Safety and Short-term Outcomes of High-Dose Erythropoietin in Preterm Infants With Intraventricular Hemorrhage

Abstract

ImportanceIntraventricular hemorrhage (IVH) is a major cause of neonatal morbidity and mortality in preterm infants without a specific medical treatment to date.ObjectiveTo assess the safety and short-term outcomes of high-dose erythropoietin in preterm infants with IVH.Design, Setting, and ParticipantsBetween April 1, 2014, and August 3, 2018, a randomized double-blind clinical trial enrolled 121 preterm infants (gestational age <32 weeks or birth weight <1500 g) aged 8 or less days with moderate to severe IVH identified by cerebral ultrasonography from 8 Swiss and Austrian tertiary neonatal units. Statistical analyses were performed between October 1, 2019, and September 12, 2022.InterventionsInfants received intravenous high-dose erythropoietin (2000 units/kg body weight) or placebo at 4 time points between weeks 1 and 4 of life.Main Outcomes and MeasuresSecondary outcomes included (1) mortality and morbidity rates and (2) brain magnetic resonance imaging findings at term-equivalent age (TEA). The primary outcome was the composite intelligence quotient at 5 years of age (not available before 2023).ResultsSixty infants (48% male [n = 29]) were randomly assigned to receive erythropoietin, and 61 infants (61% male [n = 37]) were randomly assigned to receive placebo. The median birth weight was 832 g (IQR, 687-990 g) in the erythropoietin group and 870 g (IQR, 680-1110 g) in the placebo group. Median gestation was 26.1 weeks (IQR, 24.8-27.3 weeks) in the erythropoietin group and 27.0 weeks (24.9–28.1 weeks) in the placebo group. The 2 groups had similar baseline characteristics and morbidities. Up to TEA, 10 newborns died (16.7%) in the erythropoietin group, and 5 newborns (8.2%) died in the placebo group (adjusted odds ratio, 2.24 [95% CI, 0.74-7.66]; P = .15). Infants receiving erythropoietin had higher mean hematocrit levels. Conventional magnetic resonance imaging at TEA for 100 infants showed no significant differences in global or regional brain injury scores.Conclusions and RelevanceThis preliminary report of a randomized clinical trial found no evidence that high-dose erythropoietin in preterm infants with IVH affects brain injury scores on conventional magnetic resonance imaging at TEA. Higher mortality in the erythropoietin group was not significant but should be reassessed based on future results from similar trials.Trial RegistrationClinicalTrials.gov Identifier: NCT02076373

Taking Stock After Another Negative Erythropoietin Neuroprotection Trial

“…The rationale for choosing this subset of preterm neonates was that erythropoietin might be more effective in facilitating repair of injury rather than as a prophylactic treatment. No difference was seen in term-equivalent MRI findings or in hospital outcomes, and 5-year outcomes are pending …”

“…Infants were randomized by day 8 to a dose of 2000 units/kg of body weight (or placebo) for 5 doses within the first 17 days after enrollment. 2 The rationale for choosing this subset of preterm neonates was that erythropoietin might be more effective in facilitating repair of injury rather than as a prophylactic treatment. No difference was seen in term-equivalent MRI findings or in hospital outcomes, and 5-year outcomes are pending.…”

“…No difference was seen in term-equivalent MRI findings or in hospital outcomes, and 5-year outcomes are pending. 2 Erythropoietin has a long and interesting history with respect to its clinical use. The existence of erythropoietin was first posited in 1906 by Carnot and DeFlandre 3 after the observation that blood transfused from a hemorrhaged rabbit could stimulate red cell production in another rabbit.…”

“…Wellmann et al describe the safety and short-term outcomes of the EpoRepair trial, which enrolled 121 preterm neonates born at less than 32 weeks of gestation with diagnosed grade 2 or higher intraventricular hemorrhage between April 1, 2014, and August 3, 2018. Reported interim outcomes include term-equivalent magnetic resonance imaging (MRI) findings and events up to hospital discharge.…”

“…Reported interim outcomes include term-equivalent magnetic resonance imaging (MRI) findings and events up to hospital discharge. Infants were randomized by day 8 to a dose of 2000 units/kg of body weight (or placebo) for 5 doses within the first 17 days after enrollment . The rationale for choosing this subset of preterm neonates was that erythropoietin might be more effective in facilitating repair of injury rather than as a prophylactic treatment.…”