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Evidence versus equipoise in late preterm neonates with encephalopathy; to cool or not to cool, that is the question!

Pediatric Research (2025)Cite this article

Experimentation with therapeutic hypothermia (TH) for asphyxiated newborns was reported as early as 1959.1 Extensive preclinical research has informed the development of the practice standards we now adhere to for management of term neonates with encephalopathy due to probable hypoxic-ischemic encephalopathy (HIE). However, the first modern-day trial in 40 randomized full-term neonates showed no benefit of TH.2 If researchers and clinicians had stopped there, thousands of babies worldwide may have missed the opportunity for our only proven lifesaving and brain-saving treatment for neonatal encephalopathy (NE). The subsequent series of clinical trials and an important Cochrane review confirmed the benefit of mild hypothermia for neonates ≥37 weeks with moderate-severe HIE within the first 6 h of birth.3

Questions have remained regarding eligibility criteria in the balance of benefit over risk, including uncertainty regarding limits of gestational age, timing, and type of cooling and target temperature. Animal studies and a clinical trial have largely put to rest the potential risk-benefit ratio of extending target temperatures below the current standard of 33.5–35.0 °C or extending the duration of cooling to longer than 72 h.1,4 North American guidelines5 include neonates born at 35 weeks in their recommendations to apply TH for moderate-severe HIE, based on the seven neonates who were included in two trials included in the 2013 Cochrane review. Despite these small numbers, it might seem obvious to apply this rationale in extrapolating practice from a systematic review that sits at the top of the evidence hierarchy. However, there are important differences between late preterm infants and term infants, despite the arbitrary distinction between the two groups.

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Acknowledgements

T.S. and D.G. are supported by BC Children’s Hospital Research Institute.

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Authors and Affiliations

  1. Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada

    Julia K. Charlton, Thiviya Selvanathan & Dawn Gano

  2. Neonatal Program, BC Women’s Hospital and Health Centre, Vancouver, BC, Canada

    Julia K. Charlton

  3. Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia

    Julia K. Charlton

  4. BC Children’s Hospital Research Institute, Vancouver, BC, Canada

    Julia K. Charlton, Thiviya Selvanathan & Dawn Gano

  5. Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada

    Thiviya Selvanathan

  6. Department of Neurology, University of California, San Francisco, San Francisco, CA, USA

    Dawn Gano

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  1. Julia K. Charlton
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  2. Thiviya Selvanathan
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Correspondence to Dawn Gano.

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D.G. serves as an Associate Editor at Pediatric Research and receives royalties from Up to Date for authoring chapters on neonatal encephalopathy.

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Charlton, J.K., Selvanathan, T. & Gano, D. Evidence versus equipoise in late preterm neonates with encephalopathy; to cool or not to cool, that is the question!. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04626-5

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