JOURNAL CLUB · ARTICLE OF THE WEEK
Erythropoietin added to cooling for neonatal HIE (PAEAN)
Liley HG, Hunt RW, O’Connell RL, et al; for the PAEAN Study Investigators. JAMA Pediatr. 2026. doi:10.1001/jamapediatrics.2026.3082. A phase 3, multicentre, double-blind, placebo-controlled RCT.
COOLING DID NOT
HELP HIE
No benefit on the primary outcome
Death or moderate/severe disability was 34.1% (EPO) vs 28.7% (placebo); RR 1.19 (95% CI 0.84-1.68, p=0.33).
No difference in death
Death was 15.1% vs 12.1% - not significant.
No definite harm
Unlike some earlier data, PAEAN found no clear safety signal with EPO.
The verdict
EPO adds nothing to cooling for HIE - therapeutic hypothermia remains the only proven neuroprotective treatment.
WHY THIS MATTERS
- Cooling is standard for moderate/severe HIE, but outcomes are still often poor
- Adjuncts that could add to cooling have been sought for years
- EPO looked promising in animal and early studies
- Families and clinicians want more to offer
- A well-powered ANZ trial gives a clear, locally-relevant answer
STRENGTHS
- Phase 3, double-blind, placebo-controlled - high-quality design
- Multicentre and international (ANZ and Singapore)
- A meaningful long-term outcome (death or disability at 2 years)
- Intention-to-treat with low loss to follow-up (~10%)
- Adds to a consistent picture with other EPO trials
LIMITATIONS
- Recruited over 5 years (2016-2021); practice may have shifted
- Powered for a large effect; smaller benefits are not excluded
- The primary outcome trended the wrong way (though not significant)
- Applies to cooled ≥35-week babies with moderate/severe HIE - not milder or preterm HIE
- A single agent and dose tested
Practice implications
HIE is recognised and cooling is started at or around the special care nursery before retrieval to a NICU, so the message is simple: therapeutic hypothermia remains the only proven neuroprotective treatment for moderate/severe HIE, and erythropoietin does not add to it. PAEAN, a large ANZ trial, found no benefit (and no clear harm) from adding EPO to cooling. Do not use EPO as neuroprotection for HIE outside a trial. Focus on what works: recognise HIE early, start passive cooling with accurate temperatures, avoid hyperthermia, support glucose and the ABCs, and call NETS early for retrieval to a cooling centre. Read it alongside the cooling landmark trials (TOBY, NICHD, HELIX).
Why do adjuncts to cooling keep failing to show benefit?
How does PAEAN sit alongside the HEAL trial, which suggested harm from EPO?
What is your unit’s pathway for starting cooling before retrieval?
Where should HIE neuroprotection research go next?
JAMA Pediatrics 2026 HIE
The Hub condition page COOLING TRIALS
Landmark trials JOURNAL CLUB
Article of the week & archive
Take-home message: PAEAN, a large Australia / New Zealand / Singapore RCT, tested whether adding erythropoietin to therapeutic hypothermia improves outcomes in moderate/severe HIE. It did not - death or disability at 2 years was 34% with EPO vs 29% with placebo (not significant), with no clear harm. Cooling remains the only proven neuroprotective treatment for HIE, and EPO should not be used as an adjunct outside a trial. Recognise HIE, start cooling early, and retrieve.
For educational purposes only. Journal club appraisal - figures paraphrased from the published trial; read the full article for complete data. Always align practice to your local guidelines.