Sex-specific outcomes following chorioamnionitis

Abstract Chorioamnionitis is a common cause of perinatal inflammation and is associated with adverse neonatal and long-term outcomes. Although male infants experience higher rates and greater severity of many inflammation-related morbidities, the contribution of fetal sex to chorioamnionitis-related outcomes remains understudied. This review synthesizes evidence from human studies and animal models to evaluate how sexually dimorphic placental biology and fetal immune responses shape offspring vulnerability to inflammation-induced injury. Across species, males consistently exhibit heightened acute inflammatory responses, increased neuroinflammation, and greater structural brain vulnerability following exposure to perinatal inflammation. Human studies demonstrate sex-specific alterations in cerebral blood flow and brain metabolites, with males showing patterns that place them at increased risk of cerebral palsy and neurodevelopmental impairment. Females, while mounting distinct inflammatory responses, show susceptibility in other organ systems, including impaired lung function and altered metabolic trajectories in childhood. Findings from animal models parallel human observations and reveal possible mechanistic pathways through which sex modifies neuroimmune, metabolic, and behavioral outcomes across the lifespan. Collectively, this review highlights the substantial impact of fetal sex on inflammation-driven morbidity and underscores the critical need to incorporate sex as a biological variable in perinatal research and clinical risk stratification. Impact Few investigations of chorioamnionitis-related outcomes stratify analyses by fetal sex, leaving key biologic differences unexplored. Male and female fetuses mount distinct placental and systemic inflammatory responses to chorioamnionitis, which likely contribute to differential neurodevelopmental, pulmonary, metabolic, and cardiac outcomes. This review provides the first comprehensive synthesis of sex-specific responses to chorioamnionitis and highlights the need to analyze sex as a biological variable in future outcome-related studies.