Randomized Controlled Trial

. 2023 Jul;94(1):252-259.

doi: 10.1038/s41390-022-02398-w. Epub 2022 Dec 5.

Risk of seizures in neonates with hypoxic-ischemic encephalopathy receiving hypothermia plus erythropoietin or placebo

Hannah C Glass^{1

2}, Courtney J Wusthoff^{3

4}, Bryan A Comstock⁵, Adam L Numis^{6

7}, Fernando F Gonzalez⁶, Nathalie Maitre⁸, Shavonne L Massey⁹, Dennis E Mayock¹⁰, Ulrike Mietzsch¹⁰, Niranjana Natarajan¹¹, Gregory M Sokol¹², Sonia L Bonifacio¹³, Krisa P Van Meurs¹³, Cameron Thomas^{14

15}, Kaashif A Ahmad¹⁶, Patrick J Heagerty⁵, Sandra E Juul¹⁰, Yvonne W Wu^{6

7}

Affiliations

¹ Department of Pediatrics, UCSF Benioff Children's Hospital, University of California San Francisco, San Francisco, CA, USA. Hannah.Glass@ucsf.edu.
² Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco, CA, USA. Hannah.Glass@ucsf.edu.
³ Department of Neurology, Stanford University, Palo Alto, CA, USA.
⁴ Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University, Palo Alto, CA, USA.
⁵ Department Biostatistics, University of Washington, Seattle, WA, USA.
⁶ Department of Pediatrics, UCSF Benioff Children's Hospital, University of California San Francisco, San Francisco, CA, USA.
⁷ Department of Neurology and Weill Institute for Neuroscience, University of California San Francisco, San Francisco, CA, USA.
⁸ Department of Pediatrics, and Emory + Children's Pediatric Institute, Emory University, Atlanta, GA, USA.
⁹ Departments of Neurology and Pediatrics, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁰ Department of Pediatrics, Division of Neonatology, University of Washington School of Medicine, Seattle Children's Hospital, Seattle, WA, USA.
¹¹ Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA.
¹² Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
¹³ Division of Neonatal and Developmental Medicine, Stanford University School of Medicine and Lucile Packard Children's Hospital Stanford, Palo Alto, CA, USA.
¹⁴ Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.
¹⁵ Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
¹⁶ Pediatrix Neonatology of San Antonio, San Antonio, TX, USA.

PMID: 36470964
PMCID: PMC10239788
DOI: 10.1038/s41390-022-02398-w

Randomized Controlled Trial

Risk of seizures in neonates with hypoxic-ischemic encephalopathy receiving hypothermia plus erythropoietin or placebo

Hannah C Glass et al. Pediatr Res. 2023 Jul.

. 2023 Jul;94(1):252-259.

doi: 10.1038/s41390-022-02398-w. Epub 2022 Dec 5.

Authors

Affiliations

¹ Department of Pediatrics, UCSF Benioff Children's Hospital, University of California San Francisco, San Francisco, CA, USA. Hannah.Glass@ucsf.edu.
² Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco, CA, USA. Hannah.Glass@ucsf.edu.
³ Department of Neurology, Stanford University, Palo Alto, CA, USA.
⁴ Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University, Palo Alto, CA, USA.
⁵ Department Biostatistics, University of Washington, Seattle, WA, USA.
⁶ Department of Pediatrics, UCSF Benioff Children's Hospital, University of California San Francisco, San Francisco, CA, USA.
⁷ Department of Neurology and Weill Institute for Neuroscience, University of California San Francisco, San Francisco, CA, USA.
⁸ Department of Pediatrics, and Emory + Children's Pediatric Institute, Emory University, Atlanta, GA, USA.
⁹ Departments of Neurology and Pediatrics, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁰ Department of Pediatrics, Division of Neonatology, University of Washington School of Medicine, Seattle Children's Hospital, Seattle, WA, USA.
¹¹ Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA.
¹² Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
¹³ Division of Neonatal and Developmental Medicine, Stanford University School of Medicine and Lucile Packard Children's Hospital Stanford, Palo Alto, CA, USA.
¹⁴ Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.
¹⁵ Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
¹⁶ Pediatrix Neonatology of San Antonio, San Antonio, TX, USA.

PMID: 36470964
PMCID: PMC10239788
DOI: 10.1038/s41390-022-02398-w

Abstract

Background: An ancillary study of the High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial for neonates with hypoxic-ischemic encephalopathy (HIE) and treated with therapeutic hypothermia examined the hypothesis that neonates randomized to receive erythropoietin (Epo) would have a lower seizure risk and burden compared with neonates who received placebo.

Methods: Electroencephalograms (EEGs) from 7/17 HEAL trial centers were reviewed. Seizure presence was compared across treatment groups using a logistic regression model adjusting for treatment, HIE severity, center, and seizure burden prior to the first dose. Among neonates with seizures, differences across treatment groups in median maximal hourly seizure burden were assessed using adjusted quantile regression models.

Results: Forty-six of 150 (31%) neonates had EEG seizures (31% in Epo vs 30% in placebo, p = 0.96). Maximal hourly seizure burden after the study drug was not significantly different between groups (median 11.4 for Epo, IQR: 5.6, 18.1 vs median 9.7, IQR: 4.9, 21.0 min/h for placebo).

Conclusion: In neonates with HIE treated with hypothermia who were randomized to Epo or placebo, we found no meaningful between-group difference in seizure risk or burden. These findings are consistent with overall trial results, which do not support Epo use for neonates with HIE undergoing therapeutic hypothermia.

Impact: In the HEAL trial of erythropoietin (Epo) vs placebo for neonates with encephalopathy presumed due to hypoxic-ischemic encephalopathy (HIE) who were also treated with therapeutic hypothermia, electrographic seizures were detected in 31%, which is lower than most prior studies. Epo did not reduce the proportion of neonates with acute provoked seizures (31% in Epo vs 30% in placebo) or maximal hourly seizure burden after the study drug (median 11.4, IQR 5.6, 18.1 for Epo vs median 9.7, IQR 4.9, 21.0 min/h for placebo). There was no anti- or pro-convulsant effect of Epo when combined with therapeutic hypothermia for HIE.

PubMed Disclaimer

Conflict of interest statement

Competing Interests

Kaashif A. Ahmad has nothing to disclose.

Sonia L. Bonifacio has nothing to disclose.

Bryan A. Comstock has nothing to disclose.

Hannah C. Glass has nothing to disclose.

Fernando F. Gonzalez has nothing to disclose.

Patrick J. Heagerty has nothing to disclose.

Sandra E. Juul has nothing to disclose.

Nathalie Maitre has nothing to disclose.

Shavonne L. Massey has nothing to disclose.

Dennis E. Mayock has nothing to disclose.

Ulrike Mietzsch has nothing to disclose.

Niranjana Natarajan has nothing to disclose.

Adam L. Numis has nothing to disclose.

Gregory M. Sokol has nothing to disclose.

Cameron Thomas has nothing to disclose.

Krisa P. Van Meurs has nothing to disclose.

Yvonne W. Wu has nothing to disclose.

Figures

**Figure 1.**
CONSORT diagram for seven sites participating in the HEAL-EEG ancillary study.

**Figure 2.**
Swimmer plot of 46 neonates with seizures with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia and treated with erythropoietin (Epo, panel A) or placebo (panel B) who received continuous video-EEG throughout hypothermia and rewarming. Vertical lines indicate that a seizure was observed. Panel C: Density plot of neonates with seizure in the previous hour of EEG recording.

See this image and copyright information in PMC

References

1. Glass HC et al. Contemporary Profile of Seizures in Neonates: A Prospective Cohort Study. J Pediatr 174, 98–103 e101, doi:10.1016/j.jpeds.2016.03.035 (2016). - DOI - PMC - PubMed
1. Ronen GM, Penney S & Andrews W The epidemiology of clinical neonatal seizures in Newfoundland: a population-based study. J Pediatr 134, 71–75, doi:10.1016/s0022-3476(99)70374-4 (1999). - DOI - PubMed
1. Juul S Erythropoietin in the central nervous system, and its use to prevent hypoxic-ischemic brain damage. Acta paediatrica 91, 36–42, doi:10.1111/j.1651-2227.2002.tb02904.x (2002). - DOI - PubMed
1. Yang J et al. Erythropoietin preconditioning suppresses neuronal death following status epilepticus in rats. Acta Neurobiol Exp (Wars) 67, 141–148 (2007). - PubMed
1. Nadam J et al. Neuroprotective effects of erythropoietin in the rat hippocampus after pilocarpine-induced status epilepticus. Neurobiol Dis 25, 412–426, doi:S0969–9961(06)00259–2 [pii]10.1016/j.nbd.2006.10.009 (2007). - DOI - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions

Grants and funding

P50 HD103524/HD/NICHD NIH HHS/United States

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Health Information
Research Materials
- NCI CPTC Antibody Characterization Program

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Risk of seizures in neonates with hypoxic-ischemic encephalopathy receiving hypothermia plus erythropoietin or placebo

Affiliations

Risk of seizures in neonates with hypoxic-ischemic encephalopathy receiving hypothermia plus erythropoietin or placebo

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials