Gestational Aging on Fast Forward: The Epigenetic Link to Recurrent Pregnancy Loss

ABSTRACT Problem Recurrent pregnancy loss (RPL) is a distressing complication with poorly understood causes. Increasing evidence suggests that epigenetic mechanisms, including those governing gestational age (GA), play a critical role in feto–maternal interactions and may contribute to pregnancy loss. Understanding these epigenetic alterations could provide new avenues for the prevention and management of RPL. Method We analyzed DNA methylation data from chorionic villi to evaluate epigenetic gestational age (EGA) in RPL cases. Using the Mayne clock, we compared EGA with clinical GA. Furthermore, weighted gene co‐methylation network analysis (WGCNA) was applied to assess correlations between EGA and RPL and to identify gene modules linked to key biological pathways. Results RPL samples exhibited significantly higher EGA than their clinical GA, indicating accelerated placental aging. Control samples showed close alignment between EGA and clinical GA. WGCNA revealed a strong positive correlation between elevated EGA and RPL, and identified modules associated with critical pathways. Conclusion Our findings suggest that premature epigenetic aging of the placenta and disrupted networks regulating apoptosis, DNA repair, oxidative stress, and immune responses may underlie RPL. These insights highlight the importance of epigenetic regulation in pregnancy outcomes and warrant further investigation.