Erythropoietin and Emerging Adjunct Therapies for HIE: What the Research Shows

Therapeutic cooling reduces the risk of death or disability after HIE, but it does not fully prevent injury in every baby. For years, researchers have looked for therapies that could be added to cooling to further reduce brain injury. The most-studied of these is erythropoietin (EPO), but melatonin, xenon gas, stem cells, and others have all been investigated. Families researching their baby’s HIE often encounter these names and ask why their baby wasn’t given them. The short answer is that none has yet shown clear benefit when added to cooling, and most are still confined to research settings. This guide walks through what each therapy is, what the trials have shown, and where the field currently stands.

Why Adjunct Therapies Are Being Studied

Cooling works by interrupting the secondary energy failure that follows a hypoxic-ischemic event. It is effective enough that it is now standard of care, but it does not fully prevent injury in every baby. In the pooled trials reviewed by Jacobs and colleagues (2013, Cochrane Database), cooling reduced the combined outcome of death or major disability from about 58 percent to 46 percent, a meaningful reduction, but more than four in ten cooled babies still had adverse outcomes. This gap is what drives the search for adjunct therapies.

The therapies under study each target a different mechanism: oxidative stress, excitotoxicity, apoptosis, inflammation, or tissue repair. The hope is that combining cooling with one or more of these would produce additive benefit beyond what cooling alone achieves. So far, that hope has not been clearly realized in large trials.

Erythropoietin (EPO): What the Research Shows

EPO is the most-studied adjunct therapy for HIE. Beyond its role in stimulating red blood cell production, it has anti-apoptotic, anti-inflammatory, and pro-angiogenic effects that are relevant to brain injury. Three successive trials shaped the current understanding.

Early phase II trial (Wu et al., 2016)

Wu and colleagues (2016, Pediatrics) reported a phase II trial of high-dose EPO added to cooling in 50 neonates with moderate-to-severe HIE. The study established the pharmacokinetics and safety of high-dose EPO in this population. Secondary analyses suggested potentially improved outcomes, though the study was not powered to detect efficacy. The results were encouraging enough to motivate a phase III trial.

HEAL trial (Wu et al., 2022, NEJM)

The HEAL trial (High-dose Erythropoietin for Asphyxia and encephaLopathy, Wu et al., 2022, New England Journal of Medicine) was the large phase III study that followed. It enrolled 501 infants at 17 U.S. NICUs between 2017 and 2021. All received cooling; half also received high-dose EPO, half received placebo. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months.

The HEAL results, published in 2022, showed no significant benefit from adding EPO: the primary outcome occurred in 52.5 percent of the EPO group and 49.5 percent of the placebo group. EPO did not reduce brain injury on MRI. It also did not appear to cause net harm. Based on HEAL, EPO is not currently recommended as a routine adjunct to cooling. Research continues on whether specific subgroups might benefit and whether different dosing or timing might change the result.

Darbepoetin alfa

Darbepoetin is a longer-acting form of EPO being evaluated in smaller trials. The rationale is that a single dose of darbepoetin could cover the full period during which neuroprotection might be needed. Early data are limited, and larger trials have not yet been reported.

Melatonin: An Antioxidant Adjunct

Melatonin, best known as a sleep regulator, is a potent antioxidant that crosses the blood-brain barrier. In HIE, oxidative stress is one of the mechanisms of secondary injury, so melatonin has been proposed as an adjunct to cooling.

Aly and colleagues (2015, Journal of Perinatology) reported a small randomized trial of 30 newborns with HIE who received either standard cooling or cooling plus melatonin. The melatonin group had lower rates of seizures and better early outcomes. A trial of this size is hypothesis-generating, not definitive. Larger confirmatory studies have been initiated but results are pending. Melatonin is inexpensive, widely available, and has a favorable safety profile, all of which would make it an attractive adjunct if a clear benefit emerges.

Xenon Gas: An NMDA Antagonist

Xenon is an inert anesthetic gas that, among other actions, blocks NMDA receptors. NMDA-mediated excitotoxicity is one of the mechanisms of hypoxic-ischemic injury, so xenon was proposed as an adjunct to cooling.

The TOBY-Xe trial (Azzopardi et al., 2016, Lancet Neurology) randomized 92 infants with HIE to cooling or cooling plus xenon. The results, published in Lancet Neurology, showed no improvement on MRI or in early clinical outcomes. Combined with the operational complexity of delivering xenon in the NICU, the TOBY-Xe results have largely ended clinical investigation of xenon as a routine HIE adjunct, although interest remains in specific research contexts.

Stem Cells and Cord Blood

Autologous umbilical cord blood cells (the baby’s own cord blood) have been studied for HIE, primarily at Duke University and a few other centers. Cotten and colleagues (2014, Journal of Pediatrics) reported a feasibility study of infusing autologous cord blood cells to 23 newborns with HIE. The study was small and designed to establish feasibility rather than efficacy, and meaningful outcomes could not be determined. Follow-up trials are ongoing.

Mesenchymal stem cells and other cell-based therapies are in earlier stages of investigation. Families should be cautious about commercial offerings that advertise stem cell treatment for HIE outside of properly-conducted clinical trials; such offerings often lack supporting evidence and may be ethically and legally problematic.

Other Investigated Therapies

Several additional therapies have been investigated with varying degrees of evidence:

None of these is part of routine HIE care. Each may be available through specific clinical trials at specific centers.

Why so many adjuncts have failed in large trials

A consistent pattern has emerged across the neuroprotection research: therapies that look promising in animal models and early human trials often do not show benefit when tested in large randomized studies. Several explanations have been proposed. First, cooling itself may already address the most salvageable injury, leaving a smaller window of benefit for any additional therapy. Second, the timing of adjunct therapies has been limited by the same 6-hour window as cooling, and some mechanisms may need even earlier intervention. Third, HIE is a heterogeneous condition, and treatments effective for one subgroup may be diluted by other subgroups in the overall trial. Fourth, preclinical animal models may not fully capture the complexity of the human newborn brain. These lessons shape how current and future trials are designed, including efforts to identify biomarkers that predict which babies are most likely to benefit from a specific therapy.

Questions to ask about clinical trial participation

If your NICU is a research center and your baby is offered enrollment in a trial, or if you want to understand why no trial was offered, useful questions include: What is the phase of the trial (phase 1 safety, phase 2 preliminary efficacy, phase 3 definitive efficacy)? What does “randomization” mean in this specific study and what are the arms? Is cooling being provided in all arms? What are the known risks of the investigational therapy? What are the preliminary results from similar trials? What is the plan for long-term follow-up after the NICU? Who do we contact if we change our mind or have questions during or after the trial? A good research team expects these questions and provides clear answers. Enrollment in a trial should always be a choice, never pressured, and declining participation should not affect standard care.

What This Means for Your Baby

The practical implications for parents of a baby with HIE:

• Cooling should be provided whenever the baby meets eligibility criteria. This is standard of care.
• Adjunct therapies are not currently standard. If your baby did not receive EPO, melatonin, xenon, or stem cells, this is consistent with current evidence.
• Some centers run clinical trials of new therapies. If a trial was offered, you would have been approached with an explicit informed consent process. If you were not offered a trial, it generally means none was available or your baby did not meet criteria.
• The evidence base is evolving. What is experimental today may become standard later. Following pediatric neurology guidance and periodically checking with your clinical team is the most reliable way to stay current.
• Be cautious of commercial offerings for stem cell therapy, hyperbaric oxygen, or other treatments marketed for HIE outside of established clinical trials. These often lack evidence and can be expensive or harmful.

Related reading for parents

• Who qualifies for therapeutic cooling? HIE eligibility criteria explained
• The 6-hour window for HIE cooling: why timing is everything
• Side effects and complications of therapeutic hypothermia in newborns
• Good outcomes after HIE: what the long-term research actually shows
• HIE without cerebral palsy: what happens to these children long-term