Preschool Assessment of Preterm Infants Treated With Darbepoetin and Erythropoietin

Abstract

Background: We previously reported improved neurodevelopmental outcomes at 2 years among infants treated with the erythropoiesis-stimulating agents (ESAs) darbepoetin alfa (darbepoetin) or erythropoietin. Here we characterize 4-year outcomes.

Methods: Former preterm infants randomly assigned to receive darbepoetin (10 μg/kg, once per week), erythropoietin (400 U/kg, 3 times/week), or placebo through 35 weeks' postconceptual age were evaluated at 3.5 to 4 years of age. For comparison, healthy children formerly delivered full term (term controls [TCs]) were also recruited. All participants were assessed by using measures of full-scale IQ (FSIQ) and general language from the Wechsler Preschool and Primary Scale of Intelligence, Third Edition, and an overall measure of executive function, on the basis of tests evaluating inhibitory control and spatial working memory. Rates of neurodevelopmental impairment were compared across groups.

Results: Multivariate analysis of variance compared children randomly assigned to ESAs (n = 39), placebo (n =14), and TCs (n = 24). FSIQ and performance IQ were significantly higher in the ESA group than in the placebo group (FSIQ: 91.1 ± 17.5 vs 79.2 ± 18.5, P = .036; performance IQ: 93.0 ± 17.0 vs 79.5 ± 19.5, P = .018). Follow-up analyses revealed that the children receiving ESAs performed better than those who received placebo on executive function tasks. The ESA group's performance was below that of TCs, but the results did not reach significance on executive function. The incidence of neurodevelopmental impairment was greater in the placebo group than in the ESA group.

Conclusions: ESA-treated infants had better cognitive outcomes and less developmental impairment at 3.5 to 4 years of age compared with placebo-treated infants. ESAs show promise in improving long-term cognitive outcomes of infants born prematurely.

Trial registration: ClinicalTrials.gov NCT00334737 NCT01207778.

FIGURE 1

Numbers of infants screened for eligibility for the BRITE study, were eligible for the study, and evaluated at 3.5 to 4 years. RCT, randomized controlled trial.

FIGURE 2

Comparison of FSIQ (A), language comprehension (B), and executive function (C) in placebo, ESA-treated, and TC children. Data shown are box and whisker plots of medians (first and third quartiles). ESA-treated children scored significantly higher in FSIQ (P = .036) and executive function (P = .031).

FIGURE 3

Relationship between BSID-III cognitive scores at 2 years and FSIQ at 4 years (R² = 0.414, P < .0001) (A) and BSID-III composite language scores at 2 years and VIQ at 4 years (R² = 0.592, P < .0001) (B) in former preterm children. Both cognitive and language scores correlated significantly between 2- and 4-year assessment time points.