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In a randomized trial comparing induction of labor with expectant management at 39 weeks in low-risk nulliparous women, induction did not result in a significantly lower frequency of adverse perinatal outcomes, but it did result in a lower frequency of cesarean delivery.

Stillbirth is strongly related to impaired fetal growth. However, the relationship between fetal growth and stillbirth is difficult to determine because of uncertainty in the timing of death and confounding characteristics affecting normal fetal growth. We conducted a population-based case-control study of all stillbirths and a representative sample of live births in 59 hospitals in five geographic areas in the US. Fetal growth abnormalities were categorized as small for gestational age (SGA) (<10th percentile) or large for gestational age (LGA) (>90th percentile) at death (stillbirth) or delivery (live birth) using population, ultrasound, and individualized norms. Gestational age at death was determined using an algorithm that considered the time-of-death interval, postmortem examination, and reliability of the gestational age estimate. Data were weighted to account for the sampling design and differential participation rates in various subgroups. Among 527 singleton stillbirths and 1,821 singleton live births studied, stillbirth was associated with SGA based on population, ultrasound, and individualized norms (odds ratio [OR] [95% CI]: 3.0 [2.2 to 4.0]; 4.7 [3.7 to 5.9]; 4.6 [3.6 to 5.9], respectively). LGA was also associated with increased risk of stillbirth using ultrasound and individualized norms (OR [95% CI]: 3.5 [2.4 to 5.0]; 2.3 [1.7 to 3.1], respectively), but not population norms (OR [95% CI]: 0.6 [0.4 to 1.0]). The associations were stronger with more severe SGA and LGA (<5th and >95th percentile). Analyses adjusted for stillbirth risk factors, subset analyses excluding potential confounders, and analyses in preterm and term pregnancies showed similar patterns of association. In this study 70% of cases and 63% of controls agreed to participate. Analysis weights accounted for differences between consenting and non-consenting women. Some of the characteristics used for individualized fetal growth estimates were missing and were replaced with reference values. However, a sensitivity analysis using individualized norms based on the subset of stillbirths and live births with non-missing variables showed similar findings. Stillbirth is associated with both growth restriction and excessive fetal growth. These findings suggest that, contrary to current practices and recommendations, stillbirth prevention strategies should focus on both severe SGA and severe LGA pregnancies. Please see later in the article for the Editors' Summary.

IntroductionPreterm birth is a significant contributor to pregnancy-related morbidity and mortality, particularly affecting black women. Racism is a key driver of perinatal inequities, but mechanisms remain unclear. Epigenomics research offers promise in understanding how environmental exposures, including racism, influence gene expression and adverse pregnancy outcomes. We present our study protocol describing how we will investigate the interactive effects of individual- and structural-level racism on preterm birth within and across black and white women, characterise the blood-based methylome of black pregnant women and identify whether DNA methylation mediates the association between multilevel racism and preterm birth in black women.Methods and analysisWe will conduct a secondary analysis of data from 6843 participants in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be (nuMoM2b), a longitudinal, prospective cohort study (2010–2014). Individual-level racism was collected using the Experiences of Discrimination scale. Structural racism measures include racial residential segregation, income and racial polarisation, political participation, judicial treatment, homeownership and employment. These measures will be calculated using geocoded participant addresses and publicly available census data for black and white populations. Epigenome-wide methylation analyses will be conducted on stored DNA for all enrolled black women using the EPIC 2.0 BeadChip. Preterm birth was determined by abstraction from participant electronic health records. We will determine the joint effects of individual and structural racism on preterm birth, characterise DNA methylation profiles associated with preterm birth among black women and explore the mediating role of DNA methylation in the association between multilevel racism and preterm birth.Ethics and disseminationStudy procedures were approved by the Columbia University Institutional Review Board (#AAAU0215). This study aims to fill critical knowledge gaps regarding the role of racism and epigenomics in preterm birth among black women.

Adverse pregnancy outcomes (APOs) affect a large proportion of pregnancies and represent an important cause of morbidity and mortality worldwide. Yet the pathophysiology of APOs is poorly understood, limiting our ability to prevent and treat these conditions. To search for genetic markers of maternal risk for four APOs, we performed multi-ancestry genome-wide association studies (GWAS) for pregnancy loss, gestational length, gestational diabetes, and preeclampsia. We clustered participants by their genetic ancestry and focused our analyses on three sub-cohorts with the largest sample sizes: European, African, and Admixed American. Association tests were carried out separately for each sub-cohort and then meta-analyzed together. Two novel loci were significantly associated with an increased risk of pregnancy loss: a cluster of SNPs located downstream of the TRMU gene (top SNP: rs142795512), and the SNP rs62021480 near RGMA . In the GWAS of gestational length we identified two new variants, rs2550487 and rs58548906 near WFDC1 and AC005052.1 , respectively. Lastly, three new loci were significantly associated with gestational diabetes (top SNPs: rs72956265, rs10890563, rs79596863), located on or near ZBTB20 , GUCY1A2 , and RPL7P20 , respectively. Fourteen loci previously correlated with preterm birth, gestational diabetes, and preeclampsia were found to be associated with these outcomes as well.

Stillbirth accounts for half of all perinatal mortality, but the underlying cause of a substantial portion of all cases remains elusive. We examined the umbilical cord blood microbiome in stillbirths ( n  = 60) and live births ( n  = 176) and discovered that the bacterial prevalence and abundance were significantly higher in stillbirths than live births. Stillbirths account for half of all perinatal mortality, but the underlying cause of a significant portion of the cases remains unknown. We set out to test the potential role and extent of microbial infection in stillbirth through a case-control analysis of fetal cord blood collected from the multisite Stillbirth Collaborative Research Network. Cases ( n  = 60) were defined as stillbirths at >20 weeks of gestation, and controls ( n  = 176) were live births. The bacterial presence, abundance, and composition were analyzed by endpoint PCR of full-length 16S rRNA and the V4 amplicon sequence variants (ASVs). The results demonstrate that bacterial prevalence and abundance were both significantly increased in stillbirth, even after adjusting for maternal age, race, body mass index, number of pregnancies, gestational age, and multiple gestations. Composition of bacterial communities in the cord blood also differed significantly. Using a group of 25 ASVs differentially abundant between the two groups, a Random Forest classification model achieved an accuracy score of 0.76 differentiating stillbirth and live birth, with Group B Streptococcus as the most enriched species in stillbirth. Positive PCR was also significantly associated with early preterm birth. A group of oral anaerobes, including Actinomyces , Campylobacter , Fusobacterium, Peptostreptococcus, Porphyromonas , and Prevotella, were enriched in live early preterm birth, suggesting possible oral origin of infection. Our ASV-based microbiome analysis revealed specific candidate pathogens associated with infections in stillbirth and early preterm birth. The cord blood microbial signatures may be markers of adverse pregnancy outcomes. Our study will help identify possible mechanism of infection and improve our ability to prevent stillbirth and early preterm birth. IMPORTANCE Stillbirth accounts for half of all perinatal mortality, but the underlying cause of a substantial portion of all cases remains elusive. We examined the umbilical cord blood microbiome in stillbirths ( n  = 60) and live births ( n  = 176) and discovered that the bacterial prevalence and abundance were significantly higher in stillbirths than live births. The microbial compositions also differed significantly. Group B Streptococcus was the most prevalent species detected in stillbirth. In addition, pathogens previously unknown to be associated with stillbirth were identified. A group of oral anaerobes including Fusobacterium nucleatum were found to be specifically enriched in the cord blood in early preterm live birth. This is by far the most comprehensive study to examine the microbial signatures in umbilical cord blood. Cord blood microbial signatures may be markers for adverse birth outcomes. Detection of key microbial signatures will help identify individuals at risk and develop effective preventative strategies.

Stillbirth is a common adverse pregnancy outcome, with nearly 3 million third-trimester stillbirths occurring worldwide each year. 98% occur in low-income and middle-income countries, and more than 1 million stillbirths occur in the intrapartum period, despite many being preventable. Nevertheless, stillbirth is practically unrecognised as a public health issue and few data are reported. In this final paper in the Stillbirths Series, we call for inclusion of stillbirth as a recognised outcome in all relevant international health reports and initiatives. We ask every country to develop and implement a plan to improve maternal and neonatal health that includes a reduction in stillbirths, and to count stillbirths in their vital statistics and other health outcome surveillance systems. We also ask for increased investment in stillbirth-related research, and especially research aimed at identifying and addressing barriers to the aversion of stillbirths within the maternal and neonatal health systems of low-income and middle-income countries. Finally, we ask all those interested in reducing stillbirths to join with advocates for the improvement of other pregnancy-related outcomes, for mothers and their offspring, so that a united front for improved pregnancy and neonatal care for all will become a reality.

Background Although leisure-time physical activity (PA) contributes to overall health, including pregnancy health, patterns across pregnancy have not been related to birth outcomes. We hypothesized that women with sustained low leisure-time PA would have excess risk of adverse pregnancy outcomes, and that changing patterns across pregnancy (high to low and low to high) may also be related to risk of adverse pregnancy outcomes. Methods Nulliparous women ( n  = 10,038) were enrolled at 8 centers early in pregnancy (mean gestational age in weeks [SD] = 12.05 [1.51]. Frequency, duration, and intensity (metabolic equivalents) of up to three leisure activities reported in the first, second and third trimesters were analyzed. Growth mixture modeling was used to identify leisure-time PA patterns across pregnancy. Adverse pregnancy outcomes (preterm birth, [PTB, overall and spontaneous], hypertensive disorders of pregnancy [HDP], gestational diabetes [GDM] and small-for-gestational-age births [SGA]) were assessed via chart abstraction. Results Five patterns of leisure-time PA across pregnancy were identified: High (35%), low (18%), late decreasing (24%), early decreasing (10%), and early increasing (13%). Women with sustained low leisure-time PA were younger and more likely to be black or Hispanic, obese, or to have smoked prior to pregnancy. Women with low vs. high leisure-time PA patterns had higher rates of PTB (10.4 vs. 7.5), HDP (13.9 vs. 11.4), and GDM (5.7 vs. 3.1, all p  < 0.05). After adjusting for maternal factors (age, race/ethnicity, BMI and smoking), the risk of GDM (Odds ratio 2.00 [95% CI 1.47, 2.73]) remained higher in women with low compared to high patterns. Early and late decreasing leisure-time PA patterns were also associated with higher rates of GDM. In contrast, women with early increasing patterns had rates of GDM similar to the group with high leisure-time PA (3.8% vs. 3.1%, adjusted OR 1.16 [0.81, 1.68]). Adjusted risk of overall PTB (1.31 [1.05, 1.63]) was higher in the low pattern group, but spontaneous PTB, HDP and SGA were not associated with leisure-time PA patterns. Conclusions Sustained low leisure-time PA across pregnancy is associated with excess risk of GDM and overall PTB compared to high patterns in nulliparous women. Women with increased leisure-time PA early in pregnancy had low rates of GDM that were similar to women with high patterns, raising the possibility that early pregnancy increases in activity may be associated with improved pregnancy health. Trial registration Registration number NCT02231398 .

Objective To examine maternal, psychosocial, and pregnancy factors associated with breastfeeding for at least 6 months in those giving birth for the first time. Methods We performed a planned secondary analysis of an observational cohort study of 5249 women giving birth for the first time. Women were contacted at least 6 months after delivery and provided information regarding breastfeeding initiation, duration, and exclusivity. Maternal demographics, psychosocial measures, and delivery methods were compared by breastfeeding groups. Results 4712 (89.8%) of the women breastfed at some point, with 2739 (58.2%) breastfeeding for at least 6 months. Of those who breastfed, 1161 (24.7% of the entire cohort), breastfed exclusively for at least 6 months. In the multivariable model among those who ever breastfed, not smoking in the month prior to delivery (adjusted odds ratio [aOR] 2.04, 95%CI 1.19–3.45), having a Master’s degree of higher (aOR 1.89, 95%CI 1.51–2.36), having a planned pregnancy (aOR 1.48, 95%CI 1.27–1.73), older age (aOR 1.02, 95% CI, 1.01–1.04), lower BMI (aOR 0.96 95% CI 0.95–0.97), and having less anxiety measured during pregnancy (aOR 0.990, 95%CI 0.983–0.998) were associated with breastfeeding for at least 6 months. Compared to non-Hispanic White women, Hispanic women, while being more likely to breastfeed initially (aOR 1.40, 95%CI 1.02–1.92), were less likely to breastfeed for 6 months (aOR 0.72, 95%CI 0.59–0.88). While non-Hispanic Black women were less likely than non-Hispanic White women to initiate breastfeeding (aOR 0.68, 95%CI 0.51–0.90), the odds of non-Hispanic Black women of continuing to breastfeed for at least 6 months was similar to non-Hispanic White women (aOR 0.92, 95%CI 0.71–1.19). Conclusions In this cohort of women giving birth for the first time, duration of breastfeeding was associated with several characteristics which highlight groups at greater risk of not breastfeeding as long as currently recommended. Trial registration NCT01322529 (nuMoM2b) and NCT02231398 (nuMoM2b-Heart Health)

Background Preeclampsia is characterized by decreased trophoblastic angiogenesis leading to abnormal invasion of spiral arteries, shallow implantation and resulting in compromised placentation with poor uteroplacental perfusion. Vitamin D plays an important role in pregnancy influencing implantation, angiogenesis and placental development. The objective of this study was to determine whether there is an association between serum vitamin D levels, and anti-angiogenic factors at the time of delivery and the occurrence of preeclampsia. Methods This nested case control study analyzed frozen serum samples at the time of delivery and related clinical data from women with singleton liveborn pregnancies who had participated in studies of the NICHD Stillbirth Collaborative Research Network. Women with a recorded finding of preeclampsia and who had received magnesium sulfate treatment prior to delivery were considered index cases ( N  = 56). Women without a finding of preeclampsia were controls ( N  = 341). Results Women with preeclampsia had 14.5% lower serum vitamin D levels than women in the control group (16.5 ng/ml vs. 19 ng/ml, p  = 0.014) with 64.5% higher sFlt-1 levels (11,600 pg/ml vs. 7050 pg/ml, p  < 0.001) and greater than 2 times higher endoglin levels (18.6 ng/ml vs. 8.7 ng/ml, < 0.001). After controlling for gestational age at delivery and maternal BMI, vitamin D levels were 0.88 times lower ( P  = 0.051), while endoglin levels were 2.5 times higher and sFlt-1 levels were 2.1 times higher than in control pregnancies ( P  < 0.001). Conclusions Women with preeclampsia at time of delivery have higher maternal antiangiogenetic factors and may have lower maternal serum vitamin D levels. These findings may lead to a better understanding of the underlying etiology of preeclampsia as well as possible modifiable treatment options which could include assuring adequate levels of maternal serum vitamin D prior to pregnancy.

BACKGROUNDThe effects of the novel coronavirus disease 2019 (COVID-19) in pregnancy remain relatively unknown. We present a case of second trimester pregnancy with symptomatic COVID-19 complicated by severe preeclampsia and placental abruption.METHODSWe analyzed the placenta for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through molecular and immunohistochemical assays and by and electron microscopy and measured the maternal antibody response in the blood to this infection.RESULTSSARS-CoV-2 localized predominantly to syncytiotrophoblast cells at the materno-fetal interface of the placenta. Histological examination of the placenta revealed a dense macrophage infiltrate, but no evidence for the vasculopathy typically associated with preeclampsia.CONCLUSIONThis case demonstrates SARS-CoV-2 invasion of the placenta, highlighting the potential for severe morbidity among pregnant women with COVID-19.FUNDINGBeatrice Kleinberg Neuwirth Fund and Fast Grant Emergent Ventures funding from the Mercatus Center at George Mason University. The funding bodies did not have roles in the design of the study or data collection, analysis, and interpretation and played no role in writing the manuscript.