Neuroprotective Therapy for Neonatal Hypoxic-Ischemic Encephalopathy: From Therapeutic Hypothermia to Multi-Target Combination Strategies

Corresponding author: Pengfen, 814321338@qq.com

DOI: 10.12201/bmr.202610.00008

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  Abstract: Neonatal hypoxic-ischemic encephalopathy (HIE) is a severe neurological disorder caused by reduced cerebral blood perfusion and oxygen supply during the perinatal period. Approximately 1.2 million neonates are affected worldwide each year, and the reported incidence in China is about 3‰–6‰. Therapeutic hypothermia is currently the only internationally recognized standardized neuroprotective therapy that improves long-term outcomes in neonates with moderate-to-severe HIE; however, approximately 29% of treated infants still develop adverse neurodevelopmental outcomes, and the optimal boundaries of its indications remain controversial. In recent years, multi-target strategies combining therapeutic hypothermia with pharmacological agents such as erythropoietin, melatonin, allopurinol, hydrogen, xenon, magnesium sulfate, and topiramate have become a research focus. Although some studies suggest potential benefits, large-scale randomized controlled evidence remains limited. Stem cell therapy, particularly umbilical cord blood cell infusion, has shown preliminary promise in promoting neural repair. Given that long-term dysfunction may involve motor, cognitive, and behavioral domains, establishing a multidisciplinary follow-up and rehabilitation system extending through school age is of considerable clinical importance. Future efforts should aim to achieve precise patient stratification using biomarkers and to expand therapeutic goals from short-term survival to lifelong functional optimization.

  Key words: Neonatal; Hypoxic-ischemic encephalopathy; Therapeutic hypothermia; Neuroprotective agents; Stem cells

  Submit time: 6 October 2026

  Copyright: The copyright holder for this preprint is the author/funder, who has granted biomedRxiv a license to display the preprint in perpetuity.
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