title: Association between early administration of high-dose erythropoietin in preterm infants and brain MRI abnormality at term-equivalent age.
abstract: OBJECTIVE
  Premature infants are at risk of developing encephalopathy of prematurity, which is associated with long-term neurodevelopmental delay. Erythropoietin was shown to be neuroprotective in experimental and retrospective clinical studies.
  
  
  OBJECTIVE
  To determine if there is an association between early high-dose recombinant human erythropoietin treatment in preterm infants and biomarkers of encephalopathy of prematurity on magnetic resonance imaging (MRI) at term-equivalent age.
  
  
  METHODS
  A total of 495 infants were included in a randomized, double-blind, placebo-controlled study conducted in Switzerland between 2005 and 2012. In a nonrandomized subset of 165 infants (n=77 erythropoietin; n=88 placebo), brain abnormalities were evaluated on MRI acquired at term-equivalent age.
  
  
  METHODS
  Participants were randomly assigned to receive recombinant human erythropoietin (3000 IU/kg; n=256) or placebo (n=239) intravenously before 3 hours, at 12 to 18 hours, and at 36 to 42 hours after birth.
  
  
  METHODS
  The primary outcome of the trial, neurodevelopment at 24 months, has not yet been assessed. The secondary outcome, white matter disease of the preterm infant, was semiquantitatively assessed from MRI at term-equivalent age based on an established scoring method. The resulting white matter injury and gray matter injury scores were categorized as normal or abnormal according to thresholds established in the literature by correlation with neurodevelopmental outcome.
  
  
  RESULTS
  At term-equivalent age, compared with untreated controls, fewer infants treated with recombinant human erythropoietin had abnormal scores for white matter injury (22% [17/77] vs 36% [32/88]; adjusted risk ratio [RR], 0.58; 95% CI, 0.35-0.96), white matter signal intensity (3% [2/77] vs 11% [10/88]; adjusted RR, 0.20; 95% CI, 0.05-0.90), periventricular white matter loss (18% [14/77] vs 33% [29/88]; adjusted RR, 0.53; 95% CI, 0.30-0.92), and gray matter injury (7% [5/77] vs 19% [17/88]; adjusted RR, 0.34; 95% CI, 0.13-0.89).
  
  
  CONCLUSIONS
  In an analysis of secondary outcomes of a randomized clinical trial of preterm infants, high-dose erythropoietin treatment within 42 hours after birth was associated with a reduced risk of brain injury on MRI. These findings require assessment in a randomized trial designed primarily to assess this outcome as well as investigation of the association with neurodevelopmental outcomes.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00413946.
authors.affiliation: Division of Development and Growth, Department of Pediatrics, University Hospital of Geneva, Geneva, Switzerland.
authors.forename: Russia Ha-Vinh
authors.initials: RH
authors.lastname: Leuchter
authors.affiliation: Division of Development and Growth, Department of Pediatrics, University Hospital of Geneva, Geneva, Switzerland.
authors.forename: Laura
authors.initials: L
authors.lastname: Gui
authors.affiliation: Clinical Research Center and Division of Clinical Epidemiology, Department of Health and Community Medicine, University of Geneva and University Hospital of Geneva, Geneva, Switzerland.
authors.forename: Antoine
authors.initials: A
authors.lastname: Poncet
authors.affiliation: Division of Neonatology, University Hospital, Zurich, Switzerland.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Hagmann
authors.affiliation: Division of Development and Growth, Department of Pediatrics, University Hospital of Geneva, Geneva, Switzerland.
authors.forename: Gregory Anton
authors.initials: GA
authors.lastname: Lodygensky
authors.affiliation: MR-Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Ernst
authors.initials: E
authors.lastname: Martin
authors.affiliation: Division of Neonatology, University Hospital, Zurich, Switzerland.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Koller
authors.affiliation: Division of Development and Growth, Department of Pediatrics, University Hospital of Geneva, Geneva, Switzerland.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Darqué
authors.affiliation: Division of Neonatology, University Hospital, Zurich, Switzerland.
authors.forename: Hans Ulrich
authors.initials: HU
authors.lastname: Bucher
authors.affiliation: Division of Development and Growth, Department of Pediatrics, University Hospital of Geneva, Geneva, Switzerland.
authors.forename: Petra Susan
authors.initials: PS
authors.lastname: Hüppi
mesh_terms: D001921:Brain / Q000473:pathology; D001927:Brain Diseases / Q000517:prevention & control*; D004311:Double-Blind Method; D000068817:Epoetin Alfa; D004921:Erythropoietin / Q000008:administration & dosage*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature; D008279:Magnetic Resonance Imaging; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D011994:Recombinant Proteins / Q000008:administration & dosage; D012178:Retinopathy of Prematurity / Q000517:prevention & control*
chemical_list: D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D004921:Erythropoietin; D000068817:Epoetin Alfa