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Original Investigation |

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

Giancarlo Natalucci, MD1,2; Beatrice Latal, MD, MPH2; Brigitte Koller, RN1; Christoph Rüegger, MD1; Beate Sick, PhD3; Leonhard Held, PhD3; Hans Ulrich Bucher, MD1; Jean-Claude Fauchère, MD1 ; for the the Swiss EPO Neuroprotection Trial Group
[+] Author Affiliations
1Department of Neonatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
2Child Development Center, University Children’s Hospital Zurich, Zurich, Switzerland
3Epidemiology, Biostatistics and Prevention Institute (EBPI), University of Zurich, Zurich, Switzerland
JAMA. 2016;315(19):2079-2085. doi:10.1001/jama.2016.5504.
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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

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Figure.
Participant Flow in the Clinical Trial of Erythropoietin in Preterm Infants

rhEPO indicates recombinant human erythropoietin.

aDecision to provide primary nonintervention and palliative care after delivery was made antenatally with the agreement of the parents if several known prognostic factors were so unfavorable that the initiation of intensive care measures appeared to be inappropriate.

bInfants received lower than allocated dose because after randomization, which occurred before 3 hours of life, exclusion criteria (n = 5) or nonadherence to inclusion criteria (attributable to errors in reporting of gestational age, n = 2) were discovered for some infants; thus, they were excluded after randomization.

cInfants received supplemental rhEPO later to treat anemia of prematurity during the neonatal course.

dExcluded after administration of the allocated treatment because of a uniparental disomy 16 and a dysmorphic syndrome that became evident after the third day of life (genetic investigations were still ongoing at the time of manuscript submission).

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