Maternal prenatal anxiety and the fetal origins of epigenetic aging

Abstract Background The Fetal Origins of Mental Health is a well-established framework that currently lacks a robust index of the biological embedding of prenatal adversity. The Pediatric Buccal Epigenetic (PedBE) clock is a novel epigenetic tool that associates with aspects of the prenatal environment but additional validation in longitudinal datasets is required. Likewise, the relationship between prenatal maternal mental health and the PedBE clock has not been described. Methods Longitudinal cohorts from the Netherlands (BIBO: N = 165) and Singapore (GUSTO: N = 340) provided data on prenatal maternal anxiety and longitudinal assessments of buccal cell-derived genome-wide DNA methylation assessed at 6 and 10 years of age in BIBO and at 3, 9, and 48 months of age in GUSTO. Measures of epigenetic age acceleration were calculated using the PedBE clock and benchmarked against an established multi-tissue epigenetic predictor. Results Prenatal maternal anxiety predicted child PedBE epigenetic age acceleration in both cohorts with effects largely restricted to males and not females. These results were independent of obstetric, socioeconomic, and genetic risk factors, with a larger effect size for prenatal anxiety than depression. PedBE age acceleration predicted increased externalizing symptoms in males from mid- to late-childhood in the BIBO cohort only. Conclusions These findings point to the fetal origins of epigenetic age acceleration and reveal an increased sensitivity in males. Convergent evidence underscores the societal importance of providing timely and effective mental health support to pregnant women, which may have lasting consequences for both mother and child.