Early high-dose rhEPO fails to improve neurodevelopment in very preterm infants

By Lucy Piper

Very preterm infants do not gain protection against neurodevelopmental delay with early prophylactic high-dose recombinant human erythropoietin (rhEPO), researchers report.

Their study of 448 preterm infants born between 26 and 32 weeks of gestation and randomly assigned to receive rhEPO or placebo showed similar neurodevelopmental outcomes at 2 years corrected age.

Average Mental Development Index scores on the Bayley Scales of Infant Development were a respective 93.5 and 94.5, out of a possible 100, reflecting a nonsignificant difference that failed to reach the predefined minimal clinically important difference of 5 points.

There was also no significant difference between the two treatment groups with regard to secondary outcomes, including psychomotor development, cerebral palsy, severe hearing impairment and severe visual impairment, which were generally uncommon.

"To the best of our knowledge, this study evaluated the largest population to date of very preterm infants treated with high-dose rhEPO during the first day of life. It is possible that rhEPO does not have a neuroprotective role", says the team, led by Giancarlo Natalucci (University Hospital of Zurich, Switzerland).

Treatment was given intravenously within 3 hours of birth and again at 12 to 18 hours and 36 to 42 hours afterwards. The 228 infants given rhEPO received a single dose of 25 µg (3000 IU) per kg of bodyweight dissolved in 1 mL of distilled water and then 1 mL per kg ver a period of 3 minutes up to a maximal dose of 1.5 mL for infants weighing 1.5 kg or more.

The researchers note in JAMA that this regimen differed from that of two other studies demonstrating a clinical benefit with rhEPO in which the treatment was started later (2-4 days after birth) and administered at a lower dose (400 IU/kg), more often (three times per week) and for a longer duration (up to 35 weeks' postmenstrual age).

"Therefore, one of the reasons for the lack of improved outcome with rhEPO in this study could be the timing of the first dose and shorter duration of rhEPO treatment", the team suggests.

They add: "The regimen used in this study might be insufficient in achieving neuroprotection during the postnatal period, and the standard application of rhEPO for neuroprotection in very preterm infants still needs to be clarified."

Given the negative findings, Natalucci and colleagues also question the time at which neurodevelopmental outcome was measured, which at 2 years may be poor, particularly if infants with major disabilities are excluded, and simply reflect proof of safety.

"Assessment at school age may be a better measure of efficacy, when children's cognitive performance becomes more differentiated than at 2 years, and reevaulation of the cohort at this age is planned", they report.

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