Objectives

To investigate if preterm infants administered weekly darbepoetin during the neonatal period will have greater red cell mass during hospitalization and improved neurocognitive outcome at 22-26 months corrected age compared to placebo.

Background

Advances in neonatal care have led to significant improvements in the survival of the nearly 60,000 very low birth weight (VLBW) infants born each year in the U.S. Since many of these infants experience developmental and cognitive delays, developing and evaluating novel neuroprotective strategies is a critical need in neonatal care. A potential neuroprotective therapy involves administering erythropoiesis stimulating agents (ESAs) such as erythropoietin or darbepoetin. Darbepoetin is a longer lasting ESA, allowing for less frequent dosing. The neuroprotective mechanisms of ESAs include decreased apoptosis, decreased inflammation, decreased nitric oxide-mediated injury, increased antioxidant response, and increased neurogenesis. Previous studies suggest that administration of ESAs to preterm infants results in fewer transfusions, fewer donor exposures, and improved neurodevelopmental outcome. The Darbe study was initiated to determine if preterm infants given weekly darbepoetin have improved red cell mass and cognitive outcomes at 2 years corrected gestational age compared to infants receiving placebo.

Participants

Eligible infants were born between 23 0/7 and 28 6/7 weeks gestation. Exclusion criteria included known congenital or chromosomal anomalies, hypertension, seizures, thromboses, hemolytic disease, those in whom no aggressive therapy was planned, those unlikely to survive, those already receiving ESAs clinically, and those unlikely to be available for follow-up.

A total of 650 infants were randomized to once weekly dosing of darbepoetin (n=322) or placebo (n=328).

Design

Darbe was a multicenter, randomized, masked, placebo controlled clinical study. Infants were randomized to once weekly dosing of darbepoetin (10 μg/kg) or placebo (0.4 mL/kg saline) starting within 36 hours of birth and continuing through 35 weeks postmenstrual age, discharge, or transfer to another hospital. Iron supplementation and/or red cell transfusions were performed in both groups according to study guidelines. Laboratory monitoring occurred at prescribed time points (baseline, 14 and 42 days postnatal age).

The primary outcome was the Bayley-III cognitive composite score at 2 years corrected age, where the lowest possible score of 54 was assigned to infants that died before such neurodevelopmental assessment. Secondary outcomes included estimated red cell mass, hematocrit, number and volume of transfusions, donor exposures, hospital days, adverse events, morbidity, and cerebral palsy.

Conclusions

The dose and dosing schedule of darbepoetin used in this study did not improve cognitive scores of preterm infants at 22 to 26 months corrected age. Darbepoetin significantly increased red cell mass resulting in higher hematocrit values, fewer transfusions, and fewer donor exposures.

Ohls RK, Das A, Tan S, et al. Darbepoetin, Red Cell Mass, and Neuroprotection in Preterm Infants: A Randomized Clinical Trial. JAMA Pediatr. 2025;179(8):836-845. doi:10.1001/jamapediatrics.2025.0807

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