A Randomized Trial of Erythropoietin for Neuroprotection in Preterm Infants

Abstract

Background: High-dose erythropoietin has been shown to have a neuroprotective effect in preclinical models of neonatal brain injury, and phase 2 trials have suggested possible efficacy; however, the benefits and safety of this therapy in extremely preterm infants have not been established.

Methods: In this multicenter, randomized, double-blind trial of high-dose erythropoietin, we assigned 941 infants who were born at 24 weeks 0 days to 27 weeks 6 days of gestation to receive erythropoietin or placebo within 24 hours after birth. Erythropoietin was administered intravenously at a dose of 1000 U per kilogram of body weight every 48 hours for a total of six doses, followed by a maintenance dose of 400 U per kilogram three times per week by subcutaneous injection through 32 completed weeks of postmenstrual age. Placebo was administered as intravenous saline followed by sham injections. The primary outcome was death or severe neurodevelopmental impairment at 22 to 26 months of postmenstrual age. Severe neurodevelopmental impairment was defined as severe cerebral palsy or a composite motor or composite cognitive score of less than 70 (which corresponds to 2 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition.

Results: A total of 741 infants were included in the per-protocol efficacy analysis: 376 received erythropoietin and 365 received placebo. There was no significant difference between the erythropoietin group and the placebo group in the incidence of death or severe neurodevelopmental impairment at 2 years of age (97 children [26%] vs. 94 children [26%]; relative risk, 1.03; 95% confidence interval, 0.81 to 1.32; P = 0.80). There were no significant differences between the groups in the rates of retinopathy of prematurity, intracranial hemorrhage, sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, or death or in the frequency of serious adverse events.

Conclusions: High-dose erythropoietin treatment administered to extremely preterm infants from 24 hours after birth through 32 weeks of postmenstrual age did not result in a lower risk of severe neurodevelopmental impairment or death at 2 years of age. (Funded by the National Institute of Neurological Disorders and Stroke; PENUT ClinicalTrials.gov number, NCT01378273.).

Figure 1.

Screening, Randomization, and Follow-up.

Figure 2.. Primary and Secondary Efficacy Outcomes.

The primary outcome was death or severe neurodevelopmental impairment at 22 to 26 months of postmenstrual age. Severe neurodevelopmental impairment was defined as severe cerebral palsy or a composite motor score or composite cognitive score of less than 70 (which corresponds to 2 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition (Bayley-III). Severe cerebral palsy was defined as a Gross Motor Function Classification System (GMFCS) level higher than 2 (levels range from 0 [no impairment] to 5 [most severe impairment]). Moderate-to-severe neurodevelopmental impairment was defined as moderate cerebral palsy (a GMFCS level of 2) or a Bayley-III composite motor score or composite cognitive score of less than 85 (which corresponds to 1 SD below the mean). Relative risks were generated with the use of generalized estimating equation models adjusted for gestational age at birth and recruitment site and accounting for clustering of siblings from the same pregnancy. The diamonds indicate that the result is a key measure of interest; the center of the diamond represents the point estimate, and the width of the diamond represents the 95% confidence interval.

Figure 3.. Adverse Events.

Relative-risk estimates were generated with the use of generalized estimating equation models adjusted for gestational age at birth and clustering of siblings from the same pregnancy. The relative risk and 95% confidence interval were not calculated for polycythemia because of the small number of events. The diamonds indicate that the result is a key measure of interest; the center of the diamond represents the point estimate, and the width of the diamond represents the 95% confidence interval. Necrotizing enterocolitis was classified according to Bell’s stage (stages range from 1 to 3, with higher stages indicating greater severity of disease). Intracranial hemorrhage was classified according to Papile grade. In the category of complications of prematurity, data for severe bronchopulmonary dysplasia are shown for the 459 infants in the erythropoietin group and the 446 infants in the placebo group who survived to 36 weeks of post-natal age, and data for retinopathy of prematurity are shown for the 424 infants in the erythropoietin group and the 421 infants in the placebo group who had an ophthalmologic examination before discharge. The total numbers of serious adverse events per patient were evaluated with the use of generalized estimating equation models appropriate for count data. The assessment of blood transfusions was a post hoc analysis.