Therapeutic hypothermia in neonatal encephalopathy: current challenges and future prospects

Hypoxic–ischemic encephalopathy (HIE) is a major cause of mortality and long-term neurodevelopmental impairment globally. Currently, therapeutic hypothermia (TH) represents the only evidence-based neuroprotective treatment for moderate-to-severe neonatal HIE, having resulted in consistent reductions in rates of mortality and disability. However, despite its success in advanced healthcare settings, challenges persist regarding its universal implementation, particularly in low- and middle-income countries (LMICs). This review examines the evolution of TH and outlines the challenges and controversies regarding this therapeutic approach. It also explores the complexities of applying TH in resource-constrained settings, the debates about its use in mild HIE and preterm infants, and the limitations of current diagnostic and prognostic tools such as conventional MRI and amplitude-integrated EEG. Furthermore, it discusses the emerging approaches aiming to enhance the effectiveness and precision of TH. These include adjuvant therapies, improved neuroimaging modalities, and the identification of new biomarkers to better predict outcomes and individualize care. Additionally, this review explores the utility of artificial intelligence and machine learning to improve risk stratification and real-time decision-making. As robust evidence emerges, the precision medicine framework, integrating clinical data, biomarkers, imaging, and AI tools, holds the promise of facilitating care and improving outcomes for HIE-affected infants, particularly in underserved settings where the burden remains highest.