Publications by authors named "Wessel Ganzevoort"

86 Publications

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 2020 Dec 31. Epub 2020 Dec 31.

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
December 2020

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 Feb 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 May 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

Inter- and intra-observer variability in fetal ductus venosus blood flow measurements in high-risk fetuses at 26-32 weeks.

Eur J Obstet Gynecol Reprod Biol 2019 Dec 22;243:67-71. Epub 2019 Oct 22.

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

Objectives: Early preterm fetal growth restriction is a significant contributor to perinatal morbidity and mortality. The ductus venosus pulsatility index for veins (DV PIV) is proposed as a monitoring tool because it appears to improve perinatal outcomes. The test characteristics and robustness of DV PIV have been inadequately described. The aim of this study was to investigate inter- and intra-observer variability of DV PIV.

Study Design: Nineteen women with a gestational age between 26 and 32 completed weeks were included in this study. Doppler sonographic fetal assessment was performed by two independent maternal-fetal medicine specialists. Each sonographer alternately performed three flow tracings for each participant, in the absence of the other sonographer (six tracings in total per patient). DV PIV was calculated automatically from stored tracings by a third researcher. Inter- and intra-observer variability of DV PIV and limits of agreement were assessed using the Bland-Altman method. Comparison of the distribution was performed with Kendall's related samples test, and the intraclass correlation coefficient (ICC) was calculated.

Results: In total, 114 DV measurements were taken from 19 participants with a median age of 31 years [interquartile range (IQR) 26-34 years] at a median gestational age of 28 weeks (IQR 27-29 weeks). The proportional limits of agreement for intra-observer variation were -0.48 to 0.48 and -0.39 to 0.62 for the two observers. ICCs were 0.66 [95% confidence interval (CI) 0.42-0.84] and 0.68 (95% CI 0.45-0.85). The proportional limits of agreement for inter-observer variation were -0.29 to 0.19 with an ICC of 0.89 (95% CI 0.73-0.96).

Conclusion: Inter-observer variation was far less than intra-observer variation, probably due to mitigation of biological variation by averaging three measurements. DV PIV has acceptable test characteristics for use in a clinical setting when the average of at least three consecutive measurements is used.
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http://dx.doi.org/10.1016/j.ejogrb.2019.10.028DOI Listing
December 2019

HOspital care versus TELemonitoring in high-risk pregnancy (HOTEL): study protocol for a multicentre non-inferiority randomised controlled trial.

BMJ Open 2019 10 28;9(10):e031700. Epub 2019 Oct 28.

Obstetrics and Gynaecology, UMC Utrecht, Utrecht, The Netherlands

Introduction: Pregnant women faced with complications of pregnancy often require long-term hospital admission for maternal and/or fetal monitoring. Antenatal admissions cause a burden to patients as well as hospital resources and costs. A telemonitoring platform connected to wireless cardiotocography (CTG) and automated blood pressure (BP) devices can be used for telemonitoring in pregnancy. Home telemonitoring might improve autonomy and reduce admissions and thus costs. The aim of this study is to compare the effects on patient safety, satisfaction and cost-effectiveness of spital care versus emonitoring (HOTEL) as an obstetric care strategy in high-risk pregnancies requiring daily monitoring.

Methods And Analysis: The HOTEL trial is an ongoing multicentre randomised controlled clinical trial with a non-inferiority design. Eligible pregnant women are >26+0 weeks of singleton gestation requiring monitoring because of pre-eclampsia (hypertension with proteinuria), fetal growth restriction, preterm rupture of membranes without contractions, recurrent reduced fetal movements or an intrauterine fetal death in a previous pregnancy.Randomisation takes place between traditional hospitalisation (planned n=208) versus telemonitoring (planned n=208) until delivery. Telemonitoring at home is facilitated with Sense4Baby CTG devices, Microlife BP monitor and daily telephone calls with an obstetric healthcare professional as well as weekly hospital visits.Primary outcome is a composite of adverse perinatal outcome, defined as perinatal mortality, 5 min Apgar <7 or arterial cord blood pH <7.05, maternal morbidity (eclampsia, HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, thromboembolic event), neonatal intensive care admission and caesarean section rate. Patient satisfaction and preference of care will be assessed using validated questionnaires. We will perform an economic analysis. Outcomes will be analysed according to the intention to treat principle.

Ethics And Dissemination: The study protocol was approved by the Ethics Committee of the Utrecht University Medical Center and the boards of all six participating centres. Trial results will be submitted to peer-reviewed journals.

Trial Registration Number: NTR6076.
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http://dx.doi.org/10.1136/bmjopen-2019-031700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830707PMC
October 2019

Management of non-severe pregnancy hypertension - A summary of the CHIPS Trial (Control of Hypertension in Pregnancy Study) research publications.

Pregnancy Hypertens 2019 Oct 15;18:156-162. Epub 2019 Oct 15.

Department of Women and Children's Health, King's College London, UK.

The international CHIPS Trial (Control of Hypertension In Pregnancy Study) enrolled 987 women with chronic (75%) or gestational (25%) hypertension. Pre-eclampsia developed in 48%; women remained on their allocated BP control and delivered an average of two weeks later. 'Less tight' control (target diastolic BP 100 mmHg) achieved BP that was 6/5mmHg higher (p < 0.001) than 'tight' control (target diastolic 85 mmHg, BP achieved 133/85 mmHg). 'Less tight' (vs. 'tight') control resulted in similar adverse perinatal outcomes (31.5% vs. 30.7%; p = 0.84) that balanced birthweight < 10th percentile (16.1% vs. 19.8%; p = 0.14) against preterm birth (35.6% vs. 31.5%; p = 0.18). 12-month follow-up revealed no compelling evidence for developmental programming of child growth. However, 'less tight' (vs. 'tight') control resulted in more severe maternal hypertension (40.6% vs. 27.5%; p < 0.001), and more women with platelets < 100 × 10/L (4.3% vs. 1.6%; p = 0.02) or symptomatic elevated liver enzymes (4.3% vs. 1.8%; p = 0.03), with no difference in serious maternal complications (3.7% vs. 2.0%; p = 0.17). Labetalol was the drug of choice. Methyldopa did not result in inferior outcomes. Post-hoc, severe hypertension, independent of pre-eclampsia, was associated with heightened increased risk of adverse outcomes, and in 'less tight' control, of serious maternal complications. At no gestational age at initiation of BP control was 'less tight' superior to 'tight'. Women in both groups were equally satisfied with care. 'Less tight' control tended to be more expensive by CAD$6000 (p =0.07) based on neonatal care costs. Collectively, CHIPS publications have provided evidence that women with non-severe pregnancy hypertension should receive 'tight' BP control achieved by a simple algorithm.
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http://dx.doi.org/10.1016/j.preghy.2019.08.166DOI Listing
October 2019

Association between fetal sex, birthweight percentile and adverse pregnancy outcome.

Acta Obstet Gynecol Scand 2020 01 30;99(1):48-58. Epub 2019 Aug 30.

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

Introduction: The objective was to evaluate the association between fetal sex and adverse pregnancy outcome, while correcting for fetal growth and gestational age at delivery.

Material And Methods: Data from the Netherlands Perinatal Registry (1999-2010) were used. The study population comprised all white European women with a singleton delivery between 25 and 42  weeks of gestation. Fetuses with structural or chromosomal abnormalities were excluded. Outcomes were antepartum death, intrapartum/neonatal death (from onset of labor until 28 days after birth), perinatal death (antepartum death or intrapartum/neonatal death), a composite of neonatal morbidity (including infant respiratory distress syndrome, sepsis, necrotizing enterocolitis, meconium aspiration, persistent pulmonary hypertension of the newborn, periventricular leukomalacia, Apgar score <7 at 5 minutes, and intracranial hemorrhage) and a composite adverse neonatal outcome (perinatal death or neonatal morbidity). Outcomes were expressed stratified by birthweight percentile (p90 [large for gestation]) and gestational age at delivery (25 -27 , 28 -31 , 32 -36 , 37 -42 weeks). The association between fetal sex and outcome was assessed using the fetus at risk approach.

Results: We studied 1 742 831 pregnant women. We found no increased risk of antepartum, intrapartum/neonatal and perinatal death in normal weight and large-for-gestation males born after 28 weeks compared with females. We found an increased risk of antepartum death among small-for-gestation males born after 28 weeks (relative risk [RR] 1.16-1.40). All males born after 32  weeks of gestation suffered more neonatal morbidity than females regardless of birthweight percentile (RR 1.07-1.34). Infant respiratory distress syndrome, sepsis, persistent pulmonary hypertension of the newborn, Apgar score <7 at 5 minutes, and intracranial hemorrhage all occurred more often in males than in females.

Conclusions: Small-for-gestation males have an increased risk of antepartum death and all males born after 32  weeks of gestation have an increased risk of neonatal morbidity compared with females. In contrast to findings in previous studies we found no increased risk of antepartum, intrapartum/neonatal or perinatal death in normal weight and large-for-gestation males born after 28+0 weeks.
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http://dx.doi.org/10.1111/aogs.13709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973256PMC
January 2020

Development of a Core Outcome Set and Minimum Reporting Set for intervention studies in growth restriction in the NEwbOrN (COSNEON): study protocol for a Delphi study.

Trials 2019 Aug 17;20(1):511. Epub 2019 Aug 17.

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

Background: Growth restriction in the newborn (GRN) can predispose to severe complications including hypoglycemia, sepsis, and necrotizing enterocolitis. Different interventions and treatments, such as feeding strategies, for GRN have specific benefits and risks. Comparing results from studies investigating intervention studies in GRN is challenging due to the use of different baseline and study characteristics and differences in reported study outcomes. In order to be able to compare study results and to allow pooling of data, uniform reporting of study characteristics (minimum reporting set [MRS]) and outcomes (core outcome set [COS]) are needed. We aim to develop both an MRS and a COS for interventional and treatment studies in GRN.

Methods/design: The MRS and COS will be developed according to Delphi methodology. First, a scoping literature search will be performed to identify study characteristics and outcomes in research focused on interventions/treatments in the GRN. An international group of stakeholders, including experts (clinicians working with GRN, and researchers who focus on GRN) and lay experts ([future] parents of babies with GRN), will be questioned to rate the importance of the study characteristics and outcomes in three rounds. After three rounds there will be two consensus meetings: a face-to-face meeting and an electronic meeting. During the consensus meetings multiple representatives of stakeholder groups will reach agreement upon which study characteristics and outcomes will be included into the COS and MRS. The second electronic consensus meeting will be used to test if an electronic meeting is as effective as a face-to-face meeting.

Discussion: In our opinion a COS alone is not sufficient to compare and aggregate trial data. Hence, to ensure optimum comparison we also will develop an MRS. Interventions in GRN infants are often complicated by coexisting preterm birth. A COS already has been developed for preterm birth. The majority of GRN infants are born at term, however, and we therefore chose to develop a separate COS for interventions in GRN, which can be combined (with expected overlap) in intervention studies enrolling preterm GRN babies.

Trial Registration: Not applicable. This study is registered in the Core Outcome Measures for Effectiveness ( COMET ) database. Registered on 30 June 2017.
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http://dx.doi.org/10.1186/s13063-019-3588-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697910PMC
August 2019

Early-onset fetal growth restriction: A systematic review on mortality and morbidity.

Acta Obstet Gynecol Scand 2020 02 10;99(2):153-166. Epub 2019 Sep 10.

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

Introduction: Severe early-onset fetal growth restriction is an obstetric condition with significant risks of perinatal mortality, major and minor neonatal morbidity, and long-term health sequelae. The prognosis of a fetus is influenced by the extent of prematurity and fetal weight. Clinical care is individually adjusted. In literature, survival rates vary and studies often only include live-born neonates with missing rates of antenatal death. This systematic review aims to summarize the literature on mortality and morbidity.

Material And Methods: A broad literature search was conducted in OVID MEDLINE from 2000 to 26 April 2019 to identify studies on fetal growth restriction and perinatal death. Studies were excluded when all included children were born before 2000 because (neonatal) health care has considerably improved since this period. Studies were included that described fetal growth restriction diagnosed before 32 weeks of gestation and antenatal mortality and neonatal mortality and/or morbidity as outcome. Quality of evidence was rated with the GRADE instrument.

Results: Of the 2604 publications identified, 25 studies, reporting 2895 pregnancies, were included in the systematic review. Overall risk of bias in most studies was judged as low. The quality of evidence was generally rated as very low to moderate, except for 3 large well-designed randomized controlled trials. When combining all data on mortality, in 355 of 2895 pregnancies (12%) the fetus died antenatally, 192 died in the neonatal period (8% of live-born neonates) and 2347 (81% of all pregnancies) children survived. Of the neonatal morbidities recorded, respiratory distress syndrome (34% of the live-born neonates), retinopathy of prematurity (13%) and sepsis (30%) were most common. Of 476 children that underwent neurodevelopmental assessment, 58 (12% of surviving children, 9% of all pregnancies) suffered from cognitive impairment and/or cerebral palsy.

Conclusions: When combining the data of 25 included studies, survival in fetal growth restriction pregnancies, diagnosed before 32 weeks of gestation, was 81%. Neurodevelopmental impairment was assessed in a minority of surviving children. Individual prognostic counseling on the basis of these results is hampered by differences in patient and pregnancy characteristics within the included patient groups.
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http://dx.doi.org/10.1111/aogs.13702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004054PMC
February 2020

A Core Outcome Set for the prevention and treatment of fetal GROwth restriction: deVeloping Endpoints: the COSGROVE study.

Am J Obstet Gynecol 2019 10 29;221(4):339.e1-339.e10. Epub 2019 May 29.

Fetal Medicine Unit, St George's University and St George's University Hospitals NHS Foundation Trust, London, United Kingdom; Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, United Kingdom.

Background: Fetal growth restriction refers to a fetus that does not reach its genetically predetermined growth potential. It is well-recognized that growth-restricted fetuses are at increased risk of both short- and long-term adverse outcomes. Systematic evaluation of the evidence from clinical trials of fetal growth restriction is often difficult because of variation in the outcomes that are measured and reported. The development of core outcome sets for fetal growth restriction studies would enable future trials to measure similar meaningful outcomes.

Objective: The purpose of this study was to develop core outcome sets for trials of prevention or treatment of fetal growth restriction.

Study Design: This was a Delphi consensus study. A comprehensive literature review was conducted to identify outcomes that were reported in studies of prevention or treatment of fetal growth restriction. All outcomes were presented for prioritization to key stakeholders (135 healthcare providers, 68 researchers/academics, and 35 members of the public) in 3 rounds of online Delphi surveys. A priori consensus criteria were used to reach agreement on the final outcomes for inclusion in the core outcome set at a face-to-face meeting with 5 healthcare providers, 5 researchers/academics, and 6 maternity service users.

Results: In total, 22 outcomes were included in the final core outcome set. These outcomes were grouped under 4 domains: maternal (n=4), fetal (n=1), neonatal (n=12), and childhood (n=5).

Conclusion: The Core Outcome Set for the prevention and treatment of fetal GROwth restriction: deVeloping Endpoints study identified a large number of potentially relevant outcomes and then reached consensus on those factors that, as a minimum, should be measured and reported in all future trials of prevention or treatment of fetal growth restriction. This will enable future trials to measure similar meaningful outcomes and to ensure that findings from different studies can be compared and combined.
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http://dx.doi.org/10.1016/j.ajog.2019.05.039DOI Listing
October 2019

Computerized fetal cardiotocography analysis in early preterm fetal growth restriction - a quantitative comparison of two applications.

J Perinat Med 2019 May;47(4):439-447

Department of Obstetrics, Amsterdam University Medical CenterAmsterdam, The Netherlands.

Background We developed an open-source software for the computerized analysis of antenatal fetal cardiotocography (CTG) without limitation of duration of the registration, enabling batch processing and adaptation to any digital storage system. Methods STVcalc was developed based on literature about the FetalCare system (Huntleigh Healthcare Ltd, Cardiff, UK). For comparison with FetalCare, we selected the CTGs of all women who delivered in 2011 a small-for-gestational-age (SGA) fetus between 24 and 31 weeks by cesarean section (CS) for fetal distress, or had fetal death, before labor onset. Results In 471 CTGs from 39 women, the agreement was 99% for a short-term variation (STV) cut-off of 2.6 ms below 29 weeks and 3.0 ms thereafter, and 95% for 3.5 and 4.0 ms, respectively. In 18 (4%) cases, the proportional difference in STV between FetalCare and STVcalc was more than 10%. Conclusion As only slight differences were observed between the proposed feature-rich application and the FetalCare system, it can be considered valuable for clinical practice and research purposes.
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http://dx.doi.org/10.1515/jpm-2018-0412DOI Listing
May 2019

Neonatal developmental and behavioral outcomes of immediate delivery versus expectant monitoring in mild hypertensive disorders of pregnancy: 2-year outcomes of the HYPITAT-II trial.

Am J Obstet Gynecol 2019 08 30;221(2):154.e1-154.e11. Epub 2019 Mar 30.

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

Background: Management of preterm hypertensive disorders remains a clinical dilemma. The maternal benefits of delivery need to be weighed against the adverse neonatal consequences of preterm birth. Long-term consequences of obstetric management in offspring of women with hypertensive disorders in preterm pregnancy are largely unknown. We report child neurodevelopmental and behavioral outcomes at 2 years after the Hypertension and Preeclampsia Intervention Trial at near Term (HYPITAT-II) trial, which compared immediate delivery versus expectant monitoring in mild late preterm hypertensive disorders of pregnancy.

Objective: To compare effects of immediate delivery vs expectant monitoring on neurodevelopmental and behavioral outcomes at 2 years of age in offspring of women with mild late preterm hypertensive disorders.

Materials And Methods: We studied children born in the HYPITAT-II trial, a study in which women (n = 704) with hypertensive disorders of pregnancy who were between 34 and 37 weeks' gestation were randomized to immediate delivery or expectant monitoring. Participating women were asked to complete the Ages and Stages Questionnaire for developmental outcome and the Child Behavior Checklist for behavioral problems when their toddlers were 2 years old.

Results: We approached 545 of 704 randomized women (77%); 330 of 545 (61%) returned the questionnaires. In the immediate delivery group, 45 of 162 infants (28%) had an abnormal Ages and Stages Questionnaire score compared to 27 of 148 (18%) in the expectant monitoring group (risk difference, 9.6%; 95% CI, 0.3-18.0%); P = .045. In the pregnancies (n = 94) that delivered before reaching 36 weeks, 27% (n = 25) had an abnormal Ages and Stages Questionnaire score compared to 22% (n = 47) when delivered after 36 weeks (odds ratio, 0.77; confidence interval, 0.44-1.34). An abnormal Child Behavior Checklist outcome was found in 31 of 175 (18%) in the delivery group vs 24 of 166 (15%) in the expectant monitoring group (risk difference, 3.2%; 95% CI, -4.6% to 11.0%). After correction for maternal education, management strategy remained an independent predictor of abnormal Ages and Stages Questionnaire score (odds ratio, 0.48; confidence interval, 0.24 to -0.96, P = .03). In multivariable analyses, low birth weight, low maternal education, and immediate delivery policy were all significantly associated with an abnormal Ages and Stages Questionnaire score.

Conclusion: In this study, we found that early delivery in women with late preterm hypertensive disorders is associated with poorer neurodevelopmental outcomes in their children at 2 years of age. These findings indicate an increased risk of developmental delay after early delivery compared to expectant monitoring. This follow-up study underlines the conclusion of the original HYPITAT-II study that, until the clinical situation deteriorates, expectant monitoring remains the most appropriate management strategy in the light of short- and long-term neonatal outcomes in women with preterm hypertensive disorders.
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http://dx.doi.org/10.1016/j.ajog.2019.03.024DOI Listing
August 2019

The Possible Role of Placental Morphometry in the Detection of Fetal Growth Restriction.

Front Physiol 2018 8;9:1884. Epub 2019 Jan 8.

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

Fetal growth restriction (FGR) is often the result of placental insufficiency and is characterized by insufficient transplacental transport of nutrients and oxygen. The main underlying entities of placental insufficiency, the pathophysiologic mechanism, can broadly be divided into impairments in blood flow and exchange capacity over the syncytiovascular membranes of the fetal placenta villi. Fetal growth restriction is not synonymous with small for gestational age and techniques to distinguish between both are needed. Placental insufficiency has significant associations with adverse pregnancy outcomes (perinatal mortality and morbidity). Even in apparently healthy survivors, altered fetal programming may lead to long-term neurodevelopmental and metabolic effects. Although the concept of fetal growth restriction is well appreciated in contemporary obstetrics, the appropriate detection of FGR remains an issue in clinical practice. Several approaches have aimed to improve detection, e.g., uniform definition of FGR, use of Doppler ultrasound profiles and use of growth trajectories by ultrasound fetal biometry. However, the role of placental morphometry (placental dimensions/shape and weight) deserves further exploration. This review article covers the clinical relevance of placental morphometry during pregnancy and at birth to help recognize fetuses who are growth restricted. The assessment has wide intra- and interindividual variability with various consequences. Previous studies have shown that a small placental surface area and low placental weight are associated with a slower growth of the fetus. Parameters such as placental surface area, placental volume and placental weight in relation to birth weight can help to identify FGR. In the future, a model including sophisticated antenatal placental morphometry may prove to be a clinically useful method for screening or diagnosing growth restricted fetuses, in order to provide optimal monitoring.
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http://dx.doi.org/10.3389/fphys.2018.01884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331677PMC
January 2019

Blood pressure of 12-year-old children born after foetal growth restriction due to hypertensive disorders of pregnancy; relation to neonatal, life style, and family characteristics.

Early Hum Dev 2019 03 16;130:33-37. Epub 2019 Jan 16.

Department of Pediatrics, Academic Medical Center, Amsterdam, the Netherlands.

Introduction: Children born from pregnancies that were complicated by hypertensive disorders of pregnancy (HDP, i.e. pre-eclampsia or HELLP syndrome) are at risk for elevated systolic and diastolic blood pressure (SBP/DBP) in childhood.

Aim: To examine which neonatal, life style, and family characteristics are associated with SBP/DBP.

Methods: Study design: Prospective cohort.

Subjects: 12-years-old preterm and growth restricted children born to women with severe early-onset HDP.

Outcome Measures: SBP/DBP standard deviation scores (SDS), corrected for age, gender and height.

Results: Ninety-two of the 174 mother-child pairs participated at age 12 years (mean gestational age 32 weeks, range 27 to 38 weeks, mean birth weight ratio (BWR) 0.68, range 0.33 to 0.99). Mean SBP SDS was 0.70 ± 0.81 and mean DBP SDS was 0.14 ± 0.78. SBP SDS was positively associated with very preterm birth (beta 0.53, p = .002), with child BMI SDS (beta 0.25, p = .035), and maternal BMI ≥ 25 kg/m at 12 years (beta 0.49, p = .003), and not with pre-pregnancy maternal BMI ≥ 25 kg/m. DBP SDS was positively associated with maternal BMI ≥ 25 kg/m (beta 0.35, p 0.002). BWR was not associated with blood pressure.

Conclusions: In 12-years old children born to women with HDP, higher systolic blood pressure values were associated with very preterm birth and child BMI. Higher blood pressure values were also associated with current maternal BMI ≥ 25 kg/m. Life style adaptations may benefit long-term cardio vascular health in mother and child.
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http://dx.doi.org/10.1016/j.earlhumdev.2019.01.001DOI Listing
March 2019