Publications by authors named "Wessel Ganzevoort"

97 Publications

Added prognostic value of Doppler ultrasound for adverse perinatal outcomes: A pooled analysis of three cohort studies.

Aust N Z J Obstet Gynaecol 2022 Jun 9. Epub 2022 Jun 9.

Dr Daniel Rolnik, Department of Obstetrics & Gynaecology, Monash University, Melbourne, Australia.

Background: Fetal growth restriction (FGR) is an obstetric complication associated with adverse perinatal outcomes. Doppler ultrasound can improve perinatal outcomes through monitoring at-risk fetuses and helping time delivery.

Aim: To investigate the prognostic value of different Doppler ultrasound measurements for adverse perinatal outcomes.

Materials: Individual participant data.

Methods: We performed a pooled analysis on individual participant data. We compared six prognostic models using multilevel logistic regression, where each subsequent model added a new variable to a base model that included maternal characteristics. Estimated fetal weight (EFW) and four Doppler ultrasound measurements were added in turn: umbilical artery pulsatility index (UA PI), middle cerebral artery pulsatility index (MCA PI), cerebroplacental ratio (CPR), and mean uterine artery pulsatility index (mUtA PI). The primary outcome was a composite adverse perinatal outcome, defined as perinatal mortality, emergency caesarean delivery for fetal distress, or neonatal admission. Discriminative ability was quantified with area under the curve (AUC).

Results: Three data sets (N = 3284) were included. Overall, the model that included EFW and UA PI improved AUC from 0.650 (95% CI 0.624-0.676) to 0.673 (95% CI 0.646-0.700). Adding more ultrasound measurements did not improve further the discriminative ability. In subgroup analysis, the addition of EFW and UA PI improved AUC in both preterm (AUC from 0.711 to 0.795) and small for gestational age pregnancies (AUC from 0.729 to 0.770), but they did not improve the models in term delivery or normal growth subgroups.

Conclusions: Umbilical artery pulsatility index added prognostic value for adverse perinatal outcomes to the already available information, but the combination of other Doppler ultrasound measurements (MCA PI, CPR or UtA PI) did not improve further prognostic performance.
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http://dx.doi.org/10.1111/ajo.13547DOI Listing
June 2022

Timing of Delivery for Twins With Growth Discordance and Growth Restriction: An Individual Participant Data Meta-analysis.

Obstet Gynecol 2022 Jun 2;139(6):1155-1167. Epub 2022 May 2.

Flinders Medical Centre, Adelaide, South Australia, and the Department of Obstetrics and Gynecology, Monash University, Clayton, Victoria, Australia; the Department of Obstetrics, Amsterdam Reproduction and Development Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Julius Center for Health Sciences and Primary Care & Cochrane Netherlands, University Medical Center Utrecht, Utrecht University, Utrecht, the Department of Gynaecology and Obstetrics, GROW School of Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Department of Obstetrics and Gynecology, Haga Hospital, The Hague, the Department of Obstetrics and Gynecology, Gelre Hospitals Apeldoorn, Apeldoorn, and the Department of Obstetrics and Gynaecology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; the Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Atrium Health, Charlotte, North Carolina; the Maternal Fetal Medicine Unit, Department of Obstetrics, Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain; the Department of Obstetrics and Gynecology, Hospital das Clinicas, University of São Paulo, São Paulo, Brazil; the Department of Obstetrics and Gynecology, Sheba Medical Center, Tel-Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, and the Department of Obstetrics and Gynecology, Samson Assuta Ashdod University Hospital, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; the Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, the Departments of Obstetrics and Gynecology, Medicine, Community Health Sciences, and Pediatrics, and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, and the Department of Obstetrics and Gynecology, McMaster University, Hamilton, Ontario, Canada; the Department of Obstetrics and Gynecology, ASST-Spedali Civili, and the Department of Clinical and Experimental Sciences, University of Brescia, Brescia, and the Fetal Therapy Unit "Umberto Nicolini" and the Department of Women, Mother and Newborn, Vittore Buzzi Children's Hospital, University of Milan, Milan, Italy; the Department of Maternal Fetal Medicine, Osaka Women's and Children's Hospital, Osaka, Japan; the Department of Fetal Medicine, The Aga Khan University, Karachi, Pakistan; the Department of Obstetrics and Gynecology, University Hospitals of Leuven, Leuven, Belgium; the Department of Obstetrics and Gynecology, American University of Beirut Medical Center, Beirut, Lebanon; the Departments of Clinical Biochemistry and Obstetrics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; the Epidemiology Branch, Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, Maryland; the Mednax Center for Research, Education, Quality, and Safety, Sunrise, Florida; the Obstetrix Medical Group, Campbell, California; Unidad de Medicina Materno-Fetal, Instituto Valenciano de Infertilidad, Departamento de Pediatría, Obstetricia y Ginecología, and Servicio de Obstetricia, Hospital Universitario y Politécnico La Fe, Departamento de Pediatría, Obstetricia y Ginecología, Universidad de Valencia, Valencia, Spain; and the Fetal Medicine Unit, St George's Hospital, the Vascular Biology Research Centre, Molecular and Clinical Sciences Research Institute, St George's University of London, and the Twins Trust Centre for Research and Clinical Excellence, London, the Institute of Applied Health Research, University of Birmingham, Birmingham, and the Aberdeen Centre for Women's Health Research, University of Aberdeen, Aberdeen, United Kingdom.

Objective: First, to evaluate the risks of stillbirth and neonatal death by gestational age in twin pregnancies with different levels of growth discordance and in relation to small for gestational age (SGA), and on this basis to establish optimal gestational ages for delivery. Second, to compare these optimal gestational ages with previously established optimal delivery timing for twin pregnancies not complicated by fetal growth restriction, which, in a previous individual patient meta-analysis, was calculated at 37 0/7 weeks of gestation for dichorionic pregnancies and 36 0/7 weeks for monochorionic pregnancies.

Data Sources: A search of MEDLINE, EMBASE, ClinicalTrials.gov, and Ovid between 2015 and 2018 was performed of cohort studies reporting risks of stillbirth and neonatal death in twin pregnancies from 32 to 41 weeks of gestation. Studies from a previous meta-analysis using a similar search strategy (from inception to 2015) were combined. Women with monoamniotic twin pregnancies were excluded.

Methods Of Study Selection: Overall, of 57 eligible studies, 20 cohort studies that contributed original data reporting on 7,474 dichorionic and 2,281 monochorionic twin pairs.

Tabulation, Integration, And Results: We performed an individual participant data meta-analysis to calculate the risk of perinatal death (risk difference between prospective stillbirth and neonatal death) per gestational week. Analyses were stratified by chorionicity, levels of growth discordance, and presence of SGA in one or both twins. For both dichorionic and monochorionic twins, the absolute risks of stillbirth and neonatal death were higher when one or both twins were SGA and increased with greater levels of growth discordance. Regardless of level of growth discordance and birth weight, perinatal risk balanced between 36 0/7-6/7 and 37 0/7-6/7 weeks of gestation in both dichorionic and monochorionic twin pregnancies, with likely higher risk of stillbirth than neonatal death from 37 0/7-6/7 weeks onward.

Conclusion: Growth discordance or SGA is associated with higher absolute risks of stillbirth and neonatal death. However, balancing these two risks, we did not find evidence that the optimal timing of delivery is changed by the presence of growth disorders alone.

Systematic Review Registration: PROSPERO, CRD42018090866.
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http://dx.doi.org/10.1097/AOG.0000000000004789DOI Listing
June 2022

Is home proteinuria testing pragmatic?

BJOG 2022 May 2. Epub 2022 May 2.

Department of Obstetrics and Gynaecology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

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http://dx.doi.org/10.1111/1471-0528.17202DOI Listing
May 2022

Associations of severe adverse perinatal outcomes among continuous birth weight percentiles on different birth weight charts: a secondary analysis of a cluster randomized trial.

BMC Pregnancy Childbirth 2022 Apr 30;22(1):375. Epub 2022 Apr 30.

Department of Midwifery Science, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, AVAG/Amsterdam Public Health, Amsterdam, Netherlands.

Objective: To identify neonatal risk for severe adverse perinatal outcomes across birth weight centiles in two Dutch and one international birth weight chart.

Background: Growth restricted newborns have not reached their intrinsic growth potential in utero and are at risk of perinatal morbidity and mortality. There is no golden standard for the confirmation of the diagnosis of fetal growth restriction after birth. Estimated fetal weight and birth weight below the 10 percentile are generally used as proxy for growth restriction. The choice of birth weight chart influences the specific cut-off by which birth weight is defined as abnormal, thereby triggering clinical management. Ideally, this cut-off should discriminate appropriately between newborns at low and at high risk of severe adverse perinatal outcomes and consequently correctly inform clinical management.

Methods: This is a secondary analysis of the IUGR Risk Selection (IRIS) study. Newborns (n = 12 953) of women with a low-risk status at the start of pregnancy and that received primary antenatal care in the Netherlands were included. We examined the distribution of severe adverse perinatal outcomes across birth weight centiles for three birth weight charts (Visser, Hoftiezer and INTERGROWTH) by categorizing birth weight centile groups and comparing the prognostic performance for severe adverse perinatal outcomes. Severe adverse perinatal outcomes were defined as a composite of one or more of the following: perinatal death, Apgar score < 4 at 5 min, impaired consciousness, asphyxia, seizures, assisted ventilation, septicemia, meningitis, bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia, or necrotizing enterocolitis.

Results: We found the highest rates of severe adverse perinatal outcomes among the smallest newborns (< 3 percentile) (6.2% for the Visser reference curve, 8.6% for the Hoftiezer chart and 12.0% for the INTERGROWTH chart). Discriminative abilities of the three birth weight charts across the entire range of birth weight centiles were poor with areas under the curve ranging from 0.57 to 0.61. Sensitivity rates of the various cut-offs were also low.

Conclusions: The clinical utility of all three charts in identifying high risk of severe adverse perinatal outcomes is poor. There is no single cut-off that discriminates clearly between newborns at low or high risk.

Trial Registration: Netherlands Trial Register NTR4367 . Registration date March 20, 2014.
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http://dx.doi.org/10.1186/s12884-022-04680-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9055757PMC
April 2022

Assessing trustworthiness and data integrity in systematic reviews.

BJOG 2022 Apr 16. Epub 2022 Apr 16.

Amsterdam UMC, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1111/1471-0528.17188DOI Listing
April 2022

Diagnosis and Monitoring of White Coat Hypertension in Pregnancy: an ISSHP Consensus Delphi Procedure.

Hypertension 2022 05 10;79(5):993-1005. Epub 2022 Mar 10.

Fetal Medicine Unit, St George's Hospital (A.K.), St George's University of London, United Kingdom.

Background: There is no accepted definition or standardized monitoring for white coat hypertension in pregnancy. This Delphi procedure aimed to reach consensus on out-of-office blood pressure (BP) monitoring, and white coat hypertension diagnostic criteria and monitoring.

Method: Relevant international experts completed three rounds of a modified Delphi questionnaire. For each item, the predefined cutoff for group consensus was ≥70% agreement, with 60% to 70% considered to warrant reconsideration at the subsequent round, and <60% considered insufficient to warrant consideration.

Results: Of 230 experts, 137 completed the first round and 114 (114/137, 83.2%) completed all three. For out-of-office BP monitoring, there was consensus that home BP monitoring (HBPM) should be chosen; instructions given, pairs of BP values taken, opportunity given for women to qualify values they do not regard as valid, and BP considered evaluated when ≥25% of values are above a cutoff. For HBPM, BP should be taken at least 2 to 3 d/wk, at minimum in the morning; however, many factors may affect frequency and timing. Experts endorsed a clinic BP <140/90 mm Hg as normal. While not reaching consensus, most agreed that HBPM values should be lower than clinic BP. Among those, HBPM <135/85 mm Hg was considered normal. There was consensus that white coat hypertension warrants: HBPM at least 1 d/wk before 20 weeks, 2 to 3 d/wk after 20 weeks or if persistent hypertension develops, and symptom monitoring (ie, headache, visual symptoms, and right upper quadrant/epigastric pain).

Conclusions: Consensus-based diagnostic criteria and monitoring strategies should inform clinical care and research, to facilitate evaluation of out-of-office BP monitoring on pregnancy outcomes.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.121.18356DOI Listing
May 2022

Neonatal pulmonary hypertension after severe early-onset fetal growth restriction: post hoc reflections on the Dutch STRIDER study.

Eur J Pediatr 2022 Apr 12;181(4):1709-1718. Epub 2022 Jan 12.

Amsterdam UMC, Department of Obstetrics and Gynecology, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.

The aim was to reflect on the unexpected finding of persistent pulmonary hypertension of the neonate (PPHN) and pulmonary hypertension in infants born within the Dutch STRIDER trial, its definition and possible pathophysiological mechanisms. The trial randomly assigned pregnant women with severe early-onset fetal growth restriction to sildenafil 25 mg three times a day versus placebo. Sildenafil use did not reduce perinatal mortality and morbidity, but did result in a higher rate of neonatal pulmonary hypertension (PH). The current paper reflects on the used definition, prevalence, and possible pathophysiology of the data on pulmonary hypertension. Twenty infants were diagnosed with pulmonary hypertension (12% of 163 live born infants). Of these, 16 infants had PPHN shortly after birth, and four had pulmonary hypertension associated with sepsis or bronchopulmonary dysplasia. Four infants with PPHN in the early neonatal period subsequently developed pulmonary hypertension associated with bronchopulmonary dysplasia in later life. Infants with pulmonary hypertension were at lower gestational age at delivery, had a lower birth weight and a higher rate of neonatal co-morbidity. The infants in the sildenafil group showed a significant increase in pulmonary hypertension compared to the placebo group (relative risk 3.67; 95% confidence interval 1.28 to 10.51, P = 0.02).

Conclusion: Pulmonary hypertension occurred more frequent among infants of mothers allocated to antenatal sildenafil compared with placebo. A possible pathophysiological mechanism could be a "rebound" vasoconstriction after cessation of sildenafil. Additional studies and data are necessary to understand the mechanism of action.

What Is Known: • In the Dutch STRIDER trial, persistent pulmonary hypertension in the neonate (PPHN) was more frequent among infants after antenatal sildenafil exposure versus placebo.

What Is New: • The current analysis focuses on the distinction between PPHN and pulmonary hypertension associated with sepsis or bronchopulmonary dysplasia and on timing of diagnosis and aims to identify the infants at risk for developing pulmonary hypertension. • The diagnosis pulmonary hypertension is complex, especially in infants born after severe early-onset fetal growth restriction. The research field could benefit from an unambiguous consensus definition and standardized screening in infants at risk is proposed.
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http://dx.doi.org/10.1007/s00431-021-04355-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8964651PMC
April 2022

Research Priority Setting Partnership for placental pathology.

Placenta 2022 01 8;117:154-155. Epub 2021 Dec 8.

Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

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http://dx.doi.org/10.1016/j.placenta.2021.12.008DOI Listing
January 2022

Short-term outcomes of phosphodiesterase type 5 inhibitors for fetal growth restriction: a study protocol for a systematic review with individual participant data meta-analysis, aggregate meta-analysis, and trial sequential analysis.

Syst Rev 2021 12 3;10(1):305. Epub 2021 Dec 3.

Copenhagen Trial Unit, Centre for Clinical Intervention Research, Capital Region of Denmark, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Background: Early onset fetal growth restriction secondary to placental insufficiency can lead to severe maternal and neonatal morbidity and mortality. Pre-clinical studies and a few small randomised clinical trials have suggested that phosphodiesterase type 5 (PDE-5) inhibitors may have protective effects against placental insufficiency in this context; however, robust evidence is lacking. The STRIDER Consortium conducted four randomised trials to investigate the use of a PDE-5 inhibitor, sildenafil, for the treatment of early onset fetal growth restriction. We present a protocol for the pre-planned systematic review with individual participant data meta-analysis, aggregate meta-analysis, and trial sequential analysis of these and other eligible trials. The main objective of this study will be to evaluate the effects of PDE-5 inhibitors on neonatal morbidity compared with placebo or no intervention among pregnancies with fetal growth restriction.

Methods: We will search the following electronic databases with no language or date restrictions: OVID MEDLINE, OVID EMBASE, the Cochrane Controlled Register of Trials (CENTRAL), and the clinical trial registers Clinicaltrials.gov and World Health Organisation International Clinical Trials Registry Platform (ICTRP). We will identify randomised trials of PDE-5 inhibitors in singleton pregnancies with growth restriction. Two reviewers will independently screen all citations, full-text articles, and abstract data. Our primary outcome will be infant survival without evidence of serious adverse neonatal outcome. Secondary outcomes will include gestational age at birth and birth weight z-scores. We will assess bias using the Cochrane Risk of Bias 2 tool. We will conduct aggregate meta-analysis using fixed and random effects models, Trial Sequential Analysis, and individual participant data meta-analysis using one- and two-stage approaches. The certainty of evidence will be assessed with GRADE.

Discussion: This pre-defined protocol will minimise bias during analysis and interpretation of results, toward the goal of providing robust evidence regarding the use of PDE-5 inhibitors for the treatment of early onset fetal growth restriction.

Systematic Review Registration: PROSPERO (CRD42017069688).
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http://dx.doi.org/10.1186/s13643-021-01849-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8643016PMC
December 2021

Pregnancy in women with an inferior vena cava filter: a tertiary center experience and overview of the literature.

Blood Adv 2021 10;5(20):4044-4053

Department of Vascular Medicine.

Patients with an inferior vena cava (IVC) filter that remains in situ encounter a lifelong increased risk of deep vein thrombosis and IVC filter complications including fracture, perforation, and IVC filter thrombotic occlusion. Data on the safety of becoming pregnant with an in situ IVC filter are scarce. The objective was to evaluate the risk of complications of in situ IVC filters during pregnancy. We performed a retrospective cohort study of pregnant patients with an in situ IVC filter from a tertiary center between 2000 and 2020. We collected data on complications of IVC filters and pregnancy outcomes. Additionally, we performed a systematic literature search in MEDLINE, Embase, and gray literature. We identified 7 pregnancies in 4 patients with in situ IVC filters with a mean time since IVC filter insertion of 3 years (range, 1-8). No complications of IVC filter occurred during pregnancy. Review of literature yielded five studies including 13 pregnancies in 9 patients. In 1 pregnancy a pre-existent, until then asymptomatic, chronic perforation of the vena cava wall by the IVC filter caused major bleeding and uterine trauma with fetal loss. Overall, the complication rate was 5%. It seems safe to become pregnant with an indwelling IVC filter that is intact and does not show signs of perforation, but because of the low number of cases, no firm conclusions about safety of in situ IVC filters during pregnancy can be drawn. We suggest imaging before pregnancy to reveal asymptomatic IVC filter complications.
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http://dx.doi.org/10.1182/bloodadvances.2020003930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8945633PMC
October 2021

Evaluation and Management of Suspected Fetal Growth Restriction.

Obstet Gynecol Clin North Am 2021 Jun;48(2):371-385

Department of Obstetrics and Gynecology, Amsterdam University Medical Centers, University of Amsterdam, Room H4-205, PO Box 22660, Amsterdam 1105 AZ, The Netherlands.

Impaired fetal growth owing to placental insufficiency is a major contributor to adverse perinatal outcomes. No intervention is available that improves outcomes by changing the pathophysiologic process. Monitoring in early-onset fetal growth restriction (FGR) focuses on optimizing the timing of iatrogenic preterm delivery using cardiotocography and Doppler ultrasound. In late-onset FGR, identifying the fetus at risk for immediate hypoxia and who benefits from expedited delivery is challenging. It is likely that studies in the next decade will provide evidence how to best integrate different monitoring variables and other prognosticators in risk models that are aimed to optimize individual treatment strategies.
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http://dx.doi.org/10.1016/j.ogc.2021.02.007DOI Listing
June 2021

Abnormal Fetal Growth: Small for Gestational Age, Fetal Growth Restriction, Large for Gestational Age: Definitions and Epidemiology.

Obstet Gynecol Clin North Am 2021 Jun;48(2):267-279

Department of Obstetrics and Gynaecology, University Medical Center of Groningen, CB20, Hanzeplein 1, 9700RB Groningen, the Netherlands.

Abnormal fetal growth (growth restriction and overgrowth) is associated with perinatal morbidity, mortality, and lifelong risks to health. To describe abnormal growth, "small for gestational age" and "large for gestational age" are commonly used terms. However, both are statistical definitions of fetal size below or above a certain threshold related to a reference population, rather than referring to an abnormal condition. Fetuses can be constitutionally small or large and thus healthy, whereas fetuses with seemingly normal size can be growth restricted or overgrown. Although golden standards to detect abnormal growth are lacking, understanding of both pathologic conditions has improved significantly.
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http://dx.doi.org/10.1016/j.ogc.2021.02.002DOI Listing
June 2021

The CErebro Placental RAtio as indicator for delivery following perception of reduced fetal movements, protocol for an international cluster randomised clinical trial; the CEPRA study.

BMC Pregnancy Childbirth 2021 Apr 9;21(1):285. Epub 2021 Apr 9.

Department of Obstetrics and Gynaecology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background: Routine assessment in (near) term pregnancy is often inaccurate for the identification of fetuses who are mild to moderately compromised due to placental insufficiency and are at risk of adverse outcomes, especially when fetal size is seemingly within normal range for gestational age. Although biometric measurements and cardiotocography are frequently used, it is known that these techniques have low sensitivity and specificity. In clinical practice this diagnostic uncertainty results in considerable 'over treatment' of women with healthy fetuses whilst truly compromised fetuses remain unidentified. The CPR is the ratio of the umbilical artery pulsatility index over the middle cerebral artery pulsatility index. A low CPR reflects fetal redistribution and is thought to be indicative of placental insufficiency independent of actual fetal size, and a marker of adverse outcomes. Its utility as an indicator for delivery in women with reduced fetal movements (RFM) is unknown. The aim of this study is to assess whether expedited delivery of women with RFM identified as high risk on the basis of a low CPR improves neonatal outcomes. Secondary aims include childhood outcomes, maternal obstetric outcomes, and the predictive value of biomarkers for adverse outcomes.

Methods: International multicentre cluster randomised trial of women with singleton pregnancies with RFM at term, randomised to either an open or concealed arm. Only women with an estimated fetal weight ≥ 10th centile, a fetus in cephalic presentation and normal cardiotocograph are eligible and after informed consent the CPR will be measured. Expedited delivery is recommended in women with a low CPR in the open arm. Women in the concealed arm will not have their CPR results revealed and will receive routine clinical care. The intended sample size based on the primary outcome is 2160 patients. The primary outcome is a composite of: stillbirth, neonatal mortality, Apgar score < 7 at 5 min, cord pH < 7.10, emergency delivery for fetal distress, and severe neonatal morbidity.

Discussion: The CEPRA trial will identify whether the CPR is a good indicator for delivery in women with perceived reduced fetal movements.

Trial Registration: Dutch trial registry (NTR), trial NL7557 . Registered 25 February 2019.
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http://dx.doi.org/10.1186/s12884-021-03760-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034072PMC
April 2021

Trends in singleton preterm birth in Victoria, 2007 to 2017: A consecutive cross-sectional study.

Acta Obstet Gynecol Scand 2021 07 12;100(7):1230-1238. Epub 2021 Feb 12.

Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia.

Introduction: Preterm birth is a major cause of perinatal morbidity and mortality worldwide. In many countries preterm birth rates are increasing, largely as a result of increases in iatrogenic preterm birth, whereas in other countries rates are stable or even declining. The objective of the study is to describe trends in singleton preterm births in Victoria from 2007 to 2017 in relation to trends in perinatal mortality to identify opportunities for improvements in clinical care.

Material And Methods: We conducted a consecutive cross-sectional study in all women with a singleton pregnancy giving birth at ≥20 weeks of pregnancy in Victoria, Australia, between 2007 and 2017, inclusive. Rates of preterm birth and perinatal mortality were calculated and trends were analyzed in all pregnancies, in pregnancies complicated by fetal growth problems, hypertension, (pre)eclampsia or prelabor rupture of membranes (PROM), and in (low-risk) pregnancies not complicated by any of these conditions.

Results: There were 811 534 singleton births between 2007 and 2017. Preterm birth increased from 5.9% (4074 births) to 6.4% (4893 births; P < .001), due to an increase in iatrogenic preterm birth from 2.5% (1730 births) to 3.6% (2730 births; P < .001). Comparable trends were seen in pregnancies complicated by fetal growth problems and hypertension and in pregnancies not complicated by small for gestational age (SGA), hypertension, (pre)eclampsia or PROM (all P < .001). In pregnancies complicated by SGA, hypertension, (pre)eclampsia or PROM the perinatal mortality rate from 20 weeks of gestation fell (13 to 12 per 1000 births; P < .001). In pregnancies not complicated by SGA, hypertension, (pre)eclampsia or PROM there was no significant change in the perinatal mortality from 28 weeks and no decrease in the preterm weekly prospective stillbirth risk.

Conclusions: The singleton preterm birth rate in Victoria is increasing, driven by an increase in iatrogenic preterm birth, both in pregnancies complicated by SGA and hypertension, and in pregnancies not complicated by SGA, hypertension, (pre)eclampsia or PROM. While perinatal mortality decreased in the pregnancies complicated by SGA, hypertension, (pre)eclampsia or PROM, no significant reduction in perinatal mortality from 28 weeks or in preterm weekly prospective stillbirth risk was noted in the pregnancies not complicated by any of these conditions.
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http://dx.doi.org/10.1111/aogs.14074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359202PMC
July 2021

Perinatal death in a term fetal growth restriction randomized controlled trial: the paradox of prior risk and consent.

Am J Obstet Gynecol MFM 2020 11 24;2(4):100239. Epub 2020 Sep 24.

Leiden University Medical Center, Leiden, the Netherlands.

Background: The disproportionate intrauterine growth intervention trial at term was an intention to treat analysis and compared labor induction with expectant monitoring in pregnancies complicated by fetal growth restriction at term and showed equivalence for neonatal outcomes.

Objective: To evaluate trial participation bias and to examine the generalizability of the results of an obstetrical randomized trial.

Study Design: We used data from participants and nonparticipants of a randomized controlled trial-the disproportionate intrauterine growth intervention trial at term (n=1116) -to perform a secondary analysis. This study compared induction of labor and expectant management in women with term growth restriction. Data were collected in the same manner for both groups. Baseline characteristics and neonatal and maternal outcomes were compared. The primary outcome was a composite measure of adverse neonatal outcome. Secondary outcomes were delivery by cesarean delivery and instrumental vaginal delivery; length of stay in the neonatal intensive care, neonatal ward, and the maternal hospital; and maternal morbidity.

Results: Nonparticipants were older, had a lower body mass index, had a higher level of education, smoked less, and preferred expectant management. The time between study inclusion and labor onset was shorter in participants than in nonparticipants. Notably, 4 perinatal deaths occurred among nonparticipants and none among participants. Among nonparticipants, there were more children born with a birthweight below the third centile. The nonparticipants who had expectant management were monitored less frequently than the participants in both the intervention and the expectant arm.

Conclusion: We found less favorable outcomes and more perinatal deaths in nonparticipants. Protocol-driven management, differences between participants and nonparticipants, or the fact that nonparticipants had a preference for expectant management might explain the findings.
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http://dx.doi.org/10.1016/j.ajogmf.2020.100239DOI Listing
November 2020

Prenatal Use of Sildenafil in Fetal Growth Restriction and Its Effect on Neonatal Tissue Oxygenation-A Retrospective Analysis of Hemodynamic Data From Participants of the Dutch STRIDER Trial.

Front Pediatr 2020 3;8:595693. Epub 2020 Dec 3.

University Medical Center Groningen, Beatrix Children's Hospital, Division of Neonatology, University of Groningen, Groningen, Netherlands.

Sildenafil is under investigation as a potential agent to improve uteroplacental perfusion in fetal growth restriction (FGR). However, the STRIDER RCT was halted after interim analysis due to futility and higher rates of persistent pulmonary hypertension and mortality in sildenafil-exposed neonates. This hypothesis-generating study within the Dutch STRIDER trial sought to understand what happened to these neonates by studying their regional tissue oxygen saturation (rSO) within the first 72 h after birth. Pregnant women with FGR received 25 mg placebo or sildenafil thrice daily within the Dutch STRIDER trial. We retrospectively analyzed the cerebral and renal rSO monitored with near-infrared spectroscopy (NIRS) in a subset of neonates admitted to two participating neonatal intensive care units, in which NIRS is part of standard care. Secondarily, blood pressure and heart rate were analyzed to aid interpretation. Differences in oxygenation levels and interaction with time (slope) between placebo- and sildenafil-exposed groups were tested using mixed effects analyses with multiple comparisons tests. Cerebral rSO levels were not different between treatment groups (79 vs. 77%; both = 14) with comparable slopes. Sildenafil-exposed infants ( = 5) showed lower renal rSO than placebo-exposed infants ( = 6) during several time intervals on day one and two. At 69-72 h, however, the sildenafil group showed higher renal rSO than the placebo group. Initially, diastolic blood pressure was higher and heart rate lower in the sildenafil than the placebo group, which changed during day two. Although limited by sample size, our data suggest that prenatal sildenafil alters renal but not cerebral oxygenation in FGR neonates during the first 72 post-natal hours. The observed changes in renal oxygenation could reflect a vasoconstrictive rebound from sildenafil. Similar changes observed in accompanying vital parameters support this hypothesis.
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http://dx.doi.org/10.3389/fped.2020.595693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744464PMC
December 2020

Validation and development of models using clinical, biochemical and ultrasound markers for predicting pre-eclampsia: an individual participant data meta-analysis.

Health Technol Assess 2020 12;24(72):1-252

Background: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk is needed to plan management.

Objectives: To assess the performance of existing pre-eclampsia prediction models and to develop and validate models for pre-eclampsia using individual participant data meta-analysis. We also estimated the prognostic value of individual markers.

Design: This was an individual participant data meta-analysis of cohort studies.

Setting: Source data from secondary and tertiary care.

Predictors: We identified predictors from systematic reviews, and prioritised for importance in an international survey.

Primary Outcomes: Early-onset (delivery at < 34 weeks' gestation), late-onset (delivery at ≥ 34 weeks' gestation) and any-onset pre-eclampsia.

Analysis: We externally validated existing prediction models in UK cohorts and reported their performance in terms of discrimination and calibration. We developed and validated 12 new models based on clinical characteristics, clinical characteristics and biochemical markers, and clinical characteristics and ultrasound markers in the first and second trimesters. We summarised the data set-specific performance of each model using a random-effects meta-analysis. Discrimination was considered promising for -statistics of ≥ 0.7, and calibration was considered good if the slope was near 1 and calibration-in-the-large was near 0. Heterogeneity was quantified using and τ. A decision curve analysis was undertaken to determine the clinical utility (net benefit) of the models. We reported the unadjusted prognostic value of individual predictors for pre-eclampsia as odds ratios with 95% confidence and prediction intervals.

Results: The International Prediction of Pregnancy Complications network comprised 78 studies (3,570,993 singleton pregnancies) identified from systematic reviews of tests to predict pre-eclampsia. Twenty-four of the 131 published prediction models could be validated in 11 UK cohorts. Summary -statistics were between 0.6 and 0.7 for most models, and calibration was generally poor owing to large between-study heterogeneity, suggesting model overfitting. The clinical utility of the models varied between showing net harm to showing minimal or no net benefit. The average discrimination for IPPIC models ranged between 0.68 and 0.83. This was highest for the second-trimester clinical characteristics and biochemical markers model to predict early-onset pre-eclampsia, and lowest for the first-trimester clinical characteristics models to predict any pre-eclampsia. Calibration performance was heterogeneous across studies. Net benefit was observed for International Prediction of Pregnancy Complications first and second-trimester clinical characteristics and clinical characteristics and biochemical markers models predicting any pre-eclampsia, when validated in singleton nulliparous women managed in the UK NHS. History of hypertension, parity, smoking, mode of conception, placental growth factor and uterine artery pulsatility index had the strongest unadjusted associations with pre-eclampsia.

Limitations: Variations in study population characteristics, type of predictors reported, too few events in some validation cohorts and the type of measurements contributed to heterogeneity in performance of the International Prediction of Pregnancy Complications models. Some published models were not validated because model predictors were unavailable in the individual participant data.

Conclusion: For models that could be validated, predictive performance was generally poor across data sets. Although the International Prediction of Pregnancy Complications models show good predictive performance on average, and in the singleton nulliparous population, heterogeneity in calibration performance is likely across settings.

Future Work: Recalibration of model parameters within populations may improve calibration performance. Additional strong predictors need to be identified to improve model performance and consistency. Validation, including examination of calibration heterogeneity, is required for the models we could not validate.

Study Registration: This study is registered as PROSPERO CRD42015029349.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 24, No. 72. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta24720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780127PMC
December 2020

Temporizing management vs immediate delivery in early-onset severe preeclampsia between 28 and 34 weeks of gestation (TOTEM study): An open-label randomized controlled trial.

Acta Obstet Gynecol Scand 2021 01 28;100(1):109-118. Epub 2020 Aug 28.

Department of Obstetrics and Gynecology, Amsterdam University Medical Center, Amsterdam Medical Center, Amsterdam, The Netherlands.

Introduction: There is little evidence to guide the timing of delivery of women with early-onset severe preeclampsia. We hypothesize that immediate delivery is not inferior for neonatal outcome but reduces maternal complications compared with temporizing management.

Material And Methods: This Dutch multicenter open-label randomized clinical trial investigated non-inferiority for neonatal outcome of temporizing management as compared with immediate delivery (TOTEM NTR 2986) in women between 27 and 33 weeks of gestation admitted for early-onset severe preeclampsia with or without HELLP syndrome. In participants allocated to receive immediate delivery, either induction of labor or cesarean section was initiated at least 48 hours after admission. Primary outcomes were adverse perinatal outcome, defined as a composite of severe respiratory distress syndrome, bronchopulmonary dysplasia, culture proven sepsis, intraventricular hemorrhage grade 3 or worse, periventricular leukomalacia grade 2 or worse, necrotizing enterocolitis stage 2 or worse, and perinatal death. Major maternal complications were secondary outcomes. It was estimated 1130 women needed to be enrolled. Analysis was by intention-to-treat.

Results: The trial was halted after 35 months because of slow recruitment. Between February 2011 and December 2013, a total of 56 women were randomized to immediate delivery (n = 26) or temporizing management (n = 30). Median gestational age at randomization was 30 weeks. Median prolongation of pregnancy was 2 days (interquartile range 1-3 days) in the temporizing management group. Mean birthweight was 1435 g after immediate delivery vs 1294 g after temporizing management (P = .14). The adverse perinatal outcome rate was 55% in the immediate delivery group vs 52% in the temporizing management group (relative risk 1.06; 95% confidence interval 0.67-1.70). In both groups there was one neonatal death and no maternal deaths. In the temporizing treatment group, one woman experienced pulmonary edema and one placental abruption. Analyses of only the singleton pregnancies did not result in other outcomes.

Conclusions: Early termination of the trial precluded any conclusions for the main outcomes. We observed that temporizing management resulted in a modest prolongation of pregnancy without changes in perinatal and maternal outcome. Conducting a randomized study for this important research question did not prove feasible.
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http://dx.doi.org/10.1111/aogs.13976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754130PMC
January 2021

Systematic Reviews and Meta-Analyses Across Species Are Critical to Improve Clinical Translation of Therapeutic Agents for Placental Insufficiency Syndromes.

Hypertension 2021 02 14;77(2):e11-e12. Epub 2020 Dec 14.

Department of Obstetrics (F.T., A.T.L.), University Medical Center Utrecht, Wilhelmina Children's Hospital, the Netherlands.

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16325DOI Listing
February 2021

External validation of prognostic models predicting pre-eclampsia: individual participant data meta-analysis.

BMC Med 2020 11 2;18(1):302. Epub 2020 Nov 2.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk during pregnancy is required to plan management. Although there are many published prediction models for pre-eclampsia, few have been validated in external data. Our objective was to externally validate published prediction models for pre-eclampsia using individual participant data (IPD) from UK studies, to evaluate whether any of the models can accurately predict the condition when used within the UK healthcare setting.

Methods: IPD from 11 UK cohort studies (217,415 pregnant women) within the International Prediction of Pregnancy Complications (IPPIC) pre-eclampsia network contributed to external validation of published prediction models, identified by systematic review. Cohorts that measured all predictor variables in at least one of the identified models and reported pre-eclampsia as an outcome were included for validation. We reported the model predictive performance as discrimination (C-statistic), calibration (calibration plots, calibration slope, calibration-in-the-large), and net benefit. Performance measures were estimated separately in each available study and then, where possible, combined across studies in a random-effects meta-analysis.

Results: Of 131 published models, 67 provided the full model equation and 24 could be validated in 11 UK cohorts. Most of the models showed modest discrimination with summary C-statistics between 0.6 and 0.7. The calibration of the predicted compared to observed risk was generally poor for most models with observed calibration slopes less than 1, indicating that predictions were generally too extreme, although confidence intervals were wide. There was large between-study heterogeneity in each model's calibration-in-the-large, suggesting poor calibration of the predicted overall risk across populations. In a subset of models, the net benefit of using the models to inform clinical decisions appeared small and limited to probability thresholds between 5 and 7%.

Conclusions: The evaluated models had modest predictive performance, with key limitations such as poor calibration (likely due to overfitting in the original development datasets), substantial heterogeneity, and small net benefit across settings. The evidence to support the use of these prediction models for pre-eclampsia in clinical decision-making is limited. Any models that we could not validate should be examined in terms of their predictive performance, net benefit, and heterogeneity across multiple UK settings before consideration for use in practice.

Trial Registration: PROSPERO ID: CRD42015029349 .
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http://dx.doi.org/10.1186/s12916-020-01766-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604970PMC
November 2020

A Core Outcome Set and minimum reporting set for intervention studies in growth restriction in the NEwbOrN: the COSNEON study.

Pediatr Res 2021 05 14;89(6):1380-1385. Epub 2020 Sep 14.

Department of Obstetrics and Gynaecology, University Medical Center of Groningen, University of Groningen, Groningen, The Netherlands.

Background: Different interventions and treatments are available for growth-restricted newborns to improve neonatal and long-term outcomes. Lack of outcome standardization across trials of feeding interventions limits pooled analysis of intervention effects. This study aimed to develop a core outcome set (COS) and minimum reporting set (MRS) for this research field.

Methods: A scoping search identified relevant outcomes and baseline characteristics. These outcomes were presented to two stakeholder groups (lay experience and professional experts) in three rounds of online Delphi surveys. The professional experts were involved in the development of the MRS. All items were rated for their importance on a 5-point Likert scale and re-rated in subsequent rounds after presentation of the results at the group level. During a face-to-face consensus meeting the final COS and MRS were determined.

Results: Forty-seven of 53 experts (89%) who completed the first round completed all three survey rounds. After the consensus meeting, consensus was reached on 19 outcomes and 17 baseline characteristics.

Conclusions: A COS and MRS for feeding interventions in the newborn after growth restriction were developed. Use of these sets will promote uniform reporting of study characteristics and improve data synthesis and meta-analysis of multiple studies.

Impact: Both a COS and MRS for growth restriction in the newborn were developed. This study provides the first international combined health-care professional and patient consensus on outcomes and baseline characteristics for intervention and treatment studies in growth-restricted newborns. The use of COS and MRS results in the development of more uniform study protocols, thereby facilitating data synthesis/meta-analysis of multiple studies aiming to optimize treatment and interventions in growth restriction in the newborn.
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http://dx.doi.org/10.1038/s41390-020-01119-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163598PMC
May 2021

Consensus Definition of Fetal Growth Restriction in Intrauterine Fetal Death: A Delphi Procedure.

Arch Pathol Lab Med 2021 04;145(4):428-436

From the Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (Beune, Damhuis, Gordijn).

Context.—: Fetal growth restriction is a risk factor for intrauterine fetal death. Currently, definitions of fetal growth restriction in stillborns are heterogeneous.

Objectives.—: To develop a consensus definition for fetal growth restriction retrospectively diagnosed at fetal autopsy in intrauterine fetal death.

Design.—: A modified online Delphi survey in an international panel of experts in perinatal pathology, with feedback at group level and exclusion of nonresponders. The survey scoped all possible variables with an open question. Variables suggested by 2 or more experts were scored on a 5-point Likert scale. In subsequent rounds, inclusion of variables and thresholds were determined with a 70% level of agreement. In the final rounds, participants selected the consensus algorithm.

Results.—: Fifty-two experts participated in the first round; 88% (46 of 52) completed all rounds. The consensus definition included antenatal clinical diagnosis of fetal growth restriction OR a birth weight lower than third percentile OR at least 5 of 10 contributory variables (risk factors in the clinical antenatal history: birth weight lower than 10th percentile, body weight at time of autopsy lower than 10th percentile, brain weight lower than 10th percentile, foot length lower than 10th percentile, liver weight lower than 10th percentile, placental weight lower than 10th percentile, brain weight to liver weight ratio higher than 4, placental weight to birth weight ratio higher than 90th percentile, histologic or gross features of placental insufficiency/malperfusion). There was no consensus on some aspects, including how to correct for interval between fetal death and delivery.

Conclusions.—: A consensus-based definition of fetal growth restriction in fetal death was determined with utility to improve management and outcomes of subsequent pregnancies.
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http://dx.doi.org/10.5858/arpa.2020-0027-OADOI Listing
April 2021

Trends in preterm birth in twin pregnancies in Victoria, Australia, 2007-2017.

Aust N Z J Obstet Gynaecol 2021 02 20;61(1):55-62. Epub 2020 Aug 20.

Department of Obstetrics and Gynaecology, Monash University, Melbourne, Victoria, Australia.

Background: Preterm birth is a major cause of perinatal morbidity and mortality worldwide. In many countries, the preterm birth rate in women with a multiple pregnancy is increasing, mostly due to an increase in iatrogenic preterm birth.

Aims: To investigate trends in preterm birth in twin pregnancies in Victoria, Australia, in relation to maternal and perinatal complications.

Materials And Methods: We conducted a retrospective population-based cohort study in all women with a twin pregnancy who delivered at or after 20 weeks of gestation in the state of Victoria, Australia between 2007 and 2017. Annual spontaneous and iatrogenic preterm birth rates were calculated and trends analysed. Incidence of adverse pregnancy outcomes, maternal complications and risk factors for preterm birth were analysed.

Results: We studied 12 757 women with a twin pregnancy. Between 2007 and 2017 the preterm birth rate increased from 641/1231 (52%) to 803/1158 (69%), mainly due to an increase in iatrogenic preterm birth from 342/1231 (28%) to 567/1158 (49%). This was irrespective of the presence of pregnancy complications. Our study showed neither a decrease in perinatal mortality from 28 weeks of gestation nor in preterm average weekly prospective stillbirth risk.

Conclusion: Preterm birth rates in twins in Victoria are increasing, mainly driven by an increase in iatrogenic preterm birth. This occurred both in complicated and non-complicated twin pregnancies, and has not been accompanied by reduction in perinatal mortality from 28 weeks.
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http://dx.doi.org/10.1111/ajo.13227DOI Listing
February 2021

How I treat venous thromboembolism in pregnancy.

Blood 2020 11;136(19):2133-2142

Department of Obstetrics and Gynecology, Amsterdam Reproduction & Development, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.

One to 2 pregnant women in 1000 will experience venous thromboembolism (VTE) during pregnancy or postpartum. Pulmonary embolism (PE) is a leading cause of maternal mortality, and deep vein thrombosis leads to maternal morbidity, with postthrombotic syndrome potentially diminishing quality of life for a woman's lifetime. However, the evidence base for pregnancy-related VTE management remains weak. Evidence-based guideline recommendations are often extrapolated from nonpregnant women and thus weak or conditional, resulting in wide variation of practice. In women with suspected PE, the pregnancy-adapted YEARS algorithm is safe and efficient, rendering computed tomographic pulmonary angiography to rule out PE unnecessary in 39%. Low molecular weight heparin (LMWH) in therapeutic doses is the treatment of choice during pregnancy, and anticoagulation (LMWH or vitamin K antagonists [VKAs]) should be continued until 6 weeks after delivery, with a 3-month minimum total duration. LMWH or VKA use does not preclude breastfeeding. Postpartum, direct oral anticoagulants are an option if a woman does not breastfeed and long-term use is intended. Management of delivery, including type of analgesia, requires a multidisciplinary approach and depends on local preferences and patient-specific conditions. Several options are possible, including waiting for spontaneous delivery with temporary LMWH interruption. Prophylaxis for recurrent VTE prevention in subsequent pregnancies is indicated in most women with a history of VTE.
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http://dx.doi.org/10.1182/blood.2019000963DOI Listing
November 2020

Authors' reply re: Cerebroplacental ratio in predicting adverse perinatal outcome: a meta-analysis of individual participant data.

BJOG 2020 10 20;127(11):1439-1440. Epub 2020 Jul 20.

Department of Obstetrics and Gynecology, Reproduction and Development, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1111/1471-0528.16375DOI Listing
October 2020

Maternal Sildenafil vs Placebo in Pregnant Women With Severe Early-Onset Fetal Growth Restriction: A Randomized Clinical Trial.

JAMA Netw Open 2020 06 1;3(6):e205323. Epub 2020 Jun 1.

Department of Obstetrics and Gynecology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Importance: Severe early onset fetal growth restriction caused by placental dysfunction leads to high rates of perinatal mortality and neonatal morbidity. The phosphodiesterase 5 inhibitor, sildenafil, inhibits cyclic guanosine monophosphate hydrolysis, thereby activating the effects of nitric oxide, and might improve uteroplacental function and subsequent perinatal outcomes.

Objective: To determine whether sildenafil reduces perinatal mortality or major morbidity.

Design, Setting, And Participants: This placebo-controlled randomized clinical trial was conducted at 10 tertiary referral centers and 1 general hospital in the Netherlands from January 20, 2015, to July 16, 2018. Participants included pregnant women between 20 and 30 weeks of gestation with severe fetal growth restriction, defined as fetal abdominal circumference below the third percentile or estimated fetal weight below the fifth percentile combined with Dopplers measurements outside reference ranges or a maternal hypertensive disorder. The trial was stopped early owing to safety concerns on July 19, 2018, whereas benefit on the primary outcome was unlikely. Data were analyzed from January 20, 2015, to January 18, 2019. The prespecified primary analysis was an intention-to-treat analysis including all randomized participants.

Interventions: Participants were randomized to sildenafil, 25 mg, 3 times a day vs placebo.

Main Outcomes And Measures: The primary outcome was a composite of perinatal mortality or major neonatal morbidity until hospital discharge.

Results: Out of 360 planned participants, a total of 216 pregnant women were included, with 108 women randomized to sildenafil (median gestational age at randomization, 24 weeks 5 days [interquartile range, 23 weeks 3 days to 25 weeks 5 days]; mean [SD] estimated fetal weight, 458 [160] g) and 108 women randomized to placebo (median gestational age, 25 weeks 0 days [interquartile range, 22 weeks 5 days to 26 weeks 3 days]; mean [SD] estimated fetal weight, 464 [186] g). In July 2018, the trial was halted owing to concerns that sildenafil may cause neonatal pulmonary hypertension, whereas benefit on the primary outcome was unlikely. The primary outcome, perinatal mortality or major neonatal morbidity, occurred in the offspring of 65 participants (60.2%) allocated to sildenafil vs 58 participants (54.2%) allocated to placebo (relative risk, 1.11; 95% CI, 0.88-1.40; P = .38). Pulmonary hypertension, a predefined outcome important for monitoring safety, occurred in 16 neonates (18.8%) in the sildenafil group vs 4 neonates (5.1%) in the placebo group (relative risk, 3.67; 95% CI, 1.28-10.51; P = .008).

Conclusions And Relevance: These findings suggest that antenatal maternal sildenafil administration for severe early onset fetal growth restriction did not reduce the risk of perinatal mortality or major neonatal morbidity. The results suggest that sildenafil may increase the risk of neonatal pulmonary hypertension.

Trial Registration: ClinicalTrials.gov Identifier: NCT02277132.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.5323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301225PMC
June 2020

Neonatal developmental and behavioral outcomes of immediate delivery versus expectant monitoring in mild hypertensive disorders of pregnancy: 5-year outcomes of the HYPITAT II trial.

Eur J Obstet Gynecol Reprod Biol 2020 Jan 6;244:172-179. Epub 2019 Nov 6.

Epidemiology, University Medical Centre Groningen, Groningen, The Netherlands.

Objective: To compare effects of immediate delivery vs expectant monitoring on neurodevelopmental and behavioral outcomes at 5 years of age in offspring of women with mild late preterm hypertensive disorders.

Study Design: We studied children born during the HYPITAT-II trial, in which 704 women with a hypertensive disorder between 34 and 37 weeks of gestation were randomized to immediate delivery or expectant monitoring. Participating women were asked to complete the Ages and Stages Questionnaire (ASQ) for developmental outcome and the Child Behavior Checklist (CBCL) for behavioral problems when their child was 5 years old. Outcomes were dichotomized and analyzed by logistic regression analysis. We also assessed factors influencing development and behavior at both 2 and 5 years after a hypertensive pregnancy.

Results: Five years after the original study 322(46%) women were contacted for follow-up, of whom 148 (46%) responded. In the delivery group 22%(n = 14/65) of the children had an abnormal ASQ score compared to 21% (n = 13/62) in the expectant monitoring group (p = 0.9). Abnormal CBCL-scores were found in 19% (n = 14/72) of the children in the delivery group versus in 27% (n = 20/75) in the expectant monitoring group (p = 0.3). The main predictor of development and behavior at 2 and 5 years was fetal growth restriction (for abnormal development OR 2.1, CI 1.0-4.4; for behavior problems OR 2.2, CI 1.1-5.5). Higher maternal education decreased abnormal behavior outcomes (OR 0.5, CI 0.2-0.9) and a similar tendency was observed for developmental problems (OR 0.6, CI 0.3 - 1.1).

Conclusion: We did not find different developmental and behavior outcomes at 5 years of age between a management policy of immediate delivery and expectant management in preterm hypertensive disorders. The increased risk of developmental delay at 2 years of age after immediate delivery, we found in the 2 year follow up study, did not persist at 5 years of age.
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http://dx.doi.org/10.1016/j.ejogrb.2019.11.001DOI Listing
January 2020
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