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

Abstract

Importance: Extremely 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.

Objectives: To 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 participants: The 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.

Interventions: In 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 measures: Need for transfusion, transfusion numbers and volume, number of donor exposures, and lowest daily hematocrit level are presented herein.

Results: A 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 relevance: These 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 registration: ClinicalTrials.gov Identifier: NCT01378273.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Juul reported receiving grants from the National Institutes of Health (NIH), CP Alliance, and Gates Foundation Grant during the conduct of the study. Dr Comstock reported receiving grants from the NIH during the conduct of the study. Dr Courtney reported receiving grants from the NIH during the conduct of the study. Dr Ahmad reported receiving grants from the National Institute of Neurological Disorders and Stroke (NINDS) during the conduct of the study. Dr LaGamma reported receiving grants from the NINDS during the conduct of the study. Dr Downey reported receiving grants from the NINDS during the conduct of the study. Dr Frantz reported receiving grants from the NIH during the conduct of the study. Dr Khan reported receiving grants from the NINDS during the conduct of the study. Dr Weiss reported receiving grants from the NIH during the conduct of the study. Dr Gilmore reported receiving grants from the NIH during the conduct of the study. Dr Ohls reported receiving grants from the NIH during the conduct of the study. Dr Heagerty reported receiving grants from the NIH to the University of Washington during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagram

pRBC indicates packed red blood cell.

Figure 2.. Transfusion Rate by Treatment Group and Survival Status

Moving 3-day transfusion rates (ie, proportion of infants receiving a transfusion for every 3-day window) by treatment group were calculated for all infants (A [n = 936]), those who survived (B [n = 823]), and those who died (C [n = 113]).

Figure 3.. Transfusion Exposures by Treatment Group

The number of packed red blood cell (pRBC) transfusions (A [4061 records]), cumulative volume of pRBC transfusions (B [4052 records]), and donor exposure (C [3808 records]) were compared between treatment groups. Mean values were compared using generalized estimating equation models clustering on same-birth siblings, adjusted for gestational age and site. Relative rate (RR) of less than 1.00 favored the erythropoietin group.

Figure 4.. Lowest Daily Hematocrit Level Over Time by Gestational Age at Birth

Mean weekly values by treatment group were compared using generalized estimating equation models clustering on same-birth siblings and adjusting for recruitment site. Significance was shown by P < .05 and P < .001 bars. The .001 level was chosen as an approximation to a conservative Bonferroni correction (.05 level divided by the total number of tests performed on the weekly data sets). Blue vertical line indicates week 33, at which the last erythropoietin or placebo dose was given.