Better Cognitive Outcomes in Preterm Infants Treated with Erythropoietin-Stimulating Agents

By Will Boggs MD

NEW YORK - Preterm infants randomized to receive darbepoetin or erythropoietin have better cognitive outcomes at 18 to 22 months of age than do similar infants randomized to receive placebo, according to results of a multicenter study.

"My opinion is that all extremely low birth weight infants (regardless of altitude) would benefit from ESA treatment, but studies are ongoing evaluating higher doses for neuroprotection, so research continues," Dr. Robin K. Ohls from University of New Mexico in Albuquerque told Reuters Health by email.

Dr. Ohls and colleagues previously reported improved developmental outcomes in preterm infants that had been treated with erythropoietin. Here, they investigated whether the erythropoietin-stimulating agents (ESAs) erythropoietin and darbepoetin given to preterm infants improved developmental outcomes at 18 to 22 months' adjusted age. They conducted their study at four centers located above 4800 feet elevation.

Among the 80 infants included, those randomized to ESAs had higher composite cognitive scores, scored higher on the test for object permanence, and tended to have higher language scores, compared with those randomized to placebo.

Scores were similar for the erythropoietin and darbepoetin groups, except that the latter scored higher on object permanence.

The adjusted risk of having visual impairment, hearing impairment, cerebral palsy, or composite cognitive score below 85 was 79% lower for infants treated with ESAs than for infants who received placebo, according to the May 12 Pediatrics online report.

"There is evidence (based on a prospectively designed and implemented randomized study) that ESAs improve cognitive outcomes in preterm infants 500-1250 grams birth weight," Dr. Ohls concluded.

"The mechanisms involved likely include biologic neuroprotection of ESAs, maintenance of hematocrit above that of the placebo group, and decreased transfusions," she said. "We are still trying to determine how much of a role each of these mechanisms plays in the overall improvement of ESA-treated infants."

"The least expensive measures to take include instituting transfusion guidelines and limiting laboratory evaluation (both are free)," Dr. Ohls added. "The cost of 10 weeks of Epo therapy is similar to a course of surfactant and less than a course of IV ibuprofen."

Dr. Arne Ohlsson from University of Toronto in Ontario, Canada coauthored a recent Cochrane review on the early use of erythropoietin for preventing red blood cell transfusions in preterm infants. He told Reuters Health by email, "Neurodevelopmental outcomes at 18 to 22 months vary in the few studies published to date. Long-term neurodevelopmental outcomes at 18 to 22 months have shown conflicting results with one study showing an increased risk of Psychomotor Development Indexes (PDI) < 70 (of borderline significance)."

"Ongoing research should deal with the issue of retinopathy of prematurity (ROP) and evaluate current clinical practice that will limit donor exposure," Dr. Ohlsson said. "Due to the limited benefits and the possibly increased risk of ROP, administration of Epo is not recommended. Darbepoetin requires further study. The possible neuroprotective role of Epo in neonates will be reviewed in separate Cochrane reviews."

Dr. Sandra Juul from University of Washington in Seattle has studied the neuroprotective role of ESAs in infants. She told Reuters Health via email, "The findings from the phase II study published by Ohls et al. are very promising and are consistent with the ample preclinical work done suggesting that ESAs are important for normal neurodevelopment, and can be neuroprotective. This work should encourage larger randomized controlled trials to be done to determine the safety and efficacy of Epo (or darbe), but is not sufficient evidence for recommending that all preterm babies be given ESA treatments."

"ESAs are also being evaluated for term infants with birth asphyxia, another group of children with a high percentage of death or poor neurodevelopmental outcomes," Dr. Juul said. "Overall, all phase I and II trials of ESA neuroprotection have been very encouraging, showing both safety and the promise of benefit."

She added, "Work still needs to be done to determine the optimal dose, dosing interval, and duration of treatment for ESA neuroprotection. Larger phase III trials still need to be done to prove safety and efficacy. If preterm infants were to start routinely receiving ESAs, the opportunity to do this will be lost and we may be using a suboptimal dose."

The study was funded by grants from the University of New Mexico and the University of Colorado.

SOURCE: https://bit.ly/1iXAFkH

Pediatrics 2014.

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