Objective: To derive and test the implications of a sex-specific fetal growth standard. Design: Secondary analysis of a prospective observational cohort. Setting: Eight U.S. centers. Population or Sample: Nulliparas followed longitudinally through pregnancy. A lower-risk subgroup (exclusions: chronic hypertension, pre-gestational diabetes, suspected aneuploidy, preterm delivery) was selected for fetal growth equation derivation. Methods: Fetal weights at 14-20 weeks, 22-29 weeks, and birth were used to derive a sex-specific fetal growth equation. We compared rates of SGA and LGA by sex using the sex-specific and sex-neutral (Hadlock) standards. Using the full unselected cohort, we assessed outcomes and clinical management according to SGA and LGA status. Main outcome measures: Proportion considered SGA and LGA; obstetric interventions relevant to SGA and LGA. Results: We derived a sex-specific equation using 7,280 infants. The sex-neutral standard diagnosed SGA more often in female and LGA more often in male newborns. The sex-specific standard resolved these disparities. Using the full unselected cohort (N=8,339), newborns reclassified from SGA to AGA by the sex-specific standard were more likely to be delivered for growth restriction with comparable risk of morbidity compared to newborns considered AGA by both methods. Newborns reclassified from AGA to LGA by the sex-specific standard had higher rates of cesarean for arrest of descent, cesarean for arrest of dilation, and shoulder dystocia than newborns considered AGA by both methods. Conclusions: The sex-neutral standard generates sex disparities in SGA and LGA at birth. A sex-specific standard resolves these disparities and may improve growth pathology risk stratification.

Objective To examine the association of placental and fetal DNA copy number variants (CNVs) with fetal structural malformations (FSMs) in stillborn fetuses. Design A secondary analysis of stillbirth cases in the Stillbirth Collaborative Research Network (SCRN) study. Setting Multicenter, 59 hospitals in 5 geographic regions in the USA. Population 384 stillbirth cases of the SCRN study (2006-2008). Methods FSMs were grouped by anatomic system and specific malformation type (e.g., central nervous system, thoracic, cardiac, gastrointestinal, skeletal, umbilical cord and craniofacial defects). Single-nucleotide polymorphism array detected CNVs of at least 500kb. CNVs were classified into two groups: normal, defined as no CNVs>500kb or benign CNVs, and abnormal, defined as pathogenic or variants of unknown clinical significance. Main outcome measures The proportions of abnormal CNVs and normal CNVs were compared between stillbirth cases with and without FSMs using the Wald Chi-squared test. Results The proportion of stillbirth cases with any FSMs was higher among those with abnormal CNVs compared with those with normal CNVs (46.7% vs. 19.6%; p-value<0.001). The most common organ system-specific FSMs associated with abnormal CNVs were cardiac defects, followed by craniofacial and skeletal defects. A pathogenic deletion of 1q21.1 involving 46 genes (e.g., CHD1L) and a duplication of 21q22.13 involving 4 genes (SIM2, CLDN14, CHAF1B, HLCS) were associated with a skeletal and cardiac defect, respectively. Conclusion Specific CNVs involving several genes were associated with FSMs in stillborn fetuses. The findings warrant further investigation and may inform counseling and care surrounding pregnancies affected by FSMs at risk for stillbirth.

OBJECTIVE To assess the relationship between allostatic load in early pregnancy and CVD, 2 to 7 years postpartum, and potential pathways contributing to racial disparities in CVDs. DESIGN Secondary analysis of an observational cohort study. SETTING nuMom2b Heart Health Study. POPULATION Pregnant individuals. METHODS Our primary exposure was dichotomous high allostatic load in the first trimester, defined as four or more out of 12 biomarkers in the “worst” quartile. The primary outcome was new diagnosis of composite CVD, consisting of HTN and or MD (fasting glucose greater than 100 mg/dL or medication for diabetes). Each outcome and allostatic load component was analyzed secondarily. Multivariable logistic regression was used to test the association between high allostatic load and CVD adjusted for potential confounders. Mediation and moderation analyses assessed the role of high allostatic load in racial disparities of CVD. MAIN OUTCOME MEASURE Composite CVD. RESULTS Among 4,022 individuals, CVD was identified in 1,462 (36.4%); 26.6% had HTN, and had 15.4% MD. High allostatic load was present in 33.0%. After adjustment for covariates, high allostatic load was associated with CVD (aOR 2.0, 1.8-2.3), HTN (2.1, 1.8-2.4), and MD (1.7, 1.5-2.1). There was a reduction in the magnitude of the relationship between race and CVD with the addition of allostatic load. Self-reported race did not significantly moderate the relationship between allostatic load and CVD. CONCLUSION High allostatic load is associated with CVD. Allostatic load was a partial mediator between race and CVD. Race did not moderate the relationship between allostatic load and CVD.

Objective To examine the association of DNA copy number variants (CNVs) with pathologic placental lesions (PPLs) in stillborn fetuses. Design A secondary analysis of stillbirth cases in the Stillbirth Collaborative Research Network case-control study. Setting Multicenter, 59 hospitals in 5 geographic regions in the USA. Population 387 stillbirth cases (2006-2008). Methods Using standard definitions, PPLs were categorized by type including maternal and fetal vascular, inflammatory and immune/idiopathic lesions. Using single-nucleotide polymorphism array, CNVs of at least 500 kb were detected. CNVs were classified into two groups: normal, defined as no CNVs>500 kb or benign CNVs, and abnormal, defined as pathogenic or variants of unknown clinical significance. Main outcome measures The proportions of abnormal CNVs and normal CNVs were compared between stillbirth cases with and without PPLs using the Wald Chi-squared test. Results Of 387 stillborn fetuses, 327 (84.5%) had maternal vascular PPLs and 60 (15.6%) had abnormal CNVs. Maternal vascular PPLs were more common in stillborn fetuses with abnormal CNVs compared with those with normal CNVs (81.7% vs. 64.2%; p=0.008). The proportions of fetal vascular, maternal/fetal inflammatory, and immune/idiopathic PPLs were similar among stillborn fetuses with abnormal CNVs compared to those with normal CNVs. Pathogenic CNVs in stillborn fetuses with maternal vascular PPLs spanned several genes with known relevant mechanisms. Conclusions Abnormal placental/fetal CNVs were associated with maternal vascular PPLs in stillborn fetuses. Findings may provide insight on the mechanisms of specific genetic abnormalities associated with placental dysfunction and stillbirth.