Design: Phase 3, multicentre, double-blind, placebo-controlled RCT
Population: 313 infants ≥35 weeks with moderate or severe HIE receiving hypothermia
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 in 24 neonatal units in Australia, New Zealand and Singapore. It enrolled 313 infants of 35 weeks' gestation or more with moderate or severe hypoxic-ischaemic encephalopathy who had started therapeutic hypothermia within six hours of birth, and gave intravenous erythropoietin 1000 IU/kg (five doses over the first week) or placebo.

Death or moderate-to-severe disability at two years occurred in 34.1% with erythropoietin and 28.7% with placebo (RR 1.19, 95% CI 0.84–1.68). Death, cerebral palsy and cognitive deficit did not differ, and there were no safety concerns.

This agrees with the larger HEAL trial in the US: erythropoietin adds nothing to cooling. Note that both trials were in high-income units with cooling as standard. Evidence on cooling itself in low- and middle-income settings is different and contested, so this result says nothing about whether to cool.

Do not add erythropoietin to therapeutic hypothermia for neonatal HIE.
Follow current local protocols on therapeutic hypothermia, which this trial did not test.
Arrange structured neurodevelopmental follow-up for all infants with moderate or severe HIE.
Discuss prognosis with families using two-year outcome data rather than early impressions.

Why it matters

It closes off one of the most studied neuroprotective adjuncts for HIE.

The statistics, in plain English

An RR of 1.19 with an interval from 0.84 to 1.68 includes no effect; the point estimate leans slightly towards harm, so a meaningful benefit is very unlikely.