Prenatal exposure to persistent organic pollutants (POPs) has been associated with birth size, but data on fetal growth and among racially/ethnically diverse pregnant women remain scarce.OBJECTIVES To assess the association between maternal plasma POPs in early pregnancy and fetal growth and by infant sex and maternal race/ethnicity. DESIGN, SETTING, AND PARTICIPANTSThis cohort study used the National Institute of Child Health and Human Development Fetal Growth Studies-Singleton cohort, which recruited nonobese, low-risk pregnant women before 14 weeks' gestation between July 1, 2009, and January 31, 2013, in 12 community-based clinics throughout the United States. Participants self-identified their race/ethnicity, self-reported their behavioral risk factors, and were followed up throughout their pregnancy. Data were analyzed from July 31, 2018, to June 3, 2019.EXPOSURES Levels of 76 POPs in early gestation plasma were measured: 11 perfluoroalkyl and polyfluoroalkyl substances, 1 polybrominated biphenyl, 9 polybrominated diphenyl ethers (PBDEs), 44 polychlorinated biphenyls (PCBs), and 11 organochlorine pesticides (OCPs). The bayesian kernel machine regression method was used to examine chemical class mixtures, and generalized additive mixed model was used to analyze individual chemicals. MAIN OUTCOMES AND MEASURESFourteen fetal biometrics were measured, including head circumference, abdominal circumference, and femur length, within 5 ultrasonography appointments.RESULTS A total of 2284 low-risk pregnant women were included: 606 women (26.5%) self-identified as white with a mean (SD) age of 30.3 (4.4) years, 589 (25.8%) as black with a mean (SD) age of 25.5 (5.5) years, 635 (27.8%) as Hispanic with a mean (SD) age of 27.1 (5.5) years, and 454 (19.9%) as Asian with a mean (SD) age of 30.5 (4.5) years. A comparison between the 75th and 25th percentile of exposure revealed that the OCP mixture was negatively associated with most fetal growth measures, with a reduction of 4.7 mm (95% CI, −6.7 to −2.8 mm) in head circumference, 3.5 mm (95% CI, −4.7 to −2.2 mm) in abdominal circumference, and 0.6 mm (95% CI, −1.1 to −0.2 mm) in femur length. Higher exposure to the PBDE mixture was associated with reduced abdominal circumference (-2.4 mm; 95% CI, −4.0 to −0.5 mm) and femur length (−0.5 mm; 95% CI, −1.0 to −0.1 mm), and the dioxin-like PCB mixture was associated with reduced head circumference (-6.4 mm; 95% CI, −8.4 to −4.3 mm) and abdominal circumference (-2.4 mm; 95% CI, −3.9 to −0.8 mm). Associations with individual chemicals were less consistent. There were some interactions by fetal sex, although most of the results did not vary by maternal race/ethnicity. For example, oxychlordane (-0.98 mm; 95% CI, -1.60 to -0.36 mm; P for interaction <.001), trans-nonachlor (-0.31 mm; 95% CI, -0.54 to -0.08 mm; P for interaction = .005), and p,p'-dichlorodiphenyldichloroethylene (-0.19 mm; 95% CI, -0.22 to -0.09 mm; P for interaction = .006) were associated with shorter femur length among boys only.CONCLUSIONS AND RELEVANCE This s...

Background: Ambient air pollution may affect fetal growth restriction (FGR) through several mechanisms. However, prior studies of air pollution and small-for-gestational age (SGA), a common proxy for FGR, have reported inconsistent findings. Objective: We assessed air pollution in relation to physician-diagnosed FGR and populationbased SGA in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Consecutive Pregnancy Study (2002-2010).Methods: Among 50,005 women (112,203 singleton births), FGR was captured from medical records and ICD-9 codes, and SGA determined by population standards for birthweight <10 th , <5 th and <3 rd percentile. Community Multiscale Air Quality models estimated ambient levels of seven criteria pollutants for whole pregnancy, 3-months preconception, and 1 st , 2 nd and 3 rd trimesters. Generalized estimating equations with robust standard errors accounted for interdependency of pregnancies within participant. Models adjusted for maternal age, race/ ethnicity, pre-pregnancy body mass index, smoking, alcohol, parity, insurance, marital status, asthma and temperature.Results: FGR was diagnosed in 1.5% of infants, and 6.7% were <10 th , 2.7% <5 th and 1.5% <3 rd percentile for SGA. Positive associations of SO 2 , NO 2 and PM 10 and negative associations of O 3 with FGR were observed throughout preconception and pregnancy. For example, an interquartile increase in whole pregnancy SO 2 was associated with 16% (95% CI 8%, 25%) increased FGR

Studies of air pollution effects during pregnancy generally only consider exposure in the outdoor air at the home address. We aimed to compare exposure models differing in their ability to account for the spatial resolution of pollutants, space-time activity and indoor air pollution levels. We recruited 40 pregnant women in the Grenoble urban area, France, who carried a Global Positioning System (GPS) during up to 3 weeks; in a subgroup, indoor measurements of fine particles (PM 2.5 ) were conducted at home (n=9) and personal exposure to nitrogen dioxide (NO 2 ) was assessed using passive air samplers (n=10). Outdoor concentrations of NO 2 , and PM 2.5 were estimated from a dispersion model with a fine spatial resolution. Women spent on average 16 h per day at home. Considering only outdoor levels, for estimates at the home address, the correlation between the estimate using the nearest background air monitoring station and the estimate from the dispersion model was high (r=0.93) for PM 2.5 and moderate (r=0.67) for NO 2 . The model incorporating clean GPS data was less correlated with the estimate relying on raw GPS data (r=0.77) than the model ignoring space-time activity (r=0.93). PM 2.5 outdoor levels were not to moderately correlated with estimates from the model incorporating indoor measurements and space-time activity (r=−0.10 to 0.47), while NO 2 personal levels were not correlated with outdoor levels (r=−0.42 to 0.03). In this urban area, accounting for space-time activity little influenced exposure estimates; in a subgroup of subjects (n=9), incorporating indoor pollution levels seemed to strongly modify them.

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Background Birthweight marks an important milestone of health across the lifespan, including cardiometabolic disease risk in later life. The placenta, a transient organ at the maternal-fetal interface, regulates fetal growth. Identifying genetic loci where DNA methylation in placenta is associated with birthweight can unravel genomic pathways that are dysregulated in aberrant fetal growth and cardiometabolic diseases in later life. Results We performed placental epigenome-wide association study (EWAS) of birthweight in an ethnic diverse cohort of pregnant women (n = 301). Methylation at 15 cytosine-(phosphate)-guanine sites (CpGs) was associated with birthweight (false discovery rate (FDR) < 0.05). Methylation at four (26.7%) CpG sites was associated with placental transcript levels of 15 genes (FDR < 0.05), including genes known to be associated with adult lipid traits, inflammation and oxidative stress. Increased methylation at cg06155341 was associated with higher birthweight and lower FOSL1 expression, and lower FOSL1 expression was correlated with higher birthweight. Given the role of the FOSL1 transcription factor in regulating developmental processes at the maternal-fetal interface, epigenetic mechanisms at this locus may regulate fetal development. We demonstrated trans-tissue portability of methylation at four genes (MLLT1, PDE9A, ASAP2, and SLC20A2) implicated in birthweight by a previous study in cord blood. We also found that methylation changes known to be related to maternal underweight, preeclampsia and adult type 2 diabetes were associated with lower birthweight in placenta. Conclusion We identified novel placental DNA methylation changes associated with birthweight. Placental epigenetic mechanisms may underlie dysregulated fetal development and early origins of adult cardiometabolic diseases. Clinical trial registration ClinicalTrials.gov, NCT00912132

BACKGROUND Maternal obesity prior to or during pregnancy influences fetal growth, predisposing the offspring to increased risk for obesity across the life-course. Placental epigenetic mechanisms may underlie these associations. We conducted an epigenome-wide association study to identify placental DNA methylation changes associated with maternal pre-pregnancy body mass index (BMI) and rate of gestational weight gain at first (GWG1), second (GWG2) and third trimester (GWG3). METHOD Participants of the NICHD Fetal Growth Studies with genome-wide placental DNA methylation ( n= 301) and gene expression ( n= 75) data were included. Multivariable-adjusted regression models were used to test the associations of 1kg/m 2 increase in pre-pregnancy BMI or 1kg/week increase in GWG with DNA methylation levels. Genes harboring top differentially methylated CpGs (FDR P <0.05) were evaluated for placental gene expression. We assessed whether DNA methylation sites known to be associated with BMI in child or adult tissues were also associated with maternal pre-pregnancy BMI in placenta. RESULTS Pre-pregnancy BMI was associated with DNA methylation at cg14568196[ EGFL7 ], cg15339142[ VETZ ] and cg02301019[ AC092377.1 ] (FDR P <0.05, P ranging from 1.4×10 −10 to 1.7×10 −9 ). GWG1 or GWG2 was associated with DNA methylation at cg17918270[ MYT1L ], cg20735365[ DLX5 ] and cg17451688[ SLC35F3 ] (FDR P <0.05, P ranging from 6.4×10 −10 to 1.2×10 −8 ). Both pre-pregnancy BMI and DNA methylation at cg1456819 [ EGFL7 ] were negatively correlated with EGFL7 expression in placenta ( P< 0.05). Several CpGs previously implicated in obesity traits in children and adults were associated with pre-pregnancy BMI in placenta. Functional annotations revealed that EGFL7 is highly expressed in placenta and the differentially methylated CpG sites near EGFL7 and VEZT were cis -meQTL targets in blood. CONCLUSIONS We identified placental DNA methylation changes at novel loci associated with pre-pregnancy BMI and GWG. The overlap between CpGs associated with obesity traits in placenta and other tissues in children and adults suggests that epigenetic mechanisms in placenta may give insights to early origins of obesity.

Although ambient air pollution may increase hypertension risk through endothelial damage and oxidative stress, evidence is inconsistent regarding its effect on hypertension in pregnancy. Prior research has evaluated a limited scope of pollution species and often not differentiated preeclampsia, which may have a placental origin, from gestational hypertension. Among 49 607 women with at least 2 singleton deliveries in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Consecutive Pregnancies Study (2002–2010), we estimated criteria pollutant and volatile organic compound levels during pregnancy using Community Multiscale Air Quality models and abstracted gestational hypertension and preeclampsia diagnoses from medical records. Generalized estimating equations accounted for repeat pregnancies and adjusted for ambient temperature and maternal age, race/ethnicity, body mass index, smoking, alcohol, parity, insurance, marital status, and asthma. Air pollution levels were low to moderate (eg, median 41.6 ppb [interquartile range, 38.9–43.7 ppb] for ozone and 35.1 ppb [28.9–40.3 ppb] for nitrogen oxides). Higher levels of most criteria pollutants during preconception and the first trimester were associated with lower preeclampsia risk, while higher second-trimester levels were associated with greater gestational hypertension risk. For example, an interquartile increase in first-trimester carbon monoxide was associated with a relative risk of 0.88 (95% CI, 0.81–0.95) for preeclampsia and second-trimester carbon monoxide a relative risk of 1.14 (95% CI, 1.07–1.22) for gestational hypertension. Volatile organic compounds, conversely, were not associated with gestational hypertension but consistently associated with higher preeclampsia risk. These findings further suggest air pollution may affect the development of hypertension in pregnancy, although differing causes of preeclampsia and gestational hypertension may alter these relationships.

Background Prenatal maternal plasma persistent organic pollutant (POP) concentrations have been associated with neonatal outcomes. However, the underlying mechanisms remain unknown. Placental epigenetic mechanisms may be involved, but no prior epigenome-wide studies have investigated the impact of maternal POPs on placental DNA methylation. We studied the association between maternal plasma POP concentration in early pregnancy and epigenome-wide placental DNA methylation among 260 pregnant women from the NICHD Fetal Growth Studies. Results Our analysis focused on POPs with more than 80% plasma concentrations above the limit of quantification, including 3 organochlorine pesticides (hexachlorobenzene, trans-nonachlor, p,p’ -dichlorodiphenyldichloroethylene), 1 polybrominated diphenyl ether (PBDE 47), 3 polychlorinated biphenyls (138/158, 153, 180), and 6 poly- and perfluorinated alkyl substances (PFASs) (perfluorodecanoic acid, perfluorohexanesulfonic acid, perfluorononanoic acid, perfluorooctanesulfonic acid, perfluoroundecanoic acid (PFUnDA)). Using 5% false discovery rate, POPs were associated with a total of 214 differentially methylated CpG sites (nominal p values ranging from 2.61 × 10 −21 to 2.11 × 10 −7 ). Out of the 214 CpG sites, 24 (11%) were significantly correlated with placental expression of 21 genes. Notably, higher PFUnDA was associated with increased methylation at 3 CpG sites (cg13996963, cg12089439, cg18145877) annotated to TUSC3 , and increased methylation at those 3 CpG sites was correlated with decreased expression of TUSC3 in the placenta. Increased methylation at cg18145877 ( TUSC3 ) and decreased expression of TUSC3 were correlated with shorter birth length. Out of the 214 CpG sites, methylation at 44 CpG sites was correlated ( p value < 0.10) with at least one neonatal anthropometry measure (i.e., birth weight, birth length, and head circumference). Seven CpG sites mediated ( p value < 0.05) the association between PBDE 47 and neonatal anthropometry measures. Genes annotating the top differentially methylated CpG sites were enriched in pathways related to differentiation of embryonic cells (PBDE 47) and in pathways related to brain size and brain morphology (PFASs). Conclusions DNA methylation changes in the placenta were significantly associated with maternal plasma POPs concentration. The findings suggest that placental DNA methylation and gene expression mechanism may be involved in the prenatal toxicity of POPs and their association with neonatal anthropometry measures.