Associations between chronic placental inflammation, fetal brain development and later autism traits

Prenatal inflammation is a recognized risk factor for autism spectrum disorder (ASD), but the neural pathways linking in utero immune exposure to later outcomes remain unclear. We examined whether chronic placental inflammation (CPI), a sustained immune response within the placenta, is associated with fetal brain functional connectivity differences and later ASD traits. A cohort of 105 pregnant individuals (85.7% African American/Black, 1.0% Asian American, 4.8% Bi-racial, 4.8% White, 1.0% Other, 2.9% Missing) underwent fetal resting-state fMRI between 24 and 38 weeks' gestation. After delivery, placental tissues were evaluated by expert pathologists for CPI lesions. Fetuses exposed to CPI (n = 44) showed significant differences in resting-state functional connectivity (RSFC) compared to non-exposed fetuses (n = 61) across ten network pairs, with the greatest effects in prefrontal, cerebellar, visual, and motor regions. These connectivity differences were associated with behavioral outcomes: cerebellar-medial visual RSFC was the strongest prenatal predictor of ASD traits at age 3. An exploratory structural equation modeling indicated that CPI was associated with reduced cerebellum-medial visual RSFC, which was associated with higher ASD trait scores, though the indirect pathway did not reach statistical significance. This study provides the first human evidence that chronic placental inflammation is associated with large-scale fetal brain network differences that are also associated with autism traits, suggesting that prenatal immune activity may be relevant to neurodevelopmental trajectories.