Abstract
Background
Our objective was to examine heterogeneity in the effect of therapeutic hypothermia by sex in infants with moderate or severe neonatal encephalopathy.
Methods
We conducted a post hoc analysis of the Induced Hypothermia trial, which included infants born at gestational ages ≥36 weeks, admitted at ≤6 postnatal hours with evidence of severe acidosis or perinatal complications and moderate or severe neonatal encephalopathy. Multivariate modified Poisson regression models were used to compare the treatment effect of whole-body hypothermia versus control, with an evaluation of interaction by sex, on the primary outcome of death or moderate or severe disability at 18–22 months of corrected age.
Results
A total of 101 infants (51 male, 50 female) were randomly assigned to hypothermia treatment and 104 infants (64 male, 40 female) to control. The primary outcome occurred in 45% of the hypothermia group and 63% of the control group (RR 0.73; 95% CI 0.56, 0.94). There was no significant difference (interaction P = 0.50) in the treatment effect of hypothermia on the primary outcome between females (RR 0.79; 95% CI 0.54, 1.17) compared to males (RR 0.63; 95% CI 0.44, 0.91).
Conclusion
We found no evidence that sex influences the treatment effect of hypothermia in infants with moderate or severe neonatal encephalopathy.
Impact
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Preclinical evidence suggests a differential effect in response to cooling treatment of hypoxic-ischemic injury between males and females.
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We found no evidence of heterogeneity in the treatment effect of whole-body hypothermia by sex in this post hoc subgroup analysis of infants with moderate or severe neonatal encephalopathy from the National Institute of Child Health and Human Development Neonatal Research Network Induced Hypothermia trial.
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Data availability
Data used in this paper are publicly available on the NICHD Data and Specimen Hub at https://dash.nichd.nih.gov/.
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Acknowledgements
We acknowledge the contributions of the Principle Investigators who conducted the original Induced Hypothermia trial, as well as the National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institutes of Health originally funded the Induced Hypothermia trial. We acknowledge NICHD DASH for providing the Randomized Controlled Trial of Induced Hypothermia for Hypoxic-Ischemic Encephalopathy in Term Infants data that were used for this research.
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E.K.S. contributed to the conceptualization/design, methodology, and investigation of the study and drafted the initial manuscript. S.S. contributed to the methodology, investigation, data curation, and resources of the study and critically reviewed and edited the manuscript. G.N., S.H., and M.B. contributed to the methodology and investigation of the study and critically reviewed and edited the manuscript. A.L. and M.R. contributed to the conceptualization/design and methodology of the study and critically reviewed and edited the manuscript. A.D. and S.A.M. contributed to the methodology and formal analysis of the study and critically reviewed and edited the manuscript. R.D.H. and L.C. contributed to the investigation and supervision/oversight of the study and critically reviewed and edited the manuscript. R.M.P. contributed to the conceptualization/design, methodology, investigation, supervision/oversight, and formal analysis of the study and drafted the initial manuscript.
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This was a secondary analysis of a publicly available dataset from the Induced Hypothermia Trial for which consent was obtained to participate in.
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Sewell, E.K., Shankaran, S., Natarajan, G. et al. Evaluation of heterogeneity in effect of therapeutic hypothermia by sex among infants with neonatal encephalopathy. Pediatr Res 94, 1380–1384 (2023). https://doi.org/10.1038/s41390-023-02586-2
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DOI: https://doi.org/10.1038/s41390-023-02586-2
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