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Darbepoetin, Red Cell Mass, and Neuroprotection in Preterm Infants: A Randomized Clinical Trial
Robin K Ohls1, Abhik Das2, Sylvia Tan2
1Department of Pediatrics, University of Utah Health Sciences Center, Salt Lake City.
Insights
Weekly darbepoetin did not improve cognitive outcomes in preterm infants but increased red cell mass, leading to fewer transfusions and donor exposures. This study highlights the agent's impact on hematological parameters in premature neonates.
Area of Science:
- Neonatal Medicine
- Pediatric Hematology
- Clinical Trials
Background:
- Erythropoiesis-stimulating agents like darbepoetin are used in preterm infants to reduce transfusions.
- Previous studies suggested potential neurodevelopmental benefits.
Purpose of the Study:
- To evaluate if weekly darbepoetin improves red cell mass and neurocognitive outcomes in preterm infants compared to placebo.
- To assess the long-term cognitive development at 22-26 months corrected age.
Main Methods:
- A randomized clinical trial involving 650 preterm infants (23 0/7 to 28 6/7 weeks' gestation).
- Infants received weekly darbepoetin (10 μg/kg) or placebo until 35 weeks postmenstrual age.
- Primary outcome: cognitive composite score on Bayley Scales of Infant Development, third edition (Bayley-III).
Main Results:
- Mean cognitive scores were similar between groups (80.7 in darbepoetin vs. 80.1 in placebo).
- Darbepoetin significantly increased red cell mass and hematocrit by week 2.
- Infants receiving darbepoetin had fewer transfusions (2.3 vs. 3.3) and donor exposures (1.6 vs. 2.2).
- Lower rates of bronchopulmonary dysplasia greater than grade 1 were observed in the darbepoetin group.
Conclusions:
- Weekly darbepoetin at this dose and schedule did not improve cognitive scores in preterm infants.
- Darbepoetin effectively increased red cell mass, reduced transfusion needs, and decreased donor exposures.
- Further research may explore optimal dosing or alternative agents for neurodevelopmental benefits.
Importance:
Previous studies suggest that administration of erythropoiesis-stimulating agents darbepoetin or erythropoietin to preterm infants results in fewer transfusions, fewer donor exposures, and improved neurodevelopmental outcome.
Objective:
To determine if, compared with placebo, preterm infants randomized to weekly darbepoetin would have greater red cell mass during hospitalization and better neurocognitive outcome at 22 to 26 months' corrected age.
Design, Setting, And Participants:
This randomized clinical trial was conducted between September 2017 and November 2019 for infants 23 0/7 to 28 6/7 weeks' gestation in 19 US Neonatal Research Network centers comprising 33 neonatal intensive care units. Follow-up occurred through January 2023. Infants were randomized by 36 hours after birth to weekly placebo or darbepoetin (10 μg/kg) through 35 weeks' postmenstrual age. Iron administration and transfusions were administered by protocol. Study data were analyzed from June to October 2023.
Main Outcomes And Measures:
The primary outcome was the mean cognitive composite score on the Bayley Scales of Infant Development, third edition (Bayley-III) at 22 to 26 months' corrected age. The lowest possible score (54) was assigned to infants who died.
Results:
A total of 650 infants (322 darbepoetin; 328 placebo; mean [SD] gestational age, 26.2 [1.7] weeks; 328 female [50.5%]) were enrolled. Five hundred eighty-three infants (291 darbepoetin; 292 placebo) had the primary outcome determined (90% of those enrolled). Mean (SD) cognitive scores were similar between groups: 80.7 (19.5) darbepoetin vs 80.1 (18.7) placebo, adjusted mean difference, -0.23 (95% CI, -3.09 to 2.64). Compared with infants receiving placebo, more infants in the darbepoetin group were transfusion free (40% [127 of 319] vs 21% [70 of 327]; adjusted relative risk [RR], 1.3; 95% CI, 1.2-1.5), received fewer transfusions (mean [SD], 2.3 [3.1] vs 3.3 [3.5]), were exposed to fewer donors (mean [SD], 1.6 [2.3] vs 2.2 [2.3]), had higher red cell mass by week 2 of age (adjusted mean difference, 3.2; 95% CI, 1.7-4.7), and higher mean hematocrit by week 2 of age (adjusted mean difference, 2.8; 95% CI, 2.1-3.6), and were less likely to have bronchopulmonary dysplasia greater than grade 1 (35% [91 of 261] vs 46% [128 of 277]; RR, 0.78; 95% CI, 0.64-0.96). The incidence of retinopathy of prematurity stage greater than 2 was similar between groups, 13% (35 of 273) in the darbepoetin group vs 16% (45 of 279) in the placebo group. There were no differences in adverse effects between groups.
Conclusions And Relevance:
Results of this randomized clinical trial reveal that this dose and dosing schedule of darbepoetin 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.
Trial Registration:
ClinicalTrials.gov Identifier: NCT03169881.
