Accelerated Epigenetic Gestational Aging in Monochorionic Compared with Dichorionic Twins: A Cord Blood DNA Methylation Study

<title>Abstract</title> <p>Background Biological maturity at birth does not always align with gestational age, and this discordance can be quantified as gestational age acceleration (GAA) using DNA methylation-based epigenetic clocks. Monochorionic diamniotic (MCDA) and dichorionic diamniotic (DCDA) twin pregnancies differ in placental sharing and hemodynamic environment, but whether these differences influence GAA remains unknown. We analyzed cord blood DNA methylation data from 49 monozygotic twin pairs (26 DCDA, 23 MCDA), estimating GAA using two DNA methylation-based gestational age clocks, to compare GAA between chorionicity groups among full-term neonates. Results Both clocks showed good within-pair GAA concordance, and GAA was consistently higher in MCDA than in DCDA pairs. Among full-term neonates, MCDA twins had significantly higher GAA according to one clock than DCDA twins (0.34 ± 0.96 vs. −0.27 ± 0.80 weeks; p = 0.010), while the other clock showed a similar directional trend without reaching statistical significance (p = 0.11). Regression analysis confirmed that MCDA chorionicity among full-term twins was associated with higher GAA relative to full-term DCDA twins (β = 0.64 weeks; 95% CI 0.02–1.26; p = 0.044), and this association remained robust in most sensitivity analyses adjusting for clinical and obstetric covariates. Preterm birth was not significantly associated with GAA by either clock. Conclusions Among full-term twins, chorionicity was independently associated with GAA, with MCDA twins exhibiting higher epigenetic maturity than DCDA twins, despite having the same gestational age at birth. These findings suggest that the hemodynamic environment associated with placental sharing — rather than gestational age at birth alone — may contribute to epigenetic maturation in twin pregnancies, raising the possibility that chorionicity should be further investigated as a biological variable relevant to neonatal risk stratification.</p>