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Original Investigation
October 18, 2021

Association Between Increased Seizures During Rewarming After Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy and Abnormal Neurodevelopmental Outcomes at 2-Year Follow-up: A Nested Multisite Cohort Study

Author Affiliations
  • 1Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas
  • 2Department of Pediatrics, Wayne State University, Detroit, Michigan
  • 3Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, North Carolina
  • 4Social, Statistical and Environmental Sciences Unit, RTI International, Rockville, Maryland
  • 5Department of Pediatrics, Nationwide Children’s Hospital, Ohio State University College of Medicine, Columbus
  • 6Department of Pediatrics, Women & Infants Hospital, Brown University, Providence, Rhode Island
  • 7Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine and Lucile Packard Children’s Hospital, Palo Alto, California
  • 8Department of Pediatrics, University of Iowa, Iowa City
  • 9Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas
  • 10Department of Pediatrics, University of Texas Medical School at Houston, Houston
  • 11Department of Pediatrics, Indiana University School of Medicine, Indianapolis
  • 12Emory University Hospital Midtown, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia
  • 13Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
  • 14Department of Pediatrics, University of Texas Medical School at Houston, Houston
  • 15University of Rochester School of Medicine and Dentistry, Rochester, New York
  • 16Department of Pediatrics, University of Pennsylvania, Philadelphia
  • 17Department of Pediatrics, Duke University, Durham, North Carolina
  • 18Department of Pediatrics, Children’s Mercy Hospital, Kansas City, Missouri
  • 19University of New Mexico Health Sciences Center, Albuquerque
  • 20Department of Pediatrics, University of California, Los Angeles
  • 21Division of Neonatology, University of Alabama at Birmingham, Birmingham
  • 22Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
JAMA Neurol. 2021;78(12):1484-1493. doi:10.1001/jamaneurol.2021.3723
Key Points

Question  Are seizures more likely to occur during rewarming after hypothermia, and are they are associated with abnormal outcomes in asphyxiated neonates receiving hypothermia therapy?

Findings  This cohort study reports higher odds of electrographic seizure during the rewarming phase after hypothermia associated with increased relative risk of death or disability at 2-year follow-up.

Meaning  Study findings support the American Clinical Neurophysiology Society’s Guidelines for continuous electroencephalography monitoring of neonates with suspected perinatal asphyxia during hypothermia and further suggest that monitoring should be continued until normothermia is completed and seizure control is assured.

Abstract

Importance  Compared with normothermia, hypothermia has been shown to reduce death or disability in neonatal hypoxic ischemic encephalopathy but data on seizures during rewarming and associated outcomes are scarce.

Objective  To determine whether electrographic seizures are more likely to occur during rewarming compared with the preceding period and whether they are associated with abnormal outcomes in asphyxiated neonates receiving hypothermia therapy.

Design, Setting, and Participants  This prespecified nested cohort study of infants enrolled in the Optimizing Cooling (OC) multicenter Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network trial from December 2011 to December 2013 with 2 years’ follow-up randomized infants to either 72 hours of cooling (group A) or 120 hours (group B). The main trial included 364 infants. Of these, 194 were screened, 10 declined consent, and 120 met all predefined inclusion criteria. A total of 112 (90%) had complete data for death or disability. Data were analyzed from January 2018 to January 2020.

Interventions  Serial amplitude electroencephalography recordings were compared in the 12 hours prior and 12 hours during rewarming for evidence of electrographic seizure activity by 2 central amplitude-integrated electroencephalography readers blinded to treatment arm and rewarming epoch. Odds ratios and 95% CIs were evaluated following adjustment for center, prior seizures, depth of cooling, and encephalopathy severity.

Main Outcomes and Measures  The primary outcome was the occurrence of electrographic seizures during rewarming initiated at 72 or 120 hours compared with the preceding 12-hour epoch. Secondary outcomes included death or moderate or severe disability at age 18 to 22 months. The hypothesis was that seizures during rewarming were associated with higher odds of abnormal neurodevelopmental outcomes.

Results  A total of 120 newborns (70 male [58%]) were enrolled (66 in group A and 54 in group B). The mean (SD) gestational age was 39 (1) weeks. There was excellent interrater agreement (κ, 0.99) in detection of seizures. More infants had electrographic seizures during the rewarming epoch compared with the preceding epoch (group A, 27% vs 14%; P = .001; group B, 21% vs 10%; P = .03). Adjusted odd ratios (95% CIs) for seizure frequency during rewarming were 2.7 (1.0-7.5) for group A and 3.2 (0.9-11.6) for group B. The composite death or moderate to severe disability outcome at 2 years was significantly higher in infants with electrographic seizures during rewarming (relative risk [95% CI], 1.7 [1.25-2.37]) after adjusting for baseline clinical encephalopathy and seizures as well as center.

Conclusions and Relevance  Findings that higher odds of electrographic seizures during rewarming are associated with death or disability at 2 years highlight the necessity of electroencephalography monitoring during rewarming in infants at risk.

Trial Registration  ClinicalTrials.gov Identifier: NCT01192776

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