Epigenome-wide association studies of prenatal maternal mental health and infant epigenetic profiles: a systematic review

Prenatal stress and poor maternal mental health are associated with adverse offspring outcomes; however, the biological mechanisms are unknown. Epigenetic modification has linked maternal health with offspring development. Epigenome-wide association studies (EWAS) have examined offspring DNA methylation profiles for association with prenatal maternal mental health to elucidate mechanisms of these complex relationships. The objective of this study is to provide a comprehensive, systematic review of EWASs of infant epigenetic profiles and prenatal maternal anxiety, depression, or depression treatment. We conducted a systematic literature search following PRISMA guidelines for EWAS studies between prenatal maternal mental health and infant epigenetics through May 22, 2023. Of 645 identified articles, 20 fulfilled inclusion criteria. We assessed replication of CpG sites among studies, conducted gene enrichment analysis, and evaluated the articles for quality and risk of bias. We found one repeated CpG site among the maternal depression studies; however, nine pairs of overlapping differentially methylatd regions were reported in at least two maternal depression studies. Gene enrichment analysis found significant pathways for maternal depression but not for any other maternal mental health category. We found evidence that these EWAS present a medium to high risk of bias. Exposure to prenatal maternal depression and anxiety or treatment for such was not consistently associated with epigenetic changes in infants in this systematic review and meta-analysis. Small sample size, potential bias due to exposure misclassification and statistical challenges are critical to address in future efforts to explore epigenetic modification as a potential mechanism by which prenatal exposure to maternal mental health disorders leads to adverse infant outcomes.