Histologic Chorioamnionitis and Neurodevelopment in Preterm Infants.

Importance: Exposure to inflammation from chorioamnionitis places the fetus at higher risk of premature birth and may increase the risk of neurodevelopmental impairments, though the evidence for the latter is mixed. Objective: To evaluate whether moderate to severe histologic chorioamnionitis (HCA) is directly associated with adverse motor performance, independent of the indirect mediating effects of premature birth. Design, Setting, and Participants: This prospective, population-based cohort study recruited participants between September 16, 2016, and November 19, 2019, from referral and nonreferral neonatal intensive care units of 5 southwestern Ohio hospitals. Preterm infants of gestational age (GA) 32 weeks or younger were consecutively enrolled. The data were analyzed between January 5 and July 11, 2025. Exposure: Moderate to severe HCA vs no or mild HCA. Main Outcomes and Measures: The primary outcome was the motor score on the standardized Bayley Scales of Infant and Toddler Development, Third Edition (BSID-3), and secondary outcomes were BSID-3 cognitive and language scores. Multivariable regression analyses controlling for antenatal confounding variables were used to test the independent association of HCA with BSID-3 scores, and causal mediation analysis was used to evaluate whether premature birth or birth GA would mediate the association between HCA and neurodevelopmental outcomes. Results: A total of 304 infants (median [IQR] GA, 29.4 [27.3-31.1] weeks; 152 female [50.0%]) had complete data at developmental follow-up at corrected age 22 to 26 months. In multivariable regression analyses, infants exposed to moderate to severe HCA exhibited a decrease in BSID-3 motor scores (β estimate, -7.0; 95% CI, -11.2 to -2.8), cognitive scores (β estimate, -6.0; 95% CI, -10.2 to -1.8, and language scores (β estimate, -8.8; 95% CI, -14.5 to -3.2). Infants exposed to moderate to severe HCA were born at a median GA of 2.6 weeks (IQR, 1.2-4.0 weeks) earlier than those with no or mild HCA exposure. Causal mediation analysis showed that earlier premature birth indirectly mediated 25% of the association of HCA with BSID-3 motor scores (β = -1.7; 95% CI, -2.9 to -0.6). The remaining 75% represented a direct adverse association of HCA or inflammation with motor development (β = -5.3; 95% CI, -9.9 to -0.7). A similar mediation of premature birth was observed for HCA and cognitive scores. Conclusions and Relevance: In this prospective, regional cohort study, exposure to moderate to severe HCA in preterm infants was independently associated with adverse motor neurodevelopment at corrected age 22 to 26 months. Causal mediation analysis suggests that HCA exhibits a significantly mediated association with neurodevelopment via induction of earlier preterm birth and a direct adverse association with neurodevelopmental outcomes. These findings suggest clinical implications for parental counseling and design of anti-inflammatory therapy trials for this high-risk population.