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Trial of Erythropoietin for Hypoxic–Ischemic Encephalopathy in Newborns

List of authors.
  • Yvonne W. Wu, M.D., M.P.H.,
  • Bryan A. Comstock, M.S.,
  • Fernando F. Gonzalez, M.D.,
  • Dennis E. Mayock, M.D.,
  • Amy M. Goodman, Ph.D.,
  • Nathalie L. Maitre, M.D., Ph.D.,
  • Taeun Chang, M.D.,
  • Krisa P. Van Meurs, M.D.,
  • Andrea L. Lampland, M.D.,
  • Ellen Bendel-Stenzel, M.D.,
  • Amit M. Mathur, M.D.,
  • Tai-Wei Wu, M.D.,
  • David Riley, M.D.,
  • Ulrike Mietzsch, M.D.,
  • Lina Chalak, M.D., M.S.C.S.,
  • John Flibotte, M.D.,
  • Joern-Hendrik Weitkamp, M.D.,
  • Kaashif A. Ahmad, M.D.,
  • Toby D. Yanowitz, M.D.,
  • Mariana Baserga, M.D., M.C.S.I.,
  • Brenda B. Poindexter, M.D.,
  • Elizabeth E. Rogers, M.D.,
  • Jean R. Lowe, Ph.D.,
  • Karl C.K. Kuban, M.D.,
  • T. Michael O’Shea, M.D., M.P.H.,
  • Jessica L. Wisnowski, Ph.D.,
  • Robert C. McKinstry, M.D., Ph.D.,
  • Stefan Bluml, Ph.D.,
  • Sonia Bonifacio, M.D.,
  • Kristen L. Benninger, M.D.,
  • Rakesh Rao, M.D.,
  • Christopher D. Smyser, M.D., M.S.C.I.,
  • Gregory M. Sokol, M.D.,
  • Stephanie Merhar, M.D.,
  • Michael D. Schreiber, M.D.,
  • Hannah C. Glass, M.D.C.M.,
  • Patrick J. Heagerty, Ph.D.,
  • and Sandra E. Juul, M.D., Ph.D.
  • for the HEAL Consortium*

Abstract

Background

Neonatal hypoxic–ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic–ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown.

Methods

Download a PDF of the Research Summary.

In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic–ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition.

Results

Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P=0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57).

Conclusions

The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic–ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.)

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Funding and Disclosures

Supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award numbers U01NS092764 and U01NS092553.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Drs. Heagerty and Juul contributed equally to this article.

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

We thank Donna Ferriero and Roberta Ballard for their roles as study advisors; John Feltner, Kelleen Nelson, and Stephanie Hauge for their contributions as central study coordinators; Ashok Panigrahy for his assistance in harmonizing the brain MRI studies; Ronnie Guillet, Jody Ciolino, Michael Cotten, Robin Ohls, Renee Shellhaas, and Janet Soul for their contributions as members of the data and safety monitoring board; and the parents of the infants enrolled in this trial for being willing to take part in this research effort, which would not have been possible otherwise.

Author Affiliations

From the Departments of Neurology (Y.W.W., A.M.G., H.C.G.), Pediatrics (Y.W.W., F.F.G., E.E.R., H.C.G.), and Epidemiology (H.C.G.), University of California, San Francisco, San Francisco, the Department of Pediatrics, Stanford University School of Medicine, Stanford (K.P.V.M., S. Bonifacio), and the Departments of Pediatrics (T.-W.W., J.L.W.) and Radiology (J.L.W., S. Bluml), Children’s Hospital Los Angeles, and the Departments of Pediatrics (T.-W.W., J.L.W.) and Radiology (J.L.W., S. Bluml), University of Southern California Keck School of Medicine, Los Angeles — all in California; the Department of Biostatistics, University of Washington (B.A.C., P.J.H.), and the Department of Pediatrics, University of Washington School of Medicine (D.E.M., U.M., S.E.J.) — both in Seattle; the Department of Pediatrics, Children’s Healthcare of Atlanta (N.L.M.), and the Department of Pediatrics, Emory University (N.L.M., B.B.P.) — both in Atlanta; the Division of Neurology, Children’s National Hospital, and the Department of Neurology, George Washington School of Medicine and Health Sciences — both in Washington, D.C. (T.C.); the Department of Neonatology, Children’s Minnesota, St. Paul (A.L.L.), and the Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester (E.B.-S.) — both in Minnesota; the Department of Pediatrics, Saint Louis University School of Medicine (A.M.M.), and the Departments of Radiology (R.C.M., C.D.S.), Pediatrics (R.R., C.D.S.), and Neurology (C.D.S.), Washington University in St. Louis School of Medicine — both in St. Louis; the Department of Pediatrics, Cook Children’s Medical Center, the Department of Pediatrics, Texas Christian University, and the Department of Pediatrics, University of North Texas Health Science Center, Ft. Worth (D.R.), the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas (L.C.), and Pediatrix Medical Group of San Antonio, Children’s Hospital of San Antonio, and Methodist Children’s Hospital, San Antonio (K.A.A.) — all in Texas; the Department of Pediatrics, Indiana University School of Medicine, Indianapolis (U.M., G.M.S.); the Department of Pediatrics, Children’s Hospital of Philadelphia, and the Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia (J.F.), and the Department of Pediatrics, University of Pittsburgh School of Medicine, the Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, and the Department of Pediatrics, UPMC Magee-Womens Hospital, Pittsburgh (T.D.Y.) — all in Pennsylvania; the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (J.-H.W.); the Department of Pediatrics, University of Utah, Salt Lake City (M.B.); the Department of Pediatrics, University of New Mexico School of Medicine, Albuquerque (J.R.L.); the Department of Pediatrics, Boston University Medical Center, Boston (K.C.K.K.); the Department of Pediatrics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill (T.M.O.); the Department of Pediatrics, Nationwide Children’s Hospital, Columbus (K.L.B.), and the Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, and the Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati (S.M.) — all in Ohio; and the Department of Pediatrics, University of Chicago, Chicago (M.D.S.).

Dr. Y.W. Wu can be contacted at or at the Division of Child Neurology, University of California, San Francisco, 675 Nelson Rising Lane, Suite 411, Box 0663, San Francisco, CA 94158.

The members of the HEAL Consortium are listed in the Supplementary Appendix, available at NEJM.org.

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