Erythropoietin for Neuroprotection in Preterm Infants?

Published - Written by Angela Castellanos, MD

After ensuring the survival of extremely low birth weight preterm infants born before 28 weeks of gestation, clinicians face the difficult physiological task of safely maturing a variety of organ systems outside of their usual home in the uterus. Neonatologists manage these tiny patients for months as the infants wean off respiratory support, start feeding, and grow their way out of incubators, but the challenges of prematurity do not end once the baby is discharged home. Many of these infants develop impairments (e.g., cerebral palsy and intellectual disabilities) and are at higher risk for behavioral disorders. Neonatologists have few proven tools for long-term neuroprotection, making research in this area important for the life-long well-being of these vulnerable patients.

Erythropoietin it is an important factor in fetal brain development (in addition to its hematologic effects) and has been shown to have neuroprotective effects in neonatal brain injury in preclinical trials and meta-analyses of small controlled trials. To rigorously investigate this glimmer of hope, researchers in the PENUT Trial Consortium performed a multicenter, randomized, placebo-controlled trial of early high-dose erythropoietin for neuroprotection in extremely preterm infants born between 24 and 28 weeks of gestation. They found that rates of death and severe neurodevelopmental impairment at 2 years of age were similar between the erythropoietin and placebo groups.

Although erythropoietin did not yield the expected neurodevelopmental benefits, these researchers did the challenging work of testing a hypothesis generated from previous studies with a large well-designed trial. The results provide stronger evidence against the use of erythropoietin for clinicians to consider when managing extremely low birth weight infants in the NICU. Longer follow-up of these children could help our understanding of any role high-dose erythropoietin may have in neurocognitive development. For now, it looks like high-dose erythropoietin is not the magic bullet for neuroprotection in extremely low birth weight infants.

The following NEJM Journal Watch summary explains the study and results further.


Phase III Trial of Erythropoietin for Neuroprotection in Extremely Preterm Infants

Robin H. Steinhorn, MD reviewing Juul SE et al. N Engl J Med 2020 Jan 16

Findings show no neurodevelopmental improvement at age 2 years, counter to previous findings in a meta-analysis of smaller trials.

Survival has improved for extremely preterm infants, which has sharpened the focus on developing strategies that reduce long-term neurodevelopmental disabilities. Preclinical studies in models of neonatal brain injury suggest that erythropoietin has neurotrophic and neuroprotective effects, although it is not FDA approved for these indications. Early randomized trials suggest that administration of erythropoietin improves long-term cognitive outcomes. Now, results are available from a phase III trial.

Between 2013 and 2016, 941 extremely preterm infants (gestational age between 24 weeks, 0 days, and 27 weeks, 6 days) were randomized before 24 hours of age to erythropoietin (1000 U/kg every 48 hours x 6 doses, followed by 400 U/kg 3 times weekly through 33 weeks postmenstrual age) or placebo.

Of the 741 children assessed for efficacy at 2 years of age, rates of death, neurodevelopmental impairment, and a composite endpoint of either event were similar between groups (death at 2 years: 13% and 11% in the erythropoietin and placebo groups, respectively; severe neurodevelopmental impairment at 2 years: 11% and 14%, respectively). In post hoc analysis, the erythropoietin group required fewer blood transfusions.

Comment: Erythropoietin did not improve survival or neurodevelopmental outcomes at age 2 in this definitive and well-designed trial of extremely preterm infants. It is hoped that follow-up will continue for these enrolled infants to determine outcomes through at least school age. 


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 Angela Castellanos is a general pediatrician and was an editorial fellow at the NEJM from 2018-2019.

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