The Placenta as a Connective Hub in Neonatal Seizures: Pathophysiological Links, Modulating Factors, and Emerging Therapeutic Strategies

Abstract

Abstract Neonatal seizures represent a neurological emergency with complex, multifactorial origins that extend beyond the immediate perinatal period. The placenta, as the primary interface between mother and fetus, serves as a critical connective hub linking maternal health, intrauterine environment, and fetal brain development. This review synthesizes current evidence on the placenta’s role in neonatal seizure pathogenesis through four interconnected pathways: structural and vascular dysfunction, inflammatory signaling, neuroendocrine disruption, and genetic-epigenetic dysregulation. We examine how specific placental histopathologies—including chorioamnionitis, malperfusion lesions, and chronic villitis—correlate with seizure risk and long-term neurodevelopmental outcomes. The bidirectional interplay between placental function and extrinsic modulating factors, including maternal comorbidities, nutritional status, and xenobiotic exposures, is explored. Furthermore, we critically evaluate emerging therapeutic strategies that target placental pathways for neuroprotection, including neurosteroid replacement, mesenchymal stem cell transplantation, anti-inflammatory agents, and placental biomarkers for risk stratification, while acknowledging the predominantly preclinical evidence base. By framing the placenta as a dynamic hub rather than a passive conduit, we identify novel opportunities for prenatal intervention, postnatal neuroprognostication, and personalized therapeutic approaches aimed at reducing the burden of neonatal seizures and their lifelong sequelae. Keywords: placenta, neonatal seizures, chorioamnionitis, allopregnanolone, neuroprotection, placental biomarkers, hypoxic-ischemic encephalopathy, neurosteroids