Erythropoietin for neuroprotection in preterm infants: feasiblity and safety study

Background: Long-term disability remains a major problem in very preterm infants. Novel strategies to protect developing organs, in particular the brain, are therefore of greatest interest in neonatal intensive care medicine. Erythropoietin has been shown to be protective against hypoxic-ischemic and inflammatory injuries in cell culture, animal models of brain injury, and in clinical trials in human adults. Objective: The rationale for our study was that early administration of high dose recombinant human erythropoietin (rhEpo) may reduce perinatal brain injury (IVH and PVL) in very preterm infants and improve neuro-developmental outcome. In a first step, we investigated whether high dose rhEpo given shortly after birth and subsequently over the first two days to very preterm infants is safe in terms of short-term outcome. Patients and Methods: Randomized, double masked single-centre trial with a 2 to 1 allocation in favor of rhEpo. Preterm infants (gestational age 24 0/7–31 6/7 weeks) were given rhEpo (n _t=30; 3,000 U/kg body weight) or NaCl 0.9% (n _c=15) intravenously at 3, 12–18 and 36–42 hours after birth. Results: The percentage of infants surviving without brain injury or retinopathy was 53% in the rhEpo group and 60% in the placebo group. There were no relevant differences regarding short-term outcomes such as IVH, retinopathy, sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia. In five infants of the rhEpo group with a gestational age <26 0/7 weeks, withdrawal of intensive care was decided (3/5 with severe bilateral IVH, 2/5 with pulmonary insufficiency); no infant of the control group died. rhEpo treatment did not result in significant differences in blood pressure, cerebral oxygenation, hemoglobin, leukocyte and platelet count. Conclusions: No significant adverse effects of early high-dose rhEpo treatment in very preterm infants were identified. These results enable us to embark on a large multicentre trial with the aim to determine if early high dose administration of rhEpo in very preterm infants improves neurodevelopmental outcome at 24 months and 5 years corrected age.