Emerging therapies and management for neonatal encephalopathy—controversies and current approaches

Neonatal encephalopathy (NE) continues to have a major impact on newborn survival and neurodevelopmental outcomes worldwide. In high-income settings, therapeutic hypothermia is the only established standard treatment for neonates with moderate-to-severe NE, with compelling evidence that cooling reduces mortality and major neurodevelopmental impairment in survivors. Despite therapeutic hypothermia, a significant proportion of cooled infants continue to suffer long-term disability from brain injury. Innovative therapies offer the possibility of further improving neurodevelopmental outcomes by working synergistically with therapeutic hypothermia to decrease hypoxia-ischemia-induced excitotoxicity, prevent progression to secondary energy failure, and in some cases, promote neuroregeneration in the developing neonatal brain. This review discusses emerging NE therapies currently under investigation, offers insight into controversies surrounding various approaches to clinical care during therapeutic hypothermia, and identifies ongoing knowledge deficits that hinder attainment of optimal outcomes for neonates with NE.