MANUSCRIPT CITATION

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 Randomized Clinical Trial. JAMA Pediatr 2025; e246613. PMID 39992674.

REVIEWED BY

Harisa Spahic, MD
Pediatrics Resident
Department of Pediatrics
University of Colorado, Aurora, CO

Sandra P. Zoubovsky, MD PhD
Pediatrics Resident
Department of Pediatrics
University of Colorado, Aurora, CO

Robert M. Dietz MD PhD (corresponding author)
Associate Professor of Pediatrics
Department of Pediatrics, Section of Neonatology
University of Colorado, Aurora, CO

CORRESPONDING AUTHOR

Robert M. Dietz MD PhD
Associate Professor of Pediatrics
Department of Pediatrics, Section of Neonatology
University of Colorado, Aurora, CO
robert.dietz@cuanschutz.edu

TYPE OF INVESTIGATION

Treatment

QUESTION

(P) In infants ≥ 33 to ≤ 35 weeks gestational age with neonatal encephalopathy, who meet criteria for therapeutic hypothermia, (I) does therapeutic hypothermia initiated less than 6 hours after birth (C) compared to noncooled infants (O) lead to reduced risk of death or disability at 18-22 months corrected age?

METHODS

• Design: Randomized clinical trial

• Allocation: Concealed by using computer-generated randomized permutated block algorithm with block sizes of 2 and 4, allocation ratio of 1:1. Randomization was stratified by stage of encephalopathy (moderate or severe) and was randomly assigned by a data center.

• Blinding: Un-blinded intervention; follow up assessments at 18-22 months corrected age done by examiners blinded to intervention.

• Follow-up period: In this study, infants were followed until 18-22 corrected months of age. Follow-up intended for 18 to 22 months of corrected age was delayed in 52 infants due to COVID-19 pandemic related restrictions. In those cases, data from the earliest delayed follow-up visit were used; range 23-40 months, with a mean corrected age of 26 months.

• Setting: Enrollment at 19 Neonatal Research Network centers in the United States between July 2015 – December 2022.

• Patients: Infants ≥ 33-0/7 weeks to ≤ 35-6/7 weeks gestational age (GA), within 6 hours of birth, identified to have moderate or severe neonatal encephalopathy, perinatal asphyxia, neurologic depression, or similar condition were screened for eligibility. Inclusion criteria followed previously published Neonatal Research Network (NRN) hypothermia trial criteria. Exclusion criteria consisted of infants who were already hypothermic (core temperature <34°C for longer than 1 hour), received paralytic or sedative agents obscuring Sarnat examination, had major anomalies, had encephalopathy unlikely due to hypoxia-ischemia, were moribund and not receiving intensive care, and weighed <1500g.

• Intervention: Infants meeting inclusion criteria were randomized to either the treatment group (therapeutic hypothermia [TH] with whole body cooling to 33-34°C) or control group (standard care without TH). Infants undergoing hypothermia were re-warmed to goal 37°C after 72 hours of cooling.

• Outcomes:
o Primary outcome: Composite outcome of death or moderate to severe disability at 18-22 months corrected age
o Secondary outcome: Death alone, moderate or severe disability only, death or profound disability (defined as severe disability with assignment of lowest possible cognitive score because infant untestable due to impairment), survival with normal outcome, each component of severe or moderate disability, and cause of death.

• Analysis and Sample Size: Intention-to-treat analyses were prespecified. Using a retrospective review of NICU admission records at participating centers in 2012, the number of eligible infants for a 5-year period was estimated to approach 170. Simulations showed that the trial design had greater than 75% chance of observing final posterior probability of less than or equal to 0.80 for relative risk less than 1 when true relative risk is near 0.70. Bayesian analysis was performed using three prior probabilities including a neutral prior (with 50% prior probability of better outcome and 50% of worse outcome, RR 1.0), enthusiastic prior (assuming 25% reduction in risk of death or disability, RR 0.75), and a skeptical prior (assuming 10% increase in risk of death or disability, RR 1.10).

• Patient follow-up: Among 436 infants assessed for eligibility, 268 were excluded and 168 infants were randomized (88 to the treatment hypothermia group and 80 to the control normothermia group). Primary analysis was done on 83 in the hypothermia group and 69 in the normothermia group.

MAIN RESULTS

Highlighted Maternal Demographics

Highlighted Infant Demographics

Highlighted Results

*aRD – adjusted risk difference, aRR – adjusted risk ratio, Crl – credibility interval, PPB – Posterior Probability of benefit (%)

Formal Bayesian analysis not reported due to small numbers.

CONCLUSION

The authors concluded that TH for infants with moderate to severe hypoxic-ischemic encephalopathy (HIE) born at 33 to 35 weeks GA did not show benefit compared to normothermia. The authors suggested hypothermia for these infants might increase the risk of death with a 87% probability of treatment harm for death or 74% probability of treatment harm for death or disability at 18 or more months of corrected age.

COMMENTARY

HIE is a devastating pathology, resulting in significant morbidity and mortality1. TH is the 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 GA2–6. Faix and colleagues addressed this gap by conducting a randomized control trial across multiple centers assessing the effectiveness of TH in infants born at 33-35 weeks GA with moderate/severe HIE7. The results of this study demonstrate TH does not protect infants born at 33-35 week GA from death or disability when compared to normothermia.

 

The ICE trial included 35-42 week infants and showed favorable results of TH8. Several small, single-center (primarily retrospective) studies have shown similar outcomes for term and preterm infants with moderate or severe HIE treated with TH3,4. Together, these studies prompted the American Academy of Pediatrics to recommend TH for infants “born at or greater then 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 has shown higher mortality for infants born at 34-35 week GA undergoing TH for HIE compared to term ( 37 weeks GA) infants5. Faix and colleagues astutely discuss that previous studies include small numbers of study participants at 35 weeks GA7. These data suggest that infants born at 35 weeks resemble those born at 33–34 weeks more than those ≥36 weeks7. 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 higher ratio of surface area to birth weight than term infants9, possibly contributing to higher cold stress involved in mortality and morbidity. Nevertheless, use of TH for preterm infants with HIE has been increasing6. 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.

 

REFERENCES

1. Jacobs, S. E. et al. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database of Systematic Reviews (2013) doi:10.1002/14651858.CD003311.pub3.
2. COMMITTEE ON FETUS AND NEWBORN. Hypothermia and Neonatal Encephalopathy. PEDIATRICS 133, 1146–1150 (2014).
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8. Jacobs, S. E. et al. Whole-body hypothermia for term and near-term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial. Arch Pediatr Adolesc Med 165, 692–700 (2011).
9. Laptook, A. & Jackson, G. L. Cold stress and hypoglycemia in the late preterm (‘near-term’) infant: impact on nursery of admission. Semin Perinatol 30, 24–27 (2006).