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  • Clinical Research Article
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Evaluation of heterogeneity in effect of therapeutic hypothermia by sex among infants with neonatal encephalopathy

Pediatric Research volume 94, pages 1380–1384 (2023)Cite this article

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

  • Preclinical evidence suggests a differential effect in response to cooling treatment of hypoxic-ischemic injury between males and females.

  • 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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Fig. 1: Risk of death or moderate or severe disability at 18–22 months of age by treatment arm and sex.
Fig. 2: Bayley testing at 18–22 months by treatment arm and sex.

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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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Authors and Affiliations

  1. Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, GA, USA

    Elizabeth K. Sewell, Shannon Hamrick & Ravi Mangal Patel

  2. Wayne State University, Detroit, MI, USA

    Seetha Shankaran & Girija Natarajan

  3. Brown University, Providence, RI, USA

    Abbot Laptook

  4. RTI International, Rockville, MD, USA

    Abhik Das

  5. RTI International, Research Triangle Park, NC, USA

    Scott A. McDonald

  6. University of South Dakota – Sanford School of Medicine, Sioux Falls, SD, USA

    Michelle Baack

  7. University of Texas Health Science Center at Houston, Houston, TX, USA

    Matthew Rysavy

  8. Florida Gulf Coast University, Fort Myers, FL, USA

    Rosemary D. Higgins

  9. University of Texas Southwestern, Dallas, TX, USA

    Lina Chalak

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  1. Elizabeth K. Sewell
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  12. Ravi Mangal Patel
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Contributions

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.

Corresponding author

Correspondence to Elizabeth K. Sewell.

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The authors declare no competing interests.

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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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