Mild neonatal hypoxic-ischemic encephalopathy: current evidence and ongoing controversies

Neonatal hypoxic-ischemic encephalopathy (HIE) remains a leading cause of neonatal morbidity and mortality worldwide. Therapeutic hypothermia (TH) is an established neuroprotective therapy for infants with moderate to severe HIE; however, its role in the management of mild HIE remains uncertain. This review summarizes current evidence regarding neurodevelopmental outcomes in infants with mild HIE and critically evaluates available data on the use of TH in this population. Although mild HIE was excluded from the original hypothermia trials, emerging observational studies suggest that a proportion of affected infants experience adverse short- and long-term neurodevelopmental outcomes. Interpretation of these findings is limited by challenges in the early clinical identification of mild HIE, evolving diagnostic criteria, heterogeneity in outcome definitions, and reliance on retrospective or underpowered cohorts. Consequently, evidence supporting the efficacy or safety of TH in mild HIE is inconclusive, and clinical practice varies widely across institutions and regions. Existing studies have not definitively demonstrated neurodevelopmental benefit and raise concern for potential overtreatment in some infants. Adequately powered, prospective trials are urgently needed to clarify the risk, benefit profile of TH in mild HIE, identify subgroups most likely to benefit from intervention, and establish standardized diagnostic and outcome measures. Until such evidence is available, management of infants with mild HIE should be individualized, balancing potential neuroprotective benefit against known and theoretical risks, while acknowledging persistent gaps in knowledge.