- Whole-body hypothermia within hours of birth failed to improve outcomes in preterm infants less than 36 weeks’ gestational age with hypoxic-ischemic encephalopathy.
- Death or moderate or severe disability at 18 to 22 months’ corrected age occurred in 35% of infants with hypothermia and 29% of infants with normothermia.
- With hypothermia, there was a 74% probability of treatment harm for the primary outcome (composite of death or disability) and 87% for death alone observed.
Whole-body hypothermia within hours of birth failed to improve outcomes in preterm infants less than 36 weeks’ gestational age with hypoxic-ischemic encephalopathy, a randomized clinical trial found.
Death or moderate or severe disability at 18 to 22 months’ corrected age occurred in 35% of infants with hypothermia and 29% of infants with normothermia (adjusted relative risk 1.11, 95% CI 0.74-2.00), reported Roger Faix, MD, of the University of Utah Health Sciences Center in Salt Lake City, and colleagues.
Additionally, death (examined separately from disability) occurred in 20% of infants with hypothermia and 12% of infants with normothermia (adjusted relative risk 1.38, 95% CI 0.79-2.85), they noted in JAMA Pediatrics.
“In the absence of strong supportive evidence from future trials, use of hypothermia is not indicated in infants born with hypoxic-ischemic encephalopathy at 35 weeks’ gestational age or younger,” researchers said in their conclusion.
At all gestational ages, perinatal hypoxia-ischemia is a major cause of brain injury and death. The only treatment supported by randomized clinical trials (RCT) is therapeutic hypothermia for infants at least 36 weeks’ gestational age, study authors wrote.
“Many clinicians have been extrapolating findings from infants 36-40 weeks gestation who have suffered hypoxic-ischemic insults at or near birth indicating improved survival and long-term outcomes with therapeutic hypothermia to less mature infants (<36 weeks gestation) with no supportive trial data,” Faix told MedPage Today in emailed remarks.
“This is especially concerning since less mature infants may respond very differently and are at greatly increased risk for different problems that may be triggered or exacerbated by hypothermia,” he said.
“We had hoped that there might be benefits from hypothermia in this population, since many clinicians had optimistically assumed that there would be, but we were not surprised to see that our RCT found otherwise,” Faix continued. “Implications for clinicians are that there appears to be no benefit (and possibly increased death) with therapeutic hypothermia in less mature infants who have suffered a hypoxic-ischemic insult at or near birth.”
With hypothermia, there was a 74% probability of treatment harm for the primary outcome (composite of death or disability) and 87% for death alone observed, Faix and colleagues reported.
“Although survival with moderate or severe disability appeared to be slightly better in the hypothermic group, the absolute difference was small (13% vs 16%), and this potential small benefit was accompanied by a much higher incidence of death,” they noted.
The study, conducted at 19 neonatal research centers across the U.S., included infants 33 to 35 weeks’ gestational age with moderate or severe hypoxic-ischemic encephalopathy at less than 6 hours after birth. Randomization occurred at a mean of 4.5 hours.
Infants received unblinded targeted esophageal temperature management, with those randomized to hypothermia maintained at 33.5°C for 72 hours and then rewarmed, and those randomized to normothermia maintained at 37°C.
Infants in both groups had a mean age of about 34 weeks’ gestational age, and a little more than half of infants were male.
In the hypothermic group, 31% of infants were identified as Black, 17% Hispanic, 59% white, and 10% other races and ethnicities; in the normothermic group, 39% of infants were identified as Black, 12% Hispanic, 52% white, and 9% other races and ethnicities.
Limitations of the study included its moderate sample size, an inability to assign primary outcome to 11% of normothermic and 6% of hypothermic infants, and a loss to follow-up of more patients in the normothermic group, Faix and colleagues noted.
Also, the intervention was unblinded to clinicians, though follow-up investigators were unaware of assignment, researchers said. And 47 infants were excluded from the study by clinicians who opted for hypothermia without randomization.
Disclosures
The study was supported in part by grants from the National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and from the National Center for Advancing Translational Sciences (NCATS), which provided grant support through cooperative agreements for the Neonatal Research Network. The NIH, the NICHD, the National Center for Research Resources, and the National Center for Advancing Translational Sciences provided grant support for the Neonatal Research Network’s Preemie Hypothermia trial through cooperative agreements.
Faix reported receiving grants from the NICHD and the NCATS during the conduct of the study. Co-authors also reported receiving grants from the NIH and NICHD, and from other government agencies. They further reported board membership with nonprofit organizations, grants and consulting fees from pharmaceutical companies, investment and equity in medical device companies, and royalties for a patent.
Primary Source
JAMA Pediatrics
Source Reference: Faix RG, et al “Whole-body hypothermia for neonatal encephalopathy in preterm infants 33 to 35 weeks’ gestation: a randomized clinical trial” JAMA Pediatr 2025; DOI: 10.1001/jamapediatrics.2024.6613.
Please enable JavaScript to view the