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Randomized Controlled Trial
. 2023 May 1;6(5):e2312152.
doi: 10.1001/jamanetworkopen.2023.12152.

Whole-Body Hypothermia, Cerebral Magnetic Resonance Biomarkers, and Outcomes in Neonates With Moderate or Severe Hypoxic-Ischemic Encephalopathy Born at Tertiary Care Centers vs Other Facilities: A Nested Study Within a Randomized Clinical Trial

Sudhin Thayyil  1 , Paolo Montaldo  1   2 , Vaisakh Krishnan  1 , Phoebe Ivain  1 , Stuti Pant  1 , Peter J Lally  1 , Prathik Bandiya  3 , Naveen Benkappa  3 , Chinnathambi N Kamalaratnam  4 , Rema Chandramohan  4 , Swati Manerkar  5 , Jayshree Mondkar  5 , Ismat Jahan  6 , Sadeka C Moni  6 , Mohammod Shahidullah  6 , Ranmali Rodrigo  7 , Samanmali Sumanasena  7 , Radhika Sujatha  8 , Constance Burgod  1 , Reema Garegrat  1 , Munirah Mazlan  1 , Ismita Chettri  1 , Sathyanathan Babu Peter  9 , Anagha R Joshi  10 , Ravi Swamy  1 , Kling Chong  11 , Ronit R Pressler  12 , Paul Bassett  13 , Seetha Shankaran  14
Affiliations
Randomized Controlled Trial

Whole-Body Hypothermia, Cerebral Magnetic Resonance Biomarkers, and Outcomes in Neonates With Moderate or Severe Hypoxic-Ischemic Encephalopathy Born at Tertiary Care Centers vs Other Facilities: A Nested Study Within a Randomized Clinical Trial

Sudhin Thayyil et al. JAMA Netw Open. .

Abstract

Importance: The association between place of birth and hypothermic neuroprotection after hypoxic-ischemic encephalopathy (HIE) in low- and middle-income countries (LMICs) is unknown.

Objective: To ascertain the association between place of birth and the efficacy of whole-body hypothermia for protection against brain injury measured by magnetic resonance (MR) biomarkers among neonates born at a tertiary care center (inborn) or other facilities (outborn).

Design, setting, and participants: This nested cohort study within a randomized clinical trial involved neonates at 7 tertiary neonatal intensive care units in India, Sri Lanka, and Bangladesh between August 15, 2015, and February 15, 2019. A total of 408 neonates born at or after 36 weeks' gestation with moderate or severe HIE were randomized to receive whole-body hypothermia (reduction of rectal temperatures to between 33.0 °C and 34.0 °C; hypothermia group) for 72 hours or no whole-body hypothermia (rectal temperatures maintained between 36.0 °C and 37.0 °C; control group) within 6 hours of birth, with follow-up until September 27, 2020.

Exposure: 3T MR imaging, MR spectroscopy, and diffusion tensor imaging.

Main outcomes and measures: Thalamic N-acetyl aspartate (NAA) mmol/kg wet weight, thalamic lactate to NAA peak area ratios, brain injury scores, and white matter fractional anisotropy at 1 to 2 weeks and death or moderate or severe disability at 18 to 22 months.

Results: Among 408 neonates, the mean (SD) gestational age was 38.7 (1.3) weeks; 267 (65.4%) were male. A total of 123 neonates were inborn and 285 were outborn. Inborn neonates were smaller (mean [SD], 2.8 [0.5] kg vs 2.9 [0.4] kg; P = .02), more likely to have instrumental or cesarean deliveries (43.1% vs 24.7%; P = .01), and more likely to be intubated at birth (78.9% vs 29.1%; P = .001) than outborn neonates, although the rate of severe HIE was not different (23.6% vs 17.9%; P = .22). Magnetic resonance data from 267 neonates (80 inborn and 187 outborn) were analyzed. In the hypothermia vs control groups, the mean (SD) thalamic NAA levels were 8.04 (1.98) vs 8.31 (1.13) among inborn neonates (odds ratio [OR], -0.28; 95% CI, -1.62 to 1.07; P = .68) and 8.03 (1.89) vs 7.99 (1.72) among outborn neonates (OR, 0.05; 95% CI, -0.62 to 0.71; P = .89); the median (IQR) thalamic lactate to NAA peak area ratios were 0.13 (0.10-0.20) vs 0.12 (0.09-0.18) among inborn neonates (OR, 1.02; 95% CI, 0.96-1.08; P = .59) and 0.14 (0.11-0.20) vs 0.14 (0.10-0.17) among outborn neonates (OR, 1.03; 95% CI, 0.98-1.09; P = .18). There was no difference in brain injury scores or white matter fractional anisotropy between the hypothermia and control groups among inborn or outborn neonates. Whole-body hypothermia was not associated with reductions in death or disability, either among 123 inborn neonates (hypothermia vs control group: 34 neonates [58.6%] vs 34 [56.7%]; risk ratio, 1.03; 95% CI, 0.76-1.41), or 285 outborn neonates (hypothermia vs control group: 64 neonates [46.7%] vs 60 [43.2%]; risk ratio, 1.08; 95% CI, 0.83-1.41).

Conclusions and relevance: In this nested cohort study, whole-body hypothermia was not associated with reductions in brain injury after HIE among neonates in South Asia, irrespective of place of birth. These findings do not support the use of whole-body hypothermia for HIE among neonates in LMICs.

Trial registration: ClinicalTrials.gov Identifier: NCT02387385.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Thayyil reported receiving grants from the Bill & Melinda Gates Foundation and the National Institute for Health and Care Research during the conduct of the study. Dr Pressler reported receiving personal fees from Aeglea BioTherapeutics, Kephala, Natus Medical, and UCB outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Association of Whole-Body Hypothermia With Magnetic Resonance Spectroscopic Biomarkers and Time to Target Temperature Among Inborn vs Outborn Neonates
Horizontal lines across bars represent medians, circles represent outliers, and whiskers represent ranges. NAA indicates N-acetyl aspartate.
Figure 2.
Figure 2.. Kaplan-Meier Survival Curves for Inborn and Outborn Neonates
See this image and copyright information in PMC

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