Does an Extra Medicine Help Protect a Baby's Brain After a Difficult Birth?

What a large trial in Australia, New Zealand and Singapore (Liley et al., JAMA Pediatrics 2026) found about adding erythropoietin to cooling treatment, and how it fits with an earlier trial in the United States

Some babies are short of oxygen around the time of birth, and this can injure the brain. Cooling the baby for three days is the standard treatment, and doctors hoped that adding a medicine called erythropoietin would help even more babies. A trial of 313 babies in Australia, New Zealand and Singapore found that it did not reduce deaths or disability, which matches the result of an earlier trial in the United States.

Why a baby's brain can be hurt around birth

This article explains a new study by Liley and colleagues, the Preventing Adverse Outcomes of Neonatal Hypoxic Ischaemic Encephalopathy with Erythropoietin trial, or PAEAN for short [1], and the problem it set out to solve. Occasionally, something goes wrong just before or during birth that cuts down the flow of blood and oxygen to a baby's brain. Doctors call the resulting brain injury hypoxic-ischaemic encephalopathy, or HIE: "hypoxic" means low oxygen, "ischaemic" means reduced blood flow, and "encephalopathy" means the brain is not working normally. A baby with HIE may be floppy, very sleepy, have trouble feeding or breathing, or have seizures. Moderate or severe brain problems of this general kind in newborns (from any cause, not only a shortage of oxygen) affect roughly 0.5 to 3 babies in every 1000 born in wealthy countries [2]. In Australia and New Zealand, moderate or severe HIE affects about 1 in every 1000 babies born at or near full term [1]. Researchers in Western Australia found many years ago that these problems often have several causes, and that events during labour explain only some of them [3].

How cooling changed care, and why doctors wanted more

Care for these babies changed when large studies tested a treatment called therapeutic hypothermia, or cooling. A cooling device lowers the baby's body temperature to 33.5 °C, a few degrees below normal, and keeps it there for three days before the baby is gently warmed again. In one major trial, the share of babies who died or had a moderate or severe disability fell from 62 in 100 to 44 in 100 with cooling [4]. Another, the TOBY trial of whole-body cooling in 325 babies, found that more cooled babies survived with a normal neurological examination [5]. A review that brought together 11 trials found that cooling helps, and it recommended cooling for babies born at or near term with moderate or severe HIE who are identified within 6 hours of birth [6].

Cooling is not a cure, though. The doctors who planned the new trial expected that, even with cooling, nearly half of babies with moderate or severe HIE would die or have a lasting disability [1]. So researchers looked for a medicine to give alongside cooling. One of the most promising was erythropoietin, often shortened to EPO. EPO is a hormone the body makes naturally, mainly known for telling the body to make red blood cells. The body makes more of it when oxygen is low, and the developing brain has receivers for it, so scientists wondered whether it might also protect brain cells [1]. Experiments in young rats suggested that it could [7]. Early studies in babies who were not being cooled looked hopeful [8][9]. A small study of 50 cooled babies in the United States then found less injury on brain scans when EPO was added [10]. Small studies like these can be misleading, however, so large, careful trials were needed.

The first big answer: a trial in the United States

The first large test was the High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial, which included 501 babies at 23 hospitals in the United States [11]. All the babies were cooled. Half also received EPO, and half received a placebo, a dummy treatment with no medicine in it. By about age 2 to 3, EPO had not made any difference: about 52 in 100 babies given EPO and about 50 in 100 given placebo had died or had a developmental problem of any degree. The babies given EPO also had somewhat more serious medical complications [11]. The HEAL team said that results from a second trial already under way would help clarify whether EPO was safe. That second trial is the subject of this article.

How the new trial was done

PAEAN took place in 24 newborn intensive care units: 18 in Australia, 5 in New Zealand and 1 in Singapore. Between 2016 and 2021, it enrolled 313 babies born at 35 weeks of pregnancy or later who had moderate or severe HIE and were being cooled. A central system decided by chance, like a coin toss, which babies would receive EPO (156 babies) and which would receive a salt-water placebo (157 babies). This is called randomisation, and it makes the two groups as alike as possible, so any difference later is likely to be caused by the medicine. Neither the parents nor the doctors knew which treatment each baby was getting. Babies were due to receive five doses through a drip into a vein during their first week.

The PAEAN team designed the trial together with the HEAL researchers and used the same medicine at the same dose, although the timing of the doses differed slightly [1][11]. PAEAN counted only moderate or severe problems. A child was counted if they had cerebral palsy (a condition affecting movement and posture) that affected their movement enough to place them at level 2 or higher on a five-level scale of how well children with cerebral palsy can move about [12]. A child was also counted if they scored clearly below the average range on a standard test of thinking and learning [1].

What the researchers found

When the children were about 2 years old, the researchers counted how many had died or had a moderate or severe disability. This happened to 47 of the 138 children in the EPO group whose outcome was known, about 34 in every 100. In the placebo group it happened to 41 of 143, about 29 in every 100 [1]. The difference is small and could easily have occurred by chance, so it does not show that EPO caused harm. It clearly does not show that EPO helped.

The trial faced some real-world difficulties. Only about half of the babies received all five doses, in both groups. The most common reason was a good one: many babies recovered quickly, and their drip was removed before the last dose was due. Some babies sadly died, or their families and doctors decided together to stop intensive care. The COVID-19 pandemic also delayed some check-ups, so some children were assessed as late as 3 years of age, and about 1 in 10 children could not be fully assessed. The researchers checked carefully that these gaps were very unlikely to have hidden a real benefit [1].

The researchers saw the same pattern when they looked at deaths, cerebral palsy, and test scores for thinking, language and movement. The children's average thinking scores were almost the same in both groups. Serious side effects that doctors had worried about, such as dangerously thick blood, did not occur in either group. Blood clots in a large blood vessel during the first week happened in 4 of 155 babies given EPO and 1 of 157 given placebo. This difference was too small to be sure it was real [1]. The researchers' own summary was that they found no clear sign of harm, but that because such problems were rare, they could not completely rule out either a benefit or a harm.

What these results mean for families

Putting the two trials together, the authors say the evidence "rules out even moderate treatment benefits" from adding EPO to cooling [1]. In other words, two large and carefully run trials, in different parts of the world, reached the same answer. That consistency is important, and it means EPO should not be given routinely for this purpose. Another study of HEAL babies checked their blood and found that more than 95 in 100 had received enough medicine to reach the intended levels, so a dose that was too low does not explain the result [13]. Experiments in lambs before birth suggest a likely reason: cooling and EPO seem to protect the brain in overlapping ways, so adding EPO gives little extra benefit [14].

For parents of a baby who is being cooled, the most important message is a hopeful one. In this trial, about 7 in every 10 babies who received cooling with the placebo, and whose outcome was known, survived to age 2 without moderate or severe disability. Cooling itself remains the treatment that matters most, and starting it quickly is key [6]. Regular check-ups of movement, learning and development over the first years also matter, because they help children get extra support early if they need it.

What researchers are working on next

The PAEAN researchers suggest that combining information about each individual baby from similar trials might show whether any particular group of babies could still benefit [1]. They will also report brain scan and brain-wave results separately [1]. A similar large trial of EPO in babies born very early, the Preterm Erythropoietin Neuroprotection Trial (PENUT), carried out at 30 hospitals in the United States, also found no benefit [15]. Scientists are now testing other ideas to add to cooling, such as stem-cell treatments. They are also asking how to help babies in countries with fewer resources, where the benefit of cooling itself is less certain [16]. Negative results like PAEAN's can feel disappointing, but they protect babies from treatments that do not work and point researchers towards better ones.

References

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  2. McIntyre S, Nelson KB, Mulkey SB, Lechpammer M, Molloy E, Badawi N. Neonatal encephalopathy: Focus on epidemiology and underexplored aspects of etiology. Semin Fetal Neonatal Med. 2021;26(4):101265. doi:10.1016/j.siny.2021.101265 ↩
  3. Badawi N, Kurinczuk JJ, Keogh JM, et al. Intrapartum risk factors for newborn encephalopathy: the Western Australian case-control study. BMJ. 1998;317(7172):1554-1558. doi:10.1136/bmj.317.7172.1554 ↩
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  11. Wu YW, Comstock BA, Gonzalez FF, et al. Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns. N Engl J Med. 2022;387(2):148-159. doi:10.1056/NEJMoa2119660 ↩
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