EBNEO Commentary: Is Therapeutic Hypothermia Beneficial to Infants Born Between 33 and 35 Weeks Gestation?

Faix RG, Laptook AR, Shankaran S, Eggleston B, Chowdhury D, Heyne RJ, et al. “Whole-Body Hypothermia for Neonatal Encephalopathy in Preterm Infants 33 to 35 Weeks' Gestation: A Randomised Clinical Trial,” JAMA Pediatrics, 2025; e246613. PMID 39992674. HIE is a devastating pathology, resulting in significant morbidity and mortality [1]. TH is currently the only effective treatment shown to reduce morbidity and mortality in term and late preterm infants with moderate to severe HIE [1, 2]. Despite the effectiveness of TH in infants ≥ 36 weeks, limited research has been conducted on the effects of TH for infants born at 35 weeks GA, with even less at 33–34 weeks GA [2-6]. Faix and colleagues addressed this gap by conducting a randomised control trial across multiple centres assessing the effectiveness of TH in infants born at 33–35 weeks GA with moderate/severe HIE [7]. The results of this study demonstrate TH does not protect infants born at 33–35 weeks GA from death or disability when compared to normothermia. The ICE trial included 35–42 week infants and showed favourable results of TH [8]. Several small, single-center (primarily retrospective) studies have shown similar outcomes for term and preterm infants with moderate or severe HIE treated with TH [3, 4]. Together, these studies prompted the American Academy of Paediatrics to recommend TH for infants “born at or greater than 35 weeks of gestational age” [2]. As a result, many centers have revised their criteria to include 35 week infants when considering TH for infants with HIE. However, one study demonstrated higher mortality for infants born at 34–35 week GA undergoing TH for HIE compared to term (≥ 37 weeks GA) infants [5]. Faix and colleagues astutely discuss that previous studies include small numbers of study participants at 35 weeks GA [7]. These data suggest that infants born at 35 weeks resemble those born at 33–34 weeks more than those ≥ 36 weeks [7]. Moreover, many studies have not stratified outcomes by gestational age, limiting clarity on who benefits most from therapeutic hypothermia. These findings call into question whether current AAP recommendations should be re-evaluated. Late preterm infants (33–36 weeks GA) have a relatively immature epidermal barrier and a higher ratio of surface area to birth weight than term infants [9], possibly contributing to higher cold stress involved in mortality and morbidity. Nevertheless, the use of TH for preterm infants with HIE has been increasing [6]. Previous small-cohort studies and the current RCT underscore the need for further research and cross-institutional data sharing—guided by stakeholders—to clarify the role of therapeutic hypothermia and adjunctive therapies in infants born < 37 weeks' gestation. The variable findings from these studies may lead some providers, alongside institutional stakeholders, to consider an informed consent process with caregivers when considering TH for infants born at < 36 weeks GA with moderate/severe HIE, providing an avenue to engage in shared decision making for this population. However, until guidelines like those published from the AAP are revisited, it may be difficult from a medical-legal perspective to alter practice in countries where guidelines suggest cooling infants ≥ 35 weeks. We strongly advocate for more research into the outcomes of 33–36 week GA patients (stratified by GA) with HIE who undergo TH to help inform the guidelines of national academies and individual practices. URL LINK: https://ebneo.org/ebneo-commentary-is-therapeutic-hypothermia-beneficial-to-infants-born-between-33-and-35-weeks-gestation/. Harisa Spahic: conceptualization, writing – original draft, writing – review and editing, formal analysis. Sandra P. Zoubovsky: conceptualization, writing – original draft, writing – review and editing, formal analysis. Robert M. Dietz: conceptualization, writing – original draft, writing – review and editing, formal analysis, supervision. The authors declare no conflicts of interest.