In the evolving landscape of neonatal care, therapeutic hypothermia (TH) has emerged as a transformative intervention for term infants suffering from moderate to severe hypoxic-ischemic encephalopathy (HIE), substantially improving neurological outcomes and reducing mortality. However, extending this treatment to late preterm infants, specifically those born between 33 and 35 weeks’ gestational age (GA), poses a complex and contentious clinical challenge. A recent comprehensive review published in Pediatric Research by El-Dib and colleagues meticulously examines this clinical quandary, shedding light on the biological basis, existing clinical evidence, and the nuanced real-world application of TH in this vulnerable population.

Therapeutic hypothermia operates on the principle of mitigating secondary brain injury after an initial hypoxic-ischemic insult by lowering core body temperature, thereby reducing cerebral metabolic rate, attenuating excitotoxicity, and modulating inflammatory cascades. While its efficacy in term neonates is well established through robust randomized controlled trials (RCTs) and meta-analyses, late preterm infants have historically been excluded from such trials due to concerns about their increased physiological vulnerability and developmental immaturity. The crux of the controversy lies in whether the neuroprotective benefits seen in term infants translate effectively—and safely—to those born in the late preterm window.

Preclinical animal studies provide important mechanistic insights by simulating brain injury at developmental stages comparable to human late preterm infants. These models consistently demonstrate that TH confers neuroprotection even at these earlier maturational stages, reducing inflammation, limiting neuronal apoptosis, and preserving white matter integrity. Such findings suggest a compelling biological rationale for cautiously considering TH in late preterm neonates who suffer from HIE. However, laboratory success does not always equate to clinical efficacy, and neonates in this GA bracket exhibit marked differences in organ system maturity, metabolism, and thermoregulatory capacity that may influence both the safety and effectiveness of TH.

Moving from bench to bedside, retrospective cohort studies and registry data have explored the feasibility and outcomes of applying TH to late preterm infants. These studies reveal a heterogeneous clinical landscape, with some centers reporting successful implementation of TH protocols and others documenting increased rates of adverse events such as coagulopathy, hypotension, and metabolic instability—complications that may be exacerbated by the physiological fragility of infants at 34 weeks’ GA or younger. Notably, retrospective analyses often suffer from selection bias, incomplete data, and variable treatment protocols, limiting their capacity to provide definitive guidance on practice.

The pivotal clinical evidence comes from the only randomized controlled trial specifically enrolling infants at 33 to 35 weeks’ GA with moderate to severe HIE, which paradoxically failed to demonstrate a neuroprotective benefit of TH in this group. Even more concerning, it suggested potential harm in treated infants, including heightened mortality and morbidity. Such results have led to a hesitant and circumspect approach toward TH in late preterm infants, with many clinicians reluctant to initiate cooling outside of specialized centers or research protocols. Yet, a critical examination of the trial reveals significant limitations that temper the conclusiveness of its findings.

First, baseline imbalances between treatment groups—such as differences in the severity of encephalopathy and other demographic variables—confound the interpretation of outcomes. Second, the trial lacked adequate stratification by gestational age and encephalopathy severity, variables that are crucial for understanding differential responses to TH in a heterogenous late preterm cohort. Third, the absence of detailed neuroimaging and electroencephalographic (EEG) assessments weakens the ability to precisely characterize injury patterns and neurological outcomes, which could inform patient selection and therapeutic targeting. Consequently, while the trial raises important safety concerns, it does not categorically rule out potential benefits in carefully selected late preterm neonates.

Real-world clinical practice appears to echo this ambiguity. An international survey including 88 NICUs revealed that despite the lack of unequivocal evidence supporting TH in infants born between 34 and 35 weeks’ GA, many centers continue to employ hypothermia treatment protocols. These practices vary not only by geographical region and institutional culture but also depend on individual patient characteristics and clinician experience. Intriguingly, data aggregated from 22 centers demonstrate lower mortality rates than those reported in the RCT, hinting that real-world outcomes may differ from controlled trial environments, possibly due to differences in patient selection, supportive care, or protocol nuances.

The collective evidence underscores that while TH remains a viable and potentially beneficial intervention for select infants born at 35 weeks’ GA experiencing moderate to severe HIE, its indiscriminate use in neonates born at 34 weeks or earlier warrants caution. The increased risk profile and uncertain benefit demand that routine therapeutic hypothermia in these younger preterm infants be confined to research settings where rigorous monitoring, standardized neurological assessment, and comprehensive data collection are ensured.

Looking forward, it is imperative that future investigations adopt nuanced, stratified study designs that recognize the developmental heterogeneity within the late preterm population. Implementing standardized neurological evaluation frameworks, including advanced neuroimaging and continuous EEG, will be essential to delineate which infants derive measurable benefit from TH and to identify potential biomarkers predictive of outcomes. Such data will facilitate the tailoring of cooling protocols—perhaps adjusted for gestational age and injury severity—and optimize the risk-benefit ratio.

Moreover, integrating translational science with clinical research can elucidate mechanistic pathways that underlie differential responses to hypothermia across developmental stages, potentially identifying adjunctive therapies or novel neuroprotectants tailored to late preterm physiology. Understanding the interplay of systemic immaturity, cerebral vulnerability, and TH-induced physiological perturbations will be central to refining clinical guidelines and ensuring equitable neonatal neuroprotection.

This evolving discourse exemplifies the challenges inherent to extending established therapies beyond initially studied populations, highlighting the necessity of bridging rigorous scientific inquiry with pragmatic clinical judgment. As neonatal intensive care units around the world grapple with these complex decisions, a balanced approach grounded in evidence, ongoing surveillance, and multidisciplinary collaboration will be pivotal.

In summary, therapeutic hypothermia remains a cornerstone of care for term infants with hypoxic-ischemic encephalopathy, but when it comes to late preterm neonates between 33 and 35 weeks’ gestation, the therapeutic window narrows significantly. The current landscape is characterized by encouraging preclinical data, inconclusive and sometimes conflicting clinical trial results, and diverse real-world practices that together underscore an urgent need for further robust research. Until such data emerge, cautious, individualized application of TH in this delicate group, predominantly within structured research frameworks, is the most prudent path forward.

The ongoing pursuit to optimize neurodevelopmental outcomes in late preterm infants with hypoxic-ischemic brain injury exemplifies the frontier of neonatal medicine—where cutting-edge therapies must be judiciously calibrated against intricate developmental biology and the mandates of patient safety. El-Dib and colleagues’ synthesis provides a vital compass as clinicians and researchers navigate this complex clinical terrain, signaling both the promise and perils of therapeutic hypothermia in the late preterm population.

Subject of Research: Therapeutic hypothermia for hypoxic-ischemic encephalopathy in late preterm infants

Article Title: Benefits and risks of therapeutic hypothermia for hypoxic-ischemic encephalopathy in late preterm infants

Article References: El-Dib, M., Abdelgadir, D., Ahmad, K.A. et al. Benefits and risks of therapeutic hypothermia for hypoxic-ischemic encephalopathy in late preterm infants. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04428-9

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41390-025-04428-9

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