Ketogenic Strategies in Neonatal Hypoxic–Ischemic Encephalopathy—The Road to Opening Up: A Scoping Review

TL;DR

This review explores how ketogenic diets and ketone bodies might help protect the brains of newborns with hypoxic-ischemic encephalopathy, a condition caused by lack of oxygen and blood flow.

Contribution

The paper provides a comprehensive scoping review of the potential of ketogenic strategies as a neuroprotective intervention in neonatal hypoxic-ischemic encephalopathy.

Findings

Preclinical studies show ketone bodies improve cerebral energy metabolism and reduce brain damage in neonatal models.

Ketogenic diets may offer metabolic advantages during hypoxic-ischemic stress by preferentially using β-hydroxybutyrate over glucose.

Nutritional studies suggest enteral and parenteral ketogenic feeding is feasible in critically ill neonates.

Abstract

Background: Neonatal hypoxic–ischemic encephalopathy remains a leading cause of neonatal mortality and long-term neurodevelopmental disability worldwide. Despite the widespread adoption of therapeutic hypothermia, a substantial proportion of affected infants experience death or significant neurological impairment. Given their metabolic vulnerability, ketogenic diet strategies and ketone bodies have emerged as potential adjunctive neuroprotective interventions. This scoping review aims to critically evaluate the mechanistic rationale, preclinical evidence, and clinical feasibility of ketogenic approaches. Methods: A scoping review of the literature was conducted, including experimental and clinical studies investigating ketogenic diets, endogenous ketosis, and exogenous ketone supplementation in neonatal hypoxia–ischemia. Evidence was synthesized across mechanistic, preclinical, nutritional, and clinical domains, with particular attention to developmental context, timing of intervention, safety considerations, and translational relevance in the contest of therapeutic hypothermia. Results: Preclinical studies consistently demonstrate that ketone bodies enhance cerebral energy metabolism, support mitochondrial function, reduce excitotoxic signaling, and attenuate oxidative stress and neuroinflammation in the immature brain. Neonatal models show preferential utilization of β-hydroxybutyrate over glucose during hypoxic–ischemic stress, suggesting intrinsic metabolic advantages. Emerging evidence also supports potential long-term effects on epigenetic regulation and white matter development, although direct causal validation in neonatal HIE remains limited. Nutritional studies indicate that carefully monitored enteral and parenteral feeding is feasible in critically ill neonates, identifying a potential window for metabolic interventions. Conclusions: Ketogenic strategies represent a plausible, multimodal approach to targeting the metabolic and inflammatory sequelae of neonatal HIE. While current evidence is insufficient to support clinical implementation, this scoping review provides a hypothesis-generating framework to guide future translational research and the design of carefully controlled clinical trials in neonatal neurocritical care.

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