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Management of fetal distress during term labor

Citation for published version (APA):Bullens, L. (2018). Management of fetal distress during term labor. Eindhoven: Technische UniversiteitEindhoven.

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Lauren Bullens Lauren Bullens

Management of fetal distress

during term labor

UITNODIGING

Voor het bijwonen van de openbare verdediging vanhet proefschrift

MANAGEMENT OF FETAL

DISTRESS DURING TERM

LABOR

doorLauren Bullens

Op vrijdag 21december om 16.00 uur

In de Senaatszaal van het Auditorium van de Technische Universiteit te Eindhoven

(zie www.tue.nl voor een routebeschrijving en plattegrond)

Aansluitend aan de verdediging bent u van harte uitgenoding voor de receptie ter plaatse

Lauren [email protected]

Paranimfen

Eva BullensEva van de [email protected]


Lauren Bullens

Cover design by Loes Kema, ‘Koru’, Maori symbol for new life.

Printed by GVO drukkers & vormgevers B.V.

ISBN: 978-94-6332-424-3.

A catalogue record is available from the Eindhoven University of Technology Library.

© Copyright 2018, Lauren M. Bullens.

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 this thesis has been kindly provided by: ABN AMRO, Chipsoft,

Rabobank Eindhoven-Veldhoven, Ferring BV, Stichting de Weijerhorst, Nemo

Healthcare, Vakblad Vroeg, MedSim, BMA BV (Mosos), Vifor Pharma Group,

GrafiMedics BV, Erbe, Stöpler Nederland BV, Technische Universiteit Eindhoven,

Máxima Medisch Centrum.

The research described in this thesis is performed within the IMPULS perinatology

framework.


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

vrijdag 21 december 2018 om 16.00 uur

door

Lauren Maria Bullens

Geboren te Eindhoven

Voor mijn ouders

Dit proefschrift is goedgekeurd door de promotor en de copromotores en

de samenstelling van de promotiecommissie is als volgt:

Voorzitter: Prof. dr. Ir. P.H.N. de With

Promotor: Prof. dr. S.G. Oei

1e copromotor: dr. ir. M.B. van der Hout-van der Jagt

2e copromotor: dr. P.J. van Runnard Heimel (Máxima Medisch Centrum)

Leden:

Prof. dr. M.E.A. Spaanderman (Maastricht Universitair Medisch Centrum)

Prof. dr. P.P. van den Berg (Universitair Medisch Centrum Groningen)

Prof. dr. S. Bambang Oetomo

Prof. dr. ir. F.N. van de Vosse

Het onderzoek dat in dit proefschrift wordt beschreven is uitgevoerd in

overeenstemming met de TU/e Gedragscode Wetenschapsbeoefening.

Table of contents

Chapter 1 General introduction and outline of this thesis. 9

Chapter 2 Interventions for intrauterine resuscitation in suspected fetal

distress during term labor: a systematic review.

Obstetrical & Gynecological Survey. 2015;70:524-39

25

Chapter 3 Management of intrapartum fetal distress in The Netherlands:

a clinical practice survey.

European Journal of Obstetrics and Gynecology and Reproductive

Biology. 2016;205:48-53

61

Chapter 4 A simulation model to study maternal hyperoxygenation during

labor.

Acta Obstetricia et Gynecologica Scandinavica. 2014;93:1268- 75

79

Chapter 5 Intrauterine resuscitation during term labor by maternal

hyperoxygenation: a randomized controlled trial (study protocol

INTEREST O2).

Trials. 2018;19:195

97


hyperoxygenation: a randomized controlled trial (study results).

Submitted

121

Chapter 7 Intrapartum maternal hemoglobin level: does it affect fetal and

neonatal outcome and mode of delivery?

A systematic review of the literature.

Submitted

145

Chapter 8 Maternal hemoglobin level and its relation to fetal distress, mode

of delivery, and short-term neonatal outcome: a retrospective

cohort study.

Submitted

169

Table of contents

Chapter 1 General introduction and outline of this thesis. 9

Chapter 2 Interventions for intrauterine resuscitation in suspected fetal

distress during term labor: a systematic review.


25

Chapter 3 Management of intrapartum fetal distress in The Netherlands:

a clinical practice survey.

European Journal of Obstetrics and Gynecology and Reproductive

Biology. 2016;205:48-53

61

Chapter 4 A simulation model to study maternal hyperoxygenation during

labor.

Acta Obstetricia et Gynecologica Scandinavica. 2014;93:1268- 75

79


hyperoxygenation: a randomized controlled trial (study protocol

INTEREST O2).

Trials. 2018;19:195

97


hyperoxygenation: a randomized controlled trial (study results).

Submitted

121

Chapter 7 Intrapartum maternal hemoglobin level: does it affect fetal and

neonatal outcome and mode of delivery?

A systematic review of the literature.

Submitted

145

Chapter 8 Maternal hemoglobin level and its relation to fetal distress, mode

of delivery, and short-term neonatal outcome: a retrospective

cohort study.

Submitted

169

Chapter 9 General discussion and future perspectives. 187

Chapter 10 Summary 201

Appendices List of abbreviations 221

List of publications 223

Dankwoord 227

Curriculum vitae 230

Chapter 1

General introduction and

outline of this thesis

Chapter 1

10

General introduction

Perinatal asphyxia is an important cause of neonatal morbidity and mortality. In The

Netherlands, every year approximately 250 term babies are born with signs of

perinatal asphyxia (0.15%).1,2 Apart from the emotional impact on those children and

their families, it also has a significant impact on society, accounting for a significant

amount of health costs.3 Prolonged, inadequate oxygenation may cause damage to

various fetal organs, such as kidneys, bowels, and the brain.4 Brain damage caused

by intrapartum asphyxia is called hypoxic-ischemic encephalopathy (HIE). About

25% of the asphyxiated neonates will face major handicaps later in life, such as

cerebral palsy, cognitive impairment and impaired hearing and vision. In 10-20%,

perinatal asphyxia leads to neonatal death in the first month after birth.5-7 Yet,

perinatal asphyxia accounts for only a small part of the total amount of neonates

with adverse neurologic outcome.8,9

The term “asphyxia” derives from the ancient Greek “a-sphyxis”, meaning “no

pulse”. In the 18th century, it was synonymous with “suffocation”. Nowadays, several

definitions are in use to indicate perinatal asphyxia. The American College of

Obstetrics and Gynecology (ACOG) defines perinatal asphyxia as a 5-minute Apgar

score ≤ 5,10 combined with arterial cord blood gas values indicating acidosis (pH <

7.0 and/or base deficit ≥ 16 mmol/l) and clinical signs (seizures or hypotonia).11 In

Dutch Neonatal Intensive Care Units (NICUs) diagnostic criteria are low Apgar score,

combined with arterial cord blood gas values indicating acidosis and neonatal

reanimation.1,2

Obstetricians are challenged to adequately estimate fetal well-being, and to timely

plan intervention when fetal hypoxia is suspected. It is therefore not surprising that

inadequate assessment of fetal oxygenation status, and refraining from the right

interventions when fetal distress is suspected, are frequently reported as

substandard factors that contribute to the onset of perinatal asphyxia.12-15

It is difficult to determine the best intervention to perform in case of abnormal fetal

heart rate (FHR) tracings. One should decide whether an invasive procedure is

needed to deliver the baby, or if fetal oxygenation can be restored by applying

intrauterine resuscitation. Intrauterine resuscitation aims to treat the underlying

cause of hypoxia keeping the fetus inside the uterus. This may prevent an

emergency operative delivery, which is a well-known risk factor for adverse maternal

and neonatal outcome. Since methods to continuously and reliably determine fetal

oxygenation during labor are not available in clinical practice, it is difficult to

estimate how much time is left before the fetus actually becomes asphyctic.

Risk factors for fetal distress during labor

Several risk factors for the occurrence of fetal distress can be identified, among

which maternal age, nulliparity, low placental weight, gestational age,

chorioamnionitis, previous cesarean section, fetal growth restriction, obesity,

diabetes, and preeclampsia.16-18 It is useful to have insight in factors that influence

the risk on fetal distress during labor, to enable delivery room staff to anticipate on

these risk factors, or to determine the appropriate mode of delivery.

In addition, sheep-studies have shown that maternal anemia leads to reduced

oxygen delivery in the uterus, placenta, and fetus.19,20 Also maternal hemoglobin

(Hb) level may influence the risk of fetal distress during labor. Various studies

reported on the consequences of anemia in pregnancy, with contradictory results.

An increased risk of adverse maternal and neonatal outcome is reported, including

miscarriage, stillbirth, prematurity, and low birth weight.21-31 Apart from low Hb

concentrations, high Hb levels are also associated with adverse perinatal

outcome.22,24,29-31 High Hb may be a consequence of poor plasma expansion, as seen

in hypertensive disorders such as preeclampsia. Also, relatively high Hb levels itself

lead to increased blood viscosity.32 In both ways, blood flow and fetomaternal gas

exchange in the placenta may be reduced.32 To compensate to this decreased

oxygen supply, the fetus will increase oxygen extraction from the intervillous space.

However, when maternal anemia is severe, or when compensatory mechanisms fail,

the supply of oxygen to fetal tissues will be inadequate. The effect of abnormal Hb

levels on the risk of fetal distress is not well investigated.

Assessment of fetal oxygenation

In the 1930’s, Sir Joseph Barcroft referred to the relatively low partial oxygen

pressure (pO2) in which the human fetus develops with “Mount Everest in Utero”.33

Despite the low pO2 in the fetal environment, a healthy fetus can maintain adequate

tissue oxygenation, due to several adaptive mechanisms. These include a relatively

General introduction and outline of this thesis

11

1

General introduction

Perinatal asphyxia is an important cause of neonatal morbidity and mortality. In The

Netherlands, every year approximately 250 term babies are born with signs of

perinatal asphyxia (0.15%).1,2 Apart from the emotional impact on those children and

their families, it also has a significant impact on society, accounting for a significant

amount of health costs.3 Prolonged, inadequate oxygenation may cause damage to

various fetal organs, such as kidneys, bowels, and the brain.4 Brain damage caused

by intrapartum asphyxia is called hypoxic-ischemic encephalopathy (HIE). About

25% of the asphyxiated neonates will face major handicaps later in life, such as

cerebral palsy, cognitive impairment and impaired hearing and vision. In 10-20%,

perinatal asphyxia leads to neonatal death in the first month after birth.5-7 Yet,

perinatal asphyxia accounts for only a small part of the total amount of neonates

with adverse neurologic outcome.8,9

The term “asphyxia” derives from the ancient Greek “a-sphyxis”, meaning “no

pulse”. In the 18th century, it was synonymous with “suffocation”. Nowadays, several

definitions are in use to indicate perinatal asphyxia. The American College of

Obstetrics and Gynecology (ACOG) defines perinatal asphyxia as a 5-minute Apgar

score ≤ 5,10 combined with arterial cord blood gas values indicating acidosis (pH <

7.0 and/or base deficit ≥ 16 mmol/l) and clinical signs (seizures or hypotonia).11 In

Dutch Neonatal Intensive Care Units (NICUs) diagnostic criteria are low Apgar score,

combined with arterial cord blood gas values indicating acidosis and neonatal

reanimation.1,2

Obstetricians are challenged to adequately estimate fetal well-being, and to timely

plan intervention when fetal hypoxia is suspected. It is therefore not surprising that

inadequate assessment of fetal oxygenation status, and refraining from the right

interventions when fetal distress is suspected, are frequently reported as

substandard factors that contribute to the onset of perinatal asphyxia.12-15

It is difficult to determine the best intervention to perform in case of abnormal fetal

heart rate (FHR) tracings. One should decide whether an invasive procedure is

needed to deliver the baby, or if fetal oxygenation can be restored by applying

intrauterine resuscitation. Intrauterine resuscitation aims to treat the underlying

cause of hypoxia keeping the fetus inside the uterus. This may prevent an

emergency operative delivery, which is a well-known risk factor for adverse maternal

and neonatal outcome. Since methods to continuously and reliably determine fetal

oxygenation during labor are not available in clinical practice, it is difficult to

estimate how much time is left before the fetus actually becomes asphyctic.

Risk factors for fetal distress during labor

Several risk factors for the occurrence of fetal distress can be identified, among

which maternal age, nulliparity, low placental weight, gestational age,

chorioamnionitis, previous cesarean section, fetal growth restriction, obesity,

diabetes, and preeclampsia.16-18 It is useful to have insight in factors that influence

the risk on fetal distress during labor, to enable delivery room staff to anticipate on

these risk factors, or to determine the appropriate mode of delivery.

In addition, sheep-studies have shown that maternal anemia leads to reduced

oxygen delivery in the uterus, placenta, and fetus.19,20 Also maternal hemoglobin

(Hb) level may influence the risk of fetal distress during labor. Various studies

reported on the consequences of anemia in pregnancy, with contradictory results.

An increased risk of adverse maternal and neonatal outcome is reported, including

miscarriage, stillbirth, prematurity, and low birth weight.21-31 Apart from low Hb

concentrations, high Hb levels are also associated with adverse perinatal

outcome.22,24,29-31 High Hb may be a consequence of poor plasma expansion, as seen

in hypertensive disorders such as preeclampsia. Also, relatively high Hb levels itself

lead to increased blood viscosity.32 In both ways, blood flow and fetomaternal gas

exchange in the placenta may be reduced.32 To compensate to this decreased

oxygen supply, the fetus will increase oxygen extraction from the intervillous space.

However, when maternal anemia is severe, or when compensatory mechanisms fail,

the supply of oxygen to fetal tissues will be inadequate. The effect of abnormal Hb

levels on the risk of fetal distress is not well investigated.

Assessment of fetal oxygenation

In the 1930’s, Sir Joseph Barcroft referred to the relatively low partial oxygen

pressure (pO2) in which the human fetus develops with “Mount Everest in Utero”.33

Despite the low pO2 in the fetal environment, a healthy fetus can maintain adequate

tissue oxygenation, due to several adaptive mechanisms. These include a relatively

Chapter 1

12

high Hb level with a higher affinity for oxygen (O2) than the maternal hemoglobin, a

higher heart rate, vascular bypasses (e.g. the foramen ovale and ductus arteriosus),

and differences in pO2 and carbon dioxide (CO2) gradient between the mother and

the fetus.34 In general, these mechanisms protect the fetus against the intermittent

periods of relative hypoxia due to labor contractions. However, this vulnerable

balance is easily disturbed, for example by severe or prolonged uterine contractions.

The fetus has several adaptive mechanisms allowing compensation in the case of

hypoxia. These include slowing down the FHR as a result of baro- and

chemoreceptor responses, reducing body movements, redistribution of blood flow

to the heart, brain, and adrenal glands, and a switch to anaerobic metabolism.35

These adaptations are needed to maintain blood pressure and economize

oxygenation to maintain normal function of the vital organs. To what extent these

mechanisms prevent the fetus from asphyxia depends on the general health of the

fetus and the intensity and duration of the hypoxic events.

During anaerobic metabolism H+-ions cannot bind to oxygen, and organic acids

such as lactic acid are formed, both contributing to a drop in blood pH. As CO2 is no

longer sufficiently removed from the circulation, it accumulates, leading to

respiratory acidosis.35 When buffers such as HCO3- get depleted, metabolic acidosis

occurs. When tissue pH further drops, cell-function cannot be maintained, leading to

organ damage. As asphyxia progresses, also the fetal heart and central nervous

system are affected, a decrease in cardiac output and following hypotension will

lead to further tissue damage and ultimately fetal death.4,36

To give insight in this complex process of autonomic responses leading to changes

in FHR, our research group developed a mathematical simulation model.37-39 This

model is based on physiological parameters that influence FHR and maternal,

placental, and fetal oxygenation. These parameters include maternal cardiac output,

maternal oxygenation, uterine pressure and flow, oxygen diffusion capacity in the

placenta, fetal cerebral blood flow, fetal oxygen consumption, baroreceptor and

chemoreceptor responses, and catecholamines. This model estimates physiological

parameters that cannot yet be measured in clinical practice, such as fetal

oxygenation or blood pressure, thereby enhancing insight into the physiological

processes. Besides, a model is helpful to develop hypotheses, which subsequently

can be investigated in human models.

In clinical practice methods to directly measure fetal oxygenation during labor are

not currently available.40-44 As FHR is influenced by fetal oxygenation, a combined

registration of FHR in relation to uterine contractions (the cardiotocogram (CTG)) is

used to estimate fetal well-being during labor. Judgement of the CTG is based on

several characteristics: the frequency of uterine contractions, baseline, beat-to-beat

variability, accelerations (increase from baseline of at least 15 beats per minute

(BPM) for at least 15 seconds), decelerations (decrease from baseline of at least 15

BPM for at least 15 seconds) and their relation to uterine contractions.45 Normal

variability and FHR accelerations reflect an intact, well-oxygenated autonomic

nervous system and heart, whereas decreased variability (< 5 BPM) and FHR

decelerations may be a sign of fetal hypoxia.46-48

As the CTG has a high false-positive rate in the prediction of fetal hypoxia, and a

large intra- and interobserver variability, clinicians are challenged to decide when

intervention is indicated.49-54 To distinguish a hypoxic fetus from a well-oxygenated

fetus, pH and/or lactate measurement by fetal scalp blood sampling (FSBS)55 can be

performed when FHR is nonreassuring. However, this is an invasive and sometimes

time-consuming method, which is not always available. In addition, it does not

provide us with continuous information on fetal acid-base balance.

Alternative methods to estimate fetal well-being during labor have been extensively

studied. Past decade, ST-analysis was introduced in addition to CTG monitoring, to

help diagnose fetal hypoxia, by detecting the change in the ST-segment of the fetal

electrocardiogram (fECG).56,57 In many hospitals this method of fetal monitoring has

been abandoned, since a Cochrane review in 2015 showed it did not lead to an

improvement in neonatal outcome.58 However fECG is still a potentially valuable tool

for fetal monitoring, but new algorithms are needed to make sure ST-measurements

correlate better with neonatal outcome.59 Also, transcutaneous measurement of

carbon dioxide tension (tcpCO2) and fetal arterial oxygen saturation with reflectance

pulse oximetry have been extensively studied.40-44,60,61 Transcutaneous pCO2

measurement was too complicated to be used in clinical practice.41 Also, the

measurements were frequently disturbed by many factors, for example, reduced

local perfusion of the fetal head due to the caput succedaneum.40 In contrast,

reflectance pulse oximetry was easy to use, but the accuracy needed to be further

investigated.41-43 Despite the fact that two studies indicated a reduction in the rate of

cesarean sections for fetal distress,44,60 a Cochrane review in 2014 concluded that the


13

1

high Hb level with a higher affinity for oxygen (O2) than the maternal hemoglobin, a

higher heart rate, vascular bypasses (e.g. the foramen ovale and ductus arteriosus),

and differences in pO2 and carbon dioxide (CO2) gradient between the mother and

the fetus.34 In general, these mechanisms protect the fetus against the intermittent

periods of relative hypoxia due to labor contractions. However, this vulnerable

balance is easily disturbed, for example by severe or prolonged uterine contractions.

The fetus has several adaptive mechanisms allowing compensation in the case of

hypoxia. These include slowing down the FHR as a result of baro- and

chemoreceptor responses, reducing body movements, redistribution of blood flow

to the heart, brain, and adrenal glands, and a switch to anaerobic metabolism.35

These adaptations are needed to maintain blood pressure and economize

oxygenation to maintain normal function of the vital organs. To what extent these

mechanisms prevent the fetus from asphyxia depends on the general health of the

fetus and the intensity and duration of the hypoxic events.

During anaerobic metabolism H+-ions cannot bind to oxygen, and organic acids

such as lactic acid are formed, both contributing to a drop in blood pH. As CO2 is no

longer sufficiently removed from the circulation, it accumulates, leading to

respiratory acidosis.35 When buffers such as HCO3- get depleted, metabolic acidosis

occurs. When tissue pH further drops, cell-function cannot be maintained, leading to

organ damage. As asphyxia progresses, also the fetal heart and central nervous

system are affected, a decrease in cardiac output and following hypotension will

lead to further tissue damage and ultimately fetal death.4,36

To give insight in this complex process of autonomic responses leading to changes

in FHR, our research group developed a mathematical simulation model.37-39 This

model is based on physiological parameters that influence FHR and maternal,

placental, and fetal oxygenation. These parameters include maternal cardiac output,

maternal oxygenation, uterine pressure and flow, oxygen diffusion capacity in the

placenta, fetal cerebral blood flow, fetal oxygen consumption, baroreceptor and

chemoreceptor responses, and catecholamines. This model estimates physiological

parameters that cannot yet be measured in clinical practice, such as fetal

oxygenation or blood pressure, thereby enhancing insight into the physiological

processes. Besides, a model is helpful to develop hypotheses, which subsequently

can be investigated in human models.

In clinical practice methods to directly measure fetal oxygenation during labor are

not currently available.40-44 As FHR is influenced by fetal oxygenation, a combined

registration of FHR in relation to uterine contractions (the cardiotocogram (CTG)) is

used to estimate fetal well-being during labor. Judgement of the CTG is based on

several characteristics: the frequency of uterine contractions, baseline, beat-to-beat

variability, accelerations (increase from baseline of at least 15 beats per minute

(BPM) for at least 15 seconds), decelerations (decrease from baseline of at least 15

BPM for at least 15 seconds) and their relation to uterine contractions.45 Normal

variability and FHR accelerations reflect an intact, well-oxygenated autonomic

nervous system and heart, whereas decreased variability (< 5 BPM) and FHR

decelerations may be a sign of fetal hypoxia.46-48

As the CTG has a high false-positive rate in the prediction of fetal hypoxia, and a

large intra- and interobserver variability, clinicians are challenged to decide when

intervention is indicated.49-54 To distinguish a hypoxic fetus from a well-oxygenated

fetus, pH and/or lactate measurement by fetal scalp blood sampling (FSBS)55 can be

performed when FHR is nonreassuring. However, this is an invasive and sometimes

time-consuming method, which is not always available. In addition, it does not

provide us with continuous information on fetal acid-base balance.

Alternative methods to estimate fetal well-being during labor have been extensively

studied. Past decade, ST-analysis was introduced in addition to CTG monitoring, to

help diagnose fetal hypoxia, by detecting the change in the ST-segment of the fetal

electrocardiogram (fECG).56,57 In many hospitals this method of fetal monitoring has

been abandoned, since a Cochrane review in 2015 showed it did not lead to an

improvement in neonatal outcome.58 However fECG is still a potentially valuable tool

for fetal monitoring, but new algorithms are needed to make sure ST-measurements

correlate better with neonatal outcome.59 Also, transcutaneous measurement of

carbon dioxide tension (tcpCO2) and fetal arterial oxygen saturation with reflectance

pulse oximetry have been extensively studied.40-44,60,61 Transcutaneous pCO2

measurement was too complicated to be used in clinical practice.41 Also, the

measurements were frequently disturbed by many factors, for example, reduced

local perfusion of the fetal head due to the caput succedaneum.40 In contrast,

reflectance pulse oximetry was easy to use, but the accuracy needed to be further

investigated.41-43 Despite the fact that two studies indicated a reduction in the rate of

cesarean sections for fetal distress,44,60 a Cochrane review in 2014 concluded that the

Chapter 1

14

addition of fetal pulse oximetry to CTG did not reduce the overall cesarean section

rate.61 The included studies did not provide sufficient support for the use

of fetal pulse oximetry to reduce cesarean sections for nonreassuring fetal status.

Moreover, none of the studies found an improvement in neonatal outcome.

In conclusion, CTG combined with FSBS is still the best available method to

estimate fetal oxygenation during labor. When FHR is nonreassuring, fetal hypoxia

cannot be ruled out. As prolonged fetal hypoxia may lead to asphyxia, hypoxic-

ischemic encephalopathy, and fetal death, one should attempt to improve fetal

oxygenation when fetal distress is suspected, before immediate delivery is

indicated.

Intrauterine resuscitation techniques

Since inadequate fetal oxygenation may have detrimental effects, prolonged fetal

hypoxia should be prevented. Thus, when fetal distress is suspected and fetal

oxygen level cannot be restored, one may aim for immediate delivery. Since assisted

delivery carries risks for both the mother and fetus,62,63 a spontaneous vaginal

delivery is preferred, as long as the fetal condition is adequate.

Depending on the presumable cause of the decelerations, the intervention to

restore oxygenation should be focusing on increasing oxygen delivery, alleviation of

cord compression and/or improvement of uteroplacental blood flow.

Past decades, several interventions to improve fetal oxygenation in case of fetal

distress during labor, without delivering the fetus, have been described. Commonly

used techniques are maternal hyperoxygenation, maternal repositioning,

intravenous fluid administration, amnioinfusion, discontinuation of uterotonic drugs

(e.g. oxytocin), the use of tocolytic drugs, and intermittent pushing. These

interventions aim to reduce the cause of severe uterine contractions, and/or undo

the cause of impaired oxygenation, and/or try to improve oxygenation by increasing

blood flow or oxygen levels in the blood.

First, maternal hyperoxygenation (administration of additional oxygen to the

mother), using 100% oxygen increases both maternal and fetal oxygen levels.42,64-69

However, robust data to support a beneficial effect on the distressed fetus are

limited. The mechanism of intravenous fluid administration consists of increasing the

blood flow toward the uterus, which would then increase the oxygen delivery rate.64

However, some state that this effect is nullified by the effect of hemodilution.69

The mechanisms of the other interventions are based on increasing fetoplacental

blood flow. Reduction in uterine activity by use of a tocolytic agent restores the

blood flow through the placenta and umbilical cord, as the reduction in blood flow

during contractions is related to the strength and duration of contractions.70-72

Furthermore, the addition of fluid in the uterine cavity (amnioinfusion) may relieve

umbilical cord compression. A change in labor position may both relieve umbilical

cord compression improving blood flow towards the fetus and dissolve aortocaval

compression, improving uteroplacental blood flow. In addition, during the second

stage of labor, intermittent pushing may provide the fetus more time to recover

from the contractions that compromise its condition.

Even though several studies have evaluated the effect of intrauterine resuscitation

techniques on fetal well-being, robust evidence to support a beneficial effect on the

distressed fetus is limited and sometimes contradictory.64 As a result, there is no

agreement on the use of several intrauterine resuscitation techniques during labor.

Most of the above mentioned techniques are commonly used in clinical practice,

eventhough the evidence regarding the effect on fetal and neonatal outcome is

limited. As a result, recommendations on the management of fetal distress from

clinical guidelines may differ. Consequently, a large variation in clinical practice may

exist between the obstetric departments of Dutch hospitals. One of the still

frequently debated techniques is the use of maternal hyperoxygenation.

Maternal hyperoxygenation

Maternal hyperoxygenation refers to the administration of high fractions of inspired

oxygen to the mother, in order to improve maternal and fetal partial oxygen

pressures in the blood and thereby fetal oxygenation. Hence, saturation of maternal

Hb will not be much affected, but partial oxygen pressure may increase up to five-

fold, thus contributing to a higher oxygen gradient between mother and fetus and

thus to improved pO2 and saturation levels in the fetal blood. This intervention is

much debated, because it is unclear if the beneficial effects outweigh potentially

harmful effects.


15

1

addition of fetal pulse oximetry to CTG did not reduce the overall cesarean section

rate.61 The included studies did not provide sufficient support for the use

of fetal pulse oximetry to reduce cesarean sections for nonreassuring fetal status.

Moreover, none of the studies found an improvement in neonatal outcome.

In conclusion, CTG combined with FSBS is still the best available method to

estimate fetal oxygenation during labor. When FHR is nonreassuring, fetal hypoxia

cannot be ruled out. As prolonged fetal hypoxia may lead to asphyxia, hypoxic-

ischemic encephalopathy, and fetal death, one should attempt to improve fetal

oxygenation when fetal distress is suspected, before immediate delivery is

indicated.

Intrauterine resuscitation techniques

Since inadequate fetal oxygenation may have detrimental effects, prolonged fetal

hypoxia should be prevented. Thus, when fetal distress is suspected and fetal

oxygen level cannot be restored, one may aim for immediate delivery. Since assisted

delivery carries risks for both the mother and fetus,62,63 a spontaneous vaginal

delivery is preferred, as long as the fetal condition is adequate.

Depending on the presumable cause of the decelerations, the intervention to

restore oxygenation should be focusing on increasing oxygen delivery, alleviation of

cord compression and/or improvement of uteroplacental blood flow.

Past decades, several interventions to improve fetal oxygenation in case of fetal

distress during labor, without delivering the fetus, have been described. Commonly

used techniques are maternal hyperoxygenation, maternal repositioning,

intravenous fluid administration, amnioinfusion, discontinuation of uterotonic drugs

(e.g. oxytocin), the use of tocolytic drugs, and intermittent pushing. These

interventions aim to reduce the cause of severe uterine contractions, and/or undo

the cause of impaired oxygenation, and/or try to improve oxygenation by increasing

blood flow or oxygen levels in the blood.

First, maternal hyperoxygenation (administration of additional oxygen to the

mother), using 100% oxygen increases both maternal and fetal oxygen levels.42,64-69

However, robust data to support a beneficial effect on the distressed fetus are

limited. The mechanism of intravenous fluid administration consists of increasing the

blood flow toward the uterus, which would then increase the oxygen delivery rate.64

However, some state that this effect is nullified by the effect of hemodilution.69


blood flow. Reduction in uterine activity by use of a tocolytic agent restores the

blood flow through the placenta and umbilical cord, as the reduction in blood flow

during contractions is related to the strength and duration of contractions.70-72

Furthermore, the addition of fluid in the uterine cavity (amnioinfusion) may relieve

umbilical cord compression. A change in labor position may both relieve umbilical

cord compression improving blood flow towards the fetus and dissolve aortocaval

compression, improving uteroplacental blood flow. In addition, during the second

stage of labor, intermittent pushing may provide the fetus more time to recover

from the contractions that compromise its condition.

Even though several studies have evaluated the effect of intrauterine resuscitation

techniques on fetal well-being, robust evidence to support a beneficial effect on the

distressed fetus is limited and sometimes contradictory.64 As a result, there is no

agreement on the use of several intrauterine resuscitation techniques during labor.

Most of the above mentioned techniques are commonly used in clinical practice,

eventhough the evidence regarding the effect on fetal and neonatal outcome is

limited. As a result, recommendations on the management of fetal distress from

clinical guidelines may differ. Consequently, a large variation in clinical practice may

exist between the obstetric departments of Dutch hospitals. One of the still

frequently debated techniques is the use of maternal hyperoxygenation.


Maternal hyperoxygenation refers to the administration of high fractions of inspired

oxygen to the mother, in order to improve maternal and fetal partial oxygen

pressures in the blood and thereby fetal oxygenation. Hence, saturation of maternal

Hb will not be much affected, but partial oxygen pressure may increase up to five-

fold, thus contributing to a higher oxygen gradient between mother and fetus and

thus to improved pO2 and saturation levels in the fetal blood. This intervention is

much debated, because it is unclear if the beneficial effects outweigh potentially

harmful effects.

Chapter 1

16

Some studies do indicate an increase in fetal oxygenation (pO2 and saturation

(SpO2)) and an amelioration of abnormal FHR patterns during maternal

hyperoxygenation with 100% oxygen.66-73 Yet the fetal effect of maternal

hyperoxygenation has only been studied in the non-compromised fetus, showing an

increase in SpO2 and pO2.42,64,65 However, due to the poor quality of these studies, a

Cochrane review concluded “there is not enough evidence to support the use of

prophylactic oxygen therapy for women in labor, nor to evaluate its effectiveness for

fetal distress”.74

An argument not to promote maternal hyperoxygenation as standard care is the

potential increase in free oxygen radicals in both the mother and fetus.75 This

increase in oxidative stress may lead to cell damage and altered cellular function.76

However, an increase in free oxygen radicals is present in several clinical conditions,

for example, nonreassuring fetal status, and during the use of high fractions of

inspired oxygen.77,80 Also, free oxygen radical activity in the fetus is higher after a

normal vaginal delivery, compared to an elective cesarean section.81 Whether

maternal hyperoxygenation for nonreassuring fetal status increases free oxygen

radical activity has not been investigated yet.

Apart from the potential damage due to the increase in free oxygen radicals,

maternal hyperoxygenation may as well lead to a decrease in umbilical cord arterial

pH. In one study, in which either 100% oxygen or room air was supplied to laboring

women with normal FHR tracings, they found a larger proportion of umbilical cord

pH < 7.20 in the oxygenation group.82 However, the mean umbilical cord pH was

similar in both groups. An explanation for these findings might be a reduction in

uteroplacental blood flow, since both umbilical and placenta vessels are sensitive to

high oxygen levels. These vessels may constrict with hyperoxia, leading to reduced

placental gas exchange and oxygen transport towards the fetus.83 It is not clear

whether maternal hyperoxygenation has the same effect on umbilical cord pH, when

applied in case of a distressed fetus.

In conclusion, small clinical trials performed both in the compromised and non-

compromised human fetus suggest a beneficial effect of maternal hyperoxygenation

on fetal condition, but also raises questions concerning the potential risks. The

question if these beneficial effects outweigh the potential side effects cannot be

answered yet.

Outline of this thesis

This thesis aims to answer the following questions:

1. Which intrauterine resuscitation techniques are proven to be effective for the

treatment of fetal distress during term labor?

2. Which methods are used for fetal monitoring in Dutch hospitals, and which

interventions are performed in case of suspected fetal distress?

3. Which recommendations regarding diagnosis and treatment of fetal distress are

described in international guidelines, and do differences in guidelines result in

clinical practice variation?

4. What is the effect of maternal hyperoxygenation on fetal oxygenation and FHR,

according to a mathematical simulation model?

5. What is the clinical effect of maternal hyperoxygenation applied in the case of

suspected fetal distress during the second stage of labor?

6. Does intrapartum maternal hemoglobin level influence the risk of fetal distress

during term labor?

The answers to these questions are described in the following chapters:

Chapter 2 gives a systematic overview of the currently available literature regarding

the effect of intrauterine resuscitation techniques applied in term labor. This study

was set up to answer research question 1.

Chapter 3 reports on the practice variation in the diagnosis and management of

fetal distress during labor in The Netherlands. This chapter also describes a

comparison of international recommendations regarding fetal monitoring and

treatment of fetal distress during labor. This study was set up to answer research

questions 2 and 3.


17

1

Some studies do indicate an increase in fetal oxygenation (pO2 and saturation

(SpO2)) and an amelioration of abnormal FHR patterns during maternal

hyperoxygenation with 100% oxygen.66-73 Yet the fetal effect of maternal

hyperoxygenation has only been studied in the non-compromised fetus, showing an

increase in SpO2 and pO2.42,64,65 However, due to the poor quality of these studies, a

Cochrane review concluded “there is not enough evidence to support the use of

prophylactic oxygen therapy for women in labor, nor to evaluate its effectiveness for

fetal distress”.74

An argument not to promote maternal hyperoxygenation as standard care is the

potential increase in free oxygen radicals in both the mother and fetus.75 This

increase in oxidative stress may lead to cell damage and altered cellular function.76

However, an increase in free oxygen radicals is present in several clinical conditions,

for example, nonreassuring fetal status, and during the use of high fractions of

inspired oxygen.77,80 Also, free oxygen radical activity in the fetus is higher after a

normal vaginal delivery, compared to an elective cesarean section.81 Whether

maternal hyperoxygenation for nonreassuring fetal status increases free oxygen

radical activity has not been investigated yet.

Apart from the potential damage due to the increase in free oxygen radicals,

maternal hyperoxygenation may as well lead to a decrease in umbilical cord arterial

pH. In one study, in which either 100% oxygen or room air was supplied to laboring

women with normal FHR tracings, they found a larger proportion of umbilical cord

pH < 7.20 in the oxygenation group.82 However, the mean umbilical cord pH was

similar in both groups. An explanation for these findings might be a reduction in

uteroplacental blood flow, since both umbilical and placenta vessels are sensitive to

high oxygen levels. These vessels may constrict with hyperoxia, leading to reduced

placental gas exchange and oxygen transport towards the fetus.83 It is not clear

whether maternal hyperoxygenation has the same effect on umbilical cord pH, when

applied in case of a distressed fetus.

In conclusion, small clinical trials performed both in the compromised and non-

compromised human fetus suggest a beneficial effect of maternal hyperoxygenation

on fetal condition, but also raises questions concerning the potential risks. The

question if these beneficial effects outweigh the potential side effects cannot be

answered yet.

Outline of this thesis

This thesis aims to answer the following questions:

1. Which intrauterine resuscitation techniques are proven to be effective for the

treatment of fetal distress during term labor?

2. Which methods are used for fetal monitoring in Dutch hospitals, and which

interventions are performed in case of suspected fetal distress?

3. Which recommendations regarding diagnosis and treatment of fetal distress are

described in international guidelines, and do differences in guidelines result in

clinical practice variation?

4. What is the effect of maternal hyperoxygenation on fetal oxygenation and FHR,

according to a mathematical simulation model?

5. What is the clinical effect of maternal hyperoxygenation applied in the case of

suspected fetal distress during the second stage of labor?

6. Does intrapartum maternal hemoglobin level influence the risk of fetal distress

during term labor?

The answers to these questions are described in the following chapters:

Chapter 2 gives a systematic overview of the currently available literature regarding

the effect of intrauterine resuscitation techniques applied in term labor. This study

was set up to answer research question 1.

Chapter 3 reports on the practice variation in the diagnosis and management of

fetal distress during labor in The Netherlands. This chapter also describes a

comparison of international recommendations regarding fetal monitoring and

treatment of fetal distress during labor. This study was set up to answer research

questions 2 and 3.

Chapter 1

18

Chapter 4 describes the effect of maternal hyperoxygenation on pO2 in several

fetoplacental compartments and FHR, according to a mathematical simulation

model. This study refers to research question 4.

Chapter 5 proposes a study to investigate the clinical effect of maternal

hyperoxygenation during term labor. This is the study protocol for a randomized

controlled trial, conducted to answer research question 5.

Chapter 6 provides the study results of a randomized controlled trial, by describing

the effect of maternal hyperoxygenation during the second stage of labor on FHR,

Apgar score, cord blood gas analysis, NICU admission, perinatal death, free oxygen

radical activity, maternal side effects, and mode of delivery. This study refers to

question 5.

Chapter 7 provides a systematic overview of the currently available literature on the

influence of intrapartum maternal Hb level on fetal distress, mode of delivery and

neonatal outcome. This study was set up to contribute to the answer on research

question 6.

Chapter 8 presents a retrospective study to investigate the relation between

intrapartum maternal hemoglobin level and the occurrence of fetal distress, mode of

delivery and neonatal outcome. The goal of this study was to contribute to

answering question 6.

Chapter 9 contains a general discussion on the topics presented in this thesis and

brings forward suggestions for future research.

Chapter 10 summarizes the data presented in this thesis.

Chapters 2 to 8 have been published or submitted for publication. As a

consequence, these chapters are written to be self-contained, causing some overlap

in the introduction and methods sections of these chapters.

References 1. Stichting Perined. Een nieuw thema: Perinatale audit van a ̀ terme asfyxie in 2013 &

2014. Utrecht (The Netherlands), 2016. [Dutch] 2. Stichting Perined. ‘Perinatale audit van a ̀ terme asfyxie en sterfte: Opvallende

verschillen. Utrecht, (The Netherlands), 2016. [Dutch] 3. Kruse M, Michelsen SI, Flachs EM, Bronnum-Hansen H, Madsen M, Uldall P. Lifetime

costs of cerebral palsy. Dev Med Child Neurol. 2009;51:622–8. 4. Graham EM, Ruis KA, Hartman AL, Northington FJ, Fox HE. A systematic review of the

role of intrapartum hypoxia-ischemia in the causation of neonatal encephalopathy. Am J Obstet Gynecol. 2008;199:587-95.

5. Battin MR, Dezoete JA, Gunn TR, Gluckman PD, Gunn AJ. Neurodevelopmental outcome of infants treated with head cooling and mild hypothermia after perinatal asphyxia. Pediatrics. 2001;107:480-4.

6. Doi K, Sameshima H, Kodama Y, Furukawa S, Kaneko M, Ikenoue T; Miyazaki Perinatal Data Groups. Perinatal death and neurological damage as a sequential chain of poor outcome. J Matern Fetal Neonatal Med. 2012;25:706-9.

7. Almeida MF, Kawakami MD, Moreira LM, Santos RM, Anchieta LM, Guinsburg R. Early neonatal deaths associated with perinatal asphyxia in infants ≥2500g in Brazil. J Pediatr (Rio J). 2017;93:576-84.

8. Blair E, Stanley FJ. Intrapartum asphyxia: a rare cause of cerebral palsy. J Pediatr. 1988;112:515-9.

9. Clark SL, Hankins GD. Temporal and demographic trends in cerebral palsy: fact and fiction. Am J Obstet Gynecol. 2003;188:628-33.

10. Apgar V. A proposal for a new method of evaluation of the newborn infant. Curr Res Anesth Analg. 1953;32:260-7.

11. American College of Obstetricians and Gynecologists’ Task Force on Neonatal Encephalopathy. Executive summary: Neonatal encephalopathy and neurologic outcome, second edition. Obstet Gynecol. 2014;123:896-901.

12. Berglund S, Grunewald C, Pettersson H, Cnattingius S. Severe asphyxia due to delivery-related malpractice in Sweden 1990-2005. BJOG. 2008;115:316-23.

13. Berglund S, Grunewald C, Pettersson H, Cnattingius S. Risk factors for asphyxia associated with substandard care during labor. Acta Obstet Gynecol Scand. 2010;89:39-48.

14. De Knijf A, Pattinson RC. Confidential enquiries into quality of care of women in labour using Hypoxic Ischemic Encephalopathy as a marker. Facts Views Vis Obgyn. 2010;2:219-25.

15. Evers AC, Brouwers HA, Nikkels PG, Boon J, van Egmond-Lingen A, Groenendaal F, et al. Substandard care in delivery-related asphyxia among term infants: prospective cohort study. Acta Obstet Gynecol Scand. 2013;92:85-93.

16. Cavazos-Rehg PA, Krauss MJ, Spitznagel EL, Bommarito K, Madden T, Olsen MA, et al. Maternal age and risk of labor and delivery complications. Matern Child Health J. 2015;19:1202-11.

17. Husslein H, Moswitzer B, Leipold H, Moertl M, Worda C. Low placental weight and risk for fetal distress at birth. J Perinat Med. 2012;40:693-5.


19

1

Chapter 4 describes the effect of maternal hyperoxygenation on pO2 in several

fetoplacental compartments and FHR, according to a mathematical simulation

model. This study refers to research question 4.

Chapter 5 proposes a study to investigate the clinical effect of maternal

hyperoxygenation during term labor. This is the study protocol for a randomized

controlled trial, conducted to answer research question 5.

Chapter 6 provides the study results of a randomized controlled trial, by describing

the effect of maternal hyperoxygenation during the second stage of labor on FHR,

Apgar score, cord blood gas analysis, NICU admission, perinatal death, free oxygen

radical activity, maternal side effects, and mode of delivery. This study refers to

question 5.

Chapter 7 provides a systematic overview of the currently available literature on the

influence of intrapartum maternal Hb level on fetal distress, mode of delivery and

neonatal outcome. This study was set up to contribute to the answer on research

question 6.

Chapter 8 presents a retrospective study to investigate the relation between

intrapartum maternal hemoglobin level and the occurrence of fetal distress, mode of

delivery and neonatal outcome. The goal of this study was to contribute to

answering question 6.

Chapter 9 contains a general discussion on the topics presented in this thesis and

brings forward suggestions for future research.

Chapter 10 summarizes the data presented in this thesis.

Chapters 2 to 8 have been published or submitted for publication. As a

consequence, these chapters are written to be self-contained, causing some overlap

in the introduction and methods sections of these chapters.

References 1. Stichting Perined. Een nieuw thema: Perinatale audit van a ̀ terme asfyxie in 2013 &

2014. Utrecht (The Netherlands), 2016. [Dutch] 2. Stichting Perined. ‘Perinatale audit van a ̀ terme asfyxie en sterfte: Opvallende

verschillen. Utrecht, (The Netherlands), 2016. [Dutch] 3. Kruse M, Michelsen SI, Flachs EM, Bronnum-Hansen H, Madsen M, Uldall P. Lifetime

costs of cerebral palsy. Dev Med Child Neurol. 2009;51:622–8. 4. Graham EM, Ruis KA, Hartman AL, Northington FJ, Fox HE. A systematic review of the


5. Battin MR, Dezoete JA, Gunn TR, Gluckman PD, Gunn AJ. Neurodevelopmental outcome of infants treated with head cooling and mild hypothermia after perinatal asphyxia. Pediatrics. 2001;107:480-4.

6. Doi K, Sameshima H, Kodama Y, Furukawa S, Kaneko M, Ikenoue T; Miyazaki Perinatal Data Groups. Perinatal death and neurological damage as a sequential chain of poor outcome. J Matern Fetal Neonatal Med. 2012;25:706-9.

7. Almeida MF, Kawakami MD, Moreira LM, Santos RM, Anchieta LM, Guinsburg R. Early neonatal deaths associated with perinatal asphyxia in infants ≥2500g in Brazil. J Pediatr (Rio J). 2017;93:576-84.

8. Blair E, Stanley FJ. Intrapartum asphyxia: a rare cause of cerebral palsy. J Pediatr. 1988;112:515-9.

9. Clark SL, Hankins GD. Temporal and demographic trends in cerebral palsy: fact and fiction. Am J Obstet Gynecol. 2003;188:628-33.

10. Apgar V. A proposal for a new method of evaluation of the newborn infant. Curr Res Anesth Analg. 1953;32:260-7.

11. American College of Obstetricians and Gynecologists’ Task Force on Neonatal Encephalopathy. Executive summary: Neonatal encephalopathy and neurologic outcome, second edition. Obstet Gynecol. 2014;123:896-901.

12. Berglund S, Grunewald C, Pettersson H, Cnattingius S. Severe asphyxia due to delivery-related malpractice in Sweden 1990-2005. BJOG. 2008;115:316-23.

13. Berglund S, Grunewald C, Pettersson H, Cnattingius S. Risk factors for asphyxia associated with substandard care during labor. Acta Obstet Gynecol Scand. 2010;89:39-48.

14. De Knijf A, Pattinson RC. Confidential enquiries into quality of care of women in labour using Hypoxic Ischemic Encephalopathy as a marker. Facts Views Vis Obgyn. 2010;2:219-25.

15. Evers AC, Brouwers HA, Nikkels PG, Boon J, van Egmond-Lingen A, Groenendaal F, et al. Substandard care in delivery-related asphyxia among term infants: prospective cohort study. Acta Obstet Gynecol Scand. 2013;92:85-93.

16. Cavazos-Rehg PA, Krauss MJ, Spitznagel EL, Bommarito K, Madden T, Olsen MA, et al. Maternal age and risk of labor and delivery complications. Matern Child Health J. 2015;19:1202-11.

17. Husslein H, Moswitzer B, Leipold H, Moertl M, Worda C. Low placental weight and risk for fetal distress at birth. J Perinat Med. 2012;40:693-5.

Chapter 1

20

18. Locatelli A, Incerti M, Paterlini G, Doria V, Consonni S, Provero C, et al. Antepartum and intrapartum risk factors for neonatal encephalopathy at term. Am J Perinatol. 2010;27:649-54.

19. Mostello D, Chalk C, Khoury J, Mack CE, Siddiqi TA, Clark KE. Chronic anemia in pregnant ewes: maternal and fetal effects. Am J Physiol. 1991;261(5 Pt 2):R1075-83.

20. Paulone ME, Edelstone DI, Shedd A. Effects of maternal anemia on uteroplacental and fetal oxidative metabolism in sheep. Am J Obstet Gynecol. 1987;156:230-6.

21. World Health Organization (WHO). The global prevelance of anaemia in 2011 [internet]. Geneva: WHO; 2015. Available from: http://apps.who.int/iris/bitstream/10665/177094/1/9789241564960_eng.pdf?ua=1&ua=1.

22. Gaillard R, Eilers PH, Yassine S, Hofman A, Steegers EA, Jaddoe VW. Risk factors and consequences of maternal anaemia and elevated haemoglobin levels during pregnancy: a population-based prospective cohort study. Paediatr Perinat Epidemiol. 2014;28:213-26.

23. Lone FW QR, Emanuel F. Maternal anaemia and its impact on perinatal outcome. Trop Med Int Health. 2004;9:486-90.

24. Murphy JF, O’Riordan J, Newcombe RG, Coles EC, Pearson JF. Relation of haemoglobin levels in first and second trimesters to outcome of pregnancy. Lancet. 1986;1:992-5.

25. Maghsoudlou S, Cnattingius S, Stephansson O, Aarabi M, Semnani S, Montgomery SM, et al. Maternal haemoglobin concentrations before and during pregnancy and stillbirth risk: a population-based case-control study. BMC Pregnancy Childbirth. 2016;16:135.

26. Sekhavat L DR, Hosseinidezoki S. Relationship between maternal hemoglobin concentration and neonatal birth weight. Hematology. 2011;16:373-6.

27. Räisänen S, Kancherla V, Gissler M, Kramer MR, Heinonen S. Adverse perinatal outcomes associated with moderate or severe maternal anaemia based on parity in Finland during 2006-10. Paediatr Perinat Epidemiol. 2014;28:272-80.

28. Allen LH. Anemia and iron deficiency: effects on pregnancy outcome. Am J Clin Nutr. 2000;71:1280-4S.

29. Peña-Rosas JP, De-Regil LM, Gomez Malave H, Flores-Urrutia MC, Dowswell T. Intermittent oral iron supplementation during pregnancy. Cochrane Database Syst Rev. 2015;19(10):CD009997.

30. Von Tempelhoff GF, Heilmann L, Rudig L, Pollow K, Hommel G, Koscielny J. Mean maternal second-trimester hemoglobin concentration and outcome of pregnancy: a population-based study. Clin Appl Thromb Hemost. 2008;14:19-28.

31. Cordina M, Bhatti S, Fernandez M, Syngelaki A, Nicolaides KH, Kametas NA. Association between maternal haemoglobin at 27-29 weeks gestation and intrauterine growth restriction. Pregnancy Hypertens. 2015;5:339-45.

32. Von Tempelhoff GF, Velten E, Yilmaz A, Hommel G, Heilmann L, Koscielny J. Blood rheology at term in normal pregnancy and in patients with adverse outcome events. Clin Hemorheol Microcirc. 2009;40:127-39.

33. Eastman NJ. Mount Everest in utero. Am J Obstet Gynecol. 1954;67:701-11. 34. Parer JT. Handbook of fetal heart rate monitoring. Philadelphia: W.B.Saunders Co;

2009.

35. Carter AM. Factors affecting gas transfer across the placenta and the oxygen supply to the fetus. J Dev Physiol. 1989;12:305-22.

36. Fahey J, King TL. Intrauterine asphyxia: clinical implications for providers of intrapartum care. J Midwifery Womens Health. 2005;50:498-506.

37. Van der Hout-van der Jagt MB, Oei SG, Bovendeerd PH. Simulation of reflex late decelerations in labor with a mathematical model. Early Hum Dev. 2013;89:7-19.

38. Van der Hout-van der Jagt MB, Jongen GJ, Bovendeerd PH, Oei SG. Insight into variable fetal heart rate decelerations from a mathematical model. Early Hum Dev. 2013;89:361-9.

39. Jongen GJ, van der Hout-van der Jagt MB, van de Vosse FN, Oei SG, Bovendeerd PH. A mathematical model to simulate the cardiotocogram during labor. Part B: Parameter estimation and simulation of variable decelerations. J Biomech. 2016;49:2474-80.

40. Bergmans MG, van Geijn HP, Weber T, Nickelsen C, Schmidt S, van den Berg PP. Fetal transcutaneous PCO2 measurements during labour. Eur J Obstet Gynecol Reprod Biol. 1993;51:1-7.

41. Dildy GA, van den Berg PP, Katz M, Clark SL, Jongsma HW, Nijhuis JG, et al. Intrapartum fetal pulse oximetry: fetal oxygen saturation trends during labor and relation to delivery outcome. Am J Obstet Gynecol. 1994;171:679-84.

42. Dildy GA, Clark SL, Loucks CA. Intrapartum fetal pulse oximetry: the effects of maternal hyperoxia on fetal arterial oxygen saturation. Am J Obstet Gynecol. 1994;171:1120-4.

43. Nijland R, Jongsma HW, Nijhuis JG, Oeseburg B. Accuracy of fetal pulse oximetry and pitfalls in measurements. Eur J Obstet Gynecol Reprod Biol. 1997;72 Suppl:S21-7.

44. Garite TJ, Dildy GA, McNamara H, Nageotte MP, Boehm FH, Dellinger EH, et al. A multicenter controlled trial of fetal pulse oximetry in the intrapartum management of nonreassuring fetal heart rate patterns. Am J Obstet Gynecol. 2000;183:1049-58.

45. Ayres-de-Campos D, Spong CY, Chandraharan E; for the FIGO Intrapartum Fetal Monitoring Expert Consensus Panel. FIGO consensus guidelines on intrapartum fetal monitoring: Cardiotocography. Int J Gynecol Obstet. 2015;131:13-24.

46. Elliott C, Warrick PA, Graham E, Hamilton EF. Graded classification of fetal heart rate tracings: association with neonatal metabolic acidosis and neurologic morbidity.

Am J Obstet Gynecol. 2010;202:258.e1-8. 47. Méndez-Bauer C, Arnt IC, Gulin L, Escarcena L, Caldeyro-Barcia R. Relationship

between blood pH and heart rate in the human fetus during labor. Am J Obstet Gynecol. 1967;97:530-45.

48. Kubli FW, Hon EH, Khazin AF, Takemura H. Observations on heart rate and pH in the human fetus during labor. Am J Obstet Gynecol. 1969;104:1190-206.

49. 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. BJOG. 2009;116:545-51. 50. Bernardes J, Costa-Pereira A, Ayres-de-Campos D, van Geijn HP, Pereira-Leite L.

Evaluation of interobserver agreement of cardiotocograms. Int J Gynaecol Obstet. 1997;57:33-7.

51. Donker DK, van Geijn HP, Hasman A. Interobserver variation in the assessment of fetal heart rate recordings. Eur J Obstet Gynecol Reprod Biol. 1993;52:21-8.


21

1

18. Locatelli A, Incerti M, Paterlini G, Doria V, Consonni S, Provero C, et al. Antepartum and intrapartum risk factors for neonatal encephalopathy at term. Am J Perinatol. 2010;27:649-54.



21. World Health Organization (WHO). The global prevelance of anaemia in 2011 [internet]. Geneva: WHO; 2015. Available from: http://apps.who.int/iris/bitstream/10665/177094/1/9789241564960_eng.pdf?ua=1&ua=1.

22. Gaillard R, Eilers PH, Yassine S, Hofman A, Steegers EA, Jaddoe VW. Risk factors and consequences of maternal anaemia and elevated haemoglobin levels during pregnancy: a population-based prospective cohort study. Paediatr Perinat Epidemiol. 2014;28:213-26.

23. Lone FW QR, Emanuel F. Maternal anaemia and its impact on perinatal outcome. Trop Med Int Health. 2004;9:486-90.



26. Sekhavat L DR, Hosseinidezoki S. Relationship between maternal hemoglobin concentration and neonatal birth weight. Hematology. 2011;16:373-6.







33. Eastman NJ. Mount Everest in utero. Am J Obstet Gynecol. 1954;67:701-11. 34. Parer JT. Handbook of fetal heart rate monitoring. Philadelphia: W.B.Saunders Co;

2009.

35. Carter AM. Factors affecting gas transfer across the placenta and the oxygen supply to the fetus. J Dev Physiol. 1989;12:305-22.

36. Fahey J, King TL. Intrauterine asphyxia: clinical implications for providers of intrapartum care. J Midwifery Womens Health. 2005;50:498-506.




40. Bergmans MG, van Geijn HP, Weber T, Nickelsen C, Schmidt S, van den Berg PP. Fetal transcutaneous PCO2 measurements during labour. Eur J Obstet Gynecol Reprod Biol. 1993;51:1-7.



43. Nijland R, Jongsma HW, Nijhuis JG, Oeseburg B. Accuracy of fetal pulse oximetry and pitfalls in measurements. Eur J Obstet Gynecol Reprod Biol. 1997;72 Suppl:S21-7.

44. Garite TJ, Dildy GA, McNamara H, Nageotte MP, Boehm FH, Dellinger EH, et al. A multicenter controlled trial of fetal pulse oximetry in the intrapartum management of nonreassuring fetal heart rate patterns. Am J Obstet Gynecol. 2000;183:1049-58.


46. Elliott C, Warrick PA, Graham E, Hamilton EF. Graded classification of fetal heart rate tracings: association with neonatal metabolic acidosis and neurologic morbidity.

Am J Obstet Gynecol. 2010;202:258.e1-8. 47. Méndez-Bauer C, Arnt IC, Gulin L, Escarcena L, Caldeyro-Barcia R. Relationship

between blood pH and heart rate in the human fetus during labor. Am J Obstet Gynecol. 1967;97:530-45.


49. 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. BJOG. 2009;116:545-51. 50. Bernardes J, Costa-Pereira A, Ayres-de-Campos D, van Geijn HP, Pereira-Leite L.

Evaluation of interobserver agreement of cardiotocograms. Int J Gynaecol Obstet. 1997;57:33-7.


Chapter 1

22

52. Paneth N, Bommarito M, Stricker J. Electronic fetal monitoring and later outcome. Clin Invest Med. 1993;16:159-65. 53. 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;106:1307-10.

54. Nelson KB, Dambrosia JM, Ting TY, Grether JK. Uncertain value of electronic fetal monitoring in predicting cerebral palsy. N Engl J Med. 1996;334:613-8.

55. Saling E. Technic for the endoscopic micro-sampling of blood from the fetus. Geburtshilfe Frauenheilkd. 1964;24:464-9. [German] 56. Rosén KG, Lindecrantz K. STAN--the Gothenburg model for fetal surveillance during

labour by ST analysis of the fetalelectrocardiogram. Clin Phys Physiol Meas. 1989;10 Suppl B:51-6.

57. Amer-Wåhlin I, Hellsten C, Norén H, Hagberg H, Herbst A, Kjellmer I, et al. Cardiotocography only versus cardiotocography plus ST analysis of fetal electrocardiogramfor intrapartum fetal monitoring: a Swedish randomised controlled trial. Lancet. 2001;358:534-8.

58. Neilson JP. Fetal electrocardiogram (ECG) for fetal monitoring during labour. Cochrane Database Syst Rev. 2015;12:CD000116. 59. 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 multiCenter randomised controlled trial. PLoS One. 2017;12:e0175823.

60. East CE, Brennecke SP, King JF, Chan FY, Colditz PB; FOREMOST Study Group. The effect of intrapartum fetal pulse oximetry, in the presence of a nonreassuring fetal heart rate pattern, on operative delivery rates: a multicenter, randomized, controlled trial (the FOREMOST trial). Am J Obstet Gynecol. 2006;194:606.e1-16.

61. East CE, Begg L, Colditz PB, Lau R. Fetal pulse oximetry for fetal assessment in labour. Cochrane Database Syst Rev. 2014;10:CD004075.

62. Ekéus C, Högberg U, Norman M. Vacuum assisted birth and risk for cerebral complications in term newborn infants: a population-based cohort study. BMC Pregnancy Childbirth. 2014;14:36.

63. O’Mahony F, Hofmeyr GJ, Menon V. Choice of instruments for assisted vaginal delivery. Cochrane Database Syst Rev. 2010;(11):CD005455.

64. Simpson KR. Intrauterine resuscitation during labor: review of current methods and supportive evidence. J Midwifery Womens Health. 2007;52:229-37.

65. Khazin AF, Hon EH, Hehre FW. Effects of maternal hyperoxia on the fetus. I. Oxygen tension. Am J Obstet Gynecol. 1971;109:628-37.

66. Althabe O Jr, Schwarcz RL, Pose SV, Escarcena L, Caldeyro-Barcia R. Effects on fetal heart rate and fetal pO2 of oxygen administration to the mother. Am J Obstet Gynecol. 1967;98:858-70.

67. Vasicka A, Quilligan EJ, Aznar R, Lipsitz PJ, Bloom BM. Oxygen tension in maternal and fetal blood, amniotic fluid, and cerebrospinal fluid of the mother and the baby. Am J Obstet Gynecol. 1960;79:1041-7.

68. Haydon ML, Gorenberg DM, Nageotte MP, Ghamsary M, Rumney PJ, Patillo C, et al. The effect of maternal oxygen administration on fetal pulse oximetry during labor in

fetuses with nonreassuring fetal heart rate patterns. Am J Obstet Gynecol. 2006;195:735-8.

69. Garite TJ, Simpson KR. Intrauterine resuscitation during labor. Clin Obstet Gynecol. 2011;54:28-39.

70. Greiss F. Glob Libr Women’s Med. DOI 10.3843/GLOWM.10197, 2008. 71. De Heus R, Mulder EJ, Derks JB, Kurver PH, van Wolfswinkel L, Visser GH. A

prospective randomized trial of acute tocolysis in term labour with atosiban or ritodrine. Eur J Obstet Gynecol Reprod Biol. 2008;139:139-45.

72. De Heus R, Mulder EJ, Derks JB, Visser GH. Acute tocolysis for uterine activity reduction in term labor: a review. Obstet Gynecol Surv. 2008;63:383-8.

73. Hidaka A, Komatani M, Ikeda H, Kitanaka T, Okada K, Sugawa T. A comparative study of intrauterine fetal resuscitation by beta-stimulant and O2 inhalation. Asia Oceania J Obstet Gynaecol. 1987;13:195-200.

74. Fawole B, Hofmeyr GJ. Maternal oxygen administration for fetal distress. Cochrane Database Syst Rev. 2012;12:CD000136.

75. Nesterenko TH, Acun C, Mohamed MA, Mohamed AN, Karcher D, Larsen J Jr, et al. Is it a safe practice to administer oxygen during uncomplicated delivery: a randomized controlled trial? Early Hum Dev. 2012;88:677-81.

76. Blackburn S. Free Radicals in Perinatal and Neonatal Care, Part 2O Oxidative Stress During the Perinatal and Neonatal Period. J Perinat Neonat Nurs. 2006;20:125-7.

77. Nordström L, Arulkumaran S. Intrapartum fetal hypoxia and biochemical markers: a review. Obstet Gynecol Surv. 1998;53:645-57.

78. Rogers MS, Wang W, Mongelli M, Pang CP, Duley JA, Chang AM. Lipid peroxidation in cord blood at birth: a marker of fetal hypoxia during labour. Gynecol Obstet Invest. 1997;44:229-33.

79. Dede FS, Guney Y, Dede H, Koca C, Dilbaz B, Bilgihan A. Lipid peroxidation and antioxidant activity in patients in labor with nonreassuring fetal status. Eur J Obstet Gynecol Reprod Biol. 2006;124:27-31.

80. Wang W, Pang CC, Rogers MS, Chang AM. Lipid peroxidation in cord blood at birth. Am J Obstet Gynecol. 1996;174(1 Pt 1):62-5.

81. Rogers MS, Mongelli JM, Tsang KH, Wang CC, Law KP. Lipid peroxidation in cord blood at birth: the effect of labour. BJOG. 1998;105:739-44.

82. Thorp JA, Trobough T, Evans R, Hedrick J, Yeast JD. The effect of maternal oxygen administration during the second stage of labor on umbilical cord blood gas values: a randomized controlled prospective trial. Am J Obstet Gynecol. 1995;172(2 Pt 1):465-74.

83. Nyberg R, Westin B. The influence of oxygen tension and some drugs on human placental vessels. Acta Physiol Scand. 1957;39:216-27.


23

1

52. Paneth N, Bommarito M, Stricker J. Electronic fetal monitoring and later outcome. Clin Invest Med. 1993;16:159-65. 53. 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;106:1307-10.


55. Saling E. Technic for the endoscopic micro-sampling of blood from the fetus. Geburtshilfe Frauenheilkd. 1964;24:464-9. [German] 56. Rosén KG, Lindecrantz K. STAN--the Gothenburg model for fetal surveillance during

labour by ST analysis of the fetalelectrocardiogram. Clin Phys Physiol Meas. 1989;10 Suppl B:51-6.

57. Amer-Wåhlin I, Hellsten C, Norén H, Hagberg H, Herbst A, Kjellmer I, et al. Cardiotocography only versus cardiotocography plus ST analysis of fetal electrocardiogramfor intrapartum fetal monitoring: a Swedish randomised controlled trial. Lancet. 2001;358:534-8.

58. Neilson JP. Fetal electrocardiogram (ECG) for fetal monitoring during labour. Cochrane Database Syst Rev. 2015;12:CD000116. 59. 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 multiCenter randomised controlled trial. PLoS One. 2017;12:e0175823.

60. East CE, Brennecke SP, King JF, Chan FY, Colditz PB; FOREMOST Study Group. The effect of intrapartum fetal pulse oximetry, in the presence of a nonreassuring fetal heart rate pattern, on operative delivery rates: a multicenter, randomized, controlled trial (the FOREMOST trial). Am J Obstet Gynecol. 2006;194:606.e1-16.








68. Haydon ML, Gorenberg DM, Nageotte MP, Ghamsary M, Rumney PJ, Patillo C, et al. The effect of maternal oxygen administration on fetal pulse oximetry during labor in

fetuses with nonreassuring fetal heart rate patterns. Am J Obstet Gynecol. 2006;195:735-8.


70. Greiss F. Glob Libr Women’s Med. DOI 10.3843/GLOWM.10197, 2008. 71. De Heus R, Mulder EJ, Derks JB, Kurver PH, van Wolfswinkel L, Visser GH. A

prospective randomized trial of acute tocolysis in term labour with atosiban or ritodrine. Eur J Obstet Gynecol Reprod Biol. 2008;139:139-45.

72. De Heus R, Mulder EJ, Derks JB, Visser GH. Acute tocolysis for uterine activity reduction in term labor: a review. Obstet Gynecol Surv. 2008;63:383-8.




76. Blackburn S. Free Radicals in Perinatal and Neonatal Care, Part 2O Oxidative Stress During the Perinatal and Neonatal Period. J Perinat Neonat Nurs. 2006;20:125-7.


78. Rogers MS, Wang W, Mongelli M, Pang CP, Duley JA, Chang AM. Lipid peroxidation in cord blood at birth: a marker of fetal hypoxia during labour. Gynecol Obstet Invest. 1997;44:229-33.



81. Rogers MS, Mongelli JM, Tsang KH, Wang CC, Law KP. Lipid peroxidation in cord blood at birth: the effect of labour. BJOG. 1998;105:739-44.


83. Nyberg R, Westin B. The influence of oxygen tension and some drugs on human placental vessels. Acta Physiol Scand. 1957;39:216-27.

Chapter 2

Interventions for intrauterine resuscitation in suspected

fetal distress during term labor: a systematic review

Bullens LM, van Runnard Heimel PJ,

van der Hout-van der Jagt MB, Oei SG


Chapter 2

26

Abstract

Importance

Intrauterine resuscitation techniques during term labor are commonly used in daily

clinical practice. Evidence, however, to support the beneficial effect of intrauterine

resuscitation techniques on fetal distress during labor is limited and sometimes

contradictory. In contrast, some of these interventions may even be harmful.

Objective

To give insight into the current evidence on intrauterine resuscitation techniques. In

addition, we formulate recommendations for current clinical practice and propose

directions for further research.

Evidence acquisition

We systematically searched the electronic PubMed, EMBASE, and CENTRAL

databases for studies on intrauterine resuscitation for suspected fetal distress during

term labor until February 2015. Eligible articles and their references were

independently assessed by two authors. Judgment was based on methodological

quality and study results.

Results

Our literature search identified 15 studies: four studies on amnioinfusion, one study

on maternal hyperoxygenation, one study on maternal repositioning, one study on

intravenous fluid administration, and eight studies on tocolysis. Of these 15 research

papers, three described a randomized controlled trial; all other studies were

observational reports or case reports.

Conclusions and relevance

Little robust evidence to promote a specific intrauterine resuscitation technique is

available. Based on our literature search, we support the use of tocolysis and

maternal repositioning for fetal distress. We believe the effect of amnioinfusion and

maternal hyperoxygenation should be further investigated in properly designed

randomized controlled trials to make up the balance between beneficial and

potential hazardous effects.

Interventions for fetal distress: a systematic review

27

2

Abstract

Importance

Intrauterine resuscitation techniques during term labor are commonly used in daily

clinical practice. Evidence, however, to support the beneficial effect of intrauterine

resuscitation techniques on fetal distress during labor is limited and sometimes

contradictory. In contrast, some of these interventions may even be harmful.

Objective

To give insight into the current evidence on intrauterine resuscitation techniques. In

addition, we formulate recommendations for current clinical practice and propose

directions for further research.



databases for studies on intrauterine resuscitation for suspected fetal distress during

term labor until February 2015. Eligible articles and their references were

independently assessed by two authors. Judgment was based on methodological

quality and study results.

Results

Our literature search identified 15 studies: four studies on amnioinfusion, one study

on maternal hyperoxygenation, one study on maternal repositioning, one study on

intravenous fluid administration, and eight studies on tocolysis. Of these 15 research

papers, three described a randomized controlled trial; all other studies were

observational reports or case reports.


Little robust evidence to promote a specific intrauterine resuscitation technique is

available. Based on our literature search, we support the use of tocolysis and

maternal repositioning for fetal distress. We believe the effect of amnioinfusion and

maternal hyperoxygenation should be further investigated in properly designed

randomized controlled trials to make up the balance between beneficial and

potential hazardous effects.

Chapter 2

28

Introduction Fetal heart rate (FHR) is continuously monitored during labor to estimate fetal

condition. Nonreassuring FHR patterns may be indicative of impaired fetal

oxygenation and when progressive may lead to fetal hypoxia. Fetal hypoxia may

result in decompensation of the physiological response and the fetus to become

asphyctic.1,2

As fetal asphyxia is associated with hypoxic-ischemic encephalopathy or even fetal

death, timely intervention is indicated to optimize neonatal outcome. Labor

contractions cause intermittent interruption of oxygen transfer toward the fetus by

umbilical cord occlusion or impaired placental perfusion. Healthy fetuses have

sufficient buffer capacity to maintain normal oxygenation despite an intermittent

decrease in oxygen delivery. However, when uterine contractions are prolonged or

too frequent, fetal oxygenation may become insufficient. In order to optimize fetal

oxygenation, depending on the presumable cause of the decelerations, intervention

should be focusing on increased oxygen delivery, alleviation of cord compression,

and/or improvement of uteroplacental blood flow.3,4

In the past decades, several interventions to improve fetal oxygenation in case of

fetal distress during labor have been described. Commonly used techniques are

maternal hyperoxygenation, maternal repositioning, intravenous fluid administration,

amnioinfusion, tocolysis, and intermittent pushing. These interventions aim to either

reduce the cause of severe uterine contractions or the cause of impaired

oxygenation or try to improve oxygenation by increasing blood flow or oxygen

levels in the blood. First, maternal hyperoxygenation using 100% oxygen is believed

to increase both maternal and fetal oxygenation.5-10 Some studies state that maternal

hyperoxygenation also leads to an increase in fetal pH level.5 However, robust data

to support that maternal oxygen supplementation benefits the fetus are limited, as

illustrated by a recent discussion on benefit and harm of hyperoxygenation in the

American Journal of Obstetrics and Gynecology.11-12 Intravenous fluid administration

increases blood flow toward the uterus, which would then increase oxygen

transport.6 However, some state that this effect is nullified by the effect of

hemodilution.10


blood flow. Reduction in uterine activity by use of a tocolytic agent may restore

blood flow through the placenta and umbilical cord.13,14 Furthermore, the addition of

fluid in the uterine cavity may relieve umbilical cord compression. Besides, a change

in labor position may both relieve umbilical cord compression improving blood flow

toward the fetus and dissolve aortocaval compression, improving uteroplacental

blood flow. In addition, during the second stage of labor, intermittent pushing may

provide the fetus more time to recover from the contractions that compromise its

condition. Even though several studies have evaluated the effect of intrauterine

resuscitation techniques on fetal well-being, robust evidence to support their

beneficial effect on the distressed fetus is limited and sometimes contradictory.

Despite the lack of convincing evidence, the described techniques are commonly

used in daily clinical practice, even though some of them may be harmful. As well,

application of any of these interventions may delay immediate delivery. The recently

published National Institute for Health and Care Excellence guideline, “Intrapartum

Care: Care of Healthy Women and Their Babies During Childbirth,” advises to adopt

left lateral position by the parturient and to consider the use of a tocolytic agent in

case of a nonreassuring FHR pattern.15 Interestingly, this guideline explicitly states

not to supply additional oxygen to the mother (as long as the mother is not hypoxic)

and not to use amnioinfusion for fetal distress. In contrast to the Royal College of

Obstetricians and Gynaecologists Guideline, in their Practice Bulletin, “Management

of Intrapartum Fetal Heart Rate Tracings,” the American College of Obstetricians

and Gynecologists (ACOG) recommends to apply amnioinfusion for recurrent

variable decelerations to relieve cord compression. Second, the ACOG advises to

administer maternal oxygen and intravenous fluid bolus for late decelerations.4 The

Dutch guideline on “intrapartum fetal monitoring” refers to the Cochrane review by

Hofmeyr and states that one may consider the use of amnioinfusion during labor

and does not yet advise on the use of supplemental oxygen or tocolytic drugs.16,17

In conclusion, there is no international agreement on the use of intrauterine

resuscitation techniques during labor, as a result of the lack of robust evidence

proving their beneficial effect. This apparent controversy about commonly used

interventions during labor made us decide to collect all available data and perform a

systemic review on this subject.

With this systematic review, we aim to give insight into the available evidence on the

effect of frequently applied intrauterine resuscitation techniques. First, we focus on

interventions applied in case of proven or suspected distress of the formerly healthy,


29

2

Introduction Fetal heart rate (FHR) is continuously monitored during labor to estimate fetal

condition. Nonreassuring FHR patterns may be indicative of impaired fetal

oxygenation and when progressive may lead to fetal hypoxia. Fetal hypoxia may

result in decompensation of the physiological response and the fetus to become

asphyctic.1,2

As fetal asphyxia is associated with hypoxic-ischemic encephalopathy or even fetal

death, timely intervention is indicated to optimize neonatal outcome. Labor

contractions cause intermittent interruption of oxygen transfer toward the fetus by

umbilical cord occlusion or impaired placental perfusion. Healthy fetuses have

sufficient buffer capacity to maintain normal oxygenation despite an intermittent

decrease in oxygen delivery. However, when uterine contractions are prolonged or

too frequent, fetal oxygenation may become insufficient. In order to optimize fetal

oxygenation, depending on the presumable cause of the decelerations, intervention

should be focusing on increased oxygen delivery, alleviation of cord compression,

and/or improvement of uteroplacental blood flow.3,4

In the past decades, several interventions to improve fetal oxygenation in case of

fetal distress during labor have been described. Commonly used techniques are

maternal hyperoxygenation, maternal repositioning, intravenous fluid administration,

amnioinfusion, tocolysis, and intermittent pushing. These interventions aim to either

reduce the cause of severe uterine contractions or the cause of impaired

oxygenation or try to improve oxygenation by increasing blood flow or oxygen

levels in the blood. First, maternal hyperoxygenation using 100% oxygen is believed

to increase both maternal and fetal oxygenation.5-10 Some studies state that maternal

hyperoxygenation also leads to an increase in fetal pH level.5 However, robust data

to support that maternal oxygen supplementation benefits the fetus are limited, as

illustrated by a recent discussion on benefit and harm of hyperoxygenation in the

American Journal of Obstetrics and Gynecology.11-12 Intravenous fluid administration

increases blood flow toward the uterus, which would then increase oxygen

transport.6 However, some state that this effect is nullified by the effect of

hemodilution.10


blood flow. Reduction in uterine activity by use of a tocolytic agent may restore

blood flow through the placenta and umbilical cord.13,14 Furthermore, the addition of

fluid in the uterine cavity may relieve umbilical cord compression. Besides, a change

in labor position may both relieve umbilical cord compression improving blood flow

toward the fetus and dissolve aortocaval compression, improving uteroplacental

blood flow. In addition, during the second stage of labor, intermittent pushing may

provide the fetus more time to recover from the contractions that compromise its

condition. Even though several studies have evaluated the effect of intrauterine

resuscitation techniques on fetal well-being, robust evidence to support their

beneficial effect on the distressed fetus is limited and sometimes contradictory.

Despite the lack of convincing evidence, the described techniques are commonly

used in daily clinical practice, even though some of them may be harmful. As well,

application of any of these interventions may delay immediate delivery. The recently

published National Institute for Health and Care Excellence guideline, “Intrapartum

Care: Care of Healthy Women and Their Babies During Childbirth,” advises to adopt

left lateral position by the parturient and to consider the use of a tocolytic agent in

case of a nonreassuring FHR pattern.15 Interestingly, this guideline explicitly states

not to supply additional oxygen to the mother (as long as the mother is not hypoxic)

and not to use amnioinfusion for fetal distress. In contrast to the Royal College of

Obstetricians and Gynaecologists Guideline, in their Practice Bulletin, “Management

of Intrapartum Fetal Heart Rate Tracings,” the American College of Obstetricians

and Gynecologists (ACOG) recommends to apply amnioinfusion for recurrent

variable decelerations to relieve cord compression. Second, the ACOG advises to

administer maternal oxygen and intravenous fluid bolus for late decelerations.4 The

Dutch guideline on “intrapartum fetal monitoring” refers to the Cochrane review by

Hofmeyr and states that one may consider the use of amnioinfusion during labor

and does not yet advise on the use of supplemental oxygen or tocolytic drugs.16,17

In conclusion, there is no international agreement on the use of intrauterine

resuscitation techniques during labor, as a result of the lack of robust evidence

proving their beneficial effect. This apparent controversy about commonly used

interventions during labor made us decide to collect all available data and perform a

systemic review on this subject.

With this systematic review, we aim to give insight into the available evidence on the

effect of frequently applied intrauterine resuscitation techniques. First, we focus on

interventions applied in case of proven or suspected distress of the formerly healthy,

Chapter 2

30

term fetus. Second, we will formulate recommendations for current clinical practice

based on the results of the literature search. In addition, we will describe at what

point evidence is missing in order to propose directions for further research.

Methods Inclusion and exclusion criteria The criteria for studies to be included into our systematic review are described in a

checklist (Appendix 1). This checklist contains the following criteria: first, study

population must consist of healthy women, giving birth at term gestational age

37+0 to 41+6 weeks) to a singleton healthy baby. Signs of fetal distress must be

present, and the authors must clearly describe how this is diagnosed, for example,

by a nonreassuring FHR pattern, fetal scalp blood sampling, or fetal saturation

measurement. Finally, intervention must include at least 1 of the following: maternal

hyperoxygenation, intravenous fluid administration, maternal repositioning,

tocolysis, amnioinfusion, or intermittent pushing. The intervention must be tested

against another intervention, no intervention, or placebo. Review articles are to be

excluded.

Search methods We systematically searched the electronic PubMed, EMBASE, and CENTRAL

databases for studies on intrauterine resuscitation during term labor in the presence

of fetal distress until March 1, 2015. Databases were searched without any limits in

publication date and without language restriction. We used the following keywords

for interventions: “fluid bolus,” “fluid therapy,” “oxygen administration,”

“hyperoxygenation,” “maternal oxygen,” “oxygen inhalation therapy,” “tocolysis,”

“maternal positioning,” “maternal repositioning,” “alteration of pushing efforts,”

“amnioinfusion,” and “amnio-infusion.” For labor, we used the keywords “labour”

and “labor” and for fetal distress “fetal distress” and “foetal distress.” The

conducted search was performed by combining keywords for intervention, labor,

and fetal distress.

Duplicates were removed. This search is referred to as the primary search. All

keywords used for the primary search are noted in Appendix 2. In addition, we

screened all references of selected and related articles. This process of screening

references is referred to as the secondary search.

Data collection and analysis Selection of studies Two authors (L.M.B. and P.J.v.R.H.) independently assessed for inclusion all articles

from the primary and secondary search by title and abstract (or by full text when no

abstract was available), hereby using the checklist for inclusion (Appendix 1). In case

of disagreement, a third author (S.G.O.) was consulted.

Data extraction and assessment of methodological quality of included studies

We analyzed all selected articles by reading full text and again checked their

eligibility for inclusion using the checklist from Appendix 1. The outcome measures

of interest were at least 1 of the following: FHR pattern, fetal oxygen pressure or

saturation, fetal scalp or cord blood gas and pH, Apgar score, or admission to a

neonatal intensive care unit (NICU).

Methodological quality was assessed from the following items: study type, number

of subjects, risk of selection bias, including randomization and blinding (high or low),

and description of inclusion and exclusion criteria (complete or incomplete). We

used the GRADE instrument to provide an overall judgment of the study quality.18,19

Data synthesis A meta-analysis could not be performed because the number of included articles is

limited, and the articles show large heterogeneity both in the intervention tested

and in study methods. Therefore, we described the results by presenting the various

study results in relation to the quality of each study.

Results Data search A total of 1660 articles were obtained from PubMed, EMBASE, and CENTRAL

databases and classified by title and abstract. There was no disagreement among

both reviewers, and 41 articles from the primary search were found eligible for full-

text assessment. From these 41 articles, only 8 articles presented original data

articles.20-29 We screened references from all 41 articles by title and found 59

additional articles eligible for screening by title and abstract. Five abstracts could


31

2term fetus. Second, we will formulate recommendations for current clinical practice

based on the results of the literature search. In addition, we will describe at what

point evidence is missing in order to propose directions for further research.

Methods

Inclusion and exclusion criteria

The criteria for studies to be included into our systematic review are described in a

checklist (Appendix 1). This checklist contains the following criteria: first, study

population must consist of healthy women, giving birth at term gestational age

37+0 to 41+6 weeks) to a singleton healthy baby. Signs of fetal distress must be

present, and the authors must clearly describe how this is diagnosed, for example,

by a nonreassuring FHR pattern, fetal scalp blood sampling, or fetal saturation

measurement. Finally, intervention must include at least 1 of the following: maternal

hyperoxygenation, intravenous fluid administration, maternal repositioning,

tocolysis, amnioinfusion, or intermittent pushing. The intervention must be tested

against another intervention, no intervention, or placebo. Review articles are to be

excluded.

Search methods


databases for studies on intrauterine resuscitation during term labor in the presence

of fetal distress until March 1, 2015. Databases were searched without any limits in

publication date and without language restriction. We used the following keywords

for interventions: “fluid bolus,” “fluid therapy,” “oxygen administration,”

“hyperoxygenation,” “maternal oxygen,” “oxygen inhalation therapy,” “tocolysis,”

“maternal positioning,” “maternal repositioning,” “alteration of pushing efforts,”

“amnioinfusion,” and “amnio-infusion.” For labor, we used the keywords “labour”

and “labor” and for fetal distress “fetal distress” and “foetal distress.” The

conducted search was performed by combining keywords for intervention, labor,

and fetal distress.

Duplicates were removed. This search is referred to as the primary search. All

keywords used for the primary search are noted in Appendix 2. In addition, we

screened all references of selected and related articles. This process of screening

references is referred to as the secondary search.

Data collection and analysis

Selection of studies

Two authors (L.M.B. and P.J.v.R.H.) independently assessed for inclusion all articles

from the primary and secondary search by title and abstract (or by full text when no

abstract was available), hereby using the checklist for inclusion (Appendix 1). In case

of disagreement, a third author (S.G.O.) was consulted.

Data extraction and assessment of methodological quality of included studies

We analyzed all selected articles by reading full text and again checked their

eligibility for inclusion using the checklist from Appendix 1. The outcome measures

of interest were at least 1 of the following: FHR pattern, fetal oxygen pressure or

saturation, fetal scalp or cord blood gas and pH, Apgar score, or admission to a

neonatal intensive care unit (NICU).

Methodological quality was assessed from the following items: study type, number

of subjects, risk of selection bias, including randomization and blinding (high or low),

and description of inclusion and exclusion criteria (complete or incomplete). We

used the GRADE instrument to provide an overall judgment of the study quality.18,19

Data synthesis

A meta-analysis could not be performed because the number of included articles is

limited, and the articles show large heterogeneity both in the intervention tested

and in study methods. Therefore, we described the results by presenting the various

study results in relation to the quality of each study.

Results

Data search

A total of 1660 articles were obtained from PubMed, EMBASE, and CENTRAL

databases and classified by title and abstract. There was no disagreement among

both reviewers, and 41 articles from the primary search were found eligible for full-

text assessment. From these 41 articles, only 8 articles presented original data

articles.20-29 We screened references from all 41 articles by title and found 59

additional articles eligible for screening by title and abstract. Five abstracts could

Chapter 2

32

not be obtained: 1 reference referred to a guideline, 2 references contained only

author and year of publication. Internet and database searches did not lead to

discovery of the corresponding titles. In addition, 2 articles were not available

despite the search in several databases, Internet, and the consulting of 3 academic

libraries. In conclusion, 54 were available for screening. Five articles had no abstract;

therefore, they were screened by full text. From the secondary search, we included

28 articles for full-text analysis. In total, we obtained 69 articles from the primary and

secondary search for full-text analysis.

A total of 15 articles met all inclusion criteria and were included. Flow figure 1

displays the results from the different steps in the selection process. Table 1 lists the

number and type of studies we included per intervention. Table 2 displays the study

characteristics and quality.5,24,26,28-39 Table 3 shows the outcome of each included

study.

Table 1. Number of included studies and study type per intervention. Intervention Available evidence

Maternal hyperoxygenation One prospective observational study

Intravenous fluid bolus One prospective observational study

Tocolysis Two randomized controlled trials

Three prospective observational studies

Three case studies

Amnioinfusion Two randomized controlled trials

Two prospective observational studies

Maternal repositioning One prospective observational study

Intermittent pushing None

Figure 1. Results from the literature search and the different steps in the selection

process of eligible articles.


33

2

not be obtained: 1 reference referred to a guideline, 2 references contained only

author and year of publication. Internet and database searches did not lead to

discovery of the corresponding titles. In addition, 2 articles were not available

despite the search in several databases, Internet, and the consulting of 3 academic

libraries. In conclusion, 54 were available for screening. Five articles had no abstract;

therefore, they were screened by full text. From the secondary search, we included

28 articles for full-text analysis. In total, we obtained 69 articles from the primary and

secondary search for full-text analysis.

A total of 15 articles met all inclusion criteria and were included. Flow figure 1

displays the results from the different steps in the selection process. Table 1 lists the

number and type of studies we included per intervention. Table 2 displays the study

characteristics and quality.5,24,26,28-39 Table 3 shows the outcome of each included

study.

Table 1. Number of included studies and study type per intervention. Intervention Available evidence

Maternal hyperoxygenation One prospective observational study

Intravenous fluid bolus One prospective observational study

Tocolysis Two randomized controlled trials

Three prospective observational studies

Three case studies

Amnioinfusion Two randomized controlled trials

Two prospective observational studies

Maternal repositioning One prospective observational study

Intermittent pushing None

Figure 1. Results from the literature search and the different steps in the selection

process of eligible articles.

Chapter 2

34

Tab

le 2

. Cha

ract

eris

tics

and

qual

ity o

f inc

lude

d st

udie

s.

Inte

rven

tion

Ref

eren

ce

D

rug

D

ose

C

ont

rol

Firs

t au

tho

r Ye

ar

Am

nio

infu

sio

n

10 m

l/m

in fi

rst

hour

, the

reaf

ter

3 m

l/m

in

No

cont

rol g

roup

Su

rbek

19

97

Am

nio

infu

sio

n

Bol

us 5

00 c

c st

erile

wat

er, s

low

infu

sion

of 5

00cc

C

onve

ntio

nal

trea

tmen

t

Ab

del

-Ale

em

2005

Am

nio

infu

sio

n

15-2

0 m

l/m

in s

alin

e so

lutio

n un

til v

aria

ble

dec

eler

atio

ns w

ere

reso

lved

, ad

diti

onal

250

mg

Con

vent

iona

l

trea

tmen

t

Miy

azak

i 19

85

Am

nio

infu

sio

n

15-2

0 m

l/m

in s

alin

e so

lutio

n un

til v

aria

ble

dec

eler

atio

ns w

ere

reso

lved

, ad

diti

onal

250

mg

No

cont

rol g

roup

M

iyaz

aki

1983

Oxy

gen

100%

oxy

gen

with

oro

nasa

l mas

k in

an

open

circ

uit

No

cont

rol g

roup

A

lthab

e 19

67

Left

po

sitio

ning

N

o co

ntro

l gro

up

Ab

itbol

19

85

Intr

aven

ous

flui

d

bo

lus

Dex

tran

e U

ncle

ar

No

cont

rol g

roup

St

ratu

lat

1975

Toco

lysi

s

Terb

utal

ine

0.25

mg

ter

but

alin

e or

4 g

r M

gSO

4 M

gSO

4 *

Mag

ann

1993

Toco

lysi

s N

itrog

lyce

rin

1or

2 b

olus

of 6

0-90

mcg

iv

No

cont

rol g

roup

M

erci

er

1997

Toco

lysi

s Ri

tod

rine

6 m

g b

olus

C

onve

ntio

nal

trea

tmen

t

Shey

ban

y 19

82

Toco

lysi

s Ri

tod

rine

200-

500

mg

r/m

in fo

r 15

-120

min

utes

N

o co

ntro

l gro

up

Rena

ud

1972

Toco

lysi

s Ri

tod

rine

2 m

g b

olus

, inf

usio

n up

to

350

mg

r/m

in

NA

H

utch

on

1982

Toco

lysi

s Ri

tod

rine

6

mg

bol

us

NA

Li

psh

itz

1985

Toco

lysi

s H

exop

rena

line

10 m

cg b

olus

N

A

Lip

shitz

19

77

Toco

lysi

s O

rcip

rena

line

Unc

lear

N

o co

ntro

l gro

up

Cal

dey

ro-B

arci

a 19

92

Tab

le 2

. Con

tinue

d

Part

icip

ants

Se

lect

ion

bia

s O

utco

me

Co

nfo

und

ing

Co

nclu

sio

n

Num

ber

Fe

tal

dis

tres

s

Stud

y d

esig

n D

escr

iptio

n

i n/e

xclu

sio

n

Blin

din

g R

and

om

-

i zat

ion

Ris

k o

n

s ele

ctio

n

bia

s

Feta

l/

n eo

nata

l

out

com

e

Mis

sing

r esu

lts

r ep

ort

ed C

esar

ean

s ect

ion

Co

-

i nte

rven

tions

des

crib

ed

Co

nfo

und

ing

varia

ble

s

des

crib

ed

GR

AD

E

16 (1

3)

FHR

Pros

pec

tive

obse

rvat

iona

l

stud

y

Inco

mp

lete

N

A

NA

H

igh

FHR,

del

iver

y

rout

e,

neon

atal

outc

ome

No

mis

sing

resu

lts

Som

e N

o N

o Lo

w

438

FHR

Rand

omiz

ed

clin

ical

tria

l

Com

ple

te

No

Seal

ed

opaq

ue

enve

lop

s

Low

C

esar

ean

sect

ion,

FH

R,

AS,

NIC

U

adm

issi

on

No

mis

sing

resu

lts

No

No

No

Med

ium

96

FHR

Rand

omiz

ed

clin

ical

tria

l

Inco

mp

lete

N

o Se

aled

enve

lop

s

Hig

h FH

R, A

S,

per

inat

al

dea

th

Unc

lear

So

me

Yes

No

Med

ium

42

FHR

Pros

pec

tive

obse

rvat

iona

l

stud

y

Inco

mp

lete

N

A

NA

H

igh

FHR

No

mis

sing

resu

lts

Yes,

som

e

Yes

No

Low

21

CTG

1x p

H

Pros

pec

tive

obse

rvat

iona

l

stud

y

Inco

mp

lete

N

A

NA

H

igh

feta

l pO

2, p

H,

FHR,

AS

No

mis

sing

resu

lts

Unc

lear

N

o

No

Low

902/

126

FH

R Pr

osp

ectiv

e

obse

rvat

iona

l

stud

y

Com

ple

te

NA

N

A

Hig

h FH

R N

o

mis

sing

resu

lts

Som

e N

o N

o M

ediu

m


35

2

Tab

le 2

. Cha

ract

eris

tics

and

qual

ity o

f inc

lude

d st

udie

s.

Inte

rven

tion

Ref

eren

ce

D

rug

D

ose

C

ont

rol

Firs

t au

tho

r Ye

ar

Am

nio

infu

sio

n

10 m

l/m

in fi

rst

hour

, the

reaf

ter

3 m

l/m

in

No

cont

rol g

roup

Su

rbek

19

97

Am

nio

infu

sio

n

Bol

us 5

00 c

c st

erile

wat

er, s

low

infu

sion

of 5

00cc

C

onve

ntio

nal

trea

tmen

t

Ab

del

-Ale

em

2005

Am

nio

infu

sio

n

15-2

0 m

l/m

in s

alin

e so

lutio

n un

til v

aria

ble

dec

eler

atio

ns w

ere

reso

lved

, ad

diti

onal

250

mg

Con

vent

iona

l

trea

tmen

t

Miy

azak

i 19

85

Am

nio

infu

sio

n

15-2

0 m

l/m

in s

alin

e so

lutio

n un

til v

aria

ble

dec

eler

atio

ns w

ere

reso

lved

, ad

diti

onal

250

mg

No

cont

rol g

roup

M

iyaz

aki

1983

Oxy

gen

100%

oxy

gen

with

oro

nasa

l mas

k in

an

open

circ

uit

No

cont

rol g

roup

A

lthab

e 19

67

Left

po

sitio

ning

N

o co

ntro

l gro

up

Ab

itbol

19

85

Intr

aven

ous

flui

d

bo

lus

Dex

tran

e U

ncle

ar

No

cont

rol g

roup

St

ratu

lat

1975

Toco

lysi

s

Terb

utal

ine

0.25

mg

ter

but

alin

e or

4 g

r M

gSO

4 M

gSO

4 *

Mag

ann

1993

Toco

lysi

s N

itrog

lyce

rin

1or

2 b

olus

of 6

0-90

mcg

iv

No

cont

rol g

roup

M

erci

er

1997

Toco

lysi

s Ri

tod

rine

6 m

g b

olus

C

onve

ntio

nal

trea

tmen

t

Shey

ban

y 19

82

Toco

lysi

s Ri

tod

rine

200-

500

mg

r/m

in fo

r 15

-120

min

utes

N

o co

ntro

l gro

up

Rena

ud

1972

Toco

lysi

s Ri

tod

rine

2 m

g b

olus

, inf

usio

n up

to

350

mg

r/m

in

NA

H

utch

on

1982

Toco

lysi

s Ri

tod

rine

6

mg

bol

us

NA

Li

psh

itz

1985

Toco

lysi

s H

exop

rena

line

10 m

cg b

olus

N

A

Lip

shitz

19

77

Toco

lysi

s O

rcip

rena

line

Unc

lear

N

o co

ntro

l gro

up

Cal

dey

ro-B

arci

a 19

92

Tab

le 2

. Con

tinue

d

Part

icip

ants

Se

lect

ion

bia

s O

utco

me

Co

nfo

und

ing

Co

nclu

sio

n

Num

ber

Fe

tal

dis

tres

s

Stud

y d

esig

n D

escr

iptio

n

in/e

xclu

sio

n

Blin

din

g R

and

om

-

izat

ion

Ris

k o

n

sele

ctio

n

bia

s

Feta

l/

neo

nata

l

out

com

e

Mis

sing

resu

lts

r ep

ort

ed C

esar

ean

sect

ion

Co

-

inte

rven

tions

des

crib

ed

Co

nfo

und

ing

varia

ble

s

des

crib

ed

GR

AD

E

16 (1

3)

FHR

Pros

pec

tive

obse

rvat

iona

l

stud

y

Inco

mp

lete

N

A

NA

H

igh

FHR,

del

iver

y

rout

e,

neon

atal

outc

ome

No

mis

sing

resu

lts

Som

e N

o N

o Lo

w

438

FHR

Rand

omiz

ed

clin

ical

tria

l

Com

ple

te

No

Seal

ed

opaq

ue

enve

lop

s

Low

C

esar

ean

sect

ion,

FH

R,

AS,

NIC

U

adm

issi

on

No

mis

sing

resu

lts

No

No

No

Med

ium

96

FHR

Rand

omiz

ed

clin

ical

tria

l

Inco

mp

lete

N

o Se

aled

enve

lop

s

Hig

h FH

R, A

S,

per

inat

al

dea

th

Unc

lear

So

me

Yes

No

Med

ium

42

FHR

Pros

pec

tive

obse

rvat

iona

l

stud

y

Inco

mp

lete

N

A

NA

H

igh

FHR

No

mis

sing

resu

lts

Yes,

som

e

Yes

No

Low

21

CTG

1x p

H

Pros

pec

tive

obse

rvat

iona

l

stud

y

Inco

mp

lete

N

A

NA

H

igh

feta

l pO

2, p

H,

FHR,

AS

No

mis

sing

resu

lts

Unc

lear

N

o

No

Low

902/

126

FH

R Pr

osp

ectiv

e

obse

rvat

iona

l

stud

y

Com

ple

te

NA

N

A

Hig

h FH

R N

o

mis

sing

resu

lts

Som

e N

o N

o M

ediu

m

Chapter 2

36

() =

mee

t inc

lusi

on c

riter

ia

NA

= n

ot a

pplic

able

, AS=

Apg

ar s

core

Part

icip

ants

Se

lect

ion

bia

s O

utco

me

Co

nfo

und

ing

Co

nclu

sio

n

50

FHR

Pros

pec

tive

obse

rvat

iona

l

stud

y

Inco

mp

lete

N

A

NA

H

igh

Unc

lear

N

o

mis

sing

resu

lts

Yes,

all

No

No

Low

46

FHR

Rand

omiz

ed

clin

ical

tria

l

Inco

mp

lete

Pa

rtia

lly

Seal

ed

enve

lop

s

Low

FH

R, p

H a

t

del

iver

y

No

mis

sing

resu

lts

Yes,

all

Yes

No

Med

ium

24

FHR

Pros

pec

tive

obse

rvat

iona

l

stud

y

Inco

mp

lete

N

A

NA

H

igh

FHR,

AS

No

mis

sing

resu

lts

Som

e Ye

s N

o Lo

w

47

FHR

Rand

omiz

ed

clin

ical

tria

l

Com

ple

te

No

Alte

rnat

e

mot

hers

Low

FH

R, A

S,

bre

athi

ngp

H,

neur

o-

beh

avio

r

Yes

Yes,

all

No

No

Med

ium

21 (9

) p

H

Pros

pec

tive

obse

rvat

iona

l

stu d

y

Inco

mp

lete

N

A

NA

H

igh

pH

, FH

R, A

S Ye

s U

ncle

ar

Yes

No

Low

4 (2

) FH

R C

ase

rep

orts

In

com

ple

te

NA

N

A

Hig

h U

ncle

ar

NA

So

me

No

No

Low

1 FH

R C

ase

rep

ort

In

com

ple

te

NA

N

A

Hig

h FH

R N

A

No

Yes

No

Low

6 (2

) FH

R

and

pH

Cas

e re

por

ts

Inco

mp

lete

N

A

NA

H

igh

FHR,

pH

, AS

NA

Ye

s, b

oth

Yes

No

Low

84

Unc

lear

,

at le

ast

pH

Pros

pec

tive

obse

rvat

iona

l

stud

y

Inco

mp

lete

N

A

NA

H

igh

Unc

lear

N

o

mis

sing

resu

lts

Som

e N

o N

o Lo

w

Tab

le 3

. Effe

ct o

f the

diff

eren

t int

raut

erin

e re

susc

itatio

n te

chni

ques

Inte

rven

tion

Stud

y d

esig

n Ye

ar

Eff

ect

Co

mm

ent

Am

nio

infu

sio

n Pr

osp

ectiv

e ob

serv

atio

nal

stud

y

1997

Pos

itive

In

77%

of c

ases

feta

l hea

rt r

ate

dec

eler

atio

ns im

pro

ved

, oth

er o

utco

mes

are

not

rep

orte

d

for

the

abno

rmal

CTG

gro

up o

nly.

Am

nio

infu

sio

n Ra

ndom

ized

cl

inic

al t

rial

2005

Pos

itive

Lo

wer

ces

area

n ra

te, l

ower

NIC

U a

dm

issi

ons

and

less

Ap

gar

sco

re <

7 a

t 1

and

5 m

inut

es

in a

mni

oinf

usio

n g

roup

. No

diff

eren

ces

in m

ater

nal o

utco

me.

Am

nio

infu

sio

n Ra

ndom

ized

cl

inic

al t

rial

1985

Pos

itive

In

the

infu

sion

gro

up 5

1% o

f all

case

s sh

owed

com

ple

te r

elie

ve o

f var

iab

le d

ecel

erat

ions

, an

d 4

.2%

of n

on-in

fusi

on g

roup

(P<

0.00

1), t

his

effe

ct is

mai

nly

seen

in t

he n

ullip

arou

s g

roup

. Ces

area

n se

ctio

n ra

te w

as le

ss in

the

infu

sion

gro

up in

nul

lipar

ous

wom

en. T

here

w

as n

o d

iffer

ence

in A

pg

ar s

core

bet

wee

n b

oth

gro

ups.

Am

nio

infu

sio

n Pr

osp

ectiv

e ob

serv

atio

nal

stud

y

1983

Pos

itive

V

aria

ble

dec

eler

atio

ns (g

roup

1) w

ere

relie

ved

aft

er a

mni

oinf

usio

n in

19

of 2

8 ca

ses,

all

Ap

gar

sco

res

wer

e ≥

7. I

n g

roup

2 (p

rolo

nged

dec

eler

atio

ns) 1

2 of

14

pat

ient

s ha

d r

elie

f of

dec

eler

atio

ns. A

ll A

pg

ar s

core

s w

ere ≥

7.

Oxy

gen

Pr

osp

ectiv

e ob

serv

atio

nal

stud

y

1967

Pos

itive

In

crea

se in

pO

2 in

feta

l but

tock

in n

orm

al c

ases

as

wel

l as

in t

hose

sho

win

g s

igns

of f

etal

d

istr

ess.

In 1

0 ca

ses

with

tac

hyca

rdia

oxy

gen

ad

min

istr

atio

n ca

used

a s

igni

fican

t fa

ll in

b

asal

FH

R. In

17

pat

ient

s w

ith 4

3 ad

min

istr

atio

ns, t

ype

II d

ips

bec

ame

less

pro

foun

d. 3

ca

ses

with

pro

long

ed la

bor

the

fetu

ses

wer

e ve

ry d

epre

ssed

Left

p

osi

tioni

ng

Pros

pec

tive

obse

rvat

iona

l st

udy

1985

Mod

erat

e In

102

of 1

26 p

atie

nts

late

ral p

ositi

onin

g d

id n

ot r

elie

ve la

te F

HR

dec

eler

atio

ns, i

n 24

it

did

. In

5 ca

ses

imp

rove

d fe

tal c

ond

ition

was

det

erm

ined

by

an in

crea

se in

feta

l pH

ob

tain

ed b

y fe

tal b

lood

sam

plin

g.

Intr

aven

ous

f lu

id b

olu

s Pr

osp

ectiv

e ob

serv

atio

nal

stud

y

1975

Unc

lear

D

extr

ane

allo

ws

the

fetu

s to

sur

vive

unt

il te

rmin

atio

n of

pre

gna

ncy

in c

ase

of fe

tal

bra

dyc

ard

ia.


37

2

() =

mee

t inc

lusi

on c

riter

ia

NA

= n

ot a

pplic

able

, AS=

Apg

ar s

core

Part

icip

ants

Se

lect

ion

bia

s O

utco

me

Co

nfo

und

ing

Co

nclu

sio

n

50

FHR

Pros

pec

tive

obse

rvat

iona

l

stud

y

Inco

mp

lete

N

A

NA

H

igh

Unc

lear

N

o

mis

sing

resu

lts

Yes,

all

No

No

Low

46

FHR

Rand

omiz

ed

clin

ical

tria

l

Inco

mp

lete

Pa

rtia

lly

Seal

ed

enve

lop

s

Low

FH

R, p

H a

t

del

iver

y

No

mis

sing

resu

lts

Yes,

all

Yes

No

Med

ium

24

FHR

Pros

pec

tive

obse

rvat

iona

l

stud

y

Inco

mp

lete

N

A

NA

H

igh

FHR,

AS

No

mis

sing

resu

lts

Som

e Ye

s N

o Lo

w

47

FHR

Rand

omiz

ed

clin

ical

tria

l

Com

ple

te

No

Alte

rnat

e

mot

hers

Low

FH

R, A

S,

bre

athi

ngp

H,

neur

o-

beh

avio

r

Yes

Yes,

all

No

No

Med

ium

21 (9

) p

H

Pros

pec

tive

obse

rvat

iona

l

stud

y

Inco

mp

lete

N

A

NA

H

igh

pH

, FH

R, A

S Ye

s U

ncle

ar

Yes

No

Low

4 (2

) FH

R C

ase

rep

orts

In

com

ple

te

NA

N

A

Hig

h U

ncle

ar

NA

So

me

No

No

Low

1 FH

R C

ase

rep

ort

In

com

ple

te

NA

N

A

Hig

h FH

R N

A

No

Yes

No

Low

6 (2

) FH

R

and

pH

Cas

e re

por

ts

Inco

mp

lete

N

A

NA

H

igh

FHR,

pH

, AS

NA

Ye

s, b

oth

Yes

No

Low

84

Unc

lear

,

at le

ast

pH

Pros

pec

tive

obse

rvat

iona

l

stud

y

Inco

mp

lete

N

A

NA

H

igh

Unc

lear

N

o

mis

sing

resu

lts

Som

e N

o N

o Lo

w

Tab

le 3

. Effe

ct o

f the

diff

eren

t int

raut

erin

e re

susc

itatio

n te

chni

ques

Inte

rven

tion

Stud

y d

esig

n Ye

ar

Eff

ect

Co

mm

ent

Am

nio

infu

sio

n Pr

osp

ectiv

e ob

serv

atio

nal

stud

y

1997

Pos

itive

In

77%

of c

ases

feta

l hea

rt r

ate

dec

eler

atio

ns im

pro

ved

, oth

er o

utco

mes

are

not

rep

orte

d

for

the

abno

rmal

CTG

gro

up o

nly.

Am

nio

infu

sio

n Ra

ndom

ized

cl

inic

al t

rial

2005

Pos

itive

Lo

wer

ces

area

n ra

te, l

ower

NIC

U a

dm

issi

ons

and

less

Ap

gar

sco

re <

7 a

t 1

and

5 m

inut

es

in a

mni

oinf

usio

n g

roup

. No

diff

eren

ces

in m

ater

nal o

utco

me.

Am

nio

infu

sio

n Ra

ndom

ized

cl

inic

al t

rial

1985

Pos

itive

In

the

infu

sion

gro

up 5

1% o

f all

case

s sh

owed

com

ple

te r

elie

ve o

f var

iab

le d

ecel

erat

ions

, an

d 4

.2%

of n

on-in

fusi

on g

roup

(P<

0.00

1), t

his

effe

ct is

mai

nly

seen

in t

he n

ullip

arou

s g

roup

. Ces

area

n se

ctio

n ra

te w

as le

ss in

the

infu

sion

gro

up in

nul

lipar

ous

wom

en. T

here

w

as n

o d

iffer

ence

in A

pg

ar s

core

bet

wee

n b

oth

gro

ups.

Am

nio

infu

sio

n Pr

osp

ectiv

e ob

serv

atio

nal

stud

y

1983

Pos

itive

V

aria

ble

dec

eler

atio

ns (g

roup

1) w

ere

relie

ved

aft

er a

mni

oinf

usio

n in

19

of 2

8 ca

ses,

all

Ap

gar

sco

res

wer

e ≥

7. I

n g

roup

2 (p

rolo

nged

dec

eler

atio

ns) 1

2 of

14

pat

ient

s ha

d r

elie

f of

dec

eler

atio

ns. A

ll A

pg

ar s

core

s w

ere ≥

7.

Oxy

gen

Pr

osp

ectiv

e ob

serv

atio

nal

stud

y

1967

Pos

itive

In

crea

se in

pO

2 in

feta

l but

tock

in n

orm

al c

ases

as

wel

l as

in t

hose

sho

win

g s

igns

of f

etal

d

istr

ess.

In 1

0 ca

ses

with

tac

hyca

rdia

oxy

gen

ad

min

istr

atio

n ca

used

a s

igni

fican

t fa

ll in

b

asal

FH

R. In

17

pat

ient

s w

ith 4

3 ad

min

istr

atio

ns, t

ype

II d

ips

bec

ame

less

pro

foun

d. 3

ca

ses

with

pro

long

ed la

bor

the

fetu

ses

wer

e ve

ry d

epre

ssed

Left

p

osi

tioni

ng

Pros

pec

tive

obse

rvat

iona

l st

udy

1985

Mod

erat

e In

102

of 1

26 p

atie

nts

late

ral p

ositi

onin

g d

id n

ot r

elie

ve la

te F

HR

dec

eler

atio

ns, i

n 24

it

did

. In

5 ca

ses

imp

rove

d fe

tal c

ond

ition

was

det

erm

ined

by

an in

crea

se in

feta

l pH

ob

tain

ed b

y fe

tal b

lood

sam

plin

g.

Intr

aven

ous

flu

id b

olu

s Pr

osp

ectiv

e ob

serv

atio

nal

stud

y

1975

Unc

lear

D

extr

ane

allo

ws

the

fetu

s to

sur

vive

unt

il te

rmin

atio

n of

pre

gna

ncy

in c

ase

of fe

tal

bra

dyc

ard

ia.

Chapter 2

38

Inte

rven

tion

Stud

y d

esig

n Ye

ar

Eff

ect

Co

mm

ent

Toco

lysi

s Ra

ndom

ized

cl

inic

al t

rial

1993

Pos

itive

In

21

of 2

3 w

omen

tre

ated

with

ter

but

alin

e an

d 1

6 of

23

trea

ted

with

Mg

SO4

FHR

resp

onse

was

ref

lect

ed b

y re

solu

tion

of t

he s

igns

of d

istr

ess

(NS)

. pH

< 7

.20

at b

irth

occu

rred

in 2

of 2

3 p

atie

nts

trea

ted

with

ter

but

alin

e an

d 7

of 2

3 in

Mg

SO4

gro

up (N

S).

Toco

lysi

s Pr

osp

ectiv

e ob

serv

atio

nal

stud

y

1997

Pos

itive

In

22

case

s ni

trog

lyce

rin w

as e

ffect

ive.

Effe

ctiv

e re

susc

itatio

n w

as d

efin

ed a

s fe

tal d

istr

ess

reso

lutio

n w

ithin

4-5

min

utes

with

nor

mal

izat

ion

of u

terin

e ac

tivity

. The

inte

rven

tion

was

p

artia

lly e

ffect

ive

in 2

cas

es. P

artia

lly e

ffect

ive

was

def

ined

as

feta

l dis

tres

s re

solu

tion

with

in 4

-5 m

inut

es w

ith r

esid

ual m

ild u

terin

e hy

per

activ

ity. F

our

neon

ates

had

low

1-

min

ute

Ap

gar

sco

re (3

- 6)

. At

5 m

inut

es, a

ll A

pg

ar s

core

s w

ere

9 or

10.

Toco

lysi

s Ra

ndom

ized

cl

inic

al t

rial

1982

Pos

itive

In

5 p

atie

nts

CTG

bec

ame

norm

al, l

ess

omin

ous

in 9

pat

ient

s an

d C

TG r

emai

ned

un

chan

ged

in 2

pat

ient

s, u

terin

e ac

tivity

was

red

uced

to

an a

vera

ge

of 2

2%. I

n th

e co

ntro

l g

roup

1 m

inut

e A

pg

ar s

core

was

low

er a

nd t

ime

to e

stab

lish

reg

ular

res

pira

tion

was

lo

nger

. Cor

d b

lood

gas

es w

ere

sim

ilar

in b

oth

gro

ups

and

no

diff

eren

ce w

as fo

und

in t

he

tone

and

neu

rob

ehav

iora

l sta

tus

on d

ay 4

.

Toco

lysi

s Pr

osp

ectiv

e ob

serv

atio

nal

stud

y

1972

Pos

itive

O

nly

9 ca

ses

met

our

incl

usio

n cr

iteria

. In

8 ca

ses

pH

imp

rove

d, i

n 1

case

it r

emai

ned

eq

ual.

Toco

lysi

s C

ase

rep

orts

19

82 U

ncle

ar

Effe

ct o

n fe

tal c

ond

ition

is n

ot d

escr

ibed

. Aft

er 1

1 m

onth

s th

ere

we

no n

eona

tal p

rob

lem

s an

d n

o ab

norm

aliti

es in

bot

h ca

ses.

Toco

lysi

s C

ase

rep

ort

19

85 P

ositi

ve

FHR

retu

rned

to

norm

al, i

nfan

t b

orn

with

1 a

nd 5

min

ute

Ap

gar

sco

re 9

and

9.

Toco

lysi

s C

ase

rep

orts

19

77 P

ositi

ve

2 ca

ses

that

met

our

incl

usio

n cr

iteria

: in

the

first

cas

e FH

R ra

te r

etur

ned

to

norm

al, a

fter

ce

sare

an s

ectio

n th

e 1

and

5 m

inut

e A

pg

ar s

core

was

8 a

nd 9

and

pH

7.2

5. In

the

sec

ond

ca

se F

HR

imp

rove

d a

s w

ell a

nd a

fter

ces

area

n se

ctio

n th

e 1

and

5 m

inut

e A

pg

ar s

core

was

7

and

10.

Inte

rven

tion

Stud

y d

esig

n Ye

ar

Eff

ect

Co

mm

ent

Toco

lysi

s Pr

osp

ectiv

e ob

serv

atio

nal

stud

y

1992

Pos

itive

In

68

of 8

4 ca

ses

pH

incr

ease

d m

ore

than

0.1

0 p

H u

nits

aft

er 4

0 m

in o

f inf

usio

n, in

11

case

s fe

tal p

H in

crea

sed

less

tha

n 0.

05 p

H u

nite

s, in

5 c

ases

feta

l pH

did

not

cha

nge

and

ev

en fe

ll. In

the

11

and

5 c

ases

fetu

ses

wer

e ex

trac

ted

pro

mp

tly b

y ce

sare

an s

ectio

n or

fo

rcep

s. T

he g

roup

of s

ucce

ssfu

l rea

nim

atio

n sh

ows

the

low

est

inci

den

ce o

f ab

norm

al

neur

olog

ical

dev

elop

men

t at

all

the

ages

stu

die

d. T

he g

roup

of 5

failu

res

show

s th

e hi

ghe

st p

rop

ortio

n of

ab

norm

al n

euro

log

ical

dev

elop

men

t.

CTG

= c

ardi

otoc

ogra

m, N

S =

not

sig

nific

ant


39

2

Inte

rven

tion

Stud

y d

esig

n Ye

ar

Eff

ect

Co

mm

ent

Toco

lysi

s Ra

ndom

ized

cl

inic

al t

rial

1993

Pos

itive

In

21

of 2

3 w

omen

tre

ated

with

ter

but

alin

e an

d 1

6 of

23

trea

ted

with

Mg

SO4

FHR

resp

onse

was

ref

lect

ed b

y re

solu

tion

of t

he s

igns

of d

istr

ess

(NS)

. pH

< 7

.20

at b

irth

occu

rred

in 2

of 2

3 p

atie

nts

trea

ted

with

ter

but

alin

e an

d 7

of 2

3 in

Mg

SO4

gro

up (N

S).

Toco

lysi

s Pr

osp

ectiv

e ob

serv

atio

nal

stud

y

1997

Pos

itive

In

22

case

s ni

trog

lyce

rin w

as e

ffect

ive.

Effe

ctiv

e re

susc

itatio

n w

as d

efin

ed a

s fe

tal d

istr

ess

reso

lutio

n w

ithin

4-5

min

utes

with

nor

mal

izat

ion

of u

terin

e ac

tivity

. The

inte

rven

tion

was

p

artia

lly e

ffect

ive

in 2

cas

es. P

artia

lly e

ffect

ive

was

def

ined

as

feta

l dis

tres

s re

solu

tion

with

in 4

-5 m

inut

es w

ith r

esid

ual m

ild u

terin

e hy

per

activ

ity. F

our

neon

ates

had

low

1-

min

ute

Ap

gar

sco

re (3

- 6)

. At

5 m

inut

es, a

ll A

pg

ar s

core

s w

ere

9 or

10.

Toco

lysi

s Ra

ndom

ized

cl

inic

al t

rial

1982

Pos

itive

In

5 p

atie

nts

CTG

bec

ame

norm

al, l

ess

omin

ous

in 9

pat

ient

s an

d C

TG r

emai

ned

un

chan

ged

in 2

pat

ient

s, u

terin

e ac

tivity

was

red

uced

to

an a

vera

ge

of 2

2%. I

n th

e co

ntro

l g

roup

1 m

inut

e A

pg

ar s

core

was

low

er a

nd t

ime

to e

stab

lish

reg

ular

res

pira

tion

was

lo

nger

. Cor

d b

lood

gas

es w

ere

sim

ilar

in b

oth

gro

ups

and

no

diff

eren

ce w

as fo

und

in t

he

tone

and

neu

rob

ehav

iora

l sta

tus

on d

ay 4

.

Toco

lysi

s Pr

osp

ectiv

e ob

serv

atio

nal

stud

y

1972

Pos

itive

O

nly

9 ca

ses

met

our

incl

usio

n cr

iteria

. In

8 ca

ses

pH

imp

rove

d, i

n 1

case

it r

emai

ned

eq

ual.

Toco

lysi

s C

ase

rep

orts

19

82 U

ncle

ar

Effe

ct o

n fe

tal c

ond

ition

is n

ot d

escr

ibed

. Aft

er 1

1 m

onth

s th

ere

we

no n

eona

tal p

rob

lem

s an

d n

o ab

norm

aliti

es in

bot

h ca

ses.

Toco

lysi

s C

ase

rep

ort

19

85 P

ositi

ve

FHR

retu

rned

to

norm

al, i

nfan

t b

orn

with

1 a

nd 5

min

ute

Ap

gar

sco

re 9

and

9.

Toco

lysi

s C

ase

rep

orts

19

77 P

ositi

ve

2 ca

ses

that

met

our

incl

usio

n cr

iteria

: in

the

first

cas

e FH

R ra

te r

etur

ned

to

norm

al, a

fter

ce

sare

an s

ectio

n th

e 1

and

5 m

inut

e A

pg

ar s

core

was

8 a

nd 9

and

pH

7.2

5. In

the

sec

ond

ca

se F

HR

imp

rove

d a

s w

ell a

nd a

fter

ces

area

n se

ctio

n th

e 1

and

5 m

inut

e A

pg

ar s

core

was

7

and

10.

Inte

rven

tion

Stud

y d

esig

n Ye

ar

Eff

ect

Co

mm

ent

Toco

lysi

s Pr

osp

ectiv

e ob

serv

atio

nal

stud

y

1992

Pos

itive

In

68

of 8

4 ca

ses

pH

incr

ease

d m

ore

than

0.1

0 p

H u

nits

aft

er 4

0 m

in o

f inf

usio

n, in

11

case

s fe

tal p

H in

crea

sed

less

tha

n 0.

05 p

H u

nite

s, in

5 c

ases

feta

l pH

did

not

cha

nge

and

ev

en fe

ll. In

the

11

and

5 c

ases

fetu

ses

wer

e ex

trac

ted

pro

mp

tly b

y ce

sare

an s

ectio

n or

fo

rcep

s. T

he g

roup

of s

ucce

ssfu

l rea

nim

atio

n sh

ows

the

low

est

inci

den

ce o

f ab

norm

al

neur

olog

ical

dev

elop

men

t at

all

the

ages

stu

die

d. T

he g

roup

of 5

failu

res

show

s th

e hi

ghe

st p

rop

ortio

n of

ab

norm

al n

euro

log

ical

dev

elop

men

t.

CTG

= c

ardi

otoc

ogra

m, N

S =

not

sig

nific

ant

Chapter 2

40

Maternal hyperoxygenation Only 1 study regarding maternal hyperoxygenation was identified. This is a

prospective study by Althabe et al, performed in 1967, which included 21 patients in

term labor.5 All parturients received 100% oxygen during labor. Afterward, the total

group was divided into a group with fetuses in normal condition and a group where

fetal distress was present. In 17 cases, “type II dips,” currently described as late

decelerations, were present. These decelerations became less profound during

maternal hyperoxygenation. In 10 cases where fetal tachycardia was present, the

FHR baseline dropped when oxygen was applied to the mother. In 1 case, fetal

scalp sampling as well as partial oxygen pressure (pO2) measurement in the fetal

buttock was performed: both pH and pO2 improved. The authors describe 3 cases

of prolonged labor (>15 hours) where the rise in fetal pO2 diminished with time and

the effect of maternal hyperoxygenation on FHR was much smaller than at earlier

stages of labor. When born, these 3 newborns were severely depressed.

Unfortunately, study methods are poorly described, and the duration of oxygen

administration has a wide range (2–240 minutes). Unfortunately, the authors were

not able to obtain absolute values of fetal pO2. However, they described a rise or

decline in fetal pO2 over time.

Taking into account the limited quality of this prospective study, it showed mainly a

positive effect of maternal hyperoxygenation on fetal tachycardia, type II dips, fetal

pH, and pO2. The effect on Apgar score is not described.

Intravenous fluid administration No studies on the effect of intravenous administration of colloid or crystalloid

solutions were identified. We found 1 prospective study on the administration of

“plasma expander” dextrane.26 In 50 cases where fetal distress was suspected due

to the presence of variable and late FHR decelerations, dextrane was administered

awaiting termination of pregnancy. Outcome measures are not clearly described;

however, the author concludes that “dextrane infusions were able to improve fetal

distress until the obstetrician was ready for termination of pregnancy.” The author

does not describe how the improved fetal condition was identified, and there was

no control group.

Tocolysis

We identified 8 studies on the use of betamimetics (ritodrine, hexoprenaline, or

orciprenaline) to stop uterine contractions during labor: 1 study on the use of

nitroglycerin and 1 study comparing a betamimetic drug to magnesium sulfate

(MgSO4).

Sheybany et al. performed a randomized controlled trial to investigate the effect of

6 mg ritodrine intravenously on FHR pattern.36 In total, 47 patients awaiting cesarean

delivery for fetal distress were included: the intervention group consisted of 24

patients receiving ritodrine and a control group of 23 patients receiving

conventional care. The authors showed a correction of FHR abnormalities in 5 of 24

patients receiving ritodrine. The FHR pattern became less ominous in 9 patients and

was unchanged in 2 patients. In the intervention group, uterine activity was reduced

to an average of 22%. Regarding fetal outcome, in the control group, 1-minute

Apgar score was lower, and time to establish regular respiration was longer.

Unfortunately, 5- and 10-minute Apgar scores were not reported. Cord blood gases

were similar in both groups, and no differences were found in the tone and

neurobehavioral status on days 4 to 7.

Renaud et al. performed an observational study and included a total of 21 patients

where acidosis or preacidosis was present.37 How these diagnoses were defined is

not clearly described. All patients received 200 to 500 μg ritodrine per minute, and

fetal pH levels before and after the intervention were compared. The authors

describe the characteristics of each of the 21 cases where ritodrine was used for fetal

resuscitation. Only 9 cases met our inclusion criteria. Of these 9 cases, pH improved

in 8 cases, and in 1 case, pH remained equal. Because of the small sample size as

well as the lack of a control group and lack of description of inclusion and exclusion

criteria, this study is of poor quality. Hutchon in his report describes 4 cases of

severe fetal bradycardia treated with ritodrine.38 Only 2 of these cases met our

inclusion criteria. The effect on fetal condition is not clearly described; however, in

the first case, the newborn was delivered by cesarean delivery with an Apgar score

of 1 at 1 minute, and intubation was carried out. After 5 minutes, the Apgar score

was 7. In the second case, the newborn was delivered by forceps extraction. Apgar

scores after 1 and 5 minutes were 7 and 9, respectively. After 11 months, there were

no neonatal problems and no abnormalities in both cases.


41

2

Maternal hyperoxygenation Only 1 study regarding maternal hyperoxygenation was identified. This is a

prospective study by Althabe et al, performed in 1967, which included 21 patients in

term labor.5 All parturients received 100% oxygen during labor. Afterward, the total

group was divided into a group with fetuses in normal condition and a group where

fetal distress was present. In 17 cases, “type II dips,” currently described as late

decelerations, were present. These decelerations became less profound during

maternal hyperoxygenation. In 10 cases where fetal tachycardia was present, the

FHR baseline dropped when oxygen was applied to the mother. In 1 case, fetal

scalp sampling as well as partial oxygen pressure (pO2) measurement in the fetal

buttock was performed: both pH and pO2 improved. The authors describe 3 cases

of prolonged labor (>15 hours) where the rise in fetal pO2 diminished with time and

the effect of maternal hyperoxygenation on FHR was much smaller than at earlier

stages of labor. When born, these 3 newborns were severely depressed.

Unfortunately, study methods are poorly described, and the duration of oxygen

administration has a wide range (2–240 minutes). Unfortunately, the authors were

not able to obtain absolute values of fetal pO2. However, they described a rise or

decline in fetal pO2 over time.

Taking into account the limited quality of this prospective study, it showed mainly a

positive effect of maternal hyperoxygenation on fetal tachycardia, type II dips, fetal

pH, and pO2. The effect on Apgar score is not described.

Intravenous fluid administration No studies on the effect of intravenous administration of colloid or crystalloid

solutions were identified. We found 1 prospective study on the administration of

“plasma expander” dextrane.26 In 50 cases where fetal distress was suspected due

to the presence of variable and late FHR decelerations, dextrane was administered

awaiting termination of pregnancy. Outcome measures are not clearly described;

however, the author concludes that “dextrane infusions were able to improve fetal

distress until the obstetrician was ready for termination of pregnancy.” The author

does not describe how the improved fetal condition was identified, and there was

no control group.

Tocolysis

We identified 8 studies on the use of betamimetics (ritodrine, hexoprenaline, or

orciprenaline) to stop uterine contractions during labor: 1 study on the use of

nitroglycerin and 1 study comparing a betamimetic drug to magnesium sulfate

(MgSO4).

Sheybany et al. performed a randomized controlled trial to investigate the effect of

6 mg ritodrine intravenously on FHR pattern.36 In total, 47 patients awaiting cesarean

delivery for fetal distress were included: the intervention group consisted of 24

patients receiving ritodrine and a control group of 23 patients receiving

conventional care. The authors showed a correction of FHR abnormalities in 5 of 24

patients receiving ritodrine. The FHR pattern became less ominous in 9 patients and

was unchanged in 2 patients. In the intervention group, uterine activity was reduced

to an average of 22%. Regarding fetal outcome, in the control group, 1-minute

Apgar score was lower, and time to establish regular respiration was longer.

Unfortunately, 5- and 10-minute Apgar scores were not reported. Cord blood gases

were similar in both groups, and no differences were found in the tone and

neurobehavioral status on days 4 to 7.

Renaud et al. performed an observational study and included a total of 21 patients

where acidosis or preacidosis was present.37 How these diagnoses were defined is

not clearly described. All patients received 200 to 500 μg ritodrine per minute, and

fetal pH levels before and after the intervention were compared. The authors

describe the characteristics of each of the 21 cases where ritodrine was used for fetal

resuscitation. Only 9 cases met our inclusion criteria. Of these 9 cases, pH improved

in 8 cases, and in 1 case, pH remained equal. Because of the small sample size as

well as the lack of a control group and lack of description of inclusion and exclusion

criteria, this study is of poor quality. Hutchon in his report describes 4 cases of

severe fetal bradycardia treated with ritodrine.38 Only 2 of these cases met our

inclusion criteria. The effect on fetal condition is not clearly described; however, in

the first case, the newborn was delivered by cesarean delivery with an Apgar score

of 1 at 1 minute, and intubation was carried out. After 5 minutes, the Apgar score

was 7. In the second case, the newborn was delivered by forceps extraction. Apgar

scores after 1 and 5 minutes were 7 and 9, respectively. After 11 months, there were

no neonatal problems and no abnormalities in both cases.

Chapter 2

42

Lipshitz and Klose and Lipshitz performed studies on the effect of 2 different

betamimetic drugs in the treatment of acute fetal distress.24,29 The first study,

published in 1977, describes 6 cases of fetal distress where hexoprenaline was

administered.39 Fetal distress was suspected because of abnormal FHR patterns or

low fetal scalp pH levels. Two cases met our inclusion criteria: in the first case, the

patient was first placed in left lateral position, and oxygen was administered. The

second patient was placed on left lateral position as well, but no oxygen was

administered. As these interventions were not effective, in both cases, 10 μg

hexoprenaline was administered intravenously. In the first case, FHR returned to

normal, and after cesarean delivery, the 1- and 5-minute Apgar scores were 8 and 9

and pH was 7.25. In the second case, FHR improved as well, and after cesarean

delivery, the 1- and 5-minute Apgar scores were 7 and 10, respectively. In a

consecutive article published in 1985, Lipshitz and Klose described a case report on

the use of 6 mg ritodrine in a case where fetal bradycardia was present as a result of

uterine hypertonus.24 Discontinuation of oxytocin, left lateral positioning, and

oxygen administration had no effect on FHR. After the administration of ritodrine,

FHR returned to normal, and 4 hours later, a newborn was born with Apgar scores of

9 and 9 after 1 and 5 minutes, respectively.

In 1992, Caldeyro-Barcia performed a prospective observational trial on the use of

orciprenaline. In this article, the author refers to a former study.29 He mentions only

the success or failure of intrauterine resuscitation with orciprenaline in a series of 84

fetuses. In 68 of 84 cases, pH increased more than 0.10 pH units after 40 minutes of

betamimetic infusion. Furthermore, in 11 cases, fetal pH increased less than 0.05 pH

units, whereas in the remaining 5 cases, fetal pH did not change or even fell. In the

16 cases with absent or moderate effect, fetuses were extracted promptly by

cesarean delivery or forceps. The group of 68 successful reanimations shows the

lowest incidence of abnormal neurological development at all the ages studied. The

group of 5 resuscitation failures shows the highest proportion of abnormal

neurological development.

Another betamimetic drug, terbutaline, was compared with MgSO4 in a randomized

clinical trial by Magann et al.34 A total of 46 women requiring cesarean delivery for

fetal distress was randomized to receive 0.25 mg terbutaline or 4 g MgSO4. In 21 of

23 women treated with terbutaline and in 16 of 23 treated with MgSO4, FHR

abnormalities resolved. Arterial cord blood pH of less than 7.20 at birth occurred in

2 of 23 patients treated with terbutaline and 7 of 23 in the MgSO4 group. Both out-

comes do not represent a significant difference between 1 of the 2 tocolytic agents.

A completely different tocolytic agent, nitroglycerin, was used in Mercier and

colleagues’ study.35 During a 1-year period, the authors prospectively evaluated the

use of nitroglycerin to relieve severe intrapartum distress related to uterine

hyperactivity. When left lateral position, oxygen administration, and discontinuation

of oxytocin infusion failed to improve abnormal FHR patterns, 60 to 90 μg of

nitroglycerin was injected intravenously. In 22 of 24 cases, nitroglycerin was

effective. Effective resuscitation was defined as fetal distress resolution within 4 to 5

minutes with normalization of uterine activity. The intervention was partially effective

in 2 cases, defined as fetal distress resolution within 4 to 5 minutes with residual

mild uterine hyperactivity. Four neonates had low 1-minute Apgar score. At 5

minutes, all Apgar scores were 9 or 10. Six patients developed hypotension after the

injection with nitroglycerin, but this was rapidly reversed with a single dose of

ephedrine.

Amnioinfusion We included 4 studies regarding amnioinfusion for fetal distress. Abdel-Aleem et al.

performed a randomized clinical trial evaluating the effect of amnioinfusion.30 A total

of 438 women admitted in labor with nonreassuring FHR patterns were randomized

between conventional treatment and amnioinfusion using a pediatric feeding tube.

Conventional treatment included discontinuation of oxytocin infusion, oxygen

administration, and left lateral positioning. The authors showed a lower cesarean

delivery rate (105 vs 149 cases; relative risk [RR], 0.70; confidence interval [CI], 0.60–

0.83), a lower number of NICU admissions (14 vs 31 cases; RR, 0.45; CI, 0.25–0.83),

and a lower number of Apgar scores (<7) at 1 minute (29 vs 77 cases; RR, 0.38; CI,

0.26–0.55) and 5 minutes (9 vs 29 cases; RR, 0.31; CI, 0.15–0.64) after birth in the

amnioinfusion group. There were no differences in maternal outcomes.

In the observational study by Surbek et al, 13 of 16 patients were included because

of prolonged first stage of labor and persistent severe variable decelerations; the

other 3 were included because of meconium-stained amniotic fluid.28 In 10 (77%) of

the 13 patients included because of abnormal FHR patterns, the FHR patterns

improved after amnioinfusion. Other outcome parameters are not reported for the

specific group with abnormal FHR patterns.

Miyazaki and Nevarez in 1985 and Miyazaki and Taylor in 1983 performed studies on

the effect of saline amnioinfusion.31,32 In the prospective study published in 1983,

saline amnioinfusion was performed in 42 patients having repetitive variable or


43

2

Lipshitz and Klose and Lipshitz performed studies on the effect of 2 different

betamimetic drugs in the treatment of acute fetal distress.24,29 The first study,

published in 1977, describes 6 cases of fetal distress where hexoprenaline was

administered.39 Fetal distress was suspected because of abnormal FHR patterns or

low fetal scalp pH levels. Two cases met our inclusion criteria: in the first case, the

patient was first placed in left lateral position, and oxygen was administered. The

second patient was placed on left lateral position as well, but no oxygen was

administered. As these interventions were not effective, in both cases, 10 μg

hexoprenaline was administered intravenously. In the first case, FHR returned to

normal, and after cesarean delivery, the 1- and 5-minute Apgar scores were 8 and 9

and pH was 7.25. In the second case, FHR improved as well, and after cesarean

delivery, the 1- and 5-minute Apgar scores were 7 and 10, respectively. In a

consecutive article published in 1985, Lipshitz and Klose described a case report on

the use of 6 mg ritodrine in a case where fetal bradycardia was present as a result of

uterine hypertonus.24 Discontinuation of oxytocin, left lateral positioning, and

oxygen administration had no effect on FHR. After the administration of ritodrine,

FHR returned to normal, and 4 hours later, a newborn was born with Apgar scores of

9 and 9 after 1 and 5 minutes, respectively.

In 1992, Caldeyro-Barcia performed a prospective observational trial on the use of

orciprenaline. In this article, the author refers to a former study.29 He mentions only

the success or failure of intrauterine resuscitation with orciprenaline in a series of 84

fetuses. In 68 of 84 cases, pH increased more than 0.10 pH units after 40 minutes of

betamimetic infusion. Furthermore, in 11 cases, fetal pH increased less than 0.05 pH

units, whereas in the remaining 5 cases, fetal pH did not change or even fell. In the

16 cases with absent or moderate effect, fetuses were extracted promptly by

cesarean delivery or forceps. The group of 68 successful reanimations shows the

lowest incidence of abnormal neurological development at all the ages studied. The

group of 5 resuscitation failures shows the highest proportion of abnormal

neurological development.

Another betamimetic drug, terbutaline, was compared with MgSO4 in a randomized

clinical trial by Magann et al.34 A total of 46 women requiring cesarean delivery for

fetal distress was randomized to receive 0.25 mg terbutaline or 4 g MgSO4. In 21 of

23 women treated with terbutaline and in 16 of 23 treated with MgSO4, FHR

abnormalities resolved. Arterial cord blood pH of less than 7.20 at birth occurred in

2 of 23 patients treated with terbutaline and 7 of 23 in the MgSO4 group. Both out-

comes do not represent a significant difference between 1 of the 2 tocolytic agents.

A completely different tocolytic agent, nitroglycerin, was used in Mercier and

colleagues’ study.35 During a 1-year period, the authors prospectively evaluated the

use of nitroglycerin to relieve severe intrapartum distress related to uterine

hyperactivity. When left lateral position, oxygen administration, and discontinuation

of oxytocin infusion failed to improve abnormal FHR patterns, 60 to 90 μg of

nitroglycerin was injected intravenously. In 22 of 24 cases, nitroglycerin was

effective. Effective resuscitation was defined as fetal distress resolution within 4 to 5

minutes with normalization of uterine activity. The intervention was partially effective

in 2 cases, defined as fetal distress resolution within 4 to 5 minutes with residual

mild uterine hyperactivity. Four neonates had low 1-minute Apgar score. At 5

minutes, all Apgar scores were 9 or 10. Six patients developed hypotension after the

injection with nitroglycerin, but this was rapidly reversed with a single dose of

ephedrine.

Amnioinfusion We included 4 studies regarding amnioinfusion for fetal distress. Abdel-Aleem et al.

performed a randomized clinical trial evaluating the effect of amnioinfusion.30 A total

of 438 women admitted in labor with nonreassuring FHR patterns were randomized

between conventional treatment and amnioinfusion using a pediatric feeding tube.

Conventional treatment included discontinuation of oxytocin infusion, oxygen

administration, and left lateral positioning. The authors showed a lower cesarean

delivery rate (105 vs 149 cases; relative risk [RR], 0.70; confidence interval [CI], 0.60–

0.83), a lower number of NICU admissions (14 vs 31 cases; RR, 0.45; CI, 0.25–0.83),

and a lower number of Apgar scores (<7) at 1 minute (29 vs 77 cases; RR, 0.38; CI,

0.26–0.55) and 5 minutes (9 vs 29 cases; RR, 0.31; CI, 0.15–0.64) after birth in the

amnioinfusion group. There were no differences in maternal outcomes.

In the observational study by Surbek et al, 13 of 16 patients were included because

of prolonged first stage of labor and persistent severe variable decelerations; the

other 3 were included because of meconium-stained amniotic fluid.28 In 10 (77%) of

the 13 patients included because of abnormal FHR patterns, the FHR patterns

improved after amnioinfusion. Other outcome parameters are not reported for the

specific group with abnormal FHR patterns.

Miyazaki and Nevarez in 1985 and Miyazaki and Taylor in 1983 performed studies on

the effect of saline amnioinfusion.31,32 In the prospective study published in 1983,

saline amnioinfusion was performed in 42 patients having repetitive variable or

Chapter 2

44

prolonged decelerations (defined as <100 beats/min for ≥3 minutes) that did not

respond to conventional therapy, such as maternal position changes and oxygen

administration.32 The intervention was effective for relief of variable decelerations in

19 of 28 patients and for relief of prolonged decelerations in 12 of 14 patients. All

newborns had 5-minute Apgar scores of 7 or more. In 1985, Miyazaki and Nevarez

performed a randomized clinical trial among 96 patients showing repetitive variable

decelerations.31 These patients were randomized in the amnioinfusion group or the

control group (noninfusion group) receiving standard care (oxygen or maternal

positing change). In the infusion group, 51% showed complete relief of variable

decelerations, and 4.2% of the noninfusion group (P < 0.001). After subgroup

analysis, in the multiparous infusion group, no significant difference was

demonstrated. However, in the nulliparous infusion group, 66.7% had relieve of

variable decelerations versus 0% in the noninfusion group (P < 0.001). Cesarean

delivery rate was significantly lower in the infusion group compared with the

noninfusion group in nulliparous women. There was no difference in Apgar scores

between the infusion and noninfusion groups.

All included studies show a predominantly positive effect of amnioinfusion on fetal

condition.

Maternal repositioning We identified 1 study regarding maternal repositioning in the presence of fetal

distress. Abitbol in 1985 performed a prospective study on the effect of maternal

position on FHR pattern.33 Initially, 902 women in labor were included. When FHR

abnormalities occurred, they were placed in left lateral position. The lateral

positioning did relieve the decelerations in 24 (19%) of 126 cases. In 5 cases, fetal

scalp sampling or insertion of a pH electrode in the fetal tissue was performed

before and after turning to the lateral position: in all 5 cases, fetal acidosis improved

or resolved.

Intermittent pushing No studies on intermittent pushing to improve fetal condition during labor meeting

the inclusion criteria were identified.

Discussion Maternal hyperoxygenation The only study on maternal hyperoxygenation that met our inclusion criteria showed

an improvement in FHR abnormalities when 100% oxygen was administered to the

mother.5 However, this study is of poor quality (table 2). Other studies on the effect

of maternal hyperoxygenation are available, but did also assess nonhealthy term

fetuses and nonhealthy mothers.7,8 In Simpson’s study, maternal hyperoxygenation

with 100% oxygen increases fetal saturation of peripheral oxygen (SpO2); however,

oxygen was applied in the noncompromised fetus.3,6,40

In 2012, Fawole and Hofmeyr published a Cochrane review to assess the use of

maternal oxygen administration for fetal distress, but no randomized controlled trials

could be included, thereby confirming the lack of robust evidence on this topic.41 A

recent article by Hamel et al. provides a clear overview of the available evidence

against and in favor of maternal hyperoxygenation during labor.42 The authors state

that the beneficial effect of maternal hyperoxygenation is not yet proven. Maternal

hyperoxygenation may be harmful, because of increased free radical activity in both

mothers and neonates.43,44 Also, Thorp et al. showed that maternal oxygen

administration during labor may lead to lower umbilical artery pH, at least in the

noncompromised fetus.45 Hamel et al. acknowledged that supportive evidence to

promote maternal hyperoxygenation in case of fetal distress is lacking.42 They state

that maternal oxygen supplementation should be reserved for maternal hypoxia and

should not be considered as an intervention for nonreassuring fetal status. In their

article, the authors called for a randomized controlled trial to investigate the effect

of maternal oxygen administration in suspected fetal distress.

Hence, we did not find strong evidence to support the use of maternal

hyperoxygenation for fetal distress.


45

2

prolonged decelerations (defined as <100 beats/min for ≥3 minutes) that did not

respond to conventional therapy, such as maternal position changes and oxygen

administration.32 The intervention was effective for relief of variable decelerations in

19 of 28 patients and for relief of prolonged decelerations in 12 of 14 patients. All

newborns had 5-minute Apgar scores of 7 or more. In 1985, Miyazaki and Nevarez

performed a randomized clinical trial among 96 patients showing repetitive variable

decelerations.31 These patients were randomized in the amnioinfusion group or the

control group (noninfusion group) receiving standard care (oxygen or maternal

positing change). In the infusion group, 51% showed complete relief of variable

decelerations, and 4.2% of the noninfusion group (P < 0.001). After subgroup

analysis, in the multiparous infusion group, no significant difference was

demonstrated. However, in the nulliparous infusion group, 66.7% had relieve of

variable decelerations versus 0% in the noninfusion group (P < 0.001). Cesarean

delivery rate was significantly lower in the infusion group compared with the

noninfusion group in nulliparous women. There was no difference in Apgar scores

between the infusion and noninfusion groups.

All included studies show a predominantly positive effect of amnioinfusion on fetal

condition.

Maternal repositioning We identified 1 study regarding maternal repositioning in the presence of fetal

distress. Abitbol in 1985 performed a prospective study on the effect of maternal

position on FHR pattern.33 Initially, 902 women in labor were included. When FHR

abnormalities occurred, they were placed in left lateral position. The lateral

positioning did relieve the decelerations in 24 (19%) of 126 cases. In 5 cases, fetal

scalp sampling or insertion of a pH electrode in the fetal tissue was performed

before and after turning to the lateral position: in all 5 cases, fetal acidosis improved

or resolved.

Intermittent pushing No studies on intermittent pushing to improve fetal condition during labor meeting

the inclusion criteria were identified.

Discussion Maternal hyperoxygenation The only study on maternal hyperoxygenation that met our inclusion criteria showed

an improvement in FHR abnormalities when 100% oxygen was administered to the

mother.5 However, this study is of poor quality (table 2). Other studies on the effect

of maternal hyperoxygenation are available, but did also assess nonhealthy term

fetuses and nonhealthy mothers.7,8 In Simpson’s study, maternal hyperoxygenation

with 100% oxygen increases fetal saturation of peripheral oxygen (SpO2); however,

oxygen was applied in the noncompromised fetus.3,6,40

In 2012, Fawole and Hofmeyr published a Cochrane review to assess the use of

maternal oxygen administration for fetal distress, but no randomized controlled trials

could be included, thereby confirming the lack of robust evidence on this topic.41 A

recent article by Hamel et al. provides a clear overview of the available evidence

against and in favor of maternal hyperoxygenation during labor.42 The authors state

that the beneficial effect of maternal hyperoxygenation is not yet proven. Maternal

hyperoxygenation may be harmful, because of increased free radical activity in both

mothers and neonates.43,44 Also, Thorp et al. showed that maternal oxygen

administration during labor may lead to lower umbilical artery pH, at least in the

noncompromised fetus.45 Hamel et al. acknowledged that supportive evidence to

promote maternal hyperoxygenation in case of fetal distress is lacking.42 They state

that maternal oxygen supplementation should be reserved for maternal hypoxia and

should not be considered as an intervention for nonreassuring fetal status. In their

article, the authors called for a randomized controlled trial to investigate the effect

of maternal oxygen administration in suspected fetal distress.

Hence, we did not find strong evidence to support the use of maternal

hyperoxygenation for fetal distress.

Chapter 2

46

Intravenous fluid administration We identified 1 study on the use of the plasma expander dextrane that focuses on

fetal condition.26 This study has poorly described methods, whereas outcome

measures are not clearly defined as well. We identified no studies on the use of

intravenous crystalloids or colloids on fetal outcome in suspected fetal distress.

Regarding the noncompromised fetus, Simpson’s study showed that fetal SpO2 increases after administration of a fluid bolus of 500 to 1000 mL to the

parturient.3,6,40

Hence, we cannot prove the beneficial effect of intravenous fluid administration on

fetal outcome because this is never properly studied. In certain clinical situations,

excessive fluid administration may even be harmful, for example, in preeclamptic

women, where fluid administration may induce pulmonary edema.46 Furthermore,

theoretically, the beneficial effect on oxygen transport due to increased

uteroplacental blood flow will be nullified by the effect of hemodilution. Even

though Stratulat stated that dextrane may be beneficial to the fetus, we do not

recommend the use for fetal distress in current clinical practice because neither

beneficial nor harmful effects are properly investigated.26

Tocolysis We found 8 studies on tocolytic drugs. Two randomized clinical trials and 2

prospective studies show a moderate to positive effect of the tocolytic drugs

ritodrine, terbutaline, MgSO4, orciprenaline, and nitroglycerin on fetal condition. The

remaining 4 studies describe a total of 14 cases that met our inclusion criteria, the

majority showing a positive effect of ritodrine or hexoprenaline. Despite the poor

quality of most of the studies on the use of tocolytic drugs, study results are

consistent. All included studies show a positive effect on fetal condition without

reporting any serious adverse effects.29,36,37

Simpson advises in his review to administer a single dose of terbutaline in case of

fetal distress due to hyperstimulation, to provide intrauterine resuscitation.6 Simpson

hereby refers to Kulier and Hofmeyr’s Cochrane review in 2000.47 In this review on

tocolytics for suspected intrapartum distress, the authors conclude that

betamimetics reduce the number of FHR abnormalities, but there is not enough

evidence to evaluate their effect on clinically important outcomes. The authors

suggest that intravenous betamimetics can be a useful treatment for “buying time”

when fetal distress is diagnosed, but whether the need for operative delivery can be

reduced has not yet been demonstrated.47

Amnioinfusion All 4 eligible studies on amnioinfusion, including 2 randomized controlled trials,

show a positive effect of transcervical amnioinfusion on the fetal condition.28,30-32 In

addition, Hofmeyr and Lawrie conclude in their Cochrane review that the use of

amnioinfusion for potential or suspected umbilical cord compression may be of

considerable benefit to the mother and fetus.48

However, there are methodological limitations to the trials included in the Cochrane

review, and results are only partially applicable on the distressed fetus. This review

included a total of 19 studies, but unfortunately, these studies do not exclusively

focus on the use of amnioinfusion in case of suspected fetal distress. The authors

state that the alleviation of FHR abnormalities was slightly more pronounced in the

subgroup where FHR decelerations were present, but no significant differences were

demonstrated between the subgroups (oligohydramnios, FHR decelerations, and

mixed indication group). However, no reduction in cesarean delivery rate could be

demonstrated in this subgroup analysis. Furthermore, the authors state that their

results should be interpreted with caution because of the methodological

shortcomings and small sample size of the included studies. Besides, we know from

case reports that these risks are inherent to the use of amnioinfusion. Larger

randomized controlled trials are needed to study the effect of amnioinfusion in

specific clinical situations and to survey the risk on serious complications such as

umbilical cord prolapse, placental injury, or amniotic fluid embolism.

Maternal repositioning Maternal repositioning in the presence of fetal distress is studied only in the study of

Abitbol.33 In this study, fetal distress was suspected in the presence of late

decelerations or late components. We believe such decelerations are mainly caused

by impaired placental function and not by umbilical cord occlusion. In approximately

1 in 5 patients after turning the patient to lateral position, FHR pattern improved.

Possibly this effect is caused by the recovery from aortocaval compression, although

supine-hypotensive syndrome was not demonstrated in any of the patients.

Theoretically, if this intervention would be applied in the presence of variable

decelerations, the positive effect may be more pronounced. However, because this


47

2

Intravenous fluid administration We identified 1 study on the use of the plasma expander dextrane that focuses on

fetal condition.26 This study has poorly described methods, whereas outcome

measures are not clearly defined as well. We identified no studies on the use of

intravenous crystalloids or colloids on fetal outcome in suspected fetal distress.

Regarding the noncompromised fetus, Simpson’s study showed that fetal SpO2 increases after administration of a fluid bolus of 500 to 1000 mL to the

parturient.3,6,40

Hence, we cannot prove the beneficial effect of intravenous fluid administration on

fetal outcome because this is never properly studied. In certain clinical situations,

excessive fluid administration may even be harmful, for example, in preeclamptic

women, where fluid administration may induce pulmonary edema.46 Furthermore,

theoretically, the beneficial effect on oxygen transport due to increased

uteroplacental blood flow will be nullified by the effect of hemodilution. Even

though Stratulat stated that dextrane may be beneficial to the fetus, we do not

recommend the use for fetal distress in current clinical practice because neither

beneficial nor harmful effects are properly investigated.26

Tocolysis We found 8 studies on tocolytic drugs. Two randomized clinical trials and 2

prospective studies show a moderate to positive effect of the tocolytic drugs

ritodrine, terbutaline, MgSO4, orciprenaline, and nitroglycerin on fetal condition. The

remaining 4 studies describe a total of 14 cases that met our inclusion criteria, the

majority showing a positive effect of ritodrine or hexoprenaline. Despite the poor

quality of most of the studies on the use of tocolytic drugs, study results are

consistent. All included studies show a positive effect on fetal condition without

reporting any serious adverse effects.29,36,37

Simpson advises in his review to administer a single dose of terbutaline in case of

fetal distress due to hyperstimulation, to provide intrauterine resuscitation.6 Simpson

hereby refers to Kulier and Hofmeyr’s Cochrane review in 2000.47 In this review on

tocolytics for suspected intrapartum distress, the authors conclude that

betamimetics reduce the number of FHR abnormalities, but there is not enough

evidence to evaluate their effect on clinically important outcomes. The authors

suggest that intravenous betamimetics can be a useful treatment for “buying time”

when fetal distress is diagnosed, but whether the need for operative delivery can be

reduced has not yet been demonstrated.47

Amnioinfusion All 4 eligible studies on amnioinfusion, including 2 randomized controlled trials,

show a positive effect of transcervical amnioinfusion on the fetal condition.28,30-32 In

addition, Hofmeyr and Lawrie conclude in their Cochrane review that the use of

amnioinfusion for potential or suspected umbilical cord compression may be of

considerable benefit to the mother and fetus.48

However, there are methodological limitations to the trials included in the Cochrane

review, and results are only partially applicable on the distressed fetus. This review

included a total of 19 studies, but unfortunately, these studies do not exclusively

focus on the use of amnioinfusion in case of suspected fetal distress. The authors

state that the alleviation of FHR abnormalities was slightly more pronounced in the

subgroup where FHR decelerations were present, but no significant differences were

demonstrated between the subgroups (oligohydramnios, FHR decelerations, and

mixed indication group). However, no reduction in cesarean delivery rate could be

demonstrated in this subgroup analysis. Furthermore, the authors state that their

results should be interpreted with caution because of the methodological

shortcomings and small sample size of the included studies. Besides, we know from

case reports that these risks are inherent to the use of amnioinfusion. Larger

randomized controlled trials are needed to study the effect of amnioinfusion in

specific clinical situations and to survey the risk on serious complications such as

umbilical cord prolapse, placental injury, or amniotic fluid embolism.

Maternal repositioning Maternal repositioning in the presence of fetal distress is studied only in the study of

Abitbol.33 In this study, fetal distress was suspected in the presence of late

decelerations or late components. We believe such decelerations are mainly caused

by impaired placental function and not by umbilical cord occlusion. In approximately

1 in 5 patients after turning the patient to lateral position, FHR pattern improved.

Possibly this effect is caused by the recovery from aortocaval compression, although

supine-hypotensive syndrome was not demonstrated in any of the patients.

Theoretically, if this intervention would be applied in the presence of variable

decelerations, the positive effect may be more pronounced. However, because this

Chapter 2

48

is a very simple intervention that does not cause any harm, we do promote the use

of this intervention in any type of FHR abnormalities.

Intermittent pushing On the effect of altering pushing efforts on fetal outcome, little literature can be

found, and therefore we are not able to formulate any recommendation for clinical

practice. Simpson advices to stop pushing temporarily when the FHR pattern gets

nonreassuring during the second stage of labor; however, this intervention was not

studied in clinical practice.49 As well, one may consider to push with alternate

contractions or every third contraction to minimize fetal effects and maintain a

reassuring FHR pattern.6,49,50 However, intermittent pushing may delay the second

stage of labor and therefore postpone the possibility to start neonatal resuscitation

as soon as the fetus is born.

Potential biases in the overview process Evaluation of the available evidence is complicated by the lack of a general

definition of the diagnosis “fetal distress.” In most of the studies, fetal distress is

diagnosed by abnormalities in FHR pattern, introducing an increased risk of

selection bias due to the large intraobserver variations in interpretation of the

cardiotocogram.51-53 It is important to state that in future studies fetal distress should

be diagnosed by an objective method, such as fetal blood sampling, rather than by

FHR abnormalities alone. In case fetal blood sampling methods are not available,

abnormal FHR patterns should be defined very precisely.

Apart from the methodological shortcomings of the included studies, the chosen

methods of this review may also contribute to the small amount of available

evidence. We used a list with strict inclusion criteria with respect to condition of the

mother and the fetus. Furthermore, we were not able to retrieve the abstract or full

text of 4 of the references that resulted from the primary search. We are aware of

the availability of additional articles studying intrauterine resuscitation. However, the

scope of our review was the term and formerly healthy fetus and mother.

Nevertheless, we would like to discuss some interesting studies on intrauterine

resuscitation that did not meet our inclusion criteria. Several studies on the use of

tocolytics for fetal distress did not meet our inclusion criteria. This was mainly

because the study population did not include exclusively healthy mothers giving

birth to term, healthy fetuses. Still, most studies report an amelioration of FHR

patterns and fetal pH.27,54-58 However, while Kulier and colleagues’ randomized

controlled trial reports a positive effect of hexoprenaline on FHR pattern, no effect

on fetal pH or Apgar score is seen.59

Hidaka et al. demonstrated that the use of a tocolytic agent seems to be more

effective than oxygen administration in the presence of late decelerations.22

Furthermore, Haydon and colleagues’ study shows an increase in fetal SpO2 after 30

minutes of maternal hyperoxygenation with both 40% and 100% oxygen.8 Both

studies included patients from a gestational age of 36 weeks onward. Fetuses with

lower initial oxygenation status seem to profit more from maternal oxygen

administration than fetuses that have better initial oxygenation. These findings are in

accordance with Gare and colleagues’ study performed in 1969.60 The authors show

that maternal hyperoxygenation with 100% oxygen helps to improve fetal pO2 when

fetal distress is suspected. This conclusion is in accordance with the results from the

study included in our review.5

Conclusions Although intrauterine resuscitation for suspected fetal distress in term labor is

frequently used, evidence regarding the effect on fetal and maternal outcome is

poor. Maternal hyperoxygenation, tocolysis, amnioinfusion, maternal repositioning,

and intravenous fluid administration show positive effects on fetal outcome as

described in small, outdated studies. However, because studies of a better quality

are lacking, we draw conclusions from the best available evidence, taking into

account the potential hazardous effects. Recommendations evolving from this

systematic review are valid until larger randomized controlled trials are performed.

Taking into account results from former reviews, we do recommend the use of

tocolysis and maternal repositioning for fetal distress. We believe the benefits

outweigh the minimal chance on serious adverse effects. Until further evidence is

supplied, we cannot support the use of maternal hyperoxygenation, amnioinfusion,

intravenous fluid administration, or intermittent pushing, when applied to resolve

fetal distress to improve neonatal outcome. As expected, convincing evidence to

promote or refuse any of these interventions for this specific indication still needs to

be provided.


49

2

is a very simple intervention that does not cause any harm, we do promote the use

of this intervention in any type of FHR abnormalities.

Intermittent pushing On the effect of altering pushing efforts on fetal outcome, little literature can be

found, and therefore we are not able to formulate any recommendation for clinical

practice. Simpson advices to stop pushing temporarily when the FHR pattern gets

nonreassuring during the second stage of labor; however, this intervention was not

studied in clinical practice.49 As well, one may consider to push with alternate

contractions or every third contraction to minimize fetal effects and maintain a

reassuring FHR pattern.6,49,50 However, intermittent pushing may delay the second

stage of labor and therefore postpone the possibility to start neonatal resuscitation

as soon as the fetus is born.

Potential biases in the overview process Evaluation of the available evidence is complicated by the lack of a general

definition of the diagnosis “fetal distress.” In most of the studies, fetal distress is

diagnosed by abnormalities in FHR pattern, introducing an increased risk of

selection bias due to the large intraobserver variations in interpretation of the

cardiotocogram.51-53 It is important to state that in future studies fetal distress should

be diagnosed by an objective method, such as fetal blood sampling, rather than by

FHR abnormalities alone. In case fetal blood sampling methods are not available,

abnormal FHR patterns should be defined very precisely.

Apart from the methodological shortcomings of the included studies, the chosen

methods of this review may also contribute to the small amount of available

evidence. We used a list with strict inclusion criteria with respect to condition of the

mother and the fetus. Furthermore, we were not able to retrieve the abstract or full

text of 4 of the references that resulted from the primary search. We are aware of

the availability of additional articles studying intrauterine resuscitation. However, the

scope of our review was the term and formerly healthy fetus and mother.

Nevertheless, we would like to discuss some interesting studies on intrauterine

resuscitation that did not meet our inclusion criteria. Several studies on the use of

tocolytics for fetal distress did not meet our inclusion criteria. This was mainly

because the study population did not include exclusively healthy mothers giving

birth to term, healthy fetuses. Still, most studies report an amelioration of FHR

patterns and fetal pH.27,54-58 However, while Kulier and colleagues’ randomized

controlled trial reports a positive effect of hexoprenaline on FHR pattern, no effect

on fetal pH or Apgar score is seen.59

Hidaka et al. demonstrated that the use of a tocolytic agent seems to be more

effective than oxygen administration in the presence of late decelerations.22

Furthermore, Haydon and colleagues’ study shows an increase in fetal SpO2 after 30

minutes of maternal hyperoxygenation with both 40% and 100% oxygen.8 Both

studies included patients from a gestational age of 36 weeks onward. Fetuses with

lower initial oxygenation status seem to profit more from maternal oxygen

administration than fetuses that have better initial oxygenation. These findings are in

accordance with Gare and colleagues’ study performed in 1969.60 The authors show

that maternal hyperoxygenation with 100% oxygen helps to improve fetal pO2 when

fetal distress is suspected. This conclusion is in accordance with the results from the

study included in our review.5

Conclusions Although intrauterine resuscitation for suspected fetal distress in term labor is

frequently used, evidence regarding the effect on fetal and maternal outcome is

poor. Maternal hyperoxygenation, tocolysis, amnioinfusion, maternal repositioning,

and intravenous fluid administration show positive effects on fetal outcome as

described in small, outdated studies. However, because studies of a better quality

are lacking, we draw conclusions from the best available evidence, taking into

account the potential hazardous effects. Recommendations evolving from this

systematic review are valid until larger randomized controlled trials are performed.

Taking into account results from former reviews, we do recommend the use of

tocolysis and maternal repositioning for fetal distress. We believe the benefits

outweigh the minimal chance on serious adverse effects. Until further evidence is

supplied, we cannot support the use of maternal hyperoxygenation, amnioinfusion,

intravenous fluid administration, or intermittent pushing, when applied to resolve

fetal distress to improve neonatal outcome. As expected, convincing evidence to

promote or refuse any of these interventions for this specific indication still needs to

be provided.

Chapter 2

50

Recommendations for further research We particularly recommend to study the effect of intrauterine resuscitation by

maternal hyperoxygenation in a randomized controlled trial. We believe that

regarding the potential mechanism of action and former studies, the increase in fetal

pO2 and the improvement of the FHR pattern are likely. However, whether this leads

to an improvement of fetal pH and Apgar score is unclear. Therefore, first the effect

of maternal hyperoxygenation on FHR, fetal pH, and Apgar score in the presence of

fetal distress (diagnosed by fetal blood sampling or abnormal FHR pattern) needs to

be investigated. After the positive effect on fetal condition is proven in a

randomized controlled trial, it is interesting to study the effect on the number of

instrumented deliveries and cesarean delivery rate. The potential adverse effects,

such as the increase in free oxygen radicals should then be investigated as well.

Acknowledgments The authors thank Bart de Vries and Eugenie Delvaux, librarians at Máxima Medical

Center for their support with the primary data search and collection of full-text

articles.

Appendix 1. Checklist for inclusion of studies in the systematic review. Item Yes No Birth Intervention is applied during vaginal birth

(Not antepartum, postpartum, during cesarean section or at start of induction of labor)

Fetus The fetus is a human, single and term fetus (370-416), formerly healthy (No known congenital malformations, growth restriction, signs of infection, premature rupture of membranes etc.)

Parturient The parturient is a healthy woman (No hypertension, preeclampsia, bleeding or other pre-existing illness)

Fetal distress Fetal distress is diagnosed from abnormalities in fetal pH,SpO2

# or fetal heart rate (Not exclusively meconium-stained liquor of potentially hazardous situations like umbilical cord prolapse, maternal hypertension etc.)

Fetal distress The authors clearly describe how the (suspected) fetal distress is diagnosed (For example a clear description of the fetal heart rate characteristics that are labelled ‘abnormal')

Intervention Intervention is one of the following: maternal hyperoxygenation, tocolysis, amnio-infusion, maternal repositioning, intravenous fluid bolus or intermittent pushing

Intervention The intervention is clearly described (For example including dosis, duration etc.)

Intervention Only one intervention is tested at the time Intervention Outcome is clearly described

(For example fetal pH, SpO2#, Apgarscore or neonatal

intensive care admission)

Intervention The intervention is tested against placebo, no intervention or another intervention, but not against immediate delivery

Publication Full text available in English Total All items are answered with ‘yes’ (eligible for inclusion) # SpO2 = saturation of peripheral oxygen


51

2

Recommendations for further research We particularly recommend to study the effect of intrauterine resuscitation by

maternal hyperoxygenation in a randomized controlled trial. We believe that

regarding the potential mechanism of action and former studies, the increase in fetal

pO2 and the improvement of the FHR pattern are likely. However, whether this leads

to an improvement of fetal pH and Apgar score is unclear. Therefore, first the effect

of maternal hyperoxygenation on FHR, fetal pH, and Apgar score in the presence of

fetal distress (diagnosed by fetal blood sampling or abnormal FHR pattern) needs to

be investigated. After the positive effect on fetal condition is proven in a

randomized controlled trial, it is interesting to study the effect on the number of

instrumented deliveries and cesarean delivery rate. The potential adverse effects,

such as the increase in free oxygen radicals should then be investigated as well.

Acknowledgments The authors thank Bart de Vries and Eugenie Delvaux, librarians at Máxima Medical

Center for their support with the primary data search and collection of full-text

articles.

Appendix 1. Checklist for inclusion of studies in the systematic review. Item Yes No Birth Intervention is applied during vaginal birth

(Not antepartum, postpartum, during cesarean section or at start of induction of labor)

Fetus The fetus is a human, single and term fetus (370-416), formerly healthy (No known congenital malformations, growth restriction, signs of infection, premature rupture of membranes etc.)

Parturient The parturient is a healthy woman (No hypertension, preeclampsia, bleeding or other pre-existing illness)

Fetal distress Fetal distress is diagnosed from abnormalities in fetal pH,SpO2

# or fetal heart rate (Not exclusively meconium-stained liquor of potentially hazardous situations like umbilical cord prolapse, maternal hypertension etc.)

Fetal distress The authors clearly describe how the (suspected) fetal distress is diagnosed (For example a clear description of the fetal heart rate characteristics that are labelled ‘abnormal')

Intervention Intervention is one of the following: maternal hyperoxygenation, tocolysis, amnio-infusion, maternal repositioning, intravenous fluid bolus or intermittent pushing

Intervention The intervention is clearly described (For example including dosis, duration etc.)

Intervention Only one intervention is tested at the time Intervention Outcome is clearly described

(For example fetal pH, SpO2#, Apgarscore or neonatal

intensive care admission)

Intervention The intervention is tested against placebo, no intervention or another intervention, but not against immediate delivery

Publication Full text available in English Total All items are answered with ‘yes’ (eligible for inclusion) # SpO2 = saturation of peripheral oxygen

Chapter 2

52

Appendix 2. Search strategy. PubMed The following terms were used for ‘labor’: "Labor, Obstetric"[Mesh] "Term Birth"[Mesh] "Parturition"[Mesh] "Delivery, Obstetric"[Mesh] labor[tiab] labour[tiab] term birth[tiab] term births[tiab] parturition[tiab] parturition'[tiab] parturition's[tiab] parturitional[tiab] parturitions[tiab] obstetric deliveries[tiab] obstetric delivery[tiab] The following terms were used for ‘intervention’: "Tocolysis"[Mesh] "Oxygen Inhalation Therapy"[Mesh] "Resuscitation"[Mesh] "Fluid Therapy"[Mesh] "Infusions, Intravenous"[Mesh] tocolyse[tiab] tocolysed[tiab] tocolyses[tiab] tocolysis[tiab] tocolysis'[tiab] oxygen inhalation therapy[tiab] resuscitation[tiab] fluid therapies[tiab] fluid therapy[tiab] intravenous infusion[tiab] intravenous infusions[tiab] pushing effort[tiab] pushing efforts[tiab]

amnio infusion[tiab] amnioinfusion[tiab] amnioinfusion'[tiab] amnioinfusions[tiab] maternal position[tiab] maternal positioning[tiab] maternal positions[tiab] maternal repositioning[tiab] oxygen administration[tiab] hyperoxygenation[tiab] maternal oxygen[tiab] maternal oxygenation[tiab] fluid bolus[tiab] fluid boluses[tiab] The following terms were used for ‘fetal distress’: "Fetal Distress"[Mesh] fetal condition[tiab] fetal conditions[tiab] foetal condition[tiab] foetal conditions[tiab] fetal outcome[tiab] fetal outcomes[tiab] foetal outcome[tiab] foetal outcomes[tiab] fetal distress[tiab] foetal distress[tiab] Terms for ‘labor’, ‘intervention’ and ‘fetal distress’ were combined. EMBASE The following terms were used for ‘labor’: exp labor/ exp birth/ exp delivery/ labor.tw. birth.tw. parturition.tw. delivery.tw. labour.tw.


53

2

Appendix 2. Search strategy. PubMed The following terms were used for ‘labor’: "Labor, Obstetric"[Mesh] "Term Birth"[Mesh] "Parturition"[Mesh] "Delivery, Obstetric"[Mesh] labor[tiab] labour[tiab] term birth[tiab] term births[tiab] parturition[tiab] parturition'[tiab] parturition's[tiab] parturitional[tiab] parturitions[tiab] obstetric deliveries[tiab] obstetric delivery[tiab] The following terms were used for ‘intervention’: "Tocolysis"[Mesh] "Oxygen Inhalation Therapy"[Mesh] "Resuscitation"[Mesh] "Fluid Therapy"[Mesh] "Infusions, Intravenous"[Mesh] tocolyse[tiab] tocolysed[tiab] tocolyses[tiab] tocolysis[tiab] tocolysis'[tiab] oxygen inhalation therapy[tiab] resuscitation[tiab] fluid therapies[tiab] fluid therapy[tiab] intravenous infusion[tiab] intravenous infusions[tiab] pushing effort[tiab] pushing efforts[tiab]

amnio infusion[tiab] amnioinfusion[tiab] amnioinfusion'[tiab] amnioinfusions[tiab] maternal position[tiab] maternal positioning[tiab] maternal positions[tiab] maternal repositioning[tiab] oxygen administration[tiab] hyperoxygenation[tiab] maternal oxygen[tiab] maternal oxygenation[tiab] fluid bolus[tiab] fluid boluses[tiab] The following terms were used for ‘fetal distress’: "Fetal Distress"[Mesh] fetal condition[tiab] fetal conditions[tiab] foetal condition[tiab] foetal conditions[tiab] fetal outcome[tiab] fetal outcomes[tiab] foetal outcome[tiab] foetal outcomes[tiab] fetal distress[tiab] foetal distress[tiab] Terms for ‘labor’, ‘intervention’ and ‘fetal distress’ were combined. EMBASE The following terms were used for ‘labor’: exp labor/ exp birth/ exp delivery/ labor.tw. birth.tw. parturition.tw. delivery.tw. labour.tw.

Chapter 2

54

The following terms were used for ‘intervention’: exp tocolysis/ exp oxygen therapy/ exp resuscitation/ exp fluid therapy/ exp hyperoxia/ exp patient positioning/ exp amnioinfusion/ exp body position/ tocoly$.tw. (oxygen therap$ or "oxygen admin$").tw. hyperoxygen$.tw. "maternal oxygen$".tw. resuscitat$.tw. "fluid therap$".tw. "intravenous infus$".tw. "pushing effort$".tw. amnioinfusion.tw. "amnio infusion".tw. "maternal posit$".tw. "maternal reposit$".tw. "fluid bolus".tw. hyperoxia.tw. "patient posit$".tw. "body posit$".tw. The following terms were used for ‘fetal distress’: exp fetus distress/ exp fetus outcome/ "fetal outcome".tw. "fetal distress".tw. "fetus distress".tw. "fetal condit$".tw. "foetal outcome".tw. "foetal condit$".tw. "foetal distress".tw. "foetus distress".tw. Terms for ‘labor’, ‘intervention’ and ‘fetal distress’ were combined.


55

2

The following terms were used for ‘intervention’: exp tocolysis/ exp oxygen therapy/ exp resuscitation/ exp fluid therapy/ exp hyperoxia/ exp patient positioning/ exp amnioinfusion/ exp body position/ tocoly$.tw. (oxygen therap$ or "oxygen admin$").tw. hyperoxygen$.tw. "maternal oxygen$".tw. resuscitat$.tw. "fluid therap$".tw. "intravenous infus$".tw. "pushing effort$".tw. amnioinfusion.tw. "amnio infusion".tw. "maternal posit$".tw. "maternal reposit$".tw. "fluid bolus".tw. hyperoxia.tw. "patient posit$".tw. "body posit$".tw. The following terms were used for ‘fetal distress’: exp fetus distress/ exp fetus outcome/ "fetal outcome".tw. "fetal distress".tw. "fetus distress".tw. "fetal condit$".tw. "foetal outcome".tw. "foetal condit$".tw. "foetal distress".tw. "foetus distress".tw. Terms for ‘labor’, ‘intervention’ and ‘fetal distress’ were combined.

CENTRAL The following terms were used for ‘labor’: MeSH descriptor: [Obstetric Labor Complications] explode all trees MeSH descriptor: [Parturition] explode all trees MeSH descriptor: [Term Birth] explode all trees MeSH descriptor: [Delivery, Obstetric] explode all trees labor:ti,ab,kw labour:ti,ab,kw term birth*:ti,ab,kw (Word variations have been searched) parturition*:ti,ab,kw (Word variations have been searched) obstetric deliver*:ti,ab,kw The following terms were used for ‘intervention’: MeSH descriptor: [Tocolysis] explode all trees MeSH descriptor: [Oxygen Inhalation Therapy] explode all trees MeSH descriptor: [Resuscitation] explode all trees MeSH descriptor: [Fluid Therapy] explode all trees MeSH descriptor: [Infusions, Intravenous] explode all trees tocoly*:ti,ab,kw oxygen inhalation therap*:ti,ab,kw fluid therap*:ti,ab,kw resuscitation:ti,ab,kw intravenous infusion*:ti,ab,kw pushing effort*:ti,ab,kw amnio infusion*:ti,ab,kw amnioinfusion*:ti,ab,kw maternal posit*:ti,ab,kw maternal reposit*:ti,ab,kw oxygen admin*:ti,ab,kw hyperoxygenation:ti,ab,kw maternal oxygen*:ti,ab,kw fluid bolus*:ti,ab,kw The following terms were used for ‘fetal distress’: MeSH descriptor: [Fetal Distress] explode all trees fetal condition*:ti,ab,kw foetal condition*:ti,ab,kw foetal outcome*:ti,ab,kw

Chapter 2

56

fetal outcome*:ti,ab,kw foetal distress*:ti,ab,kw fetal distress*:ti,ab,kw Terms for ‘labor’, ‘intervention’ and ‘fetal distress’ were combined.

References 1. Graham EM, Ruis KA, Hartman AL, Northington FJ, Fox HE. A systematic review of the


2. Parer JT. Effects of fetal asphyxia on brain cell structure and function: limits of tolerance. Comp Biochem Physiol A Mol Integr Physiol. 1998;119:711-6.

3. Simpson KR. Intrauterine resuscitation during labor: should maternal oxygen administration be a first-line measure? Semin Fetal Neonatal Med. 2008;13:362-7.

4. American College of Obstetricians and Gynecologists. Practice bulletin no. 116: management of intrapartum fetal heart rate tracings. Obstet Gynecol. 2010;116:1232-40.

5. Althabe O Jr, Schwarcz RL, Pose SV, Escarcena L, Caldeyro-Barcia R. Effects on heart rate and fetal pO2 of oxygen administration to the mother. Am J Obstet Gynecol. 1967;98:858-70.


7. Khazin AF, Hon EH, Hehre FW. Effects of maternal hyperoxia on the fetus. I Oxygen tension Am J Obstet Gynecol. 1971;109:628-37.

8. Haydon ML, Gorenberg DM, Nageotte MP, Ghamsary M, Rumney PJ, Patillo C, et al. The effect of maternal oxygen administration on fetal pulse oximetry during labor in fetuses with nonreassuring fetal heart rate patterns. Am J Obstet Gynecol. 2006;195:735-8.

9. Vasicka A, Quilligan EJ, Aznar R, Lipsitz PJ, Bloor BM. Oxygen tension in maternal and fetal blood, amniotic fluid, and cerebrospinal fluid of the mother and the baby. Am J Obstet Gynecol. 1960;79:1041-7.


11. Hamel MS, Hughes BL, Rouse DJ. Whither oxygen for intrauterine resuscitation? Am J Obstet Gynecol. 2015;212:461-2.

12. Garite TJ, Nageotte MP, Parer JT. Should we really avoid giving oxygen to mothers with concerning fetal heart rate patterns? Am J Obstet Gynecol. 2015;2012:459-60.

13. De Heus R, Mulder EJH, Derks JB, Visser GH. Acute tocolysis for uterine activity reduction in term labor a review. Obstet Gynecol Surv. 2008;63:383-8.

14. De Heus R, Mulder EJ, Derks JB, Kurver PH, van Wolfswinkel L, Visser GH. A prospective randomized trial of acute tocolysis in term labour with atosiban or ritodrine. Eur J Obstet Gynecol Reprod Biol. 2008;139:139-45.

15. National Institute for Health and Care Excellence. Intrapartum care: care of healthy women and their babies during childbirth [internet]. 2014. Available at: www.nice.org.uk/guidance/ cg190. Accessed December 14, 2014.

16. Hofmeyr GJ. Amnioinfusion for umbilical cord compression in labour. Cochrane Database Syst Rev. 2000;1:CD000013.

17. Nederlandse Vereniging voor Obstetrie en Gynaecologie. Intrapartum fetal monitoring at term [Intrapartum foetale bewaking a terme] [internet]. Utrecht, The Netherlands: NVOG; May 2014 [updated May 2015]. Available from: http://nvog-


57

2

fetal outcome*:ti,ab,kw foetal distress*:ti,ab,kw fetal distress*:ti,ab,kw Terms for ‘labor’, ‘intervention’ and ‘fetal distress’ were combined.

References 1. Graham EM, Ruis KA, Hartman AL, Northington FJ, Fox HE. A systematic review of the


2. Parer JT. Effects of fetal asphyxia on brain cell structure and function: limits of tolerance. Comp Biochem Physiol A Mol Integr Physiol. 1998;119:711-6.


4. American College of Obstetricians and Gynecologists. Practice bulletin no. 116: management of intrapartum fetal heart rate tracings. Obstet Gynecol. 2010;116:1232-40.



7. Khazin AF, Hon EH, Hehre FW. Effects of maternal hyperoxia on the fetus. I Oxygen tension Am J Obstet Gynecol. 1971;109:628-37.





12. Garite TJ, Nageotte MP, Parer JT. Should we really avoid giving oxygen to mothers with concerning fetal heart rate patterns? Am J Obstet Gynecol. 2015;2012:459-60.

13. De Heus R, Mulder EJH, Derks JB, Visser GH. Acute tocolysis for uterine activity reduction in term labor a review. Obstet Gynecol Surv. 2008;63:383-8.


15. National Institute for Health and Care Excellence. Intrapartum care: care of healthy women and their babies during childbirth [internet]. 2014. Available at: www.nice.org.uk/guidance/ cg190. Accessed December 14, 2014.

16. Hofmeyr GJ. Amnioinfusion for umbilical cord compression in labour. Cochrane Database Syst Rev. 2000;1:CD000013.

17. Nederlandse Vereniging voor Obstetrie en Gynaecologie. Intrapartum fetal monitoring at term [Intrapartum foetale bewaking a terme] [internet]. Utrecht, The Netherlands: NVOG; May 2014 [updated May 2015]. Available from: http://nvog-

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documenten.nl/uploaded/docs/NVOG%20richtlijn%20foetale%20bewaking%2019-05-2014%20update%2028-5-2015.pdf. [Dutch]

18. GRADE working group [internet]. 2014. Available from: http://www. gradeworkinggroup.org.

19. Guyatt G, Gutterman D, Baumann MH, Addrizzo-Harris D, Hylek EM, Phillips B, et al. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians Task Force. Chest. 2006;129:174-81.

20. Novikova N, Hofmeyr GJ, Essilfie-Appiah G. Prophylactic versus therapeutic amnioinfusion for oligohydramnios in labour. Cochrane Database Syst Rev. 2012;9:CD000176.

21. Hofmeyr GJ, Gulmezoglu AM, Nikodem VC, De Jager M. Amnioinfusion. Eur J Obstet Gynecol Reprod Biol. 1996;64:159-65.


23. Owen J, Henson BV, Hauth JC. A prospective randomized study of saline solution amnioinfusion. Am J Obstet Gynecol. 1990;162:1146-9.

24. Lipshitz J, Klose CW. Use of tocolytic drugs to reverse oxytocin-induced uterine hypertonus and fetal distress. Obstet Gynecol. 1985;66(suppl 3):16S-18S.

25. Rinehart BK, Terrone DA, Barrow JH, Isler CM, Barrilleaux PS, Roberts WE. Randomized trial of intermittent or continuous amnioinfusion for variable decelerations. Obstet Gynecol. 2000;96:571-4.

26. Stratulat S. Dextran in intrauterine resuscitation of the fetus. 7th Int. Anaesth Postgrad Course/Vienna. Verlag Hegermann; 1975. [Abstract]

27. Mendez-Bauer C, Shekarloo A, Cook V, Freese U. Treatment of acute intrapartum fetal distress by beta 2-sympathomimetics. Am J Obstet Gynecol. 1987;156:638-42.

28. Surbek DV, Hosli IM, Pavic N, Almendral A, Holzgreve W. Transcervical intrapartum amnioinfusion: a simple and effective technique. Eur J Obstet Gynecol Reprod Biol. 1997;75:123-6.

29. Caldeyro-Barcia R. Intrauterine fetal reanimation in acute intrapartum fetal distress. Early Hum Dev. 1992;29:27-33.

30. Abdel-Aleem H, Amin AF, Shokry M, Radwan RA. Therapeutic amnioinfusion for intrapartum fetal distress using a pediatric feeding tube. Int J Gynaecol Obstet. 2005;90:94-8.

31. Miyazaki FS, Nevarez F. Saline amnioinfusion for relief of repetitive variable decelerations: a prospective randomized study. Am J Obstet Gynecol. 1985;153:301-6.

32. Miyazaki FS, Taylor NA. Saline amnioinfusion for relief of variable or prolonged decelerations. Am J Obstet Gynecol. 1983;146:670-8.

33. Abitbol MM. Supine position in labor and associated fetal heart rate changes. Obstet Gynecol. 1985;65:481-6.

34. Magann EF, Cleveland RS, Dockery JR, Chauhan SP, Martin JN Jr, Morrison JC. Acute tocolysis for fetal distress: terbutaline versus magnesium sulphate. Aust N Z J Obstet Gynaecol. 1993;33:362-4.

35. Mercier FJ, Dounas M, Bouaziz H, Lhuissier C, Benhamou D. Intravenous nitroglycerin to relieve intrapartum fetal distress related to uterine hyperactivity: a prospective observational study. Anesth Analg. 1997; 84:1117-20.

36. Sheybany S, Murphy J, Evans D, Newcombe RG, Pearson JF. Ritodrine in the management of fetal distress. Br J Obstet Gynaecol. 1982;89:723-6.

37. Baumgarten K, Wessalius-de Casparis A, editors. Proceedings of the International Symposium on the Treatment of Foetal Risks. Baden, Austria; 1972. The place of betamimetics in the treatment of acute foetal distress during labour.

38. Hutchon DJ. Management of severe fetal bradycardia with ritodrine. Br J Obstet Gynaecol. 1982;89:671-674.

39. Lipshitz J. Use of a beta 2-sympathomimetic drug as a temporizing measure in the treatment of acute fetal distress. Am J Obstet Gynecol. 1977;129:31-36.

40. Simpson KR, James DC. Efficacy of intrauterine resuscitation techniques in improving fetal oxygen status during labor. Obstet Gynecol. 2005;105:1362-1368.


42. Hamel MS, Anderson BL, Rouse DJ. Oxygen for intrauterine resuscitation: of unproved benefit and potentially harmful. Am J Obstet Gynecol. 2014;211:124-127.

43. Khaw KS, Wang CC, Ngan Kee WD, Pang CP, Rogers MS. Effects of high inspired oxygen fraction during elective caesarean section under spinal anaesthesia on maternal and fetal oxygenation and lipid peroxidation. Br J Anaesth. 2002;88:18-23.


45. Thorp JA, Trobough T, Evans R, Hedrick J, Yeast JD. The effect of maternal oxygen administration during the second stage of labor on umbilical cord blood gas values: a randomized controlled prospective trial. Am J Obstet Gynecol. 1995;172(2 pt 1):465-74.

46. Stocks G. Preeclampsia: pathophysiology, old and new strategies for management. Eur J Anaesthesiol. 2014;31:183-9.

47. Kulier R, Hofmeyr GJ. Tocolytics for suspected intrapartum fetal distress. Cochrane Database Syst Rev. 2000;2:CD000035.

48. Hofmeyr GJ, Lawrie TA. Amnioinfusion for potential or suspected umbilical cord compression in labour. Cochrane Database Syst Rev. 2012;1:CD000013.

49. Simpson KR, James DC. Effects of immediate versus delayed pushing during second-stage labor on fetal wellbeing: a randomized clinical trial. Nurs Res. 2005; 54:149-57.

50. Freeman R, Garite T, Nageotte M. Fetal Heart Rate Monitoring. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003.

51. Palomaki O, Luukkaala T, Luoto R, Tuimala R. Intrapartum cardiotocography-the dilemma of interpretational variation. J Perinat Med. 2006;34:298-302.

52. Santo S, Ayres-de-Campos D. Human factors affecting the interpretation of fetal heart rate tracings: an update. Curr Opin Obstet Gynecol. 2012;24:84-88.

53. Rhose S, Heinis AM, Vandenbussche F, van Drongelen J, van Dillen J. Inter- and intraobserver agreement of non-reassuring cardiotocography analysis and subsequent clinical management. Acta Obstet Gynecol Scand. 2014;93:596-602.

54. Burke MS, Porreco RP, Day D, Watson JD, Haverkamp AD, Orleans M, et al. Intrauterine resuscitation with tocolysis. J Perinatol. 1989;9:296-300.


59

2

documenten.nl/uploaded/docs/NVOG%20richtlijn%20foetale%20bewaking%2019-05-2014%20update%2028-5-2015.pdf. [Dutch]

18. GRADE working group [internet]. 2014. Available from: http://www. gradeworkinggroup.org.

19. Guyatt G, Gutterman D, Baumann MH, Addrizzo-Harris D, Hylek EM, Phillips B, et al. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians Task Force. Chest. 2006;129:174-81.

20. Novikova N, Hofmeyr GJ, Essilfie-Appiah G. Prophylactic versus therapeutic amnioinfusion for oligohydramnios in labour. Cochrane Database Syst Rev. 2012;9:CD000176.

21. Hofmeyr GJ, Gulmezoglu AM, Nikodem VC, De Jager M. Amnioinfusion. Eur J Obstet Gynecol Reprod Biol. 1996;64:159-65.


23. Owen J, Henson BV, Hauth JC. A prospective randomized study of saline solution amnioinfusion. Am J Obstet Gynecol. 1990;162:1146-9.

24. Lipshitz J, Klose CW. Use of tocolytic drugs to reverse oxytocin-induced uterine hypertonus and fetal distress. Obstet Gynecol. 1985;66(suppl 3):16S-18S.

25. Rinehart BK, Terrone DA, Barrow JH, Isler CM, Barrilleaux PS, Roberts WE. Randomized trial of intermittent or continuous amnioinfusion for variable decelerations. Obstet Gynecol. 2000;96:571-4.

26. Stratulat S. Dextran in intrauterine resuscitation of the fetus. 7th Int. Anaesth Postgrad Course/Vienna. Verlag Hegermann; 1975. [Abstract]

27. Mendez-Bauer C, Shekarloo A, Cook V, Freese U. Treatment of acute intrapartum fetal distress by beta 2-sympathomimetics. Am J Obstet Gynecol. 1987;156:638-42.

28. Surbek DV, Hosli IM, Pavic N, Almendral A, Holzgreve W. Transcervical intrapartum amnioinfusion: a simple and effective technique. Eur J Obstet Gynecol Reprod Biol. 1997;75:123-6.

29. Caldeyro-Barcia R. Intrauterine fetal reanimation in acute intrapartum fetal distress. Early Hum Dev. 1992;29:27-33.

30. Abdel-Aleem H, Amin AF, Shokry M, Radwan RA. Therapeutic amnioinfusion for intrapartum fetal distress using a pediatric feeding tube. Int J Gynaecol Obstet. 2005;90:94-8.


32. Miyazaki FS, Taylor NA. Saline amnioinfusion for relief of variable or prolonged decelerations. Am J Obstet Gynecol. 1983;146:670-8.

33. Abitbol MM. Supine position in labor and associated fetal heart rate changes. Obstet Gynecol. 1985;65:481-6.

34. Magann EF, Cleveland RS, Dockery JR, Chauhan SP, Martin JN Jr, Morrison JC. Acute tocolysis for fetal distress: terbutaline versus magnesium sulphate. Aust N Z J Obstet Gynaecol. 1993;33:362-4.

35. Mercier FJ, Dounas M, Bouaziz H, Lhuissier C, Benhamou D. Intravenous nitroglycerin to relieve intrapartum fetal distress related to uterine hyperactivity: a prospective observational study. Anesth Analg. 1997; 84:1117-20.

36. Sheybany S, Murphy J, Evans D, Newcombe RG, Pearson JF. Ritodrine in the management of fetal distress. Br J Obstet Gynaecol. 1982;89:723-6.

37. Baumgarten K, Wessalius-de Casparis A, editors. Proceedings of the International Symposium on the Treatment of Foetal Risks. Baden, Austria; 1972. The place of betamimetics in the treatment of acute foetal distress during labour.

38. Hutchon DJ. Management of severe fetal bradycardia with ritodrine. Br J Obstet Gynaecol. 1982;89:671-674.

39. Lipshitz J. Use of a beta 2-sympathomimetic drug as a temporizing measure in the treatment of acute fetal distress. Am J Obstet Gynecol. 1977;129:31-36.






45. Thorp JA, Trobough T, Evans R, Hedrick J, Yeast JD. The effect of maternal oxygen administration during the second stage of labor on umbilical cord blood gas values: a randomized controlled prospective trial. Am J Obstet Gynecol. 1995;172(2 pt 1):465-74.

46. Stocks G. Preeclampsia: pathophysiology, old and new strategies for management. Eur J Anaesthesiol. 2014;31:183-9.


48. Hofmeyr GJ, Lawrie TA. Amnioinfusion for potential or suspected umbilical cord compression in labour. Cochrane Database Syst Rev. 2012;1:CD000013.

49. Simpson KR, James DC. Effects of immediate versus delayed pushing during second-stage labor on fetal wellbeing: a randomized clinical trial. Nurs Res. 2005; 54:149-57.

50. Freeman R, Garite T, Nageotte M. Fetal Heart Rate Monitoring. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003.

51. Palomaki O, Luukkaala T, Luoto R, Tuimala R. Intrapartum cardiotocography-the dilemma of interpretational variation. J Perinat Med. 2006;34:298-302.

52. Santo S, Ayres-de-Campos D. Human factors affecting the interpretation of fetal heart rate tracings: an update. Curr Opin Obstet Gynecol. 2012;24:84-88.

53. Rhose S, Heinis AM, Vandenbussche F, van Drongelen J, van Dillen J. Inter- and intraobserver agreement of non-reassuring cardiotocography analysis and subsequent clinical management. Acta Obstet Gynecol Scand. 2014;93:596-602.

54. Burke MS, Porreco RP, Day D, Watson JD, Haverkamp AD, Orleans M, et al. Intrauterine resuscitation with tocolysis. J Perinatol. 1989;9:296-300.

Chapter 2

60

55. Arias F. Intrauterine resuscitation with terbutaline: a method for the management of acute intrapartum fetal distress. Am J Obstet Gynecol. 1978;131:39-43.

56. Shekarloo A, Mendez-Bauer C, Cook V, Freese U. Terbutaline (intravenous bolus) for the treatment of acute intrapartum fetal distress. Am J Obstet Gynecol. 1989;160:615-8.

57. Patriarco MS, Viechnicki BM, Hutchinson TA, Klasko SK, Yeh SY. A study on intrauterine fetal resuscitation with terbutaline. Am J Obstet Gynecol. 1987;157:384-7.

58. Tejani NA, Verma UL, Chatterjee S, Mittelmann S. Terbutaline in the management of acute intrapartum fetal acidosis. J Reprod Med. 1983;28:857-61.

59. Kulier R, Gulmezoglu AM, Hofmeyr GJ, van Gelderen CJ. Betamimetics in fetal distress: a randomised controlled trial. J Perinat Med. 1997;25:97-100.

60. Gare DJ, Shime J, Paul WM, Hoskins M. Oxygen administration during labor. Am J Obstet Gynecol. 1969;105:954-61.

Chapter 3

Management of intrapartum fetal distress

in The Netherlands: a clinical practice survey

Bullens LM, Moors S, van Runnard Heimel PJ,


European Journal of Obstetrics and Gynecology and Reproductive Biology.

2016;205:48-53

55. Arias F. Intrauterine resuscitation with terbutaline: a method for the management of acute intrapartum fetal distress. Am J Obstet Gynecol. 1978;131:39-43.

56. Shekarloo A, Mendez-Bauer C, Cook V, Freese U. Terbutaline (intravenous bolus) for the treatment of acute intrapartum fetal distress. Am J Obstet Gynecol. 1989;160:615-8.

57. Patriarco MS, Viechnicki BM, Hutchinson TA, Klasko SK, Yeh SY. A study on intrauterine fetal resuscitation with terbutaline. Am J Obstet Gynecol. 1987;157:384-7.

58. Tejani NA, Verma UL, Chatterjee S, Mittelmann S. Terbutaline in the management of acute intrapartum fetal acidosis. J Reprod Med. 1983;28:857-61.

59. Kulier R, Gulmezoglu AM, Hofmeyr GJ, van Gelderen CJ. Betamimetics in fetal distress: a randomised controlled trial. J Perinat Med. 1997;25:97-100.


Chapter 3

Management of intrapartum fetal distress

in The Netherlands: a clinical practice survey

Bullens LM, Moors S, van Runnard Heimel PJ,


European Journal of Obstetrics and Gynecology and Reproductive Biology.

2016;205:48-53

Chapter 3

62

Abstract

Objective

Solid evidence on the effect of intrauterine resuscitation on neonatal outcome is

limited, and superiority of one intervention over the others is not clear. We therefore

surveyed the clinical practice variation in fetal monitoring and the management of

fetal distress during labor, in Dutch labor wards. In addition, we have compared

recommendations from international guidelines.

Study design

We conducted a survey among all 86 Dutch hospitals, using a questionnaire on fetal

monitoring and management of fetal distress. In addition, we requested

international guidelines of 28 western countries to study international

recommendations regarding labor management.

Results

The response rate of the national survey was 100%. Labor wards of all hospitals use

CTG for fetal monitoring, 98% use additional fetal scalp blood sampling, and 23%

use ST-analysis. When fetal distress is suspected, oxytocin is discontinued and

tocolytic drugs are applied in all hospitals. Nearly all hospitals (98%)

use maternal reposition for fetal resuscitation, 33% use amnioinfusion, and 58%

provide maternal hyperoxygenation. Management is mainly based on the Dutch

national guideline (58%) or on local guidelines (26%). Eight international guidelines

on fetal monitoring were obtained for analysis. Fetal scalp blood sampling facilities

are recommended in all the obtained guidelines. Use of ST-analysis is

recommended in three guidelines and advised against in three guidelines. Five

guidelines also advised on intrauterine resuscitation: discontinuation of oxytocin and

use of tocolytic drugs was advised in all guidelines, amnioinfusion was

recommended in two guidelines and advised against in two guidelines,

whereas maternal hyperoxygenation was recommended in two guidelines and

advised against in one guideline.

Conclusion

Nationwide clinical practice, and recommendations from international guidelines

agree on the use of fetal scalp blood sampling in addition to cardiotocography

during labor. The opinion on the use of ST-analysis differs per clinic and per

guideline. Discontinuation of oxytocin, administration of tocolytic drugs

and maternal repositioning are rather uniform, on national and international level.

However, there is a large variation in the use of amnioinfusion

and maternal hyperoxygenation, which may be explained by the contradictory

recommendations of the different guidelines.

A clinical practice survey

63

3

Abstract

Objective

Solid evidence on the effect of intrauterine resuscitation on neonatal outcome is

limited, and superiority of one intervention over the others is not clear. We therefore

surveyed the clinical practice variation in fetal monitoring and the management of

fetal distress during labor, in Dutch labor wards. In addition, we have compared

recommendations from international guidelines.

Study design

We conducted a survey among all 86 Dutch hospitals, using a questionnaire on fetal

monitoring and management of fetal distress. In addition, we requested

international guidelines of 28 western countries to study international

recommendations regarding labor management.

Results

The response rate of the national survey was 100%. Labor wards of all hospitals use

CTG for fetal monitoring, 98% use additional fetal scalp blood sampling, and 23%

use ST-analysis. When fetal distress is suspected, oxytocin is discontinued and

tocolytic drugs are applied in all hospitals. Nearly all hospitals (98%)

use maternal reposition for fetal resuscitation, 33% use amnioinfusion, and 58%

provide maternal hyperoxygenation. Management is mainly based on the Dutch

national guideline (58%) or on local guidelines (26%). Eight international guidelines

on fetal monitoring were obtained for analysis. Fetal scalp blood sampling facilities

are recommended in all the obtained guidelines. Use of ST-analysis is

recommended in three guidelines and advised against in three guidelines. Five

guidelines also advised on intrauterine resuscitation: discontinuation of oxytocin and

use of tocolytic drugs was advised in all guidelines, amnioinfusion was

recommended in two guidelines and advised against in two guidelines,

whereas maternal hyperoxygenation was recommended in two guidelines and

advised against in one guideline.

Conclusion

Nationwide clinical practice, and recommendations from international guidelines

agree on the use of fetal scalp blood sampling in addition to cardiotocography

during labor. The opinion on the use of ST-analysis differs per clinic and per

guideline. Discontinuation of oxytocin, administration of tocolytic drugs

and maternal repositioning are rather uniform, on national and international level.

However, there is a large variation in the use of amnioinfusion

and maternal hyperoxygenation, which may be explained by the contradictory

recommendations of the different guidelines.

Chapter 3

64

Introduction Nonreassuring fetal heart rate (FHR) patterns frequently occur during labor. They

may be indicative for impaired fetal oxygenation, which eventually may lead to fetal

asphyxia.1,2 As fetal asphyxia is associated with hypoxic-ischemic encephalopathy

and even fetal death, timely intervention is important to optimize neonatal outcome.

Intrauterine resuscitation is defined as interventions with the intention to improve

fetal oxygenation during labor, in the presence of suspected fetal distress.

Depending on the presumable cause of the abnormal FHR pattern, these

interventions aim to restore oxygenation of the fetus. Possible actions consist of

alleviation of cord compression and/or improvement of uteroplacental blood flow.3,4

Improvement of the intrauterine condition of the fetus can avoid termination of the

delivery, thereby preventing a cesarean section or vaginally assisted delivery. In the

case of an emergency cesarean section, intrauterine resuscitation may restore fetal

oxygenation during the decision to incision time period.

Several techniques to improve fetal oxygenation are used in clinical practice. The

most commonly used interventions are discontinuation of oxytocin infusion,

maternal repositioning, amnioinfusion, maternal hyperoxygenation, and the use of

tocolytic agents. Unfortunately, solid evidence on the effect of each of these

interventions on neonatal outcome is limited, and superiority of one intervention

over the others is not clear.5 This lack of evidence leads to differences in

recommendations in two important guidelines on fetal monitoring during labor and

intrapartum management.4,6 For example, the Practice Bulletin of the American

College of Obstetricians and Gynecologists (ACOG) recommends maternal

hyperoxygenation in the presence of fetal distress, whereas the Royal College of

Obstetricians and Gynaecologist (RCOG) in the United Kingdom advises against this

intervention.4,6 The Dutch Society of Obstetricians and Gynecologists (NVOG) is

currently working on a recommendation regarding the use of maternal

hyperoxygenation for fetal distress.7

Apparently, different guidelines have different recommendations regarding the

management of fetal distress during labor. This may lead to clinical practice

variation regarding the management of fetal distress during labor.

We aim to investigate the clinical practice variation in Dutch delivery wards, with

specific interest in the local methods used for fetal monitoring, and the actions

undertaken in suspected fetal distress. Local guidelines, as well as intervention

techniques to improve fetal oxygenation are inventoried. Hence, we conducted a

survey among all Dutch hospitals. In addition, we requested the national guidelines

from 28 Western countries regarding fetal monitoring and fetal distress.

Materials and methods A clinical practice survey was conducted from August to October 2015 in all 86

Dutch hospitals. Also, we aimed to obtain international guidelines of 25 European

countries, the USA, Canada, and Australia & New Zealand.

Survey among Dutch obstetricians Per hospital, one obstetrician was asked to complete a survey comprising twelve

multiple-choice questions on fetal monitoring and common interventions regarding

suspected fetal distress (Appendix 1, original version in Dutch).

Topics included: methods used for fetal monitoring; classification method of the

cardiotocogram (CTG); how to diagnose fetal distress; the indication and use of

intrauterine resuscitation techniques and the use of national and/or international

guidelines. Respondents were able to give more than one answer to each question

and were free to add more options if their answer was not listed. In case of unclear

responses, we contacted the respondent to clarify the answers.

In The Netherlands, low risk deliveries are managed by primary care midwives.

These primary midwife practices are excluded from this survey, since most

resuscitation techniques are not available during home births. Hence, in the

presence of fetal distress, the parturient will be referred to a hospital.

Statistical analysis national survey After all questionnaires were returned, we analysed the results using SPSS (IBM SPSS

Statistics, version 23). Categorical variables were expressed as frequencies and

percentages.

Survey of national guidelines of European countries We searched the Internet for international guidelines on fetal monitoring and

resuscitation of 25 European countries, the USA, Canada, and Australia & New

Zealand. If guidelines were not freely available, we approached the corresponding


65

3

Introduction Nonreassuring fetal heart rate (FHR) patterns frequently occur during labor. They

may be indicative for impaired fetal oxygenation, which eventually may lead to fetal

asphyxia.1,2 As fetal asphyxia is associated with hypoxic-ischemic encephalopathy

and even fetal death, timely intervention is important to optimize neonatal outcome.

Intrauterine resuscitation is defined as interventions with the intention to improve

fetal oxygenation during labor, in the presence of suspected fetal distress.

Depending on the presumable cause of the abnormal FHR pattern, these

interventions aim to restore oxygenation of the fetus. Possible actions consist of

alleviation of cord compression and/or improvement of uteroplacental blood flow.3,4

Improvement of the intrauterine condition of the fetus can avoid termination of the

delivery, thereby preventing a cesarean section or vaginally assisted delivery. In the

case of an emergency cesarean section, intrauterine resuscitation may restore fetal

oxygenation during the decision to incision time period.

Several techniques to improve fetal oxygenation are used in clinical practice. The

most commonly used interventions are discontinuation of oxytocin infusion,

maternal repositioning, amnioinfusion, maternal hyperoxygenation, and the use of

tocolytic agents. Unfortunately, solid evidence on the effect of each of these

interventions on neonatal outcome is limited, and superiority of one intervention

over the others is not clear.5 This lack of evidence leads to differences in

recommendations in two important guidelines on fetal monitoring during labor and

intrapartum management.4,6 For example, the Practice Bulletin of the American

College of Obstetricians and Gynecologists (ACOG) recommends maternal

hyperoxygenation in the presence of fetal distress, whereas the Royal College of

Obstetricians and Gynaecologist (RCOG) in the United Kingdom advises against this

intervention.4,6 The Dutch Society of Obstetricians and Gynecologists (NVOG) is

currently working on a recommendation regarding the use of maternal

hyperoxygenation for fetal distress.7

Apparently, different guidelines have different recommendations regarding the

management of fetal distress during labor. This may lead to clinical practice

variation regarding the management of fetal distress during labor.

We aim to investigate the clinical practice variation in Dutch delivery wards, with

specific interest in the local methods used for fetal monitoring, and the actions

undertaken in suspected fetal distress. Local guidelines, as well as intervention

techniques to improve fetal oxygenation are inventoried. Hence, we conducted a

survey among all Dutch hospitals. In addition, we requested the national guidelines

from 28 Western countries regarding fetal monitoring and fetal distress.

Materials and methods A clinical practice survey was conducted from August to October 2015 in all 86

Dutch hospitals. Also, we aimed to obtain international guidelines of 25 European

countries, the USA, Canada, and Australia & New Zealand.

Survey among Dutch obstetricians Per hospital, one obstetrician was asked to complete a survey comprising twelve

multiple-choice questions on fetal monitoring and common interventions regarding

suspected fetal distress (Appendix 1, original version in Dutch).

Topics included: methods used for fetal monitoring; classification method of the

cardiotocogram (CTG); how to diagnose fetal distress; the indication and use of

intrauterine resuscitation techniques and the use of national and/or international

guidelines. Respondents were able to give more than one answer to each question

and were free to add more options if their answer was not listed. In case of unclear

responses, we contacted the respondent to clarify the answers.

In The Netherlands, low risk deliveries are managed by primary care midwives.

These primary midwife practices are excluded from this survey, since most

resuscitation techniques are not available during home births. Hence, in the

presence of fetal distress, the parturient will be referred to a hospital.

Statistical analysis national survey After all questionnaires were returned, we analysed the results using SPSS (IBM SPSS

Statistics, version 23). Categorical variables were expressed as frequencies and

percentages.

Survey of national guidelines of European countries We searched the Internet for international guidelines on fetal monitoring and

resuscitation of 25 European countries, the USA, Canada, and Australia & New

Zealand. If guidelines were not freely available, we approached the corresponding

Chapter 3

66

national societies of obstetricians and gynecologists and requested their national

guideline on fetal monitoring and/or intrauterine resuscitation during labor.

If a guideline was not available in English, it was translated by a native speaker or by

the use of an online translation program. We compared the recommendations as

stated in the different guidelines. The following details were abstracted from the

guidelines and listed: methods of fetal monitoring systems during labor (intermittent

auscultation, fetal heart rate pattern, fetal scalp blood sampling and ST-analysis), the

classification system to judge the fetal heart rate pattern, and recommendations on

the use of intrauterine resuscitation techniques.

Ethical considerations As confirmed by the Medical Ethics Committee of Máxima Medical Center,

Veldhoven, The Netherlands, our study does not involve any patient data and

imposes no changes in general practice. Therefore, according to the Declaration of

Helsinki, no ethical approval was required.

Results Survey among Dutch obstetricians A total of 86 obstetricians, representing all 86 Dutch hospitals, completed the

questionnaire. Hospitals include eight university hospitals, 39 general teaching

hospitals, and 39 non-teaching hospitals. The response rate was 100%.

Besides the national guideline on fetal monitoring provided by the NVOG, various

local protocols exist on the diagnosis and management of fetal distress during labor.

In The Netherlands, the guideline of the NVOG is frequently used (58%), sometimes

in combination with a local guideline (26%). In 36% of the hospitals, only local

protocols are used. The American guideline, provided by the American College of

Obstetricians and Gynecologists (ACOG) is used in one hospital (1%), while the

British guideline, provided by the Royal College of Obstetricians and

Gynaecologists (RCOG) is used in six hospitals (7%). Results are shown in Fig. 1.

Figure 1. Percentage of Dutch hospitals using the represented guidelines on fetal

monitoring and fetal resuscitation.

All hospitals used fetal CTG to estimate fetal well-being during labor. Besides, in

23% (n=20) of the hospitals ST-analysis is used to monitor fetal condition, while in

98% (n=84) fetal scalp blood sampling is used in addition to CTG.

In most of the hospitals (95%), the (modified) FIGO classification is used to classify

the CTG. In two hospitals the Fischer classification is used.8 In two non-teaching

hospitals no structural classification system is implemented.

Preferences regarding the use of resuscitation techniques are different among the

hospitals. Fig. 2 shows the percentage of hospitals that use each of the mentioned

resuscitation techniques. The most used tocolytic agents are oxytocin antagonists,

6.75 mg atosiban administered intravenously. Furthermore, beta-mimetics, 5-10 mg

ritodrine administered intravenously, or nitroglycerin, administered oromucosally

with a dose of 0.4 mg are in use.

When fetal distress is suspected, immediate delivery may be expedited, depending

on the clinical situation. In almost all hospitals (98%), the attending staff will try to

improve fetal oxygenation in expectation of an emergency cesarean section or

vaginally assisted birth. Improvement of the intrauterine condition of the fetus may

also avoid termination of the delivery, thereby preventing a cesarean section or

vaginally assisted delivery. In 86% of the Dutch delivery wards, intrauterine

resuscitation techniques are applied as an attempt to prevent immediate delivery.

0

20

40

60

NVOG Local RCOG ACOG

% o

f Dut

ch h

ospi

tals


67

3

national societies of obstetricians and gynecologists and requested their national

guideline on fetal monitoring and/or intrauterine resuscitation during labor.

If a guideline was not available in English, it was translated by a native speaker or by

the use of an online translation program. We compared the recommendations as

stated in the different guidelines. The following details were abstracted from the

guidelines and listed: methods of fetal monitoring systems during labor (intermittent

auscultation, fetal heart rate pattern, fetal scalp blood sampling and ST-analysis), the

classification system to judge the fetal heart rate pattern, and recommendations on

the use of intrauterine resuscitation techniques.

Ethical considerations As confirmed by the Medical Ethics Committee of Máxima Medical Center,

Veldhoven, The Netherlands, our study does not involve any patient data and

imposes no changes in general practice. Therefore, according to the Declaration of

Helsinki, no ethical approval was required.

Results Survey among Dutch obstetricians A total of 86 obstetricians, representing all 86 Dutch hospitals, completed the

questionnaire. Hospitals include eight university hospitals, 39 general teaching

hospitals, and 39 non-teaching hospitals. The response rate was 100%.

Besides the national guideline on fetal monitoring provided by the NVOG, various

local protocols exist on the diagnosis and management of fetal distress during labor.

In The Netherlands, the guideline of the NVOG is frequently used (58%), sometimes

in combination with a local guideline (26%). In 36% of the hospitals, only local

protocols are used. The American guideline, provided by the American College of

Obstetricians and Gynecologists (ACOG) is used in one hospital (1%), while the

British guideline, provided by the Royal College of Obstetricians and

Gynaecologists (RCOG) is used in six hospitals (7%). Results are shown in Fig. 1.

Figure 1. Percentage of Dutch hospitals using the represented guidelines on fetal

monitoring and fetal resuscitation.

All hospitals used fetal CTG to estimate fetal well-being during labor. Besides, in

23% (n=20) of the hospitals ST-analysis is used to monitor fetal condition, while in

98% (n=84) fetal scalp blood sampling is used in addition to CTG.

In most of the hospitals (95%), the (modified) FIGO classification is used to classify

the CTG. In two hospitals the Fischer classification is used.8 In two non-teaching

hospitals no structural classification system is implemented.

Preferences regarding the use of resuscitation techniques are different among the

hospitals. Fig. 2 shows the percentage of hospitals that use each of the mentioned

resuscitation techniques. The most used tocolytic agents are oxytocin antagonists,

6.75 mg atosiban administered intravenously. Furthermore, beta-mimetics, 5-10 mg

ritodrine administered intravenously, or nitroglycerin, administered oromucosally

with a dose of 0.4 mg are in use.

When fetal distress is suspected, immediate delivery may be expedited, depending

on the clinical situation. In almost all hospitals (98%), the attending staff will try to

improve fetal oxygenation in expectation of an emergency cesarean section or

vaginally assisted birth. Improvement of the intrauterine condition of the fetus may

also avoid termination of the delivery, thereby preventing a cesarean section or

vaginally assisted delivery. In 86% of the Dutch delivery wards, intrauterine

resuscitation techniques are applied as an attempt to prevent immediate delivery.

0

20

40

60

NVOG Local RCOG ACOG

% o

f Dut

ch h

ospi

tals

Chapter 3

68

Figure 2. Percentage of Dutch hospitals using the represented intrauterine

resuscitation techniques in the presence of suspected intrapartum fetal distress.

Survey of national guidelines of European countries We were able to obtain national guidelines on fetal monitoring of the following

countries: United Kingdom (2015),6 United States of America (USA, 2009),4 Canada

(2007),9 Australia & New Zealand (2014),10 Germany (2013),11 Ireland (2014),12

Portugal (2012),13 and Denmark (2008).14 The years refer to the date of publication of

the most recent version of each guideline. Five of them also contained

recommendations on the use of intrauterine resuscitation techniques.4,6,9,10,12 We

were not able to obtain the guidelines of the remaining 20 countries. The national

societies of Luxembourg and Finland reported they had no national guideline and

used guidelines of surrounding countries.

All the above-mentioned guidelines were freely online available, apart from the

Portuguese guideline that was kindly provided by the Portuguese Federation of

Obstetrics and Gynecology. Germany and Portugal did have guidelines on fetal

monitoring, but not on fetal resuscitations. Denmark did have a guideline on

amnioinfusion, but no recommendations regarding the other resuscitation

techniques were reported. Recommendations from the obtained guidelines are

listed in tables 1 and 2.

0

20

40

60

80

100

% o

f Dut

ch h

ospi

tals

Table 1. Recommendations from national and international guidelines on fetal

monitoring during labor. Country Intermittent

auscultation

CTG Classification

system

FBS STAN SpO2

Netherlands Low risk High risk FIGO YES YES -

USA - YES FIGO - - -

UK Low risk High risk FIGO YES - -

Ireland Low risk High risk FIGO YES - -

Canada Low risk High risk FIGO YES NO NO

Australia &

New Zealand

Low risk High risk - YES NO NO

Germany Low risk* High risk FIGO YES NO -

Portugal NO YES FIGO YES YES -

Denmark Low risk* High risk FIGO YES YES -

Low risk = recommended in low risk population, high risk = recommended in high

risk population, CTG = cardiotocogram, FIGO = (modified) FIGO classification, FBS

= fetal scalp blood sampling, STAN = ST-analysis, SpO2 = fetal pulse oximetry

- = not mentioned, * = intermittent electronic fetal heart rate monitoring allowed in

a low risk population, under certain circumstances.

Comment The Netherlands The Dutch national guideline on fetal monitoring during labor promotes the use of

fetal scalp blood sampling, in combination with CTG.7 The Dutch national guideline

on fetal monitoring provided by the NVOG does not advise on how the individual

parameters of the CTG should be measured. Fetal heart rate can be monitored

externally, or internally with a fetal scalp electrode. Uterine contractions can be

monitored externally with an ultrasound transducer or with an electrode patch.15

Internal tocodynamometry can be performed using an intrauterine pressure

catheter. A Cochrane review by Bakker et al. shows no superiority of internal over

external tocodynamometry in induced or augmented labor.16


69

3

Figure 2. Percentage of Dutch hospitals using the represented intrauterine

resuscitation techniques in the presence of suspected intrapartum fetal distress.

Survey of national guidelines of European countries We were able to obtain national guidelines on fetal monitoring of the following

countries: United Kingdom (2015),6 United States of America (USA, 2009),4 Canada

(2007),9 Australia & New Zealand (2014),10 Germany (2013),11 Ireland (2014),12

Portugal (2012),13 and Denmark (2008).14 The years refer to the date of publication of

the most recent version of each guideline. Five of them also contained

recommendations on the use of intrauterine resuscitation techniques.4,6,9,10,12 We

were not able to obtain the guidelines of the remaining 20 countries. The national

societies of Luxembourg and Finland reported they had no national guideline and

used guidelines of surrounding countries.

All the above-mentioned guidelines were freely online available, apart from the

Portuguese guideline that was kindly provided by the Portuguese Federation of

Obstetrics and Gynecology. Germany and Portugal did have guidelines on fetal

monitoring, but not on fetal resuscitations. Denmark did have a guideline on

amnioinfusion, but no recommendations regarding the other resuscitation

techniques were reported. Recommendations from the obtained guidelines are

listed in tables 1 and 2.

0

20

40

60

80

100

% o

f Dut

ch h

ospi

tals

Table 1. Recommendations from national and international guidelines on fetal

monitoring during labor. Country Intermittent

auscultation

CTG Classification

system

FBS STAN SpO2

Netherlands Low risk High risk FIGO YES YES -

USA - YES FIGO - - -

UK Low risk High risk FIGO YES - -

Ireland Low risk High risk FIGO YES - -

Canada Low risk High risk FIGO YES NO NO

Australia &

New Zealand

Low risk High risk - YES NO NO

Germany Low risk* High risk FIGO YES NO -

Portugal NO YES FIGO YES YES -

Denmark Low risk* High risk FIGO YES YES -

Low risk = recommended in low risk population, high risk = recommended in high

risk population, CTG = cardiotocogram, FIGO = (modified) FIGO classification, FBS

= fetal scalp blood sampling, STAN = ST-analysis, SpO2 = fetal pulse oximetry

- = not mentioned, * = intermittent electronic fetal heart rate monitoring allowed in

a low risk population, under certain circumstances.

Comment The Netherlands The Dutch national guideline on fetal monitoring during labor promotes the use of

fetal scalp blood sampling, in combination with CTG.7 The Dutch national guideline

on fetal monitoring provided by the NVOG does not advise on how the individual

parameters of the CTG should be measured. Fetal heart rate can be monitored

externally, or internally with a fetal scalp electrode. Uterine contractions can be

monitored externally with an ultrasound transducer or with an electrode patch.15

Internal tocodynamometry can be performed using an intrauterine pressure

catheter. A Cochrane review by Bakker et al. shows no superiority of internal over

external tocodynamometry in induced or augmented labor.16

Chapter 3

70

Table 2. Recommendation from national and international guidelines regarding

intrauterine resuscitation during labor.

Country Maternal

repositioning

O2 Stop

oxytocin

Tocolytic

agent

Amnio

infusion

IV fluid

bolus

Netherlands YES - YES YES # -

USA YES YES YES YES YES YES

UK YES NO YES YES NO YES

Ireland YES - YES YES - NO

Canada YES YES YES - YES YES

Australia &

New Zealand

YES - YES YES NO YES

O2 = maternal hyperoxygenation, - = not mentioned, # = not recommended nor

discouraged

The use of ST-analysis is not promoted, since its use will not decrease the incidence

of intrapartum acidosis. However, its use is not discouraged either, since it may be

cost-effective in comparison to the use of only CTG and fetal scalp blood

sampling.17-19 As a result, our nationwide survey on the diagnosis and management

of intrapartum fetal distress in Dutch labor wards shows a large practice variation on

the use of ST-analysis. In contrast, the use of fetal scalp blood sampling is rather

uniform. In all but one hospital (98%), fetal scalp blood sampling facilities are

available. However, ongoing discussion exists on the use of pH or lactate as a

marker for fetal well-being during labor. The Cochrane review by East et al.

concludes that fetal scalp blood lactate estimation is more likely to succeed than

pH.20 Nevertheless, due to the lack of long term neonatal follow up, no choice of

preference has been made so far. Besides, there is no clear answer yet on the

question which level of fetal scalp blood lactate indicates the need for intervention

during labor.21-24 As a consequence, in most Dutch hospitals fetal scalp blood pH is

still used as a measure for fetal well-being during labor.

Regarding the use of intrauterine resuscitation techniques, a large practice variation

was shown in the use of amnioinfusion and maternal hyperoxygenation. According

to the Dutch guideline, the use of amnioinfusion is not helpful to improve neonatal

outcome.7 However, it may decrease the presence of variable decelerations in the

fetal heart rate pattern. Therefore the use of this intervention is not promoted, nor

discouraged. In 33% of the Dutch hospitals amnioinfusion is used in the presence of

fetal distress. So far, no recommendations are made on the use of maternal

hyperoxygenation in the Dutch guideline. In 58% of the hospitals, this intervention is

commonly used to promote fetal oxygenation.

In almost all hospitals, discontinuation of oxytocin, maternal repositioning and

administration of tocolytic drugs is common practice. The administration of tocolytic

drugs, preferably atosiban, is actually recommended in the Dutch guideline.7

Atosiban has a similar effect on uterine pressure as ritodrine, but has significantly

less side effects on maternal condition.25 However, the effect of atosiban on

neonatal outcome is not investigated, in contrast to beta-mimetic drugs and

ritodrine. A Cochrane review concludes that betamimetic therapy appears to

improve abnormal fetal heart rate tracings.26 They state that there is not enough

evidence based on clinically important outcomes to evaluate the use of

betamimetics for suspected fetal distress. Another systematic review suggests a

positive effect of ritodrine, terbutaline, MgSO4, orciprenaline and nitroglycerine on

fetal well-being.5 Tocolytic drugs may decrease the need for emergency delivery

without increasing maternal and fetal adverse side-effects.27

The available literature to base practical recommendations on, is scarce. Therefore,

local guidelines are typically based on results of small, non-randomized studies and

expert opinions. Hence, the difference in delivery ward management regarding

intrauterine resuscitation may be caused by the lack of strong evidence to promote

or refuse certain techniques. Dutch labor wards use different national and

international guidelines for their local protocol.

We believe the results are illustrative for the delivery ward management in our

country. The response rate was 100%. Although it is very likely that most

respondents are aware of the common delivery ward management in their hospitals,

we cannot exclude that other staff members in certain cases practice other policies.

International guidelines We aimed to compare the recommendations from the Dutch guideline on fetal

monitoring and intrauterine resuscitation, with international guidelines. We

managed to obtain eight international guidelines on intrapartum monitoring.4,6,9-14

Five of them also advised on the use of intrauterine resuscitation techniques.4,6,9,10,12

Canada, the United Kingdom and Australia & New Zealand have elaborate,

evidence-based guidelines on antenatal and intrapartum fetal surveillance.6,9,10


71

3

Table 2. Recommendation from national and international guidelines regarding

intrauterine resuscitation during labor.

Country Maternal

repositioning

O2 Stop

oxytocin

Tocolytic

agent

Amnio

infusion

IV fluid

bolus

Netherlands YES - YES YES # -

USA YES YES YES YES YES YES

UK YES NO YES YES NO YES

Ireland YES - YES YES - NO

Canada YES YES YES - YES YES

Australia &

New Zealand

YES - YES YES NO YES

O2 = maternal hyperoxygenation, - = not mentioned, # = not recommended nor

discouraged

The use of ST-analysis is not promoted, since its use will not decrease the incidence

of intrapartum acidosis. However, its use is not discouraged either, since it may be

cost-effective in comparison to the use of only CTG and fetal scalp blood

sampling.17-19 As a result, our nationwide survey on the diagnosis and management

of intrapartum fetal distress in Dutch labor wards shows a large practice variation on

the use of ST-analysis. In contrast, the use of fetal scalp blood sampling is rather

uniform. In all but one hospital (98%), fetal scalp blood sampling facilities are

available. However, ongoing discussion exists on the use of pH or lactate as a

marker for fetal well-being during labor. The Cochrane review by East et al.

concludes that fetal scalp blood lactate estimation is more likely to succeed than

pH.20 Nevertheless, due to the lack of long term neonatal follow up, no choice of

preference has been made so far. Besides, there is no clear answer yet on the

question which level of fetal scalp blood lactate indicates the need for intervention

during labor.21-24 As a consequence, in most Dutch hospitals fetal scalp blood pH is

still used as a measure for fetal well-being during labor.

Regarding the use of intrauterine resuscitation techniques, a large practice variation

was shown in the use of amnioinfusion and maternal hyperoxygenation. According

to the Dutch guideline, the use of amnioinfusion is not helpful to improve neonatal

outcome.7 However, it may decrease the presence of variable decelerations in the

fetal heart rate pattern. Therefore the use of this intervention is not promoted, nor

discouraged. In 33% of the Dutch hospitals amnioinfusion is used in the presence of

fetal distress. So far, no recommendations are made on the use of maternal

hyperoxygenation in the Dutch guideline. In 58% of the hospitals, this intervention is

commonly used to promote fetal oxygenation.

In almost all hospitals, discontinuation of oxytocin, maternal repositioning and

administration of tocolytic drugs is common practice. The administration of tocolytic

drugs, preferably atosiban, is actually recommended in the Dutch guideline.7

Atosiban has a similar effect on uterine pressure as ritodrine, but has significantly

less side effects on maternal condition.25 However, the effect of atosiban on

neonatal outcome is not investigated, in contrast to beta-mimetic drugs and

ritodrine. A Cochrane review concludes that betamimetic therapy appears to

improve abnormal fetal heart rate tracings.26 They state that there is not enough

evidence based on clinically important outcomes to evaluate the use of

betamimetics for suspected fetal distress. Another systematic review suggests a

positive effect of ritodrine, terbutaline, MgSO4, orciprenaline and nitroglycerine on

fetal well-being.5 Tocolytic drugs may decrease the need for emergency delivery

without increasing maternal and fetal adverse side-effects.27

The available literature to base practical recommendations on, is scarce. Therefore,

local guidelines are typically based on results of small, non-randomized studies and

expert opinions. Hence, the difference in delivery ward management regarding

intrauterine resuscitation may be caused by the lack of strong evidence to promote

or refuse certain techniques. Dutch labor wards use different national and

international guidelines for their local protocol.

We believe the results are illustrative for the delivery ward management in our

country. The response rate was 100%. Although it is very likely that most

respondents are aware of the common delivery ward management in their hospitals,

we cannot exclude that other staff members in certain cases practice other policies.

International guidelines We aimed to compare the recommendations from the Dutch guideline on fetal

monitoring and intrauterine resuscitation, with international guidelines. We

managed to obtain eight international guidelines on intrapartum monitoring.4,6,9-14

Five of them also advised on the use of intrauterine resuscitation techniques.4,6,9,10,12

Canada, the United Kingdom and Australia & New Zealand have elaborate,

evidence-based guidelines on antenatal and intrapartum fetal surveillance.6,9,10

Chapter 3

72

These guidelines describe various fetal monitoring techniques, extensive CTG

interpretation guidelines and management recommendations in case of

nonreassuring fetal heart rate patterns. The Irish and American guidelines provide

recommendations regarding intrauterine resuscitation, without an overview of the

supporting literature.4,12 Other guidelines we obtained were exclusively on fetal

monitoring during labor, or on a specific intrauterine resuscitation technique, e.g.

the Danish guideline on amnioinfusion.28 We assume that more European countries

do have national guidelines, but unfortunately we were not able to obtain more than

eight guidelines for analysis.

By comparing the eight different guidelines, we identified various contradictory

recommendations. For example, the Practice Bulletin of the ACOG recommends

maternal hyperoxygenation in the presence of fetal distress, whereas RCOG in the

United Kingdom advises against this intervention.4,6 Also, amnioinfusion is

recommended in Denmark, Canada and the United States, but advised against in

the United Kingdom, Australia and New Zealand.4,6,9,10,28 The Netherlands did not

state an explicit recommendation on the use of amnioinfusion.7

Evidence regarding the effect of the various intrauterine resuscitation techniques is

limited, and sometimes contradictory. As a consequence, guidelines are mainly

based on low-level evidence and consensus. Also, it is not clear how long the effect

of intrauterine resuscitation should be awaited, before an emergency delivery is

indicated.

To come to funded recommendations, the effect of the various resuscitation

techniques should be investigated in randomized controlled trials. The technique

studied could be compared to expectant management, or to another resuscitation

technique. Since most of the interventions have become ‘common practice’, and

therefore cannot be withholded, it will be difficult to conduct a randomized

controlled trial. In our hospital (Máxima Medical Center), we have started a

randomized controlled trial to investigate the effect of maternal hyperoxygenation

on fetal distress during labor (EudraCT number 2015-001654-15, Dutch Trial

Register number 5461, Central Committee on Research Involving Human Subjects

number NL53018.000.15). We hope more studies to investigate the benefit of other

resuscitation techniques will follow and lead to clear and uniform recommendations.

Acknowledgements This research was performed within the framework of the IMPULS perinatology. We

thank all gynecologists who agreed to participate to this survey.


73

3

These guidelines describe various fetal monitoring techniques, extensive CTG

interpretation guidelines and management recommendations in case of

nonreassuring fetal heart rate patterns. The Irish and American guidelines provide

recommendations regarding intrauterine resuscitation, without an overview of the

supporting literature.4,12 Other guidelines we obtained were exclusively on fetal

monitoring during labor, or on a specific intrauterine resuscitation technique, e.g.

the Danish guideline on amnioinfusion.28 We assume that more European countries

do have national guidelines, but unfortunately we were not able to obtain more than

eight guidelines for analysis.

By comparing the eight different guidelines, we identified various contradictory

recommendations. For example, the Practice Bulletin of the ACOG recommends

maternal hyperoxygenation in the presence of fetal distress, whereas RCOG in the

United Kingdom advises against this intervention.4,6 Also, amnioinfusion is

recommended in Denmark, Canada and the United States, but advised against in

the United Kingdom, Australia and New Zealand.4,6,9,10,28 The Netherlands did not

state an explicit recommendation on the use of amnioinfusion.7

Evidence regarding the effect of the various intrauterine resuscitation techniques is

limited, and sometimes contradictory. As a consequence, guidelines are mainly

based on low-level evidence and consensus. Also, it is not clear how long the effect

of intrauterine resuscitation should be awaited, before an emergency delivery is

indicated.

To come to funded recommendations, the effect of the various resuscitation

techniques should be investigated in randomized controlled trials. The technique

studied could be compared to expectant management, or to another resuscitation

technique. Since most of the interventions have become ‘common practice’, and

therefore cannot be withholded, it will be difficult to conduct a randomized

controlled trial. In our hospital (Máxima Medical Center), we have started a

randomized controlled trial to investigate the effect of maternal hyperoxygenation

on fetal distress during labor (EudraCT number 2015-001654-15, Dutch Trial

Register number 5461, Central Committee on Research Involving Human Subjects

number NL53018.000.15). We hope more studies to investigate the benefit of other

resuscitation techniques will follow and lead to clear and uniform recommendations.

Acknowledgements This research was performed within the framework of the IMPULS perinatology. We

thank all gynecologists who agreed to participate to this survey.

Chapter 3

74

Appendix 1. Questionnaire regarding diagnosis and management of fetal distress

during labor (original questions in Dutch).

1 Does your hospital have a delivery ward?

A Yes

B No (end of the questionnaire)

2 What techniques for fetal monitoring are used?

A Cardiotocogram

B Cardiotocogram and/or fetal scalp blood sampling

C Cardiotocogram and/or fetal scalp blood sampling and/or ST-analysis

D Other…

3 Is the cardiotocogram classified using a classification system?

A Yes, the FIGO classification system is used

B Yes, another classification system is used

C No, no classification system is used

4 How fetal distress is diagnosed?

A Suspicion due to an abnormal CTG

B Confirmed using fetal scalp blood sampling

C Confirmed using ST-analysis

D Other…

5 Which action are undertaken in case of suspected fetal distress?

A Confirmation of impaired fetal condition using fetal scalp blood sampling

B Immediate delivery (vaginally assisted birth or cesarean section)

C Application of intrauterine resuscitation techniques

6 Which intrauterine resuscitation techniques are used in your hospital?

A Discontinuation of oxytocin infusion

B Use of tocolytic agents

C Maternal repositioning

D Amnioinfusion

E Maternal hyperoxygenation

F Other…

7 In case a tocolytic drug is administered, which drug and dose are used?

A Ritodrine

B Atosiban

C Fenoterol

D Other…

Dose:

8 Are intrauterine resuscitation techniques applied while waiting for an emergency

cesarean section or vaginally assisted delivery?

A Yes

B No

9 If yes, which techniques are applied?




D Amnioinfusion


F Other…

10 On what bases one decides which intervention is applied?

A Based on a guideline

B Based on my own experience/what I have learnt

11 In case intervention is based on a guideline, which guideline is used?

A NVOG

B RCOG

C ACOG

D Local guideline

E Other…


75

3

Appendix 1. Questionnaire regarding diagnosis and management of fetal distress

during labor (original questions in Dutch).

1 Does your hospital have a delivery ward?

A Yes

B No (end of the questionnaire)

2 What techniques for fetal monitoring are used?

A Cardiotocogram

B Cardiotocogram and/or fetal scalp blood sampling

C Cardiotocogram and/or fetal scalp blood sampling and/or ST-analysis

D Other…

3 Is the cardiotocogram classified using a classification system?

A Yes, the FIGO classification system is used

B Yes, another classification system is used

C No, no classification system is used

4 How fetal distress is diagnosed?

A Suspicion due to an abnormal CTG

B Confirmed using fetal scalp blood sampling

C Confirmed using ST-analysis

D Other…

5 Which action are undertaken in case of suspected fetal distress?

A Confirmation of impaired fetal condition using fetal scalp blood sampling

B Immediate delivery (vaginally assisted birth or cesarean section)

C Application of intrauterine resuscitation techniques

6 Which intrauterine resuscitation techniques are used in your hospital?




D Amnioinfusion


F Other…

7 In case a tocolytic drug is administered, which drug and dose are used?

A Ritodrine

B Atosiban

C Fenoterol

D Other…

Dose:

8 Are intrauterine resuscitation techniques applied while waiting for an emergency

cesarean section or vaginally assisted delivery?

A Yes

B No

9 If yes, which techniques are applied?




D Amnioinfusion


F Other…

10 On what bases one decides which intervention is applied?

A Based on a guideline

B Based on my own experience/what I have learnt

11 In case intervention is based on a guideline, which guideline is used?

A NVOG

B RCOG

C ACOG

D Local guideline

E Other…

Chapter 3

76

12 Which interventions do you think are effective when applied for fetal distress?




D Amnioinfusion


F Intravenous fluid administration (not for correction of hypotension)

G Other…

References 1. Graham EM, Ruis KA, Hartman AL,Northington FJ, Fox HE. A systematic review of the

role of intrapartum hypoxia-ischemia in the causation of neonatal encephalopathy. AJOG. 2008;199:587-95.

2. Parer JT. Effects of fetal asphyxia on brain cell structure and function: limits of tolerance. Comp Biochem Physiol A: Mol Integr Physiol. 1998;119:711-6.


4. American College of Obstetricians and Gynecologists. Practice bulletin no. 116: management of intrapartum fetal heart rate tracings. Obstet Gynecol 2010;116:1232-40.

5. Bullens LM, Van Runnard Heimel PJ, Van der Hout-van der Jagt MB, Oei SG. Interventions for intrauterine resuscitation in suspected fetal distress during term labor: a systematic review. Obstet Gynecol Surv. 2015;70:524-39.

6. National Collaborating Centre for Women’s and Children’s Health (UK). Intrapartum care: care of healthy women and their babies during childbirth. London: National Institute for Health and Care Excellence (UK); 2014.

7. Nederlandse Vereniging voor Obstetrie en Gynaecologie. Intrapartum fetal monitoring at term [Intrapartum foetale bewaking a terme] [internet]. Utrecht, The Netherlands: NVOG; May 2014 [updated May 2015]. Available from: http://nvog-documenten.nl/uploaded/docs/NVOG%20richtlijn%20foetale%20bewaking%2019-05-2014%20update%2028-5-2015.pdf. [Dutch]

8. Berg D, Brandt H, Ekert WD, Fischer M, Gennser G, Halberstadt E, et al. Kardiotokographie. Diagnostische Methoden in der Perinatologie. Stuttgart - New York: Georg Thieme Verlag; 1973. [German]

9. Liston R, Sawchuck D, Young D: the Society of Obstetricians and Gynaecologists of Canada. Fetal health surveillance: antepartum and intrapartum consensus guideline. J Obstet Gynecol Can. 2007;29(9 Suppl. 4):S3-56.

10. The Royal Australian and New Zealand College of Obstetricians and Gynaecologists. Intrapartum Fetal Surveillance. Clinical Guideline, third ed. Available from: www.ranzcog.edu.au/intrapartum-fetal-surveillance-clinical- guidelines.html; May 2016.

11. Deutsche Gesellschaft für Gynäkologie und Guburtshilfe, Arbeitsgemeischaft Materno-fetale Medizin, Deutsche Gezellschaft für Pränatal und Geburtzmedizin, Deutsche Gesellschaft für Perinatale Medizin. S1 Leitlinie: Anwendung des CTG während Schwangerschaft und Geburt. Available from: www.awmf. org/uploads/tx_szleitlinien/015-036l_S1_CTG_Schwangerschaft_Ge- burt_2014-06.pdf; May 2016. [German]

12. Institute of Obstetricians and Gynecologistst, Royal College of Physicians of Ireland and Directorate of Stategy and Clinical Programmes Health Service Executive. Clinical practice guideline: Intrapartum fetal heart rate monitoring. Version 1.2. Available from: www.hse.ie/eng/about/Who/clinical/natclinprog/ obsandgynaeprogramme/guide6.pdf; May 2016.

13. Graça LM. Monitorizaçâo fetal intra-parto; 2012. [Portuguese] 14. Palmgren Colov N, Hedegaard M, Hvidman L, Stener Jørgensen J, Lenstrup C.

Fosterovervågning under fødslen ved hjælp af STAN. Available from:


77

3

12 Which interventions do you think are effective when applied for fetal distress?




D Amnioinfusion


F Intravenous fluid administration (not for correction of hypotension)

G Other…

References 1. Graham EM, Ruis KA, Hartman AL,Northington FJ, Fox HE. A systematic review of the

role of intrapartum hypoxia-ischemia in the causation of neonatal encephalopathy. AJOG. 2008;199:587-95.

2. Parer JT. Effects of fetal asphyxia on brain cell structure and function: limits of tolerance. Comp Biochem Physiol A: Mol Integr Physiol. 1998;119:711-6.


4. American College of Obstetricians and Gynecologists. Practice bulletin no. 116: management of intrapartum fetal heart rate tracings. Obstet Gynecol 2010;116:1232-40.

5. Bullens LM, Van Runnard Heimel PJ, Van der Hout-van der Jagt MB, Oei SG. Interventions for intrauterine resuscitation in suspected fetal distress during term labor: a systematic review. Obstet Gynecol Surv. 2015;70:524-39.

6. National Collaborating Centre for Women’s and Children’s Health (UK). Intrapartum care: care of healthy women and their babies during childbirth. London: National Institute for Health and Care Excellence (UK); 2014.

7. Nederlandse Vereniging voor Obstetrie en Gynaecologie. Intrapartum fetal monitoring at term [Intrapartum foetale bewaking a terme] [internet]. Utrecht, The Netherlands: NVOG; May 2014 [updated May 2015]. Available from: http://nvog-documenten.nl/uploaded/docs/NVOG%20richtlijn%20foetale%20bewaking%2019-05-2014%20update%2028-5-2015.pdf. [Dutch]

8. Berg D, Brandt H, Ekert WD, Fischer M, Gennser G, Halberstadt E, et al. Kardiotokographie. Diagnostische Methoden in der Perinatologie. Stuttgart - New York: Georg Thieme Verlag; 1973. [German]

9. Liston R, Sawchuck D, Young D: the Society of Obstetricians and Gynaecologists of Canada. Fetal health surveillance: antepartum and intrapartum consensus guideline. J Obstet Gynecol Can. 2007;29(9 Suppl. 4):S3-56.

10. The Royal Australian and New Zealand College of Obstetricians and Gynaecologists. Intrapartum Fetal Surveillance. Clinical Guideline, third ed. Available from: www.ranzcog.edu.au/intrapartum-fetal-surveillance-clinical- guidelines.html; May 2016.

11. Deutsche Gesellschaft für Gynäkologie und Guburtshilfe, Arbeitsgemeischaft Materno-fetale Medizin, Deutsche Gezellschaft für Pränatal und Geburtzmedizin, Deutsche Gesellschaft für Perinatale Medizin. S1 Leitlinie: Anwendung des CTG während Schwangerschaft und Geburt. Available from: www.awmf. org/uploads/tx_szleitlinien/015-036l_S1_CTG_Schwangerschaft_Ge- burt_2014-06.pdf; May 2016. [German]

12. Institute of Obstetricians and Gynecologistst, Royal College of Physicians of Ireland and Directorate of Stategy and Clinical Programmes Health Service Executive. Clinical practice guideline: Intrapartum fetal heart rate monitoring. Version 1.2. Available from: www.hse.ie/eng/about/Who/clinical/natclinprog/ obsandgynaeprogramme/guide6.pdf; May 2016.

13. Graça LM. Monitorizaçâo fetal intra-parto; 2012. [Portuguese] 14. Palmgren Colov N, Hedegaard M, Hvidman L, Stener Jørgensen J, Lenstrup C.

Fosterovervågning under fødslen ved hjælp af STAN. Available from:

Chapter 3

78

http://clin.au.dk/fileadmin/www.ki.au.dk/forskning/forskningsenheder/ gyn__kologisk-obstetrisk_afd__y/logistics/sandbjerg_m__der/sandb- jerg_2008/stan.pdf; May 2016. [Danish]

15. Vlemminx MW, de Lau H, Vullings R, Peters CH, Oei SG. Electrohysterography. A promising alternative for monitoring contractions. Ned Tijdschr Geneeskd 2015;159:A8535. [Dutch]

16. Bakker JJ, Janssen PF, van Halem K, van der Goes BY, Papatsonis DN, van der Post JA, et al. Internal versus external tocodynamometry during induced or augmented labour. Cochrane Database Syst Rev. 2013;8:CD006947.

17. Vijgen SM, Westerhuis ME, Opmeer BC, Visser GH, Moons KG, Porath MM, et al. Cost-effectiveness of cardiotocography plus ST-analysis of the fetal electrocardiogram compared with cardiotocography only. Acta Obstet Gynecol Scand. 2011;90:772-8.

18. Heintz E, Brodtkorb TH, Nelson N, Levin LA. The long-term cost-effectiveness of fetal monitoring during labour: a comparison of cardiotocography complemented with ST analysis versus cardiotocography alone. BJOG 2008;115:1676-87.

19. Van ‘t Hooft J, Vink M, Opmeer BC, Ensing S, Kwee A, Mol BW. ST-analysis in electronic foetal monitoring is cost-effective from both the maternal and neonatal perspective. J Matern Fetal Neonatal Med. 2016;29:3260-5.

20. East CE, Leader LR, Sheehan P, Henshall NE, Colditz PB, Lau R. Intrapartum fetal scalp lactate sampling for fetal assessment in the presence of a non-reassuring fetal heart rate trace. Cochrane Database Syst Rev. 2015;1:CD006174.

21. Kruger K, Hallberg B, Blennow M, Kublickas M, Westgren M. Predictive value of fetal scalp blood lactate concentration and pH as markers of neurologic disability. AJOG. 1999;181(5 Pt. 1):1072-8.

22. Allen RM, Bowling FG, Oats JJ. Determining the fetal scalp lactate level that indicates the need for intervention in labour. Aust N Z J Obstet Gynaecol. 2004;44:549-52.

23. Ramanah R, Martin A, Clement MC, Maillet R, Riethmuller D. Fetal scalp lactate microsampling for non-reassuring fetal status during labor: a prospective observational study. Fetal Diagn Ther. 2010;27:14-9.

24. Heinis AM, Spaanderman ME, Gunnewiek JM, Lotgering FK. Scalp blood lactate for intra-partum assessment of fetal metabolic acidosis. Acta Obstet Gynecol Scand. 2011;90:1107-14.



27. Briozzo L, Martinez A, Nozar M, Fiol V, Pons J, Alonso J. Tocolysis and delayed delivery versus emergency delivery in cases of non-reassuring fetal status during labor. J Obstet Gynaecol Res. 2007;33:266-73.

28. Brix Westergaard H, Krebs L, Weber T, Bek Helmig R, Stener Jørgensen Jan, et al. Amnioinfusion under fødslen. Available from: http://clin.au.dk/fileadmin/www .ki.au.dk/forskning/forskningsenheder/gyn__kologiskobstetrisk_afd__y/ logistics/sandb-jerg_m__der/sandbjerg_2008/amnioinfusion.pdf; May 2016. [Danish]

Chapter 4

A simulation model to study maternal hyperoxygenation

during labor

Bullens LM, van der Hout-van der Jagt MB,

van Runnard Heimel PJ, Oei SG

Acta Obstetricia et Gynecologica Scandinavica. 2014;93:1268-75

http://clin.au.dk/fileadmin/www.ki.au.dk/forskning/forskningsenheder/ gyn__kologisk-obstetrisk_afd__y/logistics/sandbjerg_m__der/sandb- jerg_2008/stan.pdf; May 2016. [Danish]

15. Vlemminx MW, de Lau H, Vullings R, Peters CH, Oei SG. Electrohysterography. A promising alternative for monitoring contractions. Ned Tijdschr Geneeskd 2015;159:A8535. [Dutch]

16. Bakker JJ, Janssen PF, van Halem K, van der Goes BY, Papatsonis DN, van der Post JA, et al. Internal versus external tocodynamometry during induced or augmented labour. Cochrane Database Syst Rev. 2013;8:CD006947.

17. Vijgen SM, Westerhuis ME, Opmeer BC, Visser GH, Moons KG, Porath MM, et al. Cost-effectiveness of cardiotocography plus ST-analysis of the fetal electrocardiogram compared with cardiotocography only. Acta Obstet Gynecol Scand. 2011;90:772-8.

18. Heintz E, Brodtkorb TH, Nelson N, Levin LA. The long-term cost-effectiveness of fetal monitoring during labour: a comparison of cardiotocography complemented with ST analysis versus cardiotocography alone. BJOG 2008;115:1676-87.

19. Van ‘t Hooft J, Vink M, Opmeer BC, Ensing S, Kwee A, Mol BW. ST-analysis in electronic foetal monitoring is cost-effective from both the maternal and neonatal perspective. J Matern Fetal Neonatal Med. 2016;29:3260-5.

20. East CE, Leader LR, Sheehan P, Henshall NE, Colditz PB, Lau R. Intrapartum fetal scalp lactate sampling for fetal assessment in the presence of a non-reassuring fetal heart rate trace. Cochrane Database Syst Rev. 2015;1:CD006174.

21. Kruger K, Hallberg B, Blennow M, Kublickas M, Westgren M. Predictive value of fetal scalp blood lactate concentration and pH as markers of neurologic disability. AJOG. 1999;181(5 Pt. 1):1072-8.

22. Allen RM, Bowling FG, Oats JJ. Determining the fetal scalp lactate level that indicates the need for intervention in labour. Aust N Z J Obstet Gynaecol. 2004;44:549-52.

23. Ramanah R, Martin A, Clement MC, Maillet R, Riethmuller D. Fetal scalp lactate microsampling for non-reassuring fetal status during labor: a prospective observational study. Fetal Diagn Ther. 2010;27:14-9.

24. Heinis AM, Spaanderman ME, Gunnewiek JM, Lotgering FK. Scalp blood lactate for intra-partum assessment of fetal metabolic acidosis. Acta Obstet Gynecol Scand. 2011;90:1107-14.



27. Briozzo L, Martinez A, Nozar M, Fiol V, Pons J, Alonso J. Tocolysis and delayed delivery versus emergency delivery in cases of non-reassuring fetal status during labor. J Obstet Gynaecol Res. 2007;33:266-73.

28. Brix Westergaard H, Krebs L, Weber T, Bek Helmig R, Stener Jørgensen Jan, et al. Amnioinfusion under fødslen. Available from: http://clin.au.dk/fileadmin/www .ki.au.dk/forskning/forskningsenheder/gyn__kologiskobstetrisk_afd__y/ logistics/sandb-jerg_m__der/sandbjerg_2008/amnioinfusion.pdf; May 2016. [Danish]

Chapter 4


during labor

Bullens LM, van der Hout-van der Jagt MB,

van Runnard Heimel PJ, Oei SG

Acta Obstetricia et Gynecologica Scandinavica. 2014;93:1268-75

Chapter 4

80

Abstract

Objective

To investigate the effect of maternal hyperoxygenation on fetal oxygenation and

fetal heart rate decelerations during labor, using a simulation model.

Design

Use of a mathematical model that simulates fetomaternal hemodynamics and

oxygenation, designed in Matlab r2012a.

Setting

Clinical and engineering departments in The Netherlands.

Methods

We simulated variable and late fetal heart rate decelerations, caused by uterine

contractions with a different contraction interval. We continuously recorded oxygen

pressure in different fetoplacental compartments and fetal heart rate,

during maternal normoxia and during hyperoxygenation with 100% oxygen.

Main outcome measures

Changes in oxygen pressure in the intervillous space, umbilical vein and arteries,

fetal cerebral and microcirculation, as well as fetal heart rate deceleration depth and

duration.

Results

Maternal hyperoxygenation leads to an increase in fetal oxygenation: in the

presence of variable decelerations, oxygen pressure in the intervillous space

increased 9-10 mmHg and in the cerebral circulation 1-2 mmHg, depending on the

contraction interval. In addition, fetal heart rate deceleration depth decreased from

45 to 20 beats per minute. In the presence of late decelerations, oxygen pressure in

the intervillous space increased 7-10 mmHg and in the cerebral circulation 1-2

mmHg, depending on the contraction interval. The fetus benefited more from

materal hyperoxygenation when contraction intervals were longer.

Conclusions

According to the simulation model, maternal hyperoxygenation leads to an increase

in fetal oxygenation, especially in the presence of variable decelerations. In addition,

in the presence of variable decelerations, maternal hyperoxygenation leads to

amelioration of the fetal heart rate pattern.


81

4

Abstract

Objective

To investigate the effect of maternal hyperoxygenation on fetal oxygenation and

fetal heart rate decelerations during labor, using a simulation model.

Design

Use of a mathematical model that simulates fetomaternal hemodynamics and

oxygenation, designed in Matlab r2012a.

Setting

Clinical and engineering departments in The Netherlands.

Methods

We simulated variable and late fetal heart rate decelerations, caused by uterine

contractions with a different contraction interval. We continuously recorded oxygen

pressure in different fetoplacental compartments and fetal heart rate,

during maternal normoxia and during hyperoxygenation with 100% oxygen.

Main outcome measures

Changes in oxygen pressure in the intervillous space, umbilical vein and arteries,

fetal cerebral and microcirculation, as well as fetal heart rate deceleration depth and

duration.

Results

Maternal hyperoxygenation leads to an increase in fetal oxygenation: in the

presence of variable decelerations, oxygen pressure in the intervillous space

increased 9-10 mmHg and in the cerebral circulation 1-2 mmHg, depending on the

contraction interval. In addition, fetal heart rate deceleration depth decreased from

45 to 20 beats per minute. In the presence of late decelerations, oxygen pressure in

the intervillous space increased 7-10 mmHg and in the cerebral circulation 1-2

mmHg, depending on the contraction interval. The fetus benefited more from

materal hyperoxygenation when contraction intervals were longer.

Conclusions

According to the simulation model, maternal hyperoxygenation leads to an increase

in fetal oxygenation, especially in the presence of variable decelerations. In addition,

in the presence of variable decelerations, maternal hyperoxygenation leads to

amelioration of the fetal heart rate pattern.

Chapter 4

82

Introduction

Labor contractions, causing alterations in intrauterine pressure, can affect uterine

and umbilical blood flow.1-5 Fluctuations in blood flow towards the fetus may

negatively influence fetal oxygenation and fetal heart rate (FHR) through several

complex pathways.2-5 Hence, abnormal FHR patterns, for example FHR decelerations

induced by labor contractions, may be a sign of fetal hypoxia.6-8 Prolonged fetal

hypoxia may lead to hypoxic–ischemic encephalopathy and fetal death.9 Therefore,

when fetal distress is suspected, attempts to improve fetal oxygenation should be

made before immediate delivery is indicated.

Former studies described several techniques to improve fetal condition, although

little evidence is available to prove the beneficial effect of these techniques on

neonatal outcome.10-12 Maternal hyperoxygenation is often used to increase oxygen

transport towards the fetus. In the last decades, several studies on the effect of

maternal hyperoxygenation on fetal condition have been performed, mainly in the

non-compromised fetus. Clinical trials performed so far provide contradictory

results.13-22 A recent Cochrane review concludes that “there is not enough evidence

to support the use of prophylactic oxygen therapy for women in labor, nor to

evaluate its effectiveness for fetal distress”, because of the lack of a randomized

controlled trial to investigate the effect of maternal hyperoxygenation on fetal

condition.20

Therefore, a randomized controlled trial would help us to investigate the effect of

maternal hyperoxygenation. It makes more sense to design a randomized controlled

trial once it has been clarified how maternal hyperoxygenation affects fetal

oxygenation and FHR. Simulation models provide the possibility to investigate

complex clinical situations, such as fetomaternal oxygenation.

Recently, our group developed a mathematical computerized simulation model to

provide insight into the complex pathways affecting fetomaternal oxygenation and

FHR.23-25 The model is based on physiological parameters that influence oxygenation

and FHR. These include maternal cardiac output, maternal oxygenation, uterine

pressure and flow, oxygen diffusion capacity in the placenta, fetal cerebral blood

flow, fetal oxygen consumption, and baroreceptor and chemoreceptor responses.

This study aimed first to demonstrate how we used this simulation model to study

fetomaternal oxygenation and FHR patterns during labor.

Second, we demonstrate how we used the model to study the effect of maternal

hyperoxygenation during decelerative FHR patterns.

Material and methods A mathematical fetomaternal oxygenation model was developed by our group and

implemented in MATLAB R2012a (MathWorks Inc., Natick, MA, USA).23-25 The model

is based on physiological principles and consists of several modules (figure 1).

Figure 1. Diagram of the fetomaternal simulation model. Uterine contractions cause

changes in uterine pressure which may alter blood pressure and flow in the fetal or

maternal circulation. Oxygen pressures as well as blood pressure in the fetus may

evoke changes in cardiovascular parameters, including fetal heart rate.

First, the cardiovascular system of mother and fetus are modeled. The model

includes cardiac function, blood flow, volume and pressure at different locations in

the fetomaternal circulation. In the maternal circulation, the uterine compartment is

explicitly modeled and the other organs are lumped into the systemic compartment.

In the fetal circulation, the systemic and umbilical compartments, as well as the

cerebral compartment are explicitly modeled.

!


83

4

Introduction

Labor contractions, causing alterations in intrauterine pressure, can affect uterine

and umbilical blood flow.1-5 Fluctuations in blood flow towards the fetus may

negatively influence fetal oxygenation and fetal heart rate (FHR) through several

complex pathways.2-5 Hence, abnormal FHR patterns, for example FHR decelerations

induced by labor contractions, may be a sign of fetal hypoxia.6-8 Prolonged fetal

hypoxia may lead to hypoxic–ischemic encephalopathy and fetal death.9 Therefore,

when fetal distress is suspected, attempts to improve fetal oxygenation should be

made before immediate delivery is indicated.

Former studies described several techniques to improve fetal condition, although

little evidence is available to prove the beneficial effect of these techniques on

neonatal outcome.10-12 Maternal hyperoxygenation is often used to increase oxygen

transport towards the fetus. In the last decades, several studies on the effect of

maternal hyperoxygenation on fetal condition have been performed, mainly in the

non-compromised fetus. Clinical trials performed so far provide contradictory

results.13-22 A recent Cochrane review concludes that “there is not enough evidence

to support the use of prophylactic oxygen therapy for women in labor, nor to

evaluate its effectiveness for fetal distress”, because of the lack of a randomized

controlled trial to investigate the effect of maternal hyperoxygenation on fetal

condition.20

Therefore, a randomized controlled trial would help us to investigate the effect of

maternal hyperoxygenation. It makes more sense to design a randomized controlled

trial once it has been clarified how maternal hyperoxygenation affects fetal

oxygenation and FHR. Simulation models provide the possibility to investigate

complex clinical situations, such as fetomaternal oxygenation.

Recently, our group developed a mathematical computerized simulation model to

provide insight into the complex pathways affecting fetomaternal oxygenation and

FHR.23-25 The model is based on physiological parameters that influence oxygenation

and FHR. These include maternal cardiac output, maternal oxygenation, uterine

pressure and flow, oxygen diffusion capacity in the placenta, fetal cerebral blood

flow, fetal oxygen consumption, and baroreceptor and chemoreceptor responses.

This study aimed first to demonstrate how we used this simulation model to study

fetomaternal oxygenation and FHR patterns during labor.

Second, we demonstrate how we used the model to study the effect of maternal

hyperoxygenation during decelerative FHR patterns.

Material and methods A mathematical fetomaternal oxygenation model was developed by our group and

implemented in MATLAB R2012a (MathWorks Inc., Natick, MA, USA).23-25 The model

is based on physiological principles and consists of several modules (figure 1).

Figure 1. Diagram of the fetomaternal simulation model. Uterine contractions cause

changes in uterine pressure which may alter blood pressure and flow in the fetal or

maternal circulation. Oxygen pressures as well as blood pressure in the fetus may

evoke changes in cardiovascular parameters, including fetal heart rate.

First, the cardiovascular system of mother and fetus are modeled. The model

includes cardiac function, blood flow, volume and pressure at different locations in

the fetomaternal circulation. In the maternal circulation, the uterine compartment is

explicitly modeled and the other organs are lumped into the systemic compartment.

In the fetal circulation, the systemic and umbilical compartments, as well as the

cerebral compartment are explicitly modeled.

!

Chapter 4

84

Second, an oxygen distribution model is used to calculate oxygen concentrations in

all compartments in the fetomaternal circulation. Oxygen transport from the mother

to the fetus is dependent on maternal oxygenation, oxygen diffusion capacity in the

placenta, fetal oxygen consumption, and fetoplacental blood flows and volumes.

Maternal arteries supply oxygenated blood into the intervillous space of the

placenta. Diffusion of oxygen from the maternal to the fetal part of the placenta is

dependent on the oxygen pressure difference between the intervillous space and

chorionic villi and on the diffusion capacity of the placental membrane. Oxygen-rich

blood from the villous capillaries mixes with venous blood before entering the fetal

heart and the arterial circulation. Arterial blood flows to the cerebral and systemic

circulation where oxygen is consumed by metabolic uptake, after which it returns to

the venous system. In addition, arterial blood enters the umbilical circulation and

placenta, where new oxygen uptake takes place.

Third, cardiovascular regulation is provided by the fetal baroreceptors and

chemoreceptors, which monitor fetal blood pressure and oxygen pressure,

respectively. Stimulation of these receptors leads to changes in parasympathetic and

sympathetic activity, which can then induce changes in cardiovascular parameters,

including FHR. In addition, cerebral autoregulation may increase cerebral flow

during hypoxia.

Finally, uterine contractions are simulated by a contraction generator. Characteristics

of the contractions can be set by the user to investigate the effect of contraction

strength, duration and interval. Intrauterine pressure changes may lead to alterations

in fetal and maternal vascular resistances through the compression of blood vessels,

so affecting blood oxygenation, (local) blood pressure and flow.

In the model, we applied uniform uterine contractions, causing variable or late

decelerations. For a complete description of inducing variable and late

decelerations, we refer to previous publications.24,25

We first simulated variable decelerations via contraction-induced umbilical cord

compression (contraction duration 60 s, peak strength 70 mmHg) with a varying

contraction interval (90, 60 or 45 s). For each simulation, the first uterine contraction

was applied during maternal normoxia level (partial oxygen pressure (pO2) of 98

mmHg).16 After the first contraction, we simulated 100% oxygen administration to

the mother via a non-rebreathing mask by a gradual increase to a maternal

pO2steady state of 475 mmHg, as reported by Vasicka et al.16 We repeated this

exact procedure during the simulation of late decelerations via contraction-induced

uterine flow reduction for a placenta with 50% reduction in oxygen diffusion

capacity.

The primary outcome measure is the difference in fetoplacental pO2 before and after

maternal hyperoxygenation in the presence of variable or late decelerations. We

compared pO2 the intervillous space, fetal arteries, umbilical vein and arteries and

the fetal cerebral and microcirculation. Second, we compared the difference in

duration and depth of FHR decelerations during maternal normoxia and hyperoxia,

as a reaction to contractions with a different interval.

As no human or animal subjects were involved in this study, no ethics approval is

required according to the Declaration of Helsinki.

Statistical analysis The simulation model represents one mother and one fetus, with fixed output values

per simulation, hence no statistical analysis can be performed.

Results Figure 2 demonstrates pO2 in different fetoplacental compartments during variable

decelerations caused by uterine contractions with an interval of 90, 60 or 45 s.

During hyperoxygenation, pO2 in all fetoplacental compartments increases. Maternal

hyperoxygenation has a greater effect on fetal pO2 when intervals are longer. When

the contraction interval is 90 s, pO2 increases most in the intervillous space (from 43

to 54 mmHg). The increase is less pronounced in the cerebral circulation, where pO2

increases from 15 to 17 mmHg. When the contraction interval is only 45 s, the

increase in pO2 is less explicit in both the intervillous space and cerebral circulation

(from 43 to 52 mmHg and from 14 to 15 mmHg, respectively).


85

4

Second, an oxygen distribution model is used to calculate oxygen concentrations in

all compartments in the fetomaternal circulation. Oxygen transport from the mother

to the fetus is dependent on maternal oxygenation, oxygen diffusion capacity in the

placenta, fetal oxygen consumption, and fetoplacental blood flows and volumes.

Maternal arteries supply oxygenated blood into the intervillous space of the

placenta. Diffusion of oxygen from the maternal to the fetal part of the placenta is

dependent on the oxygen pressure difference between the intervillous space and

chorionic villi and on the diffusion capacity of the placental membrane. Oxygen-rich

blood from the villous capillaries mixes with venous blood before entering the fetal

heart and the arterial circulation. Arterial blood flows to the cerebral and systemic

circulation where oxygen is consumed by metabolic uptake, after which it returns to

the venous system. In addition, arterial blood enters the umbilical circulation and

placenta, where new oxygen uptake takes place.

Third, cardiovascular regulation is provided by the fetal baroreceptors and

chemoreceptors, which monitor fetal blood pressure and oxygen pressure,

respectively. Stimulation of these receptors leads to changes in parasympathetic and

sympathetic activity, which can then induce changes in cardiovascular parameters,

including FHR. In addition, cerebral autoregulation may increase cerebral flow

during hypoxia.

Finally, uterine contractions are simulated by a contraction generator. Characteristics

of the contractions can be set by the user to investigate the effect of contraction

strength, duration and interval. Intrauterine pressure changes may lead to alterations

in fetal and maternal vascular resistances through the compression of blood vessels,

so affecting blood oxygenation, (local) blood pressure and flow.

In the model, we applied uniform uterine contractions, causing variable or late

decelerations. For a complete description of inducing variable and late

decelerations, we refer to previous publications.24,25

We first simulated variable decelerations via contraction-induced umbilical cord

compression (contraction duration 60 s, peak strength 70 mmHg) with a varying

contraction interval (90, 60 or 45 s). For each simulation, the first uterine contraction

was applied during maternal normoxia level (partial oxygen pressure (pO2) of 98

mmHg).16 After the first contraction, we simulated 100% oxygen administration to

the mother via a non-rebreathing mask by a gradual increase to a maternal

pO2steady state of 475 mmHg, as reported by Vasicka et al.16 We repeated this

exact procedure during the simulation of late decelerations via contraction-induced

uterine flow reduction for a placenta with 50% reduction in oxygen diffusion

capacity.

The primary outcome measure is the difference in fetoplacental pO2 before and after

maternal hyperoxygenation in the presence of variable or late decelerations. We

compared pO2 the intervillous space, fetal arteries, umbilical vein and arteries and

the fetal cerebral and microcirculation. Second, we compared the difference in

duration and depth of FHR decelerations during maternal normoxia and hyperoxia,

as a reaction to contractions with a different interval.

As no human or animal subjects were involved in this study, no ethics approval is

required according to the Declaration of Helsinki.

Statistical analysis The simulation model represents one mother and one fetus, with fixed output values

per simulation, hence no statistical analysis can be performed.

Results Figure 2 demonstrates pO2 in different fetoplacental compartments during variable

decelerations caused by uterine contractions with an interval of 90, 60 or 45 s.

During hyperoxygenation, pO2 in all fetoplacental compartments increases. Maternal

hyperoxygenation has a greater effect on fetal pO2 when intervals are longer. When

the contraction interval is 90 s, pO2 increases most in the intervillous space (from 43

to 54 mmHg). The increase is less pronounced in the cerebral circulation, where pO2

increases from 15 to 17 mmHg. When the contraction interval is only 45 s, the

increase in pO2 is less explicit in both the intervillous space and cerebral circulation

(from 43 to 52 mmHg and from 14 to 15 mmHg, respectively).

Chapter 4

86

Figure 2. pO2 in different fetoplacental compartments, during variable decelerations

caused by uterine contractions with a different interval (45–60–90 s). pO2 with and

without 100% oxygen administration is presented.

Figures 3a-c demonstrate the effect of maternal hyperoxygenation during variable

decelerations on pO2 in fetal arteries and FHR. At the end of each uterine

contraction, fetal pO2 quickly increases due to a temporary increase in oxygenated

blood flow toward the fetus as cord compression is discontinued. Maternal

hyperoxygenation leads to a quicker recovery of FHR to baseline level compared

with maternal normoxia, except when the contraction interval is very short (45 s). For

all intervals the drop in FHR is less severe during maternal hyperoxygenation:

deceleration depth decreases from 45 to 20 beats per minute.


87

4

Figure 2. pO2 in different fetoplacental compartments, during variable decelerations

caused by uterine contractions with a different interval (45–60–90 s). pO2 with and

without 100% oxygen administration is presented.

Figures 3a-c demonstrate the effect of maternal hyperoxygenation during variable

decelerations on pO2 in fetal arteries and FHR. At the end of each uterine

contraction, fetal pO2 quickly increases due to a temporary increase in oxygenated

blood flow toward the fetus as cord compression is discontinued. Maternal

hyperoxygenation leads to a quicker recovery of FHR to baseline level compared

with maternal normoxia, except when the contraction interval is very short (45 s). For

all intervals the drop in FHR is less severe during maternal hyperoxygenation:

deceleration depth decreases from 45 to 20 beats per minute.

Chapter 4

88

Figure 3. (a–c) Variable decelerations are simulated as a response to uterine

contractions with a different interval (45, 60 or 90 s, Puterus). After the first

contraction, 100% oxygen is administered to the mother, indicated by the arrow in

the figures. The increase in maternal oxygenation is indicated by pO2,m. Fetal pO2

(pO2,f) and fetal heart rate (FHR) are presented before and after 100% oxygen

administration. Time in minutes.

Figure 4 demonstrates pO2 in different fetoplacental compartments during late

decelerations in relation to uterine contractions occurring with an interval of 90, 60

or 45 s. During hyperoxygenation, as in the presence of variable decelerations, pO2

in all fetoplacental compartments increases. Maternal hyperoxygenation has a

greater effect on fetal pO2 when intervals are longer. When the contraction interval is

90 s, pO2 particularly increases in the intervillous space (45-55 mmHg). The increase

is less pronounced in the cerebral circulation and microcirculation, where pO2

increases from 15 to 17 mmHg. When the contraction interval is only 45 s, in the

intervillous space, cerebral circulation and microcirculation, the profit is less explicit

(from 45 to 52 mmHg in the intervillous space and from 15 to 16 mmHg in both the

cerebral and microcirculation).

Figure 4. pO2 in different fetoplacental compartments, during late decelerations

caused by uterine contractions with a different interval (45, 60, and 90 s). pO2 with

and without 100% oxygen administration is presented.

Figures 5a-c demonstrate the effect of maternal hyperoxygenation during late

decelerations on fetal oxygenation and FHR. There is no difference in time to

recovery to baseline level and no substantial decrease in deceleration depth during

maternal hyperoxia compared with maternal normoxia.


89

4

Figure 3. (a–c) Variable decelerations are simulated as a response to uterine

contractions with a different interval (45, 60 or 90 s, Puterus). After the first

contraction, 100% oxygen is administered to the mother, indicated by the arrow in

the figures. The increase in maternal oxygenation is indicated by pO2,m. Fetal pO2

(pO2,f) and fetal heart rate (FHR) are presented before and after 100% oxygen

administration. Time in minutes.

Figure 4 demonstrates pO2 in different fetoplacental compartments during late

decelerations in relation to uterine contractions occurring with an interval of 90, 60

or 45 s. During hyperoxygenation, as in the presence of variable decelerations, pO2

in all fetoplacental compartments increases. Maternal hyperoxygenation has a

greater effect on fetal pO2 when intervals are longer. When the contraction interval is

90 s, pO2 particularly increases in the intervillous space (45-55 mmHg). The increase

is less pronounced in the cerebral circulation and microcirculation, where pO2

increases from 15 to 17 mmHg. When the contraction interval is only 45 s, in the

intervillous space, cerebral circulation and microcirculation, the profit is less explicit

(from 45 to 52 mmHg in the intervillous space and from 15 to 16 mmHg in both the

cerebral and microcirculation).

Figure 4. pO2 in different fetoplacental compartments, during late decelerations

caused by uterine contractions with a different interval (45, 60, and 90 s). pO2 with

and without 100% oxygen administration is presented.

Figures 5a-c demonstrate the effect of maternal hyperoxygenation during late

decelerations on fetal oxygenation and FHR. There is no difference in time to

recovery to baseline level and no substantial decrease in deceleration depth during

maternal hyperoxia compared with maternal normoxia.

Chapter 4

90

Figure 5. (a–c) Late decelerations are simulated as a response to uterine contractions

with a different interval (45, 60 or 90 s, Puterus). After the first contraction, 100%

oxygen is administered to the mother, indicated by the arrow in the figures. The

increase in maternal oxygenation is indicated by pO2,m. Fetal pO2 (pO2,f) and fetal

heart rate (FHR) are presented before and after 100% oxygen administration. Time

in minutes.

Discussion

The model simulates a decrease in fetal oxygenation and FHR decelerations as a

result of uterine contractions. Simulation of maternal hyperoxygenation with 100%

oxygen shows an increase in pO2 in all fetal and placental compartments, with the

largest increase in the intervillous space and the smallest increase in the cerebral

circulation. The fetus benefits more from oxygen administration to the mother when

contraction intervals are longer. This observation is noticed in the presence of both

variable and late decelerations, and can be explained by the physiological situation

where oxygen transfer towards the placenta and the fetus continues for a longer

period of time, leading to an increase in final pO2. Amelioration of the FHR pattern

only occurs in the presence of variable decelerations.

The beneficial effect of maternal hyperoxygenation on fetal oxygenation and FHR is


91

4

Figure 5. (a–c) Late decelerations are simulated as a response to uterine contractions

with a different interval (45, 60 or 90 s, Puterus). After the first contraction, 100%

oxygen is administered to the mother, indicated by the arrow in the figures. The

increase in maternal oxygenation is indicated by pO2,m. Fetal pO2 (pO2,f) and fetal

heart rate (FHR) are presented before and after 100% oxygen administration. Time

in minutes.

Discussion

The model simulates a decrease in fetal oxygenation and FHR decelerations as a

result of uterine contractions. Simulation of maternal hyperoxygenation with 100%

oxygen shows an increase in pO2 in all fetal and placental compartments, with the

largest increase in the intervillous space and the smallest increase in the cerebral

circulation. The fetus benefits more from oxygen administration to the mother when

contraction intervals are longer. This observation is noticed in the presence of both

variable and late decelerations, and can be explained by the physiological situation

where oxygen transfer towards the placenta and the fetus continues for a longer

period of time, leading to an increase in final pO2. Amelioration of the FHR pattern

only occurs in the presence of variable decelerations.

The beneficial effect of maternal hyperoxygenation on fetal oxygenation and FHR is

Chapter 4

92

less pronounced during late decelerations. Late decelerations are often a sign of

impaired placental function and severe fetal distress. Due to an impaired oxygen

diffusion capacity of the placental membrane, the effect of maternal

hyperoxygenation is less distinct than in variable decelerations where placental

function is normal. It is possible that the level of increase of fetal pO2 during late

deceleration does not reach the threshold to considerably improve FHR.

A small number of clinical trials investigating the effect of maternal

hyperoxygenation on fetal oxygenation and FHR have been published. However,

only a few of these studies are performed in the compromised fetus. In accordance

with our findings, Althabe et al. demonstrated that 100% oxygen administration to

the mother of a fetus with a nonreassuring FHR pattern has a beneficial effect: both

FHR pattern and pO2 in the peripheral circulation (fetal buttock) improve after 1

minute of oxygen administration.13 In addition, Haydon et al. showed an increase in

fetal oxygen saturation using 40 and 100% maternal inspired oxygen in the case of

nonreassuring FHR patterns in 24 pregnant women.17 The increase in pO2 did not

result in consistent changes in FHR patterns, but the authors recommended to

further investigate these changes using a study with a larger study group. Hidaka et

al. investigated the recovery from type II dips by oxygen inhalation.14 Type II dips

are nowadays described as late decelerations.2 During the first stage of labor,

maternal hyperoxygenation successfully recovered FHR in 30% of the cases, even

though the fraction of inspired oxygen supplied remains unclear.

Sørensen et al. performed blood oxygen level dependent magnetic resonance

imaging (BOLD MRI) in pregnant sheep under hypoxic, normoxic and hyperoxic

conditions.26 An increase in BOLD MRI signal was assigned to an increase in fetal

tissue pO2 (liver, spleen and kidney). This study does not focus on the effect of fetal

pO2 on FHR. During maternal hyperoxygenation the BOLD MRI signal in fetal organs

increases, suggesting an increase in tissue pO2. Interestingly, the increase in BOLD

MRI signal in the fetal brain did not change under normoxic, hypoxic or hyperoxic

conditions. This finding is ascribed to the brain-sparing mechanism of the fetus.

Based on our study results, as produced by the simulation model, it could be useful

to apply maternal hyperoxygenation during labor in the presence of variable

decelerations. In case of late decelerations, a positive effect on fetal oxygenation is

demonstrated, but not as much as in variable decelerations. However, no effect on

FHR decelerations is shown. It is possible that the level of increase in fetal pO2 does

not reach the threshold to considerably improve FHR.

The effect of maternal hyperoxygenation in the presence of late FHR deceleration

should be further investigated.

Careful considerations should be made with the translation of model results to

clinical practice, since a simulation model is by definition a simplified representation

of the complex fetomaternal physiology. Nevertheless, modeling results may be

indicative for clinical fetal outcome and may give direction to hypothesis testing in

clinical practice.

Our model can provide estimation of physiological parameters that cannot yet be

measured in clinical practice, such as fetal oxygenation or blood pressure, thereby

enhancing insight into the physiological processes. This means that the model could

be helpful in the formulation of hypotheses and subsequently in the design of

clinical studies to evaluate the effect of resuscitation techniques.

Both patients and clinicians may benefit from the use of simulation models. The

effect of clinical interventions during labor can be safely tested in a model, before

women are exposed to therapeutic interventions. For example, the effect of

administration of oxygen, fluids or medication can be investigated without risks for

the mother or fetus.

When the simulation model indicates an adverse effect on fetal condition, this

finding could be taken into account in the design of a clinical experiment, thereby

improving women’s safety. Moreover, simulations can be run over and over again,

without exposing women to invasive procedures. Ultimately, the model has potential

to be used as a clinical support tool in future, following a thorough sensitivity

analysis. In its current status the model can be used for educational purposes such

as simulation training.

From the study described above, we conclude that this simulation model indicates a

beneficial effect of maternal hyperoxygenation on fetal oxygenation and FHR

pattern in the presence of variable and -to a lesser extent- late FHR decelerations.

We now plan a clinical trial comparing model data with clinical outcome.


93

4

less pronounced during late decelerations. Late decelerations are often a sign of

impaired placental function and severe fetal distress. Due to an impaired oxygen

diffusion capacity of the placental membrane, the effect of maternal

hyperoxygenation is less distinct than in variable decelerations where placental

function is normal. It is possible that the level of increase of fetal pO2 during late

deceleration does not reach the threshold to considerably improve FHR.

A small number of clinical trials investigating the effect of maternal

hyperoxygenation on fetal oxygenation and FHR have been published. However,

only a few of these studies are performed in the compromised fetus. In accordance

with our findings, Althabe et al. demonstrated that 100% oxygen administration to

the mother of a fetus with a nonreassuring FHR pattern has a beneficial effect: both

FHR pattern and pO2 in the peripheral circulation (fetal buttock) improve after 1

minute of oxygen administration.13 In addition, Haydon et al. showed an increase in

fetal oxygen saturation using 40 and 100% maternal inspired oxygen in the case of

nonreassuring FHR patterns in 24 pregnant women.17 The increase in pO2 did not

result in consistent changes in FHR patterns, but the authors recommended to

further investigate these changes using a study with a larger study group. Hidaka et

al. investigated the recovery from type II dips by oxygen inhalation.14 Type II dips

are nowadays described as late decelerations.2 During the first stage of labor,

maternal hyperoxygenation successfully recovered FHR in 30% of the cases, even

though the fraction of inspired oxygen supplied remains unclear.

Sørensen et al. performed blood oxygen level dependent magnetic resonance

imaging (BOLD MRI) in pregnant sheep under hypoxic, normoxic and hyperoxic

conditions.26 An increase in BOLD MRI signal was assigned to an increase in fetal

tissue pO2 (liver, spleen and kidney). This study does not focus on the effect of fetal

pO2 on FHR. During maternal hyperoxygenation the BOLD MRI signal in fetal organs

increases, suggesting an increase in tissue pO2. Interestingly, the increase in BOLD

MRI signal in the fetal brain did not change under normoxic, hypoxic or hyperoxic

conditions. This finding is ascribed to the brain-sparing mechanism of the fetus.

Based on our study results, as produced by the simulation model, it could be useful

to apply maternal hyperoxygenation during labor in the presence of variable

decelerations. In case of late decelerations, a positive effect on fetal oxygenation is

demonstrated, but not as much as in variable decelerations. However, no effect on

FHR decelerations is shown. It is possible that the level of increase in fetal pO2 does

not reach the threshold to considerably improve FHR.

The effect of maternal hyperoxygenation in the presence of late FHR deceleration

should be further investigated.

Careful considerations should be made with the translation of model results to

clinical practice, since a simulation model is by definition a simplified representation

of the complex fetomaternal physiology. Nevertheless, modeling results may be

indicative for clinical fetal outcome and may give direction to hypothesis testing in

clinical practice.

Our model can provide estimation of physiological parameters that cannot yet be

measured in clinical practice, such as fetal oxygenation or blood pressure, thereby

enhancing insight into the physiological processes. This means that the model could

be helpful in the formulation of hypotheses and subsequently in the design of

clinical studies to evaluate the effect of resuscitation techniques.

Both patients and clinicians may benefit from the use of simulation models. The

effect of clinical interventions during labor can be safely tested in a model, before

women are exposed to therapeutic interventions. For example, the effect of

administration of oxygen, fluids or medication can be investigated without risks for

the mother or fetus.

When the simulation model indicates an adverse effect on fetal condition, this

finding could be taken into account in the design of a clinical experiment, thereby

improving women’s safety. Moreover, simulations can be run over and over again,

without exposing women to invasive procedures. Ultimately, the model has potential

to be used as a clinical support tool in future, following a thorough sensitivity

analysis. In its current status the model can be used for educational purposes such

as simulation training.

From the study described above, we conclude that this simulation model indicates a

beneficial effect of maternal hyperoxygenation on fetal oxygenation and FHR

pattern in the presence of variable and -to a lesser extent- late FHR decelerations.

We now plan a clinical trial comparing model data with clinical outcome.

Chapter 4

94

References 1. Caldeyro-Barcia R, Mendez-Bauer C, Poseiro JJ, Escarena LA, Pose SV, Bieniarz J, et al.

The heart and circulation in the newborn and infant, chapter control of the human fetal heart rate during labor. New York: Grune & Stratton, 1966. pp. 7-36.

2. Murray M. Antepartal and intrapartal fetal monitoring, 3rd ed. New York: Springer Publishing Company, 2007. pp. 106-239.

3. Westgate JA, Wibbens B, Bennet L, Wassink G, Parer JT, Gunn AJ. The intrapartum deceleration in center stage: a physiologic approach to the interpretation of fetal heart rate changes in labor. Am J Obstet Gynecol. 2007;197:236.e1-11.

4. Ball RH, Parer JT. The physiologic mechanisms of variable decelerations. Am J Obstet Gynecol. 1992;166(6 Pt 1):1683-9.

5. Bennet L, Gunn AJ. The fetal heart rate response to hypoxia: insights from animal models. Clin Perinatol. 2009;36:655-72.

6. Elliott C, Warrick PA, Graham E, Hamilton EF. Graded classification of fetal heart rate tracings: association with neonatal metabolic acidocis and neurologic morbidity. Am J Obstet Gynecol. 2010;202:258.e1-e8.

7. Mendez-Bauer C, Arnt IC, Gulin L, Escarcena L, Caldeyro-Barcia R. Relationship between blood pH and heart rate in the human fetus during labor. Am J Obstet Gynecol. 1967;97:530-45.


9. Graham EM, Ruis KA, Hartman AL, Northington FJ, Fox HE. A systematic review of the role of intrapartum hypoxia-ischemia in the causation of neonatal encephalopathy. Am J Obstet Gynecol. 2008;199:587-95.


11. Hofmeyr GJ, Lawrie TA. Amnioinfusion for potential or suspected umbilical cord compression in labor. Cochrane Database Syst Rev. 2012;1:CD000013.




15. Thorp JA, Trobough T, Evans R, Hedrick J, Yeast JD. The effect of maternal oxygen administration during the second stage of labor on umbilical cord blood gas values: a randomised controlled trial. Am J Obstet Gynecol. 1995;172:465-74.


17. Haydon ML, Gorenberg DM, Nageotte MP, Ghamsary M, Rumney PJ, Patillo C, et al. The effect of maternal oxygen administration on fetal pulse oximetry during labor in fetuses with nonreassuring fetal heart rate patterns. Am J Obstet Gynecol.

2006;195:735-8. 18. Gare DJ, Shime J, Paul WM, Hoskins M. Oxygen administration during labor. Am J

Obstet Gynecol. 1969;105:954-61. 19. Prystowsky H. Fetal blood studies. XI. The Effect of prophylactic oxygen on the oxygen

pressure gradient between the maternal and fetal bloods of the human in normal and abnormal pregnancy. Am J Obstet Gynecol. 1959;78:483-8.


21. Bartnicki J, Saling E. The influence of maternal oxygen administration on the fetus. Int J Gynaecol Obstet. 1994;45:87-95.

22. Dildy GA, Clark SL, Loucks CA. Intrapartum fetal pulse oximetry: the effects of maternal hyperoxia on fetal arteriolar oxygen saturation. Am J Obstet Gynecol. 1994;171:1120-4.

23. Van der Hout-van der Jagt MB, Oei SG, Bovendeerd PH. A mathematical model for simulation of early decelerations in the cardiotocogram during labor. Med Eng Phys. 2012;34:579-89.



26. Sørensen A, Pedersen M, Tietze A, Ottosen L, Duus L, Uldbjerg N. BOLD MRI in sheep fetuses: a non-invasive method for measuring changes in tissue oxygenation. Ultrasound Obstet Gynecol. 2009;34:687-92.


95

4

References 1. Caldeyro-Barcia R, Mendez-Bauer C, Poseiro JJ, Escarena LA, Pose SV, Bieniarz J, et al.

The heart and circulation in the newborn and infant, chapter control of the human fetal heart rate during labor. New York: Grune & Stratton, 1966. pp. 7-36.

2. Murray M. Antepartal and intrapartal fetal monitoring, 3rd ed. New York: Springer Publishing Company, 2007. pp. 106-239.

3. Westgate JA, Wibbens B, Bennet L, Wassink G, Parer JT, Gunn AJ. The intrapartum deceleration in center stage: a physiologic approach to the interpretation of fetal heart rate changes in labor. Am J Obstet Gynecol. 2007;197:236.e1-11.

4. Ball RH, Parer JT. The physiologic mechanisms of variable decelerations. Am J Obstet Gynecol. 1992;166(6 Pt 1):1683-9.


6. Elliott C, Warrick PA, Graham E, Hamilton EF. Graded classification of fetal heart rate tracings: association with neonatal metabolic acidocis and neurologic morbidity. Am J Obstet Gynecol. 2010;202:258.e1-e8.



9. Graham EM, Ruis KA, Hartman AL, Northington FJ, Fox HE. A systematic review of the role of intrapartum hypoxia-ischemia in the causation of neonatal encephalopathy. Am J Obstet Gynecol. 2008;199:587-95.






15. Thorp JA, Trobough T, Evans R, Hedrick J, Yeast JD. The effect of maternal oxygen administration during the second stage of labor on umbilical cord blood gas values: a randomised controlled trial. Am J Obstet Gynecol. 1995;172:465-74.


17. Haydon ML, Gorenberg DM, Nageotte MP, Ghamsary M, Rumney PJ, Patillo C, et al. The effect of maternal oxygen administration on fetal pulse oximetry during labor in fetuses with nonreassuring fetal heart rate patterns. Am J Obstet Gynecol.

2006;195:735-8. 18. Gare DJ, Shime J, Paul WM, Hoskins M. Oxygen administration during labor. Am J

Obstet Gynecol. 1969;105:954-61. 19. Prystowsky H. Fetal blood studies. XI. The Effect of prophylactic oxygen on the oxygen

pressure gradient between the maternal and fetal bloods of the human in normal and abnormal pregnancy. Am J Obstet Gynecol. 1959;78:483-8.


21. Bartnicki J, Saling E. The influence of maternal oxygen administration on the fetus. Int J Gynaecol Obstet. 1994;45:87-95.

22. Dildy GA, Clark SL, Loucks CA. Intrapartum fetal pulse oximetry: the effects of maternal hyperoxia on fetal arteriolar oxygen saturation. Am J Obstet Gynecol. 1994;171:1120-4.

23. Van der Hout-van der Jagt MB, Oei SG, Bovendeerd PH. A mathematical model for simulation of early decelerations in the cardiotocogram during labor. Med Eng Phys. 2012;34:579-89.



26. Sørensen A, Pedersen M, Tietze A, Ottosen L, Duus L, Uldbjerg N. BOLD MRI in sheep fetuses: a non-invasive method for measuring changes in tissue oxygenation. Ultrasound Obstet Gynecol. 2009;34:687-92.

Chapter 5

Intrauterine resuscitation during term labor by maternal

hyperoxygenation: a randomized controlled trial

(study protocol INTEREST O2)

Bullens LM, Hulsenboom ODJ, Moors S, Joshi R, van Runnard Heimel PJ,

van der Hout-van der Jagt MB, van den Heuvel ER, Oei SG

Trials. 2018;19:195

Chapter 5

98

Abstract

Background

Perinatal asphyxia is, even in developed countries, one the major causes of neonatal

morbidity and mortality. Therefore, if fetal distress during labor is suspected, one

should try to restore fetal oxygen levels, or aim for immediate delivery. However,

studies on the effect of intrauterine resuscitation during labor are scarce. We

designed a randomized controlled trial to investigate the effect of maternal

hyperoxygenation on the fetal condition. In this study, maternal hyperoxygenation is

induced for the treatment of fetal distress during the second stage of term labor.

Methods

This study is a single-center randomized controlled trial, performed in a tertiary

hospital in The Netherlands. In case of a suboptimal or abnormal fetal heart rate

pattern during the second stage of term labor, a total of 116 patients will be

randomized to the control group, where normal care is provided, or to the

intervention group, where before normal care 100% oxygen is supplied to the

mother by a non-rebreathing mask until delivery. The primary outcome is change in

fetal heart rate pattern. Secondary outcomes are Apgar score, mode of delivery,

admission to the neonatal intensive care unit and maternal side effects. In addition,

blood gas values and malondialdehyde are determined in umbilical cord blood.

Discussion

This study will be the first randomized controlled trial to investigate the effect of

maternal hyperoxygenation for fetal distress during labor. This intervention should

only be recommended as a treatment for intrapartum fetal distress, when

improvement of the fetal condition is likely and outweighs maternal and neonatal

side effects.

Background

Labor contractions cause alterations in intrauterine pressure, and can thereby affect

uterine and umbilical blood flow.1-5 These fluctuations in blood flow towards the

fetus can negatively influence oxygen flow and blood pressure.1-5 Through chemo-

and baroreceptor responses, these changes in fetal oxygenation and blood pressure

affect fetal heart rate (FHR).1,2,6,7 Hence, nonreassuring FHR patterns, for example,

FHR decelerations, may be a sign of fetal hypoxia.8-10 Prolonged fetal hypoxia may

lead to an increased risk of fetal morbidity, including renal insufficiency, pulmonary

hypertension, necrotising enterocolitis and hypoxic–ischemic encephalopathy and

fetal death.11-12 A prospective cohort study of term neonates in 2010 showed that

48% of admissions to Neonatal Intensive Care Units (NICUs) of these neonates were

related to perinatal asphyxia (defined by the authors as a 5-minute Apgar score <7).

The neonatal mortality rate was 8% in this study, the largest proportion of which

(71%, n=12/17) was related to asphyxia.13

Methods to directly measure fetal oxygenation during labor are unavailable, while

methods for the continuous intrapartum monitoring of pH, saturation (SpO2), partial

carbon dioxide pressure (pCO2), and partial oxygen pressure (pO2) are not yet

suitable for clinical practice.14-16 Therefore, the cardiotocogram (CTG), with

occasional fetal scalp blood sampling (FSBS), is still the method of first choice to

estimate fetal wellbeing during labor. The CTG has very good specificity but poor

sensitivity for fetal wellbeing.17 In other words, if the FHR pattern is reassuring the

fetus is very likely to be well-oxygenated. However, when FHR patterns are

nonreassuring, the fetal condition is unclear and fetal distress cannot be ruled out.

Instead of aiming for immediate delivery in the presence of suspected fetal distress,

one may try to improve fetal oxygenation to avoid an invasive intervention. Several

intrauterine resuscitation techniques are used in clinical practice and described in

the literature.18,19 However, robust evidence regarding their effect on neonatal

outcome is limited.18 One of the interventions that still raises discussion is the

administration of additional oxygen to the mother to treat fetal distress during

labor.18,20-23

Maternal hyperoxygenation: an RCT (study protocol INTEREST 02 study)

99

5

Abstract

Background

Perinatal asphyxia is, even in developed countries, one the major causes of neonatal

morbidity and mortality. Therefore, if fetal distress during labor is suspected, one

should try to restore fetal oxygen levels, or aim for immediate delivery. However,

studies on the effect of intrauterine resuscitation during labor are scarce. We

designed a randomized controlled trial to investigate the effect of maternal

hyperoxygenation on the fetal condition. In this study, maternal hyperoxygenation is

induced for the treatment of fetal distress during the second stage of term labor.

Methods

This study is a single-center randomized controlled trial, performed in a tertiary

hospital in The Netherlands. In case of a suboptimal or abnormal fetal heart rate

pattern during the second stage of term labor, a total of 116 patients will be

randomized to the control group, where normal care is provided, or to the

intervention group, where before normal care 100% oxygen is supplied to the

mother by a non-rebreathing mask until delivery. The primary outcome is change in

fetal heart rate pattern. Secondary outcomes are Apgar score, mode of delivery,

admission to the neonatal intensive care unit and maternal side effects. In addition,

blood gas values and malondialdehyde are determined in umbilical cord blood.

Discussion

This study will be the first randomized controlled trial to investigate the effect of

maternal hyperoxygenation for fetal distress during labor. This intervention should

only be recommended as a treatment for intrapartum fetal distress, when

improvement of the fetal condition is likely and outweighs maternal and neonatal

side effects.

Background

Labor contractions cause alterations in intrauterine pressure, and can thereby affect

uterine and umbilical blood flow.1-5 These fluctuations in blood flow towards the

fetus can negatively influence oxygen flow and blood pressure.1-5 Through chemo-

and baroreceptor responses, these changes in fetal oxygenation and blood pressure

affect fetal heart rate (FHR).1,2,6,7 Hence, nonreassuring FHR patterns, for example,

FHR decelerations, may be a sign of fetal hypoxia.8-10 Prolonged fetal hypoxia may

lead to an increased risk of fetal morbidity, including renal insufficiency, pulmonary

hypertension, necrotising enterocolitis and hypoxic–ischemic encephalopathy and

fetal death.11-12 A prospective cohort study of term neonates in 2010 showed that

48% of admissions to Neonatal Intensive Care Units (NICUs) of these neonates were

related to perinatal asphyxia (defined by the authors as a 5-minute Apgar score <7).

The neonatal mortality rate was 8% in this study, the largest proportion of which

(71%, n=12/17) was related to asphyxia.13

Methods to directly measure fetal oxygenation during labor are unavailable, while

methods for the continuous intrapartum monitoring of pH, saturation (SpO2), partial

carbon dioxide pressure (pCO2), and partial oxygen pressure (pO2) are not yet

suitable for clinical practice.14-16 Therefore, the cardiotocogram (CTG), with

occasional fetal scalp blood sampling (FSBS), is still the method of first choice to

estimate fetal wellbeing during labor. The CTG has very good specificity but poor

sensitivity for fetal wellbeing.17 In other words, if the FHR pattern is reassuring the

fetus is very likely to be well-oxygenated. However, when FHR patterns are

nonreassuring, the fetal condition is unclear and fetal distress cannot be ruled out.

Instead of aiming for immediate delivery in the presence of suspected fetal distress,

one may try to improve fetal oxygenation to avoid an invasive intervention. Several

intrauterine resuscitation techniques are used in clinical practice and described in

the literature.18,19 However, robust evidence regarding their effect on neonatal

outcome is limited.18 One of the interventions that still raises discussion is the

administration of additional oxygen to the mother to treat fetal distress during

labor.18,20-23

Chapter 5

100

Summary of findings from clinical studies

In the past decades, several studies have investigated the effect of maternal

hyperoxygenation on maternal and fetal oxygenation. Indeed they found increasing

maternal pO2 and fetal SpO2 and pO2 levels,24 but unfortunately these studies are

mainly performed in the non-compromised fetus.25-27 Furthermore, only a few non-

randomized studies of poor quality have been performed in the distressed fetus.28-32

These studies suggest an improvement in FHR patterns and fetal scalp pH when

100% oxygen is applied to the mother. Based on these publications, a Cochrane

review from 2012 concludes that “there is not enough evidence to support the use

of prophylactic oxygen therapy for women in labor, nor to evaluate its effectiveness

for fetal distress”, due to the lack of randomized controlled trials (RCTs).33

An important concern in the use of maternal hyperoxygenation for fetal distress is

the potential negative effect on umbilical cord pH. In a study by Thorp et al, 86 term

parturients were randomized to receive additional oxygen or normal care, during the

second stage of labor.34 The main outcome measures were cord blood gas and co-

oximetry values. The mean cord blood gas values did not significantly differ

between the intervention and control group. However, they found significantly more

arterial pH values <7.20 in the group receiving extra oxygen. The lowest arterial pH

(pHa) value that was found was 7.09. They also found that the duration of oxygen

therapy was inversely related to arterial cord pH, while Apgar scores and hospital

admission rates did not differ between the groups. The authors concluded that

prolonged oxygen treatment during the second stage of labor leads to a

deterioration of cord blood gas values at birth. An important remark is the fact that

in this study only patients with reassuring FHR patterns were included. Therefore,

(ominous) fetal hypoxia at the start of oxygen delivery was very unlikely. Thus, this

study did not address the effect of maternal hyperoxygenation in case of suspected

fetal distress.

Another frequently stated argument to discourage maternal hyperoxygenation as

standard care, is the potential increase in free oxygen radicals in both mother and

fetus.35,36 An increase in the markers for free oxygen radical production has been

seen for the use of high fractions of inspired oxygen and in the presence of

nonreassuring FHR patterns.35-38 Also, lipid peroxide concentrations in arterial cord

blood are higher after uncomplicated vaginal delivery compared with those after

elective cesarean section.39 To a certain degree, free oxygen radicals are

physiological and known to be higher in the presence of several maternal and fetal

conditions, such as preeclampsia, diabetes, smoking, intrauterine growth restriction

and fetal distress.37,39-42 The effect of maternal hyperoxygenation on free oxygen

radical release, in response to nonreassuring fetal status, has not yet been

investigated. What we do know is that neonatal resuscitation with 100% oxygen may

lead to an increase in neonatal mortality and morbidity, including

bronchopulmonary disease and retinopathy, mainly in premature infants.43-46

However, the increase in fetal pO2 due to maternal hyperoxygenation will never

reach the levels obtained by the direct application of 100% oxygen directly to the

fetus.23 To our knowledge, the clinical implication of increased free radical

production due to maternal hyperoxygenation has not been investigated. Studies

that use maternal hyperoxygenation as a treatment for the growth restricted fetus

did not report any harmful effects.47,48

With regard to the mother, some potential side effects have to be taken into

account. The use of high fractions of inspired oxygen in the absence of tissue

hypoxia may cause toxic effects as a result of oxidative stress.49,50 This may for

example lead to mucosal inflammation, hypoperfusion and pneumonitis.51 A

reversible vasoconstriction of approximately 10% in the maternal brain has been

described.52 However, this is not expected to cause any harm.53,54 Administration of

100% oxygen during labor is not investigated. However, it is well investigated for

the treatment of cluster headaches, and no severe side effects (e.g. hypoventilation

and fainting) were reported.54

Inhaling high fractions of inspired oxygen will increase the concentration of free

oxygen radicals in maternal blood.35 Despite the adverse effects of free oxygen

radicals that have been described,55 it is unlikely these will cause clinically relevant

tissue damage due to the mature anti-oxidant system in the adult.35,36 Also, the

Dutch pharmacovigilance center Lareb has not been informed of any side effects

due to oxygen therapy.56

Current recommendations on the use of maternal hyperoxygenation

Based on current knowledge, it is difficult to determine whether the beneficial

effects outweigh the potential side effects. As a consequence, recommendations in

international guidelines and use in clinical practice are non-uniform.20 Maternal

hyperoxygenation during labor is often used in the United States of America to


101

5

Summary of findings from clinical studies

In the past decades, several studies have investigated the effect of maternal

hyperoxygenation on maternal and fetal oxygenation. Indeed they found increasing

maternal pO2 and fetal SpO2 and pO2 levels,24 but unfortunately these studies are

mainly performed in the non-compromised fetus.25-27 Furthermore, only a few non-

randomized studies of poor quality have been performed in the distressed fetus.28-32

These studies suggest an improvement in FHR patterns and fetal scalp pH when

100% oxygen is applied to the mother. Based on these publications, a Cochrane

review from 2012 concludes that “there is not enough evidence to support the use

of prophylactic oxygen therapy for women in labor, nor to evaluate its effectiveness

for fetal distress”, due to the lack of randomized controlled trials (RCTs).33

An important concern in the use of maternal hyperoxygenation for fetal distress is

the potential negative effect on umbilical cord pH. In a study by Thorp et al, 86 term

parturients were randomized to receive additional oxygen or normal care, during the

second stage of labor.34 The main outcome measures were cord blood gas and co-

oximetry values. The mean cord blood gas values did not significantly differ

between the intervention and control group. However, they found significantly more

arterial pH values <7.20 in the group receiving extra oxygen. The lowest arterial pH

(pHa) value that was found was 7.09. They also found that the duration of oxygen

therapy was inversely related to arterial cord pH, while Apgar scores and hospital

admission rates did not differ between the groups. The authors concluded that

prolonged oxygen treatment during the second stage of labor leads to a

deterioration of cord blood gas values at birth. An important remark is the fact that

in this study only patients with reassuring FHR patterns were included. Therefore,

(ominous) fetal hypoxia at the start of oxygen delivery was very unlikely. Thus, this

study did not address the effect of maternal hyperoxygenation in case of suspected

fetal distress.

Another frequently stated argument to discourage maternal hyperoxygenation as

standard care, is the potential increase in free oxygen radicals in both mother and

fetus.35,36 An increase in the markers for free oxygen radical production has been

seen for the use of high fractions of inspired oxygen and in the presence of

nonreassuring FHR patterns.35-38 Also, lipid peroxide concentrations in arterial cord

blood are higher after uncomplicated vaginal delivery compared with those after

elective cesarean section.39 To a certain degree, free oxygen radicals are

physiological and known to be higher in the presence of several maternal and fetal

conditions, such as preeclampsia, diabetes, smoking, intrauterine growth restriction

and fetal distress.37,39-42 The effect of maternal hyperoxygenation on free oxygen

radical release, in response to nonreassuring fetal status, has not yet been

investigated. What we do know is that neonatal resuscitation with 100% oxygen may

lead to an increase in neonatal mortality and morbidity, including

bronchopulmonary disease and retinopathy, mainly in premature infants.43-46

However, the increase in fetal pO2 due to maternal hyperoxygenation will never

reach the levels obtained by the direct application of 100% oxygen directly to the

fetus.23 To our knowledge, the clinical implication of increased free radical

production due to maternal hyperoxygenation has not been investigated. Studies

that use maternal hyperoxygenation as a treatment for the growth restricted fetus

did not report any harmful effects.47,48

With regard to the mother, some potential side effects have to be taken into

account. The use of high fractions of inspired oxygen in the absence of tissue

hypoxia may cause toxic effects as a result of oxidative stress.49,50 This may for

example lead to mucosal inflammation, hypoperfusion and pneumonitis.51 A

reversible vasoconstriction of approximately 10% in the maternal brain has been

described.52 However, this is not expected to cause any harm.53,54 Administration of

100% oxygen during labor is not investigated. However, it is well investigated for

the treatment of cluster headaches, and no severe side effects (e.g. hypoventilation

and fainting) were reported.54

Inhaling high fractions of inspired oxygen will increase the concentration of free

oxygen radicals in maternal blood.35 Despite the adverse effects of free oxygen

radicals that have been described,55 it is unlikely these will cause clinically relevant

tissue damage due to the mature anti-oxidant system in the adult.35,36 Also, the

Dutch pharmacovigilance center Lareb has not been informed of any side effects

due to oxygen therapy.56

Current recommendations on the use of maternal hyperoxygenation

Based on current knowledge, it is difficult to determine whether the beneficial

effects outweigh the potential side effects. As a consequence, recommendations in

international guidelines and use in clinical practice are non-uniform.20 Maternal

hyperoxygenation during labor is often used in the United States of America to

Chapter 5

102

increase oxygen transport towards the fetus.21 The American College of

Obstetricians and Gynecologists’ (ACOG) guideline on fetal resuscitation

recommends the administration of oxygen to the mother in case of fetal distress.57 In

contrast, the Royal College of Obstetricians and Gynaecologists explicitly states in

their Green Top Guideline to not apply maternal oxygenation for reasons other than

maternal hypoxia, until the beneficial effect is proven.58 A recent discussion on

benefit and harm of maternal hyperoxygenation in the American Journal of

Obstetrics and Gynecology (AJOG) emphasises the current lack of evidence.21,23 In

fact, several reviews underline an urgent need for an RCT, investigating the effect of

maternal hyperoxygenation on the fetal condition.21-23,33

Methods

Aim

The aim of this study is to investigate the effect of maternal hyperoxygenation with

100% oxygen on the fetal condition during the second stage of labor, in the

presence of suspected fetal distress during term labor. Also, we investigate the

potential side effects, to formulate recommendations for international clinical

practice and future research.

Study design

This study will be a single-center RCT, performed in a tertiary hospital in The

Netherlands, comparing maternal hyperoxygenation for the treatment of fetal

distress during the second stage of labor with conventional care. All procedures and

timeframes are displayed in figure 1 (according to the Standard Protocol Items:

Recommendations for Interventional Trials (SPIRIT)).59 Additional file 2 contains the

complete SPIRIT checklist.

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103

5

increase oxygen transport towards the fetus.21 The American College of

Obstetricians and Gynecologists’ (ACOG) guideline on fetal resuscitation

recommends the administration of oxygen to the mother in case of fetal distress.57 In

contrast, the Royal College of Obstetricians and Gynaecologists explicitly states in

their Green Top Guideline to not apply maternal oxygenation for reasons other than

maternal hypoxia, until the beneficial effect is proven.58 A recent discussion on

benefit and harm of maternal hyperoxygenation in the American Journal of

Obstetrics and Gynecology (AJOG) emphasises the current lack of evidence.21,23 In

fact, several reviews underline an urgent need for an RCT, investigating the effect of

maternal hyperoxygenation on the fetal condition.21-23,33

Methods

Aim

The aim of this study is to investigate the effect of maternal hyperoxygenation with

100% oxygen on the fetal condition during the second stage of labor, in the

presence of suspected fetal distress during term labor. Also, we investigate the

potential side effects, to formulate recommendations for international clinical

practice and future research.

Study design

This study will be a single-center RCT, performed in a tertiary hospital in The

Netherlands, comparing maternal hyperoxygenation for the treatment of fetal

distress during the second stage of labor with conventional care. All procedures and

timeframes are displayed in figure 1 (according to the Standard Protocol Items:

Recommendations for Interventional Trials (SPIRIT)).59 Additional file 2 contains the

complete SPIRIT checklist.

Act

ivity

/

a sse

ssm

ent

CR

F$

( Y/N

)

Staf

f mem

ber

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me

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Chapter 5

104

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Participants

The study population will be drawn from parturients, admitted to the labor ward of a

tertiary hospital (Máxima Medical Center, Veldhoven, The Netherlands), where

approximately 2,200 deliveries occur annually, of which approximately 1,900 term

births. CTG and, if necessary, FSBS are generally used for fetal monitoring during

labor. Maternal repositioning, discontinuation of administration of oxytocin, use of

tocolytic drugs and intermittent pushing are common interventions to achieve

intrauterine resuscitation, while amnioinfusion and maternal hyperoxygenation are

never applied as standard care in our center.

Inclusion criteria

Pregnant women ≥ 18 years, in term labor, and with an intended vaginal delivery of

a singleton in cephalic presentation can participate in this study.

Exclusion criteria

Exclusion criteria are determined with focus on the risk of excessive production of

free oxygen radicals, and reducing the influence of other factors affecting FHR

pattern. These are a recent use of any of the following medication: corticosteroids,

antihypertensives, magnesium sulphate, amiodaron, opioids, adriamycin, bleomycin,

actinomycin, menadione, promazine, thioridazine or chloroquine, or the use of

tobacco, recreational drugs or alcohol during pregnancy. Parturients suffering from

pre-existing cardiac disease, pulmonary disease with the use of medication,

diabetes, hyperthyroidism or anemia (hemoglobin < 6.5 mmol/l or 10.5 g/dL) will

also be excluded. Fetal factors leading to exclusion are: suspected infection during

labor (need for antibiotics), congenital malformations and normal or preterminal FHR

pattern, or prolonged bradycardia (according to the modified FIGO classification

(figure 2).60,61

Patient recruitment and randomization

All patients eligible to be included in this study will antepartum be asked to

participate when they visit the outpatient’s clinic, or when they are admitted to the

delivery ward. All patients will receive oral and written information about the study

from the attending midwife, doctor or a co-investigator. After informed consent, and


105

5

Participants

The study population will be drawn from parturients, admitted to the labor ward of a

tertiary hospital (Máxima Medical Center, Veldhoven, The Netherlands), where

approximately 2,200 deliveries occur annually, of which approximately 1,900 term

births. CTG and, if necessary, FSBS are generally used for fetal monitoring during

labor. Maternal repositioning, discontinuation of administration of oxytocin, use of

tocolytic drugs and intermittent pushing are common interventions to achieve

intrauterine resuscitation, while amnioinfusion and maternal hyperoxygenation are

never applied as standard care in our center.

Inclusion criteria

Pregnant women ≥ 18 years, in term labor, and with an intended vaginal delivery of

a singleton in cephalic presentation can participate in this study.

Exclusion criteria

Exclusion criteria are determined with focus on the risk of excessive production of

free oxygen radicals, and reducing the influence of other factors affecting FHR

pattern. These are a recent use of any of the following medication: corticosteroids,

antihypertensives, magnesium sulphate, amiodaron, opioids, adriamycin, bleomycin,

actinomycin, menadione, promazine, thioridazine or chloroquine, or the use of

tobacco, recreational drugs or alcohol during pregnancy. Parturients suffering from

pre-existing cardiac disease, pulmonary disease with the use of medication,

diabetes, hyperthyroidism or anemia (hemoglobin < 6.5 mmol/l or 10.5 g/dL) will

also be excluded. Fetal factors leading to exclusion are: suspected infection during

labor (need for antibiotics), congenital malformations and normal or preterminal FHR

pattern, or prolonged bradycardia (according to the modified FIGO classification

(figure 2).60,61

Patient recruitment and randomization

All patients eligible to be included in this study will antepartum be asked to

participate when they visit the outpatient’s clinic, or when they are admitted to the

delivery ward. All patients will receive oral and written information about the study

from the attending midwife, doctor or a co-investigator. After informed consent, and

Chapter 5

106

only in case of suboptimal or abnormal FHR patterns during the second stage of

labor, randomization is performed using sealed, opaque envelops. The allocation

sequence is computer-generated using random blocks of four or six patients.

CTG

classification

Baseline heart frequency Variability

Reactivity

Decelerations

Normal • 110-150 bpm • Accelerations

• 5-25 bpm

• Early uniform

decelerations

• Uncomplicated

variable decelerations

(loss of <60 beats)

Intermediary • 100-110 bpm

• 150-170 bpm

• Short bradycardia

episode

<100 bpm for >3 min

<80 bpm for >2 min

• >25 bpm (saltatory

pattern)

• <5 bpm >40 min

• Uncomplicated


(loss of >60 beats)

• A combination of 2 or several intermediary observations will result in an

abnormal CTG

Abnormal • >170 bpm

• Persistent bradycardia

<100 bpm for >10 min

<80 bpm for >3 min

(without an increasing

tendency)

• <5 bpm for >60

min

• Sinusoidal pattern

• Complicated variable

decelerations with a

duration of >60sec

• Repeated late uniform

decelerations

Preterminal • Total lack of variability (<2 bpm) and reactivity with or without

decelerations or bradycardia

Figure 2. The modified FIGO classification.

Intervention and control group

Patients will randomly be assigned to one of the two arms of the study:

Control group: normal care (according to the local standard) is provided, and

preferably started at least 10 minutes after the onset a suboptimal or abnormal FHR

pattern, according to the modified FIGO criteria (figure 2).60,61

Intervention group: in case of a suboptimal or abnormal FHR pattern according to

the modified FIGO criteria, 100% oxygen is applied to the mother at 10 l/min via a

non-rebreathing mask, and continued until delivery. Co-interventions (normal care)

may be initiated after 10 minutes of oxygen administration without a satisfactory

effect on FHR, to investigate the effect of only maternal hyperoxygenation on FHR,

without risking prolonged fetal hypoxia. In case a patient needs to undergo a

cesarean section, oxygen administration will be continued until the fetus is born.

Obviously, in case the delivery room staff believes additional interventions should

be applied for safety reasons, the study protocol can be overruled any time.

Study outcomes and data analysis

The primary outcome is the percentage reduction in the depth and duration of FHR

deceleration in the intervention group in comparison with the control group.

Secondary outcomes include fetal, neonatal and maternal outcomes.

Fetal outcome

FHR changes

Changes in specific features of the CTG including:

• Decelerations with loss of internal variability (beat to beat variability of <5

beats per minute (BPM))

• Decelerations in combination with tachycardia of bradycardia (> 160 or < 110

BPM)

• Unassignable baseline

• Phase-rectified signal averaging (PRSA); a relatively new technique to

determine fetal heart rate variability, by estimating the accelerative (ACprsa)

and decelerative capacity (DCprsa) of the fetal heart. This technique is

explained in the articles by Bauer and Huhn.62,63

• Change in modified FIGO classification (figure 2).60,61

In the next paragraph methodology regarding the comparison of FHR tracings and

timeframes are described more detailed.


107

5

only in case of suboptimal or abnormal FHR patterns during the second stage of

labor, randomization is performed using sealed, opaque envelops. The allocation

sequence is computer-generated using random blocks of four or six patients.

CTG

classification

Baseline heart frequency Variability

Reactivity

Decelerations

Normal • 110-150 bpm • Accelerations

• 5-25 bpm

• Early uniform

decelerations

• Uncomplicated


(loss of <60 beats)

Intermediary • 100-110 bpm

• 150-170 bpm

• Short bradycardia

episode

<100 bpm for >3 min

<80 bpm for >2 min

• >25 bpm (saltatory

pattern)

• <5 bpm >40 min

• Uncomplicated


(loss of >60 beats)

• A combination of 2 or several intermediary observations will result in an

abnormal CTG

Abnormal • >170 bpm

• Persistent bradycardia

<100 bpm for >10 min

<80 bpm for >3 min

(without an increasing

tendency)

• <5 bpm for >60

min

• Sinusoidal pattern

• Complicated variable

decelerations with a

duration of >60sec

• Repeated late uniform

decelerations

Preterminal • Total lack of variability (<2 bpm) and reactivity with or without

decelerations or bradycardia

Figure 2. The modified FIGO classification.

Intervention and control group

Patients will randomly be assigned to one of the two arms of the study:

Control group: normal care (according to the local standard) is provided, and

preferably started at least 10 minutes after the onset a suboptimal or abnormal FHR

pattern, according to the modified FIGO criteria (figure 2).60,61

Intervention group: in case of a suboptimal or abnormal FHR pattern according to

the modified FIGO criteria, 100% oxygen is applied to the mother at 10 l/min via a

non-rebreathing mask, and continued until delivery. Co-interventions (normal care)

may be initiated after 10 minutes of oxygen administration without a satisfactory

effect on FHR, to investigate the effect of only maternal hyperoxygenation on FHR,

without risking prolonged fetal hypoxia. In case a patient needs to undergo a

cesarean section, oxygen administration will be continued until the fetus is born.

Obviously, in case the delivery room staff believes additional interventions should

be applied for safety reasons, the study protocol can be overruled any time.

Study outcomes and data analysis

The primary outcome is the percentage reduction in the depth and duration of FHR

deceleration in the intervention group in comparison with the control group.

Secondary outcomes include fetal, neonatal and maternal outcomes.

Fetal outcome

FHR changes

Changes in specific features of the CTG including:

• Decelerations with loss of internal variability (beat to beat variability of <5

beats per minute (BPM))

• Decelerations in combination with tachycardia of bradycardia (> 160 or < 110

BPM)

• Unassignable baseline

• Phase-rectified signal averaging (PRSA); a relatively new technique to

determine fetal heart rate variability, by estimating the accelerative (ACprsa)

and decelerative capacity (DCprsa) of the fetal heart. This technique is

explained in the articles by Bauer and Huhn.62,63

• Change in modified FIGO classification (figure 2).60,61

In the next paragraph methodology regarding the comparison of FHR tracings and

timeframes are described more detailed.

Chapter 5

108

Neonatal outcome

This includes Apgar score, NICU admission, venous and arterial umbilical cord blood

gas analysis (pH, lactate, base excess, pO2 and pCO2) and malondialdehyde, (MDA,

a marker for free oxygen radical production) in arterial and venous umbilical cord

blood. Information on neonatal admission is a standard part of the maternal hospital

chart. Determination of 1- and 5-minute Apgar score and venous and arterial

umbilical cord blood gas analysis (pH, lactate, base excess, pO2 and pCO2) are

common practice. A cord blood gas analysis will be performed immediately after

birth, by the ABL 90 flex blood gas analyser (Radiometer Benelux BV, Zoetermeer,

The Netherlands), in both venous and arterial cord blood. Two additional blood

samples (one venous and one arterial sample) are drawn from the umbilical cord in

heparin tubes, and immediately centrifuged and stored at the laboratory of Máxima

Medical Center at -20°C. Once all samples are collected, they will be transported to

the laboratory of Genetic and Metabolic Diseases of the Academic Medical Center

Amsterdam, The Netherlands, where total (free and bound) MDA will be determined

as the 2,4-dinitrophenylhydrazine (DNPH) derivative. A stable isotopically labelled

analogue (2H2-MDA) will be added as internal standard, where after alkaline

hydrolysation, deproteinisation and derivatisation with DNPH, and MDA-hydrazone

will be analysed by HPLC-MS/MS and positive electrospray. Samples will be injected

on an LC-18-DB analytical column (250 × 4.6 mm, 5 µm particles, Supelco)

hyphenated to a Quattro Premier XE mass spectrometer (Waters Corporation,

Milford, MA), using an Acquity UPLC system (Waters Corporation, Milford, MA).

Analytes and internal standard will be eluted with acetonitrile/water/acetic acid

(50/50/0.2) and detected in multiple reaction monitoring mode for the transitions

m/z 235 m/z 159; m/z 237 m/z 161.

Maternal outcome

Maternal outcome measures include the mode of delivery, side effects and reasons

for discontinuation of oxygen administration. Side effects include a headache,

dizziness, discomfort of the non-rebreathing mask and any other complaint

mentioned by the participant. The delivery room staff will register on the case report

form (CRF) if the parturient experiences any side effects and/or if there are reasons

for eventual discontinuation of oxygen administration. Also, a short questionnaire

will be used to investigate experiences of all the participants with this study, to gain

insight in how laboring women experience receiving additional oxygen by a non-

rebreathing mask, compared to receiving normal care.

Analysis of outcome measures regarding FHR pattern Changes in FHR pattern

The digital CTG tracings will be extracted from Chipsoft EZIS (Amsterdam, The

Netherlands) and analysed using Matlab 2015a (MathWorks Inc USA). For the

computerised CTG analysis we will use a custom-made algorithm, based on the

OxSys system,64 that will first be validated by an expert panel. This expert panel will

also manually classify the CTG to one of the FIGO categories.60,61 Regarding the

analysis of specific CTG features, we searched the literature for CTG features that

are likely related to neonatal outcome. A large variety of CTG features have been

investigated in relation to neonatal outcome, with varying results. However, three

features are consistently mentioned as related to neonatal outcome:

• decelerations with loss of internal variability

• decelerations in combination with tachycardia or bradycardia

• periods with unassignable baseline 3,60,64-71

Besides, ACPRSA and DCPRSA turned out to predict acidaemia better than short-term

variation.62,72,73 We therefore include this parameter in as an outcome measure.

What is the timeframe of interest?

All patients serve as their own control with changes in FHR being compared before

and after the start of the study protocol, irrespective of whether the patients

belonged to the control or the intervention group. Additionally, results of the

intervention group and control group will also be compared.

For the analysis where patients serve as their own control, the timeframes of interest

for outcomes related to changes in FHR are as follows:

Control group: 10 minutes before and after the start of the study protocol. In total

20 minutes of data will be analysed (figure 3).

Intervention group: 10 minutes before the start of the study protocol up to 15

minutes after start of the study protocol. The timeframe of interest after the start of

the study protocol is determined as the period between 5 and 15 minutes after


109

5

Neonatal outcome

This includes Apgar score, NICU admission, venous and arterial umbilical cord blood

gas analysis (pH, lactate, base excess, pO2 and pCO2) and malondialdehyde, (MDA,

a marker for free oxygen radical production) in arterial and venous umbilical cord

blood. Information on neonatal admission is a standard part of the maternal hospital

chart. Determination of 1- and 5-minute Apgar score and venous and arterial

umbilical cord blood gas analysis (pH, lactate, base excess, pO2 and pCO2) are

common practice. A cord blood gas analysis will be performed immediately after

birth, by the ABL 90 flex blood gas analyser (Radiometer Benelux BV, Zoetermeer,

The Netherlands), in both venous and arterial cord blood. Two additional blood

samples (one venous and one arterial sample) are drawn from the umbilical cord in

heparin tubes, and immediately centrifuged and stored at the laboratory of Máxima

Medical Center at -20°C. Once all samples are collected, they will be transported to

the laboratory of Genetic and Metabolic Diseases of the Academic Medical Center

Amsterdam, The Netherlands, where total (free and bound) MDA will be determined

as the 2,4-dinitrophenylhydrazine (DNPH) derivative. A stable isotopically labelled

analogue (2H2-MDA) will be added as internal standard, where after alkaline

hydrolysation, deproteinisation and derivatisation with DNPH, and MDA-hydrazone

will be analysed by HPLC-MS/MS and positive electrospray. Samples will be injected

on an LC-18-DB analytical column (250 × 4.6 mm, 5 µm particles, Supelco)

hyphenated to a Quattro Premier XE mass spectrometer (Waters Corporation,

Milford, MA), using an Acquity UPLC system (Waters Corporation, Milford, MA).

Analytes and internal standard will be eluted with acetonitrile/water/acetic acid

(50/50/0.2) and detected in multiple reaction monitoring mode for the transitions

m/z 235 m/z 159; m/z 237 m/z 161.

Maternal outcome

Maternal outcome measures include the mode of delivery, side effects and reasons

for discontinuation of oxygen administration. Side effects include a headache,

dizziness, discomfort of the non-rebreathing mask and any other complaint

mentioned by the participant. The delivery room staff will register on the case report

form (CRF) if the parturient experiences any side effects and/or if there are reasons

for eventual discontinuation of oxygen administration. Also, a short questionnaire

will be used to investigate experiences of all the participants with this study, to gain

insight in how laboring women experience receiving additional oxygen by a non-

rebreathing mask, compared to receiving normal care.

Analysis of outcome measures regarding FHR pattern Changes in FHR pattern

The digital CTG tracings will be extracted from Chipsoft EZIS (Amsterdam, The

Netherlands) and analysed using Matlab 2015a (MathWorks Inc USA). For the

computerised CTG analysis we will use a custom-made algorithm, based on the

OxSys system,64 that will first be validated by an expert panel. This expert panel will

also manually classify the CTG to one of the FIGO categories.60,61 Regarding the

analysis of specific CTG features, we searched the literature for CTG features that

are likely related to neonatal outcome. A large variety of CTG features have been

investigated in relation to neonatal outcome, with varying results. However, three

features are consistently mentioned as related to neonatal outcome:

• decelerations with loss of internal variability

• decelerations in combination with tachycardia or bradycardia

• periods with unassignable baseline 3,60,64-71

Besides, ACPRSA and DCPRSA turned out to predict acidaemia better than short-term

variation.62,72,73 We therefore include this parameter in as an outcome measure.

What is the timeframe of interest?

All patients serve as their own control with changes in FHR being compared before

and after the start of the study protocol, irrespective of whether the patients

belonged to the control or the intervention group. Additionally, results of the

intervention group and control group will also be compared.

For the analysis where patients serve as their own control, the timeframes of interest

for outcomes related to changes in FHR are as follows:

Control group: 10 minutes before and after the start of the study protocol. In total

20 minutes of data will be analysed (figure 3).

Intervention group: 10 minutes before the start of the study protocol up to 15

minutes after start of the study protocol. The timeframe of interest after the start of

the study protocol is determined as the period between 5 and 15 minutes after

Chapter 5

110

maternal hyperoxygenation is initiated, motivated by the expectation that it will take

5 minutes for maternal pO2 to increase to a maximum of approximately 475

mmHg.24 After that, the effect of the intervention will be observed for 10 minutes. In

total 20 minutes of data will be analysed (figure 4).

Figure 3. The timeframe of interest for analysis of outcome measures where patients

serve as their own control: the control group.

These periods are established because during this period, maternal

hyperoxygenation can be compared to no treatment. Furthermore, we will also

compare the periods from the start of the study until birth, although these results

may be influenced by other interventions that may have been applied.

Other study endpoints and parameters

Duration of the second stage of labor, duration of time for which supplemental

oxygen was received, baseline characteristics (infant sex, gestational age and birth

weight, maternal age and parity) are recorded.

Time in minutes

Start study protocol

!10$ !5$ $$0$ $+5$ $+10$

Timeframe: 10 minutes before the start of the study protocol

Timeframe: 10 minutes after the start of the study protocol


serve as their own control: the intervention group.

Hypothesis

We hypothesise that maternal hyperoxygenation will improve FHR, without any

severe maternal side effects. We do not expect a difference in rates of vacuum-

assisted delivery or secondary cesarean sections, nor Apgar scores or umbilical cord

pH values, due to the relatively small sample size. Furthermore, we expect larger

concentrations of MDA in the intervention group than in the control group.

Handling and storage of data and documents

Data will be handled anonymously and we will adhere to the Dutch Personal Data

Protection Act (in Dutch: De Wet Bescherming Persoonsgegevens, WBP). A secured

subject identification code list will be used to link a study number to a patients name

and date of birth. This file is password protected available only to the main

investigator (LB). All other information will contain only the study number and no

data directly referring to the patient. Fetal blood gas values will be stored in the

neonates’ hospital chart since this is part of conventional care. Laboratory results

Time in minutes

Start study protocol: Maternal hyperoxygenation

!10$ !5$ $$$$0$ $+5$ $$+10$


Timeframe: 5-15 minutes after the start of the study protocol

$+15$$$


111

5

maternal hyperoxygenation is initiated, motivated by the expectation that it will take

5 minutes for maternal pO2 to increase to a maximum of approximately 475

mmHg.24 After that, the effect of the intervention will be observed for 10 minutes. In

total 20 minutes of data will be analysed (figure 4).


serve as their own control: the control group.

These periods are established because during this period, maternal

hyperoxygenation can be compared to no treatment. Furthermore, we will also

compare the periods from the start of the study until birth, although these results

may be influenced by other interventions that may have been applied.

Other study endpoints and parameters

Duration of the second stage of labor, duration of time for which supplemental

oxygen was received, baseline characteristics (infant sex, gestational age and birth

weight, maternal age and parity) are recorded.

Time in minutes

Start study protocol

!10$ !5$ $$0$ $+5$ $+10$


Timeframe: 10 minutes after the start of the study protocol


serve as their own control: the intervention group.

Hypothesis

We hypothesise that maternal hyperoxygenation will improve FHR, without any

severe maternal side effects. We do not expect a difference in rates of vacuum-

assisted delivery or secondary cesarean sections, nor Apgar scores or umbilical cord

pH values, due to the relatively small sample size. Furthermore, we expect larger

concentrations of MDA in the intervention group than in the control group.

Handling and storage of data and documents

Data will be handled anonymously and we will adhere to the Dutch Personal Data

Protection Act (in Dutch: De Wet Bescherming Persoonsgegevens, WBP). A secured

subject identification code list will be used to link a study number to a patients name

and date of birth. This file is password protected available only to the main

investigator (LB). All other information will contain only the study number and no

data directly referring to the patient. Fetal blood gas values will be stored in the

neonates’ hospital chart since this is part of conventional care. Laboratory results

Time in minutes

Start study protocol: Maternal hyperoxygenation

!10$ !5$ $$$$0$ $+5$ $$+10$


Timeframe: 5-15 minutes after the start of the study protocol

$+15$$$

Chapter 5

112

regarding markers for free oxygen radicals will be coded and will therefore be

anonymous. All data will be stored for 15 years, in accordance with the Good

Clinical Practice guidelines.

Statistical analysis Sample size calculation

The study consists of two study groups: one group with suboptimal FHR patterns,

and one group with abnormal FHR patterns. We aim for 90% power and a level of

significance of 0.05 in both groups. In one small, non-randomized study, a reduction

in FHR decelerations (type II dips) of 50 to 100% was noted.28 This is the only study

that reports on FHR changes as a result of maternal hyperoxygenation. Based on the

available literature, we expect at least 50% improvement in the oxygen-group and

0% in the control-group in both suboptimal and abnormal FHR patterns.28 We

estimated a mean improvement of 50% with a standard deviation of 50% in each

group. A power analysis performed in G*Power 3.0.10 (Kiel University, Germany) for

a two-tailed Mann Whitney test (assuming that data will not be equally distributed)

resulted in a sample size of 58 patients in each study group, given an anticipated

20% of missing data. Since we have two separate study groups (suboptimal and

abnormal FHR group) we need 116 patients to participate.

Data analysis

SPSS (version 24, IBM, Armonk, NY) will be used to perform statistical analysis of the

study results. Assuming non-normal distribution, the primary clinical outcome will be

analysed with a Mann Whitney U test for differences between the intervention and

control group, and a Wilcoxon Matched-Pairs test for changes within the same

participant. When outcome data is found to be normally distributed, independent

samples t-tests (two-tailed) will be used to analyse differences between the

intervention and control group, and paired t-tests for changes within the same

participant. Outcome measures will be calculated for the combined group and the

subgroups of suboptimal and abnormal FHR tracings, and for small for gestational

age (SGA, growth percentile <p10) and appropriate for gestational age (AGA)

neonates. In the intervention group, oxygen may not be applied due to practical

concerns such as very quick progression of labor. Therefore, we will perform both

per-protocol and intention-to-treat analysis. In the per-protocol analysis parturients

that actually received oxygen will be compared to those who did not receive

oxygen. Besides, unjust inclusions will be excluded from this analysis.

Interim analysis

On account of safety concerns, an interim analysis will be performed when 50% of

the patients are included in the study. In this analysis, we compare the number of

neonates with a 5- minute Apgar score < 7 and/or pHa< 7.05, the number of

admission to NICU and perinatal death in both groups (all neonates that received

oxygen in both suboptimal and abnormal CTG group versus ‘conventional care’

group). In case the interim analysis shows a significant difference, we will terminate

the study. This interim analysis is performed exclusively for safety reasons: since the

primary outcome measure (fetal heart rate) will not be analysed during the interim

analysis, and power analysis is based on the primary outcome, adjustment of the

significance level is not required.

Public disclosure and publication policy

All investigators agree to publish the study results in an international peer-reviewed

journal, even if the results do not correspond to the hypothesis as stated in the

methods section of the protocol. The results will be offered for publication after all

the investigators agree on the content of the article. The full protocol (version 8,

date 1st March 2017) is available upon request.

Discussion

This study is the first RCT to investigate the effect of maternal hyperoxygenation for

fetal distress during labor.18,33 So far, the effects of supplemental oxygenation in the

presence of FHR abnormalities have only been investigated in small, non-

randomized studies. Due to the lack of concrete results from clinical trials, it is hard

to compare the beneficial effects of maternal hyperoxygenation to the potential side

effects. As a result, recommendations on the use this intervention for fetal distress in

international guidelines are non-uniform.20 Thus, the results of this study will help in

filling an internationally recognised ‘research gap’.

We believe patient safety is carefully addressed in this study, and ethical concerns

are limited. One of the major concerns of administering high fractions of oxygen, is


113

5

regarding markers for free oxygen radicals will be coded and will therefore be

anonymous. All data will be stored for 15 years, in accordance with the Good

Clinical Practice guidelines.

Statistical analysis Sample size calculation

The study consists of two study groups: one group with suboptimal FHR patterns,

and one group with abnormal FHR patterns. We aim for 90% power and a level of

significance of 0.05 in both groups. In one small, non-randomized study, a reduction

in FHR decelerations (type II dips) of 50 to 100% was noted.28 This is the only study

that reports on FHR changes as a result of maternal hyperoxygenation. Based on the

available literature, we expect at least 50% improvement in the oxygen-group and

0% in the control-group in both suboptimal and abnormal FHR patterns.28 We

estimated a mean improvement of 50% with a standard deviation of 50% in each

group. A power analysis performed in G*Power 3.0.10 (Kiel University, Germany) for

a two-tailed Mann Whitney test (assuming that data will not be equally distributed)

resulted in a sample size of 58 patients in each study group, given an anticipated

20% of missing data. Since we have two separate study groups (suboptimal and

abnormal FHR group) we need 116 patients to participate.

Data analysis

SPSS (version 24, IBM, Armonk, NY) will be used to perform statistical analysis of the

study results. Assuming non-normal distribution, the primary clinical outcome will be

analysed with a Mann Whitney U test for differences between the intervention and

control group, and a Wilcoxon Matched-Pairs test for changes within the same

participant. When outcome data is found to be normally distributed, independent

samples t-tests (two-tailed) will be used to analyse differences between the

intervention and control group, and paired t-tests for changes within the same

participant. Outcome measures will be calculated for the combined group and the

subgroups of suboptimal and abnormal FHR tracings, and for small for gestational

age (SGA, growth percentile <p10) and appropriate for gestational age (AGA)

neonates. In the intervention group, oxygen may not be applied due to practical

concerns such as very quick progression of labor. Therefore, we will perform both

per-protocol and intention-to-treat analysis. In the per-protocol analysis parturients

that actually received oxygen will be compared to those who did not receive

oxygen. Besides, unjust inclusions will be excluded from this analysis.

Interim analysis

On account of safety concerns, an interim analysis will be performed when 50% of

the patients are included in the study. In this analysis, we compare the number of

neonates with a 5- minute Apgar score < 7 and/or pHa< 7.05, the number of

admission to NICU and perinatal death in both groups (all neonates that received

oxygen in both suboptimal and abnormal CTG group versus ‘conventional care’

group). In case the interim analysis shows a significant difference, we will terminate

the study. This interim analysis is performed exclusively for safety reasons: since the

primary outcome measure (fetal heart rate) will not be analysed during the interim

analysis, and power analysis is based on the primary outcome, adjustment of the

significance level is not required.

Public disclosure and publication policy

All investigators agree to publish the study results in an international peer-reviewed

journal, even if the results do not correspond to the hypothesis as stated in the

methods section of the protocol. The results will be offered for publication after all

the investigators agree on the content of the article. The full protocol (version 8,

date 1st March 2017) is available upon request.

Discussion

This study is the first RCT to investigate the effect of maternal hyperoxygenation for

fetal distress during labor.18,33 So far, the effects of supplemental oxygenation in the

presence of FHR abnormalities have only been investigated in small, non-

randomized studies. Due to the lack of concrete results from clinical trials, it is hard

to compare the beneficial effects of maternal hyperoxygenation to the potential side

effects. As a result, recommendations on the use this intervention for fetal distress in

international guidelines are non-uniform.20 Thus, the results of this study will help in

filling an internationally recognised ‘research gap’.

We believe patient safety is carefully addressed in this study, and ethical concerns

are limited. One of the major concerns of administering high fractions of oxygen, is

Chapter 5

114

the increase in free oxygen radicals. Whether this has a clinical effect remains

unclear. We excluded all patients with a higher a priori risk of exposure to increased

free oxygen radical levels from this study. Both practical and safety issues led to

limitations of this study. An important limitation is the primary outcome measure.

We recognise that changes in FHR as a primary outcome measure is not optimal

since FHR does not accurately reflect fetal oxygenation and acid-base balance.60,75,76

However, we believe this is the ‘best available’ method to record changes in the

fetal condition during labor. Furthermore, we assume that if no beneficial effect on

FHR can be shown, an improvement in neonatal outcome is unlikely. Ideally,

neonatal outcome measures such as Apgar score and umbilical cord pH are the

outcome measures of first choice. However, a study with appropriate power to

address these outcome measures would need a very large sample size. Since the

potentially harmful effects have not been properly investigated yet, we chose to not

expose a large group of women and their fetuses to this intervention. If a positive

effect on FHR pattern without severe side effects can be confirmed by this study, we

will perform a larger multicenter RCT to investigate the effect on Apgar score and

cord blood gas values.

In this study, we focus on the fetal condition during the second stage of labor and

short-term neonatal outcome. This implies that abnormalities in FHR patterns during

the first stage of labor are not taken into account. We believe that the randomization

process will limit its influence. With regard to the neonatal period, we did not

arrange long-term follow-up, as we do not expect any clinically relevant side effects

that can be attributed to maternal hyperoxygenation. Besides, the sample size is too

small to draw firm conclusions on long-term neonatal effects in this study.

Power analysis of the current study is based on the expected effect on the primary

outcome measure and is not powered to find any significant differences in Apgar

score and umbilical cord blood gas values. In the power analysis, we used an

expected improvement in deceleration depth and duration of 50%. This value is

based on small, non-randomized studies, and may be overestimated. On the other

hand, this is the only available data. Also, we believe it is unlikely that a limited

improvement in deceleration depth and duration has clinical relevance. The sample

size is calculated for each of subgroups of suboptimal and abnormal FHR tracings.

We believe it is important to assess the effect of the intervention in these subgroups,

as fetuses having lower initial pO2 levels may profit more from maternal

hyperoxygenation.29

Regarding the subgroups of AGA and SGA infants, we did not increase our sample

size to reach an adequate number of participants in the SGA group. Nevertheless,

we find it interesting to see whether there is a different effect of maternal

hyperoxygenation in SGA compared to AGA infants.Due to organizational challenges, it is not possible to conduct a double-blinded trial.

Hence patients and delivery room staff are not blinded to the patients’ allocation to

a study group and may lead to observer bias. However, analysis of FHR tracings will

be done using a computerised algorithm and the investigators judging the CTGs

and secondary outcome measures are blinded to the study arm, to minimise bias.

To investigate the effect of maternal hyperoxygenation in the presence of fetal

distress on the release of free oxygen radicals, MDA is estimated in umbilical cord

blood. MDA is the peroxidation product of membrane polyunsaturated fatty acids.

We chose to measure this marker for oxidative stress because it is used in former

studies performed during labor and it is related to vaginal birth, nonreassuring FHR

tracings, maternal hyperoxygenation and acidaemia in arterial cord blood.36,37,39,41

We realise that differences in values in umbilical cord blood may be confounded by

mode and duration of delivery; therefore, we will correct the results for the mode of

delivery. A practical ground to choose this marker is that this is the only marker for

oxidative stress that can be accurately estimated in Dutch laboratories. In the

intervention group, oxygen administration will be continued until delivery to enable

analysis of its effect on cord blood gas values and MDA.

Despite some important limitations of this study, we believe this is the best possible

way to perform a study while restricting safety issues. If the results do not show any

improvement in FHR, we believe maternal hyperoxygenation should not be used as

a treatment for fetal distress. However, if a beneficial effect is demonstrated, we will

design a multicenter RCT to investigate the effect on neonatal outcome.

Acknowledgements

This research was performed within the framework of the IMPULS perinatology, in

collaboration with Philips Healthcare, Eindhoven, The Netherlands.


115

5

the increase in free oxygen radicals. Whether this has a clinical effect remains

unclear. We excluded all patients with a higher a priori risk of exposure to increased

free oxygen radical levels from this study. Both practical and safety issues led to

limitations of this study. An important limitation is the primary outcome measure.

We recognise that changes in FHR as a primary outcome measure is not optimal

since FHR does not accurately reflect fetal oxygenation and acid-base balance.60,75,76

However, we believe this is the ‘best available’ method to record changes in the

fetal condition during labor. Furthermore, we assume that if no beneficial effect on

FHR can be shown, an improvement in neonatal outcome is unlikely. Ideally,

neonatal outcome measures such as Apgar score and umbilical cord pH are the

outcome measures of first choice. However, a study with appropriate power to

address these outcome measures would need a very large sample size. Since the

potentially harmful effects have not been properly investigated yet, we chose to not

expose a large group of women and their fetuses to this intervention. If a positive

effect on FHR pattern without severe side effects can be confirmed by this study, we

will perform a larger multicenter RCT to investigate the effect on Apgar score and

cord blood gas values.

In this study, we focus on the fetal condition during the second stage of labor and

short-term neonatal outcome. This implies that abnormalities in FHR patterns during

the first stage of labor are not taken into account. We believe that the randomization

process will limit its influence. With regard to the neonatal period, we did not

arrange long-term follow-up, as we do not expect any clinically relevant side effects

that can be attributed to maternal hyperoxygenation. Besides, the sample size is too

small to draw firm conclusions on long-term neonatal effects in this study.

Power analysis of the current study is based on the expected effect on the primary

outcome measure and is not powered to find any significant differences in Apgar

score and umbilical cord blood gas values. In the power analysis, we used an

expected improvement in deceleration depth and duration of 50%. This value is

based on small, non-randomized studies, and may be overestimated. On the other

hand, this is the only available data. Also, we believe it is unlikely that a limited

improvement in deceleration depth and duration has clinical relevance. The sample

size is calculated for each of subgroups of suboptimal and abnormal FHR tracings.

We believe it is important to assess the effect of the intervention in these subgroups,

as fetuses having lower initial pO2 levels may profit more from maternal

hyperoxygenation.29

Regarding the subgroups of AGA and SGA infants, we did not increase our sample

size to reach an adequate number of participants in the SGA group. Nevertheless,

we find it interesting to see whether there is a different effect of maternal

hyperoxygenation in SGA compared to AGA infants.Due to organizational challenges, it is not possible to conduct a double-blinded trial.

Hence patients and delivery room staff are not blinded to the patients’ allocation to

a study group and may lead to observer bias. However, analysis of FHR tracings will

be done using a computerised algorithm and the investigators judging the CTGs

and secondary outcome measures are blinded to the study arm, to minimise bias.

To investigate the effect of maternal hyperoxygenation in the presence of fetal

distress on the release of free oxygen radicals, MDA is estimated in umbilical cord

blood. MDA is the peroxidation product of membrane polyunsaturated fatty acids.

We chose to measure this marker for oxidative stress because it is used in former

studies performed during labor and it is related to vaginal birth, nonreassuring FHR

tracings, maternal hyperoxygenation and acidaemia in arterial cord blood.36,37,39,41

We realise that differences in values in umbilical cord blood may be confounded by

mode and duration of delivery; therefore, we will correct the results for the mode of

delivery. A practical ground to choose this marker is that this is the only marker for

oxidative stress that can be accurately estimated in Dutch laboratories. In the

intervention group, oxygen administration will be continued until delivery to enable

analysis of its effect on cord blood gas values and MDA.

Despite some important limitations of this study, we believe this is the best possible

way to perform a study while restricting safety issues. If the results do not show any

improvement in FHR, we believe maternal hyperoxygenation should not be used as

a treatment for fetal distress. However, if a beneficial effect is demonstrated, we will

design a multicenter RCT to investigate the effect on neonatal outcome.

Acknowledgements

This research was performed within the framework of the IMPULS perinatology, in

collaboration with Philips Healthcare, Eindhoven, The Netherlands.

Chapter 5

116

References 1. Caldeyro-Barcia R, Mendez-Bauer C, Poseiro J, Escarena L, Pose S, Bieniarz A.

Control of the human fetal heart rate during labor. In: Cassels DE, editor. The heart and circulation in the newborn and infant. New York: Grune & Stratton; 1966. p. 7-36.

2. Murray ML. Antepartal and intrapartal fetal monitoring. 3rd ed. New York: Springer Publishing Company; 2007.

3. Westgate JA, Wibbens B, Bennet L, Wassink G, Parer JT, Gunn AJ. The intrapartum deceleration in center stage: a physiologic approach to the interpretation of fetal heart rate changes in labor. Am J Obstet Gynecol. 2007;197:236 e1-11.

4. Ball RH, Parer JT. The physiologic mechanisms of variable decelerations. Am J Obstet Gynecol. 1992;166:1683-8.


6. Freeman RK, Garite TJ, Nageotte MP. Fetal heart rate monitoring. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2000.

7. Hanson MA. Do we now understand the control of the fetal circulation? Eur J Obstet Gynecol Reprod Biol. 1997;75:55-61.


9. Elliott C, Warrick PA, Graham E, Hamilton EF. Graded classification of fetal heart rate tracings: association with neonatal metabolic acidosis and neurologic morbidity. Am J Obstet Gynecol. 2010;202:258 e1-8.

10. Kubli FW, Hon EH, Khazin AF, Takemura H. Observations on heart rat and pH in the human fetus during labor. Am J Obstet Gynecol. 1969;104:1190-206.

11. Graham A, Ruis KA, Hartman A, Northington F, Fox H. A systematic review of the role of intrapartum hypoxia-ischemia in the causation of neonatal encephalopathy. Am J Obstet Gynecol. 2008;199:587-95.

12. Martin-Ancel A, Garcia-Alix A, Gaya F, Cabanas F, Burgueros M, Quero J. Multiple organ involvement in perinatal asphyxia. J Pediatr. 1995;127:786-793.

13. Evers AC, Brouwers HA, Hukkelhoven CW, Nikkels PG, Boon J, van Egmond-Linden A, et al. Perinatal mortality and severe morbidity in low and high risk term pregnancies in the Netherlands: prospective cohort study. BMJ. 2010;341:c5639.

14. McNamara HM, Dildy GA. Continuous intrapartum pH, pO2, pCO2, and SpO2 monitoring. Obstet Gynecol Clin North Am. 1999;4:671-93.



17. Schiermeier S, Pidner von Steinburg S, Thieme A, Reinhard J, Daumer M, Scholz M, Hatzmann W, Schneider KT. Sensitivity and specificity of intrapartum

computerised FIGO criteria for cardiotocography and fetal scalp pH during labour: multicentre, observational study. BJOG. 2008;115:1557-63.

18. Bullens LM, van Runnard Heimel PJ, van der Hout-van der Jagt MB, Oei SG. Interventions for Intrauterine Resuscitation in Suspected Fetal Distress During Term Labor: A Systematic Review. Obstet Gynecol Surv. 2015;70:524-39.


20. Bullens LM, Moors S, van Runnard Heimel PJ, van der Hout-van der Jagt MB, Oei SG. Practice variation in the management of intrapartum fetal distress in The Netherlands and the Western world. Eur J Obstet Gynecol Reprod Biol. 2016;205:48-53.



23. Garite TJ, Nageotte MP, Parer JT. Should we really avoid giving oxygen to mothers with concering fetal heart rate patterns? Am J Obstet Gynecol. 2015;212:459-60.


25. Aldrich CJ, Wyatt JS, Spencer JA, Reynolds EO, Delpy DT. The effect of maternal oxygen administration on human fetal cerebral oxygenation measured during labour by near infrared spectroscopy. Br J Obstet Gynaecol. 1994;101:509-13.

26. McNamara H, Johnson N, Lilford R. The effect on fetal arteriolar oxygen saturation resulting from giving oxygen to the mother measured by pulse oximetry. Br J Obstet Gynaecol. 1993;100:446-9.


28. Althabe O, Schwarcz R, Pose S, Escarcena L, Caldeyro-Barcia R. Effects on fetal heart rate and fetal pO2 of oxygen administration to the mother. Am J Obstet Gynecol. 1967;98:858-70.






117

5

References 1. Caldeyro-Barcia R, Mendez-Bauer C, Poseiro J, Escarena L, Pose S, Bieniarz A.

Control of the human fetal heart rate during labor. In: Cassels DE, editor. The heart and circulation in the newborn and infant. New York: Grune & Stratton; 1966. p. 7-36.

2. Murray ML. Antepartal and intrapartal fetal monitoring. 3rd ed. New York: Springer Publishing Company; 2007.

3. Westgate JA, Wibbens B, Bennet L, Wassink G, Parer JT, Gunn AJ. The intrapartum deceleration in center stage: a physiologic approach to the interpretation of fetal heart rate changes in labor. Am J Obstet Gynecol. 2007;197:236 e1-11.

4. Ball RH, Parer JT. The physiologic mechanisms of variable decelerations. Am J Obstet Gynecol. 1992;166:1683-8.


6. Freeman RK, Garite TJ, Nageotte MP. Fetal heart rate monitoring. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2000.

7. Hanson MA. Do we now understand the control of the fetal circulation? Eur J Obstet Gynecol Reprod Biol. 1997;75:55-61.


9. Elliott C, Warrick PA, Graham E, Hamilton EF. Graded classification of fetal heart rate tracings: association with neonatal metabolic acidosis and neurologic morbidity. Am J Obstet Gynecol. 2010;202:258 e1-8.

10. Kubli FW, Hon EH, Khazin AF, Takemura H. Observations on heart rat and pH in the human fetus during labor. Am J Obstet Gynecol. 1969;104:1190-206.

11. Graham A, Ruis KA, Hartman A, Northington F, Fox H. A systematic review of the role of intrapartum hypoxia-ischemia in the causation of neonatal encephalopathy. Am J Obstet Gynecol. 2008;199:587-95.

12. Martin-Ancel A, Garcia-Alix A, Gaya F, Cabanas F, Burgueros M, Quero J. Multiple organ involvement in perinatal asphyxia. J Pediatr. 1995;127:786-793.

13. Evers AC, Brouwers HA, Hukkelhoven CW, Nikkels PG, Boon J, van Egmond-Linden A, et al. Perinatal mortality and severe morbidity in low and high risk term pregnancies in the Netherlands: prospective cohort study. BMJ. 2010;341:c5639.

14. McNamara HM, Dildy GA. Continuous intrapartum pH, pO2, pCO2, and SpO2 monitoring. Obstet Gynecol Clin North Am. 1999;4:671-93.



17. Schiermeier S, Pidner von Steinburg S, Thieme A, Reinhard J, Daumer M, Scholz M, Hatzmann W, Schneider KT. Sensitivity and specificity of intrapartum

computerised FIGO criteria for cardiotocography and fetal scalp pH during labour: multicentre, observational study. BJOG. 2008;115:1557-63.






23. Garite TJ, Nageotte MP, Parer JT. Should we really avoid giving oxygen to mothers with concering fetal heart rate patterns? Am J Obstet Gynecol. 2015;212:459-60.


25. Aldrich CJ, Wyatt JS, Spencer JA, Reynolds EO, Delpy DT. The effect of maternal oxygen administration on human fetal cerebral oxygenation measured during labour by near infrared spectroscopy. Br J Obstet Gynaecol. 1994;101:509-13.



28. Althabe O, Schwarcz R, Pose S, Escarcena L, Caldeyro-Barcia R. Effects on fetal heart rate and fetal pO2 of oxygen administration to the mother. Am J Obstet Gynecol. 1967;98:858-70.





Chapter 5

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34. Thorp JA, Trobough T, Evans R, Hedrick J, Yeast JD. The effect of maternal oxygen administration during the second stage of labor on umbilical cord blood gas values: a randomized controlled prospective trial. Am J Obstet Gynecol. 1995;172:465-74.




38. Yalcin S, Aydogan H, Kucuk A, Yuce HH, Altay N, Karahan MA, et al. Supplemental oxygen in elective cesarean section under spinal anesthesia: Handle the sword with care. Braz J Anesthesiol. 2013;63:393-7.

39. Rogers MS, Mongelli JM, Tsang KH, Wang CC, Law KP. Lipid peroxidation in cord blood after birth: the effect of labor. Br J Obstet Gynaecol. 1998;105:739-44.

40. Blackburn S. Free radicals in perinatal and neonatal care, part 2: oxidative stress during the perinatal and neonatal period. J Perinal Neonatal Nurs. 2006;20:125-7.

41. Wang W, Pang CC, Rogers MS, Chang AM. Lipid peroxidation in cord blood at birth. Am J Obstet Gynecol. 1996;174:62-5.


43. Saugstad OD, Ramji S, Soll RF, Vento M. Resuscitation of newborn infants with 21% or 100% oxygen: an updated systematic review and meta-analysis. Neonatology. 2008;94:176-82.

44. Carlo WA, Finer NN, Walsh MC, Rich W, Gantz MG, Laptook AR, et al: SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network. Target ranges of oxygen saturation in extremely preterm infants. N Engl J Med. 2010;362:1959-69.

45. Davis PG, Tan A, O’Donnell CP, Schulze A. Resuscitation of newborn infants with 100% oxygen or air: a systematic review and meta-analysis. Lancet. 2004;364:1329-33.

46. Rabi Y, Rabi D, Yee W. Room air resuscitation of the depressed newborn: a systematic review and meta-analysis. Resuscitation. 2007;72:353-63.

47. Brantberg A, Sonesson SE. Central arterial hemodynamics in small-for-gestational-age fetuses before and during maternal hyperoxygenation: a Doppler velocimetric study with particular attention to the aortic isthmus. Ultrasound Obstet Gynecol.1999;14:237-43.

48. Bartnicki J, Saling E. Influence of maternal oxygen administration on the computer-analysed fetal heart rate patterns in small-for-gestational-age fetuses. Gynecol Obstet Invest. 1994;37:172-5.

49. Duling BR. Microvascular responses to alterations in oxygen tension. Circ Res. 1972;31:481-9.

50. Cornet AD, Kooter AJ, Peters MJ, Smulders YM. The potential harm of oxygen therapy in medical emergenciesThe potential harm of oxygen therapy in medical emergencies. Crit Care. 2013;17:313.

51. Sjöberg F, Singer M. The medical use of oxygen: a time for critical reappraisal. J Intern Med. 2013;274:505-28.

52. Fitch W. Cerebral blood flow: physiological principles and methods of measurement. In: Sebel PS, Fitch W, editors. Monitoring the Central Nervous System. Oxford: Blackwell Science; 1994. p. 78-117.

53. Watson NA, Beards SC, Altaf N, Kassner A, Jackson A. The effect of hyperoxia on cerebral blood flow: a study in healthy volunteers using magnetic resonance phase-contrast angiography. Eur J Anaesthesiol. 2000;17:152-9.

54. Bennett MH, French C, Schnabel A, Wasiak J, Kranke P. Normobaric and hyperbaric oxygen therapy for migraine and cluster headache. Cochrane Database Syst Rev. 2008;3:CD005219.

55. Kehrer JP, Klotz LO. Free radicals and related reactive species as mediators of tissue injury and disease: implications for health. Crit Rev Toxicol. 2015;45:765-98.

56. Lareb. ‘s Hertogenbosch, The Netherlands. 2017. https://www.lareb.nl/nl/databank/Result?formGroup=&atc=V03AN01&drug=ZUURSTOF+MEDICINAAL+%28ZUURSTOF%29. Accessed March 21 2017. [Dutch]

57. American College of Obstetricians and Gynecologistst. Practice bulletin no. 116: management of intrapartum fetal heart rate tracings. Obstet Gynecol. 2010;116:1232-40.

58. Royal College of Obstetricians and Gynaecologistst. Intrapartum care, NICE guideline 190. December 2014, updated February 2017. https://www.nice.org.uk/guidance/cg190/chapter/Recommendations. Accessed May 2017.

59. Chan AW, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346:e7586.


61. Neoventa. Mölndal, Sweden. http://www.neoventa.com/2015/11/bigger-is-not-always-better/. Accessed November 6th 2017.

62. Bauer A, Kantelhardt JW, Barthel P, Schneider R, Mäkikallio T, Ulm K, Hnatkova K, et al. Deceleration capacity of heart rate as a predictor of mortality after myocardial infarction: cohort study. Lancet. 2006;367:1674-81.


119

5


34. Thorp JA, Trobough T, Evans R, Hedrick J, Yeast JD. The effect of maternal oxygen administration during the second stage of labor on umbilical cord blood gas values: a randomized controlled prospective trial. Am J Obstet Gynecol. 1995;172:465-74.




38. Yalcin S, Aydogan H, Kucuk A, Yuce HH, Altay N, Karahan MA, et al. Supplemental oxygen in elective cesarean section under spinal anesthesia: Handle the sword with care. Braz J Anesthesiol. 2013;63:393-7.

39. Rogers MS, Mongelli JM, Tsang KH, Wang CC, Law KP. Lipid peroxidation in cord blood after birth: the effect of labor. Br J Obstet Gynaecol. 1998;105:739-44.

40. Blackburn S. Free radicals in perinatal and neonatal care, part 2: oxidative stress during the perinatal and neonatal period. J Perinal Neonatal Nurs. 2006;20:125-7.

41. Wang W, Pang CC, Rogers MS, Chang AM. Lipid peroxidation in cord blood at birth. Am J Obstet Gynecol. 1996;174:62-5.


43. Saugstad OD, Ramji S, Soll RF, Vento M. Resuscitation of newborn infants with 21% or 100% oxygen: an updated systematic review and meta-analysis. Neonatology. 2008;94:176-82.

44. Carlo WA, Finer NN, Walsh MC, Rich W, Gantz MG, Laptook AR, et al: SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network. Target ranges of oxygen saturation in extremely preterm infants. N Engl J Med. 2010;362:1959-69.

45. Davis PG, Tan A, O’Donnell CP, Schulze A. Resuscitation of newborn infants with 100% oxygen or air: a systematic review and meta-analysis. Lancet. 2004;364:1329-33.

46. Rabi Y, Rabi D, Yee W. Room air resuscitation of the depressed newborn: a systematic review and meta-analysis. Resuscitation. 2007;72:353-63.

47. Brantberg A, Sonesson SE. Central arterial hemodynamics in small-for-gestational-age fetuses before and during maternal hyperoxygenation: a Doppler velocimetric study with particular attention to the aortic isthmus. Ultrasound Obstet Gynecol.1999;14:237-43.

48. Bartnicki J, Saling E. Influence of maternal oxygen administration on the computer-analysed fetal heart rate patterns in small-for-gestational-age fetuses. Gynecol Obstet Invest. 1994;37:172-5.

49. Duling BR. Microvascular responses to alterations in oxygen tension. Circ Res. 1972;31:481-9.

50. Cornet AD, Kooter AJ, Peters MJ, Smulders YM. The potential harm of oxygen therapy in medical emergenciesThe potential harm of oxygen therapy in medical emergencies. Crit Care. 2013;17:313.

51. Sjöberg F, Singer M. The medical use of oxygen: a time for critical reappraisal. J Intern Med. 2013;274:505-28.

52. Fitch W. Cerebral blood flow: physiological principles and methods of measurement. In: Sebel PS, Fitch W, editors. Monitoring the Central Nervous System. Oxford: Blackwell Science; 1994. p. 78-117.

53. Watson NA, Beards SC, Altaf N, Kassner A, Jackson A. The effect of hyperoxia on cerebral blood flow: a study in healthy volunteers using magnetic resonance phase-contrast angiography. Eur J Anaesthesiol. 2000;17:152-9.

54. Bennett MH, French C, Schnabel A, Wasiak J, Kranke P. Normobaric and hyperbaric oxygen therapy for migraine and cluster headache. Cochrane Database Syst Rev. 2008;3:CD005219.

55. Kehrer JP, Klotz LO. Free radicals and related reactive species as mediators of tissue injury and disease: implications for health. Crit Rev Toxicol. 2015;45:765-98.

56. Lareb. ‘s Hertogenbosch, The Netherlands. 2017. https://www.lareb.nl/nl/databank/Result?formGroup=&atc=V03AN01&drug=ZUURSTOF+MEDICINAAL+%28ZUURSTOF%29. Accessed March 21 2017. [Dutch]

57. American College of Obstetricians and Gynecologistst. Practice bulletin no. 116: management of intrapartum fetal heart rate tracings. Obstet Gynecol. 2010;116:1232-40.

58. Royal College of Obstetricians and Gynaecologistst. Intrapartum care, NICE guideline 190. December 2014, updated February 2017. https://www.nice.org.uk/guidance/cg190/chapter/Recommendations. Accessed May 2017.

59. Chan AW, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346:e7586.


61. Neoventa. Mölndal, Sweden. http://www.neoventa.com/2015/11/bigger-is-not-always-better/. Accessed November 6th 2017.

62. Bauer A, Kantelhardt JW, Barthel P, Schneider R, Mäkikallio T, Ulm K, Hnatkova K, et al. Deceleration capacity of heart rate as a predictor of mortality after myocardial infarction: cohort study. Lancet. 2006;367:1674-81.

Chapter 5

120

63. Huhn EA, Lobmaier S, Fischer T, Schneider R, Bauer A, Schneider KT, Schmidt G. New computerized fetal heart rate analysis for suveillance of intrauterine growth restriction. Prenat Diagn. 2011;31:509-14.

64. Georgieva A, Payne SJ, Moulden M, Redman CWG. Computerized fetal heart rate analysis in labor: detection of intervals with un-assignable baseline. Physiol Meas. 2011;32:1549-60.

65. Ozden S, Demirci F. Significance for fetal outcome of poor prognostic features in fetal heart rate traces with variable decelerations. Arch Gynecol Obstet. 1999;262:141-9.

66. Gaziano EP. A study of variable decelerations in association with other heart rate patterns during monitored labor. Am J Obstet Gynecol. 1979;135:360-3.

67. Krebs HB, Petres RE, Dunn LJ. Intrapartum fetal heart rate monitoring. VIII. Atypical variable decelerations. Am J Obstet Gynecol. 1983;145:297-305.

68. Hamilton E, Warrick P, O’Keeffe D. Variable decelerations: do size and shape matter? J Matern Fetal Neonatal Med. 2012;25:648-53.

69. Kazandi M, Sendag F, Akercan F, Terek MC, Gundem G. Different types of variable decelerations and their effects to neonatal outcome. Singapore Med J. 2003;44:243-7.

70. Holzmann M, Wretler S, Cnattingius S, Nordström L. Cardiotocography patterns and risk of intrapartum fetal acidemia. J Perinal Med. 2015;43:473-9.

71. Georgieva A, Payne SJ, Moulden M, Redman CW. Relation of fetal heart rate signals with unassignable baseline to poor neonatal state at birth. Med Biol Eng Comput. 2012;50:717-25.

72. Georgieva A, Papageroghiou AT, Payne SJ, Moulden M, Redman CW. Phase-rectified signal averaging for intrapartum electronic fetal heart rate monitoring is related to acidaemia at birth. BJOG. 2014;121:889-94.

73. Lobmaier SM, Mensing van Charante N, Ferrazzi E, Giussani DA, Shaw CJ, Müller A, et al.; TRUFFLE investigators. Phase-rectified signal averaging method to predict perinatal outcome in infants with very preterm fetal growth restriction- a secondary analysis of TRUFFLE-trial. Am J Obstet Gynecol. 2016;215:630.e1-7.

74. Pocock SJ. Group sequential methods in the design and analysis of clinical trials. Biometrika. 1977;64:191-9.

75. James LS, Morishima HO, Daniel SS, Bowe ET, Cohen H, Niemann WH. Mechanism of late deceleration of the fetal heart rate. Am J Obstet Gynecol. 1972;113:578-82.

76. Morishima HO, Daniel SS, Richards RT, James LS. The effect of increased maternal PaO2 upon the fetus during labor. Am J Obstet Gynecol. 1975;123:257-64.

Chapter 6

Intrauterine resuscitation during term labor by

maternal hyperoxygenation:

a randomized controlled trial

Moors S, Bullens LM, van Runnard Heimel PJ, Dieleman JP, Kulik W,

Bakkeren DL, van den Heuvel ER, van der Hout-van der Jagt MB, Oei SG

Submitted

63. Huhn EA, Lobmaier S, Fischer T, Schneider R, Bauer A, Schneider KT, Schmidt G. New computerized fetal heart rate analysis for suveillance of intrauterine growth restriction. Prenat Diagn. 2011;31:509-14.

64. Georgieva A, Payne SJ, Moulden M, Redman CWG. Computerized fetal heart rate analysis in labor: detection of intervals with un-assignable baseline. Physiol Meas. 2011;32:1549-60.

65. Ozden S, Demirci F. Significance for fetal outcome of poor prognostic features in fetal heart rate traces with variable decelerations. Arch Gynecol Obstet. 1999;262:141-9.

66. Gaziano EP. A study of variable decelerations in association with other heart rate patterns during monitored labor. Am J Obstet Gynecol. 1979;135:360-3.

67. Krebs HB, Petres RE, Dunn LJ. Intrapartum fetal heart rate monitoring. VIII. Atypical variable decelerations. Am J Obstet Gynecol. 1983;145:297-305.

68. Hamilton E, Warrick P, O’Keeffe D. Variable decelerations: do size and shape matter? J Matern Fetal Neonatal Med. 2012;25:648-53.

69. Kazandi M, Sendag F, Akercan F, Terek MC, Gundem G. Different types of variable decelerations and their effects to neonatal outcome. Singapore Med J. 2003;44:243-7.

70. Holzmann M, Wretler S, Cnattingius S, Nordström L. Cardiotocography patterns and risk of intrapartum fetal acidemia. J Perinal Med. 2015;43:473-9.

71. Georgieva A, Payne SJ, Moulden M, Redman CW. Relation of fetal heart rate signals with unassignable baseline to poor neonatal state at birth. Med Biol Eng Comput. 2012;50:717-25.

72. Georgieva A, Papageroghiou AT, Payne SJ, Moulden M, Redman CW. Phase-rectified signal averaging for intrapartum electronic fetal heart rate monitoring is related to acidaemia at birth. BJOG. 2014;121:889-94.

73. Lobmaier SM, Mensing van Charante N, Ferrazzi E, Giussani DA, Shaw CJ, Müller A, et al.; TRUFFLE investigators. Phase-rectified signal averaging method to predict perinatal outcome in infants with very preterm fetal growth restriction- a secondary analysis of TRUFFLE-trial. Am J Obstet Gynecol. 2016;215:630.e1-7.

74. Pocock SJ. Group sequential methods in the design and analysis of clinical trials. Biometrika. 1977;64:191-9.

75. James LS, Morishima HO, Daniel SS, Bowe ET, Cohen H, Niemann WH. Mechanism of late deceleration of the fetal heart rate. Am J Obstet Gynecol. 1972;113:578-82.

76. Morishima HO, Daniel SS, Richards RT, James LS. The effect of increased maternal PaO2 upon the fetus during labor. Am J Obstet Gynecol. 1975;123:257-64.

Chapter 6

Intrauterine resuscitation during term labor by

maternal hyperoxygenation:

a randomized controlled trial

Moors S, Bullens LM, van Runnard Heimel PJ, Dieleman JP, Kulik W,

Bakkeren DL, van den Heuvel ER, van der Hout-van der Jagt MB, Oei SG

Submitted

Chapter 6

122

Abstract

Background

Maternal hyperoxygenation is widely used during labor as an intrauterine

resuscitation technique. However, robust evidence regarding its beneficial

effect and potential side effects is scarce, and available studies show

conflicting results.

Objective

To assess the effect of maternal hyperoxygenation in case of suspected fetal

distress during the second stage of term labor, on fetal heart rate, neonatal

outcome, maternal side effects, and mode of delivery.

Study design

We performed a single-center stratified randomized controlled trial with

randomized block design in a tertiary teaching hospital in The Netherlands.

Pregnant women with suboptimal or abnormal fetal heart rate (FHR) pattern

during the second stage of term labor were randomized to receive either

conventional care (control group), or 100% oxygen at 10 L/min until delivery

(intervention group). Outcomes measures were FHR pattern, Apgar score,

umbilical cord blood gas analysis, neonatal intensive care unit admission,

perinatal death, free oxygen radical activity, mode of delivery, and maternal

side effects. We performed subgroup analyses for suboptimal and abnormal

FHR pattern, and for small for gestational age fetuses.

Results

A total of 117 patients were included. Amelioration of the FHR pattern was

observed three times as often in the intervention group (16.7% versus 5.7%).

Furthermore, the incidence of FHR deterioration was significantly higher in

the control group versus the intervention group (42.9% vs. 13.9%). These

changes in FHR pattern were significant (p = 0.02). There were three (5.0%)

neonates with Apgar score <7 after five minutes in the control group,

compared to one (1.8%) in the intervention group (p = 0.62). Umbilical cord

blood gas analysis and mode of delivery showed no significant differences

either. There was no significant difference in free oxygen radicals between

both groups. Fewer episiotomies on fetal indication were performed in the

oxygenation group (24.2%) than in the control group (65.4%) among patients

with an abnormal fetal heart rate pattern (p = 0.001). In one third, oxygen

administration was stopped before the infant was born, mostly due to

discomfort. No side effects were reported in 63%, from the oxygen

admission nor the facemask.

Conclusion

Maternal hyperoxygenation has a significant positive effect on the FHR

pattern in the presence of fetal distress during the second stage of labor.

There was no significant difference in the neonatal outcome or mode of

delivery, however, significantly fewer episiotomies were performed in

mothers receiving additional oxygen in the abnormal CTG subgroup.

Whether maternal hyperoxygenation leads to an improvement of neonatal

outcome should be further investigated in a larger RCT. In any case, no

harmful effects were demonstrated.

Maternal hyperoxygenation: an RCT (study outcomes INTEREST 02 study)

123

6

Abstract

Background

Maternal hyperoxygenation is widely used during labor as an intrauterine

resuscitation technique. However, robust evidence regarding its beneficial

effect and potential side effects is scarce, and available studies show

conflicting results.

Objective

To assess the effect of maternal hyperoxygenation in case of suspected fetal

distress during the second stage of term labor, on fetal heart rate, neonatal

outcome, maternal side effects, and mode of delivery.

Study design

We performed a single-center stratified randomized controlled trial with

randomized block design in a tertiary teaching hospital in The Netherlands.

Pregnant women with suboptimal or abnormal fetal heart rate (FHR) pattern

during the second stage of term labor were randomized to receive either

conventional care (control group), or 100% oxygen at 10 L/min until delivery

(intervention group). Outcomes measures were FHR pattern, Apgar score,

umbilical cord blood gas analysis, neonatal intensive care unit admission,

perinatal death, free oxygen radical activity, mode of delivery, and maternal

side effects. We performed subgroup analyses for suboptimal and abnormal

FHR pattern, and for small for gestational age fetuses.

Results

A total of 117 patients were included. Amelioration of the FHR pattern was

observed three times as often in the intervention group (16.7% versus 5.7%).

Furthermore, the incidence of FHR deterioration was significantly higher in

the control group versus the intervention group (42.9% vs. 13.9%). These

changes in FHR pattern were significant (p = 0.02). There were three (5.0%)

neonates with Apgar score <7 after five minutes in the control group,

compared to one (1.8%) in the intervention group (p = 0.62). Umbilical cord

blood gas analysis and mode of delivery showed no significant differences

either. There was no significant difference in free oxygen radicals between

both groups. Fewer episiotomies on fetal indication were performed in the

oxygenation group (24.2%) than in the control group (65.4%) among patients

with an abnormal fetal heart rate pattern (p = 0.001). In one third, oxygen

administration was stopped before the infant was born, mostly due to

discomfort. No side effects were reported in 63%, from the oxygen

admission nor the facemask.

Conclusion



There was no significant difference in the neonatal outcome or mode of

delivery, however, significantly fewer episiotomies were performed in

mothers receiving additional oxygen in the abnormal CTG subgroup.

Whether maternal hyperoxygenation leads to an improvement of neonatal

outcome should be further investigated in a larger RCT. In any case, no

harmful effects were demonstrated.

Chapter 6

124

Introduction

During labor, maternal oxygen supplementation is widely used to improve

the fetal condition in case of suspected fetal distress.1-3 However, robust

evidence regarding its effect on fetal, neonatal, and maternal outcome is

scarce and conflicting. As a consequence, inconsistent recommendations

regarding the use of this intervention are found in international guidelines.4-6

Several small, non-randomized studies performed in the distressed fetus

show an improvement in fetal heart rate (FHR) patterns or fetal scalp pH as a

result of maternal hyperoxygenation.7-13 Fetuses with the lowest initial oxygen

saturation appear to benefit from it the most.9 Also, simulations with a

mathematical model indicate that maternal hyperoxygenation may lead to an

increase in fetal oxygenation and amelioration of the FHR pattern.14

A recent noninferiority RCT comparing maternal hyperoxygenation to

breathing room air during the active phase of labor showed no differences in

umbilical artery lactate, pH, base excess, and partial pressure of carbon

dioxide (pCO2) among patients with category II fetal heart tracings during

labor.15

In contrast, other studies report potentially harmful effects of oxygen

administration.16,17 Three randomized controlled trials (RCTs) assessed the use

of prophylactic oxygen administration during the second stage of

uncomplicated labor.18-20 Thorp et al. showed significantly more arterial cord

blood pH levels below 7.20 in the oxygenation group (face mask at 10L/min)

compared to controls.18 Although the mean pH level was not different in both

groups, this rose awareness regarding the potential side effects of maternal

hyperoxygenation. However, two other RCTs did not find any difference in

arterial cord blood pH.19,20 In these three RCTs, maternal hyperoxygenation

was applied in case of a reassuring fetal condition, i.e. in a normally

oxygenated fetus.18-20

Another argument against maternal hyperoxygenation as a standard measure

to treat fetal distress, is the potential increase in free oxygen radicals.21,22

These are reactive atoms with one more unpaired electron in their outer orbit

and are potentially damaging. To a certain degree, free oxygen radicals are

physiological,23 and known to increase in the presence of several maternal or

fetal conditions, such as preeclampsia, diabetes, smoking, intrauterine

growth restriction and fetal distress .24-28 Also during uncomplicated labor,

free oxygen radicals are formed, since uterine contractions might be

regarded as a small series of ischemia-reperfusion injuries.21 Previous

research shows that the production of free oxygen radicals is increased in

case of fetal distress, and after inhalation of high fractions of inspired oxygen

in the presence of a normal fetal condition.24 Besides, a higher amount of

free oxygen radicals was seen after vaginal birth, compared to a planned

cesarean section. The effect of maternal hyperoxygenation for nonreassuring

fetal status on free oxygen radical activity has not been investigated yet.

To our knowledge there are no RCTs studing the beneficial effect of maternal

hyperoxygenation, or whether it outweighs the potential adverse effects in

the presence of suspected fetal distress during the second stage of labor.

Several reviews underline the need for such a study.1-3 We initiated an RCT to

investigate the clinical effect and the safety of maternal hyperoxygenation

upon suspected fetal distress during the second stage of labor. Our objective

was to assess the effects of maternal hyperoxygenation in case of suspected

fetal distress during the second stage of term labor on FHR, neonatal

outcome and mode of delivery.

Materials and methods

Study design

This prospective, open label RCT was conducted in a tertiary teaching

hospital in The Netherlands. The study protocol has been published

previously.29 We included women aged ≥18 years, in labor at term with an

intended vaginal delivery of a singleton fetus in cephalic presentation with

suspected fetal distress, as defined by a suboptimal or abnormal FHR pattern

(according to the modified FIGO classification).30 Women were excluded with

any of the following: use of tobacco, recreational drugs, or alcohol during

pregnancy, pre-existing cardiac disease, pulmonary disease requiring

medication, diabetes, hyperthyroidism, anemia (hemoglobin <10.5 g/dL) or

recent use of any of the following medications: corticosteroids, anti-

hypertensives, magnesium sulphate, amiodarone, opioids, adriamycin,

bleomycin, actinomycin, menadione, promazine, thioridazine, or chloroquine.


125

6

Introduction

During labor, maternal oxygen supplementation is widely used to improve

the fetal condition in case of suspected fetal distress.1-3 However, robust

evidence regarding its effect on fetal, neonatal, and maternal outcome is

scarce and conflicting. As a consequence, inconsistent recommendations

regarding the use of this intervention are found in international guidelines.4-6

Several small, non-randomized studies performed in the distressed fetus

show an improvement in fetal heart rate (FHR) patterns or fetal scalp pH as a

result of maternal hyperoxygenation.7-13 Fetuses with the lowest initial oxygen

saturation appear to benefit from it the most.9 Also, simulations with a

mathematical model indicate that maternal hyperoxygenation may lead to an

increase in fetal oxygenation and amelioration of the FHR pattern.14

A recent noninferiority RCT comparing maternal hyperoxygenation to

breathing room air during the active phase of labor showed no differences in

umbilical artery lactate, pH, base excess, and partial pressure of carbon

dioxide (pCO2) among patients with category II fetal heart tracings during

labor.15

In contrast, other studies report potentially harmful effects of oxygen

administration.16,17 Three randomized controlled trials (RCTs) assessed the use

of prophylactic oxygen administration during the second stage of

uncomplicated labor.18-20 Thorp et al. showed significantly more arterial cord

blood pH levels below 7.20 in the oxygenation group (face mask at 10L/min)

compared to controls.18 Although the mean pH level was not different in both

groups, this rose awareness regarding the potential side effects of maternal

hyperoxygenation. However, two other RCTs did not find any difference in

arterial cord blood pH.19,20 In these three RCTs, maternal hyperoxygenation

was applied in case of a reassuring fetal condition, i.e. in a normally

oxygenated fetus.18-20

Another argument against maternal hyperoxygenation as a standard measure

to treat fetal distress, is the potential increase in free oxygen radicals.21,22

These are reactive atoms with one more unpaired electron in their outer orbit

and are potentially damaging. To a certain degree, free oxygen radicals are

physiological,23 and known to increase in the presence of several maternal or

fetal conditions, such as preeclampsia, diabetes, smoking, intrauterine

growth restriction and fetal distress .24-28 Also during uncomplicated labor,

free oxygen radicals are formed, since uterine contractions might be

regarded as a small series of ischemia-reperfusion injuries.21 Previous

research shows that the production of free oxygen radicals is increased in

case of fetal distress, and after inhalation of high fractions of inspired oxygen

in the presence of a normal fetal condition.24 Besides, a higher amount of

free oxygen radicals was seen after vaginal birth, compared to a planned

cesarean section. The effect of maternal hyperoxygenation for nonreassuring

fetal status on free oxygen radical activity has not been investigated yet.

To our knowledge there are no RCTs studing the beneficial effect of maternal

hyperoxygenation, or whether it outweighs the potential adverse effects in

the presence of suspected fetal distress during the second stage of labor.

Several reviews underline the need for such a study.1-3 We initiated an RCT to

investigate the clinical effect and the safety of maternal hyperoxygenation

upon suspected fetal distress during the second stage of labor. Our objective

was to assess the effects of maternal hyperoxygenation in case of suspected

fetal distress during the second stage of term labor on FHR, neonatal

outcome and mode of delivery.


Study design

This prospective, open label RCT was conducted in a tertiary teaching

hospital in The Netherlands. The study protocol has been published

previously.29 We included women aged ≥18 years, in labor at term with an

intended vaginal delivery of a singleton fetus in cephalic presentation with

suspected fetal distress, as defined by a suboptimal or abnormal FHR pattern

(according to the modified FIGO classification).30 Women were excluded with

any of the following: use of tobacco, recreational drugs, or alcohol during

pregnancy, pre-existing cardiac disease, pulmonary disease requiring

medication, diabetes, hyperthyroidism, anemia (hemoglobin <10.5 g/dL) or

recent use of any of the following medications: corticosteroids, anti-

hypertensives, magnesium sulphate, amiodarone, opioids, adriamycin,

bleomycin, actinomycin, menadione, promazine, thioridazine, or chloroquine.

Chapter 6

126

Fetal factors leading to exclusion were congenital malformations, signs of

infection during labor requiring antibiotics, and normal or pre-terminal FHR

pattern, or prolonged bradycardia (according to the modified FIGO

classification).30

Intervention and randomization

Patients completed informed consent at the outpatient clinic, or at the time

of their presentation to the delivery ward. Patients were randomized to

receive either conventional care (control group), or maternal

hyperoxygenation via a non-rebreathing mask with 100% oxygen at 10 L/min

until delivery (intervention group). In case co-interventions were required,

they were preferably initiated 10 minutes after randomization. If additional

interventions were required before these 10 minutes passed, the obstetric

staff could overrule the study protocol at any time. Randomization was

performed using a computer-generated sequence in random blocks of four

to six subjects. Stratification was applied for suboptimal or abnormal FHR.

Eligible women who gave informed consent were assigned a sealed opaque

envelope with treatment allocation. This envelope was opened during the

second stage of labor in case of suboptimal or abnormal FHR patterns. The

unopened, opaque and sealed envelopes were put back to be reused in the

study in the interest of the randomized block design.

Study outcomes

The primary outcome was the change of the FHR pattern after enrollment in

the study. Five aspects of the FIGO classification (baseline, variability, and

frequency, depth, and duration of decelerations), were assessed by an expert

team of three blinded gynecologists 10 minutes before and the period 5 to

15 minutes after randomization and compared between the intervention and

control group (figure 1). The gynecologists judged whether the FHR pattern

ameliorated, deteriorated or did not change. Furthermore, they also

classified the FHR according to the FIGO classification. In case of discrepancy

they reached consensus by discussion.

Neonatal outcomes included 1- and 5-minute Apgar score, venous and

arterial umbilical cord blood gas values (pH, base excess, pCO2), neonatal

intensive care unit (NICU) admission and perinatal death. Cord blood gas

analysis was performed using the ABL 90 flex blood gas analyzer (Radiometer

Benelux BV, Zoetermeer, The Netherlands). To assure validation of accurate

paired umbilical cord blood gas (UCBG) samples, the Modified Westgate

Criteria were used.31,32 In case only one valid sample was available, this was

categorized as venous.

Because of the brief lifespan of free radicals, it is extremely difficult to detect

them directly.33 Malondialdehyde (MDA), a by-product of lipid peroxidation,

is a non-invasive biomarker for free radical damage.34 To assess MDA, two

additional blood samples (one venous and one arterial sample) were drawn

from the umbilical cord in heparinized tubes and immediately centrifuged

and stored at − 20 °C. Once all samples were collected, they were

transported to the Laboratory of Genetic and Metabolic Diseases of the

Academic Medical Centre Amsterdam (Amsterdam, The Netherlands), where

total (free and bound) MDA was measured. Samples were analyzed in duplo

by stable isotope dilution with HPLC -tandem mass spectrometry, and means

were determined. Samples were analyzed by a Quattro Premier XE mass

spectrometer (Waters, Milford, MA, USA).

Maternal outcomes included mode of delivery, where assisted delivery was

defined as vacuum-assisted delivery, cesarean section, or fundal pressure.

Patient self reported side effects of oxygen admission and reasons for

discontinuation were recorded as well.

Statistical analysis

We based the sample size calculation on the limited available literature on

the expected effect of maternal hyperoxygenation on the primary outcome.

A study by Althabe et al. showed at least 50% improvement of deceleration

depth and duration in the cardiotocogram in the intervention group and 0%

improvement in the control group.7 To detect this effect using a two-tailed

Mann Whitney test, with an of 0.05 and 90% power, a sample size of 96

was required. To accommodate for 20% missing data, we planned to enroll

116 patients.


127

6

Fetal factors leading to exclusion were congenital malformations, signs of

infection during labor requiring antibiotics, and normal or pre-terminal FHR

pattern, or prolonged bradycardia (according to the modified FIGO

classification).30

Intervention and randomization

Patients completed informed consent at the outpatient clinic, or at the time

of their presentation to the delivery ward. Patients were randomized to

receive either conventional care (control group), or maternal

hyperoxygenation via a non-rebreathing mask with 100% oxygen at 10 L/min

until delivery (intervention group). In case co-interventions were required,

they were preferably initiated 10 minutes after randomization. If additional

interventions were required before these 10 minutes passed, the obstetric

staff could overrule the study protocol at any time. Randomization was

performed using a computer-generated sequence in random blocks of four

to six subjects. Stratification was applied for suboptimal or abnormal FHR.

Eligible women who gave informed consent were assigned a sealed opaque

envelope with treatment allocation. This envelope was opened during the

second stage of labor in case of suboptimal or abnormal FHR patterns. The

unopened, opaque and sealed envelopes were put back to be reused in the

study in the interest of the randomized block design.

Study outcomes

The primary outcome was the change of the FHR pattern after enrollment in

the study. Five aspects of the FIGO classification (baseline, variability, and

frequency, depth, and duration of decelerations), were assessed by an expert

team of three blinded gynecologists 10 minutes before and the period 5 to

15 minutes after randomization and compared between the intervention and

control group (figure 1). The gynecologists judged whether the FHR pattern

ameliorated, deteriorated or did not change. Furthermore, they also

classified the FHR according to the FIGO classification. In case of discrepancy

they reached consensus by discussion.

Neonatal outcomes included 1- and 5-minute Apgar score, venous and

arterial umbilical cord blood gas values (pH, base excess, pCO2), neonatal

intensive care unit (NICU) admission and perinatal death. Cord blood gas

analysis was performed using the ABL 90 flex blood gas analyzer (Radiometer

Benelux BV, Zoetermeer, The Netherlands). To assure validation of accurate

paired umbilical cord blood gas (UCBG) samples, the Modified Westgate

Criteria were used.31,32 In case only one valid sample was available, this was

categorized as venous.

Because of the brief lifespan of free radicals, it is extremely difficult to detect

them directly.33 Malondialdehyde (MDA), a by-product of lipid peroxidation,

is a non-invasive biomarker for free radical damage.34 To assess MDA, two

additional blood samples (one venous and one arterial sample) were drawn

from the umbilical cord in heparinized tubes and immediately centrifuged

and stored at − 20 °C. Once all samples were collected, they were

transported to the Laboratory of Genetic and Metabolic Diseases of the

Academic Medical Centre Amsterdam (Amsterdam, The Netherlands), where

total (free and bound) MDA was measured. Samples were analyzed in duplo

by stable isotope dilution with HPLC -tandem mass spectrometry, and means

were determined. Samples were analyzed by a Quattro Premier XE mass

spectrometer (Waters, Milford, MA, USA).

Maternal outcomes included mode of delivery, where assisted delivery was

defined as vacuum-assisted delivery, cesarean section, or fundal pressure.

Patient self reported side effects of oxygen admission and reasons for

discontinuation were recorded as well.


We based the sample size calculation on the limited available literature on

the expected effect of maternal hyperoxygenation on the primary outcome.

A study by Althabe et al. showed at least 50% improvement of deceleration

depth and duration in the cardiotocogram in the intervention group and 0%

improvement in the control group.7 To detect this effect using a two-tailed

Mann Whitney test, with an of 0.05 and 90% power, a sample size of 96

was required. To accommodate for 20% missing data, we planned to enroll

116 patients.

Chapter 6

128

Figure 1. The time frame of interest for analysis of outcome measures where

patients serve as their own control.

BPM = beats per minute, CTG = cardiotocogram

IBM SPSS Statistics software (version 25; IBM, Armonk, NY, USA) was used for

the statistical analysis. For comparison of continuous variables between

treatment groups, the independent T-test or Mann-Whitney U test was used

depending on the distribution. For categorical variables, the 2 test or

Fisher’s exact test was used depending on the expected number of

observations per category. In a post-hoc analysis, we calculated the Pearsons’

correlation coefficient and the Spearman’s correlation coefficient to explore

the relation between the duration of oxygen administration and continuous

outcome variables. The analyses were performed for the entire group, as well

as for the subgroups of suboptimal FHR pattern and abnormal FHR pattern.

In addition, we performed a subgroup analysis for the small for gestational

age (SGA) fetuses (<10th percentile). The primary analysis was an intention-

to-treat analysis in the overall study population. However, since we did not

impute missings, the FHR analysis included only women with a complete FHR

tracing. We anticipated that in some cases it might not be possible to give

oxygen admission according to study protocol. To explore the effect of these

protocol deviations we also performed per-protocol analyses, excluding

women who had received <5 minutes of oxygen admission.

Interim analysis

A planned interim analysis was performed after 50% of the patients had been

included in the study to investigate potential safety issues regarding oxygen

administration. There were no significant differences in the number of

neonates with a 5-minute Apgar score <7, pHa <7.05, NICU admissions, or

perinatal death between the intervention and control group.

Ethical considerations

This study was approved by the Central Committee on Research Involving

Human Subjects (protocol number NL53018.000.15). The study was

registered in the EudraCT database (2015-001654-15) and in the Dutch Trial

Register (NTR5461).

Results

Between March 2016 and April 2018, a total of 376 women gave informed

consent for the study. Of those, 117 women had an abnormal or suboptimal

FHR and underwent randomization for the study. A total of 57 women were

assigned to receive oxygen supplementation and 60 women were assigned

to receive conventional care (figure 2).

The baseline characteristics of the study population showed a similar

distribution for both treatment groups (table 1). Within the first 10 minutes

after randomization, 10 women received other resuscitation techniques, 8

(13%) of which were in the control group and 2 (3.5%) in the intervention

group (p = 0.10). These interventions included maternal repositioning,

discontinuation of pushing, and adjustment of the dosage of oxytocin

infusion.

FHR pattern From 71 of 117 women (61%), FHR pattern was available 10 minutes before

start of the study, and the period 5-15 minutes after start of the study. The

other 46 women delivered within the 15 minutes after start of the study,


129

6

Figure 1. The time frame of interest for analysis of outcome measures where

patients serve as their own control.

BPM = beats per minute, CTG = cardiotocogram

IBM SPSS Statistics software (version 25; IBM, Armonk, NY, USA) was used for

the statistical analysis. For comparison of continuous variables between

treatment groups, the independent T-test or Mann-Whitney U test was used

depending on the distribution. For categorical variables, the 2 test or

Fisher’s exact test was used depending on the expected number of

observations per category. In a post-hoc analysis, we calculated the Pearsons’

correlation coefficient and the Spearman’s correlation coefficient to explore

the relation between the duration of oxygen administration and continuous

outcome variables. The analyses were performed for the entire group, as well

as for the subgroups of suboptimal FHR pattern and abnormal FHR pattern.

In addition, we performed a subgroup analysis for the small for gestational

age (SGA) fetuses (<10th percentile). The primary analysis was an intention-

to-treat analysis in the overall study population. However, since we did not

impute missings, the FHR analysis included only women with a complete FHR

tracing. We anticipated that in some cases it might not be possible to give

oxygen admission according to study protocol. To explore the effect of these

protocol deviations we also performed per-protocol analyses, excluding

women who had received <5 minutes of oxygen admission.

Interim analysis

A planned interim analysis was performed after 50% of the patients had been

included in the study to investigate potential safety issues regarding oxygen

administration. There were no significant differences in the number of

neonates with a 5-minute Apgar score <7, pHa <7.05, NICU admissions, or

perinatal death between the intervention and control group.

Ethical considerations

This study was approved by the Central Committee on Research Involving

Human Subjects (protocol number NL53018.000.15). The study was

registered in the EudraCT database (2015-001654-15) and in the Dutch Trial

Register (NTR5461).

Results

Between March 2016 and April 2018, a total of 376 women gave informed

consent for the study. Of those, 117 women had an abnormal or suboptimal

FHR and underwent randomization for the study. A total of 57 women were

assigned to receive oxygen supplementation and 60 women were assigned

to receive conventional care (figure 2).

The baseline characteristics of the study population showed a similar

distribution for both treatment groups (table 1). Within the first 10 minutes

after randomization, 10 women received other resuscitation techniques, 8

(13%) of which were in the control group and 2 (3.5%) in the intervention

group (p = 0.10). These interventions included maternal repositioning,

discontinuation of pushing, and adjustment of the dosage of oxytocin

infusion.

FHR pattern From 71 of 117 women (61%), FHR pattern was available 10 minutes before

start of the study, and the period 5-15 minutes after start of the study. The

other 46 women delivered within the 15 minutes after start of the study,

Chapter 6

130

hence comparison of the FHR before and after the study for the set

timeframe was not possible. Out of 71 women in the FHR analysis, five

women (14.3%) in the control group and two women (5.6%) in the

intervention group received other resuscitation techniques within the first 10

minutes after randomization (p = 0.26).

Figure 2. Trial flow diagram.

* four women had suspected infection that was treated with antibiotics, two

women had diabetes, two women smoked during pregnancy, one woman

delivered prematurely, one woman delivered at 42 weeks and had anemia,

and there were three fetuses with congenital abnormalities

(cheilognathopalatoschisis, hypospadias, and pyelectasis).

** three women had suspected infection that was treated with antibiotics,

two women smoked during pregnancy, one woman delivered prematurely,

and one woman delivered at 42 weeks

Table 1. Patient characteristics of women randomized to hyperoxygenation

treatment or conventional treatment.

Data are mean±SD or n (%)

BMI = body-mass index, SGA = small for gestational age, FHR= fetal heart

rate

The changes in FHR were significantly different after maternal

hyperoxygenation compared to conventional care (p = 0.02, table 2).

Deterioration is seen three times more often in the control group than in the

intervention group (42.9% vs. 13.9%). Furthermore, amelioration of the FHR

is seen almost three times as often in the intervention group (16.7% vs.

5.7%). The changes in FHR were not significant in any of the subgroups (table

2).

Amelioration of FIGO classification was seen more than four times as often in

the intervention than in the control group (13.9 vs. 2.9%, p = 0.20). The

incidence of deterioration of the FIGO classification was observed three

times more often in the control group compared to the intervention group

(34.3 vs. 11.1%, table 3). The changes in FIGO classification were significant

(p = 0.03). None of the subgroup analysis for changes of FIGO classification

showed significance (table 3).

Maternal

hyperoxygenation

n=57

Conventional

care

n=60

p

Maternal age

(years)

31.8 ± 4.2 30.7 ±3.4 0.12

Gestational age

(days)

279 ±9.0 280 ±8.8 0.63

Parity ≥1 22 (38.6%) 27 (45%) 0.48

BMI (kg/m2) 25 ± 4.7 24 ± 5.0 0.24

Fetal sex male 30 (52.6%) 26 (43.3%) 0.31

Birth weight (gr) 3510 ± 471.7 3541.4 ±560.2 0.75

SGA 6 (10.5%) 5 (8.3%) 0.69

Suboptimal FHR pattern 24 (42.1%) 34 (56.7%) 0.12

Abnormal FHR pattern 33 (57.9%) 26 (43.3%) 0.12


131

6

hence comparison of the FHR before and after the study for the set

timeframe was not possible. Out of 71 women in the FHR analysis, five

women (14.3%) in the control group and two women (5.6%) in the

intervention group received other resuscitation techniques within the first 10

minutes after randomization (p = 0.26).

Figure 2. Trial flow diagram.

* four women had suspected infection that was treated with antibiotics, two

women had diabetes, two women smoked during pregnancy, one woman

delivered prematurely, one woman delivered at 42 weeks and had anemia,

and there were three fetuses with congenital abnormalities

(cheilognathopalatoschisis, hypospadias, and pyelectasis).

** three women had suspected infection that was treated with antibiotics,

two women smoked during pregnancy, one woman delivered prematurely,

and one woman delivered at 42 weeks

Table 1. Patient characteristics of women randomized to hyperoxygenation

treatment or conventional treatment.

Data are mean±SD or n (%)

BMI = body-mass index, SGA = small for gestational age, FHR= fetal heart

rate

The changes in FHR were significantly different after maternal

hyperoxygenation compared to conventional care (p = 0.02, table 2).

Deterioration is seen three times more often in the control group than in the

intervention group (42.9% vs. 13.9%). Furthermore, amelioration of the FHR

is seen almost three times as often in the intervention group (16.7% vs.

5.7%). The changes in FHR were not significant in any of the subgroups (table

2).

Amelioration of FIGO classification was seen more than four times as often in

the intervention than in the control group (13.9 vs. 2.9%, p = 0.20). The

incidence of deterioration of the FIGO classification was observed three

times more often in the control group compared to the intervention group

(34.3 vs. 11.1%, table 3). The changes in FIGO classification were significant

(p = 0.03). None of the subgroup analysis for changes of FIGO classification

showed significance (table 3).

Maternal

hyperoxygenation

n=57

Conventional

care

n=60

p

Maternal age

(years)

31.8 ± 4.2 30.7 ±3.4 0.12

Gestational age

(days)

279 ±9.0 280 ±8.8 0.63

Parity ≥1 22 (38.6%) 27 (45%) 0.48

BMI (kg/m2) 25 ± 4.7 24 ± 5.0 0.24

Fetal sex male 30 (52.6%) 26 (43.3%) 0.31

Birth weight (gr) 3510 ± 471.7 3541.4 ±560.2 0.75

SGA 6 (10.5%) 5 (8.3%) 0.69

Suboptimal FHR pattern 24 (42.1%) 34 (56.7%) 0.12

Abnormal FHR pattern 33 (57.9%) 26 (43.3%) 0.12

Chapter 6

132

Table 2. Changes in fetal heart rate (FHR) pattern following maternal

hyperoxygenations versus conventional care in the total study population.

Deterioration Equal Amelioration p

Total study population

Maternal

hyperoxygenation

Conventional care

5 (13.9%)

15 (42.9%)

25 (69.4%)

18 (51.4%)

6 (16.7%)

2 (5.7%)

0.02

Abnormal FHR

Maternal

hyperoxygenation

Conventional care

2 (10%)

5 (35.7%)

13 (65%)

7 (50%)

5 (25%)

2 (14.3%)

0.18

Suboptimal FHR

Maternal

hyperoxygenation

Conventional care

3 (18.8%)

10 (47.6%)

12 (75%)

11 (52.4%)

1 (6.3%)

0

0.12

SGA

Maternal

hyperoxygenation

Conventional care

1 (20%)

2 (66.7%)

3 (60%)

1 (33.3%)

1 (20%)

0

0.38

Data are n (%).

FHR= fetal heart rate, SGA = small for gestational age

Neonatal outcome and mode of delivery

Four neonates had a 5-minute Apgar score <7, three in the control group

(5.0%), and one (1.8%) in the intervention group (p = 0.62, table 4). In the

intervention group thirteen (28.9%) neonates had an arterial pH <7.20

compared to 22 (41.5%) in the control group (p = 0.19). Fewer episiotomies

on fetal indication were performed in the oxygen group (n=17, 29.8%),

compared to the control group (n=27, 45.0%, p = 0.09). A total of twenty

assisted deliveries were performed, of which eight in the intervention group

(14%) and twelve in the control group (20%, p = 0.39). In the intervention

group, one neonate (1.8%) was admitted to the NICU, and in the control

group, two neonates were admitted (3.3%, p = 1.00). No neonatal deaths

occurred in this study. The mean arterial MDA was higher in the maternal

hyperoxygenation group, but this was not significant (4.45 (3.74-5.59) vs 4.13

(3.39-4.75), p = 0.09). The mean venous MDA was also (non-significantly)

higher in the intervention group (4.68±1.25 vs 4.33±1.14, p = 0.15).

Table 3. Changes in FIGO classification following maternal




Maternal

hyperoxygenation

Conventional care

4 (11.1%)

12 (34.3%)

27 (75%)

22 (62.9%)

5 (13.9%)

1 (2.9%)

0.03

Abnormal FHR

Maternal

hyperoxygenation

Conventional care

1 (5.0%)

4 (28.6%)

15 (75%)

9 (64.3%)

4 (20%)

1 (7.1%)

0.12

Suboptimal FHR

Maternal

hyperoxygenation

Conventional care

3 (18.8%)

8 (38.1%)

12 (75%)

13 (61.9%)

1 (6.3%)

0

0.26

SGA

Maternal

hyperoxygenation

Conventional care

1 (20%)

1 (33.3%)

3 (60%)

2 (66.7%)

1 (20%)

0

0.69

Data are n (%)


In the subgroup analyses, we did not find statistically significant differences

between maternal hyperoxygenation and conventional care in 1- and 5-

minute Apgar score, nor in NICU admissions (table 5). In the subgroup with

abnormal FHR patterns, fewer episiotomies for fetal indication were

performed in the maternal oxygenation group than in the conventional

treatment group (n=8 (24.2%) versus n=17 (65.4%), p = 0.001). Maternal outcome

Median duration of oxygen admission was twelve minutes (range 0 to 75

minutes). A total of nineteen women (33%) stopped oxygen administration


133

6

Table 2. Changes in fetal heart rate (FHR) pattern following maternal




Maternal

hyperoxygenation

Conventional care

5 (13.9%)

15 (42.9%)

25 (69.4%)

18 (51.4%)

6 (16.7%)

2 (5.7%)

0.02

Abnormal FHR

Maternal

hyperoxygenation

Conventional care

2 (10%)

5 (35.7%)

13 (65%)

7 (50%)

5 (25%)

2 (14.3%)

0.18

Suboptimal FHR

Maternal

hyperoxygenation

Conventional care

3 (18.8%)

10 (47.6%)

12 (75%)

11 (52.4%)

1 (6.3%)

0

0.12

SGA

Maternal

hyperoxygenation

Conventional care

1 (20%)

2 (66.7%)

3 (60%)

1 (33.3%)

1 (20%)

0

0.38

Data are n (%).


Neonatal outcome and mode of delivery

Four neonates had a 5-minute Apgar score <7, three in the control group

(5.0%), and one (1.8%) in the intervention group (p = 0.62, table 4). In the

intervention group thirteen (28.9%) neonates had an arterial pH <7.20

compared to 22 (41.5%) in the control group (p = 0.19). Fewer episiotomies

on fetal indication were performed in the oxygen group (n=17, 29.8%),

compared to the control group (n=27, 45.0%, p = 0.09). A total of twenty

assisted deliveries were performed, of which eight in the intervention group

(14%) and twelve in the control group (20%, p = 0.39). In the intervention

group, one neonate (1.8%) was admitted to the NICU, and in the control

group, two neonates were admitted (3.3%, p = 1.00). No neonatal deaths

occurred in this study. The mean arterial MDA was higher in the maternal

hyperoxygenation group, but this was not significant (4.45 (3.74-5.59) vs 4.13

(3.39-4.75), p = 0.09). The mean venous MDA was also (non-significantly)

higher in the intervention group (4.68±1.25 vs 4.33±1.14, p = 0.15).

Table 3. Changes in FIGO classification following maternal




Maternal

hyperoxygenation

Conventional care

4 (11.1%)

12 (34.3%)

27 (75%)

22 (62.9%)

5 (13.9%)

1 (2.9%)

0.03

Abnormal FHR

Maternal

hyperoxygenation

Conventional care

1 (5.0%)

4 (28.6%)

15 (75%)

9 (64.3%)

4 (20%)

1 (7.1%)

0.12

Suboptimal FHR

Maternal

hyperoxygenation

Conventional care

3 (18.8%)

8 (38.1%)

12 (75%)

13 (61.9%)

1 (6.3%)

0

0.26

SGA

Maternal

hyperoxygenation

Conventional care

1 (20%)

1 (33.3%)

3 (60%)

2 (66.7%)

1 (20%)

0

0.69

Data are n (%)


In the subgroup analyses, we did not find statistically significant differences

between maternal hyperoxygenation and conventional care in 1- and 5-

minute Apgar score, nor in NICU admissions (table 5). In the subgroup with

abnormal FHR patterns, fewer episiotomies for fetal indication were

performed in the maternal oxygenation group than in the conventional

treatment group (n=8 (24.2%) versus n=17 (65.4%), p = 0.001). Maternal outcome

Median duration of oxygen admission was twelve minutes (range 0 to 75

minutes). A total of nineteen women (33%) stopped oxygen administration

Chapter 6

134

before the infant was born, seventeen (89%) of whom gave discomfort as the

reason for the premature dropout. A total of 36 women (63%) reported no

side effects at all from the oxygen admission nor the mask. One woman

stated her previous headache went away after the oxygen admission. Table 4. Neonatal outcome and mode of delivery following maternal

hyperoxygenation or conventional care in the intention-to-treat analysis.

Outcome parameter Maternal

hyperoxygenation

Conventional

care

p

Apgar score 1 min ¥ [n=117] 9 (8.5-9) 9 (8.25-9) 0.77

Apgar Score 1 min <7 * [n=117] 5 (8.8%) 6 (10%) 0.82

Apgar Score 5 min ¥ [n=117] 10 (10-10) 10 (10-10) 0.13

Apgar Score 5 min <7 ** [n=117] 1 (1.8%) 3 (5.0%) 0.62

pH arterial ¥ [n=98] 7.22 (7.19-7.26) 7.20 (7.16-

7.27)

0.35

pH arterial <7. 05 ** [n=98] 1 (2.2%) 0 0.46

pH venous ¥ [n=117] 7.30 (7.26-7.34) 7.30 (7.26-

7.35)

0.94

Base Excess arterial ¥ [n=96] -6 (-8/-3) -6 (-8/-4) 0.69

pCO2 arterial ¥ [n=97] 56 (51.5-59.5) 57 (52-62) 0.54

MDA arterial ¥ 4.45 (3.68-5.35) 4.15 (3.40-

4.75)

0.15

MDA venous § [n=99] 4.7±1.3 4.4±1.1 0.21

Episiotomy fetal indication * [n=117] 17 (29.8%) 27 (45.0%) 0.09

Assisted delivery * [n=117]

Of which:

Cesarean section

Vacuum assisted delivery

Fundal pressure

8 (14%)

2 (3.5%)

5 (8.8%)

1 (1.8%)

12 (20%)

2 (3.3%)

9(15%)

3 (5%)

0.39

Active second stage of labor (min) § [n=116] 43.5±30.3 38.8±30.6 0.40

Data are mean±SD, median (IQR), or n (%).

Data are analyzed by * 2 test, **Fisher’s exact test, ¥Mann-Whitney U test,

or §Independent t-test.

MDA = malondialdehyde, pCO2= Partial carbon dioxide pressure

Table 5. Subgroup analysis of neonatal outcomes and mode of delivery on

intention-to-treat basis.

Outcome parameter

Maternal

hyperoxygenation Conventional care p

Apgar score 1 min <7

Abnormal FHR ** [n= 59]

Suboptimal FHR ** [n= 58]

SGA [n= 11]

4 (12.1%)

1 (4.2%)

0

4 (15.4%)

2 (5.9%)

0

0.72

1.00

-




SGA [n= 11]

0

0

0

2 (7.7%)

1 (2.9%)

0

0.19

1.00

-

pH arterial <7.00


Suboptimal FHR [n= 51]

SGA [n= 10]

1 (4.3%)

0

0

0

0

0

0.49

-

-

pH venous <7.10



SGA [n= 11]

1 (3.0%)

0

0

0

0

0

1.00

-

-

pCO2 arterial

Abnormal FHR ¥ [n= 46]

Suboptimal FHR § [n= 51]

SGA § [n= 10]

57 (52-61)

54.6 ± 6.0

53.2 ± 4.6

54 (49-62)

57.6 ± 7.1

52.8 ± 11.1

0.47

0.12

0.94

pCO2 venous



SGA ¥ [n= 11]

45 (39-48.5)

39.1 ± 5.8

38.5 (36.5-45.25)

44 (40.5-47)

42.1 ± 5.0

41 (36-47)

0.87

0.04

0.54

MDA arterial



SGA ¥ [n= 9]

4.55 (3.68-5.35)

4.38±1.3

5.15 (3.03-6.98)

4.15 (3.40-4.45)

4.36±1.2

4.55 (4.31-4.75)

0.11

0.96

0.73

MDA venous



4.55 (4.05-5.40)

4.64±1.3

4.4 (3.95-5.0)

4.34±1.4

0.50

0.45


135

6

before the infant was born, seventeen (89%) of whom gave discomfort as the

reason for the premature dropout. A total of 36 women (63%) reported no

side effects at all from the oxygen admission nor the mask. One woman

stated her previous headache went away after the oxygen admission. Table 4. Neonatal outcome and mode of delivery following maternal

hyperoxygenation or conventional care in the intention-to-treat analysis.

Outcome parameter Maternal

hyperoxygenation

Conventional

care

p

Apgar score 1 min ¥ [n=117] 9 (8.5-9) 9 (8.25-9) 0.77

Apgar Score 1 min <7 * [n=117] 5 (8.8%) 6 (10%) 0.82

Apgar Score 5 min ¥ [n=117] 10 (10-10) 10 (10-10) 0.13

Apgar Score 5 min <7 ** [n=117] 1 (1.8%) 3 (5.0%) 0.62

pH arterial ¥ [n=98] 7.22 (7.19-7.26) 7.20 (7.16-

7.27)

0.35

pH arterial <7. 05 ** [n=98] 1 (2.2%) 0 0.46

pH venous ¥ [n=117] 7.30 (7.26-7.34) 7.30 (7.26-

7.35)

0.94

Base Excess arterial ¥ [n=96] -6 (-8/-3) -6 (-8/-4) 0.69

pCO2 arterial ¥ [n=97] 56 (51.5-59.5) 57 (52-62) 0.54

MDA arterial ¥ 4.45 (3.68-5.35) 4.15 (3.40-

4.75)

0.15

MDA venous § [n=99] 4.7±1.3 4.4±1.1 0.21

Episiotomy fetal indication * [n=117] 17 (29.8%) 27 (45.0%) 0.09

Assisted delivery * [n=117]

Of which:

Cesarean section

Vacuum assisted delivery

Fundal pressure

8 (14%)

2 (3.5%)

5 (8.8%)

1 (1.8%)

12 (20%)

2 (3.3%)

9(15%)

3 (5%)

0.39

Active second stage of labor (min) § [n=116] 43.5±30.3 38.8±30.6 0.40


Data are analyzed by * 2 test, **Fisher’s exact test, ¥Mann-Whitney U test,

or §Independent t-test.

MDA = malondialdehyde, pCO2= Partial carbon dioxide pressure

Table 5. Subgroup analysis of neonatal outcomes and mode of delivery on

intention-to-treat basis.

Outcome parameter

Maternal

hyperoxygenation Conventional care p




SGA [n= 11]

4 (12.1%)

1 (4.2%)

0

4 (15.4%)

2 (5.9%)

0

0.72

1.00

-




SGA [n= 11]

0

0

0

2 (7.7%)

1 (2.9%)

0

0.19

1.00

-

pH arterial <7.00



SGA [n= 10]

1 (4.3%)

0

0

0

0

0

0.49

-

-

pH venous <7.10



SGA [n= 11]

1 (3.0%)

0

0

0

0

0

1.00

-

-

pCO2 arterial



SGA § [n= 10]

57 (52-61)

54.6 ± 6.0

53.2 ± 4.6

54 (49-62)

57.6 ± 7.1

52.8 ± 11.1

0.47

0.12

0.94

pCO2 venous



SGA ¥ [n= 11]

45 (39-48.5)

39.1 ± 5.8

38.5 (36.5-45.25)

44 (40.5-47)

42.1 ± 5.0

41 (36-47)

0.87

0.04

0.54

MDA arterial



SGA ¥ [n= 9]

4.55 (3.68-5.35)

4.38±1.3

5.15 (3.03-6.98)

4.15 (3.40-4.45)

4.36±1.2

4.55 (4.31-4.75)

0.11

0.96

0.73

MDA venous



4.55 (4.05-5.40)

4.64±1.3

4.4 (3.95-5.0)

4.34±1.4

0.50

0.45

Chapter 6

136

SGA ¥ [n= 11] 4.60 (3.68-6.86) 4.20 (3.43-5.03) 0.66

Episiotomy fetal indication

Abnormal FHR * [n= 59]

Suboptimal FHR * [n=58]

SGA ** [n= 11]

8 (24.2%)

9 (37.5%)

4 (67%)

17 (65.4%)

10 (29.4%)

5 (100%)

<0.01

0.52

0.46

Assisted delivery



SGA ** [n= 11]

6 (18.2%)

2 (8.3%)

1 (16.7%)

7 (26.9%)

5 (14.7%)

1 (20%)

0.42

0.69

1.00

Active second stage of labor



SGA ¥ [n= 11]

26 (17.75-55.75)

48.4 ± 28.1

59 (38-78.75)

20.5 (11.75-55.25)

44.7±33.3

24 (8-46.5)

0.14

0.66

0.05


Data are analyzed by * 2 test, **Fisher’s exact test, ¥ Mann-Whitney U test,

or § Independent t-test.

FHR = fetal heart rate, MDA = malondialdehyde, pCO2 = Partial carbon

dioxide pressure

Per-protocol analysis

We performed a per-protocol analysis in which we excluded thirteen women

allocated to the intervention group who had oxygen administration for <5

minutes. No women in the control group received additional oxygen. In

addition, we excluded twenty women who had been included despite the

presence of exclusion. All results of the per-protocol analyses were similar to

the intention-to-treat analyses.

Post-hoc analysis

We did a post-hoc analysis on the relationship between the duration of

oxygen admission and umbilical cord blood parameters, MDA and Apgar

score. No correlation was found between duration of oxygen admission and

arterial pH, venous base excess, and arterial MDA. A small, non-significant

correlation was found between duration of oxygen and venous MDA, arterial

base excess, arterial pCO2, and 1-minute Apgar score. A negative correlation

was found between the duration of oxygen and 5-minute Apgar score (rho =

with lower 5-minute Apgar score. There was a negative correlation between

the duration of oxygen admission and venous pH (rho = -0.27, n= 57, p =

0.05), with longer duration of oxygen admission associated with lower venous

pH. A positive correlation was found between the duration of oxygen

admission and venous pCO2 (rho = 0.33, n=57, p = 0.01), with longer

duration of oxygen admission associated with higher pCO2 levels.

Discussion

Main findings

This study shows that maternal hyperoxygenation with 10L/min oxygen

supplementation has a significant positive effect on the FHR pattern in the

presence of fetal distress during the second stage of labor compared to

conventional care. Amelioration of the FHR pattern was almost three times as

often observed in the intervention group, and deterioration was seen more

than three times more often in the control group. We found no adverse

effects regarding neonatal outcome or mode of delivery or formation of free

oxygen radicals. We did find fewer episiotomies on fetal indication following

maternal hyperoxygenation compared to conventional care in the subgroup

with an abnormal FHR pattern.

Strengths and limitations

This is the first study employing a randomized design to investigate the effect

of maternal hyperoxygenation in an acute obstetric situation in the presence

of fetal distress during the second stage of labor.1 In addition, this study

takes into account both beneficial and harmful effects of maternal

hyperoxygenation.

However, practical and safety issues led to some limitations of this study.

Ideally, the primary outcome measure should have been neonatal morbidity.

To achieve sufficient power to address this outcome measure would require a

sample size of over 10,000 women.2 Because some studies raised concerns

about the potentially harmful effects of maternal hyperoxygenation, we chose

not to expose such a large group of women and their fetuses to this

intervention before its safety had been further investigated.


SGA ** [n= 11]

9 (37.5%)

4 (67%)

10 (29.4%)

5 (100%)

1

0.52

0.46

Assisted delivery


Suboptimal FHR ** [n=

58]

SGA ** [n= 11]

6 (18.2%)

2 (8.3%)

1 (16.7%)

7 (26.9%)

5 (14.7%)

1 (20%)

0.42

0.69

1.00




SGA ¥ [n= 11]

26 (17.75-55.75)

48.4 ± 28.1

59 (38-78.75)

20.5 (11.75-

55.25)

44.7±33.3

24 (8-46.5)

0.14

0.66

0.05





dioxide pressure








Post-hoc analysis








-0.3, n=57, p = 0.02), with longer duration of oxygen admission associated


137

6

SGA ¥ [n= 11] 4.60 (3.68-6.86) 4.20 (3.43-5.03) 0.66

Episiotomy fetal indication



SGA ** [n= 11]

8 (24.2%)

9 (37.5%)

4 (67%)

17 (65.4%)

10 (29.4%)

5 (100%)

<0.01

0.52

0.46

Assisted delivery



SGA ** [n= 11]

6 (18.2%)

2 (8.3%)

1 (16.7%)

7 (26.9%)

5 (14.7%)

1 (20%)

0.42

0.69

1.00




SGA ¥ [n= 11]

26 (17.75-55.75)

48.4 ± 28.1

59 (38-78.75)

20.5 (11.75-55.25)

44.7±33.3

24 (8-46.5)

0.14

0.66

0.05





dioxide pressure








Post-hoc analysis








with lower 5-minute Apgar score. There was a negative correlation between

the duration of oxygen admission and venous pH (rho = -0.27, n= 57, p =

0.05), with longer duration of oxygen admission associated with lower venous

pH. A positive correlation was found between the duration of oxygen

admission and venous pCO2 (rho = 0.33, n=57, p = 0.01), with longer

duration of oxygen admission associated with higher pCO2 levels.

Discussion

Main findings

This study shows that maternal hyperoxygenation with 10L/min oxygen

supplementation has a significant positive effect on the FHR pattern in the

presence of fetal distress during the second stage of labor compared to

conventional care. Amelioration of the FHR pattern was almost three times as

often observed in the intervention group, and deterioration was seen more

than three times more often in the control group. We found no adverse

effects regarding neonatal outcome or mode of delivery or formation of free

oxygen radicals. We did find fewer episiotomies on fetal indication following

maternal hyperoxygenation compared to conventional care in the subgroup

with an abnormal FHR pattern.

Strengths and limitations

This is the first study employing a randomized design to investigate the effect

of maternal hyperoxygenation in an acute obstetric situation in the presence

of fetal distress during the second stage of labor.1 In addition, this study

takes into account both beneficial and harmful effects of maternal

hyperoxygenation.

However, practical and safety issues led to some limitations of this study.

Ideally, the primary outcome measure should have been neonatal morbidity.

To achieve sufficient power to address this outcome measure would require a

sample size of over 10,000 women.2 Because some studies raised concerns

about the potentially harmful effects of maternal hyperoxygenation, we chose

not to expose such a large group of women and their fetuses to this

intervention before its safety had been further investigated.


SGA ** [n= 11]

9 (37.5%)

4 (67%)

10 (29.4%)

5 (100%)

1

0.52

0.46

Assisted delivery


Suboptimal FHR ** [n=

58]

SGA ** [n= 11]

6 (18.2%)

2 (8.3%)

1 (16.7%)

7 (26.9%)

5 (14.7%)

1 (20%)

0.42

0.69

1.00




SGA ¥ [n= 11]

26 (17.75-55.75)

48.4 ± 28.1

59 (38-78.75)

20.5 (11.75-

55.25)

44.7±33.3

24 (8-46.5)

0.14

0.66

0.05





dioxide pressure








Post-hoc analysis








-0.3, n=57, p = 0.02), with longer duration of oxygen admission associated

Chapter 6

138

Hence we took the FHR pattern as the primary outcome of our study, which

represents a surrogate endpoint.

We may have underestimated the added effect of maternal

hyperoxygenation by allowing the use of other intrauterine resuscitation

methods. However, it was found to be unethical to withhold the fetus from

commonly used intrauterine resuscitation techniques for a long period.

Therefore we aimed for 10 minutes without other interventions. Nevertheless,

other intrauterine resuscitation techniques were performed within these first

10 minutes in ten patients, but this number was equal in both groups.

Despite widespread use of oxygen as a form of intrauterine resuscitation,

there is no guideline regarding the optimal dose range or duration. Our dose

of 10L/min is consistent with other studies.13,15,18,35 This dose requires the use

of a non-rebreathing facemask, which impedes blinding of both participants

and delivery room staff. Other studies using a facemask neither used a sham

procedure.15,18,20,35,36 Although patients can be blinded when using a nasal

cannula attached to a covered flow meter,19,22 this was not feasible with the

administered dose. Potential bias because of the unblinded nature of our

study may have resulted in an overestimation of subjective outcomes in

either of the treatment arms, but probably has been of little influence on the

FHR assessments. We aimed to minimize the influence of bias by blinding the

FHR expert panel for treatment.

Women receiving oxygen for <5 minutes were excluded from the per-

protocol analysis. This was based on a study by Vasicka et al., showing a rise

of pO2 in maternal arterial blood, amniotic fluid, and cord blood when 100%

oxygen was breathed for 5 minutes compared to room air (21% oxygen).37

Results did not change significantly after excluding these patients.

Despite proper training of all study personnel, some irregularities occurred

pertaining to the complex setting of the study on the obstetric ward. We

chose to use sealed opaque envelopes for randomization but unfortunately,

four envelopes were used but not registered properly and we were not able

to verify which women were included.

For these cases, in the interest of blinding, we chose to randomly assign new

participants to either the intervention or control group. Furthermore, 21

women were incorrectly included having an exclusion criteria. In addition, we

included one patient more than we originally aimed for. Factors that may

have contributed to this violation of the study protocol are the acute

obstetric situation and the strict exclusion criteria. A patient could be found

eligible for the study, but become ineligible during progression of labor, e.g.

by developing fever. We decided to include all women who were

randomized to this study. The per-protocol analysis was both done with and

without excluding the incorrectly included patients and did not alter the

study results or indicate safety hazards.

This is the first RCT measuring free oxygen radical activity as a result of

maternal hyperoxygenation in a distressed fetus. We did not find an increase

in free oxygen radicals following maternal oxygenation. Since free oxygen

radicals cannot be measured directly, we chose MDA as a surrogate marker,

as this can be considered as a non-invasive biomarker for free radical

damage on DNA and cell membranes.24,26-28,34 Even though this marker is

used in previous studies, it is hard to determine normal limits. We were able

to compare MDA values between the intervention and control group, but we

were unable to compare our study results to outcomes from other studies. All

samples were analyzed in duplo, so they would function as their own

controls. Due to potentially harmful effects of increased oxygen radicals, we

intended to exclude women who had an underlying condition that potentially

caused increased oxygen radical activity by itself. However, unfortunately 21

women were wrongly included, which may have influenced the study results.

Interpretation

This study shows that maternal hyperoxygenation has a significant positive

effect on the FHR pattern, compared to conventional care. This outcome

cannot be explained by the use of cointerventions, which was similar in both

groups. The relatively high frequency of deterioration of FHR patterns in both

groups might be explained by the chosen study design, at the onset of the

second stage of labor. As a result, the FHR pattern of some participants is

compared between the end of the first stage of labor, and the start of the

second stage of labor.


139

6

Hence we took the FHR pattern as the primary outcome of our study, which

represents a surrogate endpoint.

We may have underestimated the added effect of maternal

hyperoxygenation by allowing the use of other intrauterine resuscitation

methods. However, it was found to be unethical to withhold the fetus from

commonly used intrauterine resuscitation techniques for a long period.

Therefore we aimed for 10 minutes without other interventions. Nevertheless,

other intrauterine resuscitation techniques were performed within these first

10 minutes in ten patients, but this number was equal in both groups.

Despite widespread use of oxygen as a form of intrauterine resuscitation,

there is no guideline regarding the optimal dose range or duration. Our dose

of 10L/min is consistent with other studies.13,15,18,35 This dose requires the use

of a non-rebreathing facemask, which impedes blinding of both participants

and delivery room staff. Other studies using a facemask neither used a sham

procedure.15,18,20,35,36 Although patients can be blinded when using a nasal

cannula attached to a covered flow meter,19,22 this was not feasible with the

administered dose. Potential bias because of the unblinded nature of our

study may have resulted in an overestimation of subjective outcomes in

either of the treatment arms, but probably has been of little influence on the

FHR assessments. We aimed to minimize the influence of bias by blinding the

FHR expert panel for treatment.

Women receiving oxygen for <5 minutes were excluded from the per-

protocol analysis. This was based on a study by Vasicka et al., showing a rise

of pO2 in maternal arterial blood, amniotic fluid, and cord blood when 100%

oxygen was breathed for 5 minutes compared to room air (21% oxygen).37

Results did not change significantly after excluding these patients.

Despite proper training of all study personnel, some irregularities occurred

pertaining to the complex setting of the study on the obstetric ward. We

chose to use sealed opaque envelopes for randomization but unfortunately,

four envelopes were used but not registered properly and we were not able

to verify which women were included.

For these cases, in the interest of blinding, we chose to randomly assign new

participants to either the intervention or control group. Furthermore, 21

women were incorrectly included having an exclusion criteria. In addition, we

included one patient more than we originally aimed for. Factors that may

have contributed to this violation of the study protocol are the acute

obstetric situation and the strict exclusion criteria. A patient could be found

eligible for the study, but become ineligible during progression of labor, e.g.

by developing fever. We decided to include all women who were

randomized to this study. The per-protocol analysis was both done with and

without excluding the incorrectly included patients and did not alter the

study results or indicate safety hazards.

This is the first RCT measuring free oxygen radical activity as a result of

maternal hyperoxygenation in a distressed fetus. We did not find an increase

in free oxygen radicals following maternal oxygenation. Since free oxygen

radicals cannot be measured directly, we chose MDA as a surrogate marker,

as this can be considered as a non-invasive biomarker for free radical

damage on DNA and cell membranes.24,26-28,34 Even though this marker is

used in previous studies, it is hard to determine normal limits. We were able

to compare MDA values between the intervention and control group, but we

were unable to compare our study results to outcomes from other studies. All

samples were analyzed in duplo, so they would function as their own

controls. Due to potentially harmful effects of increased oxygen radicals, we

intended to exclude women who had an underlying condition that potentially

caused increased oxygen radical activity by itself. However, unfortunately 21

women were wrongly included, which may have influenced the study results.

Interpretation

This study shows that maternal hyperoxygenation has a significant positive

effect on the FHR pattern, compared to conventional care. This outcome

cannot be explained by the use of cointerventions, which was similar in both

groups. The relatively high frequency of deterioration of FHR patterns in both

groups might be explained by the chosen study design, at the onset of the

second stage of labor. As a result, the FHR pattern of some participants is

compared between the end of the first stage of labor, and the start of the

second stage of labor.

Chapter 6

140

The analysis of the subgroups with abnormal and suboptimal FHR and SGA

fetuses showed no significant differences. This might be explained by small

samples sizes due to the number of missing values (40% for the FHR pattern),

which was higher than the accommodated 20%.

An important concern regarding the use of maternal oxygen administration

during labor is the risk of possibly lowering fetal pH.2,18 Previous research

suggested lower arterial cord blood pH levels due to maternal

hyperoxygenation.18 However, our results did not confirm this effect.

Umbilical cord blood gas analysis was comparable between both study

groups. Moreover, in the suboptimal FHR subgroup pCO2 was significantly

lower in hyperoxygenated women than in conventionally treated women.

A recent RCT compared maternal hyperoxygenation to room breathing room

air, in the presence of category II fetal heart tracings at any point in the active

phase of labor. In accordance with our results, they found umbilical cord

arterial lactate and other umbilical artery blood gas components to be similar

in both groups.15 Thorp et al. found that the duration of oxygen therapy was

inversely correlated with arterial cord pH, this relation was not replicated in

our study with distressed fetuses.18 Our results showed a correlation between

the duration of oxygen supplementation and venous pCO2 (rho = 0.3) and 5-

minute Apgar score (rho = -0.3). However, this correlation explains only 9%

of the variance. Therefore, the clinical implication of this finding is limited.

We also found a 5-minute Apgar score <7 almost three times more frequent

in the conventional care group, albeit not significant. There were no previous

studies investigating Apgar score.

Based on our study results, we cannot endorse the theoretical increased risk

of increased oxygen radical production.2,38,39 Mean MDA values were not

significantly different between the intervention and control group, but there

was a trend towards higher values in the intervention group. Possibly, a

significant difference would be found in a larger sample size. However, since

we did not find a relation between MDA values and neonatal outcome, the

clinical effect of increased MDA values will be limited.

In the SGA subgroup, a longer second stage of labor was observed in the

intervention group, but this did not lead to adverse neonatal outcomes. This

may suggest that because of the maternal hyperoxygenation the parturient

could continue pushing longer without harm to the fetus. In the abnormal

CTG subgroup, significantly fewer episiotomies on fetal indication were

performed, and a similar trend was seen in the total group. These findings

correspond with results from Haydon et al. which show that fetuses with the

lowest initial oxygen saturations benefit the most from maternal

hyperoxygenation.9 Furthermore, 6-6.5% less assisted deliveries were

performed in the oxygenation group. A possible explanation for this can be

an amelioration of FHR pattern, which results in decrease in need for

immediate termination of delivery.

Conclusion and implications



There was no significant difference in the mode of delivery, however,

significantly less episiotomies on fetal indication were performed following

maternal hyperoxygenation in the subgroup with an abnormal FHR pattern. A

larger RCT powered for an improvement in neonatal outcome is needed to

propose strong recommendations for clinical practice. In any case, no

harmful effects of maternal hyperoxygenation were demonstrated. Therefore,

there is no need to ban this intervention from delivery rooms where maternal

hyperoxygenation is a commonly used intrauterine resuscitation technique.

Acknowledgments

This research was performed within the framework of Eindhoven MedTech

Innovation Center (e/MTIC). We thank all the obstetric staff members at

Máxima Medisch Centrum for their help with this study. We also thank

Bernice Wieland and Julia Smith for their help with the data collection.


141

6

The analysis of the subgroups with abnormal and suboptimal FHR and SGA

fetuses showed no significant differences. This might be explained by small

samples sizes due to the number of missing values (40% for the FHR pattern),

which was higher than the accommodated 20%.

An important concern regarding the use of maternal oxygen administration

during labor is the risk of possibly lowering fetal pH.2,18 Previous research

suggested lower arterial cord blood pH levels due to maternal

hyperoxygenation.18 However, our results did not confirm this effect.

Umbilical cord blood gas analysis was comparable between both study

groups. Moreover, in the suboptimal FHR subgroup pCO2 was significantly

lower in hyperoxygenated women than in conventionally treated women.

A recent RCT compared maternal hyperoxygenation to room breathing room

air, in the presence of category II fetal heart tracings at any point in the active

phase of labor. In accordance with our results, they found umbilical cord

arterial lactate and other umbilical artery blood gas components to be similar

in both groups.15 Thorp et al. found that the duration of oxygen therapy was

inversely correlated with arterial cord pH, this relation was not replicated in

our study with distressed fetuses.18 Our results showed a correlation between

the duration of oxygen supplementation and venous pCO2 (rho = 0.3) and 5-

minute Apgar score (rho = -0.3). However, this correlation explains only 9%

of the variance. Therefore, the clinical implication of this finding is limited.

We also found a 5-minute Apgar score <7 almost three times more frequent

in the conventional care group, albeit not significant. There were no previous

studies investigating Apgar score.

Based on our study results, we cannot endorse the theoretical increased risk

of increased oxygen radical production.2,38,39 Mean MDA values were not

significantly different between the intervention and control group, but there

was a trend towards higher values in the intervention group. Possibly, a

significant difference would be found in a larger sample size. However, since

we did not find a relation between MDA values and neonatal outcome, the

clinical effect of increased MDA values will be limited.

In the SGA subgroup, a longer second stage of labor was observed in the

intervention group, but this did not lead to adverse neonatal outcomes. This

may suggest that because of the maternal hyperoxygenation the parturient

could continue pushing longer without harm to the fetus. In the abnormal

CTG subgroup, significantly fewer episiotomies on fetal indication were

performed, and a similar trend was seen in the total group. These findings

correspond with results from Haydon et al. which show that fetuses with the

lowest initial oxygen saturations benefit the most from maternal

hyperoxygenation.9 Furthermore, 6-6.5% less assisted deliveries were

performed in the oxygenation group. A possible explanation for this can be

an amelioration of FHR pattern, which results in decrease in need for

immediate termination of delivery.

Conclusion and implications



There was no significant difference in the mode of delivery, however,

significantly less episiotomies on fetal indication were performed following

maternal hyperoxygenation in the subgroup with an abnormal FHR pattern. A

larger RCT powered for an improvement in neonatal outcome is needed to

propose strong recommendations for clinical practice. In any case, no

harmful effects of maternal hyperoxygenation were demonstrated. Therefore,

there is no need to ban this intervention from delivery rooms where maternal

hyperoxygenation is a commonly used intrauterine resuscitation technique.

Acknowledgments

This research was performed within the framework of Eindhoven MedTech

Innovation Center (e/MTIC). We thank all the obstetric staff members at

Máxima Medisch Centrum for their help with this study. We also thank

Bernice Wieland and Julia Smith for their help with the data collection.

Chapter 6

142

References 1. Fawole B, Hofmeyr GJ. Maternal oxygen administration for fetal distress.

Cochrane Database Syst Rev. 2012;12:CD000136. 2. Hamel MS, Anderson BL, Rouse DJ. Oxygen for intrauterine resuscitation: of

unproved benefit and potentially harmful. Am J Obstet Gynecol. 2014;211:124-7.



5. American College of Obstetricians and Gynecologists. Practice bulletin no. 116: Management of intrapartum fetal heart rate tracings. Obstet Gynecol. 2010;116:1232-40.

6. Delgado Nunes V, Gholitabar M, Sims JM, Bewley S, Guideline Development Group. Intrapartum care of healthy women and their babies: summary of updated NICE guidance. BMJ. 2014;349:g6886.

7. Althabe OvJr, Schwarcz RL, Pose SV, Escarcena L, Caldeyro-Barcia R. Effects on fetal heart rate and fetal pO2 of oxygen administration to the mother. Am J Obstet Gynecol. 1967;98:858-70.





12. Willcourt RJ, King JC, Queenan JT. Maternal oxygenation administration and the fetal transcutaneous PO2. Am J Obstet Gynecol. 1983;146:714-5.


14. Bullens LM, van der Hout-van der Jagt MB, Van Runnard Heimel PJ, Oei G. A simulation model to study maternal hyperoxygenation during labor. Acta Obstet Gynecol Scand. 2014;93:1268-75.

15. Raghuraman N, Wan L, Temming LA, Woolfolk C, Macones GA, Tuuli MG, et al. Effect of oxygen vs room air on intrauterine fetal resuscitation: a randomized noninferiority clinical trial. JAMA Pediatr. 2018;172:818-23.

16. Perreault C, Blaise GA, Meloche R. Maternal inspired oxygen concentration and

fetal oxygenation during caesarean section. Can J Anaesth. 1992;39:155-7. 17. Saling E. Effect of oxygen inhalation by the mother on the blood gases and

acid-base equilibrium of the fetus. Geburtshilfe Frauenheilkd. 1963;23:528-38. [German]


19. Qian G, Xu X, Chen L, Xia S, Wang A, Chuai Y, et al. The effect of maternal low flow oxygen administration during the second stage of labour on umbilical cord artery pH: a randomised controlled trial. BJOG. 2017;124:678-85.

20. Sirimai K, Atisook R, Boriboonhirunsarn D. The correlation of intrapartum maternal oxygen administration and umbilical cord blood gas values. Acta Obstet GynecolScand.1997;76:90.

21. Khaw KS, Ngan Kee WD. Fetal effects of maternal supplementary oxygen during Caesarean section. Curr Opin Anaesthesiol. 2004;17:309-13.


23. Torres-Cuevas I, Parra-Llorca A, Sanchez-Illana A, Nunez-Ramiro A, Kuligowski J, Chafer-Pericas C, et al. Oxygen and oxidative stress in the perinatal period. Redox Biol. 2017;12:674-81.


25. Blackburn S. Free radicals in perinatal and neonatal care, part 2: oxidative stress during the perinatal and neonatal period. J Perinat Neonatal Nurs. 2006;20:125-7.

26. Nordstrom L, Arulkumaran S. Intrapartum fetal hypoxia and biochemical markers: a review. Obstet Gynecol Surv.1998;53:645-57.

27. Rogers MS, Wang W, Mongelli M, Pang CP, Duley JA, Chang AM. Lipid peroxidation in cord blood at birth: a marker of fetal hypoxia during labour. Gynecol Obstet Invest.1997;44:229-33.

28. Little RE, Gladen BC. Levels of lipid peroxides in uncomplicated pregnancy: a review of the literature. Reprod Toxicol. 1999;13:347-52.

29. Bullens LM, Hulsenboom ADJ, Moors S, Joshi R, van Runnard Heimel PJ, van der Hout-van der Jagt MB, et al. Intrauterine resuscitation during the second stage of term labour by maternal hyperoxygenation versus conventional care: study protocol for a randomised controlled trial (INTEREST O2). Trials. 201823;19:195.

30. 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;131:13-24.

31. White CR, Doherty DA, Kohan R, Newnham JP, Pennell CE. Evaluation of selection criteria for validating paired umbilical cord blood gas samples: an observational study. BJOG. 2012;119:857-65.


143

6

References 1. Fawole B, Hofmeyr GJ. Maternal oxygen administration for fetal distress.

Cochrane Database Syst Rev. 2012;12:CD000136. 2. Hamel MS, Anderson BL, Rouse DJ. Oxygen for intrauterine resuscitation: of

unproved benefit and potentially harmful. Am J Obstet Gynecol. 2014;211:124-7.



5. American College of Obstetricians and Gynecologists. Practice bulletin no. 116: Management of intrapartum fetal heart rate tracings. Obstet Gynecol. 2010;116:1232-40.

6. Delgado Nunes V, Gholitabar M, Sims JM, Bewley S, Guideline Development Group. Intrapartum care of healthy women and their babies: summary of updated NICE guidance. BMJ. 2014;349:g6886.

7. Althabe OvJr, Schwarcz RL, Pose SV, Escarcena L, Caldeyro-Barcia R. Effects on fetal heart rate and fetal pO2 of oxygen administration to the mother. Am J Obstet Gynecol. 1967;98:858-70.





12. Willcourt RJ, King JC, Queenan JT. Maternal oxygenation administration and the fetal transcutaneous PO2. Am J Obstet Gynecol. 1983;146:714-5.


14. Bullens LM, van der Hout-van der Jagt MB, Van Runnard Heimel PJ, Oei G. A simulation model to study maternal hyperoxygenation during labor. Acta Obstet Gynecol Scand. 2014;93:1268-75.

15. Raghuraman N, Wan L, Temming LA, Woolfolk C, Macones GA, Tuuli MG, et al. Effect of oxygen vs room air on intrauterine fetal resuscitation: a randomized noninferiority clinical trial. JAMA Pediatr. 2018;172:818-23.

16. Perreault C, Blaise GA, Meloche R. Maternal inspired oxygen concentration and

fetal oxygenation during caesarean section. Can J Anaesth. 1992;39:155-7. 17. Saling E. Effect of oxygen inhalation by the mother on the blood gases and

acid-base equilibrium of the fetus. Geburtshilfe Frauenheilkd. 1963;23:528-38. [German]


19. Qian G, Xu X, Chen L, Xia S, Wang A, Chuai Y, et al. The effect of maternal low flow oxygen administration during the second stage of labour on umbilical cord artery pH: a randomised controlled trial. BJOG. 2017;124:678-85.

20. Sirimai K, Atisook R, Boriboonhirunsarn D. The correlation of intrapartum maternal oxygen administration and umbilical cord blood gas values. Acta Obstet GynecolScand.1997;76:90.

21. Khaw KS, Ngan Kee WD. Fetal effects of maternal supplementary oxygen during Caesarean section. Curr Opin Anaesthesiol. 2004;17:309-13.


23. Torres-Cuevas I, Parra-Llorca A, Sanchez-Illana A, Nunez-Ramiro A, Kuligowski J, Chafer-Pericas C, et al. Oxygen and oxidative stress in the perinatal period. Redox Biol. 2017;12:674-81.


25. Blackburn S. Free radicals in perinatal and neonatal care, part 2: oxidative stress during the perinatal and neonatal period. J Perinat Neonatal Nurs. 2006;20:125-7.

26. Nordstrom L, Arulkumaran S. Intrapartum fetal hypoxia and biochemical markers: a review. Obstet Gynecol Surv.1998;53:645-57.

27. Rogers MS, Wang W, Mongelli M, Pang CP, Duley JA, Chang AM. Lipid peroxidation in cord blood at birth: a marker of fetal hypoxia during labour. Gynecol Obstet Invest.1997;44:229-33.

28. Little RE, Gladen BC. Levels of lipid peroxides in uncomplicated pregnancy: a review of the literature. Reprod Toxicol. 1999;13:347-52.

29. Bullens LM, Hulsenboom ADJ, Moors S, Joshi R, van Runnard Heimel PJ, van der Hout-van der Jagt MB, et al. Intrauterine resuscitation during the second stage of term labour by maternal hyperoxygenation versus conventional care: study protocol for a randomised controlled trial (INTEREST O2). Trials. 201823;19:195.

30. 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;131:13-24.

31. White CR, Doherty DA, Kohan R, Newnham JP, Pennell CE. Evaluation of selection criteria for validating paired umbilical cord blood gas samples: an observational study. BJOG. 2012;119:857-65.

Chapter 6

144

32. Westgate J, Garibaldi JM, Greene KR. Umbilical cord blood gas analysis at delivery: a time for quality data. Br J Obstet Gynaecol. 1994;101:1054-63.

33. Longini M, Belvisi E, Proietti F, Bazzini F, Buonocore G, Perrone S. Oxidative stress biomarkers: establishment of reference values for isoprostanes, AOPP, and NPBI in cord blood. Mediators Inflamm. 2017;2017:1758432.


35. Simon VB, Fong A, Nageotte MP. Supplemental oxygen study: a randomized controlled study on the effect of maternal oxygen supplementation during planned cesarean delivery on umbilical cord gases. Am J Perinatol. 2018;35:84-9.

36. Jozwik M, Sledziewski A, Klubowicz Z, Zak J, Sajewska G, Pietrzycki B. Use of oxygen therapy during labour and acid-base status in the newborn. Med Wieku Rozwoj. 2000;4:403-11. [Polish]



39. Suzuki S, Yoneyama Y, Sawa R, Murata T, Araki T, Power GG. Changes in fetal plasma adenosine and xanthine concentrations during fetal asphyxia with maternal oxygen administration in ewes. Tohoku J Exp Med. 2000;192:275-81.

Chapter 7

Intrapartum maternal hemoglobin level:

does it affect fetal and neonatal outcome and

mode of delivery?

A systematic review of the literature

Smith JS, Bullens LM, van Runnard Heimel PJ,


Submitted

32. Westgate J, Garibaldi JM, Greene KR. Umbilical cord blood gas analysis at delivery: a time for quality data. Br J Obstet Gynaecol. 1994;101:1054-63.

33. Longini M, Belvisi E, Proietti F, Bazzini F, Buonocore G, Perrone S. Oxidative stress biomarkers: establishment of reference values for isoprostanes, AOPP, and NPBI in cord blood. Mediators Inflamm. 2017;2017:1758432.


35. Simon VB, Fong A, Nageotte MP. Supplemental oxygen study: a randomized controlled study on the effect of maternal oxygen supplementation during planned cesarean delivery on umbilical cord gases. Am J Perinatol. 2018;35:84-9.

36. Jozwik M, Sledziewski A, Klubowicz Z, Zak J, Sajewska G, Pietrzycki B. Use of oxygen therapy during labour and acid-base status in the newborn. Med Wieku Rozwoj. 2000;4:403-11. [Polish]



39. Suzuki S, Yoneyama Y, Sawa R, Murata T, Araki T, Power GG. Changes in fetal plasma adenosine and xanthine concentrations during fetal asphyxia with maternal oxygen administration in ewes. Tohoku J Exp Med. 2000;192:275-81.

Chapter 7

Intrapartum maternal hemoglobin level:

does it affect fetal and neonatal outcome and

mode of delivery?

A systematic review of the literature

Smith JS, Bullens LM, van Runnard Heimel PJ,


Submitted

Chapter 7

146

Abstract

Importance

Both low and high maternal hemoglobin (Hb) concentration during

pregnancy are risk factors for adverse neonatal and maternal outcome. If

maternal Hb also affects the risk of fetal distress during labor, mode of

delivery, and short-term neonatal outcome is unclear. Individual studies

reporting on the course of labor and short-term neonatal outcome in relation

to maternal Hb show different results. No systematic review addressing this

topic has been performed.

Objective

We aimed to investigate the effect of maternal Hb in the second or third

trimester of pregnancy on mode of delivery, Apgar score, umbilical cord pH,

neonatal intensive care unit admission and perinatal mortality.


We systematically searched the electronic databases PubMed, EMBASE, and

Cochrane for studies that reported on the relationship between maternal Hb

and mode of delivery and/or neonatal outcome. Two independent authors

assessed all eligible articles and their and their references. We described the

results and displayed the evidence in relation to the quality of each study.

Results

A total of 13 articles, including a total of 413,036 women, met all the

inclusion criteria. Among the included articles were six prospective cohort

studies, two case-control studies, and five retrospective cohort studies.


It is plausible that maternal anemia during labor contributes to an increased

risk of cesarean section. However, evidence regarding the relationship

between anemia and low Apgar score, risk of neonatal intensive care unit

admission or perinatal death is contradictory and not conclusive. Based on

this review, we should prevent peripartum anemia to optimize the chance of

a spontaneous delivery and prevent a cesarean section.

The effect of maternal hemoglobin on fetal outcome: a systematic review

147

7

Abstract

Importance

Both low and high maternal hemoglobin (Hb) concentration during

pregnancy are risk factors for adverse neonatal and maternal outcome. If

maternal Hb also affects the risk of fetal distress during labor, mode of

delivery, and short-term neonatal outcome is unclear. Individual studies

reporting on the course of labor and short-term neonatal outcome in relation

to maternal Hb show different results. No systematic review addressing this

topic has been performed.

Objective

We aimed to investigate the effect of maternal Hb in the second or third

trimester of pregnancy on mode of delivery, Apgar score, umbilical cord pH,

neonatal intensive care unit admission and perinatal mortality.




and mode of delivery and/or neonatal outcome. Two independent authors

assessed all eligible articles and their and their references. We described the

results and displayed the evidence in relation to the quality of each study.

Results

A total of 13 articles, including a total of 413,036 women, met all the

inclusion criteria. Among the included articles were six prospective cohort

studies, two case-control studies, and five retrospective cohort studies.


It is plausible that maternal anemia during labor contributes to an increased

risk of cesarean section. However, evidence regarding the relationship

between anemia and low Apgar score, risk of neonatal intensive care unit

admission or perinatal death is contradictory and not conclusive. Based on

this review, we should prevent peripartum anemia to optimize the chance of

a spontaneous delivery and prevent a cesarean section.

Chapter 7

148

Introduction

Maternal hemoglobin (Hb) concentration drops physiologically during

pregnancy due to hemodilution. This effect reaches a maximum in the third

trimester.1,2 Therefore, the World Health Organization altered the cut-off for

anemia in pregnancy to Hb <11 g/dL, instead of <12 g/dL in non-pregnant

women.3 Anemia in pregnancy is common; in 2011 the Nutrition Impact

Model Study estimated that 38% of pregnant women worldwide are anemic,

with iron deficiency as the major cause.4,5 Other causes of anemia are

infection, heavy bleeding, hemoglobinopathies and other nutrient

deficiencies due to malnutrition.3 Various studies reported on the

consequences of anemia in pregnancy.5-15 It is thought that low maternal Hb

concentration is a risk factor for adverse neonatal and maternal outcomes.5-15

A systematic review and meta-analysis reported a higher risk of preterm birth

in case of maternal anemia in the first or second trimester,7 while a more

recent meta-analysis showed also an increased risk of low birth weight.8

Apart from low Hb, also high Hb levels are associated with adverse perinatal

outcome.4,15-17 As a result of poor plasma expansion and increased blood

viscosity, blood flow and fetomaternal exchange of oxygen and nutrients in

the placenta are reduced.15,16 High Hb concentrations are associated with

pregnancy-induced hypertension and preeclampsia.15-17 Since low as well as

high Hb levels seem to negatively influence pregnancy outcome, this may

indicate a U-shaped optimum for Hb concentration in pregnancy.14,15,18

We hypothesize that in both in anemic women, as in women with high Hb

levels, there is a suboptimal oxygen supply to the placenta. This

‘preplacental hypoxia’ may lead to impaired fetal oxygenation, thus

increasing the risk of fetal distress and possibly leading to lower Apgar

scores. In addition, anemia may impair maternal endurance during labor, thus

increasing the risk of assisted delivery or even secondary cesarean section

(CS).

Until now, no systematic review has evaluated the relation between maternal

Hb concentration, mode of delivery, and neonatal outcome. Individual

studies reporting on the course of labor and short-term neonatal outcome in

relation to maternal Hb show different results.10-12,19-20 Therefore, we aimed to

investigate the effect of maternal Hb in the second or third trimester of

pregnancy on mode of delivery, Apgar score, umbilical cord pH, neonatal

intensive care unit (NICU) admission and perinatal mortality.

Methods

Data sources



and mode of delivery and/or neonatal outcome. The search terms included;

“h(a)emoglobin”, “h(a)ematocrit”, “mode of delivery”, “f(o)etal distress”,

“pregnancy outcome”, “term birth”, and “childbirth”. This search was

performed with the help of a librarian. We used no restrictions on publication

date, but the study had to be available in the English or Dutch language. In

addition, we manually screened the list of references of the identified articles

and references from systematic reviews included in our search.


We included all studies that reported on both the maternal Hb concentration

and at least one of the following outcome measures: mode of delivery, Apgar

score, umbilical cord pH, NICU admission, or perinatal death. The study

population had to consist of women with a singleton pregnancy with the

intention of a spontaneous vaginal delivery. The maternal Hb concentration

had to be measured during the second or third trimester of pregnancy, so it

would reasonably reflect the peripartum Hb concentration.21 Exclusion criteria

were a planned CS, multiple pregnancies, or a Hb concentration measured in

the first trimester.

Study selection

Two independent investigators (JS and LB) screened all titles and abstracts of

trials found in our search to determine if they met the inclusion criteria.

Disagreements were discussed and consensus was reached. After eliminating

non-compliant articles, the two investigators (JS and LB) analyzed the full text

of the remaining studies to decide on eligibility for inclusion.


149

7

Introduction

Maternal hemoglobin (Hb) concentration drops physiologically during

pregnancy due to hemodilution. This effect reaches a maximum in the third

trimester.1,2 Therefore, the World Health Organization altered the cut-off for

anemia in pregnancy to Hb <11 g/dL, instead of <12 g/dL in non-pregnant

women.3 Anemia in pregnancy is common; in 2011 the Nutrition Impact

Model Study estimated that 38% of pregnant women worldwide are anemic,

with iron deficiency as the major cause.4,5 Other causes of anemia are

infection, heavy bleeding, hemoglobinopathies and other nutrient

deficiencies due to malnutrition.3 Various studies reported on the

consequences of anemia in pregnancy.5-15 It is thought that low maternal Hb

concentration is a risk factor for adverse neonatal and maternal outcomes.5-15

A systematic review and meta-analysis reported a higher risk of preterm birth

in case of maternal anemia in the first or second trimester,7 while a more

recent meta-analysis showed also an increased risk of low birth weight.8

Apart from low Hb, also high Hb levels are associated with adverse perinatal

outcome.4,15-17 As a result of poor plasma expansion and increased blood

viscosity, blood flow and fetomaternal exchange of oxygen and nutrients in

the placenta are reduced.15,16 High Hb concentrations are associated with

pregnancy-induced hypertension and preeclampsia.15-17 Since low as well as

high Hb levels seem to negatively influence pregnancy outcome, this may

indicate a U-shaped optimum for Hb concentration in pregnancy.14,15,18

We hypothesize that in both in anemic women, as in women with high Hb

levels, there is a suboptimal oxygen supply to the placenta. This

‘preplacental hypoxia’ may lead to impaired fetal oxygenation, thus

increasing the risk of fetal distress and possibly leading to lower Apgar

scores. In addition, anemia may impair maternal endurance during labor, thus

increasing the risk of assisted delivery or even secondary cesarean section

(CS).

Until now, no systematic review has evaluated the relation between maternal

Hb concentration, mode of delivery, and neonatal outcome. Individual

studies reporting on the course of labor and short-term neonatal outcome in

relation to maternal Hb show different results.10-12,19-20 Therefore, we aimed to

investigate the effect of maternal Hb in the second or third trimester of

pregnancy on mode of delivery, Apgar score, umbilical cord pH, neonatal

intensive care unit (NICU) admission and perinatal mortality.

Methods

Data sources



and mode of delivery and/or neonatal outcome. The search terms included;

“h(a)emoglobin”, “h(a)ematocrit”, “mode of delivery”, “f(o)etal distress”,

“pregnancy outcome”, “term birth”, and “childbirth”. This search was

performed with the help of a librarian. We used no restrictions on publication

date, but the study had to be available in the English or Dutch language. In

addition, we manually screened the list of references of the identified articles

and references from systematic reviews included in our search.


We included all studies that reported on both the maternal Hb concentration

and at least one of the following outcome measures: mode of delivery, Apgar

score, umbilical cord pH, NICU admission, or perinatal death. The study

population had to consist of women with a singleton pregnancy with the

intention of a spontaneous vaginal delivery. The maternal Hb concentration

had to be measured during the second or third trimester of pregnancy, so it

would reasonably reflect the peripartum Hb concentration.21 Exclusion criteria

were a planned CS, multiple pregnancies, or a Hb concentration measured in

the first trimester.

Study selection

Two independent investigators (JS and LB) screened all titles and abstracts of

trials found in our search to determine if they met the inclusion criteria.

Disagreements were discussed and consensus was reached. After eliminating

non-compliant articles, the two investigators (JS and LB) analyzed the full text

of the remaining studies to decide on eligibility for inclusion.

Chapter 7

150

Data extraction and risk of bias assessment

Methodological quality was assessed from the following items: study type,

number of subjects, risk of selection bias, including randomization and

blinding (high or low), and description of inclusion and exclusion criteria

(complete or incomplete). We used the GRADE instrument to provide an

overall judgment of the study quality as described in the GRADE

Handbook.22 Both reviewers evaluated the quality of eligible studies

independently. The data were extracted from the full text, tables, and

graphs. Data were entered into Microsoft Excel (Excel for Mac 2011,

Microsoft Corporation, Redmond, Washington, USA) and the two reviewers

double checked accuracy.

Data analysis

The systematic review was conducted using the PRISMA guidelines and

checklist (2009).23 A meta-analysis could not be performed because the

included articles show large heterogeneity in study population and study

methods. Therefore, we described the results and displayed the evidence in

relation to the quality of each study.

Results

Data search

After removal of duplicates, a total of 810 studies published before April

2018 was found. The studies were screened for eligibility by title and abstract

and seven articles seemed eligible for full-text assessment. All references

were screened and we found another 44 articles that were screened by title

and abstract, of which 23 articles were potentially eligible for inclusion. In

total, we performed a full-text assessment on 30 articles (figure 1). Of these

30 articles, 17 were excluded because: the article was not available in English

or Dutch (n=2); the articles were reviews or meta-analyses (n=4); the maternal

Hb concentrations were measured in the first trimester or it was not stated in

the article when the Hb concentrations were measured (n=5); no relevant

outcome measures were concerned (n=5); breech presentations were also

included (n=1). A total of 13 articles, including a total of 413,036 women, met

all the inclusion criteria. Among the included articles were six prospective

cohort studies, two case-control studies, and five retrospective cohort studies

(table 1). The study characteristics and quality assessment are displayed in

table 2 and the outcomes are shown in table 3.

Figure 1. Results from the literature search and the different steps in the

selection process of eligible articles.

Table 1. Number of included studies and study type per outcome measure. Outcome measure Available evidence

Mode of delivery 1 prospective cohort studies

4 retrospective cohort studies

Apgar score 4 prospective cohort studies

1 prospective case-control study


1 retrospective case-control study

Fetal distress None

NICU admission 2 retrospective cohort studies

Perinatal mortality 1 prospective cohort study


Umbilical cord pH None

NICU = Neonatal Intensive Care Unit


151

7

Data extraction and risk of bias assessment

Methodological quality was assessed from the following items: study type,

number of subjects, risk of selection bias, including randomization and

blinding (high or low), and description of inclusion and exclusion criteria

(complete or incomplete). We used the GRADE instrument to provide an

overall judgment of the study quality as described in the GRADE

Handbook.22 Both reviewers evaluated the quality of eligible studies

independently. The data were extracted from the full text, tables, and

graphs. Data were entered into Microsoft Excel (Excel for Mac 2011,

Microsoft Corporation, Redmond, Washington, USA) and the two reviewers

double checked accuracy.

Data analysis

The systematic review was conducted using the PRISMA guidelines and

checklist (2009).23 A meta-analysis could not be performed because the

included articles show large heterogeneity in study population and study

methods. Therefore, we described the results and displayed the evidence in

relation to the quality of each study.

Results

Data search

After removal of duplicates, a total of 810 studies published before April

2018 was found. The studies were screened for eligibility by title and abstract

and seven articles seemed eligible for full-text assessment. All references

were screened and we found another 44 articles that were screened by title

and abstract, of which 23 articles were potentially eligible for inclusion. In

total, we performed a full-text assessment on 30 articles (figure 1). Of these

30 articles, 17 were excluded because: the article was not available in English

or Dutch (n=2); the articles were reviews or meta-analyses (n=4); the maternal

Hb concentrations were measured in the first trimester or it was not stated in

the article when the Hb concentrations were measured (n=5); no relevant

outcome measures were concerned (n=5); breech presentations were also

included (n=1). A total of 13 articles, including a total of 413,036 women, met

all the inclusion criteria. Among the included articles were six prospective

cohort studies, two case-control studies, and five retrospective cohort studies

(table 1). The study characteristics and quality assessment are displayed in

table 2 and the outcomes are shown in table 3.

Figure 1. Results from the literature search and the different steps in the

selection process of eligible articles.

Table 1. Number of included studies and study type per outcome measure. Outcome measure Available evidence

Mode of delivery 1 prospective cohort studies


Apgar score 4 prospective cohort studies

1 prospective case-control study


1 retrospective case-control study

Fetal distress None

NICU admission 2 retrospective cohort studies

Perinatal mortality 1 prospective cohort study


Umbilical cord pH None

NICU = Neonatal Intensive Care Unit

Chapter 7

152

Tab

le 2

. Cha

ract

eris

tics

and

qual

ity o

f inc

lude

d st

udie

s.

Aut

hor

Year

of

pub

licat

ion

Co

untr

y o

f

orig

in

Stud

y d

esig

n H

b c

ut-o

ffs

for

anem

ia a

nd h

igh

Hb

Tim

ing

Hb

mea

sure

men

t

Sam

ple

siz

e D

escr

iptio

n

in/e

xclu

sio

n

Bo

gae

rt v

20

06

Sout

h A

fric

a re

tros

pec

tive

coho

rt s

tud

y

<10

.0 g

/dL

seco

nd t

rimes

ter

3,21

4 in

com

ple

te

Orla

ndin

i 20

16

Italy

re

tros

pec

tive

coho

rt s

tud

y

<11

.0 g

/dL

bet

wee

n G

A 3

5+0

and

36+

6 w

eeks

1,13

1 co

mp

lete

Aim

akhu

20

03

Nig

eria

p

rosp

ectiv

e

coho

rt s

tud

y

< 9

.7 g

/dL

ever

y an

tena

tal

visi

t

633

inco

mp

lete

Fare

h

2009

U

nite

d A

rab

Emira

tes

retr

osp

ectiv

e

case

-con

trol

stud

y

<11

.0 g

/dL

arou

nd G

A 3

0

wee

ks

200

com

ple

te

Zhan

g

2009

C

hina

p

rosp

ectiv

e

coho

rt s

tud

y

<10

.0 g

/dL

ever

y tr

imes

ter

164,

667

inco

mp

lete

Sekh

avat

20

11

Iran

pro

spec

tive

coho

rt s

tud

y

<10

.0 g

/dL,

>13

.0 g

/dL

(hig

h)

first

sta

ge

of la

bor

1,

842

inco

mp

lete

Lone

20

04

Paki

stan

p

rosp

ectiv

e

coho

rt s

tud

y

<11

.0 g

/dL

in la

bor

62

9 in

com

ple

te

Dru

kker

20

15

Isra

el

retr

osp

ectiv

e

coho

rt s

tud

y

<11

.0 g

/dL

in la

bor

75

,660

co

mp

lete

Hb

= h

emog

lobi

n, G

A =

ges

tatio

nal a

ge, P

VC =

pac

ked

cell

volu

me

Aut

hor

Year

of

pub

licat

ion

Co

untr

y o

f

orig

in

Stud

y d

esig

n H

b c

ut-o

ffs

for

a nem

ia a

nd h

igh

Hb

Tim

ing

Hb

mea

sure

men

t

Sam

ple

siz

e D

escr

iptio

n

i n/e

xclu

sio

n

Hw

ang

20

10

Rep

ublic

of

Kor

ea

retr

osp

ectiv

e

coho

rt s

tud

y

<10

.0 g

/dL

third

trim

este

r 3,

560

inco

mp

lete

Litt

le

2004

U

nite

d

Kin

gd

om

pro

spec

tive

coho

rt s

tud

y

<11

.0 g

/dL

seco

nd t

rimes

ter

144,

209

inco

mp

lete

Lee

20

06

Kor

ea

pro

spec

tive

coho

rt s

tud

y

<10

.8g

/dL,

≥12

.0 g

/dL

(hig

h)

seco

nd t

rimes

ter

248

inco

mp

lete

Xio

ng

2003

C

hina

re

tros

pec

tive

coho

rt s

tud

y

<10

.0 g

/dL

GA

32

wee

ks

16,9

43

inco

mp

lete

Lelic

20

14

Bos

nia

Her

zeg

ovin

a

pro

spec

tive

case

-con

trol

stud

y

<10

.5 g

/dL

seco

nd t

rimes

ter

100

com

ple

te


153

7

Tab

le 2

. Cha

ract

eris

tics

and

qual

ity o

f inc

lude

d st

udie

s.

Aut

hor

Year

of

pub

licat

ion

Co

untr

y o

f

orig

in

Stud

y d

esig

n H

b c

ut-o

ffs

for

a nem

ia a

nd h

igh

Hb

Tim

ing

Hb

mea

sure

men

t

Sam

ple

siz

e D

escr

iptio

n

i n/e

xclu

sio

n

Bo

gae

rt v

20

06

Sout

h A

fric

a re

tros

pec

tive

coho

rt s

tud

y

<10

.0 g

/dL

seco

nd t

rimes

ter

3,21

4 in

com

ple

te

Orla

ndin

i 20

16

Italy

re

tros

pec

tive

coho

rt s

tud

y

<11

.0 g

/dL

bet

wee

n G

A 3

5+0

and

36+

6 w

eeks

1,13

1 co

mp

lete

Aim

akhu

20

03

Nig

eria

p

rosp

ectiv

e

coho

rt s

tud

y

< 9

.7 g

/dL

ever

y an

tena

tal

visi

t

633

inco

mp

lete

Fare

h

2009

U

nite

d A

rab

Emira

tes

retr

osp

ectiv

e

case

-con

trol

stud

y

<11

.0 g

/dL

arou

nd G

A 3

0

wee

ks

200

com

ple

te

Zhan

g

2009

C

hina

p

rosp

ectiv

e

coho

rt s

tud

y

<10

.0 g

/dL

ever

y tr

imes

ter

164,

667

inco

mp

lete

Sekh

avat

20

11

Iran

pro

spec

tive

coho

rt s

tud

y

<10

.0 g

/dL,

>13

.0 g

/dL

(hig

h)

first

sta

ge

of la

bor

1,

842

inco

mp

lete

Lone

20

04

Paki

stan

p

rosp

ectiv

e

coho

rt s

tud

y

<11

.0 g

/dL

in la

bor

62

9 in

com

ple

te

Dru

kker

20

15

Isra

el

retr

osp

ectiv

e

coho

rt s

tud

y

<11

.0 g

/dL

in la

bor

75

,660

co

mp

lete

Hb

= h

emog

lobi

n, G

A =

ges

tatio

nal a

ge, P

VC =

pac

ked

cell

volu

me

Aut

hor

Year

of

pub

licat

ion

Co

untr

y o

f

orig

in

Stud

y d

esig

n H

b c

ut-o

ffs

for

a nem

ia a

nd h

igh

Hb

Tim

ing

Hb

mea

sure

men

t

Sam

ple

siz

e D

escr

iptio

n

i n/e

xclu

sio

n

Hw

ang

20

10

Rep

ublic

of

Kor

ea

retr

osp

ectiv

e

coho

rt s

tud

y

<10

.0 g

/dL

third

trim

este

r 3,

560

inco

mp

lete

Litt

le

2004

U

nite

d

Kin

gd

om

pro

spec

tive

coho

rt s

tud

y

<11

.0 g

/dL

seco

nd t

rimes

ter

144,

209

inco

mp

lete

Lee

20

06

Kor

ea

pro

spec

tive

coho

rt s

tud

y

<10

.8g

/dL,

≥12

.0 g

/dL

(hig

h)

seco

nd t

rimes

ter

248

inco

mp

lete

Xio

ng

2003

C

hina

re

tros

pec

tive

coho

rt s

tud

y

<10

.0 g

/dL

GA

32

wee

ks

16,9

43

inco

mp

lete

Lelic

20

14

Bos

nia

Her

zeg

ovin

a

pro

spec

tive

case

-con

trol

stud

y

<10

.5 g

/dL

seco

nd t

rimes

ter

100

com

ple

te

Chapter 7

154

Tab

le 3

a-d

. Out

com

e of

incl

uded

stu

dies

.

3a. M

ode

of d

eliv

ery

Aut

hor

Stud

y d

esig

n A

sso

ciat

ion

Co

mm

ent

Bog

aert

v

retr

osp

ectiv

e

coho

rt s

tud

y

neg

ativ

e Th

e p

reva

lenc

e of

boo

king

ane

mia

(±G

A 2

4wee

ks) i

n p

rimig

ravi

das

and

mul

tigra

vid

as w

ith a

ces

area

n se

ctio

n w

as s

igni

fican

tly h

ighe

r co

mp

ared

with

spon

tane

ous

vag

inal

del

iver

ies

(p =

0.0

02).

Orla

ndin

i re

tros

pec

tive

coho

rt s

tud

y

neg

ativ

e A

nem

ic w

omen

sho

wed

a s

igni

fican

tly h

ighe

r ra

te in

em

erg

ency

ces

area

n se

ctio

n (p

= 0

.006

).

Aim

akhu

p

rosp

ectiv

e

coho

rt s

tud

y

uncl

ear

37.5

% o

f mod

erat

e an

emic

pat

ient

s d

eliv

ered

by

cesa

rean

sec

tion

com

par

ed t

o

22.2

% o

f the

non

-ane

mic

pat

ient

s, t

here

was

no

stat

istic

al t

est

per

form

ed.

Dru

kker

re

tros

pec

tive

coho

rt s

tud

y

neg

ativ

e Ra

tes

of c

esar

ean

sect

ion

wer

e si

gni

fican

tly h

ighe

r am

ong

ane

mic

wom

en if

the

y

wer

e (g

rand

)mul

tipar

as.

Ane

mia

was

iden

tifie

d a

s a

sig

nific

ant

ind

epen

den

t ris

k fa

ctor

of c

esar

ean

sect

ion

(p

<0.

001)

.

Hw

ang

re

tros

pec

tive

coho

rt s

tud

y

neg

ativ

e A

nem

ic w

omen

sho

wed

a s

igni

fican

tly h

ighe

r ra

te o

f ces

area

n se

ctio

n fo

r fe

tal

dis

tres

s co

mp

ared

tot

non

-ane

mic

wom

en (p

<0.

001)

.

Tab

le 3

a-d

. Out

com

e of

incl

uded

stu

dies

.

3a. M

ode

of d

eliv

ery

Aut

hor

Stud

y d

esig

n A

sso

ciat

ion

Co

mm

ent

Bog

aert

v

retr

osp

ectiv

e

coho

rt s

tud

y

neg

ativ

e Th

e p

reva

lenc

e of

boo

king

ane

mia

(±G

A 2

4wee

ks) i

n p

rimig

ravi

das

and

mul

tigra

vid

as w

ith a

ces

area

n se

ctio

n w

as s

igni

fican

tly h

ighe

r co

mp

ared

with

spon

tane

ous

vag

inal

del

iver

ies

(p =

0.0

02).

Orla

ndin

i re

tros

pec

tive

coho

rt s

tud

y

neg

ativ

e A

nem

ic w

omen

sho

wed

a s

igni

fican

tly h

ighe

r ra

te in

em

erg

ency

ces

area

n se

ctio

n (p

= 0

.006

).

Aim

akhu

p

rosp

ectiv

e

coho

rt s

tud

y

uncl

ear

37.5

% o

f mod

erat

e an

emic

pat

ient

s d

eliv

ered

by

cesa

rean

sec

tion

com

par

ed t

o

22.2

% o

f the

non

-ane

mic

pat

ient

s, t

here

was

no

stat

istic

al t

est

per

form

ed.

Dru

kker

re

tros

pec

tive

coho

rt s

tud

y

neg

ativ

e Ra

tes

of c

esar

ean

sect

ion

wer

e si

gni

fican

tly h

ighe

r am

ong

ane

mic

wom

en if

the

y

wer

e (g

rand

)mul

tipar

as.

Ane

mia

was

iden

tifie

d a

s a

sig

nific

ant

ind

epen

den

t ris

k fa

ctor

of c

esar

ean

sect

ion

(p

<0.

001)

.

Hw

ang

re

tros

pec

tive

coho

rt s

tud

y

neg

ativ

e A

nem

ic w

omen

sho

wed

a s

igni

fican

tly h

ighe

r ra

te o

f ces

area

n se

ctio

n fo

r fe

tal

dis

tres

s co

mp

ared

tot

non

-ane

mic

wom

en (p

<0.

001)

.


155

7

3b. A

pgar

sco

re

Aut

hor

Stud

y d

esig

n A

sso

ciat

ion

Co

mm

ent

Orla

ndin

i re

tros

pec

tive

coho

rt s

tud

y

no

No

diff

eren

ces

wer

e ob

serv

ed in

ter

ms

of A

pg

ar s

core

s at

five

min

utes

bet

wee

n

anem

ic w

omen

and

non

-ane

mic

wom

en.

Aim

akhu

p

rosp

ectiv

e

coho

rt s

tud

y

mod

erat

e N

on-a

nem

ic p

atie

nts

had

bab

ies

with

bet

ter

Ap

gar

sco

res

at 1

min

ute

(p <

0.05

).

The

mild

ane

mic

pat

ient

s ha

d b

abie

s w

ith

slig

htly

bet

ter

Ap

gar

sco

res

at 5

min

utes

, alth

oug

h th

is w

as n

ot s

igni

fican

t.

Fare

h

retr

osp

ectiv

e

case

-con

trol

stud

y

no

Ther

e w

as n

o si

gni

fican

t d

iffer

ence

in A

pg

ar s

core

bet

wee

n th

e st

udy

gro

up a

nd

cont

rol g

roup

.

Sekh

avat

p

rosp

ectiv

e

coho

rt s

tud

y

neg

ativ

e Th

e ris

k of

low

Ap

gar

sco

re w

as s

igni

fican

tly in

crea

sed

in w

omen

with

ane

mia

(how

ever

, p =

0,8

).

Lone

p

rosp

ectiv

e

coho

rt s

tud

y

neg

ativ

e M

ultiv

aria

te a

naly

sis

show

ed t

hat

the

risk

of a

n A

pg

ar s

core

<5

at 1

min

ute

was

1.8

times

hig

her

for

anem

ic w

omen

com

par

ed t

o no

n-an

emic

wom

en.

Dru

kker

re

tros

pec

tive

coho

rt s

tud

y

neg

ativ

e A

nem

ia w

as id

entif

ied

as

a si

gni

fican

t in

dep

end

ent

risk

fact

or o

f Ap

gar

sco

re a

t 5

min

utes

<7

( p <

0.00

1).

Hw

ang

re

tros

pec

tive

coho

rt s

tud

y

no

Ther

e w

as n

o si

gni

fican

t d

iffer

ence

in A

pg

ar s

core

foun

d.

Lee

pro

spec

tive

coho

rt s

tud

y

neg

ativ

e A

nem

ic w

omen

had

sig

nific

antly

low

er A

pg

ar s

core

s at

1 a

nd 5

min

utes

com

par

ed

to n

on-a

neam

ic w

omen

(p <

0.05

).

Lelic

p

rosp

ectiv

e

case

-con

trol

stud

y

no

Ther

e w

as n

o si

gni

fican

t d

iffer

ence

in A

pg

ar s

core

bet

wee

n th

e st

udy

gro

up a

nd

cont

rol g

roup

.

3b. A

pgar

sco

re

Aut

hor

Stud

y d

esig

n A

sso

ciat

ion

Co

mm

ent

Orla

ndin

i re

tros

pec

tive

coho

rt s

tud

y

no

No

diff

eren

ces

wer

e ob

serv

ed in

ter

ms

of A

pg

ar s

core

s at

five

min

utes

bet

wee

n

anem

ic w

omen

and

non

-ane

mic

wom

en.

Aim

akhu

p

rosp

ectiv

e

coho

rt s

tud

y

mod

erat

e N

on-a

nem

ic p

atie

nts

had

bab

ies

with

bet

ter

Ap

gar

sco

res

at 1

min

ute

(p <

0.05

).

The

mild

ane

mic

pat

ient

s ha

d b

abie

s w

ith

slig

htly

bet

ter

Ap

gar

sco

res

at 5

min

utes

, alth

oug

h th

is w

as n

ot s

igni

fican

t.

Fare

h

retr

osp

ectiv

e

case

-con

trol

stud

y

no

Ther

e w

as n

o si

gni

fican

t d

iffer

ence

in A

pg

ar s

core

bet

wee

n th

e st

udy

gro

up a

nd

cont

rol g

roup

.

Sekh

avat

p

rosp

ectiv

e

coho

rt s

tud

y

neg

ativ

e Th

e ris

k of

low

Ap

gar

sco

re w

as s

igni

fican

tly in

crea

sed

in w

omen

with

ane

mia

(how

ever

, p =

0,8

).

Lone

p

rosp

ectiv

e

coho

rt s

tud

y

neg

ativ

e M

ultiv

aria

te a

naly

sis

show

ed t

hat

the

risk

of a

n A

pg

ar s

core

<5

at 1

min

ute

was

1.8

times

hig

her

for

anem

ic w

omen

com

par

ed t

o no

n-an

emic

wom

en.

Dru

kker

re

tros

pec

tive

coho

rt s

tud

y

neg

ativ

e A

nem

ia w

as id

entif

ied

as

a si

gni

fican

t in

dep

end

ent

risk

fact

or o

f Ap

gar

sco

re a

t 5

min

utes

<7

(p <

0.00

1).

Hw

ang

re

tros

pec

tive

coho

rt s

tud

y

no

Ther

e w

as n

o si

gni

fican

t d

iffer

ence

in A

pg

ar s

core

foun

d.

Lee

pro

spec

tive

coho

rt s

tud

y

neg

ativ

e A

nem

ic w

omen

had

sig

nific

antly

low

er A

pg

ar s

core

s at

1 a

nd 5

min

utes

com

par

ed

to n

on-a

neam

ic w

omen

(p <

0.05

).

Lelic

p

rosp

ectiv

e

case

-con

trol

stud

y

no

Ther

e w

as n

o si

gni

fican

t d

iffer

ence

in A

pg

ar s

core

bet

wee

n th

e st

udy

gro

up a

nd

cont

rol g

roup

.

Chapter 7

156

3c. N

eona

tal I

nten

sive

Car

e U

nit a

dmis

sion

Aut

hor

Stud

y d

esig

n A

sso

ciat

ion

Co

mm

ent

Dru

kker

re

tros

pec

tive

coho

rt s

tud

y

mod

erat

e A

nem

ia w

as id

entif

ied

as

a si

gni

fican

t in

dep

end

ent

risk

fact

or fo

r N

ICU

ad

mis

sion

(p =

0.0

18).

Whe

n an

emia

was

dis

trib

uted

by

seve

rity

(mild

, mod

erat

e/se

vere

)

ther

e w

as n

o si

gni

fican

t d

iffer

ence

foun

d b

etw

een

stud

y g

roup

s in

NIC

U

adm

issi

on.

Hw

ang

re

tros

pec

tive

coho

rt s

tud

y

no

Ther

e w

as n

o si

gni

fican

t d

iffer

ence

in N

ICU

ad

mis

sion

bet

wee

n g

roup

s.

3c. N

eona

tal I

nten

sive

Car

e U

nit a

dmis

sion

Aut

hor

Stud

y d

esig

n A

sso

ciat

ion

Co

mm

ent

Dru

kker

re

tros

pec

tive

coho

rt s

tud

y

mod

erat

e A

nem

ia w

as id

entif

ied

as

a si

gni

fican

t in

dep

end

ent

risk

fact

or fo

r N

ICU

ad

mis

sion

(p =

0.0

18).

Whe

n an

emia

was

dis

trib

uted

by

seve

rity

(mild

, mod

erat

e/se

vere

)

ther

e w

as n

o si

gni

fican

t d

iffer

ence

foun

d b

etw

een

stud

y g

roup

s in

NIC

U

adm

issi

on.

Hw

ang

re

tros

pec

tive

coho

rt s

tud

y

no

Ther

e w

as n

o si

gni

fican

t d

iffer

ence

in N

ICU

ad

mis

sion

bet

wee

n g

roup

s.


157

7

3d. P

erin

atal

mor

talit

y

PVC

= p

acke

d ce

ll vo

lum

e, C

I = c

onfid

ence

inte

rval

, Hb

= h

emog

lobi

n, N

ICU

= N

eona

tal I

nten

sive

Car

e U

nit,

GA

= g

esta

tiona

l age

Aut

hor

Stud

y d

esig

n A

sso

ciat

ion

Co

mm

ent

Aim

akhu

p

rosp

ectiv

e co

hort

stu

dy

uncl

ear

97.4

% o

f the

non

-ane

mic

pat

ient

s ha

d li

ve b

irths

com

par

ed t

o 75

% o

f the

m

oder

atel

y an

emic

pat

ient

s an

d 1

00%

of m

ild a

nem

ic p

atie

nts.

Ther

e w

ere

no

stat

istic

al t

ests

per

form

ed.

Zhan

g

pro

spec

tive

coho

rt s

tud

y m

oder

ate

No

asso

ciat

ion

bet

wee

n m

ater

nal a

nem

ia, i

ntra

par

tum

stil

lbirt

h an

d n

eona

tal

mor

talit

y w

as d

etec

ted

. In

fact

a t

rend

tow

ard

s a

slig

htly

incr

ease

d r

isk

of e

arly

ne

onat

al d

eath

in r

elat

ion

to e

leva

ted

Hb

leve

ls in

the

sec

ond

and

thi

rd t

rimes

ter

was

foun

d.

Lone

p

rosp

ectiv

e co

hort

stu

dy

no

The

risk

of p

erin

atal

mor

talit

y w

as 3

.2 t

imes

hig

her

amon

g a

nem

ic w

omen

, thi

s w

as

not

sig

nific

ant

(95%

CI 0

.7-14

.6).

Litt

le

pro

spec

tive

coho

rt s

tud

y no

A

U-s

hap

ed p

atte

rn w

as fo

und

with

low

est

reco

rded

Hb

con

cent

ratio

n (in

mos

t ca

ses

bet

wee

n G

A 2

6-28

wee

ks) f

or e

arly

neo

nata

l mor

talit

y, h

owev

er, w

hen

adju

sted

for

pre

mat

urity

the

rel

atio

nshi

p o

f ear

ly n

eona

tal m

orta

lity

with

low

est

Hb

la

rgel

y d

isap

pea

red

and

was

no

long

er s

igni

fican

t.

Xio

ng

retr

osp

ectiv

e co

hort

stu

dy

no

Ane

mia

in t

he t

hird

trim

este

r w

as n

ot a

ssoc

iate

d w

ith p

oor

birt

h ou

tcom

es. W

hen

div

ided

into

diff

eren

t d

egre

es o

f ane

mia

the

re w

ere

no s

igni

fican

t d

iffer

ence

s fo

und

in

the

freq

uenc

y of

per

inat

al m

orta

lity.

3d. P

erin

atal

mor

talit

y

PVC

= p

acke

d ce

ll vo

lum

e, C

I = c

onfid

ence

inte

rval

, Hb

= h

emog

lobi

n, N

ICU

= N

eona

tal I

nten

sive

Car

e U

nit,

GA

= g

esta

tiona

l age

Aut

hor

Stud

y d

esig

n A

sso

ciat

ion

Co

mm

ent

Aim

akhu

p

rosp

ectiv

e co

hort

stu

dy

uncl

ear

97.4

% o

f the

non

-ane

mic

pat

ient

s ha

d li

ve b

irths

com

par

ed t

o 75

% o

f the

m

oder

atel

y an

emic

pat

ient

s an

d 1

00%

of m

ild a

nem

ic p

atie

nts.

The

re w

ere

no

stat

istic

al t

ests

per

form

ed.

Zhan

g

pro

spec

tive

coho

rt s

tud

y m

oder

ate

No

asso

ciat

ion

bet

wee

n m

ater

nal a

nem

ia, i

ntra

par

tum

stil

lbirt

h an

d n

eona

tal

mor

talit

y w

as d

etec

ted

. In

fact

a t

rend

tow

ard

s a

slig

htly

incr

ease

d r

isk

of e

arly

ne

onat

al d

eath

in r

elat

ion

to e

leva

ted

Hb

leve

ls in

the

sec

ond

and

thi

rd t

rimes

ter

was

foun

d.

Lone

p

rosp

ectiv

e co

hort

stu

dy

no

The

risk

of p

erin

atal

mor

talit

y w

as 3

.2 t

imes

hig

her

amon

g a

nem

ic w

omen

, thi

s w

as

not

sig

nific

ant

(95%

CI 0

.7-1

4.6)

. Li

ttle

p

rosp

ectiv

e co

hort

stu

dy

no

A U

-sha

ped

pat

tern

was

foun

d w

ith lo

wes

t re

cord

ed H

b c

once

ntra

tion

(in m

ost

case

s b

etw

een

GA

26-

28 w

eeks

) for

ear

ly n

eona

tal m

orta

lity,

how

ever

, whe

n ad

just

ed fo

r p

rem

atur

ity t

he r

elat

ions

hip

of e

arly

neo

nata

l mor

talit

y w

ith lo

wes

t H

b

larg

ely

dis

app

eare

d a

nd w

as n

o lo

nger

sig

nific

ant.

X

iong

re

tros

pec

tive

coho

rt s

tud

y no

A

nem

ia in

the

thi

rd t

rimes

ter

was

not

ass

ocia

ted

with

poo

r b

irth

outc

omes

. Whe

n d

ivid

ed in

to d

iffer

ent

deg

rees

of a

nem

ia t

here

wer

e no

sig

nific

ant

diff

eren

ces

foun

d

in t

he fr

eque

ncy

of p

erin

atal

mor

talit

y.

3d. P

erin

atal

mor

talit

y

PVC

= p

acke

d ce

ll vo

lum

e, C

I = c

onfid

ence

inte

rval

, Hb

= h

emog

lobi

n, N

ICU

= N

eona

tal I

nten

sive

Car

e U

nit,

GA

= g

esta

tiona

l age

Aut

hor

Stud

y d

esig

n A

sso

ciat

ion

Co

mm

ent

Aim

akhu

p

rosp

ectiv

e co

hort

stu

dy

uncl

ear

97.4

% o

f the

non

-ane

mic

pat

ient

s ha

d li

ve b

irths

com

par

ed t

o 75

% o

f the

m

oder

atel

y an

emic

pat

ient

s an

d 1

00%

of m

ild a

nem

ic p

atie

nts.

The

re w

ere

no

stat

istic

al t

ests

per

form

ed.

Zhan

g

pro

spec

tive

coho

rt s

tud

y m

oder

ate

No

asso

ciat

ion

bet

wee

n m

ater

nal a

nem

ia, i

ntra

par

tum

stil

lbirt

h an

d n

eona

tal

mor

talit

y w

as d

etec

ted

. In

fact

a t

rend

tow

ard

s a

slig

htly

incr

ease

d r

isk

of e

arly

ne

onat

al d

eath

in r

elat

ion

to e

leva

ted

Hb

leve

ls in

the

sec

ond

and

thi

rd t

rimes

ter

was

foun

d.

Lone

p

rosp

ectiv

e co

hort

stu

dy

no

The

risk

of p

erin

atal

mor

talit

y w

as 3

.2 t

imes

hig

her

amon

g a

nem

ic w

omen

, thi

s w

as

not

sig

nific

ant

(95%

CI 0

.7-1

4.6)

. Li

ttle

p

rosp

ectiv

e co

hort

stu

dy

no

A U

-sha

ped

pat

tern

was

foun

d w

ith lo

wes

t re

cord

ed H

b c

once

ntra

tion

(in m

ost

case

s b

etw

een

GA

26-

28 w

eeks

) for

ear

ly n

eona

tal m

orta

lity,

how

ever

, whe

n ad

just

ed fo

r p

rem

atur

ity t

he r

elat

ions

hip

of e

arly

neo

nata

l mor

talit

y w

ith lo

wes

t H

b

larg

ely

dis

app

eare

d a

nd w

as n

o lo

nger

sig

nific

ant.

X

iong

re

tros

pec

tive

coho

rt s

tud

y no

A

nem

ia in

the

thi

rd t

rimes

ter

was

not

ass

ocia

ted

with

poo

r b

irth

outc

omes

. Whe

n d

ivid

ed in

to d

iffer

ent

deg

rees

of a

nem

ia t

here

wer

e no

sig

nific

ant

diff

eren

ces

foun

d

in t

he fr

eque

ncy

of p

erin

atal

mor

talit

y.

Chapter 7

158

Mode of delivery

We identified five articles reporting on maternal Hb concentration and mode of

delivery. Van Bogaert et al. performed a retrospective cohort study in a rural hospital

in South Africa.24 The Hb level estimated around the 24th week of pregnancy. The

study population comprised of 3,214 patients, 2,707 patients had a spontaneous

vaginal delivery and a total of 507 patients had a CS. The prevalence of anemia in

patients with a CS was significantly higher compared with spontaneous deliveries

(OR 0.55, 95% CI, 0.37-0.80, p = 0.002). Unfortunately, they did not describe the

reason to perform a CS (fetal distress or nonprogressive labor). Orlandini et al.

performed a retrospective cohort study and included 1,131 women with

uncomplicated pregnancies.12 The Hb concentrations were determined between

35+0 and 36+6 weeks of gestation. There were two groups, group A (n=156) with

Hb concentrations between 9-11.0 g/dL (mild anemia) and group B with Hb

≥11.1g/dL. All women received multivitamin intake during pregnancy. Anemic

women showed a higher rate of emergency CS than non-anemic women (p = 0.006).

Aimakhu et al. performed a prospective cohort study in a University College Hospital

in Nigeria.25 With a finger prick the packed cell volume (PCV) was measured every

antenatal visit until delivery. Spontaneous vertex delivery occurred in 76.8% of the

non-anemic women, 78.6% of the mild anemic women and 62.5% of moderate

anemic women. Consequently, there were more CS in the moderate anemic group

(37.5%), compared to the non-anemic and mildly anemic group, since they did not

perform any assisted vaginal deliveries (respectively 22.2% and 21.4%). There were

no statistical tests performed because of the small sample size of moderately anemic

women (n=24). Drukker et al. conducted a large retrospective cohort study

containing 75,660 women; the Hb values were determined on the day of labor.19

Maternal anemia was significantly associated with higher rates of CS: 2.6% vs. 2.1%

for multiparas (p = 0.039) and 3.2% vs. 2.0% for grand multiparas (defined as >5

childbirths) (p < 0.001), but there was no significant difference for nulliparous

women. In addition, they showed an increase of 1 g/dL was associated with a

reduction of 8.3% in CS rate (OR 0.92; 95% CI 0.88-0.95, p < 0.001). Two stepwise

backward logistic regression models were performed to evaluate the independent

effect of anemia on CS rate. Both models identified anemia as a significant

independent risk of CS (OR 1.30, 95% CI 1.13-1.49, p < 0.001; and OR 1.56, 95% CI

1.23-1.97, p < 0.001). Hwang et al. performed a retrospective cohort study as well,

including 3,560 women of whom 377 had anemia.20 Among the anemic group, there

were higher rates of CS for fetal distress compared to the non-anemic group. Also in

the multivariate analysis, CS for fetal distress was independently associated with

anemia (OR 1.5, 95% CI1.2-1.7, p < 0.001).

Apgar score

Nine articles reporting on Apgar score were included. Orlandini et al. did not

observe any differences in 5-minute Apgar score between the anemic- and non-

anemic group.12 The study by Aimakhu et al. reported a significantly higher mean 1-

minute Apgar scores in de non-anemic group compared with the moderate anemic

group.25 The mean Apgar score at one minute was 7.9 in the non-anemic group

(n=567), 7.8 in the mild anemia group (n=42) and 6.4 in the moderate anemia group

(n=24). However, the mean 5-minute Apgar did were not significantly different; the

mean Apgar scores for non-anemic, mild and moderate anemia were respectively

9.5, 9.6 and 8.6. Fareh et al. performed a retrospective case-control study.26 Records

of 100 consecutive anemic mothers who received antenatal care and had a vaginal

delivery in the hospital were reviewed. Within one week of the delivery, a non-

anemic patient was enrolled for inclusion in the control group. There were no

statistically significant differences in baseline characteristics between study and

control groups. Apgar scores at one and five minutes after birth were not different

between the two groups. Sekhavat et al. performed a prospective cohort study in

Iran.27 A total of 1,842 patients fulfilled inclusion criteria of whom 328 patients had

anemia and 598 patients had high Hb concentrations. The authors state that the risk

of low Apgar score was significantly increased in women with anemia, but in the

results-table a p-value of 0.8 is mentioned. Also, it is unclear whether the 1- or 5-

minute Apgar score is considered in their study. Lone et al. performed a prospective

cohort study and included 629 women.28 The univariate analysis showed that the risk

of an 1-minute Apgar score <5 and 5-minute Apgar score <7 was 2.1 and 1.7,

respectively (95% CI 1.2-3.7 and 1.0-3.1). The multivariate analysis showed that the

risk of a low 1-minute Apgar score was 1.8 times higher for anemic women

compared to non-anemic women (95% CI 1.2-3.7). The study of Drukker et al.

observed a significantly higher incidence of a 5-minute Apgar score <7 (p<0.001).19

In the multivariate logistic stepwise regression model, anemia was an independent

risk factor for 5-minute Apgar score <7 (OR 2.21, 95% CI 1.84-2.64, p<0.001). When

a multivariate logistic stepwise regression was performed by the degree of anemia,

it showed that women with moderate or severe anemia had significantly increased

risks for a low 5-minute Apgar score, compared to women with mild anemia or

normal Hb (OR 2.98, 95% CI 2.20-4.03, p<0.001).


159

7

Mode of delivery

We identified five articles reporting on maternal Hb concentration and mode of

delivery. Van Bogaert et al. performed a retrospective cohort study in a rural hospital

in South Africa.24 The Hb level estimated around the 24th week of pregnancy. The

study population comprised of 3,214 patients, 2,707 patients had a spontaneous

vaginal delivery and a total of 507 patients had a CS. The prevalence of anemia in

patients with a CS was significantly higher compared with spontaneous deliveries

(OR 0.55, 95% CI, 0.37-0.80, p = 0.002). Unfortunately, they did not describe the

reason to perform a CS (fetal distress or nonprogressive labor). Orlandini et al.

performed a retrospective cohort study and included 1,131 women with

uncomplicated pregnancies.12 The Hb concentrations were determined between

35+0 and 36+6 weeks of gestation. There were two groups, group A (n=156) with

Hb concentrations between 9-11.0 g/dL (mild anemia) and group B with Hb

≥11.1g/dL. All women received multivitamin intake during pregnancy. Anemic

women showed a higher rate of emergency CS than non-anemic women (p = 0.006).

Aimakhu et al. performed a prospective cohort study in a University College Hospital

in Nigeria.25 With a finger prick the packed cell volume (PCV) was measured every

antenatal visit until delivery. Spontaneous vertex delivery occurred in 76.8% of the

non-anemic women, 78.6% of the mild anemic women and 62.5% of moderate

anemic women. Consequently, there were more CS in the moderate anemic group

(37.5%), compared to the non-anemic and mildly anemic group, since they did not

perform any assisted vaginal deliveries (respectively 22.2% and 21.4%). There were

no statistical tests performed because of the small sample size of moderately anemic

women (n=24). Drukker et al. conducted a large retrospective cohort study

containing 75,660 women; the Hb values were determined on the day of labor.19

Maternal anemia was significantly associated with higher rates of CS: 2.6% vs. 2.1%

for multiparas (p = 0.039) and 3.2% vs. 2.0% for grand multiparas (defined as >5

childbirths) (p < 0.001), but there was no significant difference for nulliparous

women. In addition, they showed an increase of 1 g/dL was associated with a

reduction of 8.3% in CS rate (OR 0.92; 95% CI 0.88-0.95, p < 0.001). Two stepwise

backward logistic regression models were performed to evaluate the independent

effect of anemia on CS rate. Both models identified anemia as a significant

independent risk of CS (OR 1.30, 95% CI 1.13-1.49, p < 0.001; and OR 1.56, 95% CI

1.23-1.97, p < 0.001). Hwang et al. performed a retrospective cohort study as well,

including 3,560 women of whom 377 had anemia.20 Among the anemic group, there

were higher rates of CS for fetal distress compared to the non-anemic group. Also in

the multivariate analysis, CS for fetal distress was independently associated with

anemia (OR 1.5, 95% CI1.2-1.7, p < 0.001).

Apgar score

Nine articles reporting on Apgar score were included. Orlandini et al. did not

observe any differences in 5-minute Apgar score between the anemic- and non-

anemic group.12 The study by Aimakhu et al. reported a significantly higher mean 1-

minute Apgar scores in de non-anemic group compared with the moderate anemic

group.25 The mean Apgar score at one minute was 7.9 in the non-anemic group

(n=567), 7.8 in the mild anemia group (n=42) and 6.4 in the moderate anemia group

(n=24). However, the mean 5-minute Apgar did were not significantly different; the

mean Apgar scores for non-anemic, mild and moderate anemia were respectively

9.5, 9.6 and 8.6. Fareh et al. performed a retrospective case-control study.26 Records

of 100 consecutive anemic mothers who received antenatal care and had a vaginal

delivery in the hospital were reviewed. Within one week of the delivery, a non-

anemic patient was enrolled for inclusion in the control group. There were no

statistically significant differences in baseline characteristics between study and

control groups. Apgar scores at one and five minutes after birth were not different

between the two groups. Sekhavat et al. performed a prospective cohort study in

Iran.27 A total of 1,842 patients fulfilled inclusion criteria of whom 328 patients had

anemia and 598 patients had high Hb concentrations. The authors state that the risk

of low Apgar score was significantly increased in women with anemia, but in the

results-table a p-value of 0.8 is mentioned. Also, it is unclear whether the 1- or 5-

minute Apgar score is considered in their study. Lone et al. performed a prospective

cohort study and included 629 women.28 The univariate analysis showed that the risk

of an 1-minute Apgar score <5 and 5-minute Apgar score <7 was 2.1 and 1.7,

respectively (95% CI 1.2-3.7 and 1.0-3.1). The multivariate analysis showed that the

risk of a low 1-minute Apgar score was 1.8 times higher for anemic women

compared to non-anemic women (95% CI 1.2-3.7). The study of Drukker et al.

observed a significantly higher incidence of a 5-minute Apgar score <7 (p<0.001).19

In the multivariate logistic stepwise regression model, anemia was an independent

risk factor for 5-minute Apgar score <7 (OR 2.21, 95% CI 1.84-2.64, p<0.001). When

a multivariate logistic stepwise regression was performed by the degree of anemia,

it showed that women with moderate or severe anemia had significantly increased

risks for a low 5-minute Apgar score, compared to women with mild anemia or

normal Hb (OR 2.98, 95% CI 2.20-4.03, p<0.001).

Chapter 7

160

Hwang et al. performed a retrospective cohort study.20 They did not find any

significant differences between study groups for 5-minute Apgar score <7. Lee et al.

performed a prospective cohort study with 248 healthy pregnant women.29 The Hb

concentration was measured at 24-28 weeks of gestation and the women were

divided into three groups, Hb <10.8 g/dL (anemia), Hb 10.8-11.9 g/dL (normal) and

Hb ≥12.0 g/dL (high). Newborn infants from anemic mothers had significantly lower

Apgar scores at one and five minutes than the normal and high Hb groups (P <0.05).

The mean Apgar scores and standard deviation of the low, normal and high Hb

groups were respectively 7.9±2.7, 8.6±1.6 and 9.0±0.1 at one minute after birth and

9.0±2.8, 9.7±2.6 and 10.0±0.2 at five minutes after birth. They also found a

significantly positive correlation between maternal Hb concentration and Apgar

scores at one minute (r =0.231) and at five minutes (r =0.201). Lelic et al. performed

a prospective case-control study with two groups, each consisting of 50 women with

healthy term pregnancies.30 The control group contained women with no signs of

anemia or any other pregnancy disorder that could affect pregnancy outcomes. The

Apgar scores at one and five minutes after birth in both groups were similar.

NICU admission

We included two articles investigating the risk of NICU admission in relation to

maternal Hb.19,20 The study by Drukker et al. showed that NICU admission occurred

more often in anemic mothers (p <0.001).19 They also concluded that anemia was an

independent risk factor for NICU admission (OR 1.28, 95% CI 1.04-1.57, p = 0.018).

However, when distributed by the degree of anemia, there was no significant

difference in NICU admission per study group (mild anemia: OR 1.23, 95% CI 0.98-

1.56 and moderate/severe anemia: OR 1.45, 95% CI 0.99-2.13). Hwang et al. did not

show any differences in NICU admission between study groups.20

Perinatal mortality

Five articles on perinatal mortality were included. Aimakhu et al. reported a perinatal

mortality rate of 33 per 1,000 births.25 Of the non-anemic patients 97.4% had a live

birth, compared to 75% of the moderately anemic patients, and 100% of the mild

anemic patients. No statistical tests were performed. Zhang et al. performed a large

prospective cohort study in China.31 A total of 153,952 women was included in the

study. The overall perinatal mortality rate was 14.3 per 1,000 births. No association

between maternal anemia and intrapartum stillbirth or neonatal mortality was

detected. In fact, a trend towards a slightly increased risk of early neonatal death in

relation to elevated Hb concentrations in the second and third trimester was found.

This association was marginally significant for Hb ≥ 12 g/dL in the third trimester

(HR,= 1.1, 95% CI 1.0-1.2). Lone et al. reported a 3.2 times higher, but not

statistically different risk of perinatal mortality among anemic women (ARR, 3.2; 95%

CI, 0.7-14.6).28 Little et al. performed a prospective cohort study, using data of

144,209 pregnancies.32 There were 903 perinatal deaths in total, of which 689

stillbirths and 214 early neonatal deaths. A U-shaped pattern was found with lowest

recorded Hb concentration (in most cases between gestational age 26-28 weeks) for

early neonatal mortality rates. However, when adjusted for prematurity, the

relationship of early neonatal mortality with lowest Hb largely disappeared and was

no longer significant. Xiong et al. in 2003 performed a retrospective cohort study in

China.33 Their study population consisted of 15,943 women with singleton

pregnancies, 95% of the women were primigravidas. Anemia in the third trimester

was not associated with a higher risk of perinatal mortality. When divided in the

severity of anemia, there were also no differences found in the frequency of

perinatal mortality.

Fetal distress and umbilical cord pH

We did not identify any studies reporting on the outcome measures fetal distress or

umbilical cord pH.

Discussion

For this systematic review, we aimed to identify studies reporting on intrapartum

maternal Hb concentration in relation to mode of delivery and neonatal outcome.

We found a total of 13 studies, including 413,036 patients, addressing the outcome

measures mode of delivery, Apgar score, NICU admission, and perinatal death. We

did not identify studies focussing on the outcome measures fetal distress during

labor and umbilical cord pH.

Mode of delivery

We found five studies regarding the outcome measure mode of delivery. Four are

retrospective cohort studies, they show a negative association between maternal Hb

and CS rate, meaning that the CS rate is increased in anemic women. One study did


161

7

Hwang et al. performed a retrospective cohort study.20 They did not find any

significant differences between study groups for 5-minute Apgar score <7. Lee et al.

performed a prospective cohort study with 248 healthy pregnant women.29 The Hb

concentration was measured at 24-28 weeks of gestation and the women were

divided into three groups, Hb <10.8 g/dL (anemia), Hb 10.8-11.9 g/dL (normal) and

Hb ≥12.0 g/dL (high). Newborn infants from anemic mothers had significantly lower

Apgar scores at one and five minutes than the normal and high Hb groups (P <0.05).

The mean Apgar scores and standard deviation of the low, normal and high Hb

groups were respectively 7.9±2.7, 8.6±1.6 and 9.0±0.1 at one minute after birth and

9.0±2.8, 9.7±2.6 and 10.0±0.2 at five minutes after birth. They also found a

significantly positive correlation between maternal Hb concentration and Apgar

scores at one minute (r =0.231) and at five minutes (r =0.201). Lelic et al. performed

a prospective case-control study with two groups, each consisting of 50 women with

healthy term pregnancies.30 The control group contained women with no signs of

anemia or any other pregnancy disorder that could affect pregnancy outcomes. The

Apgar scores at one and five minutes after birth in both groups were similar.

NICU admission

We included two articles investigating the risk of NICU admission in relation to

maternal Hb.19,20 The study by Drukker et al. showed that NICU admission occurred

more often in anemic mothers (p <0.001).19 They also concluded that anemia was an

independent risk factor for NICU admission (OR 1.28, 95% CI 1.04-1.57, p = 0.018).

However, when distributed by the degree of anemia, there was no significant

difference in NICU admission per study group (mild anemia: OR 1.23, 95% CI 0.98-

1.56 and moderate/severe anemia: OR 1.45, 95% CI 0.99-2.13). Hwang et al. did not

show any differences in NICU admission between study groups.20

Perinatal mortality

Five articles on perinatal mortality were included. Aimakhu et al. reported a perinatal

mortality rate of 33 per 1,000 births.25 Of the non-anemic patients 97.4% had a live

birth, compared to 75% of the moderately anemic patients, and 100% of the mild

anemic patients. No statistical tests were performed. Zhang et al. performed a large

prospective cohort study in China.31 A total of 153,952 women was included in the

study. The overall perinatal mortality rate was 14.3 per 1,000 births. No association

between maternal anemia and intrapartum stillbirth or neonatal mortality was

detected. In fact, a trend towards a slightly increased risk of early neonatal death in

relation to elevated Hb concentrations in the second and third trimester was found.

This association was marginally significant for Hb ≥ 12 g/dL in the third trimester

(HR,= 1.1, 95% CI 1.0-1.2). Lone et al. reported a 3.2 times higher, but not

statistically different risk of perinatal mortality among anemic women (ARR, 3.2; 95%

CI, 0.7-14.6).28 Little et al. performed a prospective cohort study, using data of

144,209 pregnancies.32 There were 903 perinatal deaths in total, of which 689

stillbirths and 214 early neonatal deaths. A U-shaped pattern was found with lowest

recorded Hb concentration (in most cases between gestational age 26-28 weeks) for

early neonatal mortality rates. However, when adjusted for prematurity, the

relationship of early neonatal mortality with lowest Hb largely disappeared and was

no longer significant. Xiong et al. in 2003 performed a retrospective cohort study in

China.33 Their study population consisted of 15,943 women with singleton

pregnancies, 95% of the women were primigravidas. Anemia in the third trimester

was not associated with a higher risk of perinatal mortality. When divided in the

severity of anemia, there were also no differences found in the frequency of

perinatal mortality.

Fetal distress and umbilical cord pH

We did not identify any studies reporting on the outcome measures fetal distress or

umbilical cord pH.

Discussion

For this systematic review, we aimed to identify studies reporting on intrapartum

maternal Hb concentration in relation to mode of delivery and neonatal outcome.

We found a total of 13 studies, including 413,036 patients, addressing the outcome

measures mode of delivery, Apgar score, NICU admission, and perinatal death. We

did not identify studies focussing on the outcome measures fetal distress during

labor and umbilical cord pH.

Mode of delivery

We found five studies regarding the outcome measure mode of delivery. Four are

retrospective cohort studies, they show a negative association between maternal Hb

and CS rate, meaning that the CS rate is increased in anemic women. One study did

Chapter 7

162

not perform statistical analysis because of the small sample size, but they found

more CS performed in the anemic group. Even though these studies are all of low

quality according to GRADE (table 2),22 they all indicate the same increased risk of

CS in anemic women. Drukker et al. even found a dose-response relation, where

adverse neonatal and maternal outcome increased in accordance with the severity of

anemia.19 The four systematic reviews that we identified in the primary search did not

focus on this outcome measure.34-37 One of these reviews, a Cochrane review by

Pena-Rosas et al, was updated in 2015, counting for two of the four identified

reviews.34,35

Apgar score

Nine articles were identified for the relation between Hb level and Apgar score. Two

of the studies concluded that maternal anemia is a risk factor for low 5-minute Apgar

score,19 or leads to a lower mean 5-minute Apgar score compared to normal Hb.28

One other study only found a lower mean Apgar score at 1-minute after birth in the

anemic group, but no differences in 5-minute Apgar score.25 Similarly, another study

found an increased risk of low 1-minute Apgar score (<5) in the presence of anemia,

but no difference in low 5-minute Apgar score (<7).28 One study does report a

significant difference in mean Apgar score in the text, but an accompanying table

shows a p-value of 0.8, suggesting no significant effect.27 Besides, it is unclear

whether the 1 of 5-minute Apgar score is reported.27

In contrast, four studies did not find any differences in Apgar score between anemic

and non-anemic mothers.12,20,26,30 The results are inconsistent, probably due to major

differences in study design (retrospective and prospective cohort studies and case-

control studies) Furthermore, the size and characteristics of the study populations

are diverse: the number of participants varies from 100 to more than 75,000. Some

studies excluded women with known hemoglobinopathies, while in other studies

they were included. Third, different outcome measures are used: five studies report

the mean Apgar score, while others report the number of participants with an Apgar

score <5 after 1 minute or <7 after 5 minutes. In some studies, 1-minute Apgar

score is not reported. Finally, a different definition of anemia is used, varying from

Hb <10 to <11 g/dL, and one study used packed cell volume instead of Hb.25 In

conclusion, we found conflicting evidence regarding the hypothesis of intrapartum

anemia leading to lower Apgar score.

NICU admission

We identified two studies that had NICU admission as an outcome measure.19,20

Both studies were retrospective cohort studies with large sample sizes; Drukker et al.

included 75,660 patients and Hwang et al. included 3,560 patients.19,20 Drukker et al.

found that children from anemic mothers had a higher risk of NICU admission than

non-anemic mothers, with a higher OR for more a severe degree of anemia.19

However, this effect was not significant (OR 1.23, CI 0.98-1.56 in mild anemia and

OR 1.45 CI 0.99-2.13) in moderate-severe anemia, compared to 1.00 with no

anemia. Hwang et al. did not find an increased risk of NICU admission in the

presence of anemia.20 Both studies only included healthy, uncomplicated

pregnancies and had a prevalence of anemia of 10.5%. Hwang’s study defined

anemia as Hb value <10.0 g/dL while Drukker defined mild anemia as Hb 10.0 –

10.9, and moderate/severe anemia as Hb < 10.0 g/dL. Both studies did not show

any difference in NICU admissions in women with Hb < 10.0 g/dL, compared to

non-anemic women. This may be explained because the incidence of NICU

admission is low (1.7-2.4%), thus when the study group is smaller, differences cannot

be longer demonstrated. In conclusion, we cannot confirm a higher risk of NICU

admissions in the presence of maternal anemia.

Perinatal mortality

Four prospective studies and one retrospective study reporting on perinatal

mortality were included in this review.25,28,31-33 None of the studies found a significant

association between anemia and perinatal mortality. In one study the authors did

not perform statistical tests because of low incidence of perinatal mortality

(n=21/633).25 A systematic review and meta-analysis performed in 2000 concluded

that ‘the relationship between anemia and perinatal mortality was still inconclusive’.7

Zhang et al. demonstrated that high Hb values might be associated with an

increased risk of perinatal mortality.31 Little et al. also showed a U-shaped pattern for

Hb concentration and perinatal mortality, but when adjusted for birth weight and

prematurity the association disappeared.32 No other study included in this review

focused on high Hb concentrations and perinatal mortality. However, other studies

that did not meet our inclusion criteria also showed a relationship between high Hb

and perinatal mortality.6,18 These two studies were excluded from our review

because the maternal Hb level was determined in the first trimester. An explanation


163

7

not perform statistical analysis because of the small sample size, but they found

more CS performed in the anemic group. Even though these studies are all of low

quality according to GRADE (table 2),22 they all indicate the same increased risk of

CS in anemic women. Drukker et al. even found a dose-response relation, where

adverse neonatal and maternal outcome increased in accordance with the severity of

anemia.19 The four systematic reviews that we identified in the primary search did not

focus on this outcome measure.34-37 One of these reviews, a Cochrane review by

Pena-Rosas et al, was updated in 2015, counting for two of the four identified

reviews.34,35

Apgar score

Nine articles were identified for the relation between Hb level and Apgar score. Two

of the studies concluded that maternal anemia is a risk factor for low 5-minute Apgar

score,19 or leads to a lower mean 5-minute Apgar score compared to normal Hb.28

One other study only found a lower mean Apgar score at 1-minute after birth in the

anemic group, but no differences in 5-minute Apgar score.25 Similarly, another study

found an increased risk of low 1-minute Apgar score (<5) in the presence of anemia,

but no difference in low 5-minute Apgar score (<7).28 One study does report a

significant difference in mean Apgar score in the text, but an accompanying table

shows a p-value of 0.8, suggesting no significant effect.27 Besides, it is unclear

whether the 1 of 5-minute Apgar score is reported.27

In contrast, four studies did not find any differences in Apgar score between anemic

and non-anemic mothers.12,20,26,30 The results are inconsistent, probably due to major

differences in study design (retrospective and prospective cohort studies and case-

control studies) Furthermore, the size and characteristics of the study populations

are diverse: the number of participants varies from 100 to more than 75,000. Some

studies excluded women with known hemoglobinopathies, while in other studies

they were included. Third, different outcome measures are used: five studies report

the mean Apgar score, while others report the number of participants with an Apgar

score <5 after 1 minute or <7 after 5 minutes. In some studies, 1-minute Apgar

score is not reported. Finally, a different definition of anemia is used, varying from

Hb <10 to <11 g/dL, and one study used packed cell volume instead of Hb.25 In

conclusion, we found conflicting evidence regarding the hypothesis of intrapartum

anemia leading to lower Apgar score.

NICU admission

We identified two studies that had NICU admission as an outcome measure.19,20

Both studies were retrospective cohort studies with large sample sizes; Drukker et al.

included 75,660 patients and Hwang et al. included 3,560 patients.19,20 Drukker et al.

found that children from anemic mothers had a higher risk of NICU admission than

non-anemic mothers, with a higher OR for more a severe degree of anemia.19

However, this effect was not significant (OR 1.23, CI 0.98-1.56 in mild anemia and

OR 1.45 CI 0.99-2.13) in moderate-severe anemia, compared to 1.00 with no

anemia. Hwang et al. did not find an increased risk of NICU admission in the

presence of anemia.20 Both studies only included healthy, uncomplicated

pregnancies and had a prevalence of anemia of 10.5%. Hwang’s study defined

anemia as Hb value <10.0 g/dL while Drukker defined mild anemia as Hb 10.0 –

10.9, and moderate/severe anemia as Hb < 10.0 g/dL. Both studies did not show

any difference in NICU admissions in women with Hb < 10.0 g/dL, compared to

non-anemic women. This may be explained because the incidence of NICU

admission is low (1.7-2.4%), thus when the study group is smaller, differences cannot

be longer demonstrated. In conclusion, we cannot confirm a higher risk of NICU

admissions in the presence of maternal anemia.

Perinatal mortality

Four prospective studies and one retrospective study reporting on perinatal

mortality were included in this review.25,28,31-33 None of the studies found a significant

association between anemia and perinatal mortality. In one study the authors did

not perform statistical tests because of low incidence of perinatal mortality

(n=21/633).25 A systematic review and meta-analysis performed in 2000 concluded

that ‘the relationship between anemia and perinatal mortality was still inconclusive’.7

Zhang et al. demonstrated that high Hb values might be associated with an

increased risk of perinatal mortality.31 Little et al. also showed a U-shaped pattern for

Hb concentration and perinatal mortality, but when adjusted for birth weight and

prematurity the association disappeared.32 No other study included in this review

focused on high Hb concentrations and perinatal mortality. However, other studies

that did not meet our inclusion criteria also showed a relationship between high Hb

and perinatal mortality.6,18 These two studies were excluded from our review

because the maternal Hb level was determined in the first trimester. An explanation

Chapter 7

164

for the association between high Hb and perinatal death may be the association

with hypertensive disorders of pregnancy, such as preeclampsia. Furthermore, high

Hb levels are often caused by failure of normal plasma expansion, leading to

increased blood viscosity.34-37 As a result of poor plasma expansion or increased

blood viscosity, blood flow and fetomaternal exchange of oxygen and nutrients in

the placenta are reduced.34-37

In conclusion, in several observational studies, we found no evidence proving a

relation between low Hb concentration and an increased risk of perinatal death.

However, high Hb concentrations should get attention, because of its relation with

impaired placental function, potentially leading to an increased risk of perinatal

death.

Implications for clinical practice

Based on this review, we should prevent peripartum anemia to optimize the chance

of a spontaneous delivery and prevent a CS. Since the main cause of anemia in

pregnancy is iron deficiency, one should monitor and when necessary replenish iron

stores to correct maternal anemia.38 In developing countries, also parasitic diseases

such as malaria are a major cause of maternal anemia. Apart from the risks

associated with malaria-related anemia, also infection of the placenta itself

contributes to a higher risk of adverse neonatal outcome.38 Besides, from maternal

anemia, also the presence of elevated Hb levels are likely to influence maternal and

neonatal outcome. In this case, one should be cautious regarding the development

of a hypertensive disorder of pregnancy, as they may be associated with adverse

maternal and perinatal outcome.

Recommendations for future research

We recommend initiating an international, prospective, population-based database

(including low-risk pregnancies), where data on important factors such as obstetric

and medical history, the course of Hb level during pregnancy, obstetric

complications and socioeconomic status is carefully stored. Once a large, complete

and reliable database is available, the relationship between various obstetric

parameters can be addressed. For example, the relation between maternal Hb and

perinatal outcome and mode of delivery can easily be addressed, including

correction for possible confounders.

Conclusion

It is plausible that maternal anemia during labor contributes to an increased risk of

CS. However, evidence regarding the relationship between anemia and low Apgar

score, risk of NICU admission or perinatal death is contradictory and not conclusive.

Acknowledgments This research was performed within the framework of the IMPULS perinatology. We

thank Eugenie Delvaux, librarian at Máxima Medical Center for helping with the data

search.


165

7

for the association between high Hb and perinatal death may be the association

with hypertensive disorders of pregnancy, such as preeclampsia. Furthermore, high

Hb levels are often caused by failure of normal plasma expansion, leading to

increased blood viscosity.34-37 As a result of poor plasma expansion or increased

blood viscosity, blood flow and fetomaternal exchange of oxygen and nutrients in

the placenta are reduced.34-37

In conclusion, in several observational studies, we found no evidence proving a

relation between low Hb concentration and an increased risk of perinatal death.

However, high Hb concentrations should get attention, because of its relation with

impaired placental function, potentially leading to an increased risk of perinatal

death.

Implications for clinical practice

Based on this review, we should prevent peripartum anemia to optimize the chance

of a spontaneous delivery and prevent a CS. Since the main cause of anemia in

pregnancy is iron deficiency, one should monitor and when necessary replenish iron

stores to correct maternal anemia.38 In developing countries, also parasitic diseases

such as malaria are a major cause of maternal anemia. Apart from the risks

associated with malaria-related anemia, also infection of the placenta itself

contributes to a higher risk of adverse neonatal outcome.38 Besides, from maternal

anemia, also the presence of elevated Hb levels are likely to influence maternal and

neonatal outcome. In this case, one should be cautious regarding the development

of a hypertensive disorder of pregnancy, as they may be associated with adverse

maternal and perinatal outcome.

Recommendations for future research

We recommend initiating an international, prospective, population-based database

(including low-risk pregnancies), where data on important factors such as obstetric

and medical history, the course of Hb level during pregnancy, obstetric

complications and socioeconomic status is carefully stored. Once a large, complete

and reliable database is available, the relationship between various obstetric

parameters can be addressed. For example, the relation between maternal Hb and

perinatal outcome and mode of delivery can easily be addressed, including

correction for possible confounders.

Conclusion

It is plausible that maternal anemia during labor contributes to an increased risk of

CS. However, evidence regarding the relationship between anemia and low Apgar

score, risk of NICU admission or perinatal death is contradictory and not conclusive.

Acknowledgments This research was performed within the framework of the IMPULS perinatology. We

thank Eugenie Delvaux, librarian at Máxima Medical Center for helping with the data

search.

Chapter 7

166

References 1. Letsky E. Haematology of pregnancy. Medicine. 2004;32:42-5. 2. Longmuir K, Pavord S. Haematology of pregnancy. Medicine. 2013;41: 248-51. 3. World Health Organization (WHO). Haemoglobin concentrations for the diagnosis of

anaemia and assessment of severity [internet]. Geneva: WHO; 2011. Available from: http://www.who.int/iris/handle/10665/85839.

4. Stevens GA, Finucane MM, De-Regil LM, Paciorek CJ, Flaxman SR, Branca F, et al. Global, regional, and national trends in haemoglobin concentration and prevalence of total and severe anaemia in children and pregnant and non-pregnant women for 1995–2011: a systematic analysis of population-representative data. Lancet Glob Health. 2013;1:e16-e25.

5. Peña-Rosas JP, De-Regil LM, Gomez Malave H, Flores-Urrutia MC, Dowswell T. Intermittent oral iron supplementation during pregnancy. Cochrane Database Syst Rev. 2015;10:CD009997.

6. Murphy JF, O’Riordan J, Newcombe RG, Coles EC, Pearson JF. Relation of haemoglobin concentrations in first and second trimesters to outcome of pregnancy. Lancet. 1986;1:992-5.

7. Xiong X, Buekens P, Alexander S, Demianczuk N, Wollast E. Anemia during pregnancy and birth outcome: a meta-analysis. Am J Perinatol. 2000;17:137-46.

8. Haider BA, Olofin I, Wang M, Spiegelman D, Ezzati M, Fawzi WW. Anaemia, prenatal iron use, and risk of adverse pregnancy outcomes: systematic review and meta-analysis. BMJ. 2013;346:f3443.

9. Cordina M, Bhatti S, Fernandez M, Syngelaki A, Nicolaides KH, Kametas NA. Association between maternal haemoglobin at 27–29 weeks gestation and intrauterine growth restriction. Pregnancy Hypertens. 2015;5:339-45.

10. Räisänen S, Kancherla V, Gissler M, Kramer MR, Heinonen S. Adverse Perinatal Outcomes Associated with Moderate or Severe Maternal Anaemia Based on Parity in Finland during 2006–10. Paediatr Perinat Epidemiol. 2014;28:d372-80.

11. Malhotra M, Sharma JB, Batra S, Sharma S, Murthy NS, Arora R. Maternal and perinatal outcome in varying degrees of anemia. Int J Gynaecol Obstet. 2002;79:93-100.

12. Orlandini C, Torricelli M, Spirito N, Alaimo L, Di Tommaso M, Severi FM, et al. Maternal anemia effects during pregnancy on male and female fetuses: are there any differences? J Matern Fetal Neonatal Med. 2017;30:1704-8.

13. Levy A, Fraser D, Katz M, Mazor M, Sheiner E. Maternal anemia during pregnancy is an independent risk factor for low birthweight and preterm delivery. Eur J Obstet Gynecol Reprod Biol. 2005;122:182-6.

14. Chang SC, O’Brien KO, Nathanson MS, Mancini J, Witter FR. Hemoglobin concentrations influence birth outcomes in pregnant African-American adolescents. J Nutr. 2003;133:2348-55.

15. Scanlon KS, Yip R, Schieve LS, Cogswell ME. High and low hemoglobin levels during pregnancy: differential risks for preterm birth and small for gestational age. Obstet Gynecol. 2000;96:741-8.

16. Aghamohammadi A, Zafari M, Tofighi M. High maternal hemoglobin concentration in first trimester as risk factor for pregnancy induced hypertension. Caspian J Intern Med. 2011;2:194-7.

17. Phaloprakarn C, Tangjitgamol S. Impact of high maternal hemoglobin at first antenatal visit on pregnancy outcomes: a cohort study. J Perinat Med. 2008;36:115-9.

18. Dewey KG, Oaks BM. U-shaped curve for risk associated with maternal hemoglobin, iron status, or iron supplementation. Am J Clin Nutr. 2017;106(suppl_6):1694S-1702S.

19. Drukker L, Hants Y, Farkash R, Ruchlemer R, Samueloff A, Grisaru-Granovsky S. Iron deficiency anemia at admission for labor and delivery is associated with an increased risk for Cesarean section and adverse maternal and neonatal outcomes. Transfusion. 2015;55:2799-806.

20. Hwang HS, Kim YH, Kwon JY, Park YW. Uterine and umbilical artery Doppler velocimetry as a predictor for adverse pregnancy outcomes in pregnant women with anemia. J Perinat Med. 2010;38:467-71.

21. Koninklijke Nederlandse Organisatie van Verloskundigen (KNOV). Anemie in de verloskundige praktijk [internet]. KNOV: Deventer; 2010. Available from: https://www.knov.nl/serve/file/knov.nl/knov_downloads/669/file/KNOV-Standaard%20Anemie%20in%20de%20verloskundige%20praktijk.pdf. [Dutch]

22. Schünemann H, Brożek J, Guyatt G, Oxman A, editors. GRADE handbook for grading quality of evidence and strength of recommendations. The GRADE Working Group: 2013. Available from: https://gdt.gradepro.org/app/handbook/handbook.html.

23. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151:264-9.

24. Van Bogaert LJ. Anaemia and pregnancy outcomes in a South African rural population. J Obstet Gynaecol. 2006;26:617-9.

25. Aimakhu CO, Olayemi O. Maternal haematocrit and pregnancy outcome in Nigerian women. West Afr J Med. 2003;22:18-21.

26. Fareh OI, Rizk DEE, Thomas L, Berg B. Obstetric impact of anaemia in pregnant women in United Arab Emirates. J Obstet Gynaecol. 2005;25:440-4.

27. Sekhavat L, Davar R, Hosseinidezoki S. Relationship between maternal hemoglobin concentration and neonatal birth weight. Hematology. 2011;16:373-6.

28. Lone FW, Qureshi RN, Emanuel F. Maternal anaemia and its impact on perinatal outcome. Trop Med Int Health. 2004;9:486-90.

29. Lee HS, Kim MS, Kim MH, Kim YJ, Kim WY. Iron status and its association with pregnancy outcome in Korean pregnant women. Eur J Clinic Nutr. 2006;60:1130-5.

30. Lelic M, Bogdanovic G, Ramic S, Brkicevic E. Influence of maternal anemia during pregnancy on placenta and newborns. Med Arch. 2014;68:184-7.

31. Zhang Q, Ananth CV, Rhoads GG, Li Z. The impact of maternal anemia on perinatal mortality: a population-based, prospective cohort study in China. Ann Epidemiol. 2009;19:793-9.

32. Little MP, Brocard P, Elliott P, Steer PJ. Hemoglobin concentration in pregnancy and perinatal mortality: a London-based cohort study. Am J Obstet Gynecol. 2005;193:220-6.

33. Xiong X, Buekens P, Fraser WD, Guo Z. Anemia during pregnancy in a Chinese population. Int J of Gynecol Obstet. 2003;83:159-64.


35. Thorburn J, Drummond MM, Whigham KA, Lowe GD, Forbes CD, Prentice CR, et al.


167

7

References 1. Letsky E. Haematology of pregnancy. Medicine. 2004;32:42-5. 2. Longmuir K, Pavord S. Haematology of pregnancy. Medicine. 2013;41: 248-51. 3. World Health Organization (WHO). Haemoglobin concentrations for the diagnosis of

anaemia and assessment of severity [internet]. Geneva: WHO; 2011. Available from: http://www.who.int/iris/handle/10665/85839.

4. Stevens GA, Finucane MM, De-Regil LM, Paciorek CJ, Flaxman SR, Branca F, et al. Global, regional, and national trends in haemoglobin concentration and prevalence of total and severe anaemia in children and pregnant and non-pregnant women for 1995–2011: a systematic analysis of population-representative data. Lancet Glob Health. 2013;1:e16-e25.

5. Peña-Rosas JP, De-Regil LM, Gomez Malave H, Flores-Urrutia MC, Dowswell T. Intermittent oral iron supplementation during pregnancy. Cochrane Database Syst Rev. 2015;10:CD009997.

6. Murphy JF, O’Riordan J, Newcombe RG, Coles EC, Pearson JF. Relation of haemoglobin concentrations in first and second trimesters to outcome of pregnancy. Lancet. 1986;1:992-5.

7. Xiong X, Buekens P, Alexander S, Demianczuk N, Wollast E. Anemia during pregnancy and birth outcome: a meta-analysis. Am J Perinatol. 2000;17:137-46.

8. Haider BA, Olofin I, Wang M, Spiegelman D, Ezzati M, Fawzi WW. Anaemia, prenatal iron use, and risk of adverse pregnancy outcomes: systematic review and meta-analysis. BMJ. 2013;346:f3443.

9. Cordina M, Bhatti S, Fernandez M, Syngelaki A, Nicolaides KH, Kametas NA. Association between maternal haemoglobin at 27–29 weeks gestation and intrauterine growth restriction. Pregnancy Hypertens. 2015;5:339-45.

10. Räisänen S, Kancherla V, Gissler M, Kramer MR, Heinonen S. Adverse Perinatal Outcomes Associated with Moderate or Severe Maternal Anaemia Based on Parity in Finland during 2006–10. Paediatr Perinat Epidemiol. 2014;28:d372-80.

11. Malhotra M, Sharma JB, Batra S, Sharma S, Murthy NS, Arora R. Maternal and perinatal outcome in varying degrees of anemia. Int J Gynaecol Obstet. 2002;79:93-100.


13. Levy A, Fraser D, Katz M, Mazor M, Sheiner E. Maternal anemia during pregnancy is an independent risk factor for low birthweight and preterm delivery. Eur J Obstet Gynecol Reprod Biol. 2005;122:182-6.

14. Chang SC, O’Brien KO, Nathanson MS, Mancini J, Witter FR. Hemoglobin concentrations influence birth outcomes in pregnant African-American adolescents. J Nutr. 2003;133:2348-55.

15. Scanlon KS, Yip R, Schieve LS, Cogswell ME. High and low hemoglobin levels during pregnancy: differential risks for preterm birth and small for gestational age. Obstet Gynecol. 2000;96:741-8.

16. Aghamohammadi A, Zafari M, Tofighi M. High maternal hemoglobin concentration in first trimester as risk factor for pregnancy induced hypertension. Caspian J Intern Med. 2011;2:194-7.

17. Phaloprakarn C, Tangjitgamol S. Impact of high maternal hemoglobin at first antenatal visit on pregnancy outcomes: a cohort study. J Perinat Med. 2008;36:115-9.

18. Dewey KG, Oaks BM. U-shaped curve for risk associated with maternal hemoglobin, iron status, or iron supplementation. Am J Clin Nutr. 2017;106(suppl_6):1694S-1702S.



21. Koninklijke Nederlandse Organisatie van Verloskundigen (KNOV). Anemie in de verloskundige praktijk [internet]. KNOV: Deventer; 2010. Available from: https://www.knov.nl/serve/file/knov.nl/knov_downloads/669/file/KNOV-Standaard%20Anemie%20in%20de%20verloskundige%20praktijk.pdf. [Dutch]

22. Schünemann H, Brożek J, Guyatt G, Oxman A, editors. GRADE handbook for grading quality of evidence and strength of recommendations. The GRADE Working Group: 2013. Available from: https://gdt.gradepro.org/app/handbook/handbook.html.

23. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151:264-9.

24. Van Bogaert LJ. Anaemia and pregnancy outcomes in a South African rural population. J Obstet Gynaecol. 2006;26:617-9.

25. Aimakhu CO, Olayemi O. Maternal haematocrit and pregnancy outcome in Nigerian women. West Afr J Med. 2003;22:18-21.

26. Fareh OI, Rizk DEE, Thomas L, Berg B. Obstetric impact of anaemia in pregnant women in United Arab Emirates. J Obstet Gynaecol. 2005;25:440-4.



29. Lee HS, Kim MS, Kim MH, Kim YJ, Kim WY. Iron status and its association with pregnancy outcome in Korean pregnant women. Eur J Clinic Nutr. 2006;60:1130-5.

30. Lelic M, Bogdanovic G, Ramic S, Brkicevic E. Influence of maternal anemia during pregnancy on placenta and newborns. Med Arch. 2014;68:184-7.

31. Zhang Q, Ananth CV, Rhoads GG, Li Z. The impact of maternal anemia on perinatal mortality: a population-based, prospective cohort study in China. Ann Epidemiol. 2009;19:793-9.

32. Little MP, Brocard P, Elliott P, Steer PJ. Hemoglobin concentration in pregnancy and perinatal mortality: a London-based cohort study. Am J Obstet Gynecol. 2005;193:220-6.

33. Xiong X, Buekens P, Fraser WD, Guo Z. Anemia during pregnancy in a Chinese population. Int J of Gynecol Obstet. 2003;83:159-64.


35. Thorburn J, Drummond MM, Whigham KA, Lowe GD, Forbes CD, Prentice CR, et al.

Chapter 7

168

Blood viscosity and haemostatic factors in late pregnancy, pre-eclampsia and fetal growth retardation. Br J Obstet Gynaecol. 1982;89:117-22.

36. Yip R. Significance of an abnormally low or high hemoglobin concentration during pregnancy: special consideration of iron nutrition. Am J Clin Nutr. 2000;72:272S-279S.

37. Garn SM, Ridella SA, Petzold AS, Falkner F. Maternal hematologic levels and pregnancy outcomes. Semin Perinatol. 1981;5:155-62.

38. World Health Organization (WHO). Global malaria report [internet]. Geneva: WHO; 2017. Available from: http://www.who.int/malaria/publications/world-malaria-report-2017/report/en/.

Chapter 8

Maternal hemoglobin level and its relation to fetal

distress, mode of delivery, and short-term neonatal

outcome: a retrospective cohort study

Bullens LM, Smith JS, Truijens SE, van Runnard Heimel PJ,


Submitted

Blood viscosity and haemostatic factors in late pregnancy, pre-eclampsia and fetal growth retardation. Br J Obstet Gynaecol. 1982;89:117-22.

36. Yip R. Significance of an abnormally low or high hemoglobin concentration during pregnancy: special consideration of iron nutrition. Am J Clin Nutr. 2000;72:272S-279S.

37. Garn SM, Ridella SA, Petzold AS, Falkner F. Maternal hematologic levels and pregnancy outcomes. Semin Perinatol. 1981;5:155-62.

38. World Health Organization (WHO). Global malaria report [internet]. Geneva: WHO; 2017. Available from: http://www.who.int/malaria/publications/world-malaria-report-2017/report/en/.

Chapter 8

Maternal hemoglobin level and its relation to fetal

distress, mode of delivery, and short-term neonatal

outcome: a retrospective cohort study

Bullens LM, Smith JS, Truijens SE, van Runnard Heimel PJ,


Submitted

Chapter 8

170

Abstract Aim

We aimed to investigate if the risk of fetal distress during term labor is related to the

intrapartum maternal hemoglobin (Hb) level. Second, we investigated the relation

between mode of delivery, reason for instrumental delivery and short-term neonatal

outcome and maternal Hb. Third, we aimed to identify factors influencing

intrapartum maternal Hb level.

Methods

A retrospective cohort study was performed in a tertiary hospital in The Netherlands,

including data from women who gave birth between 2009 and 2016. To determine

whether the likelihood of fetal distress to occur was dependent on intrapartum Hb,

multivariate regression models were run with intrapartum Hb as the main

independent variable of interest. Hb was used as a continuous value. We repeated

this procedure for the likelihood of instrumental vaginal delivery (IVD), cesarean

section (CS), 5-minute Apgar score < 7, and umbilical cord arterial pH ≤ 7.05 to

occur. Also, we identified factors influencing intrapartum Hb level using linear

regression analysis.

Results

Data of 9,144 patients were analysed. Intrapartum Hb did not contribute to the

prediction of the likelihood of fetal distress, IVD for nonprogressive labor, CS for

fetal condition, 5-minute Apgar score < 7, and pHa ≤ 7.05. However, there was a

unique statistically significant contribution of Hb to the prediction of the likelihood

of IVD for any reason and IVD for fetal distress and CS for any reason and CS for

nonprogressive labor. IVD for fetal distress was related to a higher intrapartum Hb

level, whereas CS for nonprogressive labor was related to a lower intrapartum Hb

level. Intrapartum Hb level was influenced by maternal age, ethnicity, parity, fetal

sex, and birth weight.

Conclusions

The risk of fetal distress and adverse neonatal outcome is not related to intrapartum

Hb levels. However, IVD for fetal distress was related to a higher intrapartum Hb


level.

The relationship between maternal Hb and fetal outcome: a retrospective study

171

8

Abstract Aim

We aimed to investigate if the risk of fetal distress during term labor is related to the

intrapartum maternal hemoglobin (Hb) level. Second, we investigated the relation

between mode of delivery, reason for instrumental delivery and short-term neonatal

outcome and maternal Hb. Third, we aimed to identify factors influencing

intrapartum maternal Hb level.

Methods

A retrospective cohort study was performed in a tertiary hospital in The Netherlands,

including data from women who gave birth between 2009 and 2016. To determine

whether the likelihood of fetal distress to occur was dependent on intrapartum Hb,

multivariate regression models were run with intrapartum Hb as the main

independent variable of interest. Hb was used as a continuous value. We repeated

this procedure for the likelihood of instrumental vaginal delivery (IVD), cesarean

section (CS), 5-minute Apgar score < 7, and umbilical cord arterial pH ≤ 7.05 to

occur. Also, we identified factors influencing intrapartum Hb level using linear

regression analysis.

Results

Data of 9,144 patients were analysed. Intrapartum Hb did not contribute to the

prediction of the likelihood of fetal distress, IVD for nonprogressive labor, CS for

fetal condition, 5-minute Apgar score < 7, and pHa ≤ 7.05. However, there was a

unique statistically significant contribution of Hb to the prediction of the likelihood

of IVD for any reason and IVD for fetal distress and CS for any reason and CS for

nonprogressive labor. IVD for fetal distress was related to a higher intrapartum Hb


level. Intrapartum Hb level was influenced by maternal age, ethnicity, parity, fetal

sex, and birth weight.

Conclusions

The risk of fetal distress and adverse neonatal outcome is not related to intrapartum

Hb levels. However, IVD for fetal distress was related to a higher intrapartum Hb


level.

Chapter 8

172

Introduction

Perinatal asphyxia is one of the main causes of neonatal morbidity and mortality.1

Causes of impaired fetal oxygenation during labor include severe or prolonged

uterine contractions, intrauterine infection, umbilical cord prolapse or placental

abruption. As maternal anemia during pregnancy may cause preplacental hypoxia,2

also intrapartum maternal hemoglobin (Hb) level may influence fetal oxygenation

before and during labor.

Various studies reported on the consequences of anemia in pregnancy, with

contradictory results.3-13 A systematic review reported a higher risk of low birth

weight and preterm birth in case of maternal anemia in the first or second

trimester.14 Also, high Hb levels are associated with adverse perinatal outcome.4,15-17

As a result of poor plasma expansion or increased blood viscosity, blood flow and

fetomaternal exchange of oxygen and nutrients in the placenta are reduced.15,16

Thus, maternal Hb level influences the risk of adverse pregnancy outcomes.

Hypothetically, maternal Hb may also influence the risk of fetal distress during labor

and mode of delivery. Maternal Hb affects fetomaternal oxygen exchange, and

anemia may impede maternal endurance during labor; either increases the risk of

non-spontaneous delivery. The influence of maternal Hb on short-term neonatal

outcome and the course of labor has been formerly studied, showing different

results.9, 18-22 A large retrospective study found an increased risk of cesarean section

(CS), 5-minute Apgar Score <7 and Neonatal Intensive Care Unit (NICU)-admission

in the presence of maternal anemia.18 Two studies confirmed the increased risk of a

CS20,21, while others contradicted these results.19,22 Also, the presumed increased risk

of adverse neonatal outcome in terms of Apgar Score and NICU admission was

opposed in other studies.19-22 To our knowledge, the relationship between the risk of

fetal distress during labor and intrapartum maternal Hb level and has not been

investigated yet.

Aim

We aimed to investigate if the occurrence of fetal distress during term labor is

related to intrapartum maternal Hb level. Also, we examined the relationship

between mode of delivery, reason for instrumental delivery (instrumental vaginal

delivery (IVD) and CS) and short-term neonatal outcome and maternal Hb. Besides,

we aimed to identify factors influencing intrapartum maternal Hb level.

Hypothesis

Based on the theory of “preplacental hypoxia”, we hypothesized that fetal distress is

related to relatively lower Hb levels. Both fetal distress and reduced endurance

increase the chance of having a non-spontaneous delivery, therefore we

hypothesized that also these events are inherent to lower intrapartum Hb levels.


Study design and population

A retrospective study was conducted in Máxima Medical Center; a tertiary hospital

in The Netherlands, with approximately 2,200 deliveries annually. Generally used

methods for fetal monitoring were continuous cardiotocography (CTG) and fetal

scalp blood sampling (FSB). Between 2009 and 2012 also ST-analysis was used for

fetal monitoring.23

Since 2009, details about the initiation, course, and outcome of each delivery are

recorded in electronic patient files (Chipsoft EZIS, Amsterdam, The Netherlands).

For this study, we used the electronic patient files from January 2009 until

December 2016. Inclusion criteria were term labor, a living singleton fetus in

cephalic presentation without evident congenital malformations. Women scheduled

for elective CS were excluded. Hb level of less than two weeks prior to delivery had

to be available, since these values reasonably correspond to the intrapartum Hb

level.24

Outcome parameters

The primary outcome was the relationship between the occurrence of fetal distress

and intrapartum Hb level. The definition used for “fetal distress” is mentioned

below. Secondary outcome parameters were relationship between mode of delivery

(spontaneous, IVD, and secondary CS) and short-term neonatal outcome (5-minute

Apgar score and arterial umbilical cord pH (pHa)) and maternal Hb level.


173

8

Introduction

Perinatal asphyxia is one of the main causes of neonatal morbidity and mortality.1

Causes of impaired fetal oxygenation during labor include severe or prolonged

uterine contractions, intrauterine infection, umbilical cord prolapse or placental

abruption. As maternal anemia during pregnancy may cause preplacental hypoxia,2

also intrapartum maternal hemoglobin (Hb) level may influence fetal oxygenation

before and during labor.

Various studies reported on the consequences of anemia in pregnancy, with

contradictory results.3-13 A systematic review reported a higher risk of low birth

weight and preterm birth in case of maternal anemia in the first or second

trimester.14 Also, high Hb levels are associated with adverse perinatal outcome.4,15-17

As a result of poor plasma expansion or increased blood viscosity, blood flow and

fetomaternal exchange of oxygen and nutrients in the placenta are reduced.15,16

Thus, maternal Hb level influences the risk of adverse pregnancy outcomes.

Hypothetically, maternal Hb may also influence the risk of fetal distress during labor

and mode of delivery. Maternal Hb affects fetomaternal oxygen exchange, and

anemia may impede maternal endurance during labor; either increases the risk of

non-spontaneous delivery. The influence of maternal Hb on short-term neonatal

outcome and the course of labor has been formerly studied, showing different

results.9, 18-22 A large retrospective study found an increased risk of cesarean section

(CS), 5-minute Apgar Score <7 and Neonatal Intensive Care Unit (NICU)-admission

in the presence of maternal anemia.18 Two studies confirmed the increased risk of a

CS20,21, while others contradicted these results.19,22 Also, the presumed increased risk

of adverse neonatal outcome in terms of Apgar Score and NICU admission was

opposed in other studies.19-22 To our knowledge, the relationship between the risk of

fetal distress during labor and intrapartum maternal Hb level and has not been

investigated yet.

Aim

We aimed to investigate if the occurrence of fetal distress during term labor is

related to intrapartum maternal Hb level. Also, we examined the relationship

between mode of delivery, reason for instrumental delivery (instrumental vaginal

delivery (IVD) and CS) and short-term neonatal outcome and maternal Hb. Besides,

we aimed to identify factors influencing intrapartum maternal Hb level.

Hypothesis

Based on the theory of “preplacental hypoxia”, we hypothesized that fetal distress is

related to relatively lower Hb levels. Both fetal distress and reduced endurance

increase the chance of having a non-spontaneous delivery, therefore we

hypothesized that also these events are inherent to lower intrapartum Hb levels.


Study design and population

A retrospective study was conducted in Máxima Medical Center; a tertiary hospital

in The Netherlands, with approximately 2,200 deliveries annually. Generally used

methods for fetal monitoring were continuous cardiotocography (CTG) and fetal

scalp blood sampling (FSB). Between 2009 and 2012 also ST-analysis was used for

fetal monitoring.23

Since 2009, details about the initiation, course, and outcome of each delivery are

recorded in electronic patient files (Chipsoft EZIS, Amsterdam, The Netherlands).

For this study, we used the electronic patient files from January 2009 until

December 2016. Inclusion criteria were term labor, a living singleton fetus in

cephalic presentation without evident congenital malformations. Women scheduled

for elective CS were excluded. Hb level of less than two weeks prior to delivery had

to be available, since these values reasonably correspond to the intrapartum Hb

level.24

Outcome parameters

The primary outcome was the relationship between the occurrence of fetal distress

and intrapartum Hb level. The definition used for “fetal distress” is mentioned

below. Secondary outcome parameters were relationship between mode of delivery

(spontaneous, IVD, and secondary CS) and short-term neonatal outcome (5-minute

Apgar score and arterial umbilical cord pH (pHa)) and maternal Hb level.

Chapter 8

174

Data collection

The following baseline parameters were recorded: maternal age, ethnicity, parity,

fetal sex, and birth weight. Maternal and neonatal outcomes included: suspected

fetal distress and how fetal distress was diagnosed, mode of delivery, reason for IVD

or CS, Apgar score at 5 minutes and umbilical cord pHa.

Data was automatically extracted from the electronic patient files. Missing or unusual

data were manually checked by analyzing the medical file. The maternal Hb

concentration prior to delivery was obtained manually, to make sure the time frame

between determination of the Hb level and delivery was not more than two weeks.

All maternal blood samples were drawn, transported and analyzed according to

local protocols.

Definitions

The cut-off values for anemia in pregnancy are different from those in the general

population; anemia during pregnancy is defined as Hb < 11.0 g/dL by the World

Health Organization.25 Therefore, we defined “severe anemia” as intrapartum Hb <

7.0 g/dL, “anemia” as < 11.0 g/dL, “normal Hb” as 11.0-12.9 g/dL. We did not find

a strict definition of “high Hb” and we chose to define “high Hb” as Hb > 12.9 g/dL,

following other studies.4,6

“Fetal distress” was defined as the suspicion of (ominous) fetal hypoxia, based on an

abnormal FHR pattern according to the modified FIGO criteria,26 FSBS pH < 7.20 or

significant ST-event.25 “Ethnicity” was classified as either European or non-

European. IVD and CS were separated into three groups: “IVD/CS for any reason”,

“IVD/CS for fetal condition”, and “IVD/CS for nonprogressive labor”.


The data were analyzed using SPSS (version 24, IBM, Chicago, Illinois, USA).

Hb was used as a continuous value in all analyses. The distribution of Hb was

assessed for normality; visually by the use of histograms and extreme outliers in a

box plot, and mathematically by checking for values of skewness and kurtosis

between -1 and 1. Hb was normally distributed.

Maternal age and fetal birth weight were evaluated as continuous data. Ethnicity,

parity and fetal sex were evaluated as dichotomous values. Univariate analysis with

independent t-tests was used for the calculation of differences in mean Hb between

several demographic, obstetric and outcome variables. Pearson’s R was used to

correlate Hb to continuous variables.

Subsequently, we selected continuous variables to be included in multiple

regression analysis if they significantly correlated to Hb (p < 0.05), and categorical

variables if mean Hb levels were significantly different between groups with or

without a certain condition (p < 0.05). First, we used linear regression analysis to

define the unique contribution of each of the independent variables on intrapartum

Hb level. Then, we constructed a logistic regression model in order to assess

whether Hb influences delivery outcome and to identify possible confounders. Odds

ratios and 95% confidence intervals (CI) were computed.

Ethical approval

Since this study is a retrospective study of anonymous data and the study imposes

no changes in general practice, no ethical approval was required according to the

Declaration of Helsinki. This was confirmed by the Medical Ethics Committee of

Máxima Medical Center, Veldhoven, The Netherlands.

Results

During the study period, 13,388 term singleton deliveries were documented. We

excluded 3,103 cases because the Hb level prior to delivery was lacking. Another

1,017 women were scheduled for elective CS and therefore excluded, and 124 cases

were excluded because of evident congenital malformations of the fetus. Finally,

9,144 files were available for analysis.

Baseline characteristics

The study population existed of 5,120 primiparous women (56%), mean age 30.6

years (± 4.4, 15-52), and 183 neonates (2%) had a birth weight < 2,500 grams.

The mean Hb concentration at admission was 12.2 g/dL (±1.2, 7.7-16.4). Intrapartum

Hb concentration was low in 1,163 (12.7%) women, normal in 5,525 (60.4%) women


175

8

Data collection

The following baseline parameters were recorded: maternal age, ethnicity, parity,

fetal sex, and birth weight. Maternal and neonatal outcomes included: suspected

fetal distress and how fetal distress was diagnosed, mode of delivery, reason for IVD

or CS, Apgar score at 5 minutes and umbilical cord pHa.

Data was automatically extracted from the electronic patient files. Missing or unusual

data were manually checked by analyzing the medical file. The maternal Hb

concentration prior to delivery was obtained manually, to make sure the time frame

between determination of the Hb level and delivery was not more than two weeks.

All maternal blood samples were drawn, transported and analyzed according to

local protocols.

Definitions

The cut-off values for anemia in pregnancy are different from those in the general

population; anemia during pregnancy is defined as Hb < 11.0 g/dL by the World

Health Organization.25 Therefore, we defined “severe anemia” as intrapartum Hb <

7.0 g/dL, “anemia” as < 11.0 g/dL, “normal Hb” as 11.0-12.9 g/dL. We did not find

a strict definition of “high Hb” and we chose to define “high Hb” as Hb > 12.9 g/dL,

following other studies.4,6

“Fetal distress” was defined as the suspicion of (ominous) fetal hypoxia, based on an

abnormal FHR pattern according to the modified FIGO criteria,26 FSBS pH < 7.20 or

significant ST-event.25 “Ethnicity” was classified as either European or non-

European. IVD and CS were separated into three groups: “IVD/CS for any reason”,

“IVD/CS for fetal condition”, and “IVD/CS for nonprogressive labor”.


The data were analyzed using SPSS (version 24, IBM, Chicago, Illinois, USA).

Hb was used as a continuous value in all analyses. The distribution of Hb was

assessed for normality; visually by the use of histograms and extreme outliers in a

box plot, and mathematically by checking for values of skewness and kurtosis

between -1 and 1. Hb was normally distributed.

Maternal age and fetal birth weight were evaluated as continuous data. Ethnicity,

parity and fetal sex were evaluated as dichotomous values. Univariate analysis with

independent t-tests was used for the calculation of differences in mean Hb between

several demographic, obstetric and outcome variables. Pearson’s R was used to

correlate Hb to continuous variables.

Subsequently, we selected continuous variables to be included in multiple

regression analysis if they significantly correlated to Hb (p < 0.05), and categorical

variables if mean Hb levels were significantly different between groups with or

without a certain condition (p < 0.05). First, we used linear regression analysis to

define the unique contribution of each of the independent variables on intrapartum

Hb level. Then, we constructed a logistic regression model in order to assess

whether Hb influences delivery outcome and to identify possible confounders. Odds

ratios and 95% confidence intervals (CI) were computed.

Ethical approval

Since this study is a retrospective study of anonymous data and the study imposes

no changes in general practice, no ethical approval was required according to the

Declaration of Helsinki. This was confirmed by the Medical Ethics Committee of

Máxima Medical Center, Veldhoven, The Netherlands.

Results

During the study period, 13,388 term singleton deliveries were documented. We

excluded 3,103 cases because the Hb level prior to delivery was lacking. Another

1,017 women were scheduled for elective CS and therefore excluded, and 124 cases

were excluded because of evident congenital malformations of the fetus. Finally,

9,144 files were available for analysis.

Baseline characteristics

The study population existed of 5,120 primiparous women (56%), mean age 30.6

years (± 4.4, 15-52), and 183 neonates (2%) had a birth weight < 2,500 grams.

The mean Hb concentration at admission was 12.2 g/dL (±1.2, 7.7-16.4). Intrapartum

Hb concentration was low in 1,163 (12.7%) women, normal in 5,525 (60.4%) women

Chapter 8

176

and high in 2,456 (26.9%) women. No women had severe anemia. In 1,971 deliveries

fetal distress was diagnosed (21.6%), in 42% of these deliveries an instrumental

delivery was performed (540 IVD’s and 291 CS’s). In 407 cases fetal distress was

proven by FSBS or an ST-event (20.6%).

The relationship between demographic characteristics and outcome variables and

maternal Hb.

We calculated the correlation between Hb and maternal age and between Hb and

fetal birth weight. Second, we calculated differences in mean Hb level for several

demographic characteristics and outcome variables. There was a positive correlation

between Hb and maternal age (r = 0.05, p = 0.01) and a negative correlation

between Hb and fetal birth weight (r = -0.12, p = 0.01). Mean Hb was significantly

different between European and non-European women, and between primiparous

and multiparous women, but not between women having a male or female fetus.

Results are shown in table 1.

Mean Hb levels were significantly different between the group of women whose

labor was complicated by fetal distress, in comparison to the group of women

delivering a fetus in a reassuring condition. Also, mean Hb levels were significantly

different between women who had an IVD for fetal distress, who had an IVD for

nonprogressive labor, and who had a CS for nonprogressive labor, compared to the

women where these specific assisted-delivery measures were not undertaken (table

1). The absolute difference in mean Hb levels was 0.1-0.5 g/dL and the effect size

was small (range Cohen’s d 0.01-0.03).

Is the risk of fetal distress related to the maternal Hb level?

Initially, Hb levels were found to be significantly different between the groups where

fetal distress was present or absent. Logistic regression was performed to assess the

influence of other independent variables (confounders). The model contained five

independent variables (Hb, maternal age, parity, ethnicity, and birth weight),

selected from the univariate analyses if p < 0.05. Three variables (age, parity, and

birth weight) made a unique statistically significant contribution to the model,

indicating that after correction for these possible confounders, Hb did not have a

significant unique contribution to the likelihood of fetal distress (p = 0.37). The

strongest predictor of the occurrence of fetal distress was parity, recording an odds

ratio of 0.46 (95% CI 0.41-0.52). This indicated that fetal distress was 0.46 less likely

to occur in multiparous women, in comparison to primiparous women.

Table 1. The relationship between several characteristics and mean hemoglobin

level.

Variable Pearson’s r

correlation

Independent

samples t-test p

Demographic variables

Maternal age 0.05 <0.001*

Ethnicity (European/

non-European 9.03 < 0.001*

Obstetric baseline variables

Parity (primiparous/

multiparous) 15.88 < 0.001*

Fetal sex 1.64 0.10

Birth weight -0.12 <0.001*

Obstetric outcome variables

5 min Apgar score < 7 or > 7 1.32 0.19

Fetal distress yes/no 4.44 < 0.001*

IVD for fetal distress yes/no 4.96 < 0.001*

IVD for nonprogressive labor yes/no 4.57 < 0.001*

CS for fetal condition yes/no 0.87 0.39

CS for nonprogressive labor yes/no -3.48 0.001*

pHa ≤ 7.05 or > 7.05 2.30 0.02*

* Significant at 0.05 level

IVD = instrumental vaginal delivery, CS = cesarean section

What is the relationship between mode of delivery, reason for instrumental delivery and short-term neonatal outcome and maternal Hb?

We repeated logistic regression analysis for the prediction of the outcome

parameters regarding mode of delivery and short-term neonatal outcome: IVD for

any reason, IVD for fetal distress, IVD for nonprogressive labor, CS for any reason,

CS for fetal condition, CS for nonprogressive labor, 5-minute Apgar score < 7, and

pHa ≤ 7.05. Hb level did not contribute to the prediction of the likelihood of IVD for

nonprogressive labor, CS for fetal condition, 5-minute Apgar score < 7, and pHa ≤

7.05. However, there was a unique statistically significant contribution of Hb for the


177

8

and high in 2,456 (26.9%) women. No women had severe anemia. In 1,971 deliveries

fetal distress was diagnosed (21.6%), in 42% of these deliveries an instrumental

delivery was performed (540 IVD’s and 291 CS’s). In 407 cases fetal distress was

proven by FSBS or an ST-event (20.6%).

The relationship between demographic characteristics and outcome variables and

maternal Hb.

We calculated the correlation between Hb and maternal age and between Hb and

fetal birth weight. Second, we calculated differences in mean Hb level for several

demographic characteristics and outcome variables. There was a positive correlation

between Hb and maternal age (r = 0.05, p = 0.01) and a negative correlation

between Hb and fetal birth weight (r = -0.12, p = 0.01). Mean Hb was significantly

different between European and non-European women, and between primiparous

and multiparous women, but not between women having a male or female fetus.

Results are shown in table 1.

Mean Hb levels were significantly different between the group of women whose

labor was complicated by fetal distress, in comparison to the group of women

delivering a fetus in a reassuring condition. Also, mean Hb levels were significantly

different between women who had an IVD for fetal distress, who had an IVD for

nonprogressive labor, and who had a CS for nonprogressive labor, compared to the

women where these specific assisted-delivery measures were not undertaken (table

1). The absolute difference in mean Hb levels was 0.1-0.5 g/dL and the effect size

was small (range Cohen’s d 0.01-0.03).

Is the risk of fetal distress related to the maternal Hb level?

Initially, Hb levels were found to be significantly different between the groups where

fetal distress was present or absent. Logistic regression was performed to assess the

influence of other independent variables (confounders). The model contained five

independent variables (Hb, maternal age, parity, ethnicity, and birth weight),

selected from the univariate analyses if p < 0.05. Three variables (age, parity, and

birth weight) made a unique statistically significant contribution to the model,

indicating that after correction for these possible confounders, Hb did not have a

significant unique contribution to the likelihood of fetal distress (p = 0.37). The

strongest predictor of the occurrence of fetal distress was parity, recording an odds

ratio of 0.46 (95% CI 0.41-0.52). This indicated that fetal distress was 0.46 less likely

to occur in multiparous women, in comparison to primiparous women.

Table 1. The relationship between several characteristics and mean hemoglobin

level.

Variable Pearson’s r

correlation

Independent

samples t-test p

Demographic variables

Maternal age 0.05 <0.001*

Ethnicity (European/

non-European 9.03 < 0.001*

Obstetric baseline variables

Parity (primiparous/

multiparous) 15.88 < 0.001*

Fetal sex 1.64 0.10

Birth weight -0.12 <0.001*

Obstetric outcome variables

5 min Apgar score < 7 or > 7 1.32 0.19

Fetal distress yes/no 4.44 < 0.001*

IVD for fetal distress yes/no 4.96 < 0.001*

IVD for nonprogressive labor yes/no 4.57 < 0.001*

CS for fetal condition yes/no 0.87 0.39

CS for nonprogressive labor yes/no -3.48 0.001*

pHa ≤ 7.05 or > 7.05 2.30 0.02*

* Significant at 0.05 level

IVD = instrumental vaginal delivery, CS = cesarean section

What is the relationship between mode of delivery, reason for instrumental delivery and short-term neonatal outcome and maternal Hb?

We repeated logistic regression analysis for the prediction of the outcome

parameters regarding mode of delivery and short-term neonatal outcome: IVD for

any reason, IVD for fetal distress, IVD for nonprogressive labor, CS for any reason,

CS for fetal condition, CS for nonprogressive labor, 5-minute Apgar score < 7, and

pHa ≤ 7.05. Hb level did not contribute to the prediction of the likelihood of IVD for

nonprogressive labor, CS for fetal condition, 5-minute Apgar score < 7, and pHa ≤

7.05. However, there was a unique statistically significant contribution of Hb for the

Chapter 8

178

prediction of IVD for any reason, IVD for fetal distress, CS for any reason, and CS for

nonprogressive labor. Odds ratios are shown in table 2. For every increase in Hb

level of 1 g/dL, women were 1.1 times more likely to have an IVD for any reason and

for fetal distress. In contrast, for every increase in Hb level of 1 g/dL, the likelihood

of having a CS for any indication or for nonprogressive labor was 0.91 and 0.89,

respectively.

Table 2. Multiple logistic regression analyses with hemoglobin predicting the

likelihood of non-spontaneous delivery.

Outcome parameter B Standardized

Beta

SE OR 95% CI p

IVD 0.10 0.01 0.03 1.10 1.04-1.17 0.00$

IVD for fetal distress 0.09 0.00$ 0.05 1.10 1.00$-1.21 0.05$

CS -0.10 -0.01 0.04 0.91 0.84-0.98 0.01

CS for nonprogressive

labor

-0.12 -0.01 0.05 0.89 0.81-0.97 0.01

$ Value rounded on two decimals

IVD = instrumental vaginal delivery, CS = cesarean section, OR = odds ratio,

CI = confidence interval

Which factors influence intrapartum maternal maternal Hb level?

We used linear regression to assess the ability of three demographic variables (age,

ethnicity, and parity) and two fetal variables (sex and birth weight) to predict

intrapartum Hb levels. As all the included variables had a significant contribution in

predicting Hb level according to univariate regression analyses, we included them in

a forward linear regression analysis. We found that all five factors had a significant

unique contribution to the ability of the model to predict Hb (table 3), with parity

making the strongest unique contribution to the model (Standardized Beta 0.17).

Table 3. Multivariate linear regression analysis with intrapartum Hb as dependent variable. Independent

variable

B Standardized

Beta

95% CI R2 ΔR2 F change

Parity 0.41 0.17 0.35-0.47 0.03 0.03 < 0.001

Ethnicity 0.45 0.12 0.37-0.54 0.04 0.01 < 0.001

Birth weight 0.00$ -0.12 0.00-0.00$ 0.05 0.01 < 0.001

Maternal age 0.03 0.10 0.02-0.03 0.06 0.01 < 0.001

Fetal sex 0.08 0.04 0.03-0.14 0.06 0.00$ 0.003

$ Values rounded on two decimals


Discussion

The main goal of this study was to investigate if the risk of fetal distress was

influenced by intrapartum Hb. We showed that mean Hb levels were slightly higher

in the group where fetal distress was suspected, compared to the group where fetal

condition was reassuring. However, after correction for possible confounders, Hb

did not have a significant unique contribution to the likelihood of fetal distress.

Hence, our study results did not support the hypothesis that the risk of fetal distress

during labor is related to lower intrapartum Hb levels.

Since we identified no other studies investigating this outcome, our study results

cannot be compared to the literature. However, we can compare related outcome

measures as instrumented delivery for fetal distress and neonatal outcome.

Regarding mode of delivery, in our study mean Hb levels significantly differed in

groups having a spontaneous delivery, compared to groups having a non-

spontaneous delivery. Mean Hb was higher in women having an IVD for any reason

or for fetal distress, but lower in the group having a CS for any reason or for

nonprogressive labor. When fetal distress occurred, only in 42% of the deliveries an

instrumental delivery was performed.

Our study showed a relatively lower Hb in women having a CS. These results are in

line with findings from other studies.18,20,21 However, these studies did not use Hb as

a continuous value. Consequently, we can only compare our results with studies


variable

B Standardized Beta 95% CI R2 ΔR2 F change

Parity 0.41 0.17 0.35-0.47 0.03 0.03 < 0.001

Ethnicity 0.45 0.12 0.37-0.54 0.04 0.01 < 0.001

Birth weight 0.00$ -0.12 0.00-0.00$ 0.05 0.01 < 0.001

Maternal age 0.03 0.10 0.02-0.03 0.06 0.01 < 0.001

Fetal sex 0.08 0.04 0.03-0.14 0.06 0.00$ 0.003



Discussion


















line with findings from other studies indicating an increased risk of CS in the

presence of maternal anemia.18,20,21 However, these studies did not use Hb as a


179

8

prediction of IVD for any reason, IVD for fetal distress, CS for any reason, and CS for

nonprogressive labor. Odds ratios are shown in table 2. For every increase in Hb

level of 1 g/dL, women were 1.1 times more likely to have an IVD for any reason and

for fetal distress. In contrast, for every increase in Hb level of 1 g/dL, the likelihood

of having a CS for any indication or for nonprogressive labor was 0.91 and 0.89,

respectively.

Table 2. Multiple logistic regression analyses with hemoglobin predicting the

likelihood of non-spontaneous delivery.

Outcome parameter B Standardized

Beta

SE OR 95% CI p

IVD 0.10 0.01 0.03 1.10 1.04-1.17 0.00$

IVD for fetal distress 0.09 0.00$ 0.05 1.10 1.00$-1.21 0.05$

CS -0.10 -0.01 0.04 0.91 0.84-0.98 0.01

CS for nonprogressive

labor

-0.12 -0.01 0.05 0.89 0.81-0.97 0.01

$ Value rounded on two decimals

IVD = instrumental vaginal delivery, CS = cesarean section, OR = odds ratio,


Which factors influence intrapartum maternal maternal Hb level?

We used linear regression to assess the ability of three demographic variables (age,

ethnicity, and parity) and two fetal variables (sex and birth weight) to predict

intrapartum Hb levels. As all the included variables had a significant contribution in

predicting Hb level according to univariate regression analyses, we included them in

a forward linear regression analysis. We found that all five factors had a significant

unique contribution to the ability of the model to predict Hb (table 3), with parity

making the strongest unique contribution to the model (Standardized Beta 0.17).


variable

B Standardized

Beta

95% CI R2 ΔR2 F change

Parity 0.41 0.17 0.35-0.47 0.03 0.03 < 0.001

Ethnicity 0.45 0.12 0.37-0.54 0.04 0.01 < 0.001

Birth weight 0.00$ -0.12 0.00-0.00$ 0.05 0.01 < 0.001

Maternal age 0.03 0.10 0.02-0.03 0.06 0.01 < 0.001

Fetal sex 0.08 0.04 0.03-0.14 0.06 0.00$ 0.003



Discussion


















line with findings from other studies.18,20,21 However, these studies did not use Hb as

a continuous value. Consequently, we can only compare our results with studies


variable

B Standardized Beta 95% CI R2 ΔR2 F change

Parity 0.41 0.17 0.35-0.47 0.03 0.03 < 0.001

Ethnicity 0.45 0.12 0.37-0.54 0.04 0.01 < 0.001

Birth weight 0.00$ -0.12 0.00-0.00$ 0.05 0.01 < 0.001

Maternal age 0.03 0.10 0.02-0.03 0.06 0.01 < 0.001

Fetal sex 0.08 0.04 0.03-0.14 0.06 0.00$ 0.003



Discussion


















line with findings from other studies indicating an increased risk of CS in the

presence of maternal anemia.18,20,21 However, these studies did not use Hb as a

Chapter 8

180

continuous value. Consequently, we can only compare our results with studies where

outcomes are compared between groups of anemic and non-anemic women. In

these studies, a higher CS rate was noted in anemic women, compared to non-

anemic women. 18,20,21 Also in Drukker’s study, including more than 75,000 women,

the CS rate was higher in anemic women, however, the CS rate for the specific

indications of fetal distress or nonprogressive labor was similar in both groups.18

Hwang et al. and Orlandini et al. found an increased risk of CS for the specific

indication of fetal distress in anemic women.20,21

We acknowledge the high false-positive rate and large inter- and intraobserver

variability of the CTG.27-33 Often, interventions are initiated based on abnormal CTG

tracings, and therefore based on suspected fetal distress. In our study, the term

“fetal distress” included both suspected fetal distress based on the CTG and proven

fetal distress (based on FSBS pH < 7.20 or significant ST-event).23,27 As a result, when

interventions were based on “fetal distress”, we do not know whether the fetus was

actually hypoxic or not.

Our results show that mean Hb was relatively higher in women having an IVD for any

reason or for fetal distress. In contrast, Malhotra’s study revealed an increased risk of

IVD in women having severe anemia (Hb <7 g/dL). They also found an increase in

duration of labor when maternal anemia was more severe.22 Low Hb may cause

fatigue, and therefore may impede proper progression of labor. In fact, in our study

population mean Hb was lower in the group that had an IVD for nonprogressive

labor (table 1). In Malhotra’s study no subdivision for the reason for an IVD was

displayed. A different rate of women having an IVD for fetal distress or for

nonprogressive labor may be an explanation for the discrepancy between Malhotra’s

and our study results. Also, the number of women with severe anemia in Malhotra’s

study is higher than in our population (6.9% versus 0%).22 We identified one other

study regarding the risk of IVD in relation to maternal anemia; they found no

difference in the chance of having a spontaneous delivery between anemic and non-

anemic women.19

In our study, we did not find a significant relationship between Hb level and short-

term neonatal outcome. Similar to our results, in four other studies no significant

difference in Apgar score or NICU admission was demonstrated.19-22. However,

Drukker et al. found a higher rate of 5-minute Apgar score < 7 (1% versus 2.1%) and

more NICU admissions (2.4% versus 1.7%) in the anemic population.18 In our study,

the total number of neonates with 5-minute Apgar score < 7 was 1.9%. Raisanen et

al. only revealed an increase in NICU admission in a subgroup of anemic multiparous

women.9 The differences with our results may be due to an essential difference in

study methods: we used Hb as a continuous value, while in all other studies an

arbitrary division in Hb-groups was imposed. Also, our study population includes all

women giving term vaginal birth in a tertiary hospital, while in other studies women

having pre-gravid diseases or obstetric complications were excluded.18, 20-22

Maternal age, parity, ethnicity and fetal sex and birth weight significantly influenced

intrapartum Hb level, although effect sizes were small. Apparently, other

confounders as diet, Body Mass Index (BMI), and smoking also contribute to the

prediction of intrapartum Hb level.4

To our knowledge, this is the first study to investigate if fetal distress, mode of

delivery, and neonatal outcome are related to maternal Hb, where Hb is used as a

continuous value. Also, this is one of few studies focusing on fetal distress and

several aspects of the delivery mode: both IVS and CS were considered, as well as

the reason for an instrumental delivery. This study has a large sample size of more

than 9,000 pregnant women and presents some interesting outcomes. The study

population was recruited in a tertiary hospital, but no other selection based on

obstetric or general history or pregnancy-related diseases was imposed.

Nevertheless, to determine the implications of the results for clinical practice, some

limitations need to be taken into account.

While the proportion of anemic women in our study was comparable to other

Western countries,34,35 the proportion of women with high Hb levels was relatively

high (26.9%).4 High Hb may be due to poor adaptation to pregnancy and impeded

plasma expansion, which may lead to hypertensive disorders. A possible explanation

for the relatively high fraction of women having high Hb is the setting in which this

study was performed; a tertiary hospital providing care to women having mainly

high-risk pregnancies. Since we used the complete unselected hospital population

for our analysis, we did not correct our results for pregnancy-related disorders.

As stated earlier, we chose to consider Hb as a continuous value, in order to

investigate whether several intrapartum events are related to different mean

maternal Hb levels. From a clinicians point of view, the results may be more

informative if a subdivision in low, normal and high Hb level would be imposed.


181

8

continuous value. Consequently, we can only compare our results with studies where

outcomes are compared between groups of anemic and non-anemic women. In

these studies, a higher CS rate was noted in anemic women, compared to non-

anemic women. 18,20,21 Also in Drukker’s study, including more than 75,000 women,

the CS rate was higher in anemic women, however, the CS rate for the specific

indications of fetal distress or nonprogressive labor was similar in both groups.18

Hwang et al. and Orlandini et al. found an increased risk of CS for the specific

indication of fetal distress in anemic women.20,21

We acknowledge the high false-positive rate and large inter- and intraobserver

variability of the CTG.27-33 Often, interventions are initiated based on abnormal CTG

tracings, and therefore based on suspected fetal distress. In our study, the term

“fetal distress” included both suspected fetal distress based on the CTG and proven

fetal distress (based on FSBS pH < 7.20 or significant ST-event).23,27 As a result, when

interventions were based on “fetal distress”, we do not know whether the fetus was

actually hypoxic or not.

Our results show that mean Hb was relatively higher in women having an IVD for any

reason or for fetal distress. In contrast, Malhotra’s study revealed an increased risk of

IVD in women having severe anemia (Hb <7 g/dL). They also found an increase in

duration of labor when maternal anemia was more severe.22 Low Hb may cause

fatigue, and therefore may impede proper progression of labor. In fact, in our study

population mean Hb was lower in the group that had an IVD for nonprogressive

labor (table 1). In Malhotra’s study no subdivision for the reason for an IVD was

displayed. A different rate of women having an IVD for fetal distress or for

nonprogressive labor may be an explanation for the discrepancy between Malhotra’s

and our study results. Also, the number of women with severe anemia in Malhotra’s

study is higher than in our population (6.9% versus 0%).22 We identified one other

study regarding the risk of IVD in relation to maternal anemia; they found no

difference in the chance of having a spontaneous delivery between anemic and non-

anemic women.19

In our study, we did not find a significant relationship between Hb level and short-

term neonatal outcome. Similar to our results, in four other studies no significant

difference in Apgar score or NICU admission was demonstrated.19-22. However,

Drukker et al. found a higher rate of 5-minute Apgar score < 7 (1% versus 2.1%) and

more NICU admissions (2.4% versus 1.7%) in the anemic population.18 In our study,

the total number of neonates with 5-minute Apgar score < 7 was 1.9%. Raisanen et

al. only revealed an increase in NICU admission in a subgroup of anemic multiparous

women.9 The differences with our results may be due to an essential difference in

study methods: we used Hb as a continuous value, while in all other studies an

arbitrary division in Hb-groups was imposed. Also, our study population includes all

women giving term vaginal birth in a tertiary hospital, while in other studies women

having pre-gravid diseases or obstetric complications were excluded.18, 20-22

Maternal age, parity, ethnicity and fetal sex and birth weight significantly influenced

intrapartum Hb level, although effect sizes were small. Apparently, other

confounders as diet, Body Mass Index (BMI), and smoking also contribute to the

prediction of intrapartum Hb level.4

To our knowledge, this is the first study to investigate if fetal distress, mode of

delivery, and neonatal outcome are related to maternal Hb, where Hb is used as a

continuous value. Also, this is one of few studies focusing on fetal distress and

several aspects of the delivery mode: both IVS and CS were considered, as well as

the reason for an instrumental delivery. This study has a large sample size of more

than 9,000 pregnant women and presents some interesting outcomes. The study

population was recruited in a tertiary hospital, but no other selection based on

obstetric or general history or pregnancy-related diseases was imposed.

Nevertheless, to determine the implications of the results for clinical practice, some

limitations need to be taken into account.

While the proportion of anemic women in our study was comparable to other

Western countries,34,35 the proportion of women with high Hb levels was relatively

high (26.9%).4 High Hb may be due to poor adaptation to pregnancy and impeded

plasma expansion, which may lead to hypertensive disorders. A possible explanation

for the relatively high fraction of women having high Hb is the setting in which this

study was performed; a tertiary hospital providing care to women having mainly

high-risk pregnancies. Since we used the complete unselected hospital population

for our analysis, we did not correct our results for pregnancy-related disorders.

As stated earlier, we chose to consider Hb as a continuous value, in order to

investigate whether several intrapartum events are related to different mean

maternal Hb levels. From a clinicians point of view, the results may be more

informative if a subdivision in low, normal and high Hb level would be imposed.

Chapter 8

182

Therefore, we also the analyzed the data comparing the events of fetal distress,

instrumented delivery and adverse neonatal outcome between three groups of

normal, low and high Hb. After correction for confounders, no differences in the

occurrence of the intrapartum events was demonstrated (appendix 1, data not

published).

In conclusion, our data suggest that the risk of fetal distress or adverse short-term

neonatal outcome is not related to intrapartum maternal Hb levels. However, the

chance of IVD for any reason and for fetal distress are related to a higher

intrapartum Hb level, while the risk of CS for any reason and for nonprogressive

labor are related to a lower intrapartum Hb level, in an unselected population in a

tertiary hospital.

We cannot promote to avoid maternal anemia in order to prevent fetal distress

during labor, even though we should aim for normal Hb values to avoid other

negative effects of maternal anemia during labor.3-17 A larger database providing

more data and possible confounders is needed to discover a potential relationship

between (relatively infrequent) adverse neonatal outcome and maternal Hb.

Acknowledgments

This research was performed within the framework of the IMPULS perinatology. We

thank Annemarie Koster for helping with the data extraction from the electronic

patient files, and Jeanne Dieleman for helping with the statistical analysis.

Appendix 1. Multivariate linear regression analysis with fetal distress as dependent

variable (data not published).


B S.E. Wald df Sig. Exp(B) 95% CI for Exp(B)

Lower Upper

Hb: normal ,042 2 ,979

Hb: low ,010 ,083 ,016 1 ,900 1,011 ,859 1,189

Hb: high ,011 ,059 ,035 1 ,852 1,011 ,900 1,136

Birth weight -,001 ,000 89,862 1 ,000 ,999 ,999 1,000

Fetal sex ,256 ,053 23,699 1 ,000 1,292 1,165 1,432

Nulliparous ,725 ,056 167,760 1 ,000 2,065 1,850 2,305

Constant -,034 ,201 ,028 1 ,867 ,967


183

8

Therefore, we also the analyzed the data comparing the events of fetal distress,

instrumented delivery and adverse neonatal outcome between three groups of

normal, low and high Hb. After correction for confounders, no differences in the

occurrence of the intrapartum events was demonstrated (appendix 1, data not

published).

In conclusion, our data suggest that the risk of fetal distress or adverse short-term

neonatal outcome is not related to intrapartum maternal Hb levels. However, the

chance of IVD for any reason and for fetal distress are related to a higher

intrapartum Hb level, while the risk of CS for any reason and for nonprogressive

labor are related to a lower intrapartum Hb level, in an unselected population in a

tertiary hospital.

We cannot promote to avoid maternal anemia in order to prevent fetal distress

during labor, even though we should aim for normal Hb values to avoid other

negative effects of maternal anemia during labor.3-17 A larger database providing

more data and possible confounders is needed to discover a potential relationship

between (relatively infrequent) adverse neonatal outcome and maternal Hb.

Acknowledgments

This research was performed within the framework of the IMPULS perinatology. We

thank Annemarie Koster for helping with the data extraction from the electronic

patient files, and Jeanne Dieleman for helping with the statistical analysis.

Appendix 1. Multivariate linear regression analysis with fetal distress as dependent

variable (data not published).


B S.E. Wald df Sig. Exp(B) 95% CI for Exp(B)

Lower Upper

Hb: normal ,042 2 ,979

Hb: low ,010 ,083 ,016 1 ,900 1,011 ,859 1,189

Hb: high ,011 ,059 ,035 1 ,852 1,011 ,900 1,136

Birth weight -,001 ,000 89,862 1 ,000 ,999 ,999 1,000

Fetal sex ,256 ,053 23,699 1 ,000 1,292 1,165 1,432

Nulliparous ,725 ,056 167,760 1 ,000 2,065 1,850 2,305

Constant -,034 ,201 ,028 1 ,867 ,967

Chapter 8

184

References 1. Lawn JE, Cousens S, Zupan J. 4 million neonatal deaths: When? Where? Why? Lancet.

2005:365;891-900. 2. Kingdom JCP, Kaufmann P. Oxygen and placental villous development: origins of fetal

hypoxia. Placenta. 1997;18:613-621. 3. Xiong X, Buekens P, Alexander S, Demianczuk N, Wollast E. Anemia during pregnancy

and birth outcome: a meta-analysis. Am J Perinat. 2000;17:137-46. 4. Gaillard R, Eilers PHC, Yassine S, Hofman A, Steegers EA, Jaddoe VW. Risk factors and

consequences of maternal anaemia and elevated haemoglobin levels during pregnancy: a population-based prospective cohort study. Paediatr Perinat Epidemiol. 2014;28:213-26.










14. Haider BA, Olofin I, Wang M, Spiegelman D, Ezzati M, Fawzi WW; Nutrition Impact Model Study Group (anaemia). Anaemia, prenatal iron use, and risk of adverse pregnancy outcomes: systematic review and meta-analysis. BMJ. 2013;346:f3443.


16. Thorburn J, Drummond MM, Whigham KA, Lowe GD, Forbes CD, Prentice CR, et al. Blood viscosity and haemostatic factors in late pregnancy, pre-eclampsia and fetal growth retardation. Br J Obstet Gynaecol. 1982;89:117-22.

17. Scanlon KS, Yip R, Schieve LA, Cogswell ME. High and low hemoglobin levels during pregnancy: differential risks for preterm birth and small for gestational age. Obstet Gynecol. 2000;96(5 pt 1):741-48.


19. Sehgal R, Kriplani A, Vanamail P, Maiti L, Kandpal S, Kumar N. Assessment and comparison of pregnancy outcome among anaemic and non anaemic primigravida mothers. Ind J Public Health. 2016;60:188-194.


21. Hwang HS, Young HK, Kwon JY, Park YW. Uterine and umbilical artery Doppler velocimetry as a predictor for adverse pregnancy outcomes in pregnant women with anemia. J Perinat Med. 2010;38:467-471.

22. Malhotra M, Sharma JB, Batra S, Sharma S, Murthy NS, Arora R. Maternal and perinatal outcome in varying degrees of anemia. Int J Gynecol Obstet. 2002;79:93-100.

23. Amer-Wåhlin I, Ingemarsson I, Marsal K, Herbst A. Fetal heart rate patterns and ECG ST segment changes preceding metabolic acidaemia at birth. BJOG. 2005;112:160-5.

24. Steegers EAP, Thomas CMG, de Boo TM, Knapen MFCM, Merkus JMWM. Klinisch-chemische referentiewaarden in de zwangerschap. Doetinchem, The Netherlands: Reed Business; 2003. [Dutch]

25. World Health Organization (WHO). The global prevalance of anaemia in 2011 [internet]. Geneva: WHO; 2015. Available from: http://apps.who.int/iris/bitstream/10665/177094/1/9789241564960_eng.pdf?ua=1&ua=1.

26. Ayres-de-Campos D, Spong CY, Chandraharan E: for the FIGO Intrapartum Fetal Monitoring Expert Panel. FIGO consensus guidelines on intrapartum fetal monitoring: Cardiotocography. Int J Gynaecol Obstet. 2015:131;13-24.

27. Saccone G, Schuit E, Amer-Wåhlin I, Xodo S, Berghella V. Electrocardiogram ST analysis during labor: a systematic review and meta-analysis of randomized controlled trials. Obstet Gynecol. 2016;127:127-35.

28. 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. BJOG. 2009;116:545-51.

29. Bernardes J, Costa-Pereira A, Ayres-de-Campos D, van Geijn HP, Pereira-Leite L. Evaluation of interobserver agreement of cardiotocograms. Int J Gynaecol Obstet. 1997;57:33-7.


31. Paneth N, Bommarito M, Stricker J. Electronic fetal monitoring and later outcome. Clin Invest Med. 1993;16:159-65.

32. 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;106:1307-10.


185

8

References 1. Lawn JE, Cousens S, Zupan J. 4 million neonatal deaths: When? Where? Why? Lancet.

2005:365;891-900. 2. Kingdom JCP, Kaufmann P. Oxygen and placental villous development: origins of fetal

hypoxia. Placenta. 1997;18:613-621. 3. Xiong X, Buekens P, Alexander S, Demianczuk N, Wollast E. Anemia during pregnancy

and birth outcome: a meta-analysis. Am J Perinat. 2000;17:137-46. 4. Gaillard R, Eilers PHC, Yassine S, Hofman A, Steegers EA, Jaddoe VW. Risk factors and

consequences of maternal anaemia and elevated haemoglobin levels during pregnancy: a population-based prospective cohort study. Paediatr Perinat Epidemiol. 2014;28:213-26.










14. Haider BA, Olofin I, Wang M, Spiegelman D, Ezzati M, Fawzi WW; Nutrition Impact Model Study Group (anaemia). Anaemia, prenatal iron use, and risk of adverse pregnancy outcomes: systematic review and meta-analysis. BMJ. 2013;346:f3443.


16. Thorburn J, Drummond MM, Whigham KA, Lowe GD, Forbes CD, Prentice CR, et al. Blood viscosity and haemostatic factors in late pregnancy, pre-eclampsia and fetal growth retardation. Br J Obstet Gynaecol. 1982;89:117-22.

17. Scanlon KS, Yip R, Schieve LA, Cogswell ME. High and low hemoglobin levels during pregnancy: differential risks for preterm birth and small for gestational age. Obstet Gynecol. 2000;96(5 pt 1):741-48.


19. Sehgal R, Kriplani A, Vanamail P, Maiti L, Kandpal S, Kumar N. Assessment and comparison of pregnancy outcome among anaemic and non anaemic primigravida mothers. Ind J Public Health. 2016;60:188-194.


21. Hwang HS, Young HK, Kwon JY, Park YW. Uterine and umbilical artery Doppler velocimetry as a predictor for adverse pregnancy outcomes in pregnant women with anemia. J Perinat Med. 2010;38:467-471.

22. Malhotra M, Sharma JB, Batra S, Sharma S, Murthy NS, Arora R. Maternal and perinatal outcome in varying degrees of anemia. Int J Gynecol Obstet. 2002;79:93-100.

23. Amer-Wåhlin I, Ingemarsson I, Marsal K, Herbst A. Fetal heart rate patterns and ECG ST segment changes preceding metabolic acidaemia at birth. BJOG. 2005;112:160-5.

24. Steegers EAP, Thomas CMG, de Boo TM, Knapen MFCM, Merkus JMWM. Klinisch-chemische referentiewaarden in de zwangerschap. Doetinchem, The Netherlands: Reed Business; 2003. [Dutch]

25. World Health Organization (WHO). The global prevalance of anaemia in 2011 [internet]. Geneva: WHO; 2015. Available from: http://apps.who.int/iris/bitstream/10665/177094/1/9789241564960_eng.pdf?ua=1&ua=1.

26. Ayres-de-Campos D, Spong CY, Chandraharan E: for the FIGO Intrapartum Fetal Monitoring Expert Panel. FIGO consensus guidelines on intrapartum fetal monitoring: Cardiotocography. Int J Gynaecol Obstet. 2015:131;13-24.

27. Saccone G, Schuit E, Amer-Wåhlin I, Xodo S, Berghella V. Electrocardiogram ST analysis during labor: a systematic review and meta-analysis of randomized controlled trials. Obstet Gynecol. 2016;127:127-35.

28. 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. BJOG. 2009;116:545-51.

29. Bernardes J, Costa-Pereira A, Ayres-de-Campos D, van Geijn HP, Pereira-Leite L. Evaluation of interobserver agreement of cardiotocograms. Int J Gynaecol Obstet. 1997;57:33-7.


31. Paneth N, Bommarito M, Stricker J. Electronic fetal monitoring and later outcome. Clin Invest Med. 1993;16:159-65.

32. 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;106:1307-10.

Chapter 8

186


34. Jans SM, Daemers DO, de Vos R, Lagro-Jansen AL. Are pregnant women of non-Northern European descent more anaemic than women of Northern European descent? A study into the prevalence of anaemia in pregnant women in Amsterdam. Midwifery. 2009;25:766-73.

35. Stevens GA, Finucane MM, De-Regil LM, Paciorek CJ, Flaxman SR, Branca F, et al.; Nutrition Impact Model Study Group (Anaemia). Global, regional, and national trends in haemoglobin concentration and prevalence of total and severe anaemia in children and pregnant and non-pregnant women for 1995-2011: a systematic analysis of population- representative data. Lancet Glob Health. 2013;1:e16-25.

Chapter 9

General discussion and

future perspectives


34. Jans SM, Daemers DO, de Vos R, Lagro-Jansen AL. Are pregnant women of non-Northern European descent more anaemic than women of Northern European descent? A study into the prevalence of anaemia in pregnant women in Amsterdam. Midwifery. 2009;25:766-73.

35. Stevens GA, Finucane MM, De-Regil LM, Paciorek CJ, Flaxman SR, Branca F, et al.; Nutrition Impact Model Study Group (Anaemia). Global, regional, and national trends in haemoglobin concentration and prevalence of total and severe anaemia in children and pregnant and non-pregnant women for 1995-2011: a systematic analysis of population- representative data. Lancet Glob Health. 2013;1:e16-25.

Chapter 9

General discussion and

future perspectives

Chapter 9

188

Introduction

To both future parents and obstetricians, it is of utmost importance to have a child

born in a healthy condition. Due to the physical, psychological, socioeconomic, and

also the medicolegal impact of perinatal asphyxia, the rate of interventions for

suspected fetal distress during labor is increasing.1,2 Obstetricians are challenged to

timely intervene when fetal hypoxia is suspected, but to prevent at the same time

unnecessary interventions due to their potential harm to the mother and her child.3,4

Until now, it is unclear which action should be undertaken in case of suspected fetal

distress, to prevent perinatal asphyxia. One should decide whether an immediate

intervention to deliver the baby is needed, or if fetal oxygenation can be restored by

intrauterine resuscitation. Intrauterine resuscitation may reduce the duration of the

fetus being hypoxic, and thus decrease the risk of organ damage (e.g. hypoxic-

ischemic encephalopathy). In case of successful restoration of the fetal oxygenation,

an invasive procedure to deliver the baby immediately may even be prevented.

In this thesis, we presented the current knowledge on the use and effect of

intrauterine resuscitation during term labor. We focused on one of the techniques

that is still frequently debated: maternal hyperoxygenation. Furthermore, we aimed

to identify factors that contribute to the risk of fetal distress during term labor. The

answers to these questions provide insight to improve perinatal care, and may thus

contribute to a reduction in neonatal morbidity and mortality.

Which intrauterine resuscitation techniques are proven to be effective for the treatment of fetal distress during term labor?

In the past decades, a wide range of techniques aiming to improve fetal

oxygenation during labor has been introduced. Many of these intrauterine

resuscitation techniques are commonly used in clinical practice. As we discuss in

chapter 2 of this thesis, little robust evidence exists on the effect and potential side

effects of the various techniques. Our review revealed that the amount of studies

evaluating the effect of the interventions in the presence of suspected fetal distress

is limited. Moreover, most of the available studies have a small sample size, poorly

described methods, and they did not use randomization to allocate participants to

an intervention or control group. As a consequence, it is not easy to propose

recommendations regarding the use of these techniques in clinical practice.

Obviously, the effectiveness of intrauterine resuscitation is largely dependent on the

presumable cause of fetal distress.

After reviewing the current literature, and taking into account potential side effects

and practical issues, we propose the following recommendations: discontinuation of

uterotonic drugs and administration of a tocolytic agent may be useful, mainly in

case of uterine hyperstimulation. In addition, we recommend repositioning of the

parturient, preferably to left lateral tilt, since this is a quick and safe method that

may be beneficial. Since amnioinfusion does not improve neonatal outcome, but

may cause some serious complications, we do not recommend this as a standard

procedure. As the benefit and harm of an intravenous fluid bolus and maternal

hyperoxygenation as a treatment for fetal distress is not properly investigated yet,

we recommend not using this as routine procedures until its effectiveness is

surveyed.

Current practices of fetal monitoring and use of intrauterine resuscitation techniques.

Which methods are used for fetal monitoring in Dutch hospitals, and which actions are set-up in case of suspected fetal distress?

We hypothesized that the lack of solid evidence regarding the use of intrauterine

resuscitation techniques would result in variation in delivery room management. To

investigate how fetal distress is diagnosed and treated in Dutch hospitals, we

performed a nationwide survey, with a 100% response rate. The full study is

described in chapter 3 of this thesis. The availability and use of FSBS increased from

87% of all hospitals in 2009, to 98% in 2015.5 The use of ST-analysis (STAN,

Neoventa Medical, Mölndal, Sweden) decreased from 30% in 2012, to 23% in 2015.6

Discontinuation of oxytocin, use of tocolytic drugs and maternal repositioning are

commonly used resuscitation techniques in all hospitals. In contrast, the use of

amnioinfusion and maternal hyperoxygenation is inconsistent. These techniques are

used for intrauterine resuscitation in 33% and 58% of all hospitals, respectively. This

practice variation may exist because in 58% of the hospitals delivery room

management is mainly based on the Dutch national guideline, which does not state

a clear opinion on the use of these interventions.

General discussion and future perspectives

189

9

Introduction

To both future parents and obstetricians, it is of utmost importance to have a child

born in a healthy condition. Due to the physical, psychological, socioeconomic, and

also the medicolegal impact of perinatal asphyxia, the rate of interventions for

suspected fetal distress during labor is increasing.1,2 Obstetricians are challenged to

timely intervene when fetal hypoxia is suspected, but to prevent at the same time

unnecessary interventions due to their potential harm to the mother and her child.3,4

Until now, it is unclear which action should be undertaken in case of suspected fetal

distress, to prevent perinatal asphyxia. One should decide whether an immediate

intervention to deliver the baby is needed, or if fetal oxygenation can be restored by

intrauterine resuscitation. Intrauterine resuscitation may reduce the duration of the

fetus being hypoxic, and thus decrease the risk of organ damage (e.g. hypoxic-

ischemic encephalopathy). In case of successful restoration of the fetal oxygenation,

an invasive procedure to deliver the baby immediately may even be prevented.

In this thesis, we presented the current knowledge on the use and effect of

intrauterine resuscitation during term labor. We focused on one of the techniques

that is still frequently debated: maternal hyperoxygenation. Furthermore, we aimed

to identify factors that contribute to the risk of fetal distress during term labor. The

answers to these questions provide insight to improve perinatal care, and may thus

contribute to a reduction in neonatal morbidity and mortality.

Which intrauterine resuscitation techniques are proven to be effective for the treatment of fetal distress during term labor?

In the past decades, a wide range of techniques aiming to improve fetal

oxygenation during labor has been introduced. Many of these intrauterine

resuscitation techniques are commonly used in clinical practice. As we discuss in

chapter 2 of this thesis, little robust evidence exists on the effect and potential side

effects of the various techniques. Our review revealed that the amount of studies

evaluating the effect of the interventions in the presence of suspected fetal distress

is limited. Moreover, most of the available studies have a small sample size, poorly

described methods, and they did not use randomization to allocate participants to

an intervention or control group. As a consequence, it is not easy to propose

recommendations regarding the use of these techniques in clinical practice.

Obviously, the effectiveness of intrauterine resuscitation is largely dependent on the

presumable cause of fetal distress.

After reviewing the current literature, and taking into account potential side effects

and practical issues, we propose the following recommendations: discontinuation of

uterotonic drugs and administration of a tocolytic agent may be useful, mainly in

case of uterine hyperstimulation. In addition, we recommend repositioning of the

parturient, preferably to left lateral tilt, since this is a quick and safe method that

may be beneficial. Since amnioinfusion does not improve neonatal outcome, but

may cause some serious complications, we do not recommend this as a standard

procedure. As the benefit and harm of an intravenous fluid bolus and maternal

hyperoxygenation as a treatment for fetal distress is not properly investigated yet,

we recommend not using this as routine procedures until its effectiveness is

surveyed.

Current practices of fetal monitoring and use of intrauterine resuscitation techniques.

Which methods are used for fetal monitoring in Dutch hospitals, and which actions are set-up in case of suspected fetal distress?

We hypothesized that the lack of solid evidence regarding the use of intrauterine

resuscitation techniques would result in variation in delivery room management. To

investigate how fetal distress is diagnosed and treated in Dutch hospitals, we

performed a nationwide survey, with a 100% response rate. The full study is

described in chapter 3 of this thesis. The availability and use of FSBS increased from

87% of all hospitals in 2009, to 98% in 2015.5 The use of ST-analysis (STAN,

Neoventa Medical, Mölndal, Sweden) decreased from 30% in 2012, to 23% in 2015.6

Discontinuation of oxytocin, use of tocolytic drugs and maternal repositioning are

commonly used resuscitation techniques in all hospitals. In contrast, the use of

amnioinfusion and maternal hyperoxygenation is inconsistent. These techniques are

used for intrauterine resuscitation in 33% and 58% of all hospitals, respectively. This

practice variation may exist because in 58% of the hospitals delivery room

management is mainly based on the Dutch national guideline, which does not state

a clear opinion on the use of these interventions.

Chapter 9

190

Which recommendations regarding diagnosis and treatment of fetal distress are described in international guidelines, and do these differences result in clinical practice variation?

In chapter 3, we also compared recommendations regarding fetal monitoring and treatment of fetal distress from the national guidelines of several Western countries. We obtained eight guidelines that advised in the monitoring of fetal condition during labor and delivery. While FSBS facilities are recommended in all the obtained guidelines, the use of ST-analysis is recommended in three guidelines and advised against in three guidelines. Five guidelines also advised on intrauterine resuscitation: discontinuation of oxytocin and use of tocolytic drugs was advised in all guidelines, amnioinfusion was recommended in two guidelines and advised against in two other guidelines, whereas maternal hyperoxygenation was recommended in two guidelines and advised against in one guideline. Even in leading guidelines, such as those of the Royal College of Obstetricians and Gynaecologists (RCOG) in the United Kingdom, and the American College of Obstetricians and Gynecologists (ACOG) in the United States, recommendations are contradictory.

As the results from the nationwide survey indicated, even in a small country as The

Netherlands quite a large practice variation is present. How can this be explained?

Due to the lack of evidence, it is hard to propose firm recommendations regarding

the use of intrauterine resuscitation techniques. Obviously, when clinical practice is

based on a certain guideline, delivery room management is dependent on the

recommendations in the guideline that is followed.

Sometimes guidelines are not available, or not found to be useful. In fact, guidelines

are often outdated and not updated as soon as new evidence is available. The

current guideline on fetal monitoring of the Dutch Society of Obstetrics and

Gynaecology (NVOG) was published in 2013, and is currently being updated.6 Also,

the interpretation of study results may differ between doctors. For example in the

case of amnioinfusion for fetal distress; since amnioinfusion does not improve

neonatal outcome or reduce cesarean section (CS) rate, some doctors find this

intervention not useful, especially in the light of severe complications that may occur

during amnioinfusion.7-9 On the contrary, since FHR patterns do improve as a result

of amnioinfusion, other doctors support its use to in the presence of FHR

decelerations. In conclusion, clinical practice variation exists because of sometimes-

contradictory recommendation in guidelines, and also a different interpretation of

study results among delivery room staff.


Maternal hyperoxygenation is a commonly used, but frequently debated intrauterine

resuscitation technique. Some small clinical studies suggest a beneficial effect from

maternal hyperoxygenation.10 In contrast, other studies question its effectiveness,

and propose potential severe side effects.11-13 More evidence of its beneficial and

potentially harmful effects in the presence of fetal distress was urgently needed. This

need for more research was underlined in several publications. In most European

countries, including The Netherlands, maternal hyperoxygenation for fetal distress is

not a standard procedure. Therefore, this provided an excellent opportunity to

investigate this intervention in our country.

What is the effect of maternal hyperoxygenation on fetal oxygenation and fetal heart rate, according to a mathematical simulation model?

As described in chapter 4, we first simulated the effect of maternal

hyperoxygenation with 100% oxygen in a mathematical model. We hypothesized

that maternal hyperoxygenation would improve fetal oxygenation and fetal heart

rate (FHR), in the presence of variable FHR decelerations. This model also predicts

FHR pattern as a function of different (physiological) input parameters.14-16

Maternal hyperoxygenation with 100% oxygen led to a vast increase of maternal

pO2 (98 to 475 mmHg within 5 minutes),17 followed by an increase in pO2 in all

placental and fetal compartments. Also, the depth and duration of the simulated

variable decelerations decreased. This effect was not present in late decelerations.

Late decelerations are associated with impaired placental function and severe fetal

distress. Due to an impaired oxygen diffusion capacity of the placental membrane,

the effect of maternal hyperoxygenation is less distinct than in variable decelerations

where placental function is normal. It is possible that the level of increase of fetal

pO2 during late decelerations does not reach the threshold to considerably improve

FHR.

Thus, the model suggests a beneficial effect of maternal hyperoxygenation on fetal


191

9

Which recommendations regarding diagnosis and treatment of fetal distress are described in international guidelines, and do these differences result in clinical practice variation?

In chapter 3, we also compared recommendations regarding fetal monitoring and treatment of fetal distress from the national guidelines of several Western countries. We obtained eight guidelines that advised in the monitoring of fetal condition during labor and delivery. While FSBS facilities are recommended in all the obtained guidelines, the use of ST-analysis is recommended in three guidelines and advised against in three guidelines. Five guidelines also advised on intrauterine resuscitation: discontinuation of oxytocin and use of tocolytic drugs was advised in all guidelines, amnioinfusion was recommended in two guidelines and advised against in two other guidelines, whereas maternal hyperoxygenation was recommended in two guidelines and advised against in one guideline. Even in leading guidelines, such as those of the Royal College of Obstetricians and Gynaecologists (RCOG) in the United Kingdom, and the American College of Obstetricians and Gynecologists (ACOG) in the United States, recommendations are contradictory.

As the results from the nationwide survey indicated, even in a small country as The

Netherlands quite a large practice variation is present. How can this be explained?

Due to the lack of evidence, it is hard to propose firm recommendations regarding

the use of intrauterine resuscitation techniques. Obviously, when clinical practice is

based on a certain guideline, delivery room management is dependent on the

recommendations in the guideline that is followed.

Sometimes guidelines are not available, or not found to be useful. In fact, guidelines

are often outdated and not updated as soon as new evidence is available. The

current guideline on fetal monitoring of the Dutch Society of Obstetrics and

Gynaecology (NVOG) was published in 2013, and is currently being updated.6 Also,

the interpretation of study results may differ between doctors. For example in the

case of amnioinfusion for fetal distress; since amnioinfusion does not improve

neonatal outcome or reduce cesarean section (CS) rate, some doctors find this

intervention not useful, especially in the light of severe complications that may occur

during amnioinfusion.7-9 On the contrary, since FHR patterns do improve as a result

of amnioinfusion, other doctors support its use to in the presence of FHR

decelerations. In conclusion, clinical practice variation exists because of sometimes-




























FHR.


Chapter 9

192

pO2. These results are in line with findings from the few available clinical

studies.10,18,19 Since these studies are performed in a small group of participants, the

authors of these studies recommended to further investigate these changes using a

study with a larger study population.

Furthermore, as any simulation model is a simplified representation of the complex

fetomaternal oxygenation and cardiovascular system, the model results need to be

confirmed in clinical trials.

What is the effect of maternal hyperoxygenation applied in the case of suspected fetal distress in the second stage of labor, on fetal, neonatal, and maternal outcome?

To test the hypothesis of maternal hyperoxygenation improving fetal condition in a

clinical setting, we designed and initiated a single-center randomized controlled

clinical trial (RCT) called “Intrauterine resuscitation during term labor by maternal

hyperoxygenation (INTEREST O2)”. This study is the first randomized trial evaluating

the effect of maternal hyperoxygenation for fetal distress during labor. A detailed

description of the study protocol can be found in chapter 5 of this thesis.

The participants were randomly allocated to either the intervention group, where 100% oxygen was applied to the mother in the presence of a suboptimal of abnormal CTG, or the control group, where normal care was provided. Specific attention was paid to the subgroups in which a suboptimal or abnormal FHR pattern was observed. In addition, we separately analyzed the results of the group of small for gestational age fetuses (birth weight <p10). We chose changes in FHR as the primary outcome. Secondary outcome measures include different neonatal and maternal outcomes: Apgar score, blood gas values and free oxygen radicals in umbilical cord blood, admission to the Neonatal Intensive Care Unit (NICU), mode of delivery, and maternal side effects. The study results show that maternal hyperoxygenation has a positive effect on the FHR pattern in the presence a suboptimal or abnormal FHR pattern during the second stage of labor. No statistically significant difference was found in 5-minute Apgar score <7 between both groups. Also, blood gas analysis from umbilical cord blood was not different, and no difference was demonstrated in the amount of free oxygen radicals or the mode of delivery. However, less often an episiotomy was carried out on fetal indication in the mothers who received extra oxygen. In the
















group with an abnormal CTG this difference was statistically significant. All other outcomes were similar in the described subgroups. In conclusion, we found a positive effect of maternal hyperoxygenation on a suboptimal or abnormal FHR pattern during the second stage of term labor. The study also shows that it is safe to administer a high fraction of oxygen to the parturient for the treatment of fetal distress.

The choice of the primary outcome, FHR, may be topic of debate. As described in

the introduction of this thesis, FHR is only partly dependent on fetal oxygenation.

However, we believe that if no beneficial effect on FHR could be demonstrated, an

improvement in neonatal outcome was unlikely. Besides, a study with appropriate

power to show a reduction in important outcome measures as adverse neonatal

outcome would require a very large sample size. Since the potentially harmful

effects of maternal hyperoxygenation were not properly investigated yet, we chose

not to expose a large group of women and their fetuses to the intervention. Now a

positive effect on FHR pattern without severe side effects is confirmed by our study,

we will use the study results to design a larger, multicenter RCT to investigate the

effect on Apgar score and cord blood gas values. In this study, changes in FHR

pattern and FIGO category were judged by an expert team. We will investigate if

computerized analysis of the various features of the FHR pattern show the same

results. Since no harmful effects were demonstrated, there is no need to ban this

intervention from delivery rooms where maternal hyperoxygenation is a commonly

used intrauterine resuscitation technique.

Does maternal hemoglobin level during labor influence the risk of fetal distress during term labor?

It is useful to have insight in factors that influence the risk on fetal distress during

labor. One of the factors that may contribute to the fetal condition during labor is

maternal hemoglobin (Hb) level. Sheep-studies have shown that maternal anemia

leads to reduced fetoplacental oxygen delivery, so called ‘preplacental hypoxia’.20,21

Thus, maternal Hb level may influence the risk of fetal distress during labor, as

fetomaternal oxygen exchange may be impaired in the presence of anemia. Our

goal was to investigate how intrapartum maternal Hb relates to the risk of fetal

distress, neonatal outcome, and mode of delivery.

Systematic review



























Systematic review



























Systematic review



























Systematic review



























Systematic review



























Systematic review



























Systematic review




























FHR.


The study results are described in chapter 6.


193

9

























































Systematic review



























Systematic review



























Systematic review



























Systematic review



























Systematic review



























Systematic review



























Systematic review




























FHR.


Chapter 9

194

We started by conducting a systematic review of the available literature

investigating the effect of intrapartum maternal Hb on the risk of fetal distress, mode

of delivery, Apgar score, NICU admission and perinatal death. The complete study is

presented in chapter 7 of this thesis. We found 13 articles that met the inclusion

criteria. In these articles, the risk of fetal distress, various neonatal outcome

measures and mode of delivery were compared between anemic and non-anemic

mothers.

Unfortunately, the included articles mostly describe the results of small, non-

randomized studies carried out in developing countries. Therefore, it is hard to draw

firm conclusions based on the available evidence. Besides, the clinical setting in

which most of these studies were performed is different from the Dutch situation.

Taking into account the limitations of this systematic review, we proposed the

following conclusions: there seems to be an increased risk of an unplanned CS in

case of anemia, but not all studies have focused on the indication for the CS itself

(such as nonprogressive labor or fetal distress). Thus, we do not know whether the

risk of a CS for fetal distress is increased in anemic mothers.

The different studies give conflicting results about the effect on Apgar score and

NICU admission. There was also non-significant difference between the risk of

perinatal mortality in anemic versus non-anemic mothers, although this may partly

be explained by the relatively low incidence of perinatal death. In conclusion, apart

from the general health benefits for both mother and child, it also seems to be

worthwhile to strive for a normal Hb at the time of birth to increase the chance of

having a spontaneous delivery.

Retrospective study

As only a few studies on the influence of maternal Hb on fetal distress and mode of

delivery are performed in a high resource setting, we initiated a retrospective study

using data from electronic patient files of more than 9,000 women that gave birth in

Máxima Medical Center between 2009 and 2016. The results of this study are

presented in chapter 8 of this thesis.

After correction for possible confounders, Hb did not contribute to the likelihood of

fetal distress in this population. Thus, we could not support the hypothesis that

intrapartum Hb levels influence the risk of fetal distress during labor.

Possibly, only in severe anemia the fetoplacental oxygen delivery is insufficient to

maintain adequate fetal oxygenation. As the lowest Hb value in our study was 7.7

g/dL, none of the women included in our study suffered from severe anemia (<6.9

g/dL). Furthermore, as explained in the introduction of this thesis, it is not easy to

diagnose “fetal distress”. Often, interventions are initiated based on abnormal CTG

tracings, and therefore based on suspected fetal distress. Thus, since we do not

know whether the fetus was actually hypoxic or not, we cannot relate intrapartum Hb

to fetal hypoxia.

Regarding mode of delivery, mean Hb levels did significantly differ in groups having

a spontaneous delivery, compared to groups not having a spontaneous delivery.

Remarkably, instrumental vaginal delivery for any reason or for fetal distress was

related to a higher Hb, while a CS for any reason or for nonprogressive labor was

related to a lower Hb. The latter is in line with findings from other studies included in

our review, where a higher CS rate was noticed in anemic women, compared non-

anemic women.22-24 These studies did not assess the effect of Hb on the chance of

having an instrumental vaginal delivery. Also, they did not use Hb as a continuous

value. Consequently, we can only compare our results with the available studies

where outcome parameters are compared between groups of anemic and non-

anemic women.

Even though we found a lower Hb in the group that had a CS for any reason or for

nonprogressive labor, compared to the group that had a vaginal delivery, the

absolute difference in Hb between both groups was small (0.16 g/dL).

Furthermore, other studies did not explicitly state whether a CS was performed for

nonprogressive labor, fetal distress or both. This makes it difficult to compare our

results to the results found in the literature.

As compared to the results of several studies included in our systematic review, we

did not find a relation between Hb level and short-term neonatal outcome.

In conclusion, our data suggest that intrapartum Hb level does not influence the risk

of fetal distress and short-term neonatal outcome. However, in accordance with the



























Systematic review


195

9

After correction for possible confounders, Hb did not contribute to the likelihood of

fetal distress in this population. Thus, we could not support the hypothesis that

intrapartum Hb levels influence the risk of fetal distress during labor.

Possibly, only in severe anemia the fetoplacental oxygen delivery is insufficient to

maintain adequate fetal oxygenation. As the lowest Hb value in our study was 7.7

g/dL, none of the women included in our study suffered from severe anemia (<6.9

g/dL). Furthermore, as explained in the introduction of this thesis, it is not easy to

diagnose “fetal distress”. Often, interventions are initiated based on abnormal CTG

tracings, and therefore based on suspected fetal distress. Thus, since we do not

know whether the fetus was actually hypoxic or not, we cannot relate intrapartum Hb

to fetal hypoxia.

Regarding mode of delivery, mean Hb levels did significantly differ in groups having

a spontaneous delivery, compared to groups not having a spontaneous delivery.

Remarkably, instrumental vaginal delivery for any reason or for fetal distress was

related to a higher Hb, while a CS for any reason or for nonprogressive labor was

related to a lower Hb. The latter is in line with findings from other studies included in

our review, where a higher CS rate was noticed in anemic women, compared non-

anemic women.22-24 These studies did not assess the effect of Hb on the chance of

having an instrumental vaginal delivery. Also, they did not use Hb as a continuous

value. Consequently, we can only compare our results with the available studies

where outcome parameters are compared between groups of anemic and non-

anemic women.

Even though we found a lower Hb in the group that had a CS for any reason or for

nonprogressive labor, compared to the group that had a vaginal delivery, the

absolute difference in Hb between both groups was small (0.16 g/dL).

Furthermore, other studies did not explicitly state whether a CS was performed for

nonprogressive labor, fetal distress or both. This makes it difficult to compare our

results to the results found in the literature.

As compared to the results of several studies included in our systematic review, we

did not find a relation between Hb level and short-term neonatal outcome.

In conclusion, our data suggest that intrapartum Hb level does not influence the risk

of fetal distress and short-term neonatal outcome. However, in accordance with the



























Systematic review

Chapter 9

196

results from the systematic review, it may influence the risk of having a secondary

cesarean section.

Clinical implications and future perspectives

1. The INTEREST O2-study shows a beneficial effect of maternal

hyperoxygenation on FHR. Besides, the results show that maternal

hyperoxygenation for fetal distress is a safe procedure. Consequently, we do

not advise against the use of this intervention in clinical practice. We

recommend performing a larger prospective multicenter study to focus on

neonatal outcome measures. In general, a core outcome set to address

neonatal outcome should be developed. This enables future researchers to

compare the results from different studies.

2. In addition to the research on maternal hyperoxygenation during labor, other

potentially beneficial resuscitation techniques should be further investigated

in a prospective clinical study. For example, the use of an intravenous fluid

bolus to improve maternal cardiovascular function and placental blood flow,

and thereby possibly improve fetal oxygenation should be further

investigated. Initially, this hypothesis can be tested in a simulation model.

Those model results can be useful for the design of a clinical study.

3. When more evidence from clinical trials investigating the effect of intrauterine

resuscitation techniques becomes available, we can propose solid

recommendations regarding the choice for intrauterine resuscitation

techniques. Besides, existing clinical guidelines should be updated more

frequently, since many currently used clinical guidelines are outdated. These

measures may reduce the clinical practice variation that is currently observed

in the delivery ward.

4. Reliable methods to continuously determine fetal oxygenation during labor

should be developed. Then, interventions can be initiated when the fetus

becomes actually hypoxic, while unnecessary interventions can be avoided.

Potentially useful techniques are analysis of heart rate variability (e.g. spectral

analysis and phase rectified signal averaging (PRSA)) and fetal ECG.

5. Further investigations should be performed to investigate the role of

maternal, fetal and obstetric factors in the risk of fetal distress during labor.

We recommend to initiate a prospective, population-based study (including

low-risk pregnancies), where important factors such as obstetric and medical

history, the course of Hb level during pregnancy, obstetric complications and

socioeconomic status are taken into account.

6. Ideally, detailed information should be entered in a widely available

database. A benefit of such databases is that a large amount of data is

directly and freely available for research purposes. However, a problem with

such a database might be soundness and completeness of the data, as the

input most of the times derive directly from electronic patient files, thus

incorrect or incomplete input will result in errors in the database, and as a

consequence, in research outcomes. We recognize the administrative

workload that healthcare workers already have to handle, and believe we

should forefend spending even more time on non-patient-related

(administrative) tasks. However, once large, complete and reliable databases

are available, several sources can be linked and a large amount of data will be

available for cohort studies.

7. The Perined database is an example of a nationwide database containing

data of all deliveries in The Netherlands. When for example specific labor-

related details would be carefully entered in this database during one year,

this could leads to a large amount of information. Which details to prioritize

will depend on the most important research gaps, as defined by the NVOG.

This implies that we could quickly turn knowledge gaps into answers. More

and more research shows that the same effects are measured in observational

studies as in RCTs.25,26 Even though an RCT is considered the gold standard to

investigate clinical issues, valuable information can be obtained from

observational studies much faster. Besides, RCT are generally performed

under ‘ideal’ circumstances, while results from observational studies represent

‘the real world’. More and more research shows that the same effects are

measured in observational studies as in RCTs. Without doubt, there will still

be questions that can only be solved with an RCT. But the time has passed to

only consider RCTs ‘evidence-based’.

8. Another advantage of creating a large, reliable database based is that it

offers the possibility to perform ‘personalized medicine’. In the future,

artificial intelligence, such as machine learning and deep learning, will

support decision making of obstetricians when they have to decide which

intervention is best for the individual patient.


197

9

results from the systematic review, it may influence the risk of having a secondary

cesarean section.

Clinical implications and future perspectives

1. The INTEREST O2-study shows a beneficial effect of maternal

hyperoxygenation on FHR. Besides, the results show that maternal

hyperoxygenation for fetal distress is a safe procedure. Consequently, we do

not advise against the use of this intervention in clinical practice. We

recommend performing a larger prospective multicenter study to focus on

neonatal outcome measures. In general, a core outcome set to address

neonatal outcome should be developed. This enables future researchers to

compare the results from different studies.

2. In addition to the research on maternal hyperoxygenation during labor, other

potentially beneficial resuscitation techniques should be further investigated

in a prospective clinical study. For example, the use of an intravenous fluid

bolus to improve maternal cardiovascular function and placental blood flow,

and thereby possibly improve fetal oxygenation should be further

investigated. Initially, this hypothesis can be tested in a simulation model.

Those model results can be useful for the design of a clinical study.

3. When more evidence from clinical trials investigating the effect of intrauterine

resuscitation techniques becomes available, we can propose solid

recommendations regarding the choice for intrauterine resuscitation

techniques. Besides, existing clinical guidelines should be updated more

frequently, since many currently used clinical guidelines are outdated. These

measures may reduce the clinical practice variation that is currently observed

in the delivery ward.

4. Reliable methods to continuously determine fetal oxygenation during labor

should be developed. Then, interventions can be initiated when the fetus

becomes actually hypoxic, while unnecessary interventions can be avoided.

Potentially useful techniques are analysis of heart rate variability (e.g. spectral

analysis and phase rectified signal averaging (PRSA)) and fetal ECG.

5. Further investigations should be performed to investigate the role of

maternal, fetal and obstetric factors in the risk of fetal distress during labor.

We recommend to initiate a prospective, population-based study (including

low-risk pregnancies), where important factors such as obstetric and medical

history, the course of Hb level during pregnancy, obstetric complications and

socioeconomic status are taken into account.

6. Ideally, detailed information should be entered in a widely available

database. A benefit of such databases is that a large amount of data is

directly and freely available for research purposes. However, a problem with

such a database might be soundness and completeness of the data, as the

input most of the times derive directly from electronic patient files, thus

incorrect or incomplete input will result in errors in the database, and as a

consequence, in research outcomes. We recognize the administrative

workload that healthcare workers already have to handle, and believe we

should forefend spending even more time on non-patient-related

(administrative) tasks. However, once large, complete and reliable databases

are available, several sources can be linked and a large amount of data will be

available for cohort studies.

7. The Perined database is an example of a nationwide database containing

data of all deliveries in The Netherlands. When for example specific labor-

related details would be carefully entered in this database during one year,

this could leads to a large amount of information. Which details to prioritize

will depend on the most important research gaps, as defined by the NVOG.

This implies that we could quickly turn knowledge gaps into answers. More

and more research shows that the same effects are measured in observational

studies as in RCTs.25,26 Even though an RCT is considered the gold standard to

investigate clinical issues, valuable information can be obtained from

observational studies much faster. Besides, RCT are generally performed

under ‘ideal’ circumstances, while results from observational studies represent

‘the real world’. More and more research shows that the same effects are

measured in observational studies as in RCTs. Without doubt, there will still

be questions that can only be solved with an RCT. But the time has passed to

only consider RCTs ‘evidence-based’.

8. Another advantage of creating a large, reliable database based is that it

offers the possibility to perform ‘personalized medicine’. In the future,

artificial intelligence, such as machine learning and deep learning, will

support decision making of obstetricians when they have to decide which

intervention is best for the individual patient.

Chapter 9

198

References 1. Ensing S, Abu-Hanna A, Schaaf JM, Mol BW, Ravelli AC. Trends in birth asphyxia,

obstetric interventions and perinatal mortality among term singletons: a nationwide cohort study. J Matern Fetal Neonatal Med. 2015;28:632-7.

2. Schifrin BS, Cohen WR. The effect of malpractice claims on the use of caesarean section. Best Pract Res Clin Obstet Gynaecol. 2013;27:269-83.



5. Westerhuis ME, Strasser SM, Moons KG, Mol BW, Visser GH, Kwee A. Intrapartum [Intrapartum foetal monitoring: from stethoscope to ST analysis of the ECG]. Ned Tijdschr Geneeskd. 2009;153:B259. [Dutch]

6. Nederlandse Vereniging voor Obstetrie en Gynaecologie. Intra- partum fetal monitoring at term [Intrapartum foetale bewaking a terme]. 2014. [Dutch]



9. Regi A, Alexander N, Jose R, Lionel J, Varghese L, Peedicayil A. Amnioinfusion for relief of recurrent severe and moderate variable decelerations in labor. J Reprod Med. 2009;54:295-302.




13. ThorpJA, Trobough T, Evans R, Hedrick J, Yeast JD. The effect of maternal oxygen administration during the second stage of labor on umbilical cord blood gas values: a randomized controlled prospective trial. Am J Obstet Gynecol. 1995;172(2 Pt 1):465-74.











24. Drukker L, Hants Y, Farkash R, Ruchlemer R, Samueloff A, Grisaru-Granovsky S. Iron deficiencyanemiaat admission for labor and delivery is associated with an increased risk for Cesarean section and adverse maternal and neonatal outcomes.Transfusion. 2015;55:2799-806.

25. Faraoni D, Schaefer ST. Randomized controlled trials vs. observational studies: why not just live together? BMC Anesthesiol. 2016;16:102.

26. Anglemyer A, Horvath HT, Bero L. Healthcare outcomes assessed with observational study designs compared with those assessed in randomized trials. Cochrane Database Syst Rev. 2014;4:MR000034.


199

9

References 1. Ensing S, Abu-Hanna A, Schaaf JM, Mol BW, Ravelli AC. Trends in birth asphyxia,

obstetric interventions and perinatal mortality among term singletons: a nationwide cohort study. J Matern Fetal Neonatal Med. 2015;28:632-7.

2. Schifrin BS, Cohen WR. The effect of malpractice claims on the use of caesarean section. Best Pract Res Clin Obstet Gynaecol. 2013;27:269-83.



5. Westerhuis ME, Strasser SM, Moons KG, Mol BW, Visser GH, Kwee A. Intrapartum [Intrapartum foetal monitoring: from stethoscope to ST analysis of the ECG]. Ned Tijdschr Geneeskd. 2009;153:B259. [Dutch]

6. Nederlandse Vereniging voor Obstetrie en Gynaecologie. Intra- partum fetal monitoring at term [Intrapartum foetale bewaking a terme]. 2014. [Dutch]



9. Regi A, Alexander N, Jose R, Lionel J, Varghese L, Peedicayil A. Amnioinfusion for relief of recurrent severe and moderate variable decelerations in labor. J Reprod Med. 2009;54:295-302.




13. ThorpJA, Trobough T, Evans R, Hedrick J, Yeast JD. The effect of maternal oxygen administration during the second stage of labor on umbilical cord blood gas values: a randomized controlled prospective trial. Am J Obstet Gynecol. 1995;172(2 Pt 1):465-74.











24. Drukker L, Hants Y, Farkash R, Ruchlemer R, Samueloff A, Grisaru-Granovsky S. Iron deficiencyanemiaat admission for labor and delivery is associated with an increased risk for Cesarean section and adverse maternal and neonatal outcomes.Transfusion. 2015;55:2799-806.

25. Faraoni D, Schaefer ST. Randomized controlled trials vs. observational studies: why not just live together? BMC Anesthesiol. 2016;16:102.

26. Anglemyer A, Horvath HT, Bero L. Healthcare outcomes assessed with observational study designs compared with those assessed in randomized trials. Cochrane Database Syst Rev. 2014;4:MR000034.

Chapter 10

Summary

Chapter 10

202

Summary This thesis describes various techniques to improve fetal oxygenation during labor, when fetal distress is suspected. In the introduction (chapter 1) problems regarding the diagnosis and treatment of fetal distress are addressed. Also, the (patho)physiological process of fetal oxygenation influencing fetal heart rate (FHR) is described. In addition, we explain why it is important to prevent perinatal asphyxia and what implications it may have for later life. The following questions are answered in this thesis:

1. Which methods are effective to treat fetal distress during term labor? 2. Which methods of fetal monitoring are applied in Dutch hospitals and which

interventions are used in the case of suspected fetal distress? 3. Which recommendations regarding the monitoring of the fetal condition,

diagnosis of fetal distress and its treatment are made in international guidelines? Do differences in these recommendations lead to clinical practice variation in Dutch hospitals?

4. What is the effect of maternal hyperoxygenation on fetal oxygenation and fetal heart rate, according to simulations in a mathematical model?

5. What are the effects of maternal hyperoxygenation as a treatment for fetal distress with regard to fetal, neonatal, and maternal outcome?

6. Does intrapartum maternal hemoglobin level influence the risk of fetal distress, mode of delivery and neonatal outcome?

Treatment of impaired fetal oxygenation during labor is called intrauterine resuscitation. Chapter 2 gives a systematic overview of previous studies investigating the effect of different intrauterine resuscitation techniques on fetal and neonatal outcome. Different techniques are described in literature: repositioning of the parturient (for example, from back to side position), discontinuation of drugs stimulating uterine contractions (usually oxytocin), administration of drugs inhibiting contractions, administration of fluid into the uterine cavity (amnioinfusion), administration of high fractions of oxygen to the mother (maternal hyperoxygenation), administration of an intravenous (iv) fluid bolus, and intermittent pushing during the second stage of labor. After searching different databases (PubMed, Embase, Central), we initially obtained 1,660 articles. The title and abstract of these articles were screened for eligibility criteria. Articles had to be written in English, and the intervention of interest needed to be applied in the presence of fetal distress, during natural labor of a formerly healthy, singleton, term fetus. Only 15 articles fulfilled these eligibility criteria. One article described the

effect of repositioning the parturient, eight articles were about the effect of tocolytic drugs, four articles described the effect of amnioinfusion, one article the effect of maternal hyperoxygenation, and one that of an iv fluid bolus. We found no articles on the effect of intermittent pushing. Despite that many of these techniques are commonly used in the delivery ward, our systematic review shows that there is little evidence regarding the effect of these interventions. Moreover, most of the described studies are of poor quality, because of a limited sample size, lack of randomizations and poorly described methods. This makes it difficult to draw firm conclusions regarding the efficacy of the different techniques. Also, the choice for a particular technique depends on the presumable cause of the abnormal FHR pattern. Based on our systematic review, we came to the following conclusions: Discontinuation of uterotonic drugs has not been studied, but is a logical first step, mainly in case of hyperstimulation. We concluded that also the administration of tocolytic drugs would be appropriate in such cases. In addition, we support repositioning of the parturient, since this easy and quick intervention may be beneficial to fetal oxygenation, and it has no harmful side effects. The effect of an iv fluid bolus has not been properly examined. Therefore, we do not recommend applying this as a standard intervention. Studies on amnioinfusion and maternal hyperoxygenation initially showed a positive effect on fetal condition. However, other studies cited potentially dangerous side effects and complications of these techniques. Therefore we advised not to routinely use these techniques in clinical practice, until both positive and negative effects are properly examined. Afterwards, we can weigh the beneficial effects against possible side effects of these interventions.

Due to the lack of robust evidence regarding the effectiveness of the different interventions, it seemed obvious that delivery room management would vary as well. In chapter 3, we compared recommendations regarding fetal monitoring and treatment of fetal distress from the national guidelines of several Western countries. Unfortunately, not all national guidelines were publicly (online) available. In those cases, we requested the specific guideline from the national societies of Obstetricians and Gynecologists. In the end, we obtained eight guidelines that advised in the monitoring of fetal condition during labor and delivery. They all advised facilitating fetal scalp blood sampling (FSBS) in addition to cardiotocography (CTG) for fetal monitoring. With FSBS, umbilical cord blood gas values can be determined in a blood sample taken from the baby’s head, including pH, base excess and in some clinics also lactate, pO2, and pCO2. Three guidelines recommended the use of ST-analysis for fetal monitoring, while this was discouraged in three other guidelines.

Summary

203

10

Summary This thesis describes various techniques to improve fetal oxygenation during labor, when fetal distress is suspected. In the introduction (chapter 1) problems regarding the diagnosis and treatment of fetal distress are addressed. Also, the (patho)physiological process of fetal oxygenation influencing fetal heart rate (FHR) is described. In addition, we explain why it is important to prevent perinatal asphyxia and what implications it may have for later life. The following questions are answered in this thesis:

1. Which methods are effective to treat fetal distress during term labor? 2. Which methods of fetal monitoring are applied in Dutch hospitals and which

interventions are used in the case of suspected fetal distress? 3. Which recommendations regarding the monitoring of the fetal condition,

diagnosis of fetal distress and its treatment are made in international guidelines? Do differences in these recommendations lead to clinical practice variation in Dutch hospitals?

4. What is the effect of maternal hyperoxygenation on fetal oxygenation and fetal heart rate, according to simulations in a mathematical model?

5. What are the effects of maternal hyperoxygenation as a treatment for fetal distress with regard to fetal, neonatal, and maternal outcome?

6. Does intrapartum maternal hemoglobin level influence the risk of fetal distress, mode of delivery and neonatal outcome?

Treatment of impaired fetal oxygenation during labor is called intrauterine resuscitation. Chapter 2 gives a systematic overview of previous studies investigating the effect of different intrauterine resuscitation techniques on fetal and neonatal outcome. Different techniques are described in literature: repositioning of the parturient (for example, from back to side position), discontinuation of drugs stimulating uterine contractions (usually oxytocin), administration of drugs inhibiting contractions, administration of fluid into the uterine cavity (amnioinfusion), administration of high fractions of oxygen to the mother (maternal hyperoxygenation), administration of an intravenous (iv) fluid bolus, and intermittent pushing during the second stage of labor. After searching different databases (PubMed, Embase, Central), we initially obtained 1,660 articles. The title and abstract of these articles were screened for eligibility criteria. Articles had to be written in English, and the intervention of interest needed to be applied in the presence of fetal distress, during natural labor of a formerly healthy, singleton, term fetus. Only 15 articles fulfilled these eligibility criteria. One article described the

effect of repositioning the parturient, eight articles were about the effect of tocolytic drugs, four articles described the effect of amnioinfusion, one article the effect of maternal hyperoxygenation, and one that of an iv fluid bolus. We found no articles on the effect of intermittent pushing. Despite that many of these techniques are commonly used in the delivery ward, our systematic review shows that there is little evidence regarding the effect of these interventions. Moreover, most of the described studies are of poor quality, because of a limited sample size, lack of randomizations and poorly described methods. This makes it difficult to draw firm conclusions regarding the efficacy of the different techniques. Also, the choice for a particular technique depends on the presumable cause of the abnormal FHR pattern. Based on our systematic review, we came to the following conclusions: Discontinuation of uterotonic drugs has not been studied, but is a logical first step, mainly in case of hyperstimulation. We concluded that also the administration of tocolytic drugs would be appropriate in such cases. In addition, we support repositioning of the parturient, since this easy and quick intervention may be beneficial to fetal oxygenation, and it has no harmful side effects. The effect of an iv fluid bolus has not been properly examined. Therefore, we do not recommend applying this as a standard intervention. Studies on amnioinfusion and maternal hyperoxygenation initially showed a positive effect on fetal condition. However, other studies cited potentially dangerous side effects and complications of these techniques. Therefore we advised not to routinely use these techniques in clinical practice, until both positive and negative effects are properly examined. Afterwards, we can weigh the beneficial effects against possible side effects of these interventions.

Due to the lack of robust evidence regarding the effectiveness of the different interventions, it seemed obvious that delivery room management would vary as well. In chapter 3, we compared recommendations regarding fetal monitoring and treatment of fetal distress from the national guidelines of several Western countries. Unfortunately, not all national guidelines were publicly (online) available. In those cases, we requested the specific guideline from the national societies of Obstetricians and Gynecologists. In the end, we obtained eight guidelines that advised in the monitoring of fetal condition during labor and delivery. They all advised facilitating fetal scalp blood sampling (FSBS) in addition to cardiotocography (CTG) for fetal monitoring. With FSBS, umbilical cord blood gas values can be determined in a blood sample taken from the baby’s head, including pH, base excess and in some clinics also lactate, pO2, and pCO2. Three guidelines recommended the use of ST-analysis for fetal monitoring, while this was discouraged in three other guidelines.

Chapter 10

204

Five guidelines advised in the treatment of fetal distress. All guidelines recommended the use of tocolytic drugs. Amnioinfusion was recommended in two guidelines, and advised against in two other guidelines. The point of view regarding maternal hyperoxygenation was contradictory as well. Leading guidelines, such as those of the Royal College of Obstetricians and Gynaecologists (RCOG) in the United Kingdom, and the American College of Obstetricians and Gynecologists (ACOG) in the United States, are often used in other countries. Also in The Netherlands the above-mentioned guidelines are often used, together with our national guideline provided by the Dutch Society of Obstetrics and Gynaecology (NVOG) and local guidelines.

It seemed likely that the differences in recommendations would lead to differences in clinical practice. To test this hypothesis, we conducted a survey of all Dutch hospitals. The questions included in the survey were about how fetal condition was monitored, how it was diagnosed, what actions were undertaken in case of suspected fetal distress, and on what basis decisions were made. All Dutch hospitals responded to this survey. The results showed that in 98% of the hospitals FSBS is used to monitor fetal condition, in addition to CTG. In 23% of the hospitals, ST-analysis is used. In case of suspected fetal distress, amnioinfusion is performed in one-third of the hospitals, and in 58% maternal hyperoxygenation is applied. In 58% management is based on the national guideline (NVOG), and in 26% local guidelines are followed, although these are often based on the NVOG guideline. The differences in recommendations and clinical practice may –among others- be attributed to the lack of evidence from clinical studies. In addition, the guidelines are published between 2008 and 2015. Thus, results from newer studies are not yet included in the older guidelines. Supported by our review, we feel an urgent need to investigate in particular amnioinfusion and maternal hyperoxygenation. Recommendations in international guidelines regarding these two interventions are contradictory, and also the use of these interventions is inconsequent in clinical practice in The Netherlands. This thesis further focuses on the effect of maternal hyperoxygenation on fetal oxygenation and fetal heart rate pattern. We started investigating the effect of maternal hyperoxygenation in a mathematical model, suitable to simulate the fetomaternal oxygenation and circulation, and to simulate the FHR pattern.

The model values are user set, implying that changes in the imposed values lead to changes in the generated output. The results of the model simulations are described

in chapter 4. We applied uterine contractions, with a varying contraction intensity, duration, and interval. Previous research showed that the model was suitable to generate changes in the FHR pattern as a result of different uterine contractions.1

Indeed, the simulated contractions with varying strength and duration led to variable decelerations of different frequency, depth, and duration. Then, we simulated a rise in maternal pO2 from 100 to 475 mmHg, as a result of inhaling 100% oxygen.2

Consequently, pO2 increased in the intervillous space of the placenta, in the umbilical cord vessels, and also in the fetal cerebral microcirculation. Besides, depth and duration of variable decelerations decreased, as previously described in the literature.3

Based on these simulations, we postulate that maternal hyperoxygenation positively influences fetal oxygenation, leading to improvement of the FHR pattern. The model can provide insight into physiological and pathophysiological changes as a result of different clinical scenarios, in this case maternal hyperoxygenation. The results may help to set up clinical trials to support the model results with clinical data. Another advantage of this model is that the effect of clinical interventions can be studied, without exposing patients to potentially harmful interventions. However, careful considerations should be made with the translation of the model results to clinical practice, since this model is by definition a simplified representation of the complex fetomaternal physiology. Besides, potential side effects of maternal hyperoxygenation were not examined. The results can therefore not replace clinical studies. That is why we designed and initiated a clinical randomized controlled trial to investigate the effect of maternal hyperoxygenation in a clinical setting. This study, performed in Máxima Medical Center, is called the INTEREST O2-study (intrauterine resuscitation by maternal hyperoxygenation). The study protocol is described in chapter 5. In case of suspected fetal distress during the second stage of labor, patients will be allocated to either of two study arms. Fetal distress was diagnosed based on a suboptimal or abnormal CTG, according to the modified FIGO criteria. In the first study-arm, the control group, normal care is initiated. This includes all interventions that are commonly used. Maternal hyperoxygenation is not part of normal care in Máxima Medical Center. In the intervention group, 100% oxygen is applied by a non-rebreathing mask. If this does not lead to satisfactory improvement of the CTG within 10 minutes, normal care will be initiated. The main outcome measure is a change in the FHR pattern. Secondary outcomes are the following neonatal and maternal outcome measures: Apgar score, cord blood gas analysis, NICU admission, neonatal death, free oxygen radical activity, maternal side effects, and mode of delivery.

We compared the above-mentioned items, before and after the start of the study protocol, and between the intervention and control group. The specific CTG

Summary

205

10

Five guidelines advised in the treatment of fetal distress. All guidelines recommended the use of tocolytic drugs. Amnioinfusion was recommended in two guidelines, and advised against in two other guidelines. The point of view regarding maternal hyperoxygenation was contradictory as well. Leading guidelines, such as those of the Royal College of Obstetricians and Gynaecologists (RCOG) in the United Kingdom, and the American College of Obstetricians and Gynecologists (ACOG) in the United States, are often used in other countries. Also in The Netherlands the above-mentioned guidelines are often used, together with our national guideline provided by the Dutch Society of Obstetrics and Gynaecology (NVOG) and local guidelines.

It seemed likely that the differences in recommendations would lead to differences in clinical practice. To test this hypothesis, we conducted a survey of all Dutch hospitals. The questions included in the survey were about how fetal condition was monitored, how it was diagnosed, what actions were undertaken in case of suspected fetal distress, and on what basis decisions were made. All Dutch hospitals responded to this survey. The results showed that in 98% of the hospitals FSBS is used to monitor fetal condition, in addition to CTG. In 23% of the hospitals, ST-analysis is used. In case of suspected fetal distress, amnioinfusion is performed in one-third of the hospitals, and in 58% maternal hyperoxygenation is applied. In 58% management is based on the national guideline (NVOG), and in 26% local guidelines are followed, although these are often based on the NVOG guideline. The differences in recommendations and clinical practice may –among others- be attributed to the lack of evidence from clinical studies. In addition, the guidelines are published between 2008 and 2015. Thus, results from newer studies are not yet included in the older guidelines. Supported by our review, we feel an urgent need to investigate in particular amnioinfusion and maternal hyperoxygenation. Recommendations in international guidelines regarding these two interventions are contradictory, and also the use of these interventions is inconsequent in clinical practice in The Netherlands. This thesis further focuses on the effect of maternal hyperoxygenation on fetal oxygenation and fetal heart rate pattern. We started investigating the effect of maternal hyperoxygenation in a mathematical model, suitable to simulate the fetomaternal oxygenation and circulation, and to simulate the FHR pattern.

The model values are user set, implying that changes in the imposed values lead to changes in the generated output. The results of the model simulations are described

in chapter 4. We applied uterine contractions, with a varying contraction intensity, duration, and interval. Previous research showed that the model was suitable to generate changes in the FHR pattern as a result of different uterine contractions.1

Indeed, the simulated contractions with varying strength and duration led to variable decelerations of different frequency, depth, and duration. Then, we simulated a rise in maternal pO2 from 100 to 475 mmHg, as a result of inhaling 100% oxygen.2

Consequently, pO2 increased in the intervillous space of the placenta, in the umbilical cord vessels, and also in the fetal cerebral microcirculation. Besides, depth and duration of variable decelerations decreased, as previously described in the literature.3

Based on these simulations, we postulate that maternal hyperoxygenation positively influences fetal oxygenation, leading to improvement of the FHR pattern. The model can provide insight into physiological and pathophysiological changes as a result of different clinical scenarios, in this case maternal hyperoxygenation. The results may help to set up clinical trials to support the model results with clinical data. Another advantage of this model is that the effect of clinical interventions can be studied, without exposing patients to potentially harmful interventions. However, careful considerations should be made with the translation of the model results to clinical practice, since this model is by definition a simplified representation of the complex fetomaternal physiology. Besides, potential side effects of maternal hyperoxygenation were not examined. The results can therefore not replace clinical studies. That is why we designed and initiated a clinical randomized controlled trial to investigate the effect of maternal hyperoxygenation in a clinical setting. This study, performed in Máxima Medical Center, is called the INTEREST O2-study (intrauterine resuscitation by maternal hyperoxygenation). The study protocol is described in chapter 5. In case of suspected fetal distress during the second stage of labor, patients will be allocated to either of two study arms. Fetal distress was diagnosed based on a suboptimal or abnormal CTG, according to the modified FIGO criteria. In the first study-arm, the control group, normal care is initiated. This includes all interventions that are commonly used. Maternal hyperoxygenation is not part of normal care in Máxima Medical Center. In the intervention group, 100% oxygen is applied by a non-rebreathing mask. If this does not lead to satisfactory improvement of the CTG within 10 minutes, normal care will be initiated. The main outcome measure is a change in the FHR pattern. Secondary outcomes are the following neonatal and maternal outcome measures: Apgar score, cord blood gas analysis, NICU admission, neonatal death, free oxygen radical activity, maternal side effects, and mode of delivery.

We compared the above-mentioned items, before and after the start of the study protocol, and between the intervention and control group. The specific CTG

Chapter 10

206

characteristics include variable decelerations with loss of variability, and variable decelerations in combination with fetal bradycardia or tachycardia. Secondary outcome measures include different neonatal and maternal outcomes: Apgar score, blood gas values and free oxygen radicals in umbilical cord blood, admission to the Neonatal Intensive Care Unit (NICU), maternal side effects and patient experiences with participation in this study. We needed 116 patients to participate in this study to achieve a power of 90% with an α of 0.05. This sample size calculation is based on the only available study that investigated the effect of oxygen on FHR. In this study, a substantial decrease (50-100%) in the amplitude of variable decelerations was found.3 Based on these data, we expect a decrease in the combined duration and depth of variable decelerations of at least 50%. The fetal, neonatal and maternal outcomes of the INTEREST O2-study are described in chapter 6. The outcome parameters were compared between the group of women who were given extra oxygen and the group of women who did not receive extra oxygen. Specific attention was paid to the subgroups in which a suboptimal or abnormal FHR pattern was observed. In addition, we separately analyzed the results of the group of small for gestational age fetuses (birth weight <p10). Amelioration of the FHR pattern was observed three times as often in the intervention group (16.7 vs. 5.7%). Furthermore, the incidence of FHR deterioration was significantly higher in the control group versus the intervention group (42.9% vs. 13.9%). These changes in FHR pattern were significant (p = 0.02). There were three (5.0%) neonates with Apgar score <7 after five minutes in the control group, compared to one (1.8%) in the intervention group (p = 0.62). Umbilical cord blood gas analysis and mode of delivery showed no significant differences either. There was no significant difference in free oxygen radicals between both groups. Fewer episiotomies on fetal indication were performed in the oxygenation group (24.2%) than in the control group (65.4%) among patients with an abnormal fetal heart rate pattern (p = 0.001). In one third of all births, oxygen administration was stopped before the infant was born, mostly due to discomfort. No side effects were reported in 63%, from the oxygen admission nor the facemask. In conclusion, maternal hyperoxygenation has a positive effect on the FHR pattern in the presence of fetal distress during the second stage of labor. There was no significant difference in the neonatal outcome or mode of delivery, however, significantly fewer episiotomies were performed in mothers receiving additional oxygen in the abnormal CTG subgroup. No harmful effects were demonstrated.

Finally, we aimed to identify factors that may influence the risk of fetal distress during labor. In former studies, several risk factors were identified, including maternal age, parity, and previous cesarean section. Sheep-studies have shown that maternal anemia leads to reduced fetoplacental oxygen delivery. Thus, as fetomaternal oxygen exchange is impaired, we hypothesized that maternal hemoglobin (Hb) level may influence the risk of fetal distress during labor. Chapter 7 provides a systematic overview of the available studies investigating the effect of maternal Hb on the risk of fetal distress, mode of delivery, Apgar score, NICU admission and perinatal death. We found 810 articles in different databases (PubMed, Embase, Central). These articles were screened by title and abstract, leaving 13 articles that met the inclusion criteria. These are mostly small, non-randomized studies carried out in developing countries. One larger, retrospective study including more than 75,000 women was identified.4 In these articles the risk of fetal distress, various neonatal outcome measures and mode of delivery was compared between anemic and non-anemic mothers. No articles were found that had umbilical cord pH or the risk of fetal distress as an outcome measure. Nine articles focused on the outcome measure Apgar score, two on NICU admission, six on perinatal mortality, and five on mode of delivery. There seems to be an increased risk of an unplanned cesarean episode in case of anemia, but not all studies have focused on the reason for the cesarean section (such as non-progressive birth or fetal distress). The different studies give conflicting results about the effect on Apgar score and NICU admission. No clear difference was found in the risk of perinatal mortality in anemic versus non-anemic mothers, although this may partly be explained by the relatively low incidence of perinatal death. Apart from the general health benefits for both mother and child, it also seems to be worthwhile to strive for a normal Hb at the time of the birth to increase the chance of having a spontaneous delivery. We carried out a retrospective analysis of data from more than 9,000 women who gave birth in Máxima Medical Center, Veldhoven. We wanted to investigate whether the risk of fetal distress is related to the maternal Hb at the time of delivery. Secondly, we examined the relationship between mode of delivery, the reason for non-spontaneous delivery, neonatal outcomes, and the maternal Hb. Finally, various factors have determined that affect the intrapartum maternal Hb. These results are described in chapter 8.

All women who gave birth in Máxima Medical Center between 2009 and 2016 were included. In our study, we have taken Hb as a continuous value and therefore not categorized in low, normal, or high Hb at the time of the birth. Our study shows that

Summary

207

10

characteristics include variable decelerations with loss of variability, and variable decelerations in combination with fetal bradycardia or tachycardia. Secondary outcome measures include different neonatal and maternal outcomes: Apgar score, blood gas values and free oxygen radicals in umbilical cord blood, admission to the Neonatal Intensive Care Unit (NICU), maternal side effects and patient experiences with participation in this study. We needed 116 patients to participate in this study to achieve a power of 90% with an α of 0.05. This sample size calculation is based on the only available study that investigated the effect of oxygen on FHR. In this study, a substantial decrease (50-100%) in the amplitude of variable decelerations was found.3 Based on these data, we expect a decrease in the combined duration and depth of variable decelerations of at least 50%. The fetal, neonatal and maternal outcomes of the INTEREST O2-study are described in chapter 6. The outcome parameters were compared between the group of women who were given extra oxygen and the group of women who did not receive extra oxygen. Specific attention was paid to the subgroups in which a suboptimal or abnormal FHR pattern was observed. In addition, we separately analyzed the results of the group of small for gestational age fetuses (birth weight <p10). Amelioration of the FHR pattern was observed three times as often in the intervention group (16.7 vs. 5.7%). Furthermore, the incidence of FHR deterioration was significantly higher in the control group versus the intervention group (42.9% vs. 13.9%). These changes in FHR pattern were significant (p = 0.02). There were three (5.0%) neonates with Apgar score <7 after five minutes in the control group, compared to one (1.8%) in the intervention group (p = 0.62). Umbilical cord blood gas analysis and mode of delivery showed no significant differences either. There was no significant difference in free oxygen radicals between both groups. Fewer episiotomies on fetal indication were performed in the oxygenation group (24.2%) than in the control group (65.4%) among patients with an abnormal fetal heart rate pattern (p = 0.001). In one third of all births, oxygen administration was stopped before the infant was born, mostly due to discomfort. No side effects were reported in 63%, from the oxygen admission nor the facemask. In conclusion, maternal hyperoxygenation has a positive effect on the FHR pattern in the presence of fetal distress during the second stage of labor. There was no significant difference in the neonatal outcome or mode of delivery, however, significantly fewer episiotomies were performed in mothers receiving additional oxygen in the abnormal CTG subgroup. No harmful effects were demonstrated.

Finally, we aimed to identify factors that may influence the risk of fetal distress during labor. In former studies, several risk factors were identified, including maternal age, parity, and previous cesarean section. Sheep-studies have shown that maternal anemia leads to reduced fetoplacental oxygen delivery. Thus, as fetomaternal oxygen exchange is impaired, we hypothesized that maternal hemoglobin (Hb) level may influence the risk of fetal distress during labor. Chapter 7 provides a systematic overview of the available studies investigating the effect of maternal Hb on the risk of fetal distress, mode of delivery, Apgar score, NICU admission and perinatal death. We found 810 articles in different databases (PubMed, Embase, Central). These articles were screened by title and abstract, leaving 13 articles that met the inclusion criteria. These are mostly small, non-randomized studies carried out in developing countries. One larger, retrospective study including more than 75,000 women was identified.4 In these articles the risk of fetal distress, various neonatal outcome measures and mode of delivery was compared between anemic and non-anemic mothers. No articles were found that had umbilical cord pH or the risk of fetal distress as an outcome measure. Nine articles focused on the outcome measure Apgar score, two on NICU admission, six on perinatal mortality, and five on mode of delivery. There seems to be an increased risk of an unplanned cesarean episode in case of anemia, but not all studies have focused on the reason for the cesarean section (such as non-progressive birth or fetal distress). The different studies give conflicting results about the effect on Apgar score and NICU admission. No clear difference was found in the risk of perinatal mortality in anemic versus non-anemic mothers, although this may partly be explained by the relatively low incidence of perinatal death. Apart from the general health benefits for both mother and child, it also seems to be worthwhile to strive for a normal Hb at the time of the birth to increase the chance of having a spontaneous delivery. We carried out a retrospective analysis of data from more than 9,000 women who gave birth in Máxima Medical Center, Veldhoven. We wanted to investigate whether the risk of fetal distress is related to the maternal Hb at the time of delivery. Secondly, we examined the relationship between mode of delivery, the reason for non-spontaneous delivery, neonatal outcomes, and the maternal Hb. Finally, various factors have determined that affect the intrapartum maternal Hb. These results are described in chapter 8.

All women who gave birth in Máxima Medical Center between 2009 and 2016 were included. In our study, we have taken Hb as a continuous value and therefore not categorized in low, normal, or high Hb at the time of the birth. Our study shows that

Chapter 10

208

the Hb concentration has no influence on the risk of fetal distress, a vaginally assisted birth due to non-progressive labor, cesarean section for fetal condition, Apgar score <7 at 5 minutes, and umbilical cord pH ≤ 7,05. A relationship was found between the Hb concentration and the probability of a vaginally assisted delivery for whatever reason, and a vaginally assisted delivery due to fetal distress. Also, a relationship was found between the Hb concentration and the chance of a cesarean section for whatever reason, and on a cesarean section for non-progressive labor. A vaginally assisted birth was related to a relatively lower Hb at the time of delivery, while a cesarean section for non-progressive labor was related to a relatively higher Hb. The intrapartum Hb concentration was related to the maternal age and ethnicity, the number of previous births, fetal sex, and neonatal birth weight. In conclusion, the risk of fetal distress and an unfavorable neonatal outcome was not related to the Hb of the mother. However, there seems to be an increased risk of a non-spontaneous delivery in the presence of anemia. In chapter 9 the content of this thesis is summarized. A general discussion of the topics covered by this thesis is provided in chapter 10, where after recommendations for further research are proposed. The main conclusions of this thesis are:

1. Despite that intrauterine resuscitation techniques are commonly used in clinical practice, evidence regarding the effect on fetal and neonatal outcome is lacking.

2. There are major differences between the recommendations of the international guidelines on which interventions to use in case of suspected fetal distress.

3. As a result, a large practice variation exists between Dutch hospitals in the use of ST-analysis for fetal monitoring, and the use of amnioinfusion and maternal hyperoxygenation for fetal distress.

4. Model simulation suggests that maternal hyperoxygenation yields an improvement in placental and fetal oxygenation, leading to a decrease in variable decelerations in the fetal heart rate pattern.

5. Maternal hyperoxygenation has a positive effect on the FHR pattern in the presence of fetal distress during the second stage of labor, without any severe side effects.

6. Intrapartum maternal hemoglobin does not seem to influence the risk of fetal distress. It is unclear if maternal anemia increases the risk of low Apgar score, NICU admission, or perinatal death. However, it may increases the risk of a non-spontaneous delivery, especially a secondary cesarean section.

Also, a relationship was found between the Hb concentration and the chance of a

cesarean section for whatever reason, and on a cesarean section for non-progressive

labor. A vaginally assisted birth was related to a relatively higher Hb at the time of

delivery, while a cesarean section for non-progressive labor was related to a

relatively lower Hb. The intrapartum Hb concentration was related to the maternal

age and ethnicity, the number of previous births, fetal sex, and neonatal birth

weight.

In conclusion, the risk of fetal distress and an unfavorable neonatal outcome was not

related to the Hb of the mother. However, the data suggest a relationship between

Hb and mode of delivery.

In chapter 9 the content of this thesis is summarized. A general discussion of the

topics covered by this thesis is provided in chapter 10, where after

recommendations for further research are proposed.

The main conclusions of this thesis are:

1. Despite that intrauterine resuscitation techniques are commonly used in

clinical practice, evidence regarding the effect on fetal and neonatal outcome

is lacking.

2. There are major differences between the recommendations of the

international guidelines on which interventions to use in case of suspected

fetal distress.

3. As a result, a large practice variation exists between Dutch hospitals in the

use of ST-analysis for fetal monitoring, and the use of amnioinfusion and

maternal hyperoxygenation for fetal distress.

4. Model simulation suggests that maternal hyperoxygenation yields an

improvement in placental and fetal oxygenation, leading to a decrease in

variable decelerations in the fetal heart rate pattern.

5. Maternal hyperoxygenation has a positive effect on the FHR pattern in the

presence of fetal distress during the second stage of labor, without any

severe side effects.

6. Intrapartum maternal hemoglobin does not seem to influence the risk of fetal

distress. It is unclear if maternal anemia increases the risk of low Apgar score,

NICU admission, or perinatal death. However, it may increase the risk of a

secondary cesarean section.







weight.










is lacking.



fetal distress.














References 1. Van der Hout-van der Jagt MB, Jongen GJLM, Bovendeerd PHM, Oei SG. Insight into

variable fetal heart rate decelerations from a mathematical model. Early Human Dev. 2013; 89:361-9.



4. Drukker L, Hants Y, Farkash R, Ruchlemer R, Samueloff A, Grisaru-Granovsky S. Iron deficiency anemia at admission for labor and delivery is associated with an increased risk for cesarean section and adverse maternal and neonatal outcomes. Transfusion. 2015;55:2799-806.

Apgar score <7 at 5 minutes, and umbilical cord pH ≤ 7,05. A relationship was

found between the Hb concentration and the probability of a vaginally assisted

delivery for whatever reason, and a vaginally assisted delivery due to fetal distress.



labor. A vaginally assisted birth was related to a relatively lower Hb at the time of


relatively higher Hb. The intrapartum Hb concentration was related to the maternal


weight.


related to the Hb of the mother. However, there seems to be an increased risk of a

non-spontaneous delivery in the presence of anemia.

A general discussion of the topics covered by this thesis is provided in chapter 9,

whereafter recommendations for further research are proposed. In chapter 10, the

content of this thesis is summarized.




is lacking.


international guidelines on interventions in case of suspected fetal distress.











distress. Maternal anemia does not increase the risk of low Apgar score, NICU

Summary

209

10

the Hb concentration has no influence on the risk of fetal distress, a vaginally assisted birth due to non-progressive labor, cesarean section for fetal condition, Apgar score <7 at 5 minutes, and umbilical cord pH ≤ 7,05. A relationship was found between the Hb concentration and the probability of a vaginally assisted delivery for whatever reason, and a vaginally assisted delivery due to fetal distress. Also, a relationship was found between the Hb concentration and the chance of a cesarean section for whatever reason, and on a cesarean section for non-progressive labor. A vaginally assisted birth was related to a relatively lower Hb at the time of delivery, while a cesarean section for non-progressive labor was related to a relatively higher Hb. The intrapartum Hb concentration was related to the maternal age and ethnicity, the number of previous births, fetal sex, and neonatal birth weight. In conclusion, the risk of fetal distress and an unfavorable neonatal outcome was not related to the Hb of the mother. However, there seems to be an increased risk of a non-spontaneous delivery in the presence of anemia. In chapter 9 the content of this thesis is summarized. A general discussion of the topics covered by this thesis is provided in chapter 10, where after recommendations for further research are proposed. The main conclusions of this thesis are:

1. Despite that intrauterine resuscitation techniques are commonly used in clinical practice, evidence regarding the effect on fetal and neonatal outcome is lacking.

2. There are major differences between the recommendations of the international guidelines on which interventions to use in case of suspected fetal distress.

3. As a result, a large practice variation exists between Dutch hospitals in the use of ST-analysis for fetal monitoring, and the use of amnioinfusion and maternal hyperoxygenation for fetal distress.

4. Model simulation suggests that maternal hyperoxygenation yields an improvement in placental and fetal oxygenation, leading to a decrease in variable decelerations in the fetal heart rate pattern.

5. Maternal hyperoxygenation has a positive effect on the FHR pattern in the presence of fetal distress during the second stage of labor, without any severe side effects.

6. Intrapartum maternal hemoglobin does not seem to influence the risk of fetal distress. It is unclear if maternal anemia increases the risk of low Apgar score, NICU admission, or perinatal death. However, it may increases the risk of a non-spontaneous delivery, especially a secondary cesarean section.







weight.










is lacking.



fetal distress.




















weight.










is lacking.



fetal distress.














References 1. Van der Hout-van der Jagt MB, Jongen GJLM, Bovendeerd PHM, Oei SG. Insight into





Apgar score <7 at 5 minutes, and umbilical cord pH ≤ 7,05. A relationship was

found between the Hb concentration and the probability of a vaginally assisted

delivery for whatever reason, and a vaginally assisted delivery due to fetal distress.



labor. A vaginally assisted birth was related to a relatively lower Hb at the time of


relatively higher Hb. The intrapartum Hb concentration was related to the maternal


weight.


related to the Hb of the mother. However, there seems to be an increased risk of a

non-spontaneous delivery in the presence of anemia.

A general discussion of the topics covered by this thesis is provided in chapter 9,

whereafter recommendations for further research are proposed. In chapter 10, the

content of this thesis is summarized.




is lacking.


international guidelines on interventions in case of suspected fetal distress.











distress. Maternal anemia does not increase the risk of low Apgar score, NICU

Nederlandse samenvatting

Dit proefschrift beschrijft mogelijke behandelingen voor foetale nood tijdens de à

terme baring.

In de introductie (hoofdstuk 1) worden problemen t.a.v. de diagnosestelling en

behandeling van (dreigend) zuurstofgebrek tijdens de baring benoemd. Ook wordt

beschreven hoe verandering in foetale oxygenatie het foetale hartslagpatroon kan

beïnvloeden. Hiernaast wordt uitgelegd welke consequenties het optreden van

perinatale asfyxie kan hebben in het latere leven, en waarom het dus belangrijk is dit

te voorkomen. Tenslotte wordt beschreven welke vragen in dit proefschrift worden

beantwoord:

1. Welke methoden zijn bewezen effectief ter behandeling van foetale nood

tijdens de à terme baring?

2. Welke methoden van foetale bewaking worden toepast in Nederlandse

ziekenhuizen en welke interventies worden ingezet bij de verdenking op

foetale nood?

3. Welke aanbevelingen ten aanzien van het bewaken van de foetale conditie,

diagnosticeren van foetale nood en behandeling hiervan worden gedaan in

internationale richtlijnen? Leiden verschillen in deze aanbevelingen tot

variatie in de klinische praktijkvoering in Nederland?

4. Wat is, op basis van simulatie met een mathematisch model, het effect van

maternale hyperoxygenatie op foetale oxygenatie en foetaal hartritme?

5. Wat zijn de positieve en negatieve effecten van maternale hyperoxygenatie

als behandeling van foetale nood tijdens de à terme baring?

6. Heeft maternaal hemoglobine (Hb) ten tijde van de baring invloed op de kans

op het optreden van foetale nood en de modus partus?

Het behandelen van (dreigend) zuurstofgebrek tijdens de baring wordt ook wel

intra-uteriene resuscitatie genoemd. Hoofdstuk 2 geeft een systematisch overzicht

van gepubliceerde onderzoeken die het effect van verschillende intra-uteriene

resuscitatietechnieken beschrijven. Verschillende behandelingen worden genoemd

in de literatuur: het herpositioneren van de barende (bijvoorbeeld van rug- naar

zijligging), het stoppen van toegediende uterotonica (weeënstimulerende middelen,

meestal oxytocine), het toedienen van tocolytica (weeënremmende middelen),

amnio-infusie (het toedienen van vocht in de baarmoederholte), maternale

Samenvatting

211

10

Nederlandse samenvatting

Dit proefschrift beschrijft mogelijke behandelingen voor foetale nood tijdens de à

terme baring.

In de introductie (hoofdstuk 1) worden problemen t.a.v. de diagnosestelling en

behandeling van (dreigend) zuurstofgebrek tijdens de baring benoemd. Ook wordt

beschreven hoe verandering in foetale oxygenatie het foetale hartslagpatroon kan

beïnvloeden. Hiernaast wordt uitgelegd welke consequenties het optreden van

perinatale asfyxie kan hebben in het latere leven, en waarom het dus belangrijk is dit

te voorkomen. Tenslotte wordt beschreven welke vragen in dit proefschrift worden

beantwoord:

1. Welke methoden zijn bewezen effectief ter behandeling van foetale nood

tijdens de à terme baring?

2. Welke methoden van foetale bewaking worden toepast in Nederlandse

ziekenhuizen en welke interventies worden ingezet bij de verdenking op

foetale nood?

3. Welke aanbevelingen ten aanzien van het bewaken van de foetale conditie,

diagnosticeren van foetale nood en behandeling hiervan worden gedaan in

internationale richtlijnen? Leiden verschillen in deze aanbevelingen tot

variatie in de klinische praktijkvoering in Nederland?

4. Wat is, op basis van simulatie met een mathematisch model, het effect van

maternale hyperoxygenatie op foetale oxygenatie en foetaal hartritme?

5. Wat zijn de positieve en negatieve effecten van maternale hyperoxygenatie

als behandeling van foetale nood tijdens de à terme baring?

6. Heeft maternaal hemoglobine (Hb) ten tijde van de baring invloed op de kans

op het optreden van foetale nood en de modus partus?

Het behandelen van (dreigend) zuurstofgebrek tijdens de baring wordt ook wel

intra-uteriene resuscitatie genoemd. Hoofdstuk 2 geeft een systematisch overzicht

van gepubliceerde onderzoeken die het effect van verschillende intra-uteriene

resuscitatietechnieken beschrijven. Verschillende behandelingen worden genoemd

in de literatuur: het herpositioneren van de barende (bijvoorbeeld van rug- naar

zijligging), het stoppen van toegediende uterotonica (weeënstimulerende middelen,

meestal oxytocine), het toedienen van tocolytica (weeënremmende middelen),

amnio-infusie (het toedienen van vocht in de baarmoederholte), maternale

Chapter 10

212

hyperoxygenatie (het toedienen van hoge doseringen zuurstof aan de barende), het

intraveneus toedienen van extra vocht aan de barende en het intermitterend persen

tijdens de uitdrijvingsfase van de bevalling. Aanvankelijk vonden we 1660 artikelen

in verschillende databases (PubMed, Embase, Central). Deze artikelen werden

gescreend op titel en samenvatting, waarna slechts 15 bruikbare artikelen

overbleven. Eén artikel beschreef het effect van herpositionering van de barende,

acht artikelen gingen over het effect van het toedienen van tocolytica, vier artikelen

beschreven het effect van amnio-infusie, één artikel het effect van maternale

hyperoxygenatie, en één artikel het effect van het intraveneus toedienen van vocht

aan de barende. We vonden geen artikelen waarin het effect van intermitterend

persen tijdens de uitdrijving op de foetale conditie werd onderzocht.

Ondanks dat veel van deze technieken dagelijks worden toegepast op de

verloskamers, blijkt uit dit overzicht dat er relatief weinig onderzoek gedaan naar het

effect hiervan. Omdat vaak weinig patiënten geïncludeerd zijn, patiënten niet

gerandomiseerd werden en methoden matig omschreven zijn, zijn de meeste van

de beschreven studies van matige kwaliteit. Dit maakt dat het lastig is om harde

conclusies te trekken t.a.v. de werkzaamheid van de verschillende technieken.

Tevens is de keuze voor een bepaalde techniek afhankelijk van de vermeende

oorzaak van het verslechterende foetale hartslagpatroon.

Op basis van het overzicht zijn wij tot de volgende conclusies gekomen: het stoppen

van toediening van uterotonica is niet onderzocht, maar lijkt een logische eerste

stap in geval van hyperstimulatie. Met name in geval van hyperstimulatie, lijkt ook

het gebruik van tocolytica zinvol. Ook adviseren we het repositioneren van de

barende, aangezien dit een makkelijke, snelle interventie is die geen bijwerkingen

kent, en mogelijk een positief effect heeft op de foetale oxygenatie. Het nut van het

toedienen van extra vocht aan de moeder is niet onderzocht, daarom raden wij aan

deze interventie niet standaard toe te passen. De door ons geselecteerde

onderzoeken laten een positief effect zien van amnio-infusie en maternale

hyperoxygenatie op de foetale conditie. Echter, in de discussie worden studies

aangehaald die potentieel gevaarlijke bijwerkingen en complicaties van deze

technieken beschrijven. Daarom adviseren wij deze technieken niet routinematig in

de klinische praktijk te gebruiken, maar eerst zowel de positieve- als negatieve

effecten goed te onderzoeken. Daarna moet de balans worden opgemaakt tussen

de beschermende, en eventueel schadelijke effecten van deze interventies.

Omdat er weinig hard bewijs is t.a.v. de effectiviteit van de verschillende

interventies, leek het voor de hand liggend dat adviezen hierover zouden variëren.

In hoofdstuk 3 zetten we uiteen welke adviezen we vonden in nationale richtlijnen

van verschillende Westerse landen. Elk land heeft zijn eigen nationale organisatie

van obstetrici en gynaecologen, die nationale richtlijnen opstelt voor gebruik in de

klinische praktijk. Helaas zijn niet alle richtlijnen vrij (online) inzichtelijk, en zijn niet in

alle landen richtlijnen beschikbaar over het diagnosticeren en behandelen van

foetale nood tijdens de baring. Na het online zoeken naar richtlijnen en het

aanschrijven van de verschillende internationale beroepsverenigingen, beschikten

we over acht internationale richtlijnen die allen adviseerden om de foetale conditie

te monitoren tijdens de bevalling. Hieruit bleek dat alle richtlijnen aanbevelen om

naast cardiotocografie (CTG) ook te beschikken over de mogelijkheid tot het

verrichten van een microbloedonderzoek (MBO), waarbij in een druppeltje bloed -

afgenomen van het foetale hoofd - de pH-waarde, base excess en in sommige

klinieken ook lactaat, partiële zuurstofdruk (pO2) en partiële kooldioxide druk (pCO2)

worden bepaald. Drie richtlijnen raden het gebruik van ST-analyse aan, terwijl drie

andere richtlijnen dit juist afraden. In vijf richtlijnen worden aanbevelingen gedaan

t.a.v. de behandeling van foetale nood. In al deze richtlijnen wordt het gebruikt van

tocolytica aangeraden. Het toedienen van amnio-infusie wordt geadviseerd in twee

richtlijnen, maar juist afgeraden in twee andere richtlijnen. Ook het advies t.a.v.

maternale hyperoxygenatie is tegenstrijdig. Toonaangevende richtlijnen, zoals die

van de Royal College of Obstetricians and Gynaecologists (RCOG) in het Verenigd

Koninkrijk en de American College of Obstetricians and Gynecologists (ACOG) in de

Verenigde staten, worden vaak ook in andere landen gebruikt. Ook in Nederland

worden bovengenoemde richtlijnen vaak gebruikt, samen met de richtlijn van de

Nederlandse Vereniging voor Obstetrie en Gynaecologie (NVOG) en lokale

richtlijnen.

Het leek ons aannemelijk dat het verschil in aanbevelingen gemakkelijk kon leiden

tot verschillen in het klinisch handelen op de werkvloer. Om dit te onderzoeken

legden wij aan alle Nederlandse ziekenhuizen een enquête voor. In deze enquête

werden onder andere vragen gesteld over hoe de foetale conditie werd

gemonitord, hoe foetale nood werd gediagnosticeerd, welke acties werden

ondernomen bij verdenking op foetale nood en volgens welke richtlijnen werd

gehandeld. Alle Nederlandse ziekenhuizen hebben geantwoord op deze enquête.

Hieruit bleek dat in 98% van de ziekenhuizen naast CTG, ook MBO wordt gebruikt

om de foetale conditie vast te stellen. In 23% wordt ST-analyse gebruikt. In geval

Samenvatting

213

10

hyperoxygenatie (het toedienen van hoge doseringen zuurstof aan de barende), het

intraveneus toedienen van extra vocht aan de barende en het intermitterend persen

tijdens de uitdrijvingsfase van de bevalling. Aanvankelijk vonden we 1660 artikelen

in verschillende databases (PubMed, Embase, Central). Deze artikelen werden

gescreend op titel en samenvatting, waarna slechts 15 bruikbare artikelen

overbleven. Eén artikel beschreef het effect van herpositionering van de barende,

acht artikelen gingen over het effect van het toedienen van tocolytica, vier artikelen

beschreven het effect van amnio-infusie, één artikel het effect van maternale

hyperoxygenatie, en één artikel het effect van het intraveneus toedienen van vocht

aan de barende. We vonden geen artikelen waarin het effect van intermitterend

persen tijdens de uitdrijving op de foetale conditie werd onderzocht.

Ondanks dat veel van deze technieken dagelijks worden toegepast op de

verloskamers, blijkt uit dit overzicht dat er relatief weinig onderzoek gedaan naar het

effect hiervan. Omdat vaak weinig patiënten geïncludeerd zijn, patiënten niet

gerandomiseerd werden en methoden matig omschreven zijn, zijn de meeste van

de beschreven studies van matige kwaliteit. Dit maakt dat het lastig is om harde

conclusies te trekken t.a.v. de werkzaamheid van de verschillende technieken.

Tevens is de keuze voor een bepaalde techniek afhankelijk van de vermeende

oorzaak van het verslechterende foetale hartslagpatroon.

Op basis van het overzicht zijn wij tot de volgende conclusies gekomen: het stoppen

van toediening van uterotonica is niet onderzocht, maar lijkt een logische eerste

stap in geval van hyperstimulatie. Met name in geval van hyperstimulatie, lijkt ook

het gebruik van tocolytica zinvol. Ook adviseren we het repositioneren van de

barende, aangezien dit een makkelijke, snelle interventie is die geen bijwerkingen

kent, en mogelijk een positief effect heeft op de foetale oxygenatie. Het nut van het

toedienen van extra vocht aan de moeder is niet onderzocht, daarom raden wij aan

deze interventie niet standaard toe te passen. De door ons geselecteerde

onderzoeken laten een positief effect zien van amnio-infusie en maternale

hyperoxygenatie op de foetale conditie. Echter, in de discussie worden studies

aangehaald die potentieel gevaarlijke bijwerkingen en complicaties van deze

technieken beschrijven. Daarom adviseren wij deze technieken niet routinematig in

de klinische praktijk te gebruiken, maar eerst zowel de positieve- als negatieve

effecten goed te onderzoeken. Daarna moet de balans worden opgemaakt tussen

de beschermende, en eventueel schadelijke effecten van deze interventies.

Omdat er weinig hard bewijs is t.a.v. de effectiviteit van de verschillende

interventies, leek het voor de hand liggend dat adviezen hierover zouden variëren.

In hoofdstuk 3 zetten we uiteen welke adviezen we vonden in nationale richtlijnen

van verschillende Westerse landen. Elk land heeft zijn eigen nationale organisatie

van obstetrici en gynaecologen, die nationale richtlijnen opstelt voor gebruik in de

klinische praktijk. Helaas zijn niet alle richtlijnen vrij (online) inzichtelijk, en zijn niet in

alle landen richtlijnen beschikbaar over het diagnosticeren en behandelen van

foetale nood tijdens de baring. Na het online zoeken naar richtlijnen en het

aanschrijven van de verschillende internationale beroepsverenigingen, beschikten

we over acht internationale richtlijnen die allen adviseerden om de foetale conditie

te monitoren tijdens de bevalling. Hieruit bleek dat alle richtlijnen aanbevelen om

naast cardiotocografie (CTG) ook te beschikken over de mogelijkheid tot het

verrichten van een microbloedonderzoek (MBO), waarbij in een druppeltje bloed -

afgenomen van het foetale hoofd - de pH-waarde, base excess en in sommige

klinieken ook lactaat, partiële zuurstofdruk (pO2) en partiële kooldioxide druk (pCO2)

worden bepaald. Drie richtlijnen raden het gebruik van ST-analyse aan, terwijl drie

andere richtlijnen dit juist afraden. In vijf richtlijnen worden aanbevelingen gedaan

t.a.v. de behandeling van foetale nood. In al deze richtlijnen wordt het gebruikt van

tocolytica aangeraden. Het toedienen van amnio-infusie wordt geadviseerd in twee

richtlijnen, maar juist afgeraden in twee andere richtlijnen. Ook het advies t.a.v.

maternale hyperoxygenatie is tegenstrijdig. Toonaangevende richtlijnen, zoals die

van de Royal College of Obstetricians and Gynaecologists (RCOG) in het Verenigd

Koninkrijk en de American College of Obstetricians and Gynecologists (ACOG) in de

Verenigde staten, worden vaak ook in andere landen gebruikt. Ook in Nederland

worden bovengenoemde richtlijnen vaak gebruikt, samen met de richtlijn van de

Nederlandse Vereniging voor Obstetrie en Gynaecologie (NVOG) en lokale

richtlijnen.

Het leek ons aannemelijk dat het verschil in aanbevelingen gemakkelijk kon leiden

tot verschillen in het klinisch handelen op de werkvloer. Om dit te onderzoeken

legden wij aan alle Nederlandse ziekenhuizen een enquête voor. In deze enquête

werden onder andere vragen gesteld over hoe de foetale conditie werd

gemonitord, hoe foetale nood werd gediagnosticeerd, welke acties werden

ondernomen bij verdenking op foetale nood en volgens welke richtlijnen werd

gehandeld. Alle Nederlandse ziekenhuizen hebben geantwoord op deze enquête.

Hieruit bleek dat in 98% van de ziekenhuizen naast CTG, ook MBO wordt gebruikt

om de foetale conditie vast te stellen. In 23% wordt ST-analyse gebruikt. In geval

Chapter 10

214

van foetale nood wordt in een derde van de ziekenhuizen amnio-infusie toegediend

en in 58% wordt maternale hyperoxygenatie toegepast. In 58% worden de adviezen

van de NVOG gevolgd, en in 26% wordt het beleid gebaseerd op lokale richtlijnen,

al zijn deze vaak gebaseerd op de NVOG-richtlijn.

De variatie in de geformuleerde aanbevelingen en de klinische praktijkvoering zal

deels berusten op het gebrek aan resultaten van goede klinische onderzoeken.

Daarnaast zijn de richtlijnen gepubliceerd in de periode van 2008 tot 2015,

waardoor de resultaten uit nieuwere studies nog niet zullen zijn meegenomen in de

oudere richtlijnen.

Uit het door ons opgestelde overzicht van de beschikbare literatuur over het effect

van de verschillende intra-uteriene resuscitatietechnieken, bleek dat met name de

voor- en nadelen van amnio-infusie en maternale hyperoxygenatie verder onderzoek

vergden. In internationale richtlijnen werden tegenstrijdige adviezen gegeven t.a.v.

de toepassing van deze technieken, en ook in de Nederlandse klinische praktijk

worden deze interventies zeer wisselend gebruikt. Dit proefschrift richt zich verder

dan ook op het bestuderen van het effect van maternale hyperoxygenatie op de

foetale oxygenatie en het foetale hartslagpatroon.

We zijn gestart met het onderzoeken van het effect van maternale hyperoxygenatie

in een mathematisch model, geschikt om de foetomaternale oxygenatie en

circulatie, en het foetale hartslagpatroon te simuleren. In dit model kunnen

verschillende waarden worden aangepast, waarna in de gegenereerde output het

effect van deze veranderingen kan worden weergegeven. De uitkomsten staan

beschreven in hoofdstuk 4. De maternale oxygenatie zal binnen enkele minuten

toenemen van circa 100 tot 475 mmHg, als gevolg van het inademen van 100%

zuurstof.1 We gaven het model opdracht uteriene contracties met een wisselende

frequentie, duur en intensiteit te simuleren. Eerder onderzoek door onze

onderzoeksgroep had al aangetoond dat het model geschikt was om veranderingen

in de foetale hartslag ten gevolge van contracties te onderzoeken.2 Inderdaad

leidden gesimuleerde contracties met een wisselende kracht en duur, tot het

ontstaan van variabele deceleraties van verschillende frequentie, diepte en duur.

Vervolgens simuleerden we een stijging van de maternale pO2 tot 475 mmHg, om

zo het effect van maternale hyperoxygenatie na te bootsen. Als gevolg hiervan liet

het model zien dat de pO2 zowel in de intervilleuze ruimte van de placenta, als in de

navelstrengvaten, als ook in de foetale cerebrale- en microcirculatie toenam. Ook

werd duidelijk dat de duur en diepte van variabele deceleraties afnamen, zoals

eerder in de literatuur werd beschreven.3 Op basis van deze simulaties kunnen we

stellen dat maternale hyperoxygenatie een positief effect kan hebben op de foetale

oxygenatie, hetgeen leidt tot verbetering van het hartslagpatroon. Het model geeft

inzicht in fysiologische en pathofysiologische veranderingen ten gevolge van

verschillende klinische scenario’s, in dit geval maternale hyperoxygenatie. De

resultaten kunnen aanleiding geven tot, en helpen bij het opzetten van klinische

studies. Een ander voordeel van dit model is dat het effect van klinische interventies

kan worden bestudeerd, zonder patiënten aan de interventies bloot te stellen.

Echter, het simulatiemodel is een vereenvoudiging van de werkelijkheid, en

potentiele neveneffecten van maternale hyperoxygenatie konden hiermee niet

worden onderzocht. Derhalve kunnen simulaties klinische studies niet volledig

vervangen.

Om die reden hebben wij tevens een klinisch gerandomiseerd onderzoek opgezet

om in vivo het effect van maternale hyperoxygenatie, en eventuele neveneffecten te

onderzoeken. Het studieprotocol van deze INTEREST O2-studie (Intrauterine

resuscitation by maternal hyperoxygenation) staat beschreven in hoofdstuk 5. Deze

studie is een gerandomiseerd onderzoek, welke werd uitgevoerd in Máxima

Medisch Centrum. Wanneer er een verdenking bestond op foetale nood tijdens de

uitdrijving, werd middels loting worden bepaald volgens welke van de twee studie-

armen de patiënte behandeld zou worden. De diagnose ‘verdenking foetale nood’

werd gesteld o.b.v. een suboptimaal of abnormaal CTG volgens de internationale

FIGO-criteria.

In de eerste studie-arm, de controlegroep, werd normale zorg gestart. Dit omvat

alle interventies die normaliter in Máxima Medisch Centrum kunnen worden gestart

ter behandeling van foetale nood. Maternale hyperoxygenatie is geen onderdeel

van standaard zorg. In de interventiegroep werd gestart met 100% zuurstof via een

mond-neus masker. Indien dit binnen 10 minuten geen acceptabele verbetering van

het CTG liet zien, werd alsnog normale zorg gestart. De belangrijkste uitkomstmaat

was verandering van het CTG. Secundaire uitkomstmaten bevatten verschillende

neonatale en maternale uitkomsten: Apgar-score, navelstreng pH, vrije

zuurstofradicalen in navelstrengbloed, opname op de Neonatale Intensive Care Unit

(NICU), maternale bijwerkingen en patiënten-ervaringen met het onderzoek.

Samenvatting

215

10

van foetale nood wordt in een derde van de ziekenhuizen amnio-infusie toegediend

en in 58% wordt maternale hyperoxygenatie toegepast. In 58% worden de adviezen

van de NVOG gevolgd, en in 26% wordt het beleid gebaseerd op lokale richtlijnen,

al zijn deze vaak gebaseerd op de NVOG-richtlijn.

De variatie in de geformuleerde aanbevelingen en de klinische praktijkvoering zal

deels berusten op het gebrek aan resultaten van goede klinische onderzoeken.

Daarnaast zijn de richtlijnen gepubliceerd in de periode van 2008 tot 2015,

waardoor de resultaten uit nieuwere studies nog niet zullen zijn meegenomen in de

oudere richtlijnen.

Uit het door ons opgestelde overzicht van de beschikbare literatuur over het effect

van de verschillende intra-uteriene resuscitatietechnieken, bleek dat met name de

voor- en nadelen van amnio-infusie en maternale hyperoxygenatie verder onderzoek

vergden. In internationale richtlijnen werden tegenstrijdige adviezen gegeven t.a.v.

de toepassing van deze technieken, en ook in de Nederlandse klinische praktijk

worden deze interventies zeer wisselend gebruikt. Dit proefschrift richt zich verder

dan ook op het bestuderen van het effect van maternale hyperoxygenatie op de

foetale oxygenatie en het foetale hartslagpatroon.

We zijn gestart met het onderzoeken van het effect van maternale hyperoxygenatie

in een mathematisch model, geschikt om de foetomaternale oxygenatie en

circulatie, en het foetale hartslagpatroon te simuleren. In dit model kunnen

verschillende waarden worden aangepast, waarna in de gegenereerde output het

effect van deze veranderingen kan worden weergegeven. De uitkomsten staan

beschreven in hoofdstuk 4. De maternale oxygenatie zal binnen enkele minuten

toenemen van circa 100 tot 475 mmHg, als gevolg van het inademen van 100%

zuurstof.1 We gaven het model opdracht uteriene contracties met een wisselende

frequentie, duur en intensiteit te simuleren. Eerder onderzoek door onze

onderzoeksgroep had al aangetoond dat het model geschikt was om veranderingen

in de foetale hartslag ten gevolge van contracties te onderzoeken.2 Inderdaad

leidden gesimuleerde contracties met een wisselende kracht en duur, tot het

ontstaan van variabele deceleraties van verschillende frequentie, diepte en duur.

Vervolgens simuleerden we een stijging van de maternale pO2 tot 475 mmHg, om

zo het effect van maternale hyperoxygenatie na te bootsen. Als gevolg hiervan liet

het model zien dat de pO2 zowel in de intervilleuze ruimte van de placenta, als in de

navelstrengvaten, als ook in de foetale cerebrale- en microcirculatie toenam. Ook

werd duidelijk dat de duur en diepte van variabele deceleraties afnamen, zoals

eerder in de literatuur werd beschreven.3 Op basis van deze simulaties kunnen we

stellen dat maternale hyperoxygenatie een positief effect kan hebben op de foetale

oxygenatie, hetgeen leidt tot verbetering van het hartslagpatroon. Het model geeft

inzicht in fysiologische en pathofysiologische veranderingen ten gevolge van

verschillende klinische scenario’s, in dit geval maternale hyperoxygenatie. De

resultaten kunnen aanleiding geven tot, en helpen bij het opzetten van klinische

studies. Een ander voordeel van dit model is dat het effect van klinische interventies

kan worden bestudeerd, zonder patiënten aan de interventies bloot te stellen.

Echter, het simulatiemodel is een vereenvoudiging van de werkelijkheid, en

potentiele neveneffecten van maternale hyperoxygenatie konden hiermee niet

worden onderzocht. Derhalve kunnen simulaties klinische studies niet volledig

vervangen.

Om die reden hebben wij tevens een klinisch gerandomiseerd onderzoek opgezet

om in vivo het effect van maternale hyperoxygenatie, en eventuele neveneffecten te

onderzoeken. Het studieprotocol van deze INTEREST O2-studie (Intrauterine

resuscitation by maternal hyperoxygenation) staat beschreven in hoofdstuk 5. Deze

studie is een gerandomiseerd onderzoek, welke werd uitgevoerd in Máxima

Medisch Centrum. Wanneer er een verdenking bestond op foetale nood tijdens de

uitdrijving, werd middels loting worden bepaald volgens welke van de twee studie-

armen de patiënte behandeld zou worden. De diagnose ‘verdenking foetale nood’

werd gesteld o.b.v. een suboptimaal of abnormaal CTG volgens de internationale

FIGO-criteria.

In de eerste studie-arm, de controlegroep, werd normale zorg gestart. Dit omvat

alle interventies die normaliter in Máxima Medisch Centrum kunnen worden gestart

ter behandeling van foetale nood. Maternale hyperoxygenatie is geen onderdeel

van standaard zorg. In de interventiegroep werd gestart met 100% zuurstof via een

mond-neus masker. Indien dit binnen 10 minuten geen acceptabele verbetering van

het CTG liet zien, werd alsnog normale zorg gestart. De belangrijkste uitkomstmaat

was verandering van het CTG. Secundaire uitkomstmaten bevatten verschillende

neonatale en maternale uitkomsten: Apgar-score, navelstreng pH, vrije

zuurstofradicalen in navelstrengbloed, opname op de Neonatale Intensive Care Unit

(NICU), maternale bijwerkingen en patiënten-ervaringen met het onderzoek.

Chapter 10

216

We onderzochten of bovengenoemde uitkomstmaten veranderden vóór en ná het

starten van het studieprotocol, en we maakten een vergelijking tussen de

interventie- en controlegroep. Er namen 117 patiënten deel aan dit onderzoek, om

een power van 90% te behalen met een α van 0,05. Deze samplesizeberekening is

gebaseerd op het enige beschikbare onderzoek dat het effect van zuurstof op het

CTG eerder heeft onderzocht. In dit onderzoek werd een forse afname (50-100%) in

de amplitude van variabele deceleraties gevonden.3 Wij verwachten op basis van

deze gegevens een afname van de gecombineerde duur en diepte van variabele

deceleraties van minimaal 50%.

De maternale en neonatale uitkomsten van de INTEREST O2-studie werden

geanalyseerd en beschreven in hoofdstuk 6. Omdat eerdere onderzoeken

beschreven dat maternale hyperoxygenatie mogelijk schadelijk was voor de foetus

en/of moeder, hebben wij in deze studie onderzocht of er verschil is in neonatale

uitkomst en de modus partus (de manier van bevallen), en of de moeder

bijwerkingen heeft ervaren bij het gebruik van zuurstof. Bij het analyseren van de

resultaten werden de uitkomsten vergeleken tussen de groep vrouwen die extra

zuurstof kregen toegediend, en de groep vrouwen waarbij geen extra zuurstof werd

toegediend. Ook werd specifiek gekeken naar de groepen waarin een suboptimaal,

dan wel abnormaal hartslagpatroon gezien werd. Daarnaast werd apart gekeken

naar de groep neonaten met een laag geboortegewicht (<p10).

Verbetering van het foetale hartslagpatroon werd bijna drie keer zo vaak

waargenomen in de interventiegroep dan in de controlegroep (16,7 versus 5,7%).

Ook verslechterde het hartslagpatroon significant vaker in de controlegroep, ten

opzichte van de interventiegroep (42,9% versus 13,9%). Deze veranderingen zijn

significant (p = 0,02). Er waren drie (5,0%) neonaten met Apgar-score <7 na vijf

minuten in de controlegroep, vergeleken met één (1,8%) in de interventiegroep (p =

0,62). Bloedgasanalyse in navelstrengbloed en de wijze van bevallen waren niet

verschillend tussen de groepen. Er was ook geen verschil in de hoeveelheid vrije

zuurstofradicalen in beide groepen. Minder episiotomieën op foetale indicatie

werden uitgevoerd in de oxygenatiegroep (24,2%) dan in de controlegroep (65,4%),

in de subgroep van foetussen met een abnormaal hartslagpatroon (p = 0,001). Alle

andere uitkomsten waren vergelijkbaar in de beschreven subgroepen. Bij een derde

van de bevallingen werd het toedienen van zuurstof gestopt voordat het kind werd

geboren, voornamelijk als gevolg van discomfort ervaren door de moeder. 63% van

de deelneemster meldde geen bijwerkingen van de zuurstoftoevoer of het

gelaatsmasker.

Concluderend heeft maternale hyperoxygenatie een positief effect op het foetaal

hartslagpatroon tijdens de uitdrijvingsfase, in geval van een suboptimaal of

abnormaal CTG. Er is geen significant verschil in neonatale uitkomst of wijze van

bevallen. Echter, significant minder episiotomieën werden uitgevoerd bij moeders in

de subgroep met een abnormaal CTG, die extra zuurstof kregen. Alle andere

uitkomsten waren vergelijkbaar in de beschreven. Er werden geen schadelijke

effecten aangetoond van maternale hyperoxygenatie.

Tenslotte hebben wij onderzocht of maternaal Hb ten tijde van de bevalling

voorspellend is voor het optreden van foetale nood tijdens de vaginale baring, en

de wijze van bevallen. Studies in schapen wezen uit dat bloedarmoede bij de

moeder leidt tot verminderde zuurstoftoevoer naar het kind. Dit zou kunnen het

risico op foetale nood en het beloop van de baring kunnen beïnvloeden.

Hoofdstuk 7 geeft een systematisch overzicht van de beschikbare studies waarin het

effect van maternaal Hb op de kans op foetale nood, modus partus, Apgar-score,

NICU-opname en perinatale sterft is onderzocht. We vonden 810 artikelen in

verschillende databases (PubMed, Embase, Central). Deze artikelen werden

gescreend op titel en samenvatting, waarna 13 artikelen overbleven die voldeden

aan de inclusiecriteria. Het zijn veelal kleine, niet gerandomiseerde studies,

uitgevoerd in ontwikkelingslanden. Er werd één grotere, retrospectieve studie

geïncludeerd waaraan ruim 75.000 vrouwen deelnamen.4

In deze artikelen werd de kans op foetale nood, verschillende neonatale

uitkomstmaten en modus partus vergeleken tussen anemische en niet-anemische

moeders (wel of geen bloedarmoede). Er werden geen artikelen gevonden die

keken naar navelstreng pH of naar het optreden van foetale nood tijdens de

bevalling. Negen artikelen keken naar de uitkomstmaat Apgar-score, twee naar

NICU-opname, zes naar perinatale sterfte (overlijden van de baby rondom de

bevalling), en vijf naar de modus partus.

Er lijkt een toegenomen kans op een niet-geplande keizersnede in geval van

anemie, er is echter niet in alle studies gekeken naar de reden voor de keizersnede

(zoals niet-vorderende baring of foetale nood). Over het effect op Apgar-score en

Samenvatting

217

10

We onderzochten of bovengenoemde uitkomstmaten veranderden vóór en ná het

starten van het studieprotocol, en we maakten een vergelijking tussen de

interventie- en controlegroep. Er namen 117 patiënten deel aan dit onderzoek, om

een power van 90% te behalen met een α van 0,05. Deze samplesizeberekening is

gebaseerd op het enige beschikbare onderzoek dat het effect van zuurstof op het

CTG eerder heeft onderzocht. In dit onderzoek werd een forse afname (50-100%) in

de amplitude van variabele deceleraties gevonden.3 Wij verwachten op basis van

deze gegevens een afname van de gecombineerde duur en diepte van variabele

deceleraties van minimaal 50%.

De maternale en neonatale uitkomsten van de INTEREST O2-studie werden

geanalyseerd en beschreven in hoofdstuk 6. Omdat eerdere onderzoeken

beschreven dat maternale hyperoxygenatie mogelijk schadelijk was voor de foetus

en/of moeder, hebben wij in deze studie onderzocht of er verschil is in neonatale

uitkomst en de modus partus (de manier van bevallen), en of de moeder

bijwerkingen heeft ervaren bij het gebruik van zuurstof. Bij het analyseren van de

resultaten werden de uitkomsten vergeleken tussen de groep vrouwen die extra

zuurstof kregen toegediend, en de groep vrouwen waarbij geen extra zuurstof werd

toegediend. Ook werd specifiek gekeken naar de groepen waarin een suboptimaal,

dan wel abnormaal hartslagpatroon gezien werd. Daarnaast werd apart gekeken

naar de groep neonaten met een laag geboortegewicht (<p10).

Verbetering van het foetale hartslagpatroon werd bijna drie keer zo vaak

waargenomen in de interventiegroep dan in de controlegroep (16,7 versus 5,7%).

Ook verslechterde het hartslagpatroon significant vaker in de controlegroep, ten

opzichte van de interventiegroep (42,9% versus 13,9%). Deze veranderingen zijn

significant (p = 0,02). Er waren drie (5,0%) neonaten met Apgar-score <7 na vijf

minuten in de controlegroep, vergeleken met één (1,8%) in de interventiegroep (p =

0,62). Bloedgasanalyse in navelstrengbloed en de wijze van bevallen waren niet

verschillend tussen de groepen. Er was ook geen verschil in de hoeveelheid vrije

zuurstofradicalen in beide groepen. Minder episiotomieën op foetale indicatie

werden uitgevoerd in de oxygenatiegroep (24,2%) dan in de controlegroep (65,4%),

in de subgroep van foetussen met een abnormaal hartslagpatroon (p = 0,001). Alle

andere uitkomsten waren vergelijkbaar in de beschreven subgroepen. Bij een derde

van de bevallingen werd het toedienen van zuurstof gestopt voordat het kind werd

geboren, voornamelijk als gevolg van discomfort ervaren door de moeder. 63% van

de deelneemster meldde geen bijwerkingen van de zuurstoftoevoer of het

gelaatsmasker.

Concluderend heeft maternale hyperoxygenatie een positief effect op het foetaal


abnormaal CTG. Er is geen significant verschil in neonatale uitkomst of wijze van

bevallen. Echter, significant minder episiotomieën werden uitgevoerd bij moeders in

de subgroep met een abnormaal CTG, die extra zuurstof kregen. Alle andere

uitkomsten waren vergelijkbaar in de beschreven. Er werden geen schadelijke

effecten aangetoond van maternale hyperoxygenatie.

Tenslotte hebben wij onderzocht of maternaal Hb ten tijde van de bevalling

voorspellend is voor het optreden van foetale nood tijdens de vaginale baring, en

de wijze van bevallen. Studies in schapen wezen uit dat bloedarmoede bij de

moeder leidt tot verminderde zuurstoftoevoer naar het kind. Dit zou kunnen het

risico op foetale nood en het beloop van de baring kunnen beïnvloeden.

Hoofdstuk 7 geeft een systematisch overzicht van de beschikbare studies waarin het

effect van maternaal Hb op de kans op foetale nood, modus partus, Apgar-score,

NICU-opname en perinatale sterft is onderzocht. We vonden 810 artikelen in

verschillende databases (PubMed, Embase, Central). Deze artikelen werden

gescreend op titel en samenvatting, waarna 13 artikelen overbleven die voldeden

aan de inclusiecriteria. Het zijn veelal kleine, niet gerandomiseerde studies,

uitgevoerd in ontwikkelingslanden. Er werd één grotere, retrospectieve studie

geïncludeerd waaraan ruim 75.000 vrouwen deelnamen.4

In deze artikelen werd de kans op foetale nood, verschillende neonatale

uitkomstmaten en modus partus vergeleken tussen anemische en niet-anemische

moeders (wel of geen bloedarmoede). Er werden geen artikelen gevonden die

keken naar navelstreng pH of naar het optreden van foetale nood tijdens de

bevalling. Negen artikelen keken naar de uitkomstmaat Apgar-score, twee naar

NICU-opname, zes naar perinatale sterfte (overlijden van de baby rondom de

bevalling), en vijf naar de modus partus.

Er lijkt een toegenomen kans op een niet-geplande keizersnede in geval van

anemie, er is echter niet in alle studies gekeken naar de reden voor de keizersnede

(zoals niet-vorderende baring of foetale nood). Over het effect op Apgar-score en

Chapter 10

218

NICU-opname geven de verschillende onderzoeken tegenstrijdige resultaten. Er

werd geen duidelijk verschil gevonden in het risico op perinatale sterfte bij

anemische versus niet-anemische moeder, al zal dit deels te verklaren zijn door het

relatief weinig voorkomen van perinatale sterfte. Naast de andere voordelen voor

de gezondheid van moeder en kind, lijkt het dus ook voor het beloop van de baring

zinvol te streven naar een normaal Hb ten tijde van de baring.

Wij hebben een retrospectieve analyse uitgevoerd op data van ruim 9.000 à terme

bevallen vrouwen uit ons eigen ziekenhuis (Máxima Medisch Centrum, Veldhoven).

We wilden onderzoeken of het risico op foetale nood gerelateerd is aan het Hb van

de moeder ten tijde van de bevalling. Ten tweede onderzochten we de relatie

tussen de modus partus, de reden voor een niet-spontane baring, neonatale

uitkomsten en het Hb van de moeder. Tenslotte hebben we verschillende factoren

bepaald die invloed hebben op het Hb van de moeder ten tijde van de bevalling.

Deze uitkomsten staan beschreven in hoofdstuk 8.

Alle vrouwen die zijn bevallen in Máxima Medisch Centrum tussen 2009 en 2016

werden geïncludeerd. In ons onderzoek hebben wij Hb als continue waarde

genomen en zodoende niet gecategoriseerd in wel of geen anemie ten tijde van de

baring. Uit ons onderzoek blijkt dat de hoogte van het Hb geen invloed heeft op de

kans op foetale nood, een vacuümextractie (zuignapbevalling) wegens niet-

vorderende baring, keizersnede voor foetale conditie, Apgar-score na 5 minuten <7

en navelstreng pH ≤ 7,05. Er werd wel een relatie gevonden tussen de Hb-waarde

en de kans op een vacuümextractie om welke reden dan ook, en op een

vacuümextractie wegens foetale nood. Ook werd een relatie gevonden tussen de

hoogte van het Hb en de kans op een keizersnede om welke reden dan ook, en op

een keizersnede wegens een niet-vorderende baring. Een vacuümextractie was

gerelateerd aan een relatief lager Hb ten tijde van de baring, terwijl een keizersnede

wegens een niet-vorderende baring juist gerelateerd was aan een relatief hoger Hb.

Het Hb ten tijde van de baring bleek gerelateerd aan de leeftijd van de moeder,

etniciteit, het aantal eerdere bevallingen, geslacht en geboortegewicht van de

neonaat.

Concluderend bleek het risico op foetale nood en een ongunstige neonatale

uitkomst niet gerelateerd aan het Hb van de moeder. Wel lijkt er een hoger risico te

bestaan op een niet-spontane bevalling in geval van anemie.


























gerelateerd aan een relatief hoger Hb ten tijde van de baring, terwijl een

keizersnede wegens een niet-vorderende baring juist gerelateerd was aan een

relatief lager Hb. Het Hb ten tijde van de baring bleek gerelateerd aan de leeftijd

van de moeder, etniciteit, het aantal eerdere bevallingen, geslacht en

geboortegewicht van de neonaat.



bestaan op een niet-geplande keizersnede in geval van anemie.

Hoofdstuk 9 bevat deze Nederlandse en een Engelse samenvatting van dit

proefschrift. Een algemene discussie van de onderwerpen die in de proefschrift aan

bod zijn gekomen wordt gevoerd in hoofdstuk 10, waarna aanbevelingen voor

verder onderzoek worden gedaan.

De belangrijkste conclusies uit dit proefschrift zijn:

1. Er is weinig goed onderzoek gedaan naar het effect van intra-uteriene

resuscitatietechnieken op de foetale en neonatale conditie, terwijl deze in de

klinische praktijk dagelijks worden toegepast.

2. Er zijn grote verschillen tussen de aanbevelingen van de internationale

richtlijnen over welke interventies toe te passen bij de verdenking op foetale

nood.

3. Het beleid rondom diagnostiek en behandeling van foetale nood verschilt in

Nederland per kliniek.

4. De uitkomsten van het nabootsen van het effect van maternale

hyperoxygenatie in een simulatiemodel suggereren dat deze interventie zorgt

voor verbetering van de placentaire- en foetale oxygenatie, en leidt tot een

verbetering van het foetaal hartslagpatroon.

5. Maternale hyperoxygenatie heeft een positief effect op het foetaal


abnormaal CTG. Er werden geen schadelijke effecten aangetoond van

maternale hyperoxygenatie.

6. Maternaal Hb ten tijde van de baring lijkt niet van invloed te zijn op de kans

op het ontstaan van foetale nood. Het is onduidelijk of het meer risico geeft

op lage Apgar-score of NICU-opname. Wel lijkt het risico op een niet-

geplande keizersnede verhoogd.




neonaat.


uitkomst niet gerelateerd aan het Hb van de moeder. Concluderend bleek het risico

op foetale nood en een ongunstige neonatale uitkomst niet gerelateerd aan het Hb

van de moeder. Wel lijkt er een hoger risico te bestaan op een niet-spontane

bevalling in geval van anemie.

Een algemene discussie van de onderwerpen die in de proefschrift aan bod zijn

gekomen wordt gevoerd in hoofdstuk 9, waarna aanbevelingen voor verder

onderzoek worden gedaan. Hoofdstuk 10 bevat deze Nederlandse en een Engelse

samenvatting van dit proefschrift.



resuscitatietechnieken op de foetale conditie, terwijl deze in de klinische praktijk

dagelijks worden toegepast.

2. Er zijn grote verschillen tussen de aanbevelingen van de internationale richtlijnen

over interventies bij foetale nood.



4. De uitkomsten van het nabootsen van het effect van maternale hyperoxygenatie

in een simulatiemodel suggereren dat deze interventie leidt tot verbetering van

de placentaire- en foetale oxygenatie, en leidt tot een verbetering van het

foetaal hartslagpatroon.



abnormaal CTG. Er werden geen schadelijke effecten aangetoond van maternale

hyperoxgenatie.

6. Maternaal Hb ten tijde van de baring lijkt niet van invloed te zijn op de kans op

het ontstaan van foetale nood. Het is onduidelijk of het meer risico geeft op lage

Apgar-score, NICU-opname of een keizersnede.

Samenvatting

219

10


























gerelateerd aan een relatief lager Hb ten tijde van de baring, terwijl een keizersnede




neonaat.



bestaan op een niet-spontane bevalling in geval van anemie.


























gerelateerd aan een relatief hoger Hb ten tijde van de baring, terwijl een

keizersnede wegens een niet-vorderende baring juist gerelateerd was aan een

relatief lager Hb. Het Hb ten tijde van de baring bleek gerelateerd aan de leeftijd

van de moeder, etniciteit, het aantal eerdere bevallingen, geslacht en

geboortegewicht van de neonaat.



bestaan op een niet-geplande keizersnede in geval van anemie.

Hoofdstuk 9 bevat deze Nederlandse en een Engelse samenvatting van dit

proefschrift. Een algemene discussie van de onderwerpen die in de proefschrift aan

bod zijn gekomen wordt gevoerd in hoofdstuk 10, waarna aanbevelingen voor

verder onderzoek worden gedaan.



resuscitatietechnieken op de foetale en neonatale conditie, terwijl deze in de

klinische praktijk dagelijks worden toegepast.

2. Er zijn grote verschillen tussen de aanbevelingen van de internationale

richtlijnen over welke interventies toe te passen bij de verdenking op foetale

nood.



4. De uitkomsten van het nabootsen van het effect van maternale

hyperoxygenatie in een simulatiemodel suggereren dat deze interventie zorgt

voor verbetering van de placentaire- en foetale oxygenatie, en leidt tot een

verbetering van het foetaal hartslagpatroon.



abnormaal CTG. Er werden geen schadelijke effecten aangetoond van

maternale hyperoxygenatie.

6. Maternaal Hb ten tijde van de baring lijkt niet van invloed te zijn op de kans

op het ontstaan van foetale nood. Het is onduidelijk of het meer risico geeft

op lage Apgar-score of NICU-opname. Wel lijkt het risico op een niet-

geplande keizersnede verhoogd.




neonaat.


uitkomst niet gerelateerd aan het Hb van de moeder. Concluderend bleek het risico

op foetale nood en een ongunstige neonatale uitkomst niet gerelateerd aan het Hb

van de moeder. Wel lijkt er een hoger risico te bestaan op een niet-spontane

bevalling in geval van anemie.

Een algemene discussie van de onderwerpen die in de proefschrift aan bod zijn

gekomen wordt gevoerd in hoofdstuk 9, waarna aanbevelingen voor verder

onderzoek worden gedaan. Hoofdstuk 10 bevat deze Nederlandse en een Engelse

samenvatting van dit proefschrift.



resuscitatietechnieken op de foetale conditie, terwijl deze in de klinische praktijk

dagelijks worden toegepast.

2. Er zijn grote verschillen tussen de aanbevelingen van de internationale richtlijnen

over interventies bij foetale nood.



4. De uitkomsten van het nabootsen van het effect van maternale hyperoxygenatie

in een simulatiemodel suggereren dat deze interventie leidt tot verbetering van

de placentaire- en foetale oxygenatie, en leidt tot een verbetering van het

foetaal hartslagpatroon.



abnormaal CTG. Er werden geen schadelijke effecten aangetoond van maternale

hyperoxgenatie.

6. Maternaal Hb ten tijde van de baring lijkt niet van invloed te zijn op de kans op

het ontstaan van foetale nood. Het is onduidelijk of het meer risico geeft op lage

Apgar-score, NICU-opname of een keizersnede.

Chapter 10

220

Referenties 1. Van der Hout-van der Jagt MB, Jongen GJLM, Bovendeerd PHM, Oei SG. Insight into










List of abbreviations

ACOG American College of Obstetricians and Gynecologists

ACPRSA Phase-rectified signal averaging accelerative capacity

AGA Appropriate for gestational age

AJOG American Journal of Obstetrics and Gynecology

BMI Body Mass Index

BOLD MRI Blood oxygen level dependent magnetic resonance imaging

BPM Beats per minute

CI Confidence interval

CO2 Carbon dioxide

CRF Case report form

CS Cesarean section

CTG Cardiotocogram

DCPRSA Phase-rectified signal averaging decelerative capacity

DNPH 2,4-dinitrophenylhydrazine

e/MTIC Eindhoven MedTech Innovation Center

fECG Fetal ECG

FHR Fetal heart rate

FIGO International Federation of Gynecology and Obstetrics

FSBS Fetal scalp blood sampling

Hb Hemoglobin

HIE Hypoxic-ischemic encephalopathy

HPLC-MS/MS High-performance liquid chromatography–tandem mass spectrometry

IVS Instrumental vaginal delivery

MDA Malondialdehyde

MgSO4 Magnesiumsulphate

NICU Neonatal Intensive Care Unit

NVOG The Dutch Society of Obstetricians and Gynecologists (in Dutch:

Nederlandse Vereniging voor Obstetrie en Gynaecologie)

O2 Oxygen

pCO2 Partial carbon dioxide pressure

pHa pH in arterial blood gas

pO2 Partial oxygen pressure

PRSA Phase-rectified signal averaging

RCOG Royal College of Obstetricians and Gynaecologists


221












ACOG American College of Obstetricians and Gynecologists

ACPRSA Phase-rectified signal averaging accelerative capacity

AGA Appropriate for gestational age

AJOG American Journal of Obstetrics and Gynecology

BMI Body Mass Index

BOLD MRI Blood oxygen level dependent magnetic resonance imaging

BPM Beats per minute

CI Confidence interval

CO2 Carbon dioxide

CRF Case report form

CS Cesarean section

CTG Cardiotocogram

DCPRSA Phase-rectified signal averaging decelerative capacity

DNPH 2,4-dinitrophenylhydrazine

e/MTIC Eindhoven MedTech Innovation Center

fECG Fetal ECG

FHR Fetal heart rate

FIGO International Federation of Gynecology and Obstetrics

FSBS Fetal scalp blood sampling

Hb Hemoglobin

HIE Hypoxic-ischemic encephalopathy

HPLC-MS/MS High-performance liquid chromatography–tandem mass spectrometry

IVS Instrumental vaginal delivery

MDA Malondialdehyde

MgSO4 Magnesiumsulphate

NICU Neonatal Intensive Care Unit

NVOG The Dutch Society of Obstetricians and Gynecologists (in Dutch:

Nederlandse Vereniging voor Obstetrie en Gynaecologie)

O2 Oxygen

pCO2 Partial carbon dioxide pressure

pHa pH in arterial blood gas

pO2 Partial oxygen pressure

PRSA Phase-rectified signal averaging

RCOG Royal College of Obstetricians and Gynaecologists

Appendices

222

RCT Randomized controlled trial

RR Relative risk

SGA Small for gestational age

SID Stable isotope dilution

SPIRIT Standard Protocol Items: Recommendations for Interventional Trials

SpO2 Oxygen saturation

UCBG Umbilical cord blood gas

USA United States of America

WBP Personal Data Protection Act (in Dutch: Wet Bescherming

Persoonsgegevens)

WMO Medical Research Involving Human Subjects Act (in Dutch: Wet

Medisch-wetenschappelijk Onderzoek met Mensen)

List of publications

Journal papers

Moors S, Bullens LM, Van Runnard Heimel PJ, Van der Hout- van der Jagt MB, Oei

SG. Effect of intrauterine resuscitation by maternal hyperoxygenation during the

second stage of term labor; a randomized controlled trial. Submitted.

Bullens LM, Dietz V, Damoiseaux A. Osteomyelitis after sacrospinous ligament

fixation: a rare but severe complication. Submitted.

Smith JS, Bullens LM, Dieleman J, Van Runnard Heimel PJ, Van der Hout- van der

Jagt MB, Oei SG. Intrapartum maternal hemoglobin level, does it affect fetal and

neonatal outcome and mode of delivery? A systematic review of the literature.

Submitted.

Bullens LM, Smith JS, Truijens SE, Van Runnard Heimel PJ, Van der Hout- van der

Jagt MB, Oei SG. Maternal hemoglobin level and its relation to fetal distress, mode

of delivery, and short-term neonatal outcome - a retrospective cohort study.

Submitted.

Goossens SMTA, Speck BRGM, Bullens LM, Truijens SEM, Oei SG. Training and

practical issues of breech and twin deliveries in The Netherlands. Eur J Obstet

Gynecol Reprod Biol. 2018;224:205-7.

Bullens LM, Hulsenboom ADJ, Moors S, Joshi R, Van Runnard Heimel PJ, Van der

Hout- van der Jagt MB, Van den Heuvel E, Oei SG. Intrauterine resuscitation during

term labor by maternal hyperoxygenation: a randomised controlled trial (INTEREST

O2). Trials. 2018;19:195.

Bullens LM, Moors S, Van Runnard Heimel PJ, Van der Hout- van der Jagt MB, Oei

SG. Management of intrapartum fetal distress in The Netherlands: a clinical practice

survey. Eur J Obstet Gynecol Reprod Biol. 2016;205:48-53.

Bullens LM, van Runnard Heimel PJ, van der Hout-van der Jagt MB, Oei SG.

Interventions for intrauterine resuscitation in suspected fetal distress during term

labor: a systematic review. Obstet Gynecol Surv. 2015;70:524-39.


223

RCT Randomized controlled trial

RR Relative risk

SGA Small for gestational age

SID Stable isotope dilution

SPIRIT Standard Protocol Items: Recommendations for Interventional Trials

SpO2 Oxygen saturation

UCBG Umbilical cord blood gas

USA United States of America

WBP Personal Data Protection Act (in Dutch: Wet Bescherming

Persoonsgegevens)

WMO Medical Research Involving Human Subjects Act (in Dutch: Wet

Medisch-wetenschappelijk Onderzoek met Mensen)


Journal papers

Moors S, Bullens LM, Van Runnard Heimel PJ, Van der Hout- van der Jagt MB, Oei

SG. Effect of intrauterine resuscitation by maternal hyperoxygenation during the

second stage of term labor; a randomized controlled trial. Submitted.

Bullens LM, Dietz V, Damoiseaux A. Osteomyelitis after sacrospinous ligament

fixation: a rare but severe complication. Submitted.

Smith JS, Bullens LM, Dieleman J, Van Runnard Heimel PJ, Van der Hout- van der

Jagt MB, Oei SG. Intrapartum maternal hemoglobin level, does it affect fetal and

neonatal outcome and mode of delivery? A systematic review of the literature.

Submitted.



of delivery, and short-term neonatal outcome - a retrospective cohort study.

Submitted.

Goossens SMTA, Speck BRGM, Bullens LM, Truijens SEM, Oei SG. Training and

practical issues of breech and twin deliveries in The Netherlands. Eur J Obstet

Gynecol Reprod Biol. 2018;224:205-7.

Bullens LM, Hulsenboom ADJ, Moors S, Joshi R, Van Runnard Heimel PJ, Van der

Hout- van der Jagt MB, Van den Heuvel E, Oei SG. Intrauterine resuscitation during

term labor by maternal hyperoxygenation: a randomised controlled trial (INTEREST

O2). Trials. 2018;19:195.


SG. Management of intrapartum fetal distress in The Netherlands: a clinical practice

survey. Eur J Obstet Gynecol Reprod Biol. 2016;205:48-53.

Bullens LM, van Runnard Heimel PJ, van der Hout-van der Jagt MB, Oei SG.

Interventions for intrauterine resuscitation in suspected fetal distress during term

labor: a systematic review. Obstet Gynecol Surv. 2015;70:524-39.

Appendices

224

Bullens LM, van der Hout- van der Jagt MB, van Runnard Heimel PJ, Oei SG. A

simulation model to study maternal hyperoxygenation during labour. Acta Obstet

Gynecol Scand. 2014;93:1268-75.

Bullens LM*, Arnts I*, Groeneveld J, Liem D. Comparison of complication rates

between umbilical and peripherally inserted central venous catheters in newborns.

J Obst Gynecol Neonat Nurs. 2014;43:205-15. *Both authors equally contributed to

this article.

Thijssen DH, Bullens LM, van Bemmel MM, Dawson EA, Hopkins N, Tinken TM,

Black MA, Hopman, MT, Cable NT, Green DJ. Does arterial shear explain the

magnitude of flow-mediated dilation?: a comparison between young and older

humans. Am J Physiol Heart Circ Physiol. 2009;296:H57-64.

Thijssen DH, van Bemmel MM, Bullens LM, Dawson EA, Hopkins ND, Tinken TM,

Black MA, Hopman MT, Cable NT, Green DJ. The impact of baseline diameter on

flow-mediated dilation differs in young and older humans. Am J Physiol Heart Circ

Physiol. 2008;295:H1594-8.

Conference presentations

Bullens LM. Oxygen of oxy-geen? 49th Gynaecongres, 19-20 May 2016, Eindhoven,

The Netherlands.

Bullens LM, Van der Hout- van der Jagt MB, Jongen GJ, Van Runnard Heimel PJ,

Oei SG. Sensitivity analysis for validation of a model to simulate fetal heart rate

during labor. 41st annual meeting of the Fetal and Neonatal Physiological Society

(FNPS), 31 Aug - 3 Sept 2014, St. Vincent, Italy.

Bullens LM, Van der Hout- van der Jagt MB, Van Runnard Heimel PJ, Oei SG. A

mathematical model to evaluate the effect of maternal hyperoxygenation during

labor. 19th Annual meeting of the Society in Europe for Simulation Applied to

Medicine (SESAM), 12-15 June 2013, Paris, France, and Beneken Conference, 25-26

April 2013, Eindhoven, The Netherlands.

Bullens LM, Van der Hout- van der Jagt MB, Van Runnard Heimel PJ, Oei SG. Push it

to the limit: a simulation model used to evaluate a clinical intervention during labor.

19th Annual meeting of the Society in Europe for Simulation Applied to Medicine

(SESAM), 12-15 June 2013, Paris, France, and Beneken Conference, 25-26 April

2013, Eindhoven, The Netherlands.

Bullens LM, Van Runnard Heimel PJ, Oei SG, Andriessen P. Extreem prematuren:

kansrijk maar kwetsbaar. ObNeo congress, March 2012, Veldhoven, The

Netherlands.

Bullens LM, Artns IJJ, Groenewoud JHH, Liem KD. Geeft een centraal veneuze

umbilicalis lijn meer complicaties in vergelijking met andere centraal veneuze lijnen

bij neonaten? Nederlandse Vereniging voor Kindergeneeskunde (NVK), November

2008, Veldhoven, The Netherlands.

Conference posters



of delivery, and short-term neonatal outcome: a retrospective cohort study. Birth

Congress, 14-17 Nov 2018, Venice, Italy.


SG. Practice variation in the management of intrapartum fetal distress in The

Netherlands and the Western world. Practical Obstetric Multi-Professional Training

(PROMPT) symposium, 2-3 March 2017, Bath, UK.

Bullens LM, Van der Hout- van der Jagt MB, Van Runnard Heimel PJ, Oei SG.

Intrauterine resuscitation by hyperoxygenation evaluated in a simulation model.

International Meeting on Simulation in Healthcare (IMSH), 26-30 Jan 2013, Orlando,

USA.

Bullens LM, Artns IJJ, Groenewoud JHH, Liem KD. Central venous catheters in

neonates: a benefit or not? 50th Annual Meeting of the European Society for

Paediatric Research (ESPR), 8-12 Oct 2009, Hamburg, Germany.


225

Bullens LM, van der Hout- van der Jagt MB, van Runnard Heimel PJ, Oei SG. A

simulation model to study maternal hyperoxygenation during labour. Acta Obstet

Gynecol Scand. 2014;93:1268-75.

Bullens LM*, Arnts I*, Groeneveld J, Liem D. Comparison of complication rates

between umbilical and peripherally inserted central venous catheters in newborns.

J Obst Gynecol Neonat Nurs. 2014;43:205-15. *Both authors equally contributed to

this article.

Thijssen DH, Bullens LM, van Bemmel MM, Dawson EA, Hopkins N, Tinken TM,

Black MA, Hopman, MT, Cable NT, Green DJ. Does arterial shear explain the

magnitude of flow-mediated dilation?: a comparison between young and older

humans. Am J Physiol Heart Circ Physiol. 2009;296:H57-64.

Thijssen DH, van Bemmel MM, Bullens LM, Dawson EA, Hopkins ND, Tinken TM,

Black MA, Hopman MT, Cable NT, Green DJ. The impact of baseline diameter on

flow-mediated dilation differs in young and older humans. Am J Physiol Heart Circ

Physiol. 2008;295:H1594-8.

Conference presentations

Bullens LM. Oxygen of oxy-geen? 49th Gynaecongres, 19-20 May 2016, Eindhoven,

The Netherlands.

Bullens LM, Van der Hout- van der Jagt MB, Jongen GJ, Van Runnard Heimel PJ,

Oei SG. Sensitivity analysis for validation of a model to simulate fetal heart rate

during labor. 41st annual meeting of the Fetal and Neonatal Physiological Society

(FNPS), 31 Aug - 3 Sept 2014, St. Vincent, Italy.

Bullens LM, Van der Hout- van der Jagt MB, Van Runnard Heimel PJ, Oei SG. A

mathematical model to evaluate the effect of maternal hyperoxygenation during

labor. 19th Annual meeting of the Society in Europe for Simulation Applied to

Medicine (SESAM), 12-15 June 2013, Paris, France, and Beneken Conference, 25-26

April 2013, Eindhoven, The Netherlands.

Bullens LM, Van der Hout- van der Jagt MB, Van Runnard Heimel PJ, Oei SG. Push it

to the limit: a simulation model used to evaluate a clinical intervention during labor.

19th Annual meeting of the Society in Europe for Simulation Applied to Medicine

(SESAM), 12-15 June 2013, Paris, France, and Beneken Conference, 25-26 April

2013, Eindhoven, The Netherlands.

Bullens LM, Van Runnard Heimel PJ, Oei SG, Andriessen P. Extreem prematuren:

kansrijk maar kwetsbaar. ObNeo congress, March 2012, Veldhoven, The

Netherlands.

Bullens LM, Artns IJJ, Groenewoud JHH, Liem KD. Geeft een centraal veneuze

umbilicalis lijn meer complicaties in vergelijking met andere centraal veneuze lijnen

bij neonaten? Nederlandse Vereniging voor Kindergeneeskunde (NVK), November

2008, Veldhoven, The Netherlands.

Conference posters



of delivery, and short-term neonatal outcome: a retrospective cohort study. Birth

Congress, 14-17 Nov 2018, Venice, Italy.


SG. Practice variation in the management of intrapartum fetal distress in The

Netherlands and the Western world. Practical Obstetric Multi-Professional Training

(PROMPT) symposium, 2-3 March 2017, Bath, UK.

Bullens LM, Van der Hout- van der Jagt MB, Van Runnard Heimel PJ, Oei SG.

Intrauterine resuscitation by hyperoxygenation evaluated in a simulation model.

International Meeting on Simulation in Healthcare (IMSH), 26-30 Jan 2013, Orlando,

USA.

Bullens LM, Artns IJJ, Groenewoud JHH, Liem KD. Central venous catheters in

neonates: a benefit or not? 50th Annual Meeting of the European Society for

Paediatric Research (ESPR), 8-12 Oct 2009, Hamburg, Germany.

Dankwoord Basta! Graag wil ik iedereen bedanken die mij geholpen heeft bij het schrijven van dit proefschrift. Prof. dr. Oei, beste Guid, mijn promotor. Je gaf me de kans om binnen jouw FUN-groep, in samenwerking met de TU/e, mijn eigen onderzoek op te zetten. Het was even zoeken naar een mooi project dat paste bij mijn klinische werk, maar het is gelukt! Ik ben je heel dankbaar voor je vertrouwen, positiviteit en zelfs ik ben jaloers op jouw onuitputtelijke voorraad energie! Hoe jij alles voor elkaar krijgt moet wel berusten op illusionisme! Dr. Ir. van der Hout-van der Jagt, beste Beatrijs, veel dank voor je hulp en af en toe het steuntje in de rug dat nodig was om vol goede moed door te gaan. Jij bent de perfecte brug tussen de (voor mij soms onbegrijpelijke) technische en medische kant van het onderzoek, en iemand op wie ik altijd kon rekenen. Beste Dr. van Runnard Heimel, beste Pieter, dank voor jouw verhelderende input, vaak gepaard gaande met jouw levensmotto ‘Perinatologie is het mooiste wat er is’ (ja dè is!). Daarnaast leverde jij vaak een kritische noot vanuit medisch oogpunt, wat de stukken telkens weer beter maakte! Prof. Dr. Bongers, lieve Marlies. Zo groen als gras kwam ik in MMC te werken als ANIOS. Jij geloofde dat ik het in me had om gynaecoloog te worden, waardoor ik de kans en het zelfvertrouwen kreeg om me binnen MMC te ontwikkelen. Jij bent voor mij een groot voorbeeld en inspiratiebron, een echte power woman. Ik ben heel trots en dankbaar dat ik samen met je mag werken en nog veel van jouw adviezen kan leren. Dank aan iedereen die heeft meegeholpen aan de studies beschreven in dit proefschrift, waaronder alle mede-auteurs, semi-artsen, medewerkers van het laboratorium, de bibliotheek, de TU/e, het wetenschapsbureau, het secretariaat, de polikliniek en de verloskamers. Enorm bedankt voor jullie inzet! Alle gynaecologen met wie ik de afgelopen jaren met heel veel plezier heb mogen samenwerken: veel dank voor jullie actieve interesse en jullie voorbeeldfunctie. Met name de opleiders bedankt voor de ruimte die ik kreeg voor het uitvoeren van mijn onderzoek. Lieve arts-assistenten, mijn maatjes, heel veel dank voor jullie gezelligheid, collegialiteit en vriendschap! Julie zijn geweldig!

Dankwoord

227

Dankwoord Basta! Graag wil ik iedereen bedanken die mij geholpen heeft bij het schrijven van dit proefschrift. Prof. dr. Oei, beste Guid, mijn promotor. Je gaf me de kans om binnen jouw FUN-groep, in samenwerking met de TU/e, mijn eigen onderzoek op te zetten. Het was even zoeken naar een mooi project dat paste bij mijn klinische werk, maar het is gelukt! Ik ben je heel dankbaar voor je vertrouwen, positiviteit en zelfs ik ben jaloers op jouw onuitputtelijke voorraad energie! Hoe jij alles voor elkaar krijgt moet wel berusten op illusionisme! Dr. Ir. van der Hout-van der Jagt, beste Beatrijs, veel dank voor je hulp en af en toe het steuntje in de rug dat nodig was om vol goede moed door te gaan. Jij bent de perfecte brug tussen de (voor mij soms onbegrijpelijke) technische en medische kant van het onderzoek, en iemand op wie ik altijd kon rekenen. Beste Dr. van Runnard Heimel, beste Pieter, dank voor jouw verhelderende input, vaak gepaard gaande met jouw levensmotto ‘Perinatologie is het mooiste wat er is’ (ja dè is!). Daarnaast leverde jij vaak een kritische noot vanuit medisch oogpunt, wat de stukken telkens weer beter maakte! Prof. Dr. Bongers, lieve Marlies. Zo groen als gras kwam ik in MMC te werken als ANIOS. Jij geloofde dat ik het in me had om gynaecoloog te worden, waardoor ik de kans en het zelfvertrouwen kreeg om me binnen MMC te ontwikkelen. Jij bent voor mij een groot voorbeeld en inspiratiebron, een echte power woman. Ik ben heel trots en dankbaar dat ik samen met je mag werken en nog veel van jouw adviezen kan leren. Dank aan iedereen die heeft meegeholpen aan de studies beschreven in dit proefschrift, waaronder alle mede-auteurs, semi-artsen, medewerkers van het laboratorium, de bibliotheek, de TU/e, het wetenschapsbureau, het secretariaat, de polikliniek en de verloskamers. Enorm bedankt voor jullie inzet! Alle gynaecologen met wie ik de afgelopen jaren met heel veel plezier heb mogen samenwerken: veel dank voor jullie actieve interesse en jullie voorbeeldfunctie. Met name de opleiders bedankt voor de ruimte die ik kreeg voor het uitvoeren van mijn onderzoek. Lieve arts-assistenten, mijn maatjes, heel veel dank voor jullie gezelligheid, collegialiteit en vriendschap! Julie zijn geweldig!

Appendices

228

Ook veel dank aan FUN-onderzoekgroep: een inspirerende en enthousiaste groep mensen. Het hardlopen rond de Eiffeltoren, speurtocht in Italië, escape room in Guids tuinhuisje en de zwembad/pannenkoekenparty in Orlando geven blijk van een hoge FUN-factor! Dank aan de leden van de promotiecommissie voor het kritisch beoordelen van dit proefschrift. Cara famiglia Masala, grazie a voi l’ anno in Sardegna è stato indimenticabile! Ormai sono passati più di 15 anni, e nel frattempo siete sempre stati vicini. Vi voglio un mondo di bene! Lieve familie en vrienden, heel erg bedankt voor jullie interesse in mijn onderzoek, maar vooral voor gezelligheid en nodige ontspanning tussendoor! Jullie zijn onmisbaar! Mijn paranimfen, Eva en Eva, hoe toepasselijk voor een proefschrift rondom nieuw leven! Lieve Eva, mijn vriendinnetje, drie jaar geleden mocht ik tijdens jouw promotie aan je zijde staan, nu mag jij eindelijk deze plaats naast mij innemen. Wat heerlijk dat je met Dennis eindelijk een eigen plek heb gevonden in Tilburg, als ook jullie derde telg ter wereld is gekomen is het weer tijd om wijntjes te drinken in de tuin! Lieve Eva, mijn zusje, vriendin en nu ook paranimf, met jou is het altijd een feestje! Onze levens zijn ‘a world apart’, maar eigenlijk lijken we toch erg veel op elkaar. Ik ben heel trots op jou en bewonder je enorm door je creativiteit, eigenzinnigheid en doorzettingsvermogen. Jij zet me weer met 2 benen op de grond. Heel knap dat jij deze ceremonie hebt weten te doorstaan! Martijn, wat fijn dat je al zo lang part of the family bent. Ik waardeer je enorm om je nuchterheid, gastvrijheid, uitgebreide bierkennis, en dat je zo goed op mijn zusje past! Beste familie Lauret, mijn schoonfamilie, Marijke, Heinz-Peter, Yola en Robbert. Bedankt voor jullie interesse in ons, en dat jullie altijd voor ons en ons kleine meisje klaar staan. Lieve pap en mam, bedankt voor jullie onvoorwaardelijke steun en nuchterheid, een ‘doe maar normaal, dan doe je al gek genoeg’ mentaliteit. Jullie hebben me zoveel kansen gegeven in mijn leven, wat heeft gemaakt dat ik me kon ontwikkelen tot wie ik ben. Ik ben jullie erg dankbaar!

Liefste Gert-Jan, mijn ‘Gertje’. Jij hebt dit klusje 3 jaar geleden geklaard, daar ben ik heel erg trots op! Je werkt hard om je doelen te bereiken, terwijl je mij opdraagt om op zijn tijd wat rustiger aan te doen en meer aan mezelf te denken. We zijn een goed team, en weten ondanks ons drukke leven ook te genieten van het leven en ons kleine meisje Mare. Nu deze bevalling achter de rug is kunnen we ons voorbereiden op de volgende, waarna we nog een mooie dochter rijker zijn. Wat hebben we het goed samen! Ik hou heel veel van jou!

Dankwoord

229

Ook veel dank aan FUN-onderzoekgroep: een inspirerende en enthousiaste groep mensen. Het hardlopen rond de Eiffeltoren, speurtocht in Italië, escape room in Guids tuinhuisje en de zwembad/pannenkoekenparty in Orlando geven blijk van een hoge FUN-factor! Dank aan de leden van de promotiecommissie voor het kritisch beoordelen van dit proefschrift. Cara famiglia Masala, grazie a voi l’ anno in Sardegna è stato indimenticabile! Ormai sono passati più di 15 anni, e nel frattempo siete sempre stati vicini. Vi voglio un mondo di bene! Lieve familie en vrienden, heel erg bedankt voor jullie interesse in mijn onderzoek, maar vooral voor gezelligheid en nodige ontspanning tussendoor! Jullie zijn onmisbaar! Mijn paranimfen, Eva en Eva, hoe toepasselijk voor een proefschrift rondom nieuw leven! Lieve Eva, mijn vriendinnetje, drie jaar geleden mocht ik tijdens jouw promotie aan je zijde staan, nu mag jij eindelijk deze plaats naast mij innemen. Wat heerlijk dat je met Dennis eindelijk een eigen plek heb gevonden in Tilburg, als ook jullie derde telg ter wereld is gekomen is het weer tijd om wijntjes te drinken in de tuin! Lieve Eva, mijn zusje, vriendin en nu ook paranimf, met jou is het altijd een feestje! Onze levens zijn ‘a world apart’, maar eigenlijk lijken we toch erg veel op elkaar. Ik ben heel trots op jou en bewonder je enorm door je creativiteit, eigenzinnigheid en doorzettingsvermogen. Jij zet me weer met 2 benen op de grond. Heel knap dat jij deze ceremonie hebt weten te doorstaan! Martijn, wat fijn dat je al zo lang part of the family bent. Ik waardeer je enorm om je nuchterheid, gastvrijheid, uitgebreide bierkennis, en dat je zo goed op mijn zusje past! Beste familie Lauret, mijn schoonfamilie, Marijke, Heinz-Peter, Yola en Robbert. Bedankt voor jullie interesse in ons, en dat jullie altijd voor ons en ons kleine meisje klaar staan. Lieve pap en mam, bedankt voor jullie onvoorwaardelijke steun en nuchterheid, een ‘doe maar normaal, dan doe je al gek genoeg’ mentaliteit. Jullie hebben me zoveel kansen gegeven in mijn leven, wat heeft gemaakt dat ik me kon ontwikkelen tot wie ik ben. Ik ben jullie erg dankbaar!

Liefste Gert-Jan, mijn ‘Gertje’. Jij hebt dit klusje 3 jaar geleden geklaard, daar ben ik heel erg trots op! Je werkt hard om je doelen te bereiken, terwijl je mij opdraagt om op zijn tijd wat rustiger aan te doen en meer aan mezelf te denken. We zijn een goed team, en weten ondanks ons drukke leven ook te genieten van het leven en ons kleine meisje Mare. Nu deze bevalling achter de rug is kunnen we ons voorbereiden op de volgende, waarna we nog een mooie dochter rijker zijn. Wat hebben we het goed samen! Ik hou heel veel van jou!

Appendices

230

Curriculum Vitae

Lauren Bullens werd op 16 augustus 1985

geboren in het St. Joseph ziekenhuis in

Eindhoven (thans Máxima Medisch Centrum). In

2004 behaalde zij haar VWO-diploma aan het

Pius X College in Bladel. Het schooljaar 2001-

2002 studeerde zij aan het Liceo Classico Siotto

Pintor in Cagliari (Sardinië, Italië). Na het

afronden van de middelbare school startte zij de

opleiding Geneeskunde aan de Radboud

Universiteit in Nijmegen. Zij deed een

seniorcoschap Obstetrie en Gynaecologie aan

het Horacio E. Oduber Hospitaal op Aruba, en deed haar eerst onderzoekservaring

op aan de John Moores University in Liverpool (UK). In december 2010 begon zij als

arts-assistent Obstetrie en Gynaecologie in Máxima Medisch Centrum, waar zij kort

hierna startte met het onderzoek naar foetale oxygenatie binnen de

onderzoeksgroep Fundamentele Perinatologie onder leiding van Prof. Dr. Guid Oei.

In 2013 startte zij de opleiding tot gynaecoloog in Máxima Medisch Centrum (Prof.

Dr. Bongers en Dr. Maas). In 2014-2015 doorliep zij het academische deel van de

opleiding in het Maastricht Universitair Medisch Centrum (Prof. Dr. Kruitwagen en

Dr. Dunselman). Na het voltooien van het 4e opleidingsjaar in Máxima Medisch

Centrum startte zij in juni 2017 in het Catharina Ziekenhuis met de differentiatie

Urogynaecologie, en in november 2018 met de differentiatie Minimaal Invasieve

Chirurgie in Máxima Medisch Centrum. Lauren woont samen met Gert-Jan Lauret en

hun dochter Mare in Eindhoven, in maart 2019 verwachten zij hun tweede kindje.

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Lauren Bullens Lauren Bullens

Management of fetal distress

during term labor

UITNODIGING

Voor het bijwonen van de openbare verdediging vanhet proefschrift

MANAGEMENT OF FETAL

DISTRESS DURING TERM

LABOR

doorLauren Bullens

Op vrijdag 21december om 16.00 uur

In de Senaatszaal van het Auditorium van de Technische Universiteit te Eindhoven

(zie www.tue.nl voor een routebeschrijving en plattegrond)

Aansluitend aan de verdediging bent u van harte uitgenoding voor de receptie ter plaatse

Lauren [email protected]

Paranimfen

Eva BullensEva van de [email protected]

management of fetal distress during term labor · management of fetal distress during term labor...

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