Comment on “Histologic Chorioamnionitis and Neurodevelopment in Preterm Infants”

Chorioamnionitis, or intrauterine inflammation with or without infection, affects more than half of preterm births. While chorioamnionitis is diagnosed using clinical symptoms, histologic analysis is more accurate. Chorioamnionitis can trigger preterm labor and alter fetal homeostasis. The evidence is mixed as to whether there is a direct association between chorioamnionitis and adverse neurodevelopmental outcomes, such as structural brain changes, delays in motor and language development, cerebral palsy, weak memory and learning functions, and cognitive deficits. While some studies have found an association between chorioamnionitis and adverse outcomes, other studies have not. Gestational age (GA) may also act as a mediator between chorioamnionitis and adverse neurodevelopment. In a recent study, premature birth based on GA was found to have mediated about 50% of histologic chorioamnionitis (HCA) and MRI brain abnormalities, while the inflammation itself was directly associated with brain abnormalities in the remaining 50%. The aim of this study was to analyze the association between HCA and neurodevelopmental outcomes of preterm infants. This was a prospective, population-based cohort study of preterm infants (GA ≤32 wk) who received care at neonatal intensive care units (NICUs) at 5 southwestern Ohio hospitals between September 2016 and November 2019. Excluded were infants with cyanotic heart disease or chromosomal or congenital anomalies affecting the central nervous system. The Bayley Scales of Infant Toddler Development, Third Edition (BSID-3) were used to test all infants between 22 and 26 months. The primary outcome was the motor composite score. Secondary outcomes were cognitive and language scores. A total of 304 infants with complete placental histology and BSID-3 scores were included in the analysis. Of these, 16.8% had moderate to severe HCA, 13. 8% had mild HCA, and 11.7% had funisitis. Infants with moderate to severe HCA had a lower median composite BSID-3 score than those with mild or no HCA motor: 91 (IQR, 82 to 97) vs 94 (IQR, 88 to 100); P = 0.01; cognitive: 90 (IQR, 70 to 100) vs 95 (IQR, 85 to 100); P = 0.02; and language: 89 (IQR, 62 to 97) vs 94 (IQR, 79 to 106); P = 0.007. In causal mediation analysis, GA indirectly mediated about 25% of the association of moderate to severe HCA with BSID-3 motor scores (β = –1.7; 95% CI, –2.9 to –0.6; P = 0.003), with the remaining 75% representing a direct adverse association of HCA on motor development (β = –5.3; 95% CI, –9.9 to –0.7; P = 0.03). GA mediated 25% of the association of HCA with cognitive scores (β = –1.5; 95% CI, –2.8 to –0.2; P = 0.02). While the MRI brain abnormalities did not mediate an association of moderate to severe HCA with BSID-3 scores, the remaining 78% to 86% represented a direct and significant adverse association of HCA or inflammation with BSID-3 outcomes for motor (β = –5.5; 95% CI, –9.7 to –1.3; P = 0.01), cognitive (β = –4.7; 95% CI, –9.2 to –0.2; P = 0.04), and language (β= –7.6; 95% CI, –12.7 to –2.4; P = 0.04). In conclusion, moderate to severe HCA was associated with lower motor, cognitive, and language outcomes at 22 to 26 months in preterm infants exposed to chorioamnionitis. (Summarized from Peterson LS, Roy S, Jain VG, et al. Histologic chorioamnionitis and neurodevelopment in preterm infants. JAMA Netw Open 2025;8(9):e2531158. doi: https://doi.org/10.1001/jamanetworkopen.2025.31158.)