Neuroimmune and Neurovascular Remodeling After Perinatal Hypoxia: Mechanistic Pathways Linking Early-Life Injury to...

Perinatal hypoxia and hypoxic-ischemic encephalopathy (HIE) remain major causes of neonatal seizures and subsequent epilepsy. Increasing evidence suggests that neuroimmune and neurovascular mechanisms contribute to delayed epileptogenesis; however, these mechanisms have not been comprehensively synthesized within an integrated conceptual framework.

To conduct a transparent and reproducible scoping review mapping neuroimmune, neurovascular, and autonomic mechanisms potentially linking perinatal hypoxia to epileptogenesis.

This scoping review followed PRISMA-ScR recommendations. PubMed, Scopus, and Web of Science were systematically searched from January 1990 to January 2025 using predefined search strategies. Study selection and data charting were conducted by a single reviewer. To enhance internal consistency, a randomly selected 10% subset was re-screened after a two-week interval. No second independent reviewer participated in screening or data extraction. Extracted data included study design, mechanistic domain, biomarkers, developmental stage, and seizure-related outcomes. In accordance with scoping review methodology, neither quantitative synthesis nor formal risk-of-bias assessment was performed; instead, methodological and translational limitations were qualitatively evaluated.

Of 1,284 records identified, 118 studies met the inclusion criteria. The evidence was synthesized across five principal mechanistic domains: microglial priming, blood-brain barrier dysfunction, cytokine-mediated synaptic remodeling, developmental vulnerability, and autonomic network involvement. Experimental animal studies consistently demonstrated persistent neuroimmune activation and neurovascular remodeling following neonatal hypoxia, whereas comparable longitudinal human evidence remained limited. Evidence concerning autonomic manifestations originated predominantly from the broader epilepsy literature and is therefore considered exploratory rather than established for perinatal hypoxia cohorts.

Current evidence suggests that perinatal hypoxia is associated with sustained neuroimmune and neurovascular alterations that may contribute to delayed epileptogenesis. Although experimental findings are biologically compelling, longitudinal human validation remains limited. Autonomic manifestations and inflammatory biomarkers should not currently be considered reliable standalone predictors of epilepsy risk following perinatal hypoxia. Future prospective studies integrating immune, vascular, neurophysiological, and imaging biomarkers are needed to improve mechanistic understanding and support clinical translation.