Effect of Early Prophylactic High-Dose Recombinant Human Erythropoietin in Very Preterm Infants on Neurodevelopmental Outcome at 2 Years: A Randomized Clinical Trial

JAMA. 2016 May 17;315(19):2079-85. doi: 10.1001/jama.2016.5504.


Importance: Very preterm infants are at risk of developing encephalopathy of prematurity and long-term neurodevelopmental delay. Erythropoietin treatment is neuroprotective in animal experimental and human clinical studies.

Objective: To determine whether prophylactic early high-dose recombinant human erythropoietin (rhEPO) in preterm infants improves neurodevelopmental outcome at 2 years' corrected age.

Design, setting, and participants: Preterm infants born between 26 weeks 0 days' and 31 weeks 6 days' gestation were enrolled in a randomized, double-blind, placebo-controlled, multicenter trial in Switzerland between 2005 and 2012. Neurodevelopmental assessments at age 2 years were completed in 2014.

Interventions: Participants were randomly assigned to receive either rhEPO (3000 IU/kg) or placebo (isotonic saline, 0.9%) intravenously within 3 hours, at 12 to 18 hours, and at 36 to 42 hours after birth.

Main outcomes and measures: Primary outcome was cognitive development assessed with the Mental Development Index (MDI; norm, 100 [SD, 15]; higher values indicate better function) of the Bayley Scales of Infant Development, second edition (BSID-II) at 2 years corrected age. The minimal clinically important difference between groups was 5 points (0.3 SD). Secondary outcomes were motor development (assessed with the Psychomotor Development Index), cerebral palsy, hearing or visual impairment, and anthropometric growth parameters.

Results: Among 448 preterm infants randomized (mean gestational age, 29.0 [range, 26.0-30.9] weeks; 264 [59%] female; mean birth weight, 1210 [range, 490-2290] g), 228 were randomized to rhEPO and 220 to placebo. Neurodevelopmental outcome data were available for 365 (81%) at a mean age of 23.6 months. In an intention-to-treat analysis, mean MDI was not statistically significantly different between the rhEPO group (93.5 [SD, 16.0] [95% CI, 91.2 to 95.8]) and the placebo group (94.5 [SD, 17.8] [95% CI, 90.8 to 98.5]) (difference, -1.0 [95% CI, -4.5 to 2.5]; P = .56). No differences were found between groups in the secondary outcomes.

Conclusions and relevance: Among very preterm infants who received prophylactic early high-dose rhEPO for neuroprotection, compared with infants who received placebo, there were no statistically significant differences in neurodevelopmental outcomes at 2 years. Follow-up for cognitive and physical problems that may not become evident until later in life is required.

Trial registration: clinicaltrials.gov Identifier: NCT00413946.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child Development
  • Child, Preschool
  • Developmental Disabilities / prevention & control
  • Double-Blind Method
  • Drug Administration Schedule
  • Erythropoietin / administration & dosage*
  • Female
  • Humans
  • Infant, Newborn
  • Infant, Premature
  • Intention to Treat Analysis
  • Male
  • Neurodevelopmental Disorders / prevention & control*
  • Neuroprotective Agents / administration & dosage*
  • Recombinant Proteins / administration & dosage
  • Treatment Outcome


  • Neuroprotective Agents
  • Recombinant Proteins
  • Erythropoietin

Associated data

  • ClinicalTrials.gov/NCT00413946