Neonatal Inflammation Predicts Adolescent Brain Volume and Neurologic Outcomes in Extremely Preterm Births

Children born extremely preterm (< 28 weeks gestation) face elevated risks for neurodevelopmental disorders and reduced brain volumes. This study examined whether neonatal inflammation predicts adolescent brain volume and whether these associations vary by sex or presence of a major neurologic disorder. Using data from the Extremely Low Gestational Aged Newborns (ELGAN) Study, inflammatory protein levels measured during the first two postnatal weeks were used to classify neonates into low, moderate, or high inflammation groups. At age 15, participants underwent 3T MRI scans, and total and regional brain volumes were quantified using FreeSurfer. Neurologic status was assessed at ages 2, 10, and 15. Higher neonatal inflammation was associated with reduced volumes in the cerebral cortex, subcortical gray matter, thalamus, ventral diencephalon, and brainstem. Sex-specific effects were observed: females with moderate inflammation had reduced volumes in the total brain, cerebellum, thalamus, and ventral diencephalon; males with moderate or high inflammation showed reductions in the brainstem, cerebellar gray matter, and corpus callosum. Among adolescents with a major neurologic disorder, higher inflammation correlated with reduced brainstem and cerebellar volumes. These findings suggest neonatal inflammation has lasting effects on brain development in extremely preterm individuals. Early interventions to reduce inflammation may improve long-term neurologic outcomes.