Effect of High-Dose Erythropoietin on Blood Transfusions in Extremely Low Gestational Age Neonates: Post Hoc Analysis of a Randomized Clinical Trial

This post hoc analysis of data from a randomized clinical trial assesses whether high-dose erythropoietin given within 24 hours of birth through postmenstrual age of 32 completed weeks will decrease the need for blood transfusions in extremely low gestational age neonates. Key PointsQuestionDoes high-dose erythropoietin given within 24 hours of birth to postmenstrual age of 32 weeks decrease the number of blood transfusions, cumulative volume of transfusions, and unique donor exposures in extremely preterm infants? FindingsIn this randomized phase 3 clinical trial that included 941 infants with gestational age of 24 weeks (0-7 days) to 27 weeks (6-7 days) at birth, erythropoietin given according to protocol significantly decreased the number of transfusions, the cumulative volume of transfusions, and the unique donor exposures. MeaningThese findings suggest that high-dose erythropoietin decreases transfusion requirements in infants with a gestational age of 24 to 27 weeks and increases the number who remain transfusion free. ImportanceExtremely preterm infants are among the populations receiving the highest levels of transfusions. Erythropoietin has not been recommended for premature infants because most studies have not demonstrated a decrease in donor exposure. ObjectivesTo determine whether high-dose erythropoietin given within 24 hours of birth through postmenstrual age of 32 completed weeks will decrease the need for blood transfusions. Design, Setting, and ParticipantsThe Preterm Erythropoietin Neuroprotection Trial (PENUT) is a randomized, double-masked clinical trial with participants enrolled at 19 sites consisting of 30 neonatal intensive care units across the United States. Participants were born at a gestational age of 24 weeks (0-6 days) to 27 weeks (6-7 days). Exclusion criteria included conditions known to affect neurodevelopmental outcomes. Of 3266 patients screened, 2325 were excluded, and 941 were enrolled and randomized to erythropoietin (n=477) or placebo (n=464). Data were collected from December 12, 2013, to February 25, 2019, and analyzed from March 1 to June 15, 2019. InterventionsIn this post hoc analysis, erythropoietin, 1000 U/kg, or placebo was given every 48 hours for 6 doses, followed by 400 U/kg or sham injections 3 times a week through postmenstrual age of 32 weeks. Main Outcomes and MeasuresNeed for transfusion, transfusion numbers and volume, number of donor exposures, and lowest daily hematocrit level are presented herein. ResultsA total of 936 patients (488 male [52.1%]) were included in the analysis, with a mean (SD) gestational age of 25.6 (1.2) weeks and mean (SD) birth weight of 799 (189) g. Erythropoietin treatment (vs placebo) decreased the number of transfusions (unadjusted mean [SD], 3.5 [4.0] vs 5.2 [4.4]), with a relative rate (RR) of 0.66 (95% CI, 0.59-0.75); the cumulative transfused volume (mean [SD], 47.6 [60.4] vs 76.3 [68.2] mL), with a mean difference of -25.7 (95% CI, 18.1-33.3) mL; and donor exposure (mean [SD], 1.6 [1.7] vs 2.4 [2.0]), with an RR of 0.67 (95% CI, 0.58-0.77). Despite fewer transfusions, erythropoietin-treated infants tended to have higher hematocrit levels than placebo-treated infants, most noticeable at gestational week 33 in infants with a gestational age of 27 weeks (mean [SD] hematocrit level in erythropoietin-treated vs placebo-treated cohorts, 36.9% [5.5%] vs 30.4% [4.6%] (P<.001). Of 936 infants, 160 (17.1%) remained transfusion free at the end of 12 postnatal weeks, including 43 in the placebo group and 117 in the erythropoietin group (P<.001). Conclusions and RelevanceThese findings suggest that high-dose erythropoietin as used in the PENUT protocol was effective in reducing transfusion needs in this population of extremely preterm infants. Trial RegistrationClinicalTrials.gov Identifier: NCT01378273