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Counseling women with hypertensive disorders of pregnancy

van Oostwaard, M.F.

Publication date2015Document VersionFinal published version

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Citation for published version (APA):van Oostwaard, M. F. (2015). Counseling women with hypertensive disorders of pregnancy.

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Counseling Womenwith

Hypertensive Disordersof

Pregnancy

Miriam van Oostwaard

Counseling Wom

en with H

ypertensive Disorders of Pregnancy M

iriam van Oostw

aard

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Pregnancy

Miriam Francisca van Oostwaard

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© 2015 Copyright

ISBN: 978-90-6464-944-8

Lay-out and cover by Ferdinand van Nispen tot Pannerden, Citroenvlinder DTP&Vormgeving, my-thesis.nl, Bilthoven

Printed by GVO drukkers & vormgevers B.V., Ede

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Pregnancy

ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad van doctoraan de Universiteit van Amsterdamop gezag van de Rector Magnificus

prof. dr. D.C. van den Boomten overstaan van een door het College voor Promoties ingestelde commissie,

in het openbaar te verdedigen in de Agnietenkapelop woensdag 16 december 2015, te 10:00 uur

door

Miriam Francisca van Oostwaardgeboren te De Bilt

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Promotiecommissie

Promotores: Prof. dr. B.W.J. Mol Universiteit van Amsterdam Prof. dr. E.A.P. Steegers Erasmus Universiteit Rotterdam

Co-promotores: Dr. W. Ganzevoort Universiteit van Amsterdam Dr. D.N.M. Papatsonis Amphia Ziekenhuis

Overige leden: Prof. dr. J.A.M. van der Post Universiteit van Amsterdam Prof. dr. J.I.P. de Vries Vrije Universiteit Amsterdam Prof. dr. S. Middeldorp Universiteit van Amsterdam Prof. dr. M.E.A. Spaanderman Universiteit Maastricht Dr. B.J.H. van den Born Universiteit van Amsterdam Dr. W. Visser Erasmus MC Rotterdam

Faculteit der Geneeskunde

Financial support by the Dutch Heart Foundation for the publication of this thesis is gratefully acknowledged.

Publication of this thesis was also financially supported by:Stichting HELLP Syndroom, Chipsoft and ABN AMRO

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Contents

Introduction, aims and outline of the Thesis 8

Part I Management of extreme early onset hypertensive disorders of pregnancy

15

Chapter 1 Comparison of immediate delivery versus expectant management in women with severe early onset preeclampsia before 26 weeks of gestation, a retrospective cohort study

17

Chapter 2 Terminating pregnancy for severe hypertension when neonatal prognosis is extremely bad: a retrospective cohort study

39

Part II Recurrence and recurrence prediction of hypertensive disorders in subsequent pregnancies

55

Chapter 3 Prediction of recurrence of hypertensive disorders of pregnancy between 34 and 37 weeks of gestation: a retrospective cohort study

57

Chapter 4 Prediction of recurrence of hypertensive disorders of pregnancy in the term period, a retrospective cohort study

75

Chapter 5 Recurrence of hypertensive disorders of pregnancy, an Individual Patient Data Meta-Analysis

95

Chapter 6 External validation of prognostic models for recurrence of hypertensive disorders of pregnancy in a pooled dataset of observational cohorts

123

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Part III Long term health risks 145

Chapter 7 Cerebrovascular, cardiovascular and renal hypertensive disease after hypertensive disorders of pregnancy

147

General discussion 165

Summary 183

Samenvatting 189

Addendum 197

List of co-authors and their affiliations 198

List of references in alphabetical order 204

Bibliography 211

PhD Portfolio 213

Dankwoord 215

Curriculum Vitae 216

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8

Introduction, aims and outline of the Thesis

IntroductionHypertensive disorders of pregnancy (HDP) are a common health problem and occur in approximately 2 to 8 per cent of all pregnancies.1-3 They are the second most common cause of maternal death worldwide. They comprise gestational hypertension (GH), preeclampsia (PE), superimposed PE and HELLP (Hemolysis, Elevated Liver enzymes and Low Platelets) syndrome, and in a varying percentage of cases they are related to intrauterine growth restriction.

The exact etiology remains unknown and there is important heterogeneity in clinical phenotypes and probably essential heterogeneity in related pathophysiology. There appears to be significant overlap but also some differences in underlying risk factors and processes between early-onset and late-onset preeclampsia (before and after 34 weeks). Whereas maternal endothelial dysfunction has been indicated as a central phenomenon, associated poor early placentation and maternal vascular dysfunction seems to be more involved in early preeclampsia (‘placental PE’), whereas the metabolic syndrome (a group of cardiovascular risk factors as: obesity, elevated blood pressure, elevated fasting plasma glucose and hypercholesterolemia) seems to be more associated with late preeclampsia (‘maternal PE’).3,4

We have little information on management options for HDP in the extreme premature period. HDP also have a risk for recurrence in subsequent pregnancies. Unfortunately, consistent information on recurrence risks is lacking. Furthermore, HDP identify women at increased risk for cardiovascular disease later in life, probably due to shared risk factors and pathophysiology.1,3 Nevertheless, the pathophysiological background of these associations and the phenotypes of the cardiovascular disorders involved remain largely unclear.

In clinical practice is it of utmost importance to be able to counsel women and their partners on these matters. Besides the medical sequelae, HDP can have a major psychological impact on women and their families.5 Therefore there is great need for new information on management options during pregnancy, recurrence rates and long term health risks.

Management of extreme early onset hypertensive disorders of pregnancy The options for management of hypertensive disorders of pregnancy remain limited and involve symptomatic treatment and termination of pregnancy. Conflicting interests between mother and fetus raise a dilemma in clinical decision making, especially in

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9

extreme early onset of the disease (before 24 weeks gestational age). Prolongation of pregnancy may improve fetal prognosis on the one hand, but increases maternal risks of severe morbidity and mortality on the other hand.9 It is largely unknown what management options are currently being offered to our patients in the Netherlands and what related risks are present for the mother and child.

Recurrence and recurrence prediction of hypertensive disorders in subsequent pregnancies Recurrence of hypertensive disorders of pregnancy has been the focus of investigation in other studies as well. Many cohorts have been established, each with a specific case mix of different clinical phenotypes and each with different study methodologies, containing many potential sources of bias. This hampers interpretation of these studies. Reported recurrence rates range from a few percent, up to 65%.6 Similarly, heterogeneous pathophysiology and study methodology causes the performance of individualized risk prediction models to be disappointing.7

New to prognostic research is Individual Participant Data (IPD) meta-analysis.8 In contrast to conventional meta-analysis it uses the IPD of the original studies. Next to enlarging the study population and increasing statistical power to detect subtle relationships, it permits data synthesis at an individual level, creating flexibility in choosing outcome and subgroups. Additionally, it allows redefinition of outcomes or predictors based on continuous variables and use of information that did not reach publication in the original research. These qualities make IPD meta-analysis the ideal instrument to address the inconsistent reporting of recurrence rates of HDP in literature.

Long term Health risksRecently it has become apparent that there is a strong association between HDP and long-term maternal morbidity.3 As such, a pregnancy complicated by a HDP can be regarded as a window of opportunity to assess future expected health. Long term morbidity include coronary heart disease, stroke and kidney failure.3 These associations are likely an expression of shared underlying pathophysiology, such as the classic cardiovascular risk factors. But it may also be that HDP themselves cause persistent subclinical vascular damage after pregnancy, independently leading to later vascular disease.10,11

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10

Aims of the thesis

The aims of this thesis were to address several counseling issues: to describe management options in extreme early onset HDP in current clinical practice in the Netherlands, to predict recurrence of hypertensive disorders of pregnancy and to study to long term maternal health consequences after a pregnancy complicated by HDP.

The issues are addressed in the following questions:1. What are differences in maternal and neonatal outcome after immediate

delivery or expectant management for preeclampsia in extreme early onset of the disease?

2. What is the incidence of termination of pregnancy in the Netherlands for hypertensive disorders of pregnancy and which characteristics contributed to the decision to terminate after counseling?

3. What is the recurrence risk of a hypertensive disorder of pregnancy, after a hypertensive disorder of pregnancy and a delivery in the near term period?

4. What is the recurrence risk of a hypertensive disorder of pregnancy, after a hypertensive disorder of pregnancy and a delivery in the term period?

5. What is the overall recurrence risk for hypertensive disorders of pregnancy? 6. What is the performance of individual prognostic models for the recurrence of

hypertensive disorders of pregnancy?7. Are hypertensive disorders of pregnancy directly related to cardiovascular

disease, stroke or hypertensive kidney disease?

Outline of the thesis

Part I Management of extreme early onset hypertensive disorders of pregnancyIn Part I – Management of extreme early onset hypertensive disorders of pregnancy – two cohort studies are described that focus on the dilemma of management of HDP at an extreme premature gestational age.

Chapter 1 answers the first question. In a nationwide cohort study we investigate the maternal and neonatal outcomes of management of hypertensive disorders of pregnancy at extreme early onset in pregnancy in the Netherlands. It addresses the dilemma between maternal and neonatal interests in management options. Also,

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11

trends in management and outcome over the years and recurrence of preeclampsia in a subsequent pregnancy are investigated.

Chapter 2 answers the second question. In a nationwide cohort study we investigate the frequency of termination of pregnancy for hypertensive disorders prior to fetal viability in the Netherlands and the clinical characteristics involved in the decision to terminate the pregnancy.

Part II Recurrence and recurrence prediction of hypertensive disorders in subsequent pregnanciesIn Part II – Recurrence and recurrence prediction of hypertensive disorders in subsequent pregnancies- two cohort studies performed in the Netherlands are described, that focus on recurrence and prediction of HDP in the near-term or term gestational age period. Furthermore, an IPD project is described, based on a pooled database using original data from previous research from all over the world. It focuses again on recurrence and prediction of HDP, but this time at a much larger scale.

Chapter 3 answers the third question. In a multicenter cohort study, performed in the Netherlands, we investigated the recurrence and prediction of recurrence of hypertensive disorders of pregnancy after a history of a delivery between 34 and 37 weeks of gestation, due to a HDP. We also created a prediction model for recurrence using demographic and pregnancy characteristics.

Chapter 4 answers the fourth question. In a multicenter cohort study, performed in the Netherlands, we investigated the recurrence and prediction of recurrence of hypertensive disorders of pregnancy after a history of a delivery after 37 weeks of gestation, complicated with a HDP. We also created a prediction model for recurrence using demographic and pregnancy characteristics.

Chapter 5 answers the fifth question. In an Individual Patient Data Meta-analysis (IPD PREPARe), using data of 22 studies and 99.415 women, we studied the recurrence of hypertensive disorders of pregnancy. We also investigated recurrence for different gestational age groups and different hypertensive syndromes.

Chapter 6 answers the sixth question. In an Individual Patient Database (IPD PREPARe), was used to validate 4 existing prognostic models for recurrence of hypertensive disorders of pregnancy.

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12

Part III Long-term health risks In Part III – Long-term health risks – a cohort study is described that concentrates on long term health consequences after experiencing HDP.

Chapter 7 answers the seventh question. In a cohort study we investigate the occurrence of previous hypertensive disorders of pregnancy in women who subsequently experienced a stroke, coronary disease or renal failure at relative young age. It explores possible common risk factors but also investigates HDP as an independent risk factor for later vascular disease.

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13

References1 Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005;365:785-799.2 Hauth JC, Ewell MG, Levine RL, Esterlitz JR, Sibai BM, Curet LB. Pregnancy outcomes in healthy nulliparous

women who subsequently developed hypertension. Obstet Gynecol 2000; 95:24–28.3 Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet 2010;376:631-44.4 Roberts JM, Hubel CA. The two stage model of preeclampsia: variations on the theme. Placenta 2009; 30

(suppl A): 32–37.5 Rep A, Ganzevoort W, Bonsel GJ, Wolf H, de Vries JI. Psychosocial impact of early-onset hypertensive disorders

and related complications in pregnancy. Am J Obstet Gynecol 2007;197(2):158e1-6.6 Sibai BM, Mercer B, Sarinoglu C. Severe preeclampsia in the second trimester: recurrence risk and long-term

prognosis. Am J Obstet Gynecol 1991;165:1408–12.7 Sep S, Smits L, Prins M, Peeters L. Prediction tests for recurrent hypertensive disease in pregnancy, a systematic

review. Hypertens Pregnancy 2010;29(2):206-30. 8 Broeze KA, Opmeer BC, Bachmann LM, Broekmans FJ, Bossuyt PM, Coppus SF. Individual patient data meta-

analysis of diagnostic and prognostic studies in obstetrics, gynaecology and reproductive medicine. BMC Med Res Methodol 2009;27:9-22.

9 Sibai BM, Akl S, Fairlie F, Moretti M. A protocol for managing severe preeclampsia in the second trimester. Am J Obstet Gynecol 1990 Sep;163(3):733-8.

10 Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ 2007; 335:974.

11 Berks D, Steegers EA, Molas M, Visser W. Resolution of hypertension and proteinuria after preeclampsia. Obstet Gynecol 2009;114(6):1307-14.

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Part I

Management of extreme early onset hypertensive disorders of pregnancy

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Chapter 1

Comparison of immediate delivery versus

expectant management in women with severe

early onset preeclampsia before 26 weeks of

gestation, a retrospective cohort study

M.F. van OostwaardL. van EerdenM.W. de Laat

J.J. DuvekotJ.J.H.M. Erwich

K.W.M. BloemenkampA. Bolte

J. Bosma, S.V. Koenen

B. RethansP. van Runnard Heimel

H.C.J. ScheepersR. Kornelisse

W. GanzevoortB.W.J. Mol

C.J. de GrootI. Gaugler-Senden

Submitted

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Chapter 1

18

Abstract

Objective: To compare maternal and neonatal outcomes of immediate delivery or expectant management in women with severe, early onset preeclampsia before 26 weeks’ gestation.

Design: Nationwide retrospective cohort study.

Setting: All Dutch tertiary perinatal care centres.

Population: All women, diagnosed with severe preeclampsia, who delivered between 22 and 26 weeks’ gestation in a tertiary perinatal care centre in the Netherlands in between 2008 and 2014.

Methods: Patients were identified through computerized hospital databases. We collected data using the medical records. We compared women who delivered immediately to women that were managed expectantly.

Main Outcome Measures: Maternal and neonatal outcomes.

Results: We studied 133 women, of whom 34 (26%) were delivered immediately and of whom 99 (74%) were managed expectantly. Time interval between admittance and delivery was 4 days shorter in immediate delivery (2 versus 6 days, 95%CI: 2.45 – 5.55). Active neonatal support was offered in 5 (14%) in immediately delivered children and in 45 (43%) after expectant care. Immediate delivery compared to expectant management was more often associated with perinatal mortality (94% versus 76%; OR: 5.4, 95%CI: 1.2 - 24), but no differences were found for maternal complications (69% versus 71%; OR: 1.5, 95%CI: 0.17 – 14). Before a gestational age of 24 weeks, prolongation had no effect on perinatal mortality (100 versus 89%, p-value: .192). Neonatal morbidity occurred in 84% of the 27 surviving neonates.

Conclusions: In women with severe, early onset preeclampsia, expectant management improves neonatal survival without compromising maternal condition between 24 and 26 weeks of gestation.

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Management of severe early onset preeclampsia

19

1Introduction

Preeclampsia (PE) is a common pregnancy disorder with still high maternal and neonatal mortality and morbidity. It affects 2-5% of pregnancies1, and occurs most commonly at term. At extreme premature gestational age, severe preeclampsia and HELLP syndrome (Haemolysis, Elevated Liver enzymes and Low Platelets) are rare. At present, delivery of the foetus is the only curative treatment of hypertensive pregnancy complications, but for women with early preeclampsia this inevitably leads to extreme prematurity, with high risk of neonatal mortality and morbidity. Conversely, expectant management of severe early onset PE may increase the risk of maternal morbidity.2 Prolongation of pregnancy (expectant management) may improve foetal prognosis on one hand, but increases maternal risks of severe morbidity and mortality on the other hand.3-7

These conflicting interests between mother and foetus raise a dilemma in clinical decision making. This discussion is even more pressing as foetuses in early preeclampsia are often also severely growth restricted, further limiting their chances for (healthy) survival, both intra-uterine and extra-uterine. In 2006, Gaugler et al.4 described high rates of major maternal complications (65%) and perinatal mortality (82%) after expectant management of pregnancies complicated by severe early onset PE. In line with these fi ndings, there is consensus that prolongation of pregnancy should not be offered as routine treatment option in women with severe preeclampsia with onset

Chapter 1

20

January 2008 and January 2014, and were diagnosed with severe preeclampsia. In each perinatal center we identified women from electronic databases and subsequently extracted data from their medical files. Women with a pregnancy complicated by foetal abnormalities or an intra uterine foetal death (IUFD) prior to the first choice of management were excluded. Ultrasound dating was standard practice for determination of gestational age. The acknowledged ethical advisory board of the Academic Medical Center, Amsterdam approved the study (W13_106 # 13.17.0123).

Severe preeclampsia was defined as hypertension (diastolic blood pressure ≥110 mmHg or systolic blood pressure ≥160 mmHg on two occasions) in combination with proteinuria (defined as a protein/creatinine ratio of ≥30 mg/mmol in a random sample or a urine protein excretion of ≥300 mg per 24 hrs) with oliguria, cerebral or visual disturbances, pulmonary oedema, epigastric or upper-quadrant pain, impaired liver function, thrombocytopenia, after 20 weeks of pregnancy.12 Chronic hypertension was defined as pre-existing hypertension or hypertension before 20 weeks of gestation. Superimposed preeclampsia includes de novo proteinuria, or a sudden increase in proteinuria if already present, in a woman with chronic hypertension.12 HELLP syndrome was defined by haemolysis (elevated lactate dehydrogenase (LDH) levels ≥ 600 U/L), elevated liver enzymes by levels of aspartate transaminase (ASAT) or alanine transferase (ALAT) ≥ 70 U/L and low platelets < 100,000/mm.13 Small for Gestational Age (SGA), was defined as birth weight below the 5th percentile.

We defined immediate delivery as induction of labour or caesarean section, targeting at a delivery as soon as possible after a diagnosis of severe preeclampsia between 22 and 26 weeks’ gestation. Expectant management was defined as the intention to postpone the delivery beyond 2 days after admittance. If active neonatal support was pursued, a course of 12 mg intramuscular betamethasone was given and repeated after 24 hours to accelerate foetal lung maturation.

Demographic data included: maternal age at delivery, parity, medical and obstetric history and cardiovascular risk factors like: smoking, body mass index (BMI) before pregnancy, chronic hypertension diagnosed before pregnancy and thrombophilia. We recorded pregnancy data (e.g. maximal blood pressures, proteinuria, maximal laboratory abnormalities, use of medication, concomitant HELLP syndrome or delivery of a SGA child, placental abruption and intra uterine foetal death (IUFD)). We documented management and alterations in management, which were the results of counselling of future parents by gynaecologists and neonatologists. Finally, maternal and perinatal outcome were registered, including gestational age at delivery, mode of delivery and time between first admission and delivery. Maternal complications were defined as:

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1HELLP syndrome, eclampsia, pulmonary oedema (clinical and radiographic diagnosis), cerebrovascular incidents, hepatic capsular rupture, placenta abruption, renal failure (with need for dialysis) and maternal death. Neonatal complications if admitted to a Neonatal Intensive Care Unit (NICU) were defi ned as: Intraventricular Haemorrhage (IVH) (defi ned as ≥ grade 3, according to Papile et al.14, retinopathy of Prematurity (ROP) (defi ned as ≥ grade 3 in accordance with the International Classifi cation for ROP)15, Necrotizing Enterocolitis (NEC) (defi ned as ≥ stage 2 in accordance with the staging by Bell et al.16, Bronchopulmonary Dysplasia (BPD) (defi ned according to the consensus BPD defi nition17: as the need for supplemental oxygen at 36 weeks postmenstrual age, and classifi ed as moderate if < 30% oxygen and as severe if ≥ 30% oxygen or continuous positive airway pressure (CPAP) was needed) and sepsis (defi ned as the presence of clinical symptoms and a positive blood culture). If information on a subsequent pregnancy was available, these data were also documented.

Statistical analysisStatistical analysis was performed using SPSS 20.0 (SPSS Inc., Chicago, IL, USA). Continuous variables were expressed as means with standard deviations (SD) or medians with interquartile ranges (IQR). We compared women undergoing expectant management and women having immediate delivery. Differences in baseline characteristics or outcomes between groups were tested with parametric (unpaired t-test) or non-parametric (Mann-Whitney-U test) tests as appropriate. Categorical variables were compared with Chi square tests. P values less than 0.05 were considered to indicate statistical signifi cance. Differences in maternal and perinatal outcome were assessed using multivariable logistic regression analysis. We corrected for the following confounders: parity, maternal age, medical history, gestational age at admittance, maximal blood pressures, maximal laboratory abnormalities and estimated foetal weight. Using the ‘enter method’ in the regression analysis, no selection or hierarchy of the confounders was made, since we are unaware which confounder would affect the outcome most. Outcomes are shown as odds ratios (OR) with 95% confi dence interval (95%CI).

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Chapter 1

22

Figure 1. Overview of management in the 133 pregnancies with severe, early onset preeclampsia.

Chapter 1

Indication:

Initial expectant management N = 99 (74%)

Subsequent indication for delivery

N = 99 (100%)

IUFD 22 (22%)

Maternal 54 (55%)

Foetal 23 (23%)

Neonatal comfort care

37 (45%)

Active neonatal support 45 (55%)

34 +3*

20 +2*

23

Indication:

Immediate delivery N = 34 (26%)

Maternal 31 (91%)

Foetal 3 (8.8%)

Neonatal comfort care

31 (86%)

Active neonatal support 5 (14%)

3 2 29 +2*

F i gu r e 1 . Ov e r v i e w o f m an a g e m e n t in t h e 1 3 3 p r e g n an c ie s w it h s e v e r e , e a r ly o n s e t p r e e c la m p si a.

* additional children from multiple pregnancies

Results

PopulationDuring the study period, 133 women fulfi lled the inclusion criteria, delivering 140 neonates, including 8 multiple pregnancies. In one woman with a multiple pregnancy, an IUFD was discovered of one of the foetuses at 16 weeks and was considered a singleton pregnancy in the neonatal analyses. Immediate delivery was pursued in 34 of the 133 women (26%), which was accomplished after a median of 2 days (IQR 1 - 3). The immediate delivery group included 14 women (41%) with a gestational age of less than 24 weeks at time of management. Immediate delivery was indicated for maternal reasons in 31 women (91%) and foetal indication in 3 women (8.8%). Active neonatal support was offered in 5 neonates (14%) born after immediate delivery.

In 99 women (74%) expectant management was initiated, of whom 45 women (45%) had a gestational age of less than 24 weeks at time of management. Fifty-four women (55%) were eventually delivered for maternal reasons and 23 (23%) for foetal indications after a median of 6 days (IQR: 4 - 11). In 22 women (22%) IUFD occurred during expectant care, after which labour was induced. In one case spontaneous preterm

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23

1labour followed 5 days after admittance, which was classifi ed as maternal indication. Active neonatal support was offered in 45 (55%) neonates born after initial expectant management. An overview of management is given in Figure 1.

Caesarean section was performed in 48 women (36%), of which 24 (50%) were performed for foetal indication. Cesarean section was performed in 6 women (18%) in the immediate delivery group and in 42 (42%) after expectant management. Perinatal death occurred in 21 (44%) after caesarean section.

Immediate delivery versus expectant managementTable 1 lists the baseline characteristics of the 34 women that were delivered

immediately and the 99 women that were managed expectantly. Women receiving expectant management had on average a lower maximum systolic blood pressure.Table 2 shows outcomes of women with immediate delivery or expectant management. Immediate delivery or expectant management did not differ with respect to the occurrence of maternal complications: 24 (71%) versus 68 (69%) (OR: 1.5, 95%CI: 0.17 – 14). HELLP syndrome was the most common maternal indication for delivery (36 women, 67%).

Active neonatal support was offered less often after immediate delivery: 5 (43%) versus 45 (14%) (OR: 0.21, 95%CI: 0.067 – 0.59). Immediate delivery compared to expectant management was more often associated with perinatal mortality: 34 (94%) versus 79 (76%) (OR: 5.4, 95%CI: 1.2 - 24). The median time interval between admittance and delivery was 4 days shorter in immediate delivery (2 versus 6 days, 95%CI 2.45 – 5.55). Furthermore, women who were delivered immediately, delivered at a younger gestational age, less often had caesarean sections and were hospitalized shorter than women treated with expectant management.

The incidence of neonatal complications in the 27 surviving children is shown in Table 3. Surviving neonates experience complications in 84%. Neonatal mortality was associated with NEC in 5 (19%), sepsis in 11 (41%), IVH in 5 (19%) and infant respiratory distress syndrome (IRDS) in 5 neonates (19%), mostly in combinations. Other complications leading to neonatal death consisted of: arrhythmia, intracardial thrombus and multi-organ failure.

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Chapter 1

24

Table 1. Baseline and clinical characteristics of the 34 women who were delivered immediately and 99 women managed expectantly

Immediate delivery N = 34

Expectant care N = 99

P*

Demographic characteristicsMaternal age at delivery (years)SmokingBody mass index, BMI (kg/m2)Chronic hypertension before pregnancy

30 (6.2) 1 (2.9%) 28 (6.0) 7 (21%)

31 (5.5) 10 (10%) 28 (6.7) 28 (28%)

.409

.218

.966

.379History of disease - Obesity (BMI> 30)

- Pulmonary disease - Thrombophilia - Kidney disease

- Diabetes Mellitus - Coronary disease - SLE - Other**

7 (21%) 1 (2.9%) 2 (5.9%) 1 (2.9%) 1 (1.5%) 0 (0%) 1 (2.9%) 4 (12%)

27 (27%) 5 (5.1%) 2 (2.0%) 2 (2.0%) 2 (2.0%) 1 (1.0%) 0 (0%) 8 (8.1%)

.441

.609

.255

.755

.425

.404

.078

.518Obstetrical historyNulliparous MultiparousPreeclampsia in a former pregnancyMultiple pregnancy

20 (59%) 21 (41%) 5 (33%) 3 (8.8%)

65 (66%) 34 (34%) 16 (53%) 5 (5.1%)

.189

.189

.205

.225Clinical syndromePreeclampsiaHELLP syndromePostpartum HELLP syndrome

34 (100%) 23 (68%) 0 (0%)

99 (100%) 62 (63%) 2 (2.0%)

-.653-

Maximum blood - Systolicpressure (mmHg) - Diastolic

185 (23) 112 (14)

177 (18) 110 (10)

.033

.574Maximal laboratory - ASAT (IU/L)Abnormalities - Platelets (*109/L) - Proteinuria (mg/24h) - PCR***

104 (33 - 158) 115 (68 - 194) 1100 (401 - 3245) 165 (43 - 483)

85 (40 - 160) 87 (57 - 148) 810 (386 - 3800) 206 (30 - 692)

.793

.152

.548

.958Use of medication - oral antihypertensive - iv antihypertensive - iv anticonvulsive

29 (85%) 30 (88%) 32 (94%)

88 (89%) 77 (78%) 88 (89%)

.578

.158

.376Gestational age at admittance (wks+ days) Estimated foetal weight at admittance (grams)Abnormal umbilical artery Doppler flow

24+1 (23+3 - 24+6) 460 (149) 27 (82%)

24+0 (23+0 - 24+5) 491 (114) 65 (69%)

.254

.206

.161Continuous data are presented as means (SD); lab abnormalities and gestational ages in median (IQR)*p-values for the comparison between women managed expectantly and women treated with immediate delivery. ** Other medical history: hemoglobinopathy (3), HIV, thrombotic thrombocytopenic purpura, hypothyroidism, Cohn’s disease, sarcoidosis, mixed connective tissue disease and cutaneous lupus erythematosus*** PCR: Protein / Creatinin Ratio, registered if a 24 hour collection of urine was not performed (N=17)Significant differences are indicated in bold.

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25

1Table 2. Outcomes of the 34 women who were delivered immediately and 99 women managed expectantly

Immediate delivery N = 34

Expectant care N = 99

P

Interval between admittance and deliveryGestational age at delivery (wks+days)Caesarean SectionHospitalization (days)

2 (1 - 3) 24+3 (24+0 - 25+1) 6 (18%) 7 (6 - 8)

6 (4 - 11) 25+1 (24+5 - 25+5) 42 (42%) 12 (9 - 16)

Chapter 1

26

Table 3. Neonatal complications in the 27 surviving children.

Neonatal complications N (%) IVH ≥ grade 3 ROP ≥ grade 3 NEC ≥ stage 2 BPD – moderate BPD – severe Sepsis Other* Any complication

1 (4%) 4 (21%) 3 (12%) 13 (48%) 7 (28%) 15 (56%) 16 (60%) 22 (84%)

*Other neonatal complications: patent arterial duct, cerebellar haemorrhage, lung bleeding, focal bowel perforation.

Time interval, caesarean section, neonatal and maternal complications according to gestational age at admittance and primary management is presented in Table 4. Median time interval between admittance and delivery ranged from 2.0 days to 3.5 days in immediate delivery groups and from 4.5 to 13 days in the expectant groups. Caesarean section rates ranged from 0 to 42% in immediate delivery groups and from 16 to 85% in the expectant groups. Maternal complications ranged from 67 to 75% in immediate delivery groups and from 60 to 81% in the expectant groups. Perinatal death ranged from 77 to 100% in immediate delivery groups and from 43 to 95% in the expectant groups. Neonatal survival in the immediate group occurred only after 25 weeks. Neonatal complications ranged from 50 to 100%.

Gestational age of the surviving children in the total cohort was on average 7 days longer (24+6 versus 23+6, p-value


27

1Ta

ble 4

. Tim

e int

erva

l, ce

sare

an se

ctio

n an

d ne

onat

al a

nd m

ater

nal c

ompl

icatio

ns a

ccor

ding

to g

esta

tiona

l age

at m

anag

emen

t and

man

agem

ent.

Gest

atio

nal

age a

t m

anag

emen

tW

eeks

+day

s

Prim

ary

man

agem

ent:

Med

ian

time

inte

rval

bet

wee

n ad

mitt

ance

and

deliv

ery -

day

s (IQ

R)

Caes

area

n se

ctio

nn

(%)

Mat

erna

l com

plica

tions

n

(%

)Pe

rinat

al d

eath

n

(%)

Neo

nata

l com

plica

tions

n

(%)

< 22

+6

Expe

ctan

t m

anag

emen

t

N =

19

13

(6

- 18)

3 (16

)

HEL

LP sy

ndro

me:

11

(5

8)Pu

lmon

ary o

edem

a:

1 (5

.3)

Abru

ptio

n:

1 (5

.3)

Any:

11

(5

8)

IUFD

: 8

(38)

Intra

part

um d

eath

: 11

(5

2)N

eona

tal d

eath

<7d

: 1

(4.8

)To

tal:

20

(9

5)

Surv

ival

: 1

BPD

: 1

(100

)An

y:

1 (1

00)

Imm

edia

te

deliv

ery

N =

4

2.

0

(1 –

3.75

)0

(0)

HEL

LP sy

ndro

me:

3

(75)

Rena

l fai

lure

: 1

(17)

An

y:

3 (7

5)

Intra

part

um d

eath

: 4

(100

)To

tal:

4

(100

)-

23+0

– 2

3+6

Expe

ctan

t m

anag

emen

t

N =

26

10

(6

.75 -

12)

8 (3

1)

HEL

LP sy

ndro

me:

21

(8

1)Pu

lmon

ary o

edem

a:

2 (7

.7)

Abru

ptio

n:

1 (3

.8)

Any:

21

(8

1)

IUFD

: 9

(32)

Intra

part

um d

eath

: 10

(3

6)N

eona

tal d

eath

<7d

: 4

(14)

Neo

nata

l dea

th >

7d:

1 (3

.6)

Tota

l:

24

(86)

Surv

ival

: 4

ROP:

2

(50)

BPD

: 4

(100

)Se

psis:

2

(50)

Any:

4

(100

)Im

med

iate

de

liver

y

N =

10

3.

5 (2

– 4

.25)

1 (10

)H

ELLP

synd

rom

e:

6 (6

0)An

y:

7 (7

0)In

trapa

rtum

dea

th:

11

(100

)To

tal:

11

(1

00)

-

24+0

– 2

4+6

Expe

ctan

t m

anag

emen

t

N =

34

5.5

(4 - 9

)14

(41)

HEL

LP sy

ndro

me:

22

(6

5)Pu

lmon

ary o

edem

a:

3 (8

.8)

Abru

ptio

n:

3 (8

.8)

Any:

24

(7

1)

IUFD

: 6

(18)

Intra

part

um d

eath

: 13

(3

8)N

eona

tal d

eath

<7d

: 3

(8.8

) Neo

nata

l de

ath

>7d:

4

(12)

Tota

l:

26

(77)

Surv

ival

: 8

IVH

: 1

(13)

ROP:

1

(13)

NEC

: 2

(25)

BPD

: 6

(75)

Seps

is:

4 (5

0)An

y:

6 (7

5)Im

med

iate

de

liver

y

N =

11

2.

0

(1 - 3

)0

(0)

HEL

LP sy

ndro

me:

8

(73)

Ecla

mps

ia:

1 (9

)An

y:

8 (7

3)

IUFD

: 2

(17)

Intra

part

um d

eath

: 10

(8

3)To

tal:

12

(1

00)

-

36927 Oostwaard.indd 27 27-10-15 10:16

Chapter 1

28

Gest

atio

nal

age a

t m

anag

emen

tW

eeks

+day

s

Prim

ary

man

agem

ent:

Med

ian

time

inte

rval

bet

wee

n ad

mitt

ance

and

deliv

ery -

day

s (IQ

R)

Caes

area

n se

ctio

nn

(%)

Mat

erna

l com

plica

tions

n

(%

)Pe

rinat

al d

eath

n

(%)

Neo

nata

l com

plica

tions

n

(%)

25+0

– 2

6+0

Expe

ctan

t m

anag

emen

t

N =

20

4.

5 (3

.25 -

6)

17 (8

5)

HEL

LP sy

ndro

me:

8

(40)

Post

part

um H

ELLP

: 2

(10)

Pulm

onar

y oed

ema:

3

(15)

Live

r hem

atom

a:

1 (5

.0)

Rena

l fai

lure

: 1

(5.0

) An

y:

12

(60)

IUFD

: 1

(4.8

)In

trapa

rtum

dea

th:

3 (1

4)N

eona

tal d

eath

<7d

: 1

(4.8

)N

eona

tal d

eath

>7d

: 4

(19)

Tota

l:

9 (4

3)

Surv

ival

: 12

ROP:

1

(8.3

)N

EC:

1 (8

.3)

BPD

: 8

(67)

Seps

is:

8 (6

7)An

y:

11

(92)

Imm

edia

te

deliv

ery

N =

9

2.0

(1

– 2

.5)

5 (42

)

HEL

LP sy

ndro

me:

6

(67)

Ecla

mps

ia:

3 (3

3)Pu

lmon

ary o

edem

a:

1 (1

1)An

y:

6 (6

7)

IUFD

: 1

(11)

I ntra

part

um d

eath

: 3

(33)

Neo

nata

l dea

th<

7d:

2 (2

2)N

eona

tal d

eath

>7d

: 1

(11)

Tota

l:

7 (7

8)

Surv

ival

: 2

BPD

: 1

(50)

Seps

is:

1 (5

0)An

y:

1 (5

0)

Tabl

e 4. C

ontin

ued

36927 Oostwaard.indd 28 27-10-15 10:16


29

1Figure 2A Trends in expectant management

7175 74

8275

70

0

10

20

30

40

50

60

70

80

90

100

2008 2009 2010 2011 2012 2013

%

25+0 - 26+0

24+0 - 24+6

23+0 - 23+6

< 22+6

all

The percentage of initial expectant management is shown for each year, with distribution of 4 gestational age groups at time of management.N= 133 women (2008: N=17, 2009: N=24, 2010: N=27, 2011: N=22, 2012: N=16, 2013: N=27)

Figure 2B Trends in Caesarean sections

3529

33

62

38

26

0

10

20

30

40

50

60

70

80

90

100

2008 2009 2010 2011 2012 2013

%

25+0 - 26+0

24+0 - 24+6

23+0 - 23+6

< 22+6

all

The percentage of caesarean sections is shown for each year, with distribution of 4 gestational age groups at time of delivery.N= 132 women (2008: N=17, 2009: N=24, 2010: N=27, 2011: N=21, 2012: N=16, 2013: N=27)

36927 Oostwaard.indd 29 27-10-15 10:16

Chapter 1

30

Figure 2C Trends in maternal complications

88 88

59

68

56 56

0

10

20

30

40

50

60

70

80

90

100

2008 2009 2010 2011 2012 2013

%

25+0 - 26+0

24+0 - 24+6

23+0 - 23+6

< 22+6

all

The percentage of women with any maternal complications is shown for each year, with distribution of 4 gestational age groups at time of management.Maternal complications: HELLP syndrome, eclampsia, pulmonary oedema, cerebrovascular incidents, liver bleeding, placenta abruption, kidney failure with need for dialysis and maternal death.N= 133 women (2008: N=17, 2009: N=24, 2010: N=27, 2011: N=22, 2012: N=16, 2013: N=27)

Figure 2D Trends in neonatal survival after active neonatal management

5763

70

4650

40

0

10

20

30

40

50

60

70

80

90

100

2008 2009 2010 2011 2012 2013

%

25+0 - 26+0

24+0 - 24+6

23+0 - 23+6

< 22+6

all

The percentage of neonatal survival, after active neonatal management, is shown for each year, with distribution of 4 gestational age groups at birth. No active neonatal management was executed in neonates born under 24 weeks of gestation.N= 50 neonates (2008: N=7, 2009: N=8, 2010: N=10, 2011: N=14, 2012: N=6, 2013: N=5)

36927 Oostwaard.indd 30 27-10-15 10:16


31

1TrendsWe investigated trends in management or outcome over the years in the study period. Figure 2A-D shows graphics of percentages with distribution of 4 gestational age groups at time of management (e.g.

Chapter 1

32

maternal complications, i.e. gestational diabetes, placental abruption and severe haemorraghia postpartum due to placenta accreta. Perinatal death occurred in 5 (9.6%) subsequent pregnancies: 2 pregnancies were terminated (trisomy 18 and foetal intracerebral haemorrhage), in 2 other pregnancies IUFD occurred and one neonatal death was aaociated with severe growth restriction. NICU admittance was indicated in 10 (20%) neonates (7 related to PE) and neonatal complications occurred in 3 (30%) and consisted of NEC and BPD. Eventually, 50 women (91%) had a living child from the subsequent pregnancy.

Discussion

Main findingsIn the Netherlands, women with severe early onset preeclampsia are more often managed expectantly than treated with immediate delivery. Prolongation added 4 days to the interval between admittance and delivery. Unsurprisingly, immediate delivery versus expectant management was more often associated with perinatal death, since it was guided towards active neonatal management more often. But when presenting before 24 week’s gestation with severe preeclampsia, expectant management did not improve perinatal survival. Maternal complications occurred frequently, but no differences in occurrence of maternal complications were found. Surviving neonates were on average 7 days older and were estimated 144 grams heavier than non-surviving neonates.

The recurrence rate of preeclampsia was 31%, however at significant later gestational age (mean: 35+4) with 91% neonatal survival. The occurrence of a next pregnancy was similar between the treatment groups, but immediate delivery was more often associated with recurrence of PE (50 versus 23%, OR 3.4, 95%CI: 1.0 - 12).

Strengths and limitationsThis contemporary nationwide cohort is unique as all Dutch perinatal centres took part in this study, and we were therefore able to include all women who met the inclusion criteria. Data collection was complete since we collected information from the medical files.

Baseline characteristics between women receiving expectant management and women that were treated with immediate delivery were comparable, except for maximal systolic blood pressure. Some clinical aspects, that have led women and their care-takers

36927 Oostwaard.indd 32 27-10-15 10:16


33

1to decide to prolong or end the pregnancy, may not always translate to statistics well. A few clinical aspects of the syndrome were more serious in the immediate delivery group (more often eclampsia and higher maximum systolic blood pressure), which may explain the more aggressive management. A prospective randomized trial would eliminate this bias, but the severity of the disease and complications makes this type of study design unethical. In the majority of cases, an establishing or deteriorating HELLP syndrome contributed to the maternal reason to deliver after expectant management. We do not know if HELLP syndrome or deterioration of HELLP syndrome could have been prevented by immediate delivery. This challenges the comparison of the frequency of HELLP syndrome between the management groups. It was to be expected that in the expectant management group, caesarean sections were performed more often, active neonatal support occurred more often and perinatal mortality was lower.

The size of our cohort is rather small, then again, severe early onset preeclampsia is a rare condition. In literature, all studies describing preeclampsia in this extreme premature period involve cohorts of around or less than 50 women.4,5,6,7 Comparisons of neonatal complications in surviving children between the treatment groups is hampered due to the small sample size.

InterpretationIn this study we describe management of women with severe early onset preeclampsia. The overall maternal complication rate of 69% is comparable to literature.4,5,6,7 Although a decreasing trend may be seen in the occurrence of maternal complications over the study period, it is too soon to draw any conclusions about the reasons. Perinatal death and neonatal complications are also comparable to literature on severe early onset preeclampsia.4,5,6,7 However, compared to perinatal death rates of 45% in extreme premature neonates in a Swedish nationwide cohort11 without maternal preeclampsia, perinatal death was much higher in our cohort. This concurs with the concept that neonates born from mothers with severe early onset preeclampsia are not comparable to spontaneous premature born children. On the other hand, the neonatal survival rate after active support (27/50, 54%) is comparable to the results of the Swedish study.11 Neonatal survival after extreme premature preeclampsia in this cohort does not seem to have improved over recent years, but after 2010 active support is offered at an earlier gestational age, which may have effect on survival.

Management was expectant in three quarters of the women included in this study, despite the high maternal complication rate and perinatal mortality. Prolongation of pregnancy was in general 6 days in the expectantly managed pregnancies, comparable

36927 Oostwaard.indd 33 27-10-15 10:16

Chapter 1

34

to the results of some studies.5,6 In other studies much longer prolongation of up to 32 days is reported.4,7,10 Prolongation added only 4 days in comparison with immediate delivery. Even in the immediate delivery group, clinical stabilisation as well as the discussion of management took time 2 days time. An interesting finding in this study is that expectant management did not differ significantly from immediate delivery regarding the occurrence of maternal complications, while neonatal survival was higher. Possibly, the women in the immediate delivery group were considered to have a more serious illness than the women in the expectant group, even though statistical differences between groups were minimal. If presenting before 24 weeks at time of management, perinatal mortality was very high: 86-100% (Table 4) and prolongation did not increase survival.

Not many studies have compared expectant management with immediate delivery at this early gestational age. Sibai10 and Ganzevoort8 reviewed the different types of management in in literature. They conclude that before 24 weeks of gestation, because of the absence of perinatal benefits and high maternal complication rate, an expectant management approach should not be offered routinely. Our finding that before 24 weeks of gestation, prolongation had no effect on neonatal survival, endorses this consensus. After 24 weeks, in a select group of women, prolongation of pregnancy can be safe and perinatal outcome could benefit. In our study, maternal complications, perinatal death and neonatal complications after 24 weeks were still very high. In 56 women (57%) that were managed expectantly, the criteria for active neonatal support (59 neonates) were never met (Figure 1), despite prolongation of up to 23 days from admittance (median 8 days). In line with other studies, this study does not provide selection criteria of women who are eligible for expectant care. Presented differences between pregnancies with and without surviving neonates could give guidance to counselling on this matter.

In general, women need to be counselled carefully, weighing the risk for maternal complications versus high perinatal mortality. Estimated foetal weight, growth restriction and Doppler abnormalities should be taken into account. Furthermore, we should also provide information on the improved maternal and neonatal outcomes in the next pregnancies of these women.

Improved care and survival rate resulted in a new Dutch guideline regarding active neonatal resuscitation in spontaneously born premature neonates at a gestational age beyond 24 completed weeks in September 2010.18 Before the introduction of the guideline, active neonatal resuscitation was not performed before 25 weeks of

36927 Oostwaard.indd 34 27-10-15 10:16


35

1gestation, unless an active resuscitation seemed justifi ed. Expectant care may seem defendable at an earlier gestational age in hope of neonatal survival, iatrogenic prematurity in preeclampsia however does not resemble spontaneous premature delivery. The group of investigators in this study was concerned that the introduction of this guideline may have had a ‘side effect’ on management of severe early onset preeclampsia in the Netherlands. Because the introduction was preceded by discussion between the centres and correspondence, not all centres implemented the guideline at the same time. Disregarding 2010 as a year of transition in analysis, we found that the introduction of the guideline on spontaneous extreme preterm birth had no effect on management choices for extreme preterm preeclampsia. Expectant management was registered in 49 of 65 women (75%) after, and in 30 of 41 (73%) before the new guideline (OR 0.97, 95%CI: 0.27 – 3.5, p-value: 0.965). Although we have to keep in mind that the number of patients due to the rareness of this clinical dilemma does not warrant too fi rm conclusions, in 2012 and 2013 expectant management was rarely offered after 25 weeks of gestation. Also, a peak appears in caesarean section rate in 2011. These fi ndings could suggest a subtle influence of this guideline, with presumed better neonatal survival chances after 25 weeks and after caesarean section. Furthermore, the mean prolongation of pregnancies that were managed expectantly, increases with younger gestational age. This supports the theory that prolongation was aimed at reaching a viable gestational age at around 24 weeks.

ConclusionSevere preeclampsia in the extreme premature period is a rare but serious condition with high rates of maternal and neonatal complications and perinatal death. Expectant management was often applied in the Netherlands, although the consensus in international literature indicates that prolongation of pregnancy should not be offered as routine treatment option. Expectant care improves neonatal survival without compromising maternal condition between 24 and 26 weeks of gestation, but before 24 completed weeks prolongation has no effect on neonatal survival. Prolongation does not necessarily lead to foetal viability. Women need to be counselled carefully, weighing the risk of high perinatal mortality and/or extreme prematurity and its sequelae versus maternal risks, considering the positive prospects regarding neonatal outcome in a future pregnancy.

36927 Oostwaard.indd 35 27-10-15 10:16

Chapter 1

36

References1 Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005;365:785-799.2 Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet 2010;376:631-44.3 Sibai BM, Akl S, Fairlie F, Moretti M. A protocol for managing severe preeclampsia in the second trimester. Am

J Obstet Gynecol 1990;163(3):733-8.4 Gaugler-Senden IP, Huijssoon AG, Visser W, Steegers EA, de Groot CJ. Maternal and perinatal outcome

of preeclampsia with an onset before 24 weeks’ gestation. Audit in a tertiary referral center. Eur J Obstet Gynecol Reprod Biol 2006;128:216-21.

5 Belghiti J, Kayem G, Tsatsaris V, Goffinet F, Sibai BM, Haddad B. Benefits and risks of expectant management of severe preeclampsia at less than 26 weeks gestation: the impact of gestational age and severe fetal growth restriction. Am J Obstet Gynecol 2011;205(5):465.e1-6.

6 Bombrys AE, Barton JR, Nowacki EA, Habli M, Pinder L, How H, Sibai BM. Expectant management of severe preeclampsia at less than 27 weeks’ gestation: maternal and perinatal outcomes according to gestational age by weeks at onset of expectant management. Am J Obstet Gynecol 2008;199:247.e1–247.e6.

7 Budden A, Wilkinson L, Buksh MJ, McCowan L. Pregnancy outcome in women presenting with pre-eclampsia at less than 25 weeks gestation. Aust N Z J Obstet Gynaecol 2006;46 407–412.

8 Ganzevoort W, Sibai BM. Temporising versus interventionist management (preterm and at term). Best Pract Res Clin Obstet Gynaecol 2011;25(4):463-76.

9 Hall DR, Odendaal HJ, Steyn DW, Grové D. Expectant management of early onset, severe pre-eclampsia: maternal outcome. BJOG 2000;107(10):1252-7.

10 Sibai BM, Barton JR. Expectant management of severe preeclampsia remote from term: patient selection, treatment, and delivery indications. Am J Obstet Gynecol 2007;196:514.e1-514.e9.

11 EXPRESS Group, Fellman V, Hellström-Westas L, Norman M, Westgren M, Källén K, Lagercrantz H, Marsál K, Serenius F, Wennergren M. One-year survival of extremely preterm infants after active perinatal care in Sweden. JAMA 2009;301(21):2225-33.

12 ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. American College of Obstetricians and Gynecologists Int Gynaecol Obstet 2002;77(1):67-75.

13 Sibai BM. The HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): much ado about nothing? Am J Obstet Gynecol 1990;162(2):311-316.

14 Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 1978 Apr;92(4):529-34.

15 International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol 2005;123(7):991-9.

16 Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg 1978;187(1):1–7.

17 Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163(7):1723-1729.18 NVOG Guideline: ‘Perinatal policy in extreme premature birth’. September 2010. www.nvog.nl

36927 Oostwaard.indd 36 27-10-15 10:16


37

1

Contribution to AuthorshipMiriam van Oostwaard is the primary author, created the database, performed part of the data collection and did most of the writing of the article. Leonoor van Eerden helped design the study, performed data collection and reviewed the article. Monique de Laat helped to design the study, performed data collection and reviewed the article. Hans Duvekot, Jan Jaap Erwich, Kitty Bloemenkamp, Annemieke Bolte, Joost Bosma, Steven Koenen, Bente Rethans, Pieter Van Runnard Heimel and Liesbeth Scheepers performed data collection and reviewed the article. René Kornelisse reviewed the article from a neonatologist’s perspective. Wessel Ganzevoort, Ben Willem Mol and Christianne de Groot contributed to the design of the study, supervised with data collection and reviewed the article. Ingrid Gaugler-Senden initiated and designed the study, supervised with data collection and reviewed the article.

36927 Oostwaard.indd 37 27-10-15 10:16

36927 Oostwaard.indd 38 27-10-15 10:16

Chapter 2

Terminating pregnancy for severe

hypertension when neonatal

prognosis is extremely bad:

a retrospective cohort study

L van EerdenM.F. van Oostwaard

G.G. ZeemanL.C.M. Page-Christiaens

E. PajkrtJ.J. Duvekot

F. Vandenbussche G.G. Oei

H.C.J. ScheepersJ. van Eyck

J.M. MiddeldorpS.V. Koenen

C.J.M. de GrootA.C. Bolte

Submitted

36927 Oostwaard.indd 39 27-10-15 10:16

Chapter 2

40

Abstract

Objective: To investigate frequency and practise of termination of pregnancy for hypertensive disorders where the foetus is judged to be non- viable

Design: Retrospective cohort study.

Setting: All Dutch tertiary perinatal care centres.

Population: All women who underwent termination of pregnancy, without foetal surveillance or intention to intervene for foetal reasons, for a hypertensive disorder in pregnancy between January 2000 and January 2014.

Methods: Women eligible for this study were identified in the local delivery databases. Thereafter we collected data from the medical records.

Results: We included 161 women, including 6 women with a twin pregnancy. More than half of the pregnancies were terminated for HELLP syndrome (59%). Mean gestational age at termination was 172 days (GA 244/7) ± 9.4 days. In 70% of the cases termination was performed at or after 24 weeks’ gestation. More than 75% of women developed HELLP syndrome, eclampsia or needed admission to an ICU. Perinatal mortality was nearly 100%. In 69% of the cases the estimated foetal weight was within a 10% margin of the actual birth weight. Furthermore we found considerable differences in prevalence between centres.

Conclusion: Termination of pregnancy for hypertensive disorders without intervention on fetal indication occurs approximately 12 times per year in The Netherlands. This study indicates that there might be a need for consensus to reduce the practise variability regarding termination of pregnancy for hypertensive indications at the limits of foetal viability.

36927 Oostwaard.indd 40 27-10-15 10:16

Terminating pregnancy for severe hypertension

41

2

Introduction

The incidence of severe early onset preeclampsia (PE) is increasing worldwide1. Preeclampsia is annually accountable for approximately 60.000 maternal deaths worldwide. Cerebral complications, such as eclampsia and intracranial haemorrhage account for at least 75% of these2. Causes for the increase in prevalence of preeclampsia include: advanced maternal age at fi rst pregnancy and more women with pre-existing disorders such as hypertension, renal disease or auto-immune disorders who become pregnant1.

In situations where maternal health is severely compromised and where prognosis for healthy foetal survival is virtually non-existent due to early gestational age complicated by severe growth restriction, termination of pregnancy may be considered3-5,8. In an authorative review, Sibai et al. describe a maternal complication rate of 57%, and an overall foetal mortality rate of 83% when very early onset preeclampsia is managed expectantly. The authors therefore state that in case of severe preeclampsia before 24 weeks, termination of pregnancy should be seriously considered in order to prevent severe maternal morbidity or mortality5.

Literature on the prevalence and practise of termination of pregnancy for maternal preeclampsia is scarce. It is unknown how often pregnancies are terminated for hypertensive disorders in the Netherlands. Aim of this study is to investigate the prevalence of termination of pregnancy for hypertensive disorders in pregnancies considered previable between 2000 and 2014 in all Dutch tertiary care centres. Termination of pregnancy in this context is defi ned as delivering the foetus in ways or with medication that do not consider its health or survival, in the assumption that it is too premature or too small to survive. Secondarily, we looked at foetal characteristics on which the dismal foetal prognosis is based and accuracy of foetal weight estimation. Furthermore we looked at the prevalence of termination of pregnancy for hypertensive disorders per tertiary care centre.

Methods

We performed a Dutch nationwide retrospective cohort study between January 2000 and January 2014. We included all women who underwent termination of pregnancy because of severe maternal hypertension between 22 and 276/7 weeks of pregnancy in tertiary care centres. In all cases the foetus was judged to be non-viable. Exclusion

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criteria were termination of pregnancy for other maternal indications, congenital anomalies or intra-uterine foetal death (Table 1).

Recruitment was limited to all tertiary care centres (n = 10), because according to the Dutch Society of Obstetrics and Gynaecology guideline on hypertensive disorders in pregnancy, women who develop preeclampsia prior to 32 weeks’ gestation should be referred to and treated in a tertiary care centre. These centres are equipped with a maternal obstetrical high care unit as well as a Neonatal Care Unit (NICU)6,17. After identification of cases in the local delivery databases, records were reviewed for inclusion and exclusion criteria. Relevant demographic and clinical data were extracted and transferred to a standardized data collection form. Demographic data included maternal age at termination, parity, and medical and obstetrical history. Clinical data included information about the index pregnancy and delivery including gestational age at admission, gestational age at delivery, birth weight and gender. Gestational age was based on menstrual date confirmed by first trimester ultrasound. Furthermore, specific data used for clinical decision making were recorded; gestational age, the last estimated foetal weight (EFW) prior to termination, suspected growth restriction (EFW < 10th percentile), Doppler profiles (pulsatility index in the uterine artery) and the amount of amniotic fluid.

Table 1: inclusion- and exclusion criteria

Inclusion criteria Termination of pregnancy between GA 220/7 and 276/7Hypertensive disorder of pregnancyLive foetus at decision of terminationDecision to refrain from foetal monitoringNo intended active neonatal management

Exclusion criteria Other maternal indication for terminationFoetus with suspected congenital anomalies Foetal indication for terminationFoetal death

To control for potential underreporting, we cross-checked the prevalence data with the Netherlands perinatal registry (PRN-registry)7. Definitions of preeclampsia and HELLP syndrome were derived from the guidelines of the International Society for the Study of Hypertension in Pregnancy (ISSHP)9 and the NICE guideline Hypertension in Pregnancy10. Severe preeclampsia is defined as hypertension (diastolic blood pressure ≥110 mmHg or systolic blood pressure ≥160 mmHg on two occasions) in combination with proteinuria (defined as a protein/creatinine ratio of ≥30 mg/mmol in a random sample or a urine protein excretion of ≥300 mg per 24 hrs) and one or more of the following; oliguria, cerebral or visual disturbances, pulmonary oedema, epigastric

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or upper-quadrant pain, impaired liver function, thrombocytopenia or foetal growth restriction, after 20 weeks of pregnancy. Severe maternal morbidity was defi ned as HELLP syndrome (haemolysis (elevated lactate dehydrogenase (LDH) levels ≥ 600 U/L), elevated liver enzymes by levels of aspartate transaminase (ASAT) or alanine transferase (ALAT) ≥ 70 U/L and low platelets < 100,000/mm), eclampsia or admission to an ICU.

Statistical analysis was performed using SPSS 20.0 (SPSS Inc., Chicago, IL, USA). Continuous variables were expressed as means with standard deviations (SD). We compared estimated foetal weight by ultrasound and actual birthweight. Differences between the groups were tested with a parametric (unpaired t-test) test as appropriate. P value less than 0.05 was considered to indicate statistical signifi cance.An acknowledged ethical advisory board approved the study (VUmc # 29-2010/200).

Results

Between January 2000 and January 2014, 2.456.584 women delivered in The Netherlands, of which 238.448 (9.7%) in a tertiary care centre. Pregnancy was terminated for severe early onset preeclampsia in 161 women (6.55 per 100.000). Among these, 6 women had a twin pregnancy. A cross-check with the Netherlands Perinatal Registry demonstrated that 100% of the deliveries were identifi ed7.

Maternal demographics and obstetric and general history are shown in table 2. The mean maternal age was 31 years and more than 70% were nulliparous. The medical history was unremarkable in 51% of the women.

Table 3 shows the number of terminations for hypertensive disorders before and after 24 weeks gestation. According to Dutch guidelines, valid during the study period, a foetus at a gestational age of less than 24 weeks is considered previable. There is general consensus between obstetricians and neonatologists in the Netherlands that in these cases, foetal monitoring or active neonatal support is not performed11. The mean gestational age at termination was 172 days (244/7 weeks) ± 9.4 days. Admission at a gestational age of less than 24 weeks occurred in 92 women (57%). In 23 women (25%), induction of labour was commenced immediately after initial stabilization. In the remaining 69 women (75%) pregnancy management was initially expectant. The mean interval between admission and start of termination was 9.3 days ± 5.4 days. In 113 women (70%) termination was performed at or beyond 24 weeks (mean GA 252/7 ± 9.4 days). In these cases a multidisciplinary team, consisting of at least obstetricians,

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neonatologists and other specialists, when indicated, discussed the case and examined alternative options before coming to a recommendation to the parents. The main reason to terminate a pregnancy after 24 weeks’ gestation was rapid maternal deterioration, such as the development of progressive HELLP syndrome, eclampsia or refractory hypertension. The decision to refrain from foetal monitoring and interventions for foetal indication was guided by poor foetal prognosis, based on: gestational age, EFW (51% < 500 grams), suspected growth restriction (73% EFW < 10th percentile), lack of growth between 2 assessments, abnormal Doppler profiles and the amount of amniotic fluid.

Table 5 shows the neonatal characteristics. We have data of 167 neonates, originating from 155 singleton and 6 twin pregnancies. The mean birth weight for the entire cohort was 460 grams ± 103 grams. In 145 neonates estimated foetal weight based on antenatal ultrasound parameters was recorded. The interval between measurement of EFW and day of birth was 5.4 days ± 2.1 days. In 69% of the cases the EFW was within a 10% margin of the actual birth weight. In 25 cases (22%) the EFW was more than 10% underestimated and in 10 cases (9%) the EFW was more than 10% overestimated.

In the 113 pregnancies that were terminated at or beyond 24 weeks, the mean EFW was 495 grams ± 113 grams, while the mean actual birth weight was 508 g grams ± 117 grams (mean difference EFW and birth weight: 13.3 gram 95%ci: - 24.30 to – 2.30 p = 0.018).

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Table 2. Maternal characteristics. Continuous data are presented as means (SD) or N (%)

N = 161Mean (SD) or N (%)

Age (y) 30.6 (5.2)Parity Nulliparous (no pregnancies > GA 16 weeks) 1 foetal loss < 16 weeks 2 foetal losses < 16 weeks 3 or more foetal losses < 16 weeks Multiparous Total number of previous pregnancies Live offspring Previous perinatal death Women with foetal loss < 16 weeks Women with previous PE or HELLP Women with previous preterm delivery Women with previous term delivery Women with previous termination for maternal indication

116 (72) 21 (18) 6 (5.2) 2 (1.7) 45 (28) 100 57 (57) 15 (15) 15 (33) 14 (31) 13 (62) 24 (53) 2 (4.4)

Medical History* No preexisting disease Nulliparous Multiparous Chronic Hypertension Nulliparous Multiparous SLE Nulliparous Multiparous Trombofi lia** Nulliparous Multiparous Kidney disease Nulliparous Multiparous Other*** Nulliparous Multiparous

82 (51) 61 21 33 (21) 23 10 3 (1.9) 2 1 10 (6.2) 5 5 5 (3.1) 3 2 13 (8.1) 9 4

* several women had more than one relevant condition in their history ** Thrombophilia: antiphospholipid syndrome, protein S defi ciency, Factor V Leiden mutation*** Other: diabetes mellitus, Crohn’s disease, haemoglobinopathy, malignancyTable 4 demonstrates maternal outcome. No maternal deaths were recorded. Ninety-six women (59%) developed HELLP syndrome and ten women suffered from eclamptic fi ts. All pregnancies were terminated with prostaglandins (i.e. intravenous sulprostone or misoprostol vaginally). One patient with a uterine scar from a previous caesarean section underwent an emergency caesarean section because of uterine rupture and hypovolemic shock.

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Table 3. Indications for termination of pregnancy before and after 24 weeks’ gestation.

Indication for termination N = 48 GA < 24 0/7 (%)

N = 113GA ≥ 24 0/7 (%)

HELLP syndrome 29 (60) 67 (59)Preeclampsia 18 (38) 34 (30)Eclampsia 0 9 (8.0)Severe refractory hypertension 1 (2.1) 3 (2.7)Total 48 (30) 113 (70)

Table 4. maternal outcome

Maternal outcome N = 161 n (%)

HELLP syndrome 96 (59)Maternal death 0Eclampsia 10 (6.2)Admission to the ICU pulmonary edema refractory hypertension eclampsia heart failure hypovolemic shock*

14 (8.4) 7 (50) 2 (14) 2 (14) 2 (14) 1 (7.1)

* Hypovolemic shock resulted in right-sided paralysis and aphasia. Ten years after the event she is not fully recovered

Table 5. neonatal outcome

Neonatal outcome N = 167Mean (SD) or N (%)

Sex Male Female Unknown

167 60 (36) 99 (59) 8 (4.9)

Perinatal mortality 166 (99.6)Gestational age (weeks) 22-236/7 weeks 24-256/7 weeks ≥ 260/7 weeks

244/7 (220/7 – 27

6/7) (9.4) days 48 (30) 84 (52) 29 (18)

Birth weight (grams) >10th percentile


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Table 6 shows the estimated foetal weight prior to decision of termination and actual birth weight per gestational week. At a gestational age of 236/7 or less the estimated foetal weight or Doppler profi le of the umbilical artery did not play an important role in the decision to terminate the pregnancy. In the 113 cases at or beyond 24 weeks’ gestation besides the estimated foetal weight specifi c data on Doppler profi les of the umbilical artery and the amount of amniotic fluid was recorded in 48/113 cases (43%).

Table 6. Estimated foetal weight (EFW) and actual birth weight, according to gestational age in weeks

Gestational age at termination Neonates (N) Prenatal EFW N (%) Birth weight N (%)220 - 226 22 < 500 g: 20 (100)

≥ 500 g: -Unknown: 2

< 500 g: 21 (100)≥ 500 g: 0Unknown: 1

230 - 236 28 < 500 g: 19 (90)≥ 500 g: 2 (10)Unknown: 7

< 500 g: 24 (100)≥ 500 g: 0unknown: 4

240 - 246 43 < 500 g: 29 (71)≥ 500 g: 12 (29) Unknown: 2

< 500 g: 27 (64)≥ 500 g: 15 (36)*unknown: 1

250 - 256 45 < 500 g: 21 (51)≥ 500 g: 20 (49)Unknown: 4

< 500 g: 23 (51)≥ 500 g: 22 (49)**

260 - 266 23 < 500 g: 5 (26)≥ 500 g: 14 (74)Unknown: 4

< 500 g: 7 (30)≥ 500 g: 16 (70)***

270 - 276 6 < 500 g: 2 (33)≥ 500 g: 4 (66)Unknown: -

< 500 g: 1 (17)≥ 500 g: 5 (83)****

Percentages are shown according to the number of available records* mean 560 grams ± 117 grams** mean 593 grams ± 117 grams*** mean 612 grams ± 122 grams**** mean 578 grams ± 121 grams

The perinatal mortality was 99.6%. One baby girl was born alive and admitted to the NICU. After 4 years of follow up she has a normal development. The mother had two previous pregnancies, of which the fi rst was uncomplicated. The second pregnancy was complicated by multiple pulmonary embolisms and an intrauterine foetal death at 33 weeks’ gestation. Afterwards she was diagnosed with antiphospholipid syndrome and she was treated with low molecular weight heparin and aspirin in the third and last pregnancy. This pregnancy was terminated for severe HELLP syndrome using intravenous sulprostone at a GA of 255/7 weeks. Ultrasound prior to termination showed growth restriction and oligohydramnios and an EFW of 550 grams. The birth weight was 600 grams (16th percentile).

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Figure 1 shows the number of terminations per centre per 10.000 deliveries. The prevalence varies from 2.1 per 10.000 deliveries in one centre to 17.2 per 10.000 deliveries in another centre.

Figure 1. Number of terminations per center, corrected for the total number of deliveries

20 18 16 14 12 10 8 6 4 2 0

1 2 3 4 5 6 7 8 9 10

Num

ber o

f ter

min

atio

ns p

er

ten

thou

sand

del

iver

ies

centre

Comment

Main findingsBetween 2000 and 2014, 161 women underwent termination of pregnancy for severe preeclampsia prior to foetal viability (incidence 6.5/100.000). The main reason to terminate was rapid maternal deterioration (progressive HELLP syndrome, eclampsia or refractory hypertension). In 75% management was initially expectant. More than 75% of women developed HELLP syndrome, eclampsia or needed admission to an ICU. In the majority of women (70%) termination was performed at or beyond 24 weeks. For the decision to refrain from foetal monitoring and active neonatal support the following parameters were taken into consideration: gestational age, estimated fetal weight, growth restriction, lack of growth, pulsatility index in the umbilical artery and the amount of amniotic fluid. In 22% of the cases EFW was more than 10% underestimated compared to the actual birth weight.

Strengths and weaknessesThe strength of this study is that it describes a large cohort, considering the rareness of the condition, and that it is a nationwide study. It fills a knowledge gap on factors contributing to the decision to terminate pregnancy for hypertensive disorders. Furthermore, we have detailed medical history and outcome information since data was gathered from the medical records. During the study period national guidelines for management of pre-eclampsia were uniform6,17.

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A limitation of the study is that it is a retrospective cohort study. We did however do a major effort to ensure completeness of cases. Furthermore we did not analyze the women in which an intrauterine foetal death (IUFD) occurred prior to termination of pregnancy. If an IUFD occurred during expectant management in a woman with severe early onset preeclampsia, she was not included in this study.

Interpretation

Gestational age and foetal growthIn our cohort, 57% of women were admitted prior to a gestational age of 24 weeks’. Despite international literature and guidelines, stating that such women should be counselled towards termination, 75% of these pregnancies were initially prolonged with 9.3 days on average. This expectant management, with increased risk of maternal complications did not result in improved foetal prognosis.

In women who develop severe preeclampsia at 240/7 to 326/7 weeks’ gestation, mode and method of delivery will depend on prospects for healthy survival of the infant3-5. We also describe a cohort of cases that progressed beyond 24 weeks where disease severity and dismal prognosis of the foetus led to the diffi cult decision to terminate the pregnancy precluding infant survival. Prolongation of pregnancy with increased maternal complications and increased foetal survival is weighed against termination of pregnancy with reduction of maternal complications and poor neonatal outcome. This decision was made after interdisciplinairy consultation and extensive counselling of the parents. Studies on perinatal mortality and morbidity in these severely growth restricted premature infants do not support active neonatal management12-14.

The accuracy of foetal weight estimation by ultrasound has been debated15. A recent study shows that determining the EFW in extreme preterm ànd SGA foetuses is less accurate than for AGA foetuses and that EFW is more likely to be overestimated. The authors recommend to consider this overestimation when counselling parents with growth restricted foetuses at the limits of foetal viability15. Our study shows that in one third of neonates the birth weight was more than 10% different from the estimated foetal weight. However, overestimation occurred only in 9%.

Di�ferences between centresWe found considerable differences in prevalence between the centres. These differences between centres are diffi cult to interpret due to the effect of small numbers. It is possible that part of these differences may be explained by the socioeconomic

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differences of the adherent populations of these centres. Dutch studies show marked differences in maternal mortality and perinatal mortality between cities, provinces and neighbourhoods16. The Maternal Mortality Rate (MMR) in the four largest cities in The Netherlands is significantly higher than the overall MMR in The Netherlands, with preeclampsia being the most frequent direct cause of death18.

Some of the variation in prevalence may also be explained by different policies as to initiation of active neonatal support in infants born at the limits of viability between centres. A recent study shows that centres, in which active support at an earlier gestational age is more often initiated, have a higher neonatal survival rate19. The neonatologists in such centres are likely to be more willing to start active support at an earlier gestational age and therefore termination of pregnancy without active support may be less frequent in such centres19. Future study should elucidate whether such between-hospital differences on active neonatal management contribute significantly to the decision-making process concerning termination of pregnancy at the limits of foetal viability.

Conclusion Termination of pregnancy for hypertensive disorders in foetuses considered non-viable, is extremely rare. We identified on average 1 to 2 cases per year per tertiary obstetric care centre in The Netherlands. To reach the decision to terminate a pregnancy at the limits of foetal viability is very difficult for parents as well as health care providers. This is reflected in an average interval between admission an intervention of 9.3 days. Differences per centre may be explained by regional differences in incidence of severe preeclampsia in the Netherlands and by local differences in active neonatal support at the limits of foetal viability. As neonatal intensive care continues to improve and enables survival at earlier gestational ages and lower birth weights it is prudent to continuously monitor the practice and outcomes. This study indicates that there might be a need for consensus to reduce the practice variability. To facilitate such discussion in The Netherlands we propose that all such cases are reported to a review or audit committee of the Dutch Society of Obstetricians and Gynecologists.

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late-onset disease. Am J Obstet Gynecol 2013;209:544.e1-12.2 Zeeman GG. Neurologic complications of pre-eclampsia. Semin. Perinatol. 2009 Jun;33(3):166-72. doi:

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5 Sibai BM, Barton JR. Expectant management of severe preeclampsia remote from term: patient selection, treatment, and delivery indications. AM J Obstet Gynecol 2007;196:514.e1-9

6 NVOG Guideline: ‘Hypertensieve aandoeningen in de zwangerschap’. March 2012. www.nvog.nl7 The Netherlands Perinatal Registry. www.perinatreg.nl8 Jenkins SM, Head BB, Hauth JC. Severe preeclampsia at < 25 weeks of gestation: Maternal and neonatal

outcomes. Am J Obstet Gynecol 2002;186:790-59 The classifi cation and diagnosis of the hypertensive disorders of pregnancy: statement of the International

Society for the Study of Hypertension in Pregnancy (ISSHP), Hypertension in Pregnancy 20(1), ix-xiv (2001)10 NICE guideline Hypertension in Pregnancy August 2010. Available at: www.nice.org.uk/guidance/CG10711 NVOG guideline: ‘Perinataal beleid bij extreme vroeggeboorte’. September 2010. www.nvog.nl12 Garite TJ, Clark R, Thorp JA. Intrauterine growth restriction increases morbidity and mortality among

premature neonates. Am J Obstet Gynecol 2004;191:481e7.13 Tsai L-Y, Chen YL, Tsou KI, Mu SC. The Impact of Small for Gestational Age on Neonatal Outcome among Very

Low Birth Weight Infants, Pediatrics and Neonatology (2014)14 Bernstein IM, Horbar JD, Badger GJ, Ohlsson A, Golan A. Morbidity and mortality among very-low-birth-

weight neonates with intrauterine growth restriction. The Vermont Oxford Network. Am J Obstet Gynecol 2000;182:198e206

15 Stefanelli S, Groom KM. The accuracy of ultrasound-estimated fetal weight in extremely preterm infants: a comparison of small for gestational age and appropriate for gestational age. Aus N Z J Obstet Gynaecol. 2014 Apr;54(2):126-31

16 Tromp M, Eskes M, Reitsma JB, Erwich J

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