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Shifting outlooks after neonatal encephalopathy in the era of therapeutic hypothermia

Pediatric Research (2025)Cite this article

Abstract

In the era of therapeutic hypothermia (TH), more infants are surviving moderate to severe hypoxic-ischemic encephalopathy (HIE) with no or less apparent injury on neonatal brain magnetic resonance imaging (MRI). Despite a reduction in death and severe neurodisability for infants with neonatal encephalopathy from HIE, children remain at risk for challenges in learning, language, coordination, behavior, and socioemotional development. Neither neonatal MRI nor early developmental testing is completely predictive of outcomes at school age. This review summarizes current data on long-term outcomes of infants who have received TH for HIE, most in the absence of cerebral palsy or significant neonatal brain injury. Many children with a history of neonatal HIE face challenges in their motor skills, emotion regulation and behavior, language and communication, cognition and learning, and academic achievement. All children with a history of neonatal HIE can benefit from close neurodevelopmental surveillance into adolescence. It is important for providers to counsel families about the spectrum of long-term outcomes and potential effects on later stages of neurodevelopment even when brain MRI is reassuring. Understanding the broader spectrum of neurodevelopmental impairment at school-age in children with neonatal HIE can inform new therapies, early intervention strategies, and pre-school readiness to optimize outcomes.

Impact Statement

  • Children with a history of moderate to severe hypoxic ischemic encephalopathy (HIE) without evidence of significant brain injury on post-cooling neonatal MRI are still at risk for a range of neurodevelopmental challenges at school-age and beyond.

  • Neonatal neuroimaging and early neurodevelopmental evaluations do not reliably indicate outcomes at school-age, making early prognostication and counseling families in the NICU period and during neonatal follow-up clinics challenging.

  • All children with perinatal HIE, regardless of MRI findings, should have long-term follow up and support through school age.

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Funding

Dr. Mulkey receives support for research from the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health (grant number R01HD102445 [to SBM]). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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  1. Zickler Family Prenatal Pediatrics Institute, Children’s National Hospital, Washington, DC, USA

    Kelsey Christoffel & Sarah B. Mulkey

  2. Department of Neurology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA

    Kelsey Christoffel & Sarah B. Mulkey

  3. Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA

    Kelsey Christoffel & Sarah B. Mulkey

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  1. Kelsey Christoffel
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  2. Sarah B. Mulkey
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Correspondence to Sarah B. Mulkey.

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Christoffel, K., Mulkey, S.B. Shifting outlooks after neonatal encephalopathy in the era of therapeutic hypothermia. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04156-0

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