Longitudinal Epigenetic Aging in Pregnancy and Associations With Adverse Outcomes.

Abstract

OBJECTIVE To understand the relationship between pregnancy and epigenetic aging estimated by DNA methylation "clocks," which offers a molecular measure of biologic aging. METHODS This was a prospective cohort study of nulliparous women (age 18-50 years) seeking obstetric (pregnant 10-14 weeks) or gynecologic (nonpregnant) care in 2020-2021. Blood was collected at enrollment (time 1) and postpartum day 1 (pregnant, time 2) or 7 months later (nonpregnant, time 2). Epigenetic age was measured with 11 established clocks from Illumina EPIC 2 arrays. Within-person changes in epigenetic age were compared with mixed-effects linear regression models adjusted for confounders and interval duration (days). Results were scaled per 200-day interval. P values were corrected for multiple testing. Multivariable logistic regression explored associations between first-trimester epigenetic age and a composite of potentially immune-mediated complications (hypertensive disorders, gestational diabetes mellitus, preterm birth before 37 weeks of gestation, and small-for-gestational-age birth weight) adjusted for age and body mass index (BMI) higher than 30 at time 1. RESULTS In total, 75 women enrolled; 45 (60.0%) were pregnant, and 61 (81.3%) completed the study. Pregnant women exhibited significant within-person epigenetic age acceleration compared with nonpregnant women in six clocks (Hannum, PhenoAge, GrimAge, GrimAge2, Stem Cell Division, DunedinPACE). Additional epigenetic age acceleration per 200 days in the pregnant cohort ranged from 1.58 years (Hannum, 95% CI, 0.45-2.72, P=.01) to 5.28 years (PhenoAge, 95% CI, 2.97-7.61, P<.01). Each additional year of first-trimester GrimAge2 increased odds of the composite of pregnancy complications by 36% (adjusted odds ratio [aOR] 1.36, 95% CI, 1.01-1.84), while chronologic age (in continuous years) showed no association (aOR 1.00, 95% CI, 0.83-1.21). CONCLUSION Pregnancy accelerated within-person epigenetic aging by up to 5.3 years. Older first-trimester GrimAge2, but not chronologic age, was associated with a composite of pregnancy complications. These findings suggest that gestation may influence biologic aging and support further investigation into epigenetic age as a potential marker of pregnancy health.