Association of fetal inflammatory response with brain MRI findings and neurodevelopmental outcomes in preterm infants

BACKGROUND: Fetal inflammatory response (FIR), a histological indicator of intrauterine inflammation, is associated with adverse outcomes in extremely preterm infants. While FIR has been linked to early brain injury, its long-term impact on neurodevelopment remains underexplored. To assess the relationship between FIR severity and neurodevelopmental outcomes at two years in infants born <29 weeks' gestation and to examine whether term-equivalent MRI brain abnormalities are associated with these outcomes. METHODS: In this prospective cohort study, 93 preterm infants underwent standardized placental histopathologic assessment for FIR, term-equivalent brain MRI scored using the Kidokoro system, and Bayley-III assessments at two years. Primary analyses compared infants with no FIR versus any FIR. Stratified analyses by FIR severity (Stage 1 vs ≥Stage 2) were conducted as secondary, exploratory analyses. Multivariable linear regression models adjusted for gestational age were used to assess associations among FIR, MRI findings, and neurodevelopmental scores. Exploratory attenuation analyses were performed to assess whether MRI abnormalities influenced observed associations. RESULTS: Among 93 infants included in the analysis, FIR was present in 52%. Compared with infants without FIR, those with FIR had higher global brain abnormality scores on term-equivalent MRI, driven primarily by white matter injury. In adjusted models, FIR was associated with differences in cognitive and language outcomes at two years. Exploratory stratified analyses suggested heterogeneity by FIR severity; MRI abnormalities attenuated associations between FIR and neurodevelopmental outcomes, suggesting that early brain injury may represent an important correlate along the pathway linking inflammation and later development. CONCLUSIONS: In extremely preterm infants, placental FIR is associated with early brain MRI abnormalities and neurodevelopmental outcomes at two years. These findings highlight the importance of intrauterine inflammation as an early biologic exposure while underscoring the contribution of cumulative prenatal and postnatal factors to brain injury and long-term development. Larger studies incorporating detailed postnatal inflammatory trajectories are needed to confirm these associations and clarify underlying mechanisms. IMPACT: Demonstrates that severity of placental fetal inflammatory response is associated with neurodevelopmental outcomes at two years of age in extremely preterm infants Identifies a biphasic relationship between FIR severity and neurodevelopment, underscoring that severe intrauterine inflammation may confer disproportionate risk compared with milder inflammatory exposure Provides evidence that term-equivalent brain MRI abnormalities, particularly white matter injury, partially mediate the association between intrauterine inflammation and later cognitive and language development.