Issue 13 – September 2022

Therapeutic hypothermia is the standard of care in high-income countries for treatment of hypoxic-ischemic encephalopathy (HIE) due to perinatal asphyxia. We examined the use of therapeutic hypothermia for term and late preterm infants from 2012 to 2021.

Overall, 23,047 of 1,932,346 (1.2%) infants reported to the Vermont Oxford Network expanded database of all neonatal intensive care unit admissions received therapeutic hypothermia. The rate of cooling increased linearly from 0.9% in 2012 to 1.5% in 2021 (Figure 1). Of those who received therapeutic hypothermia, 6.8% were less than 36 weeks gestational age at birth (Figure 2). The proportion of infants receiving therapeutic hypothermia who were less than 36 weeks gestational age at birth increased 1% from 2012 to 2021, but not linearly (Figure 3).

In the past decade there has been an increase in the reported use of therapeutic hypothermia in both term and late preterm infants. Many factors may contribute to this increased utilization, including improved recognition of hypoxic-ischemic encephalopathy, increased willingness to treat late preterm infants, and treatment of infants with less severe hypoxic-ischemic encephalopathy. While a Cochrane review demonstrated a reduction in the risk of death and neurodevelopmental disability in infants with moderate-to-severe HIE treated with therapeutic hypothermia without an increase in systemic adverse affects¹, few trials addressed infants less than 35 weeks gestation or with mild HIE.

Infants with mild encephalopathy were long believed to have outcomes similar to those of infants without encephalopathy, but recently it has been demonstrated that these infants may be at risk for neurodevelopmental disability^2,3, with outcomes similar to those with moderate encephalopathy who have undergone therapeutic hypothermia⁴. A 2018 survey in the UK noted that 75% of cooling centers offered treatment to infants with mild encephalopathy⁵, citing concerns such as difficulties in grading encephalopathy and concerns for long-term neurodevelopmental impairment. However, in a meta-analysis of therapeutic hypothermia in infants with mild encephalopathy there was no evidence for improvement in death or neurodevelopmental disability⁶. Given a paucity of evidence regarding the efficacy of hypothermia for infants with mild encephalopathy, the potential risks of escalating intensive care treatment must be considered.

Increasing use of therapeutic hypothermia in infants less 35 weeks gestation persists despite a dearth of data regarding safety and efficacy. The preterm infant brain is uniquely vulnerable to neuronal injury⁷, and infants 34 to 35 weeks gestation undergoing hypothermia have a greater risk of early discontinuation of cooling and death⁸ compared to term infants, as well as an increased risk of IVH⁹.  A clinical trial is currently underway to assess the safety and efficacy of hypothermia in infants 33 to 35 weeks gestational age.

The temptation to cool preterm infants and those with mild hypoxic-ischemic encephalopathy is understandable, but we must proceed with caution. Until more data are available, consideration should be given to the American Academy of Pediatrics Committee on Fetus and Newborn 2014 statement¹⁰, “Cooling infants who are born at less than 35 weeks gestation or those who have mild encephalopathy… should only be performed in a research setting and with informed parental consent.” For these infants, we must ensure that families are aware of potential risks and benefits before proceeding with cooling.

1. Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis, PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev. 2013 Jan 31;2013(1):CD003311.
2. Murray DM, O’Connor CM, Ryan CA, Korotchikova I, and Boylan GB. Early EEG grade and outcome at 5 years after mild neonatal hypoxic ischemic encephalopathy. Pediatrics. 2016; 138(4), e20160659.
3. Chalak LF, Nguyen KA, Prempunpong C, Heyne R, Thayyil S, Shankaran S, Laptook AR, Rollins N, Pappas A, Koclas L, Shah B, Montaldo P, Techasaensiri B, Sánchez PJ, Sant’Anna G. Prospective research in infants with mild encephalopathy identified in the first six hours of life: neurodevelopmental outcomes at 18-22 months. Pediatric Research. 2018; 84(6), 861-868.
4. Finder M, Boylan GB, Twomey D, Ahearne C, Murray DM, Hallberg B. Two-year neurodevelopmental outcomes after mild hypoxic ischemic encephalopathy in the era of therapeutic hypothermia. JAMA Pediatrics. 2020; 174(10), 48-55.
5. Oliveira V, Singhvi DP, Montaldo P, Lally P, Mendoza J, Manerkar S, Shankaran S, Thayyil S. Therapeutic hypothermia in mild neonatal encephalopathy: a national survey of practice in the UK. Arch Dis Child Fetal Neonatal Ed. 2018 Jul;103(4):F388-F390. doi: 10.1136/archdischild-2017-313320.
6. Conway JM, Walsh BH, Boylan GB, Murray DM. Mild hypoxic ischaemic encephalopathy and long term neurodevelopmental outcome – A systematic review. Early Human Development. 2018; 120, 80-87.
7. Gopagondanahalli KR, Li J, Fahey MC, Hunt RW, Jenkin G, Miller SL and Malhotra A. Preterm hypoxic-ischemic encephalopathy. Front Pediatr. 2016 October 20; 4:114.
8. Rao R, Trivedi S, Vesoulis Z, Liao SM, Smyser CD, Mathur AM. Safety and Short-Term Outcomes of therapeutic hypothermia in preterm neonates 34-35 weeks gestational age with hypoxic-ischemic encephalopathy. J Pediatrics. 2016; 183: 37-42.
9. Garfinkle J, Wintermark P, Shevell MI, Oskou M on behalf of the Canadian Cerebral Palsy Registry. Children born at 32 to 35 weeks with birth asphyxia and later cerebral palsy are different from those born after 35 weeks. Journal of Perinatology. 2017; 37: 963–968.
10. Committee on Fetus and Newborn; Papile LA, Baley JE, Benitz W, Cummings J, Carlo WA, Eichenwald E, Kumar P, Polin RA, Tan RC, Wang KS. Hypothermia and neonatal encephalopathy. Pediatrics. 2014; 133 (6): 1146–1150.

This report is made possible by Vermont Oxford Network members who voluntarily contribute data in a global effort to improve the care of high-risk newborns. VON members can view center-specific data by logging on to Nightingale and benchmark against this NICU by the Numbers report.

Editor: Erika Edwards, PhD, MPH

Analyst: Lucy Greenberg, MS

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