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Background: Gestational age is positively associated with cognitive development, but socio-demographic factors also influence school performance. Previous studies suggested possible interaction, putting children with low socio-economic status (SES) at increased risk of the negative effects of prematurity. Objectives: To investigate the association between gestational age in weeks, socio-demographic characteristics, and school performance at the age of 12 years among children in regular primary education. Methods: Population-based cohort study among liveborn singletons (N = 860,332) born in the Netherlands in 1999–2006 at 25–42 weeks' gestation, with school performance from 2011 to 2019. Regression analyses were conducted investigating the association of gestational age and sociodemographic factors with school performance and possible interaction. Results: School performance increased with gestational age up to 40 weeks. This pattern was evident across socio-demographic strata. Children born at 25 weeks had −0.57 SD (95% confidence interval −0.79, −0.35) lower school performance z-scores and lower secondary school level compared to 40 weeks. Low maternal education, low maternal age, and non-European origin were strongly associated with lower school performance. Being born third or later and low socioeconomic status (SES) were also associated with lower school performance, but differences were smaller than among other factors. When born preterm, children from mothers with low education level, low or high age, low SES or children born third or later were at higher risk for lower school performance compared to children of mothers with intermediate education level, aged 25–29 years, with intermediate SES or first borns (evidence of interaction). Conclusions: Higher gestational age is associated with better school performance at the age of 12 years along the entire spectrum of gestational age, beyond the cut-off of preterm birth and across socio-demographic differences. Children in socially or economically disadvantaged situations might be more vulnerable to the negative impact of preterm birth. Other important factors in school performance are maternal education, maternal age, ethnicity, birth order and SES. Results should be interpreted with caution due to differential loss to follow-up.

Abstract 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).

Pregnancy is often considered to be a “cardiometabolic stress-test” and pregnancy complications including hypertensive disorders of pregnancy can be the first indicator of increased risk of future cardiovascular disease. Over the last two decades, more evidence on the association between hypertensive disorders of pregnancy and cardiovascular disease has become available. However, despite the importance of addressing existing racial and ethnic differences in the incidence of cardiovascular disease, most research on the role of hypertensive disorders of pregnancy is conducted in white majority populations. The fragmented knowledge prohibits evidence-based targeted prevention and intervention strategies in multi-ethnic populations and maintains the gap in health outcomes. In this review, we present an overview of the evidence on racial and ethnic differences in the occurrence of hypertensive disorders of pregnancy, as well as evidence on the association of hypertensive disorders of pregnancy with cardiovascular risk factors and cardiovascular disease across different non-White populations, aiming to advance equity in medicine.

OBJECTIVE: Induction of labour (IOL) from 37 weeks for various indications is associated with a reduction in perinatal deaths compared to expectant management, though absolute rates are small. The incidence of IOL has been rising. The effects of IOL from 37 weeks on childhood neurodevelopment however are not well studied. We aimed to study the influence of IOL for each week of 12 years. STUDY DESIGN: We performed a population-based study among liveborn singletons from 37+0-42+6 weeks of gestation in cephalic presentation born in 2003-2008 from uncomplicated pregnancies (no hypertensive disorders, diabetes or birthweight < p5). Children with congenital anomalies, of non-Western ethnicity and born after planned cesarean section were excluded. Birth records were linked with national data on standardized school achievement at age 11-12 (rates 501-550). We compared, using a fetus-at-risk approach and per week of gestation, school performance in those born after IOL to those born after expectant management, i.e. spontaneous onset of labour in the same week plus all those born at later gestations. Education scores were standardized to a mean of 0 and a S.D. of 1 and adjusted in the regression analyses. RESULTS: We included 226,684 children. At each week of gestation, IOL was associated with a decreased mean education score compared with expectant management (at 37 weeks -0.96, 95%CI -1.43 to -0.50; at 42 weeks -0.52, 95%CI -1.00 to -0.04; Table 1). Adjusted mean education z-score was -0.10 (-0.15 to -0.05) lower after IOL compared to expectant management at 37 weeks (Figure 1). At each gestational week between 38 and 42 weeks we found comparable differences in mean education z-score, favoring expectant management. CONCLUSION: Consistently, at every week of gestation from 37-42 weeks, IOL at term in uncomplicated pregnancies significantly reduces offspring school performance at age 12 compared to expectant management. Residual confounding may remain. These long-term effects should be incorporated in decisions around IOL.

CONTEXT.—: Fetal growth restriction is a risk factor for intrauterine fetal death. Currently, definitions of fetal growth restriction in stillborn 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.

Additional file 1. Interviews for women and physicians - translated from Dutch.

Invitation to participate. (PDF 197 kb)

The National Research Ethics Service (NRES) has advised that ethical approval is not required. (PDF 164kb)

This book provides a comprehensive resource on the pathology of the human singleton placenta. Agreed nomenclature, nosology, definitions and, where possible, thresholds for meaningful clinical corrections for lesions ideal for practical application in clinical practice are presented. Evidence is also featured on relevant potential clinical correlations to aid the reader in deciding upon the most appropriate management strategy. Areas of current uncertainty are also covered for potential future research. Pathology of the Placenta systematically describes placental pathology, and represents a valuable resource for practising and trainee pathologists, obstetricians, neonatologists and epidemiologists.

Populated Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Checklist. (DOC 120 kb)

SPIRIT checklist. (PDF 99 kb)

Maximum percent of deaths classified as “other” and “unexplained” by classification systems according to type of death classified. (DOCX 62 kb)

Year of creation/modification of classification systems for causes of stillbirth and neonatal death developed or used between 2009 and 2014. (DOCX 48 kb)

Decision tree for inclusion/exclusion. (DOCX 45 kb)

Classification systems for causes of stillbirth and neonatal death used in highest-burden countries, 2009-2014. (DOCX 83 kb)

81 included systems and selected features. (DOCX 59.8 kb)

PRISMA checklist. (DOCX 51 kb)

Sensitivity analyses. (DOCX 62.6 kb)

Selected shortcomings of existing systems and rationale for development of new systems/modification of existing systems. (DOCX 44 kb)

List of variables extracted. (DOCX 46 kb)

Variables used to assess system alignment with expert-identified characteristics for an effective global classification system for causes of stillbirth and neonatal death. (DOCX 89.1 kb)

Sensitivity of number of “widely used” systems to cut-offs for number of countries in which used and number of deaths classified. (DOCX 46 kb)

National classification systems for causes of stillbirth and neonatal death in use 2009-2014. (DOCX 53 kb)

Countries in which more than one system was used to classify causes of stillbirths and/or neonatal deaths, 2009-2014. (DOCX 45 kb)

All included publications with reason for inclusion and author intent. (DOCX 223 kb)

Kappa scores from reliability testing of classification systems for causes of stillbirth and neonatal death in use 2009-2014. (DOCX 66 kb)

Examples of the classification of substandard factors. (PDF 37 kb)

This thesis describes the impact and the complexity of the diagnosis and management of late-onset fetal growth restriction. Fetal growth restriction is a condition in which the fetus is unable to reach its intrinsic growth potential due to reduced placental function. The lack of oxygen and nutrients hampers the fetus from optimal growth and development. Late-onset fetal growth restriction affects a high number of pregnancies and has a large societal impact in terms of adverse outcomes and an increased risk for the development of cardiovascular disease later in life. This thesis emphasizes that the detection of these fetuses at risk is challenging because symptoms may be subtle at term gestation. Small size as stand-alone modality is only moderately predictive and unreliable. The condition affects both small fetuses and fetuses who are within ‘normal’ birth weight ranges. Small- or large fetal size does not necessarily reflect pathology but puts the fetus at a higher risk and an appropriate size is not a guarantee of normal outcomes. The observed large heterogeneity in Dutch hospital protocols underlines the complexity of the condition. To overcome some of the inconsistencies, a consensus definition and core outcome set were developed. Furthermore, two research protocols to investigate the role of Doppler ultrasound as a marker of placental function in the management of late-onset fetal growth restriction are outlined. The challenge for the coming decade is to implement the consensus definitions and to evaluate (new) placental markers to improve identification of the compromised fetuses at (near) term gestation.

This thesis describes the characteristics of placental oxidative stress in relation to placental pathology, biomarkers in maternal blood and clinical characteristics. In a retrospective study (DIGITAT) of cases with fetal growth restriction (FGR) a term indicated that induction of labor showed less histomorfologic ischemic placental changes (known as maternal vascular malperfusion) compared to an expectant management of delivery. Oxidative stress can result from inflammatory processes. Little is known however about the contribution of specific inflammatory processes to the rise of specific placental lesions and pregnancy complications. In pregnancies complicated by FGR an increase of M1-type (pro-inflammatory) macrophages was found. Also, an increase in regulatory T-cells and a decrease in chymase-positive mast cells in pregnancies complicated by FGR or stillbirth was seen. In FGR combined with preeclampsia significant differences in levels of oxidative stress was found compared to healthy pregnancies and pregnancies complicated by FGR only. By evaluating these characteristics we hope to discover new potential targets for intervention and possible treatment(s) of pregnancy complications. The thesis concludes with a review of different diet-related therapies in relation to pregnancy-related oxidative stress.

For the development of study protocols, data analysis and comparisons of cohorts, and through this to determine the best fitting treatment for a patient, there has to be agreement on the basic principles of the condition concerned. This starts with consensus on the definition. Regarding fetal growth restriction, this consensus was missing. Fetal growth restriction is a frequently studied condition because of the major impact on perinatal morbidity and mortality. The diversity in currently used definitions was described in a systematic review, with 44 different definitions found in 2014. This heterogeneity makes it impossible to compare the results of these studies.Expert consensus is the method of choice, in lack of a gold standard and when empirical evidence is impossible to obtain. A Delphi procedure is a systematic, interactive, group-communication process, to reach consensus in an expert panel. The existing consensus-methodology itself is also founded with little evidence and mainly based on expert-consensus.This thesis aimed to develop consensus on the topic of fetal growth restriction. We succeeded in developing a consensus definition for fetal growth restriction diagnosed in singleton pregnancy (separate for early- and late-onset), in twin pregnancy (separate for monochorionic and dichorionic), the stillborn and the neonate. Additionally, some of the consensus methodology was tested to provide underlying evidence.