A recent study published in JAMA Network Open reveals that erythropoietin (rhEpo) does not provide long-term neuroprotective benefits in preterm infants. The research followed up on a subset of participants from the Swiss EPO Neuroprotection Trial, assessing neurodevelopmental outcomes at a mean age of 10.4 years. The initial trial, which included 448 newborns between 26 and 31 weeks of gestation, randomized infants to receive either rhEpo (3000 IU/kg) or a placebo shortly after birth, with the primary outcome being neurodevelopment at 2 years corrected age.
Long-Term Follow-Up
The current study focused on 214 of the original participants (117 rhEpo-treated, 97 placebo-treated) and found no significant differences in executive function, processing speed, or IQ between the two groups. While term-born children showed better working memory, fluency, planning, and higher estimated IQ compared to the preterm cohort, erythropoietin treatment did not bridge this gap.
Consistent Negative Results
These findings align with other phase III trials, including the Preterm Erythropoietin Neuroprotection (PENUT) Trial, Erythropoietin for the Repair of Cerebral Injury in Very Preterm Infants (EpoRepair) trial, and the High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial, all of which failed to demonstrate a neuroprotective benefit from erythropoietin in early neurodevelopment (approximately 2 years).
Lessons Learned
Sandra E. Juul, MD, PhD, from the University of Washington and corresponding author of the JAMA Network Open article, emphasizes the importance of adequately powered, well-designed phase III randomized clinical trials. She notes that meta-analyses of smaller phase II trials should not substitute for rigorous phase III studies, as they may lead to incorrect conclusions.
Preclinical Considerations
Dr. Juul also highlights the necessity of conducting preclinical trials in multiple animal models before testing potential neurotherapeutics in human infants. While early preclinical data in rodents suggested neuroprotective effects of erythropoietin, more recent work in larger preclinical models with gyrified brains (ferrets, fetal sheep, and piglets) has shown less promising results, underscoring the differences between rodent and human inflammatory responses.
Implications for Future Research
The erythropoietin story serves as a cautionary tale, emphasizing the need for thorough preclinical evaluation in diverse animal models and the critical role of well-designed phase III trials in assessing the true safety and efficacy of new therapies. The initial interest in erythropoietin as a neurotherapeutic stemmed from the discovery of erythropoietin receptors on neuronal cell lines and subsequent studies demonstrating its potential to decrease inflammation, increase antioxidant activity, and reduce excitotoxic cell injury in culture systems and rodents. However, these promising early findings did not translate into clinical benefits for preterm infants.
