Design: Phase 3, multicentre, double-blind, placebo-controlled randomised trial
Population: 313 infants ≥35 weeks with moderate or severe HIE receiving hypothermia, Australia, New Zealand, Singapore
Primary outcome: Death or moderate-to-severe disability at 2 years
Effect: 34.1% vs 28.7%; RR 1.19 (95% CI 0.84–1.68)

PAEAN was a phase 3, double-blind, placebo-controlled trial at 24 neonatal units in Australia, New Zealand and Singapore. It enrolled 313 infants of 35 weeks' gestation or more with perinatal depression and moderate or severe hypoxic-ischaemic encephalopathy, all of whom had started therapeutic hypothermia within six hours of birth. They received intravenous erythropoietin 1000 IU/kg, five doses over the first week, or placebo.

At two years, death or moderate-to-severe motor or cognitive disability occurred in 34.1% with erythropoietin and 28.7% with placebo (RR 1.19, 95% CI 0.84–1.68). Death (15.1% vs 12.1%), cerebral palsy, motor deficit and cognitive deficit were also similar, and there were no safety signals. Follow-up was 90%.

This matches the earlier HEAL trial in the United States, which also found no benefit. Two adequately powered trials pointing the same way mean erythropoietin should not be added to cooling outside research. Therapeutic hypothermia, started early in a unit equipped to deliver it, remains the only proven neuroprotective treatment for term encephalopathy in well-resourced settings.

Do not add erythropoietin to therapeutic hypothermia for neonatal encephalopathy outside a trial.
Start cooling within six hours of birth in eligible infants; that window is what the evidence supports.
Point estimates leaned slightly against erythropoietin, though the difference was not significant.
Arrange structured neurodevelopmental follow-up to two years for every infant treated for encephalopathy.

Why it matters

A second large trial has closed off the most promising add-on to cooling.

The statistics, in plain English

A relative risk of 1.19 with an interval of 0.84 to 1.68 is compatible with modest harm or modest benefit, but not with the large benefit the trial was looking for. Taken with a second negative trial, the chance that erythropoietin helps meaningfully is small.