Preterm Risk Factors, Epigenetic Age, and Neurodevelopmental Outcomes

Importance: Studies examining biological factors associated with neurodevelopment in the preterm population are limited. It was previously demonstrated that epigenetic age acceleration was associated with better neurodevelopmental outcomes among children born preterm. It is unclear whether this association is modified by clinical and environmental preterm risk factors. Objective: To examine whether the association between epigenetic aging and neurodevelopmental outcomes is modified by preterm brain injury and socioeconomic status. Design, Setting, and Participants: This was a prospective cohort study of children born at 24 to 32 weeks' gestation, recruited from 2 neonatal intensive care units from 2015 to 2019 and followed up to January 2026. The cohort was well characterized with clinical data, brain magnetic resonance imaging, and neurodevelopmental assessments (Bayley-III cognitive and motor domains) at 3 years. Participants with buccal epithelial cell DNA collected at 3 years were included. Exposure: Epigenetic age (in weeks) at 3 years was determined using the pediatric buccal epigenetic clock and corrected for chronological age to give epigenetic age difference. Main Outcomes and Measures: Primary analyses used linear regression to examine the association between epigenetic age difference, preterm risk factors (any brain injury, severe brain injury, maternal educational level), and cognitive and motor outcomes at 3 years. Secondary analyses examined whether brain injury and maternal education level modified the associations between epigenetic age difference and cognitive and motor outcomes at 3 years. Results: A total of 102 study participants (median gestational age, 27.0 weeks [IQR, 25.6-28.9 weeks]; 54 female [53%]) were included. Higher maternal educational level (β = 11.65; 95% CI, 3.55-19.76; P = .005) and epigenetic age acceleration (β = 0.07; 95% CI, 0.01-0.14; P = .04) were associated with higher cognitive scores. Epigenetic age acceleration was also associated with higher motor scores (β = 0.16; 95% CI, 0.06-0.27; P = .003), while extreme prematurity (β = -5.66; 95% CI, -10.85 to -0.46; P = .03) and severe brain injury (β = -10.99; 95% CI, -21.32 to -0.66; P = .04) were associated with lower motor scores. Severe brain injury modified the association between epigenetic aging and motor outcomes (β = 0.41; 95% CI, 0.08-0.74; P = .02), and children with epigenetic age acceleration in the presence of severe brain injury had higher motor scores. Conclusions and Relevance: In this prospective preterm cohort study, epigenetic aging, severe brain injury, and socioeconomic status were associated with neurodevelopmental outcomes. Children with severe brain injury along with epigenetic age acceleration had higher motor scores. These findings suggest the association between epigenetic aging and neurodevelopment is context dependent and can vary based on the presence of preterm risk factors.