Epigenetic Signals in Perinatal Depression: A Systematic Review of Maternal-Fetal Stress, Hormonal, and Neurodevelopmental Pathways

Perinatal depression and related psychosocial stressors may be shaped by epigenetic mechanisms across stress, endocrine, circadian, and neurodevelopmental systems. Following PRISMA guidelines, we systematically reviewed 11 original human studies examining predominantly DNA methylation, alongside histone/chromatin-associated alterations, across placental, peripheral blood, and infant tissues. NR3C1/NR3C2 methylation was associated with maternal depressive symptoms and infant cortisol reactivity. Hormone-responsive TTC9B and HP1BP3 loci predicted postpartum depression, and a prospective cohort linked third-trimester, immune-adjusted TTC9B/HP1BP3 biomarker positivity with greater perinatal anxiety, perceived stress, and subsequent postpartum depression, supporting a context-sensitive vulnerability phenotype rather than a clinically validated standalone predictor. Only one study assessed histone/chromatin-associated alterations: placental proteomics identified altered H2A-, H2B-, H3-, and H4-family protein abundance in relation to antenatal depressive symptoms and SRI exposure, without measuring histone post-translational modifications or chromatin accessibility. Oxytocin-dependent CRY1/CRY2 methylation was associated with mood and anxiety symptoms, while Wnt-related neurodevelopmental pathways were enriched in infant methylation profiles linked to maternal attachment insecurity and childhood maltreatment. Timing and tissue specificity were important, with some patterns associated with current perinatal mood and hormonal context and others with cumulative childhood trauma. Candidate-gene studies provided mechanistic insight, whereas epigenome-wide analyses were often underpowered and yielded sparse associations. Overall, perinatal depression appears to involve convergent stress-responsive, endocrine, circadian, and neurodevelopmental epigenetic alterations. Longitudinal multi-omics studies integrating endocrine, immune, and psychosocial measures are needed to validate biomarkers, clarify causality, and guide targeted interventions.