosis,
with better specificity and comparable sensitivity in comparison to conventional ST analysis.
Relative ST analysis seems to be a promising method to detect metabolic acidosis during
labour. However, further research and validation are highly recommended.

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 Relative versus absolute rises in T/QRS ratio

Introduction
Due to poor specificity of cardiotocography (CTG), which is used for fetal monitoring during
labour, unnecessary caesarean deliveries are performed without improvement in long-term
neonatal outcome1. ST analysis of the fetal electrocardiogram (ECG) was introduced in the
1990s as a promising technique to accurately detect metabolic acidosis and improve perinatal
outcome2. Two large randomised trials (RCTs), both comparing CTG monitoring to CTG moni-
toring plus ST analysis, showed promising results with a decrease in metabolic acidosis3 and
operative deliveries2,3. Subsequent RCTs did not confirm these results4-7, and meta-analyses
report conflicting results8-12.

The physiological basis for ST analysis was found in sheep studies. Rosén et al.13-15 found
that hypoxia in fetal lambs leads to an adrenalin surge in the fetal heart, resulting in local
glycogenolysis and potassium release. This local increase in potassium ions leads to an
increase in T wave amplitude in the fetal ECG13,15,16. In ST analysis (STAN®, Neoventa Medical
AB, Mölndal, Sweden), the T wave amplitude is normalised against the QRS amplitude,
resulting in the T/QRS ratio. In case there is a rise in T/QRS ratio, an alarm is generated. The
STAN® method discriminates three types of events (alarms): episodic, baseline, and biphasic
events. Biphasic ST events will not be considered in this paper.

The relevance of a ST event depends on the visual assessment of the CTG. In case the CTG
is classified as normal, all ST events given by the STAN® monitor can be ignored17-19. In this
case, the ST event can be classified as a false event. In clinical practice, these false events
are encountered frequently20. In case the CTG is classified as suboptimal or abnormal, ST
events are considered to be significant and a clinical intervention should be prompted19.
The dependence on subjective CTG interpretation, which is known to have a large inter- and
intra-observer variability1,21, has a negative impact on the practical value of ST analysis.

Previously, we described a physiological explanation for false ST events. We demonstrated

that the orientation of the fetal electrical heart axis varies considerably between fetuses22. The
relation between the orientation of the electrical heart axis and the orientation of the scalp
electrode, yields different T/QRS baseline values, due to differences in ECG morphology. We
found that fetuses with a higher T/QRS baseline are more prone to ST events, independent
of the fetal condition23. In contrast, we found that fetuses with a lower T/QRS baseline are 11
less prone to exceed the threshold for a ST event. Becker et al.24 described that higher T/QRS
baseline values are not related to poor neonatal outcome or hypoxia. In other words, it is
expected that a high initial T/QRS baseline increases the incidence of false positive ST events
and that a low initial T/QRS baseline increases the incidence of false negative ST events.

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Both the T/QRS baseline value and the rise in T wave amplitude are affected by the
orientation of the electrical heart axis. We hypothesise that analysing relative, rather than the
conventional, “absolute” T/QRS rises from baseline, could improve the diagnostic value of ST
analysis. In case of relative ST analysis (T/QRS rises as a percentage from baseline), there is a
correction for the “ease” of increment of the T wave amplitude. In conventional ST analysis,
an absolute rise in T/QRS value will lead to an event; irrespective of the height of the T/QRS
baseline. This study aims to explore whether relative ST analysis has a distinctive value in
detecting metabolic acidosis. In addition, we aim to compare the test characteristics of both
relative and absolute ST analysis. This is the first study that describes relative ST analysis.
In order to directly compare both methods, we only focussed on objective information.
Therefore, we omitted subjective CTG interpretations.

Material and Methods

Patient inclusion
We performed a case-control study on a dataset collected by van Laar et al.25. We included
fetuses of at least 36 weeks of gestation with intrapartum fetal ECG recordings, whose arterial
and venous umbilical cord blood gasses were determined directly after birth. The included
mothers were healthy, had an uncomplicated pregnancy and did not use any medication
except oxytocin or epidural analgesia. Only good quality fetal ECG recordings were included,
defined as absence of ectopic beats and no missing data in the last 10 minutes before birth.
We excluded fetuses with fetal growth restriction (defined as birth weight below the 10th
percentile) and congenital heart disease.

Cases had an arterial cord pH <7.05 and controls had an arterial cord pH >7.20. Cases were
consecutively selected between January 2006 and December 2007 in the Máxima Medical
Centre, Veldhoven, the Netherlands. As a result of the strict inclusion and exclusion criteria,
only five fetuses with acidemia could be included. In addition, five fetuses with acidemia
from the University Medical Centre Utrecht, the Netherlands were selected between January
2001 and July 2002. Both hospitals are tertiary-care teaching hospitals. The ten controls
were consecutively selected between January 2007 and August 2007 in the Máxima Medical
Centre, Veldhoven, the Netherlands.

Data acquisition and signal processing

Fetal ECG recordings were obtained during labour with a single helix scalp electrode
(Goldtrace™), a maternal skin electrode, and a STAN S31® monitor (Neoventa Medical AB,
Mölndal, Sweden). For every heartbeat, the STAN® detects an ECG complex. After 30 good
quality ECG complexes, an average ECG complex (aECG) is calculated. This aECG is used to

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determine the amplitudes of the T wave and QRS complex which, in turn, are used to calculate
the T/QRS ratio. For every registration, we extracted all T/QRS ratios.

In absolute ST analysis, first a T/QRS baseline is determined. Following T/QRS ratios are
compared to this baseline and in case they exceed the baseline by 0.05 for at least 10
minutes16, a baseline ST event is generated. When the T/QRS ratio exceeds the baseline by
0.10 within 10 minutes, an episodic ST event is generated. We used the “event log” window
in the STAN® viewer software (Neoventa) to determine whether baseline and episodic ST
events occurred. For relative ST analysis, instead of assessing the difference between T/QRS
ratios and the baseline, we calculated the quotient. We defined the baseline via a two-step
procedure, which is similar to the STAN® method. First, for every T/QRS ratio the median over
the last 20 preceding T/QRS ratios was calculated. Second, the T/QRS baseline was defined
as the minimum value of this median T/QRS ratio within a three hour window preceding the
current T/QRS ratio. In case the 20 preceding T/QRS ratios did not fall within a 20-minute
window from the current T/QRS ratio, we classified the signal as low quality and did not
update the baseline.

As mentioned previously, we want to assess the test characteristics of absolute and relative
ST analysis in a cohort of 10 cases and 10 controls. Ideally, for cases both methods give at
least one ST event. For controls, both methods should give no ST events. Hence, in this study
we analysed whether the largest rise from baseline exceeds the absolute and/or the relative
threshold for generating an event. In case the largest rise does not exceed the threshold, none
of the other T/QRS ratios will trigger an event. In case the largest rise exceeds the threshold,
at least one event was triggered. Based on whether the patient was a case or a control, we
classified the event as true or false.

Outcome measures
The primary outcome was neonatal acidosis, defined as umbilical artery pH <7.05. Secondary
outcomes were neonatal intensive care admission and 5 minute Apgar scores. Relative and
absolute ST analysis were compared with respect to sensitivity (Sn), specificity (Sp), positive
likelihood ratio (LR+) and negative likelihood ratio (LR-).

Statistical analysis 11
Baseline characteristics were compared with a Mann-Whitney U test for continuous variables
and a Fisher exact test for categorical variables. To determine the optimal threshold for
relative ST analysis, the largest rise from baseline per patient was plotted in a receiver
operating characteristic curve (ROC curve) in SPSS 22 for Mac (IBM corp. Armonk, NY, USA).
The threshold to predict neonatal acidosis was determined at the optimal cut-off in the ROC

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curve (the point closest to 0.1). This threshold was subsequently used to compute other test
characteristics. We used a McNemar test to compare true positives and true negatives. A
p-value <0.05 was considered statistically significant.

Results
Baseline characteristics
For all 20 fetuses, good quality ECG data were available until nine minutes before birth. In
nine fetuses (four cases, five controls), fetal ECG data could be obtained until the last minute
before birth. Table 1 shows the baseline characteristics of the included patients. Significant
differences were found between both groups regarding the frequency of fetal blood sampling,
Apgar score after 1 minute, Apgar score after 5 minutes, umbilical cord artery and venous pH
and umbilical artery base excess.

Relative versus absolute ST analysis

Figure 1 shows the ROC curve for relative ST analysis. The area under the ROC curve for
relative T/QRS ratio changes in this population was 0.99 (p <0.001; 95% CI 0.96-1.00), with a
standard error of 0.016. The cut-off value was determined at a relative T/QRS rise of 0.70.

We compared the test characteristics of absolute and relative ST analysis in our study popu-
lation (Table 2). Sensitivity was equal for both methods, while specificity, LR+, and LR- were
better for relative ST analysis.

Table 3 shows the number of correctly defined patients. When using a cut-off value of 0.70
as threshold for relative ST analysis, the detection of healthy fetuses is significantly better
in comparison to absolute ST analysis (p = 0.031). We did not find significant differences
between both methods to discriminate in neonatal hospital admission or Apgar score <7 at
5 minutes.

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 Relative versus absolute rises in T/QRS ratio

Table 1. Baseline characteristics and outcome of included patients.

a
= Fisher exact test
b
= Mann-Whitney U test

Abbreviations: BE = base excess, CS = caesarean section, FBS = fetal blood sampling, GA = gestational
age, NICU = neonatal intensive care unit, NS = not significant, α = 0.05, SD = standard deviation,
VE = vacuum extraction.

Table 2. Test characteristics of absolute and relative ST analysis.

*: cut-off value 0.70

Abbreviations: CI = confidence interval, LR+ = positive likelihood ratio, LR- = negative likelihood ratio, 11
Sn = sensitivity, Sp = specificity.

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Table 3. Number of correctly defined patients.

* Significance was set as α = 0.05

Abbreviations: MC = medium care, NICU = neonatal intensive care unit.

Figure 1. ROC curve of relative ST analysis.

Discussion
ST analysis is used to obtain additional information regarding the fetal condition during
labour. In current clinical practice, absolute ST analysis has a good sensitivity, but is known
to generate false events20. The aim of this study was to explore whether relative ST analysis
has a distinctive value in detecting metabolic acidosis, while restricting the number of false
events. This study demonstrates that relative ST analysis can identify fetuses with metabolic

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 Relative versus absolute rises in T/QRS ratio

acidosis at birth, as evidenced by the high AUC in the ROC curve. To explore whether relative
ST analysis could be a solution for the false events encountered currently, we compared
the test characteristics of both relative and absolute ST analysis. In the studied population,
relative ST analysis showed to be superior in specificity, LR+ and LR-. Sensitivity was equal in
both methods.

Neonatal hospital admission and low 5 minute Apgar score prevalence were low in our popu-
lation. Nevertheless, we can observe a non-significant trend that relative ST analysis is more
accurate in detecting false events; relative ST analysis is better in correctly defining patients
with no hospital admission and a good Apgar score (>7 at 5 minutes). However, hospital
admission and low Apgar score can both be caused by numerous other factors that are not
necessarily related to acidosis, such as neonatal infection, respiratory insufficiency, meconium
aspiration, and so on. Therefore, these factors should be assessed taking the abovementioned
in consideration.

In absolute ST analysis, false events are encountered regularly20. This could lead to alarm
fatigue, which can have life threatening consequences in the labour room. This study shows
that ST monitoring is capable of identifying fetuses with acidosis without many false events,
once one corrects for the orientation of the electrical heart axis.

In clinical practice, ST analysis is used in addition to CTG and therefore, the effect of false
events can be limited by strict CTG interpretation. However, CTG interpretation is known
to have a high intra- and inter-observer variability1,21. This can lead to different decisions
regarding obstetric management following the same objective information.

As previously described, biphasic events were not evaluated in this study. The aim of our
study was to compare baseline dependent ST events, since these are known to be related to
the orientation of the electrical heart axis23. In addition, a recent study showed that biphasic
events do not discriminate in the prediction of fetal distress or adverse outcome26.

The difference between absolute and relative ST analysis is based on different analyses of
the same raw data. In both methods the fetal ECG is acquired by a fetal scalp electrode, and
thus invasiveness of the technique is equal for patients. In addition, there is no difference in 11
application or work load for the obstetric caregiver.

Although the results from this first study describing relative ST analysis are promising, there
are some important limitations. This study was designed as a case-control study, to determine
if relative ST analysis could detect metabolic acidosis with a high sensitivity and low number

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of false events (high specificity). As a result of this study design, we did not evaluate the full
spectrum of patients. Only cases with evident metabolic acidosis and controls with normal
blood gas values at birth were included. A middle group with a pH between 7.05 and 7.20
is missing, while this group represents the majority of neonates born in clinical practice. In
addition, the studied sample size was small; 10 cases and 10 controls. This can be explained
by the low prevalence of metabolic acidosis (0.1-1%)3-7, combined with our strict inclusion
criteria (availability of good quality fetal ECG recordings until at least 10 minutes before birth
and availability of umbilical cord blood gasses).

Taken the limitations of our study into account, validity of relative ST analysis should be
evaluated in a larger patient group, including the full spectrum of perinatal outcome. This
allows to determine a more reliable and representative threshold value for relative ST analysis.
Subsequently, this threshold needs to be validated in a different group of patients. We expect
that the test characteristics of relative ST analysis determined in the latter group will be
slightly less optimistic as those presented in the current work. In addition, only patients with
good quality fetal ECG recordings and available umbilical cord blood gasses were included
in this study. In following studies these conditions are likely to be less optimal, which might
influence the test characteristics. Future studies could also focus on non-invasive abdominal
registration of the fetal ECG, since this can also be used for fetal monitoring during pregnancy,
before the onset of labour.

Conclusion
This study shows that relative T/QRS analysis provides a good distinctive value to detect
metabolic acidosis during labour. In comparison to conventional absolute ST analysis, relative
ST analysis shows better specificity with a comparable sensitivity. Therefore, relative ST
analysis is a promising method for monitoring of fetal wellbeing during labour and needs to
be studied in a larger population.

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 Relative versus absolute rises in T/QRS ratio

References
1. Alfirevic Z, Devane D, Gyte GM. Continuous cardiotocography (CTG) as a form of electronic fetal
monitoring (EFM) for fetal assessment during labour. Cochrane Database Syst Rev 2013 May
31;(5):CD006066.
2. Westgate J, Harris M, Curnow JS, Greene KR. Plymouth randomized trial of cardiotocogram only
versus ST waveform plus cardiotocogram for intrapartum monitoring in 2400 cases. Am J Obstet
Gynecol 1993 Nov;169(5):1151-1160.
3. Amer-Wåhlin I, Hellsten C, Noren H, e.a. Intrapartum fetal monitoring: cardiotocography versus
cardiotocography plus ST analysis of the fetal ECG: a Swedish randomised controlled trial. Lancet
2001;358:534– 538.
4. Belfort MA, Saade GR, Thom E, Blackwell SC, Reddy UM, Thorp JM,Jr, et al. A Randomized Trial of
Intrapartum Fetal ECG ST-Segment Analysis. N Engl J Med 2015 Aug 13;373(7):632-641.
5. Ojala K, Vaarasmaki M, Makikallio K, Valkama M, Tekay A. A comparison of intrapartum automated
fetal electrocardiography and conventional cardiotocography--a randomised controlled study.
BJOG 2006 Apr;113(4):419-423.
6. Vayssiere C, David E, Meyer N, Haberstich R, Sebahoun V, Roth E, et al. A French randomized
controlled trial of ST-segment analysis in a population with abnormal cardiotocograms during
labor. Am J Obstet Gynecol 2007 Sep;197(3):299.e1-299.e6.
7. Westerhuis ME, Visser GH, Moons KG, Zuithoff N, Mol BW, Kwee A. Cardiotocography plus ST
analysis of fetal electrocardiogram compared with cardiotocography only for intrapartum
monitoring: a randomized controlled trial. Obstet Gynecol 2011 Feb;117(2 Pt 1):406-407.
8. Schuit E, Amer-Wahlin I, Ojala K, Vayssiere C, Westerhuis ME, Marsal K, et al. Effectiveness of elec-
tronic fetal monitoring with additional ST analysis in vertex singleton pregnancies at >36 weeks of
gestation: an individual participant data metaanalysis. Am J Obstet Gynecol 2013 Mar;208(3):187.
e1-187.e13.
9. Blix E, Brurberg KG, Reierth E, Reinar LM, Oian P. ST waveform analysis versus cardiotocography
alone for intrapartum fetal monitoring: a systematic review and meta-analysis of randomized trials.
Acta Obstet Gynecol Scand 2016 Jan;95(1):16-27.
10. Neilson JP. Fetal electrocardiogram (ECG) for fetal monitoring during labour. Cochrane Database
Syst Rev 2015 Dec 21;(12):CD000116.
11. Saccone G, Schuit E, Amer-Wahlin I, Xodo S, Berghella V. Electrocardiogram ST Analysis During
Labor: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Obstet Gynecol
2016 Jan;127(1):127-135.
12. Vayssiere C, Ehlinger V, Paret L, Arnaud C. Is STAN monitoring associated with a significant decrease
in metabolic acidosis at birth compared with cardiotocography alone? Review of the three 11
meta-analyses that included the recent US trial. Acta Obstet Gynecol Scand 2016 Oct;95(10):1190-
1191.
13. Rosen KG, Dagbjartsson A, Henriksson BA, Lagercrantz H, Kjellmer I. The relationship between
circulating catecholamines and ST waveform in the fetal lamb electrocardiogram during hypoxia.
Am J Obstet Gynecol 1984 May 15;149(2):190-195.

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14. Rosén K, Isaksson O. Alterations in Fetal Heart Rate and ECG Correlated to Glycogen, Creatine
Phosphate and ATP Levels during Graded Hypoxia. Biol Neonate 1976;30:17-24.
15. Greene KR, Dawes GS, Lilja H, Rosen KG. Changes in the ST waveform of the fetal lamb electrocardi-
ogram with hypoxemia. Am J Obstet Gynecol 1982 Dec 15;144(8):950-958.
16. Sundström A, Rosén D, Rosén K. Fetal Surveillance. Tech. Rep., Neoventa Medical AB. 2006.
17. Amer-Wahlin I, Kwee A. Combined cardiotocographic and ST event analysis: A review. Best Pract
Res Clin Obstet Gynaecol 2016 Jan;30:48-61.
18. Visser GH, Ayres-de-Campos D, FIGO Intrapartum Fetal Monitoring Expert Consensus Panel. FIGO
consensus guidelines on intrapartum fetal monitoring: Adjunctive technologies. Int J Gynaecol
Obstet 2015 Oct;131(1):25-29.
19. Amer-Wahlin I, Arulkumaran S, Hagberg H, Marsal K, Visser GH. Fetal electrocardiogram: ST
waveform analysis in intrapartum surveillance. BJOG 2007 Oct;114(10):1191-1193.
20. Kwee A, Dekkers AH, van Wijk HP, van der Hoorn-van den Beld CW, Visser GH. Occurrence of
ST-changes recorded with the STAN S21-monitor during normal and abnormal fetal heart rate
patterns during labour. Eur J Obstet Gynecol Reprod Biol 2007 Nov;135(1):28-34.
21. Ayres-de-Campos D, Bernardes J, Costa-Pereira A, Pereira-Leite L. Inconsistencies in classification
by experts of cardiotocograms and subsequent clinical decision. Br J Obstet Gynaecol 1999
Dec;106(12):1307-1310.
22. Verdurmen KMJ, Hulsenboom ADJ, van Laar JOEH, Wijn PFF, Vullings R, Oei SG. Orientation of the
electrical heart axis in mid-term pregnancy. Eur J Obstet Gynecol Reprod Biol 2016.
23. Vullings R, Verdurmen KMJ, Hulsenboom ADJ, Scheffer S, de Lau H, Kwee A, et al. The electrical heart
axis and ST events in fetal monitoring: a post-hoc analysis following a multicentre randomised
controlled trial. PLoS One. 2017;12(4):e0175823. doi: 10.1371/journal.pone.
24. Becker JH, Kuipers LJ, Schuit E, Visser GH, Van Den Akker ES, Van Beek E, et al. Predictive value of the
baseline T-QRS ratio of the fetal electrocardiogram in intrapartum fetal monitoring: a prospective
cohort study. Acta Obstet Gynecol Scand 2012 Feb;91(2):189-197.
25. van Laar JO, Peters CH, Vullings R, Houterman S, Bergmans JW, Oei SG. Fetal autonomic response to
severe acidaemia during labour. BJOG 2010 Mar;117(4):429-437.
26. Becker JH, Krikhaar A, Schuit E, Martendal A, Marsal K, Kwee A, et al. The added predictive value of
biphasic events in ST analysis of the fetal electrocardiogram for intrapartum fetal monitoring. Acta
Obstet Gynecol Scand 2015 Feb;94(2):175-182.

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11

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General discussion

12

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In this thesis, the prospects of fetal electrocardiography (ECG) during pregnancy and labour
are described. Fetal ECG is a technique that is still evolving. It can be applied non-invasively
via electrodes on the maternal abdomen during pregnancy, or invasively with a fetal scalp
electrode during labour.

Congenital heart disease (CHD) is the most common severe congenital anomaly worldwide1.
The detection rate following fetal cardiac screening during the anomaly ultrasound around
20 weeks of gestation, varies between 65% and 81%2. Diagnosing CHD early in pregnancy is
important, and therefore there is need for a reliable non-invasive diagnostic method that can
complement ultrasonography.

Nowadays, we mainly use cardiotocography (CTG) to assess the fetal condition. However,
it is known that the specificity and positive predictive value of CTG are rather poor3 and no
improvement in long-term neonatal outcome is seen4. During pregnancy, besides a biophysical
profile and Doppler ultrasonography there are no complementary diagnostics to give us
information concerning the fetal condition. During labour, fetal scalp blood sampling and ST
analysis of the fetal ECG can be performed to give additional information. Yet, these methods
are both invasive and not applicable in case of prematurity. Therefore, there is need for a
non-invasive method that provides more reliable information concerning the fetal condition.

Chapter 1 discusses the abovementioned issues considering fetal monitoring, that are
encountered in daily clinical practice. This thesis aims to answer the following questions;

1. Is fetal electrocardiography valuable in diagnosing congenital heart disease in fetuses?

2. What is the influence of corticosteroids and tocolytics on fetal heart rate variability?

3. Are the changes in fetal heart rate variability following corticosteroid administration in
the time-domain (obtained by Doppler ultrasound cardiotocography) comparable to the
changes in fetal heart rate variability in the frequency-domain (obtained by non-invasive
fetal electrocardiogram recordings)?

4. Is the variation in orientation of the fetal electrical heart axis in premature fetuses
comparable to the variation seen in term fetuses?

5. Is variation in orientation of the electrical heart axis the cause of false ST events in ST
analysis during labour?

6. Can we improve the method of ST analysis for fetal monitoring during labour?

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 General discussion

Background information considering the physiology of the fetal heart is provided in

chapter 2. The embryology, circulation of the fetal heart and the postnatal changes in circu-
lation are described. In response to hypoxia, chemoreceptors and baroreceptors influence
the autonomic nervous system. It is known that changes in the ECG that are seen following
hypoxia precede cerebral damage, and can therefore be seen as a marker for fetal distress5.
The counteracting autonomic influences of the sympathetic and parasympathetic nervous
system cause the variability in the fetal heart rate6.

In chapter 3, technical background information is provided regarding the CTG, the fetal ECG,
spectral analysis of fetal heart rate variability, and ST analysis. The transabdominal CTG derives
fetal heart rate information via Doppler ultrasound. The fetal heart rate is averaged over
several heartbeats and beat-to-beat information is not available. From fetal ECG recordings,
beat-to-beat fetal heart rate information can be extracted and therefore accurate spectral
analysis (frequency analysis) can be performed with these recordings. By means of spectral
analysis, changes in the autonomic regulation can be quantified7-12. The low-frequency
(LF)-component reflects baroreceptor reflex activity, and is both sympathetically and
parasympathetically mediated13. The high-frequency (HF)-component is associated with fetal
respiration, and is solely parasympathetically mediated13.

In case of sustained hypoxia, there is a switch from aerobic to anaerobic metabolism with
glycogenolysis. This is accompanied by an increase in potassium ions in the myocard14,
causing an increase in T wave amplitude in the fetal ECG15. The consequent rise in T/QRS ratio
is the basis of ST analysis.

This thesis is divided in three parts, that all describe one prospect of fetal ECG.

Part I: fetal ECG and congenital heart disease

CHD is six times more common than chromosomal anomalies and four times more common
than neural tube defects16,17. The detection rate following the congenital anomaly scan that
is performed around 20 weeks of gestation varies from 65-81%16,18-20. Diagnosing CHD in
pregnancy is important, since it enables the identification of associated anomalies, it gives
parents the option to decide for a termination of pregnancy, and an adequate treatment
plan can be developed, which is known to increase the survival rates and decrease long-term
morbidity21.

In chapter 4, the possibilities of fetal ECG as a screening tool for the detection of CHD are 12
reviewed. Not much research has been performed in this field; only five studies could be

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included. Fetal ECG is described to reflect the intimate relation between the cardiac nerve
conduction system and the structural morphology of the heart22. In case of CHD, arrhythmias
and changes in PR, QRS and QT interval have been described. Fetal ECG is particularly helpful
in detecting the electrophysiological effects of cardiac anatomical defects (e.g. hypotrophy,
hypertrophy, and conduction interruption) and it seems to be a promising clinical tool to
complement ultrasonography in the screening for CHD. However, before we can detect
CHD with fetal ECG we need to establish the normal range and values of amplitudes and
segment intervals of the fetal ECG in the healthy fetus. Therefore, we designed a prospec-
tive cohort study, including patients with an uneventful pregnancy. Non-invasive fetal ECG
measurements were performed between 18 and 24 weeks of gestation. The study protocol is
described in chapter 5 of this thesis.

Part II: fetal ECG in preterm labour

Preterm birth, defined as birth before 37 weeks of gestation, is one of the major causes of
perinatal mortality and morbidity worldwide. In Europe, the preterm delivery rate is approx-
imately 5-9%23. In case of threatened preterm labour between 24 and 34 weeks of gestation,
fetal lung maturation can be enhanced by maternal administration of corticosteroids. This
is associated with a reduction in neonatal mortality and morbidity24. In case of spontaneous
preterm labour, tocolytics can be administered in order to attempt to postpone delivery for
at least 48 hours. This will gain time to transfer the patient to a centre with neonatal intensive
care facilities and to await maximal beneficial effect of corticosteroids.

Both corticosteroids and most tocolytics are known to have influence on fetal heart rate
and fetal heart rate variability. It is known that fetal heart rate variability is one of the most
important markers to assess fetal wellbeing25. Therefore, it is important to know the exact
effects of corticosteroids and tocolytics on fetal heart rate parameters. Only then we can
prevent iatrogenic preterm delivery due to misinterpretation of the CTG.

In chapter 6, the influence of corticosteroids (betamethasone and dexamethasone) on

fetal heart rate parameters is described. We performed a review of the literature, eventually
including 15 articles. During the first day after corticosteroid administration, there was a
decrease in fetal heart rate, and an increase in fetal heart rate variability. During days 2 and 3,
fetal heart rate increased while fetal heart rate variability decreased. All parameters returned
to baseline by day 4. We also described confounding factors like the influence of other drugs,
gestational age, diurnal rhythm, and fetal growth restriction. Since the administration of corti-
costeroids is often accompanied by the administration of tocolytics, their influence on fetal
heart rate parameters is described in chapter 7. In this review, it was found that nifedipine,

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 General discussion

atosiban and indomethacin administration show no clinically important effect on fetal heart
rate variability. Magnesium sulphate can result in a decrease in fetal heart rate variability and
cases of bradycardia were described. Fenoterol causes a slight increase in heart rate, with no
changes in fetal heart rate variability. Following ritodrine, an increase in fetal heart rate and a
decrease in variability was seen.

The measurements in the studies regarding the influence of corticosteroids on fetal heart rate
variability, as described in chapter 6, used CTG (Doppler ultrasound). As a consequence, it is
not possible to perform reliable spectral analysis with these measurements. We designed a
prospective cohort study, including patients that required betamethasone during pregnancy.
During five successive days, non-invasive abdominal fetal ECG recordings were performed.
The aim of this study was to quantify the effects of maternally administered betamethasone
on spectral analysis of fetal heart rate variability. In chapter 8, the results of this study are
described. The changes in fetal heart rate variability following betamethasone administration
show the same pattern when calculated by spectral analysis of the fetal ECG, as when calcu-
lated by CTG. The change in absolute spectral values is likely to correspond to the change in
quiet and active state of the fetus. Since normalised spectral values show little changes, the
influence of autonomic modulation is minor.

Part III: fetal ECG to prevent asphyxia

Analysis of the ST segment of the fetal ECG complex can give additional information
regarding fetal hypoxia during labour. In chapter 3, the technical details considering ST
analysis are described. Initially, the combination of CTG and ST analysis was described to
significantly lower the rates of metabolic acidosis5 and operative delivery5,26. However, subse-
quent trials could not reproduce these findings27-30 and conflicting results have been reported
in recent meta-analyses31-35. In addition, false positive alarms are often encountered in clinical
practice36.

In this thesis we hypothesise that the abovementioned issues might be related to the orien-
tation of the fetal electrical heart axis, since this orientation alters the shape and amplitude
of the ECG. It is known that in term fetuses, neonates, and adults, there can be a significant
inter-person variation in the orientation of the electrical heart axis37-41. The orientation of
the fetal electrical heart axis during mid-pregnancy has never been described before. As
elaborated in chapter 9, we performed a post-hoc analysis containing inclusions from two
prospective cohort studies. This study showed that the main direction of the electrical heart
axis is towards the right in mid-pregnancy fetuses, and that the variation in this orientation 12
varies significantly from a normal distribution (p = 0.016).

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The orientation of the electrical heart axis can cause a relatively high, or a relatively low T/QRS
baseline value. In case of fetal hypoxia, the efflux of potassium ions in the myocard causes
a rise in amplitude of the T wave. This results in a rise in T/QRS value, which is repetitively
compared to the baseline value. In case of an initial high baseline value (due to the orienta-
tion of the electrical heart axis), the subsequent rise in T wave amplitude following hypoxia
will be higher in comparison to a case where the initial baseline value is low, where the same
amount of hypoxia will cause a smaller rise in T wave amplitude. In ST analysis, an alarm is
generated following an absolute rise in T/QRS value above the baseline value. Therefore, in
case of a high baseline the threshold for an alarm will be exceeded more often compared to a
lower baseline where the T/QRS value rise is smaller.

In chapter 10, we test our hypothesis that the orientation of the electrical heart axis (and thus
the height of the T/QRS baseline) is related to the occurrence of ST events. We performed a
post-hoc analysis following a randomised trial. Only healthy fetuses, born in good condition
without metabolic acidosis (defined as cord artery pH <7.05 and base deficit >12 mmol/l)
were included. We found that there was a significant increment in ST events with increasing
height of the T/QRS baseline; p <0.0001, which was irrespective of the fetal condition.
Following this finding, we hypothesised that we can correct for the effect of the electrical
heart axis by analysing the T/QRS rise following hypoxia as a percentage from baseline
(yielding a relative ST event). A retrospective case-control study was performed, including 20
term fetuses during labour. Ten fetuses were cases with a cord artery pH <7.05 and ten were
controls with a cord artery pH >7.20. As described in chapter 11, in this highly contrasting
study population the optimal cut-off value for relative T/QRS ratio rises was determined at
0.70. The specificity of relative and absolute ST analysis was 100% and 40% (p = 0.031)
respectively, while the sensitivity was 90% for both methods. Following this first explorative
study, relative ST analysis seems to be promising.

Clinical implications and future directions

The results of the fundamental research reported in this thesis show that fetal ECG has
multiple promising prospects, both during pregnancy and labour. Although the first studies
describing fetal ECG measurements date back to 190642, the development of fetal ECG lagged
behind in comparison to other techniques for fetal monitoring. Multiple technical challenges
had to be overcome, as described in chapter 3. In 1942, it was already suggested that the
effect of drugs, hypoxia, and labour could be conveniently studied by fetal ECG43. Nowadays,
it is feasible to conduct a fetal ECG relatively easy, and it has been demonstrated that the
recordings obtained by non-invasive measurements correlate very well with fetal ECG signals
obtained directly via a scalp electrode11. With the fetal ECG technique being available, more

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 General discussion

sophisticated, easy to apply and safe to use, more and more research with this technique has
been performed. Not all possible applications of fetal ECG are yet known, and researchers
from all over the world are currently performing studies to elaborate these possible applica-
tions44-46.

In our review as described in chapter 4, it was confirmed that fetal ECG can be a promising
tool to complement ultrasonography in diagnosing CHD. This is intuitively logical, since it has
been long known in children and adults that ECG can aid in the diagnosis of heart diseases.
In particular, it seems that secondary effects due to CHD can be detected; hypotrophy, hyper-
trophy and conduction interruption. However, the fetal circulation is markedly different in
comparison to the neonatal and adult circulation, as described in chapter 2. In order to distin-
guish abnormal fetal ECGs from normal ECGs, it is first required that we know the normal
ECG in healthy fetuses. In chapter 5, the study protocol is described that will investigate the
normal ranges for fetal ECG values around 20 weeks of gestation.

The collected data regarding the changes observed in fetal ECG in case of CHD is still limited.
There is need for future trials that include multiple types of CHDs and have a reasonable
sample size per type of CHD. In order to achieve this, these studies will most likely have to be
performed as a collaboration between multiple expert centres. The ECG characteristics found
in case of CHD should be compared to the characteristics found in healthy fetuses. When
conducting these trials, one should take the gestational age of the fetus into account. The
duration of the P wave, QRS complex and PR interval increase progressively from 18 weeks of
gestation onwards until term47,48.

If pregnancy is complicated by threatened preterm labour, multiple drugs are administered.

This is done in a highly vulnerable population, since preterm fetuses can tolerate contractions
and labour less well compared to term fetuses. In addition, only non-invasive fetal monitoring
is available which can be complicated due to movements of the fetus in-utero. Further, it is
important to be aware of the effects that the administered medication can have on fetal heart
rate parameters, to prevent iatrogenic preterm delivery. In this thesis, the effects of cortico-
steroids and tocolytics were studied. However, in clinical practice some patients receive other
drugs like antihypertensive agents or antibiotics. The effects of these drugs on fetal heart rate
parameters should be studied as well. In addition, other confounding factors should be taken
into account when studying the preterm fetus, such as gestational age, diurnal rhythm and
fetal growth restriction. A challenging factor in studies including fetuses at risk for preterm
labour is time of inclusion (most patients are transferred from secondary care hospitals,
where medication is already started) and loss of study participants, e.g. due to preterm labour
12
or discharge before the end of the study period. Nearly all studies considering this topic

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published so far used CTG (Doppler ultrasound) to perform measurements and evaluate fetal
heart rate parameters. However, as previously described in this thesis, CTG measurements
do not acquire fetal heart rate information on a beat-to-beat basis. Future studies should
perform measurements using fetal ECG equipment that can extract the fetal heart rate on
a beat-to-beat basis, since only then reliable spectral analysis can be performed and more
reliable estimates for fetal heart rate variability can be calculated.

During term labour, ST analysis of the fetal ECG was developed to provide additional infor-
mation regarding fetal wellbeing. However, in clinical practice it appeared that false positive
events were encountered regularly36. This made some clinicians and researchers wonder
whether the STAN® monitor was indeed a reliable method for fetal monitoring. In this thesis,
we described that our hypothesis that false alarms can be caused by the variation in orienta-
tion of the electrical heart axis indeed holds true. In addition, we provide a possible solution;
relative ST analysis. Our study results should be verified in a study with a larger sample size,
including the whole patient spectrum. In this group a reliable cut-off value for relative ST
analysis can be defined, which should be validated in a second study. If the results of relative
ST analysis are still promising, a prospective or randomised controlled trial can be performed.
In addition, the clinical value of relative ST analysis in conjunction with CTG should be
evaluated.

What can be learned from the above, is that when a new technique is introduced in clinical
practice, we should not take this technology for granted. When unexpected findings arise,
one should go back to basic physiology and anatomy and wonder if some influence might
have been overlooked.

With multi-lead fetal ECG recordings being available, the applicability of antepartum ST
analysis in preterm deliveries should be a field of future studies49.

Advantages of fetal ECG

A major advantage of fetal ECG measurements is that they can provide additional and
objective information; e.g. ECG segment intervals, values for spectral analysis, and ST analysis.
This objective information can aid current technologies. Thereby, the influence of, for
instance, performer variability (in ultrasonography) and inter- and intra-observer variability (in
CTG assessment) might be decreased. Spectral analysis can objectively quantify the changes
in fetal heart rate variability that can be obscured in visual interpretation of fetal heart rate
tracings. Spectral analysis might also be added to ST analysis; it has been described that a
relative change in LF/HF ratio >30%, in combination with a significant ST event is a better
predictor for metabolic acidosis in the arterial cord blood than a significant ST event alone50.

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 General discussion

Another advantage is that fetal ECG has the potential to be widely versatile. A fetal ECG is easy
to conduct, by placing electrodes on the maternal abdomen. The electrodes are attached to
small and mobile equipment, which is likely to be relatively cheap in the future. Application
of the fetal ECG system requires minimum training. In addition, the raw information can be
analysed by computerised algorithms or can be sent for analysis elsewhere.

Since the fetal ECG can be conducted both invasively (with a fetal scalp electrode) and
non-invasively (with electrodes on the maternal abdomen), the fetal ECG is applicable from
early pregnancy (from 18 weeks of gestation onwards) until delivery. Since it can be applied
non-invasively and can provide additional information such as spectral estimates, it could be
used for fetal monitoring in high-risk pregnancies; e.g. in case of extreme prematurity, fetal
growth restriction and fetuses from mothers with diabetes. In addition, home monitoring
with non-invasive fetal ECG measurements in high-risk pregnancies is an additional field
that has been studied recently51. When this would be feasible, it would lead to a significant
reduction in health care costs due to less hospitalisation.

Disadvantages of fetal ECG

Despite all efforts to enhance the signal quality in fetal ECG measurements, there is still a lot to
gain in this area. Therefore, future research should keep focussing on further progress in signal
acquisition and processing. The signal quality is reduced due to presence of vernix caseosa on
the fetal skin. This fatty layer surrounds the fetus and results in an electrical isolation, which
diminishes the signal amplitude of the fetal ECG. Especially between 30 and 34 weeks of
gestation, this layer causes a poor signal-to-noise ratio46,52.

As with all new techniques, differences in acquiring and processing of the data exist. It is
highly recommended that all future studies regarding fetal ECG measurements and spectral
analysis use a standardised method. This will enable comparability, reproducibility, reliable
physiological interpretation and clinical applicability.

In addition, every study regarding fetal ECG should consider the influence of the orientation
of the electrical heart axis on their study results. For instance in case of ST monitoring, as
described in this thesis, the physiological variation in orientation of the electrical heart axis
might be responsible for the encountered false alarms. When calculating the electrical heart
axis, it is important to take the fetal position in the uterus into account.

In the studies described in this thesis, data processing and calculation of spectral estimates, 12
the electrical heart axis, etc. was performed off-line. In order to be clinically applicable,
real-time monitoring should become available in the future.

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In conclusion, this thesis describes the prospects of fetal ECG during pregnancy and labour.
Although non-invasive fetal ECG is not yet clinically applied, this thesis shows that fetal ECG is
promising in providing complementary diagnostic information. The additional value of fetal
ECG in multiple fields has been addressed, and it has been shown that it can be used both
during pregnancy and during labour.

200
 General discussion

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12

205
206
 Appendices

List of abbreviations
List of publications
Nederlandse samenvatting
Dankwoord
Curriculum vitae

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 Appendices

List of abbreviations
aECG average ECG
ANS Autonomic nervous system
BDecf Base deficit in the extracellular fluid
BE Base excess
BMI Body Mass Index
BPM Beats per minute
CHD Congenital heart disease
CI Confidence interval
CNS Central nervous system
CRH Corticotrophin-releasing hormone
CS Caesarean section
CTG Cardiotocography / Cardiotocogram
DM Diabetes Mellitus
DvU Diagnostiek voor U
ECG Electrocardiography / Electrocardiogram
FBS Fetal blood sampling
fHR fetal heart rate
fHRV fetal heart rate variability
fMGC fetal magnetocardiography
GA Gestational age
GR Glucocorticoid receptor
HELLP Hemolysis, elevated liver enzymes, and low platelet count syndrome
HF High-frequency (power)
HFn normalised high-frequency (power)
HPA-axis Hypothalamic-pituitary-adrenal axis
HR Heart rate
HRV Heart rate variability
HSD Hydroxysteroid dehydrogenase
HT Hypertension
IQR Interquartile range
IUGR Intra-uterine growth restriction
i.v. intravenous
LEEP Loop electrosurgical excision procedure of the cervix
LF Low-frequency (power)
LFn normalised low-frequency (power)

208
 List of abbreviations

LMWH Low molecular weight heparin

LR + Positive likelihood ratio
LR - Negative likelihood ratio
LTV Long-term variability
MC Medium care
mFHR mean fetal heart rate
MgSO4 Magnesium sulphate
NICU Neonatal intensive care unit
NS Not significant
PE Pre-eclampsia
pHart pH of the arterial cord blood
PPROM Premature prelabour rupture of membranes
PROM Preterm rupture of membranes
PSD Power spectral density
QTc Fetal QT interval corrected for heart rate
RCT Randomised controlled trial
ROC Receiver operator characteristic
SD Standard deviation
Sn Sensitivity
Sp Specificity
STAN ST analysis
STV Short-term variability
TPL Threatened preterm labour
VBL Vaginal blood loss
VCG Vectorcardiogram
VE Vacuum extraction
VLF Very low-frequency (power)
wG weeks of gestation
wGA weeks of gestational age

209
 Appendices

List of publications
Journal papers

K.M.J. Verdurmen, J. Renckens, J.O.E.H. van Laar, S.G. Oei. The influence of corticosteroids on fetal
heart rate variability: a systematic review of the literature. Obstet Gynecol Surv. 2013;68(12):811-24. doi:
10.1097/OGX.

J.O.E.H. van Laar, G.J.J. Warmerdam, K.M.J. Verdurmen, R. Vullings, C.H.L. Peters, S. Houterman, P.F.F.
Wijn, P. Andriessen, C. van Pul, S.G. Oei. Fetal heart rate variability during pregnancy, obtained from
non-invasive electrocardiogram recordings. Acta Obstet Gynecol Scand. 2014;93(1):93-101. doi: 10.1111/
aogs.

K.M.J. Verdurmen, C. Lempersz, R. Vullings, C. Schroer, T. Delhaas, J.O.E.H. van Laar, S.G. Oei. Normal
ranges for fetal electrocardiogram values for the healthy fetus of 18-24 weeks of gestation: a prospective
cohort study. BMC Pregnancy Childbirth. 2016;16:227. doi: 10.1186/s12884-016-1021-x.

K.M.J. Verdurmen, N.B. Eijsvoogel, C. Lempersz, R. Vullings, C. Schroer, J.O.E.H. van Laar, S.G. Oei. A
systematic review of prenatal screening for congenital heart disease by fetal electrocardiography. Int J
Gynaecol Obstet. 2016;135(2):129-134. doi: 10.1016/j.ijgo.

K.M.J. Verdurmen, A.D.J. Hulsenboom, J.O.E.H. van Laar, S.G. Oei. Effect of tocolytic drugs on fetal heart
rate variability: a systematic review. J Matern Fetal Neonatal Med. 2016:1-8. doi: 10.1080/14767058.

K.M.J. Verdurmen, A.D.J. Hulsenboom, J.O.E.H. van Laar, P.F.F. Wijn, R. Vullings, S.G. Oei. Orientation of
the electrical heart axis in mid-term pregnancy. Eur J Obstet Gynecol Reprod Biol. 2016;207:243-246. doi:
10.1016/j.ejogrb.

R. Vullings, K.M.J. Verdurmen, A.D.J. Hulsenboom, S. Scheffer, H. de Lau, A. Kwee, P.F.F. Wijn, I. Amer-
Wåhlin, J.O.E.H. van Laar, S.G. Oei. The electrical heart axis and ST events in fetal monitoring: a post-hoc
analysis following a multicentre randomised controlled trial. PLoS One. 2017;12(4):e0175823. doi:
10.1371/journal.pone.

K.M.J. Verdurmen, G.J.J. Warmerdam, C. Lempersz, A.D.J. Hulsenboom, J. Renckens, J.P. Dieleman,
R. Vullings, J.O.E.H. van Laar, S.G. Oei. The influence of betamethasone on fetal heart rate variability,
obtained by non-invasive fetal electrocardiogram recordings. Revision pending.

A.D.J. Hulsenboom, K.M.J. Verdurmen, R. Vullings, M.B. van der Hout-van der Jagt, A. Kwee, J.O.E.H. van
Laar, S.G. Oei. Relative versus absolute rises in T/QRS ratio: a case-control study. Manuscript submitted for
publication.

R. Vullings, C. Lempersz, S.A.B. Clur, K.M.J. Verdurmen, G.J.J. Warmerdam, J. van der Post, N.A. Blom, T.
Delhaas, J.O.E.H. van Laar, S.G. Oei. The normal fetal electrocardiogram in mid-pregnancy, an additional
tool for the prenatal detection of congenital heart disease. Manuscript submitted for publication.

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 List of publications

Conference presentations

K.M.J. Verdurmen, J.O.E.H. van Laar, S.G. Oei. “Corticosteroids and fetal heart rate variability.” European
Congress of Perinatal Medicine, Florence, 4-7 June, 2014.

K.M.J. Verdurmen, A.D.J. Hulsenboom, R. Vullings, J.O.E.H. van Laar, A. Kwee, S.G. Oei. “Improving STAN
fetal monitoring”. European Congress on Intrapartum Care, Porto, 21-23 May 2015. Invited speaker at the
pre-congress Intrapartum Fetal Monitoring meeting.

K.M.J. Verdurmen, R. Vullings. A.D.J. Hulsenboom, J.O.E.H. van Laar, A. Kwee, S.G. Oei. “De denkfout van
de STAN”. Gynaecongres, Amersfoort, 28-29 May 2015.
Wim Schellekensprice; 1st price in the category “Talent in Onderzoek”.

K.M.J. Verdurmen. “De relatieve STAN bij foetale asfyxie: wat zegt het?” Gynaecongres, Eindhoven, 19-20
May 2016. Invited speaker.

Conference posters

K.M.J. Verdurmen, J.O.E.H. van Laar, G.J.J. Warmerdam, S.G. Oei. Fetal heart rate variability during
pregnancy. Symposium on Advances in Perinatal Monitoring, Eindhoven, 24 April 2013.

K.M.J. Verdurmen, J.O.E.H. van Laar, G.J.J. Warmerdam, S.G. Oei. Fetal heart rate variability during
pregnancy. European Congress of Perinatal Medicine, Florence, 4-7 June, 2014.

K.M.J. Verdurmen, A.D.J. Hulsenboom, R. Vullings, J.O.E.H. van Laar, A. Kwee, S.G. Oei. Fetal ST
monitoring, towards improved perinatal outcome; a three-phase study. European Congress on
Intrapartum Care, Porto, 21-23 May 2015.

K.M.J. Verdurmen, G.J.J. Warmerdam, C. Lempersz, A.D.J. Hulsenboom, J. Renckens, J.P. Dieleman,
R. Vullings, J.O.E.H. van Laar, S.G. Oei. The influence of betamethasone on fetal heart rate variability,
obtained by non-invasive fetal electrocardiogram recordings. European Congress on Intrapartum Care,
Stockholm, 25-27 May 2017.

211
 Appendices

Nederlandse samenvatting
In dit proefschrift worden drie verschillende toepassingsmogelijkheden van het foetale
electrocardiogram (ECG) tijdens de zwangerschap en de bevalling beschreven. Ten eerste
wordt het foetale ECG als screeningsmethode bij aangeboren hartafwijkingen bestudeerd.
Ten tweede onderzoeken we wat het effect van medicatie bij een dreigende vroeggeboorte
is op het foetale hartritme, en ten derde toetsen we onze ideeën over valse alarmen bij het
gebruik van foetaal ECG tijdens de bevalling (ST-analyse). Het foetale ECG is een techniek
die nog in ontwikkeling is. Het kan niet-invasief verkregen worden met behulp van
elektroden op de maternale buikhuid tijdens de zwangerschap, en invasief middels een
foetale schedelelektrode tijdens de bevalling. Bij gebruik van foetaal ECG wordt slag-tot-slag
informatie verkregen van het foetale hartritme. Hierdoor is het mogelijk om spectraalanalyse
(frequentie analyse) te verrichten op het hartritme. Door middel van deze spectraalanalyse
kunnen veranderingen in het autonome zenuwstelsel (sympathische en parasympathische
activiteit) gekwantificeerd worden.

Aangeboren hartafwijkingen
Wereldwijd zijn aangeboren hartafwijkingen de meest voorkomende ernstige aangeboren
afwijkingen. Deze hartafwijkingen komen zes keer vaker voor dan chromosomale afwijkingen
(bijvoorbeeld syndroom van Down) en vier keer vaker dan neurale buisdefecten (bijvoorbeeld
open rug). Momenteel wordt op aangeboren hartafwijkingen gescreend tijdens de 20-weken
echo. Echter, deze echo spoort slechts 65-81% van de aangeboren hartafwijkingen op. Het
diagnosticeren van een aangeboren hartafwijking vroeg in de zwangerschap is belangrijk;
er kunnen extra onderzoeken plaatsvinden naar bijkomende aandoeningen, ouders hebben
de mogelijkheid om te opteren voor een zwangerschapsafbreking en er kan voor gekozen
worden de zwangere in een gespecialiseerd ziekenhuis te laten bevallen. Daarom is het van
belang dat er onderzoek gedaan wordt naar een aanvullende, betrouwbare, niet-invasieve
methode om aangeboren hartafwijkingen op te sporen.

We hebben een literatuurstudie uitgevoerd, waaruit bleek dat er tot nu toe weinig onderzoek
verricht is naar het foetale ECG als screeningsmethode voor aangeboren hartafwijkingen.
Wel wordt beschreven dat het foetale ECG de nauwe relatie tussen het cardiale geleidings-
systeem en de structurele morfologie van het hart weergeeft. In het geval van een aange-
boren hartafwijking worden onder andere hartritmestoornissen en veranderingen in PR, QRS
en QT interval beschreven. Het foetale ECG is geschikt voor het opsporen van elektrofysio-
logische effecten van hartafwijkingen; hypotrofie of hypertrofie van de hartspier en onder-
breking in het geleidingssysteem. Het lijkt er dus op dat het foetale ECG een veelbelovende
aanvullende methode zou kunnen zijn voor het opsporen van aangeboren hartafwijkingen.

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 Nederlandse samenvatting

Voordat we aangeboren hartafwijkingen met behulp van het foetale ECG kunnen opsporen,
is het belangrijk dat we een goed beeld hebben van de normaalwaarden van, onder andere,
intervallen en amplitudes van het foetale ECG. In dit proefschrift wordt het studieprotocol
beschreven van een prospectieve cohortstudie, waarin zwangeren met een ongecompliceer-
de zwangerschap geïncludeerd worden. Bij deze zwangeren wordt een niet-invasief foetaal
ECG gemaakt tussen de 18 en 24 weken zwangerschap. De resultaten van deze studie zijn
nog niet bekend.

Dreigende vroeggeboorte
Op dit moment wordt de conditie van het ongeboren kind tijdens de zwangerschap bewaakt
met behulp van het cardiotocogram (CTG). Tijdens de zwangerschap kan dit transabdo-
minaal, via de buik van de moeder, verkregen worden met behulp van een echo-Doppler
signaal. De foetale hartslag wordt hierbij gemiddeld over een aantal opeenvolgende hart-
slagen, waardoor er bij deze registratie geen slag-tot-slag informatie beschikbaar is. Het is
bekend dat de specificiteit en positief voorspellende waarde van het CTG beperkt is. Tijdens
de zwangerschap zijn er naast echografie geen aanvullende onderzoeken die verricht kunnen
worden om ons meer informatie te geven over de foetale conditie.

Een vroeggeboorte, gedefinieerd als een geboorte voor de 37 weken zwangerschap, is één
van de belangrijkste oorzaken van perinatale mortaliteit en morbiditeit wereldwijd. In Europa
is circa 5-9% van alle bevallingen een vroeggeboorte. Bij een dreigende vroeggeboorte
tussen de 24 en 34 weken zwangerschap kan de foetale longrijping bevorderd worden door
middel van het toedienen van corticosteroïden aan de moeder. Dit resulteert in een signifi-
cante afname in neonatale mortaliteit en morbiditeit. Bij een spontane vroeggeboorte wordt
dit vaak gecombineerd met het toedienen van weeënremmers; tocolyse. Hiermee wordt
geprobeerd de bevalling tenminste 48 uur uit te stellen, zodat een patiënte overgeplaatst
kan worden naar een centrum met een neonatale intensive care en om de corticosteroïden te
laten inwerken.

Zowel corticosteroïden als weeënremmers hebben invloed op het foetale hartritme en de

hartritmevariabiliteit. Uit eerder onderzoek is gebleken dat hartritmevariabiliteit één van
de belangrijkste indicatoren is voor een goede foetale conditie. Daarom is het belangrijk
om exact te weten wat het effect is van bijvoorbeeld corticosteroïden en weeënremmers
op verschillende foetale hartritme parameters. Alleen dan kunnen we een iatrogene vroeg-
geboorte door misinterpretatie van het CTG voorkomen.

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 Appendices

We hebben twee literatuurstudies uitgevoerd waarin zowel het effect van corticosteroïden
als dat van weeënremmers op het foetale hartritme wordt beschreven. Na toediening van
corticosteroïden is op de eerste dag een afname van het foetale hartritme zichtbaar, terwijl de
hartritmevariabiliteit toeneemt. Op dag 2 en 3 zien we een stijging in hartritme en een daling
in hartritmevariabiliteit. Op dag 4 zijn alle waarden weer vergelijkbaar met de waarden voor
toediening van medicatie. Echter, er zijn ook andere factoren die invloed hebben op deze
waarden, zoals het toedienen van andere medicatie, de zwangerschapsduur, het slaap-waak
ritme en een eventuele foetale groeivertraging. Als we kijken naar weeënremmers blijkt uit de
bestaande literatuur dat nifedipine, atosiban en indometacine geen duidelijk effect hebben
op de hartritmevariabiliteit. Magnesiumsulfaat kan een vermindering van hartritmevariabili-
teit veroorzaken, en er zijn ook casus met langdurige bradycardie beschreven. Na toediening
van fenoterol wordt een geringe toename van het hartritme gezien, zonder veranderingen
in variabiliteit. Bij ritodrine wordt een toename in hartritme en een afname in variabiliteit
gezien.

Alle studies die tot nu toe zijn verricht, hebben gebruik gemaakt van CTG (echo-Doppler).
Daarom is het niet mogelijk om betrouwbaar spectraalanalyse van hartritmevariabiliteit
uit te voeren aan de hand van deze metingen. Om het effect van corticosteroïden op het
autonome zenuwstelsel meer in detail te kunnen bestuderen, hebben we een prospectieve
cohortstudie uitgevoerd waarbij we gedurende vijf dagen een niet-invasief foetaal ECG
gemaakt hebben bij zwangeren die corticosteroïden toegediend kregen in verband met
een dreigende vroeggeboorte. We zien dat de veranderingen die we meten met behulp
van spectraalanalyse overeenkomen met de veranderingen die eerder beschreven zijn bij
studies die met CTG verricht zijn. Daarnaast zien we dat genormaliseerde waarden weinig
verandering laten zien gedurende de vijfdaagse studieperiode; dit wijst op weinig invloed
vanuit het autonome zenuwstelsel. Duidelijk zichtbaar is dat foetussen na toediening van
corticosteroïden meer tijd doorbrengen in een rustige gedragstoestand, in vergelijking met
de actieve gedragstoestand. Na vier dagen is de verdeling tussen de gedragstoestanden
weer zoals voor toediening van de corticosteroïden. We zien dus dat foetussen rustiger zijn
en minder hartritmevariabiliteit laten zien, maar dat er geen sprake is van foetale stress (geen
veranderingen in autonome modulatie).

Foetale nood tijdens de bevalling

Tijdens de bevalling kan de foetale hartslag bewaakt worden met behulp van een foetale
schedelelektrode, waarbij invasief een foetaal ECG verkregen wordt. Deze registratie geeft
slag-tot-slag informatie over het foetale hartritme. Tijdens de bevalling kan een micro-
bloedonderzoek en/of ST-analyse van het foetale ECG aanvullende informatie geven. Echter,
beide methoden zijn invasief en niet toe te passen in het geval van prematuriteit. Daarnaast

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 Nederlandse samenvatting

is het zo dat ST-analyse in de praktijk veel valse alarmen geeft en uit eerdere studies is
niet evident duidelijk geworden dat ST-analyse een positieve invloed heeft op neonatale
uitkomsten.

In het geval van (aanhoudend) zuurstoftekort, schakelt de foetus van het aërobe
metabolisme over naar het anaërobe metabolisme, waarbij glycogenolyse plaatsvindt.
Als gevolg hiervan is er een toename van kalium-ionen in de hartspier. Dit veroorzaakt een
stijging in T-top amplitude in het foetale ECG. De stijging in T/QRS-ratio die hierop volgt is
de basis van ST-analyse. Er vindt ook activatie van chemo- en baroreceptoren plaats, met
als gevolg modulatie van het autonome zenuwstelsel. Deze modulatie, die invloed heeft
op het parasympathische en sympathische zenuwstelsel, zorgt voor veranderingen in
hartritmevariabiliteit. Het is bekend dat de veranderingen die in het foetale ECG gezien
worden in geval van hypoxie vóórlopen op cerebrale schade; daarom kan het foetale ECG
gezien worden als een diagnosticum voor foetale stress.

Een deel van de problemen die we ervaren met ST-analyse zou verklaard kunnen worden
door de inter-patiënt variatie in oriëntatie, ofwel de richting, van de elektrische hartas.
Deze oriëntatie heeft namelijk invloed op de vorm en amplitude van het ECG-complex. Uit
eerdere studies is bekend dat de oriëntatie van de elektrische hartas sterk kan variëren tussen
personen, zowel bij à terme foetussen, neonaten als volwassenen. We hebben een post-hoc
analyse verricht op data van twee prospectieve cohortstudies, om te onderzoeken of deze
variatie ook bestaat bij premature foetussen. Hierbij zagen we dat de gemiddelde oriëntatie
van de elektrische hartas bij foetussen tussen de 18 en 29 weken zwangerschap richting
rechts is, en dat de variatie in deze oriëntatie significant varieert van een normale verdeling
(p = 0.016).

De oriëntatie van de elektrische hartas kan een relatief hoge of juist relatief lage T/QRS-
basiswaarde veroorzaken. Ook de T-top stijging die plaatsvindt in geval van hypoxie kan
hoger danwel lager zijn door deze oriëntatie, bij een zelfde mate van zuurstoftekort. Bij een
initieel hoge T/QRS-basiswaarde zal de T-top stijging in het geval van hypoxie hoger zijn, in
vergelijking met een foetus waarbij de initiële T/QRS-basiswaarde lager is. Op dit moment
wordt bij ST-analyse gekeken naar een absolute stijging in T/QRS-waarde ten opzichte van de
basiswaarde. Onze hypothese is dat er bij een hogere initiële basiswaarde sneller een alarm
gegeven wordt dan bij een lagere initiële basiswaarde, onafhankelijk van de foetale conditie.

Om onze hypothese te onderzoeken hebben we een post-hoc analyse uitgevoerd met data
van de gerandomiseerde, Nederlandse ST-analyse studie. Alleen gezonde foetussen die in
goede conditie geboren zijn zonder metabole acidose (gedefinieerd als navelstreng pH

215
 Appendices

arterieel <7.05 en base deficit >12 mmol/l) werden geïncludeerd. We vonden een significante
toename in ST-alarmen bij een toename van de hoogte van de initiële T/QRS-basiswaarde
(p <0.0001), welke dus onafhankelijk was van de foetale conditie.

Om deze valse alarmen in de toekomst te kunnen voorkomen, was onze volgende

hypothese dat we voor de inter-patiënt variatie in oriëntatie van de elektrische hartas
kunnen corrigeren tijdens ST-analyse door de T/QRS stijging als gevolg van hypoxie te
kwantificeren als een percentuele stijging vanaf de basiswaarde; “relatieve ST-analyse”.
We hebben een retrospectieve case-controle studie uitgevoerd met 20 à terme foetussen,
waarbij invasieve ECG monitoring was tijdens de bevalling. Tien foetussen hadden tekenen
van zuurstoftekort bij de bevalling (een arteriële navelstreng pH <7.05) en de tien controles
hadden een goede foetale conditie (arteriële navelstreng pH >7.20). In deze specifieke groep
bleek de optimale afkapwaarde voor een ST-alarm een relatieve T/QRS stijging van 70% te
zijn. De specificiteit van relatieve en absolute ST-analyse in deze groep was 100% en 40% (p =
0.031), respectievelijk. De sensitiviteit van beide methoden was 90%. Aan de hand van deze
eerste exploratieve studie kunnen we dus stellen dat relatieve ST-analyse een veelbelovende
techniek is om het aantal valse alarmen te reduceren.

Conclusie
Concluderend beschrijft dit proefschrift verschillende toepassingsmogelijkheden van
het foetale ECG, zowel tijdens de zwangerschap als tijdens de bevalling. Hoewel het niet-
invasieve foetale ECG nog niet klinisch toepasbaar is, laat dit proefschrift duidelijk zien dat
het een veelbelovende manier is om aanvullende informatie te verkrijgen over de foetale
conditie.

216
 Dankwoord

Dankwoord
Lange tijd heb ik toegewerkt naar het schrijven van dit dankwoord; het slotstuk van mijn
proefschrift. Een proefschrift afronden in vier jaar, met daarnaast een fulltime baan als arts-
assistent, al wonende in een caravan is niet makkelijk. Dat lukt alleen met hulp en steun van
veel mensen. Nu ligt mijn proefschrift voor u, en is het tijd om iedereen die hier aan heeft
bijgedragen te bedanken.

Allereerst wil ik de vrouwen en hun ongeboren baby’s bedanken die het onderzoek in dit
proefschrift mogelijk hebben gemaakt.

Prof. dr. Oei, beste Guid. Het begon allemaal na een poli-ochtend tijdens mijn coschap
gynaecologie in het Máxima Medisch Centrum. Mijn wetenschapsstage was eigenlijk al
elders geregeld, maar gedurende het coschap zorgde jij ervoor dat ik steeds enthousiaster
werd over de mogelijkheden binnen jouw onderzoeksgroep. Daarna is alles in een snel-
treinvaart gegaan; het opzetten van studies, mijn eerste publicatie en voor ik het wist een
kleurrijk plan voor mijn proefschrift. Bedankt voor alle kansen die je mij gegeven hebt. Het
was heel bijzonder om in 2015 uit jouw handen de Wim Schellekens prijs te ontvangen op
het Gynaecongres. Niet alleen op wetenschappelijk gebied, maar ook als gynaecoloog heb
ik ontzettend veel van je geleerd. Het is inspirerend om met iemand als jij samen te werken.

Dr. van Laar, lieve Judith. Ik mocht jouw “kindje”, het foetaal ECG-onderzoek, overnemen. Je
hebt me ingewijd in de wereld van wetenschappelijk onderzoek, en met jouw gave om zowel
te stimuleren als kritische feedback te geven weet je ieder manuscript weer te verbeteren.
Daarnaast ben je mijn maatje in de kliniek, eerst als oudstejaars assistent en later als gynae-
coloog. We hebben samen veel mooie dingen kunnen doen, zoals een keizersnede bij een
drieling. Maar ook als het even moeilijk is, sta je altijd voor me klaar. Lieve Judith, bedankt
voor al je begeleiding. Het is een eer dat ik de eerste mag zijn van wie jij copromotor bent.

Dr. ir. Vullings, beste Rik. Zonder jou als copromotor was het me nooit gelukt om op zo’n
technisch onderwerp te promoveren. Ik sta er altijd van versteld hoe jij iets technisch
kan uitleggen aan een “leek”, waardoor het ineens begrijpelijk wordt. Daarnaast voel je
als technicus haarfijn aan wat er in de kliniek leeft. Je kunt je verplaatsen in een klinisch
probleem en gaat altijd terug naar de fysiologie om vanuit daar een oplossing te bedenken.
Bedankt voor je begeleiding, ik heb veel van je geleerd.

217
 Appendices

Prof. dr. ir. Wijn, prof. dr. ir. Bergmans, prof. dr. Nijhuis, prof. dr. Visser en dr. Haak, bedankt voor
het beoordelen van mijn manuscript en het zitting nemen in mijn promotiecommissie.

Dank aan alle onderzoekers en semi-artsen die hebben geholpen met het uitvoeren van de
ontelbare metingen. Het was soms frustrerend en niet altijd makkelijk, maar dankzij jullie hulp
hebben we de prospectieve studie goed kunnen voltooien. Daarnaast heel veel dank aan Guy
Warmerdam voor het analyseren van deze metingen. Hoofdstuk 8 is het mooie resultaat van
onze samenwerking.

Jeanne Dieleman en andere medewerkers van het Wetenschapsbureau in het Máxima

Medisch Centrum. Bedankt voor alle hulp in de afgelopen jaren. Jeanne, je bent altijd bereid
om mee te denken over (statistische) problemen en betrokken bij al het onderzoek in het
Máxima. Het is heel fijn om jou als aanspreekpunt te hebben. Bart en Eugenie van het Kennis
& Informatiecentrum in het Máxima Medisch Centrum, bedankt voor jullie hulp met het
opsporen van oude en niet-inzichtelijke artikelen. Jullie hebben indirect enorm bijgedragen
aan mijn review-artikelen.

Gynaecologen van het Máxima Medisch Centrum. Wat ben ik blij dat ik na mijn weten-
schapsstage mocht blijven als arts-assistent. Ik heb ongelooflijk veel geleerd in de jaren die
volgden. Het is erg motiverend om in een groep te werken die zo enthousiast is. Mede door
jullie stimulans en de ruimte voor onderzoek die ik heb gekregen, heb ik mijn proefschrift
zo snel kunnen afronden. Jullie zijn een echt team en ik voelde me altijd erg gewaardeerd.
De persoonlijke betrokkenheid die jullie uitstralen is uniek. Bedankt voor al jullie steun en
vertrouwen.

Joggem, bedankt dat je mijn mentor bent. We zien elkaar misschien niet vaak, maar ik weet
dat ik altijd bij je terecht kan. Door de vragen die je stelt weet je me iedere keer aan het
denken te zetten, en komen de antwoorden na verloop van tijd vanzelf.

Verloskundigen, verpleging, POK- en polimedewerksters en secretaresses van het Máxima

Medisch Centrum. Het voelt als een warm bad als ik de afdeling op loop. Jullie hebben mij
zien “opgroeien” en mede gemaakt tot de arts die ik nu ben. Bedankt voor jullie hulp en
geduld, maar ook voor jullie betrokkenheid en passie voor het werk.

Gynaecologen en alle gynaecologie medewerkers van het Maastricht UMC+. Dat ik mijn tijd
in Maastricht mocht beginnen met een maand schrijftijd heeft ervoor gezorgd dat ik de eind-
sprint in kon zetten. Na een periode van wennen kan ik nu zeggen dat ik op m’n plek ben in
het MUMC+. Ik kijk er naar uit om nog een jaar veel van jullie te leren.

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 Dankwoord

Lieve collega-AIOS, wat hebben we een leuke groep! Ook al is het vaak hard werken, vele
handen maken licht werk. Het is fijn dat er altijd iemand is bij wie je even je verhaal kwijt kan.
Daarnaast is er gelukkig ook veel gezelligheid. Bedankt voor het overnemen van mijn taken
tijdens mijn schrijftijd en bij een acute aanval van promotie-stress.

Lieve collega-onderzoekers uit de FUN-groep, wat hebben we een gevarieerde en inspireren-

de onderzoeksgroep! Het is uniek om als onderzoeker zo laagdrempelig gebruik te kunnen
maken van alle expertise die binnen deze groep aanwezig is. De FUN-meetings en verschil-
lende congressen zijn ideaal om even bij te kletsen met elkaar. Bedankt voor al jullie feedback
en kritische vragen; het onderzoek en mijn presentaties zijn hier stuk voor stuk beter van
geworden. Nanette, dank voor de gastvrijheid!

Mijn carpoolmaatjes Marion, Loes, Patty en Anne en interim-carpoolmaatjes Josien en

Anne-Lotte. De dagelijkse reis naar Maastricht zou een stuk langer zijn zonder jullie! Naast alle
gezelligheid is er ook altijd een luisterend oor; enorm belangrijk in ons vak. Loes en Josien,
bedankt voor alle tips als gepromoveerde ervaringsdeskundigen! Marion, Patty, Anne en
Anne-Lotte; met onze tips moet het bij jullie zeker goedkomen!

Mijn vriendinnen “thuis”; Joke, Judith, Katrijn, Nastasja en Mariska. De meeste van jullie ken
ik al vanaf de basisschool, en het voelt altijd als thuiskomen bij jullie. Ook al zie ik jullie veel
te weinig en is de afstand naar Zeeuws-Vlaanderen soms net iets te groot, ik voel me altijd
welkom en kan altijd op jullie rekenen. Bedankt voor de gezellige avonden en ons jaarlijkse
weekendje weg, dat waren heerlijke uitjes in deze drukke tijden. Ik ga nu écht beginnen aan
het boek “Nooit meer te druk” dat ik vorig jaar voor mijn verjaardag heb gekregen. Bedankt
voor al jullie steun.

Jan & Tessa, Stephan & Naomi, Tijs & Yasmina, Kevin & Mandy, Stefan & Máire, Eugene & Irene
en Quinten. Bedankt voor jullie vriendschap! De gezellige avonden met jullie zorgde voor
de nodige ontspanning tussen het schrijven en werken door. Lieve Máire, zonder jou was
dit boekje nooit zo mooi geworden! Heel knap hoe je mijn wensen hebt omgezet in een
ontwerp, waar heel veel symboliek in schuil gaat. Lieve Quinten, alvast bedankt voor de foto’s;
ze worden vast prachtig!

Mijn studie-vriendinnen; Désirée, Evelien, Nicolle, Marca en Zoë. Bedankt voor de gezellige
studententijd! We hadden het er vaak over; voor welk specialisme zouden we kiezen, en waar
zouden we terechtkomen? Nu heeft ieder van ons z’n plekje gevonden. Jeske, per toeval
kwamen we elkaar tegen in een onderwijsgroep en bleken we allebei Zeeuws-Vlamingen te
zijn. Dat was genoeg bodem om een dierbare vriendschap op te bouwen. Het is altijd heerlijk
om even bij te kletsen met een hapje en een drankje erbij.
219
 Appendices

Lieve Marion. Je bent niet alleen mijn carpoolmaatje, maar ook mijn onderzoeksmaatje en
opleidingsmaatje. Ik ben enorm blij dat “paranimf” nu aan dit rijtje toegevoegd mag worden!
Het is altijd gezellig en vaak hebben we aan één woord genoeg. Hopelijk gaan we samen nog
veel meer congressen en cursussen volgen. Ik kijk al uit naar jouw promotie!

Lieve Marieke. Dat ik jou graag naast me wil hebben op deze bijzondere dag is een inkop-
pertje. Wat hebben we al veel bijzonders meegemaakt samen. Buurmeisjes vanaf ons 8e jaar
en altijd vriendinnen gebleven sindsdien. Later werd onze vriendschap steeds hechter, vooral
toen we gingen studeren. Ik mocht getuige zijn op jouw huwelijk met Ermano, en Stijn was
ceremoniemeester. Een jaar geleden had ik de eer om jullie te mogen begeleiden tijdens de
geboorte van Samuel. Ik ben nog steeds zó trots op je! Bedankt voor jullie dierbare vriend-
schap.

Naast zoveel lieve vrienden heb ik ook het geluk een hechte familie te hebben. Lieve oma, ik
ben erg dankbaar dat je deze dag mee kunt maken in goede gezondheid. We hebben altijd
veel tijd bij jullie doorgebracht toen we klein waren, bedankt voor al die fijne momenten!
Lieve familie Verdurmen en Janssens en schoonfamilie Taelman, de Bakker en Burm, het is
altijd fijn om met jullie samen te zijn. Bedankt voor de betrokkenheid bij mijn onderzoek, bij
mij en Stijn als personen en bij de bouw van ons huis.

Tiny & Frank, Jojanneke & Ralph & Hiske en Ynske & Laurens. Wat heb ik het getroffen met
jullie als schoonouders, –zussen, en –broers. Ook jullie hebben mij zien groeien sinds de
middelbare school, via de universiteit naar de persoon die ik nu ben. Bedankt voor al jullie
steun de afgelopen jaren. Mannen, en Frank in het bijzonder, bedankt voor al jullie hulp bij de
bouw.

Lieve papa, mama en Thomas. Wat een cliché, maar zonder jullie zou ik nooit de persoon
zijn die ik nu ben. Papa & mama, jullie hebben ons altijd gestimuleerd en gesteund waar dat
mogelijk was. Nog altijd staan jullie dag en nacht voor ons klaar. Papa, jij leerde me analytisch
te denken en door te pakken. Daarnaast leerde je me dromen na te jagen, zoals je zelf ook
hebt gedaan in Qatar. Mama, van jou heb ik zeker dat zorgzame karakter geërfd. Ik bewonder
het enorm hoe je nog steeds voor mij en Thomas zorgt; dankzij jouw hulp kon ik vaak in het
weekend nog een paar uur extra schrijven, of een keer iets leuks met Stijn gaan doen. We
horen elkaar bijna dagelijks, en deze gesprekken zijn enorm waardevol voor mij. Het is heerlijk
om te zien dat jullie na al die jaren nog steeds gek op elkaar zijn. Jullie zijn een voorbeeld
voor ons.

220
 Dankwoord

Thomas, hoe anders kunnen een broer en een zus zijn? We hebben dezelfde opvoeding
gehad, maar door andere levenservaringen zijn we heel verschillende personen geworden. Je
hebt een hart van goud. Ik ben trots op je en bewonder je om de persoon die je bent.

Lieve Stijn, wat een tijd hebben we achter de rug. We zijn ondertussen meer dan 12 jaar
samen en hebben altijd onze dromen nagejaagd. Ik ging studeren in Maastricht, jij in Zwolle,
ik ging een tijdje naar India, jij naar China. Onze relatie is hierin nooit een beperkende factor
geweest. Toen ik een baan kreeg als arts-assistent hebben we dan ook niet lang moeten
nadenken; het was tijd voor onze volgende droom. Een oude boerderij opknappen in een
klein dorpje, helemaal zelfstandig. En wat ben ik trots op je; het wordt prachtig! Daarnaast
ben ik je enorm dankbaar voor de vrijheid die je mij geeft, om ook mijn eigen dromen na
te jagen. Ik werk veel en hard, en jij zult nooit klagen als ik weer eens een avond achter de
laptop doorbreng. Je bent mijn rots in de branding. Hopelijk kunnen we nog veel van onze
dromen werkelijkheid laten worden. Ik hou van je.

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 Appendices

Curriculum vitae
Kim Verdurmen werd op 17 juli 1989 geboren
in Terneuzen. In 2007 haalde zij haar VWO-
diploma aan het Reynaertcollege te Hulst. Na
aanvankelijk uitgeloot te zijn, kon ze alsnog
in hetzelfde jaar starten met de opleiding
geneeskunde aan de Universiteit Maastricht.
Haar keuzecoschap verloskunde volgde ze
in het Mahatma Gandhi Institute of Medical
Sciences te Sevagram, India. Hierna volgde haar
eerste kennismaking met wetenschappelijk
onderzoek tijdens haar wetenschapsstage in
het Máxima Medisch Centrum te Veldhoven,
onder leiding van prof. dr. Guid Oei. Hierdoor
raakte ze betrokken bij de onderzoeksgroep
“fundamenteel perinatologisch onderzoek” en
werd de basis gelegd voor wat later zou uitmonden in dit proefschrift. In 2013 ging Kim na
het behalen van haar diploma als basisarts aan het werk als arts-assistent niet in opleiding
bij de afdeling gynaecologie & obstetrie in het Máxima Medisch Centrum. In 2015 startte ze
met de opleiding tot gynaecoloog in cluster Maastricht. Haar eerste opleidingsjaar doorliep
ze in het Máxima Medisch Centrum. Haar opleiders waren hier prof. dr. M.Y. Bongers en dr. J.W.
Maas. Ze is nu aan het eind van haar tweede opleidingsjaar, dat ze doorliep in het MUMC+,
met als opleiders prof. dr. R.F.P.M. Kruitwagen en dr. T. van Gorp.

Kim woont in Soerendonk met Stijn Taelman, waar ze samen bouwen aan hun droomhuis.

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