Systematic review examines early erythropoiesis-stimulating agents for preterm infants across multiple clinical outcomes and safety endpoints

Rationale Preterm and low‐birthweight infants are at risk of anemia due to a variety of factors, including low levels of erythropoietin. They may therefore benefit from erythropoiesis‐stimulating agents (ESAs). However, controversy remains about their effectiveness and safety, not only in reducing blood transfusions but also in improving clinical outcomes. Objectives To assess the benefits and harms of early administration of ESAs in preterm or low‐birthweight infants. Search methods We searched CENTRAL, MEDLINE, Embase, Scopus, DOAJ, and trial registries to 31 March 2025, and checked the reference lists of studies and systematic reviews for potentially relevant studies. Eligibility criteria Randomized controlled trials (RCTs) comparing early (initiated before eight days of life) ESAs (erythropoietin or darbepoetin) to placebo or no intervention among preterm (< 37 weeks' gestation) or low‐birthweight (< 2500 g) infants. Outcomes Outcomes included mortality during initial hospital stay (all‐cause mortality), moderate to severe neurodevelopmental impairment (NDI) at 18 to 26 months' corrected age, proportion of infants exposed to one or more red blood cell (RBC) transfusions, retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), and severe intraventricular hemorrhage (sIVH). Risk of bias We used the Cochrane RoB 1 tool to assess risk of bias. Synthesis methods We performed data collection and analyses according to the methods of Cochrane Neonatal (fixed‐effect meta‐analysis using the inverse‐variance method). We analyzed categorical data using risk ratio (RR) and continuous data using mean difference (MD), and reported the 95% confidence interval (CI) on all estimates. We used GRADE to assess the certainty of evidence. Included studies We included 37 studies (n = 6724), five (n = 3052) of which are new. Two studies (n = 752) investigated darbepoetin, and 35 studies (n = 5972) investigated erythropoietin. Synthesis of results ESAs compared to placebo or no intervention Mortality: ESAs probably result in little to no difference in mortality during initial hospital stay (RR 0.93, 95% CI 0.80 to 1.09; I² = 0%; 24 studies, 5217 participants; moderate‐certainty evidence). Subgroup analysis suggests that early use of erythropoietin probably results in little to no difference in mortality (RR 0.91, 95% CI 0.77 to 1.09; I² = 0%; 23 studies, 4505 participants), and early use of darbepoetin probably results in little to no difference in mortality (RR 1.00, 95% CI 0.71 to 1.43; I² = 0%; 2 studies, 712 participants). NDI: ESAs may reduce moderate to severe NDI at 18 to 26 months’ corrected age (RR 0.81, 95% CI 0.68 to 0.95; I² = 86%; 3 studies, 1707 participants; low‐certainty evidence). Subgroup analysis suggests that early use of erythropoietin may reduce moderate to severe NDI at 18 to 26 months’ corrected age (RR 0.79, 95% CI 0.66 to 0.95; I² = 93%; 2 studies, 1239 participants), while early use of darbepoetin may result in little to no difference in moderate to severe NDI at 18 to 26 months’ corrected age (RR 0.87, 95% CI 0.59 to 1.28; I² not applicable; 1 study, 468 participants). Transfusions: ESAs may reduce the proportion of infants exposed to one or more RBC transfusions (RR 0.79, 95% CI 0.76 to 0.83; I² = 56%; 21 studies, 3507 participants; low‐certainty evidence). Subgroup analysis suggests that erythropoietin may reduce the proportion of infants exposed to one or more RBC transfusions (RR 0.80, 95% CI 0.76 to 0.84; I² = 56%; 20 studies, 2795 participants); darbepoetin may reduce the proportion of infants exposed to one or more RBC transfusions (RR 0.75, 95% CI 0.68 to 0.84; I² = 0%; 2 studies, 712 participants). ROP (any stage): ESAs result in little to no difference in incidence of ROP (RR 0.91, 95% CI 0.83 to 1.00; I² = 0%; 14 studies, 3844 participants; high‐certainty evidence). Subgroup analysis suggests the use of either erythropoietin (RR 0.92, 95% CI 0.84 to 1.02; I² = 0%; 13 studies, 3230 participants) or darbepoetin (RR 0.83, 95% CI 0.58 to 1.17; I² = 0%; 2 studies, 614 participants) results in little to no difference in incidence of ROP. NEC (any stage): ESAs probably reduce the incidence of NEC (RR 0.74, 95% CI 0.62 to 0.87; I² = 0%; 20 studies, 5749 participants; moderate‐certainty evidence). Subgroup analysis suggests that early use of erythropoietin probably reduces the incidence of NEC (RR 0.72, 95% CI 0.61 to 0.85; I² = 0%; 19 studies, 5041 participants), while early use of darbepoetin probably results in little to no difference in incidence of NEC (RR 1.08, 95% CI 0.54 to 2.15; I² = 0%; 2 studies, 708 participants). sIVH (grade ≥ 3): ESAs probably reduce the incidence of sIVH (RR 0.70, 95% CI 0.56 to 0.89; I² = 43%; 9 studies, 2458 participants; moderate‐certainty evidence). Subgroup analysis suggests that early use of erythropoietin probably reduces the incidence of sIVH (RR 0.72, 95% CI 0.57 to 0.91; I² = 47%; 9 studies, 2396 participants), while early use of darbepoetin probably results in little to no difference in incidence of sIVH (RR 0.40, 95% CI 0.11 to 1.41; I² not applicable; 1 study, 62 participants). Of note, the test for subgroup differences between erythropoietin and darbepoetin revealed no evidence of a difference for the outcomes of mortality, moderate to severe NDI, NEC, sIVH, ROP, and the proportion of infants exposed to RBC transfusion. We downgraded the certainty of evidence for inconsistency, imprecision, and high risk of bias in the included studies. Authors' conclusions Early use of ESAs probably results in little to no difference in mortality (moderate‐certainty evidence); may reduce moderate to severe NDI at 18 to 26 months’ corrected age (low‐certainty evidence); has little to no effect on ROP (high‐certainty evidence); may reduce the proportion of infants exposed to one or more RBC transfusions (low‐certainty evidence); and probably reduces both NEC and sIVH (moderate‐certainty evidence). Given the benefits of ESAs, future research should focus on cost‐effectiveness, equity, feasibility of implementation, and acceptability to different stakeholders of the routine use of erythropoietin or darbepoetin among preterm or low‐birthweight infants. Funding No funding was received for this review. Registration Protocol (and previous versions) available via 10.1002/14651858.CD004863; 10.1002/14651858.CD004863.pub2; 10.1002/14651858.CD004863.pub3; 10.1002/14651858.CD004863.pub4; 10.1002/14651858.cd004863.pub5; 10.1002/14651858.CD004863.pub6. PICOs PICOs Population Intervention Comparison Outcome