No Benefit for High-Dose rhEPO for Neuroprotection in Preemies

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No Benefit for High-Dose rhEPO for Neuroprotection in Preemies
No Benefit for High-Dose rhEPO for Neuroprotection in Preemies

High-dose prophylactic human recombinant erythropoietin had no statistically significant benefit over placebo for neuroprotection in very preterm infants after 2 years of follow up, according to data published in JAMA.

Despite advances, very preterm infants are at risk for long-term neurodevelopmental delay from encephalopathy of prematurity. Erythropoietin (EPO) is thought to be a promising treatment option with evidence of neuroprotection in animal models. Retrospective studies of  anemia in preterm infants found that recombinant human EPO (rhEPO) improved neurodevelopmental outcomes. Doses as high as 2000 to 5000 IU/kg are required to allow EPO to cross the blood-brain barrier but appear to be well tolerated by preterm babies.

Giancarlo Natalucci, MD, of the Department of Neonatology at the University Hospital of Zurich in Switzerland, and colleagues conducted a randomized, double-blind, placebo-controlled trial to assess the 2-year neurodevelopmental outcome in preterm infants given high-dose rhEPO. Infants born between 26 weeks and 0 days and 31 weeks and 6 days were randomized to receive 3 doses of an isotonic saline placebo or rhEPO 3000 IU/kg intravenously 3 hours, 12-18 hours, and 36-42 hours after birth. The primary outcome was cognitive development at 2 years assessed with the Mental Developmental Index (MDI) of the Bayley Scales of Infant Development (BSID-II). Secondary outcomes included growth parameters, visual or hearing impairment, cerebral palsy, and motor development measured by the Psychomotor Development Index (PDI). Infants were excluded for conditions affecting neurodevelopment or life expectancy, palliative care, or severe intraventricular hemorrhage.  

The study included 450 preterm infants (59% female) with a mean age of 29 weeks. The rhEPO group included 230 infants and 220 in the placebo group. Data was available at 2 years for 83% (n=191) of the rhEPO group and 79% (n=174) of the placebo group.

There was no statistically significant difference in MDI scores between the rhEPO and placebo group (93.5 vs 94.5, 95% CI: -4.5 to 2.5, P=.56) in the intention to treat analysis. Similarly, there was no statistical difference between the groups in the per-protocol analysis (MDI mean difference -0.7, 95% CI: -3.0 to 4.4, P=.70). Motor development as measured by PDI was also not significantly different between the study groups (89.5 vs 92.1, -2.9, 99% CI: -7.7 to 1.7, P=.15).  There were no observed significant differences for the other secondary outcomes, as well.

Further analysis did not find differences between the rhEPO and placebo group for survival without severe neurodevelopmental impairment (84% vs 87%, OR 0.9, 99% CI: 0.4 to 1.9, P=.76).

The study was temporarily suspended after an infant in the rhEPO group died secondary to a severe intracranial hemorrhage. An independent expert review found no causal link between the hemorrhage and rhEPO.

The authors hypothesized that the regimen used in the study may be insufficient for neuroprotection compared to previous studies that were small but suggested benefits from EPO. Further, timing of the primary outcome assessments at a period of more differentiated cognitive performance such as school-age may provide a better measurement.

“To date there is not enough evidence to support the administration of rhEPO for neuroprotection in very preterm infants,” the authors wrote.

Reference

Natalucci G, Latal B, Koller B, et al. 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;315(19):2079-2085.
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