Long-Term Neurodevelopmental Outcomes After Hypoxic-Ischemic Encephalopathy Treated With Therapeutic Hypothermia: A Systematic Review.

Therapeutic hypothermia (TH) is the cornerstone of treatment for infants with moderate-to-severe hypoxic-ischemic encephalopathy (HIE). The long-term neurodevelopmental outcomes after 18 to 24 months and the persistence or onset of impairments throughout later childhood, however, are still up for discussion. This systematic review evaluates the long-term neurodevelopmental outcomes (≥18 months) of babies with moderate-to-severe HIE treated with TH. A comprehensive literature search of PubMed/Medical Literature Analysis and Retrieval System Online (MEDLINE), Scopus, Web of Science, and Cochrane Controlled Register of Trials (CENTRAL) yielded 213 records. Following duplicate removal and screening, 10 studies encompassing 1,134 neonates met eligibility criteria. Two reviewers independently extracted the data and performed a design-specific risk of bias assessment. Methodological quality was evaluated using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for cohort studies, the Quality in Prognosis Studies (QUIPS) tool for prognostic factor studies, and the Cochrane Risk of Bias 2 (RoB 2) tool for randomized trials. Across the included studies, 52%-81% of survivors treated with therapeutic hypothermia achieved normal or mildly abnormal neurodevelopment at 18-36 months, with mortality ranging from 3.8% to 19.6%. Consistent predictors of adverse outcomes included delayed cooling, elevated lactate, severe EEG abnormalities, rewarming seizures, abnormal MRI, and prolonged birth depression. Novel biomarkers showed prognostic promise but require validation. Outcomes in low- and middle-income countries (LMICs) were variable, with high attrition limiting generalisability, and evidence suggested that impairments may emerge at school age, supporting surveillance beyond 24 months. TH is associated with positive long-term outcomes for the majority of survivors with moderate-to-severe HIE. However, neurodevelopmental impairments may emerge or persist into school age, necessitating surveillance beyond 24 months. While TH is effective in high-income settings, its benefits in LMICs depend on adequate resources and follow-up infrastructure. Validation of novel biomarkers and standardization of outcome measures are priorities for future research.