Darbepoetin, Red Cell Mass, and Neuroprotection in Preterm Infants
Authors: Robin K. Ohls, Abhik Das, Sylvia Tan, Jean R. Lowe, Kurt Schibler, Sandra Sundquist Beauman, Edward F. Bell, Abbot R. Laptook, Mariana Baserga, Ravi M. Patel, David P. Carlton, John Flibotte, Cathy Grisby, Rosemary D. Higgins, Seetha Shankaran, Kristi Watterberg, Anna Maria Hibbs, Waldemar A. Carlo, Tarah T. Colaizy, Krisa P. Van Meurs, Stephen D. Kicklighter, Ryan Moore, Christina Sollinger, Lina F. Chalak, Sarvin Ghavam, Brenda B. Poindexter, Jon E. Tyson, C. Michael Cotten, Michelle L. Baack, Omid Fathi, Sara B. DeMauro, Matthew M. Laughon, Ann Marie Reynolds, Andrea F. Duncan, Sarah Winter, Deanne E. Wilson-Costello, Myriam Peralta-Carcelen, Betty R. Vohr, Heidi M. Harmon, Susan R. Hintz, Brenna Cavanaugh, Roy J. Heyne, Stephanie Merhar, Ricardo Mosquera, Elizabeth Sewell, William F. Malcolm, Laurie A. Richards, Kristen L. Benninger, Andrea Trembath, Andrew A. Bremmer, Stephanie Wilson Archer, Traci H. Mondoro, Richard A. Polin, Martin Keszler, Angelita M. Hensman, Elisa Vieira, Lucille St. Pierre, Barbara Alksninis, Andrea Knoll, Mary L. Keszler, Teresa M. Leach, Elisabeth C. McGowan, Victoria Watson, Nancy S. Newman, Bonnie S. Siner, Elizabeth Roth, Tanya E. Cahill, Kristin Kirker, Sandra Wuertz, Juanita Dudley, Julia Thompson, Lisa Henkes, Sara Stacey, Devan Hayes, Traci Beiersdorfer, Ronald N. Goldberg, Patricia L. Ashley, Deesha Mago-Shah, Mollie Warren, Joanne Propst, Kimberley A. Fisher, Kathryn E. Gustafson, Cindy Clark, Gennie Bose, Janice Wereszczak, Jennifer Talbert, Alexandra Bentley, Laura Edwards, Donna White, Ira Adams-Chapman, Yvonne Loggins, Diane Bottcher, Sheena L. Carter, Salathiel Kendrick-Allwood, Maureen Mulligan LaRossa, Judith Laursen, Colleen Mackie, Amy Sanders, Gloria Smikle, Lynn Wineski, Amir M. Khan, Barbara J. Stoll, Nora Alaniz, Fatima Boricha, Allison G. Dempsey, Donna J. Hall, Janice John, Ann Kubanda, Karen Martin, Georgia E. McDavid, Kimberly Rennie, Daniel K. Sperry, Emily Stephens, Tina Reddy, Michelle White, Sharon L. Wright, Kristen Webber, Dinorah Zanger, Leif D. Nelin, Jonathan L. Slaughter, Sudarshan R. Jadcherla, Christopher Tinman, Patricia L. Luzader, Demi R. Beckford, Julie Gutentag, Melanie Stein, Rox Ann Sullivan, Mary Ann Nelin, Kristi Small, Jacqueline McCool, Lindsay Pietruszewski, Jessica Purnell, Kyrstin Warnimont, Laura Marzec, Bethany Miller, Hallie Baugher, Julia Newton, Katelyn Levengood, Nancy Batterson, Brittany DeSantis, Jessica Schiering, Kelly Schmidt, Eduardo Finol Mark, Jordan Knox, Abbie M. Tice, Chelsea Cobe, Marissa Trotta, Emily Smith, Jeanette O. Auman, James A. Pickett, Anna Mazur, Jamie E. Newman, Lindsay Parlberg, Kristin M. Zaterka-Baxter, Valerie Y. Chock, David K. Stevenson, Dona Bahmani, Elizabeth N. Reichert, Lilia Rutkowska, M. Bethany Ball, Meera N. Sankar, Anne M. DeBattista, Barbara P. Recine, Casey E. Krueger, Hali E. Weiss, Heather L. Taylor, Janice Lowe, Jessica Patel, Lynne C. Huffman, Maria Elena DeAnda, Namasivayam Ambalavanan, Fred J. Biasini, Shirley S. Cosby, Kristy A. Domnanovich, Chantel J. Jno-Finn, Morissa Ladinsky, Tara E. McNair, Kimberlly Stringer, Sally Whitley, Sheree York Chapman, Cindie L. Buie, Jane E. Brumbaugh, Karen J. Johnson, Mendi L. Schmelzel, Jacky R. Walker, Claire A. Goeke, Diane Eastman, Megan M. Henning, Chelsey Elekiwich, Megan Broadbent, Sarah Van Muyden, Dan L. Ellsbury, Tracy L. Tud, Janell Fuller, Conra Backstrom Lacey, Carol Hartenberger, Mary Ruffner Hanson, Elizabeth Kuan, Eric C. Eichenwald, Karen M. Pupolo, Aasma S. Chaudhary, Toni Mancini, Jonathan Snyder, Kristina Ziolkowski, Megan Dhawan, Christina Catts, Ronnie Guillet, Rosemary L. Jensen, Joanne Merzbach, Osman Farooq, Ann Marie Scorsone, Constance Orme, Rachel Jones, Elizabeth Boylin, Jennifer Kachelmeyer, Kimberly G. McKee, Kelly R. Coleman, Deanna Maffett, Alison Kent, Carl D'Angio, Cassandra Horihan, Satyan Lakshminrusimha, William Zorn, Michelle Hartley-McAndrew, Emily Li, Myra H. Wyckoff, Luc P. Brion, Diana M. Vasil, Frances Eubanks, E. Rebecca McDougald, Pollieanna Sepulveda, Elizabeth Heyne, Lizette E. Lee, Anna Puentez, Azucena Vera, Jillian Waterbury, Cathy Twell Boatman, Kristine Tolentino-Plata, Bradley A. Yoder, Carrie A. Rau, Shawna Baker, Sean D. Cunningham, Becky Hall, Erika R. Jensen, Manndi C. Loertscher, Trisha Marchant, Kandace M. McGrath, Hena G. Mickelsen, Galina Morshedzadeh, Kelly Stout, Ashley L. Stuart, Kathryn D. Woodbury, Dawn Bentley, Laura C. Bledsoe, Kathleen Coleman, Brixen A. Reich, Micall P. Sagers, Stephen D. Minton, Erick B Gerday, Susan Christensen, Jennifer O. Elmont, Mark J. Sheffield, Melody Parry, Jamie Jordan, Katherine Tice, Earl Maxson, Barbara L. Francom, Kimberlee Weaver-Lewis, Tara L. Dupont
Journal: JAMA Pediatrics (2025)

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