Erythropoiesis-stimulating agents linked to improved cognition in preterm infants

1. Preterm infants receiving erythropoiesis-stimulating agents (ESAs) performed better than placebo-receiving babies on cognitive tests assessing full-scale intelligence quotient (IQ), verbal IQ, and executive function.

2. ESAs were observed to reduce the incidence of neurodevelopmental impairments such as cerebral palsy in preterm infants.

Evidence Rating Level: 2 (Good)

Study Rundown: Extremely low birth weight preterm infants have a greater risk of developing neurodevelopmental disorders than babies carried to term. ESAs such as erythropoietin and darbepoetin given soon after birth have been shown to have neuroprotective effects in animal models, and short-term cognitive benefits were previously reported in ESA-treated preterm babies assessed at 18 to 22 months’ corrected age. To determine whether such cognitive benefits would remain evident through the preschool years (3.5 to 4 years of age), cognitive assessments were again performed on eligible, previously studied preemies. Although not performing as well as term controls, preterm infants who had received an ESA scored higher on full-scale IQ and verbal IQ tests than those who had not received an ESA. Executive function of ESA-treated preterm infants was also stronger than that of the placebo group and consistent with that of term infants. Limitations of this study included inter-group variation, as maternal education was significantly different between the ESA and placebo groups; inter-site variation, as infants from different centers participated in the study; and the possibility for additional confounding variables. Considering the mounting evidence in favor of ESAs conferring cognitive benefits and the lack of reported adverse events with the use of these medicines, clinicians may wish to seriously consider such prophylactic therapy for extremely low birth weight preterm infants.

Click to read the study, published today in Pediatrics

Relevant Reading: Erythropoietin signaling promotes oligodendrocyte development following prenatal systemic hypoxic-ischemic brain injury

Study Author, Dr. Robin K. Ohls, MD, talks to 2 Minute Medicine: University of New Mexico, Department of Pediatrics, Albuquerque, New Mexico.

“Ours is the first study to report on long term developmental outcomes of children formerly born prematurely who were treated with the erythropoiesis-stimulating agents (ESAs) erythropoietin and darbepoetin (a long acting growth factor). Children originally randomized to Epo [erythropoietin] or darbe [darbepoetin] scored significantly better on tests of cognition and executive function than did children randomized to placebo. ESAs show great promise in improving neurocognitive outcomes of extremely preterm infants.”

In-Depth [randomized control trial]: Participants included 53 preterm infants (< 32 weeks’ gestation, birth weight from 500 to 1250 g) at 2 centers (New Mexico and Utah) who were among 99 preterm infants from 3 centers previously randomized to receive erythropoietin, darbepoetin, or placebo. These participants were from a pool eligible for the BRain Imaging and Developmental Follow-up of Infants Treated with Erythropoietin (BRITE) Study. Twenty-four healthy term controls (TCs) were also enrolled at the New Mexico site. Of the 80 preterm infants whose cognitive function had been previously assessed at 18 to 22 months’ corrected age, 53 (66%) participated in the present study. Observing no significant cognitive functional differences between the 2 ESA groups, preterm infants receiving either of these agents (n = 39 children) were compared to those that received the placebo (n = 14 children). At 3.5 to 4 years of age, ESA-treated preterm infants scored significantly higher than placebo-receiving babies on full-scale IQ (FSIQ, p = 0.034) and verbal IQ (VIQ, p = 0.015); however, the ESA group still underperformed compared to TCs (FSIQ: p = 0.011; VIQ: p = 0.006). Executive function assessment of the ESA-receiving group was significantly better than that of the placebo group (p = 0.035) and not significantly different than that of the TCs. Additionally, while none of the 39 children in the ESA group had been diagnosed with cerebral palsy, 3 of the 14 children in the placebo group (21%) had mild forms of this condition. The General Language Composite scores of placebo and ESA-treated preterm infants, however, were comparable and significantly lower than that of term controls. Interestingly, besides maternal educational differences, the only other measured variable that significantly differed between the placebo and ESA-receiving groups was the proportion of children who had a head circumference less than the 10th percentile (ESA-receiving: 5%, placebo: 29%; p = 0.036).

Image: PD

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