This study evaluated the hypothesis that prenatal maternal socioeconomic status (SES) adversity is associated with DNA methylation in the placenta. SES adversity was defined by the presence of, as well as a summative count of, four factors: less than college education, single marital status, food and nutritional service assistance, and public health insurance. Epigenome-wide DNA methylation was assessed using the Illumina EPIC array in 426 placentas from a sample of infants born < 28 weeks of gestation from the Extremely Low Gestational Age Newborn cohort. Associations between SES adversity and DNA methylation were assessed with robust linear regressions adjusted for covariates and controlled the false discovery rate at < 10%. We also examined whether such associations were sex specific. Indicators of SES adversity were associated with differential methylation at 33 CpG sites. Of the 33 identified CpG sites, 19 (57.6%) displayed increased methylation, and 14 (42.4%) displayed decreased methylation in association with at least one of the SES adversity factors. Sex differences were observed in DNA methylation associated with summative SES score; in which placentas derived from female pregnancies showed more robust differential CpG methylation than placentas from male pregnancies. Maternal SES adversity was associated with differential methylation of genes with key role in gene transcription and placental function, potentially altering immunity and stress response. Further investigation is needed to evaluate the role of epigenetic differences in mediating the association between maternal socioeconomic status during pregnancy and later life health outcomes in children.

Background: Children born extremely preterm are at heightened risk for intellectual and social impairment, including Autism Spectrum Disorder (ASD). There is increasing evidence for a key role of the placenta in prenatal developmental programming, suggesting that the placenta may, in part, contribute to origins of neurodevelopmental outcomes.Methods: We examined associations between placental transcriptomic and epigenomic profiles and assessed their ability to predict intellectual and social impairment at age 10 years in 379 children from the Extremely Low Gestational Age Newborn (ELGAN) cohort. Assessment of intellectual ability (IQ) and social function was completed with the Differential Ability Scales-II and Social Responsiveness Scale (SRS), respectively. Examining IQ and SRS allows for studying ASD risk beyond the diagnostic criteria, as IQ and SRS are continuous measures strongly correlated with ASD. Genome-wide mRNA, CpG methylation and miRNA were assayeds with the Illumina Hiseq 2500, HTG EdgeSeq miRNA Whole Transcriptome Assay, and Illumina EPIC/850 K array, respectively. We conducted genome-wide differential analyses of placental mRNA, miRNA, and CpG methylation data. These molecular features were then integrated for a predictive analysis of IQ and SRS outcomes using kernel aggregation regression. We lastly examined associations between ASD and the multi-omic-predicted component of IQ and SRS.Results: Genes with important roles in neurodevelopment and placental tissue organization were associated with intellectual and social impairment. Kernel aggregations of placental multi-omics strongly predicted intellectual and social function, explaining approximately 8% and 12% of variance in SRS and IQ scores via cross-validation, respectively. Predicted in-sample SRS and IQ showed significant positive and negative associations with ASD case–control status.Limitations: The ELGAN cohort comprises children born pre-term, and generalization may be affected by unmeasured confounders associated with low gestational age. We conducted external validation of predictive models, though the sample size (N = 49) and the scope of the available out-sample placental dataset are limited. Further validation of the models is merited.Conclusions: Aggregating information from biomarkers within and among molecular data types improves prediction of complex traits like social and intellectual ability in children born extremely preterm, suggesting that traits within the placenta-brain axis may be omnigenic.

Given inconsistent evidence on preconception or prenatal tobacco use and offspring autism spectrum disorder (ASD), this study assessed associations of maternal smoking with ASD and ASD‐related traits. Among 72 cohorts in the Environmental Influences on Child Health Outcomes consortium, 11 had ASD diagnosis and prenatal tobaccosmoking (n = 8648). and 7 had Social Responsiveness Scale (SRS) scores of ASD traits (n = 2399). Cohorts had diagnoses alone (6), traits alone (2), or both (5). Diagnoses drew from parent/caregiver report, review of records, or standardized instruments. Regression models estimated smoking‐related odds ratios (ORs) for diagnoses and standardized mean differences for SRS scores. Cohort‐specific ORs were meta‐analyzed. Overall, maternal smoking was unassociated with child ASD (adjusted OR, 1.08; 95% confidence interval [CI], 0.72–1.61). However, heterogeneity across studies was strong: preterm cohorts showed reduced ASD risk for exposed children. After excluding preterm cohorts (biased by restrictions on causal intermediate and exposure opportunity) and small cohorts (very few ASD cases in either smoking category), the adjusted OR for ASD from maternal smoking was 1.44 (95% CI, 1.02–2.03). Children of smoking (versus non‐smoking) mothers had more ASD traits (SRS T‐score + 2.37 points, 95% CI, 0.73–4.01 points), with results homogeneous across cohorts. Maternal preconception/prenatal smoking was consistently associated with quantitative ASD traits and modestly associated with ASD diagnosis among sufficiently powered United States cohorts of non‐preterm children. Limitations resulting from self‐reported smoking and unmeasured confounders preclude definitive conclusions. Nevertheless, counseling on potential and known risks to the child from maternal smoking is warranted for pregnant women and pregnancy planners.Lay Summary: Evidence on the association between maternal prenatal smoking and the child's risk for autism spectrum disorder has been conflicting, with some studies reporting harmful effects, and others finding reduced risks. Our analysis of children in the ECHO consortium found that maternal prenatal tobacco smoking is consistently associated with an increase in autism‐related symptoms in the general population and modestly associated with elevated risk for a diagnosis of autism spectrum disorder when looking at a combined analysis from multiple studies that each included both pre‐ and full‐term births. However, this study is not proof of a causal connection. Future studies to clarify the role of smoking in autism‐like behaviors or autism diagnoses should collect more reliable data on smoking and measure other exposures or lifestyle factors that might have confounded our results.