Neonatal Therapeutic Hypothermia for Hypoxic-ischemic Encephalopathy
Daniel E. Sloniewsky, MD, FCCM
07/22/2025
This Concise Critical Appraisal explores a recent randomized clinical trial on whether therapeutic hypothermia initiated at six hours of age reduces the probability of death or disability in infants born at 33 to 35 weeks’ gestation.
Perinatal hypoxic-ischemic encephalopathy (HIE) is a major cause of brain injury in infants of all gestational ages, leading to significant morbidity and high mortality rates. Although research has yielded conflicted findings in specific populations (e.g., mild HIE and moderate to severe HIE in low- and middle-income countries), therapeutic hypothermia (TH) has emerged as the only effective intervention in infants born at 36 weeks’ gestation or older with moderate to severe HIE.1-3
Despite the potential for adverse events and the lack of randomized controlled trials, expanded TH use has been reported, including in neonates younger than 36 weeks. Faix et al sought to assess the effectiveness of TH in infants born at 33-35 weeks’ gestation in a randomized clinical trial conducted by members of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.4
Faix et al screened all infants less than six hours old who had been born at 33-35 weeks’ gestation and who had a diagnosis of encephalopathy, perinatal asphyxia, or neurologic depression. Inclusion criteria included specified blood pH, low Apgar scores, and seizures or modified Sarnat score, which is used to grade the severity of encephalopathic states. Exclusion criteria included the use of paralytics, core temperature less than 34.0 °C (93.2 °F), other causes of encephalopathy, major anomalies, birth weight less than 1500 g (3.3 lb), and clinician-declined enrollment.
Patients were randomized using a computer-generated permutated block algorithm. One group was cooled to an esophageal temperature of 33.5 °C (92.3 °F) for 72 hours (hypothermic group). The other group had a target esophageal temperature of 37 °C (98.6 °F) (normothermic group). The primary outcome was death or disability at 18 to 22 months’ corrected age. Bayley Scales of Infant Development, Gross Motor Function Classification System levels, and vision and hearing status were used to assess disability. Secondary outcomes included death alone, severe or moderate neurologic disability, and survival with normal outcomes. Neuroimaging was performed with ultrasound and MRI, but these data were reported separately. The authors used Bayesian principles to assess outcomes.
Overall, 436 infants were screened, and168 infants were randomized. Ultimately, 69 were in the normothermic group and 88 in the hypothermic group. The maternal and neonatal characteristics at randomization were equivalent between groups. As expected, the temperatures differed between groups—33.4 °C (92.1 °F) in the hypothermic group and 37.2 °C (99 °F) in the normothermic group.
The primary outcome of death or moderate-to-severe disability occurred in 35% of the hypothermic group and 29% of the normothermic group. The adjusted risk ratio for hypothermia was 1.11, which yielded a benefit probability of 26% and harm probability of 74%. The secondary outcome of death alone occurred in 20% of the hypothermic group and 12% of the normothermic group, which led to a hypothermia benefit probability of 13% and harm probability of 87%. Survival with moderate-to-severe disability alone was better in the hypothermic group (13%) compared with the normothermic group (16%). Other safety events were comparable between the two groups.
The authors claim that the use of hypothermia in infants with HIE born between 33 and 35 weeks’ gestation is not indicated, although the reasons for this are unclear. The authors suggest that developmental differences and antepartum environments between preterm and term infants may each play a role. Additionally, many infants in the hypothermic group were cooled to temperatures less than 32.0 °C (89.6 °F) before they could equilibrate, suggesting an inability to thermoregulate, which may have played a role in the outcomes. Limitations of this study include its small sample size, leading to wide confidence intervals; significant variability in the time to perform the outcome assessments; and the lack of neuroimaging data.5 However, despite these limitations, this article provides the strongest evidence for withholding TH in this cohort of premature infants.
References
Shankaran S, Laptook AR, Ehrenkranz RA, et al; National Institute of Child Health and Human Development Neonatal Research Network. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005 Oct 13;353(15):1574-1584.
Thayyil S, Pant S, Montaldo P, et al; HELIX Consortium. Hypothermia for moderate or severe neonatal encephalopathy in low-income and middle-income countries (HELIX): a randomised controlled trial in India, Sri Lanka, and Bangladesh. Lancet Glob Health. 2021 Sep;9(9):e1273-e1285.
Montaldo P, Cirillo M, Burgod C, et al; COMET Trial Group. Whole-body hypothermia vs targeted normothermia for neonates with mild encephalopathy: a multicenter pilot randomized clinical trial. JAMA Netw Open. 2024 May 1;7(5):e249119.
Faix RG, Laptook AR, Shankaran S, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Whole-body hypothermia for neonatal encephalopathy in preterm infants 33 to 35 weeks' gestation: a randomized clinical trial. JAMA Pediatr. 2025 Apr 1;179(4):396-406.
El-Dib M, Inder T. Data and analysis concerns in trial of whole-body hypothermia for neonatal encephalopathy in preterm infants. JAMA Pediatr. 2025 Jun 9. Online ahead of print.
Author
Daniel E. Sloniewsky, MD, FCCM
Daniel E. Sloniewsky, MD, FCCM, is an associate professor in the Division of Pediatric Critical Care Medicine in the Department of Pediatrics at Stony Brook Long Island Children’s Hospital. Dr. Sloniewsky is an editor of Concise Critical Appraisal.
