Neuroprotection for neonatal hypoxic-ischemic encephalopathy: A review of novel therapies evaluated in clinical studies.

Therapeutic hypothermia is an effective therapy for moderate-to-severe hypoxic-ischemic encephalopathy (HIE) in infants born at term or near-term in high-resource settings. Yet there remains a substantial proportion of infants who do not benefit or who will have significant disability despite therapeutic hypothermia. Novel investigational therapies that may confer additional neuroprotection by targeting known pathogenic mechanisms of hypoxic-ischemic brain injury are under development. This review focuses on putative neuroprotective agents that have shown promise in animal models of HIE, and that have been translated to clinical studies in neonates with HIE. We include agents that have been studied both with and without concurrent therapeutic hypothermia. Our review therefore addresses not just neonatal HIE in high-resource countries where therapeutic hypothermia is the standard of care, but also neonatal HIE in low- and middle-income countries where therapeutic hypothermia has been shown to be ineffective, and where the greatest burden of HIE-related morbidity and mortality exists.