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Randomized Controlled Trial
. 2025 Aug 1;179(8):836-845.
doi: 10.1001/jamapediatrics.2025.0807.

Darbepoetin, Red Cell Mass, and Neuroprotection in Preterm Infants: A Randomized Clinical Trial

Robin K Ohls  1 , Abhik Das  2 , Sylvia Tan  2 , Jean R Lowe  3 , Kurt Schibler  4 , Sandra Sundquist Beauman  3 , Edward F Bell  5 , Abbot R Laptook  6 , Mariana Baserga  1 , Ravi M Patel  7 , David P Carlton  7 , John Flibotte  8 , Cathy Grisby  4 , Rosemary D Higgins  9 , Seetha Shankaran  10 , Kristi Watterberg  3 , Anna Maria Hibbs  11 , Waldemar A Carlo  12 , Tarah T Colaizy  5 , Krisa P Van Meurs  13 , Stephen D Kicklighter  14 , Ryan Moore  15 , Christina Sollinger  16 , Lina F Chalak  17 , Sarvin Ghavam  18 , Brenda B Poindexter  7 , Jon E Tyson  19 , C Michael Cotten  20 , Michelle L Baack  21 , Omid Fathi  22 , Sara B DeMauro  8 , Matthew M Laughon  23 , Ann Marie Reynolds  24 , Andrea F Duncan  8   25 , Sarah Winter  1 , Deanne E Wilson-Costello  11 , Myriam Peralta-Carcelen  13 , Betty R Vohr  6 , Heidi M Harmon  5 , Susan R Hintz  13 , Brenna Cavanaugh  16 , Roy J Heyne  17 , Stephanie Merhar  4 , Ricardo Mosquera  19 , Elizabeth Sewell  7 , William F Malcolm  20 , Laurie A Richards  21 , Kristen L Benninger  22 , Andrea Trembath  23 ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network
Collaborators, Affiliations
Randomized Controlled Trial

Darbepoetin, Red Cell Mass, and Neuroprotection in Preterm Infants: A Randomized Clinical Trial

Robin K Ohls et al. JAMA Pediatr. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Ohls reported receiving grants from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Child Health and Human Development (NICHD) during the conduct of the study. Dr Das reported receiving grants from the National Institutes of Health (NIH), NHLBI, and NICHD during the conduct of the study. Dr Schibler reported receiving grants from NICHD during the conduct of the study. Ms Beauman reported grants from the NIH during the conduct of the study. Dr Bell reported receiving grants from the NIH outside the submitted work. Dr Laptook reported receiving grants from the NICHD Neonatal Research Network (NRN) during the conduct of the study. Dr Patel reported receiving grants from the NIH during the conduct of the study. Dr Shankaran reported receiving grants from the NICHD during the conduct of the study. Dr Watterberg reported receiving grants from the NICHD during the conduct of the study. Dr Hibbs reported receiving grants from the NICHD NRN and NIH outside the submitted work. Dr Van Meurs reported receiving grants from the NICHD/NIH during the conduct of the study. Dr Cotten reported receiving grants from the NICHD, advisory board fees from ReAlta Life Sciences, and having a patent for Cryo-Cell International with royalties paid from Duke University. Dr DeMauro reported receiving grants from the NIH during the conduct of the study. Dr Laughon reported receiving grants from the NIH during the conduct of the study. Dr Reynolds reported receiving grants from the NIH during the conduct of the study. Dr Winter reported receiving consultant fees from ReAlta outside the submitted work. Dr Peralta-Carcelen reported receiving grants from the NICHD NRN, which covered her salary during the conduct of the study. Dr Hintz reported receiving grants from the NICHD NRN during the conduct of the study. Dr Heyne reported receiving grants from the University of Texas Southwestern Medical School during the conduct of the study. Dr Mosquera reported receiving grants from the NRN and NIH during the conduct of the study. Dr Malcolm reported receiving grants from the NICHD NRN during the conduct of the study, speaker fees from Abbott Nutrition, and book royalties from McGraw Hill outside the submitted work. Dr Sewell reported receiving grants from the NIH during the conduct of the study and personal fees from Hospicom and Sun Pharmaceutical Industries Inc outside the submitted work. Dr Benninger reported receiving grants from NIH/NICHD via NRN during the conduct of the study. No other disclosures were reported.

References

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