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Erythropoietin was no help for newborns with hypoxic-ischemic encephalopathy already undergoing therapeutic hypothermia in the phase III HEAL trial.

Combined death or neurodevelopmental impairment by 22-36 months of age was not less likely for infants randomized to the hormone rather than placebo (52.5% vs 49.5%; RR 1.03, 95% CI 0.86-1.24), according to researchers led by Yvonne Wu, MD, a neurologist at the University of California San Francisco.

Additionally, serious adverse events -- counting death, hypertension, hematocrit, thrombosis, cardiopulmonary arrest, and other unexpected life-threatening events -- were more common among infants receiving erythropoietin (mean 0.86 vs 0.67 per child; RR 1.26, 95% CI 1.01-1.57).

These results, published in the , contradict the investigators' that had suggested erythropoietin was more effective than placebo and wasn't associated with an increased risk of serious adverse events.

"These results show the importance of large clinical trials," Wu said in a press release. "Previous research indicated a protective effect from erythropoietin, but with 500 babies instead of 50, there was enough statistical power to reveal a different outcome, as well as an unexpected effect."

is a glycoprotein hormone secreted by the kidneys that stimulates the production of red blood cells in response to falling oxygen levels in the body. In some countries, a minority of hospitals reportedly to treat hypoxic-ischemic encephalopathy in infants, with or without hypothermia.

Wu's group said it is unclear why erythropoietin would be associated with more serious adverse events, as there were no significant excesses for any such event in the study -- even hypertension, thrombosis, or polycythemia, three established side effects of long-term erythropoietin use in adults.

The ongoing testing high-dose erythropoietin and therapeutic hypothermia is expected to provide more safety data in newborns.

In any case, the hormone's disappointing performance as adjuvant therapy in HEAL leaves therapeutic hypothermia as the only neuroprotective treatment for neonatal hypoxic-ischemic encephalopathy.

The condition is characterized by brain dysfunction caused by a lack of blood flow and oxygen to the brain. More than 10,000 infants each year in the U.S. suffer from hypoxic-ischemic encephalopathy, which can lead to death or lasting neurodevelopmental impairments, according to the study authors.

The multicenter, double-blind, randomized, placebo-controlled HEAL trial included 501 infants born at 36 or more weeks gestation in the U.S. Babies were eligible if they were receiving passive or active therapeutic hypothermia that had been started within 6 hours after birth and continued for 72 hours.

Over half of participating newborns were boys. Severity of encephalopathy was moderate in 77.4% and severe in 22.6% of cases.

Infants were assigned to receive either recombinant human erythropoietin (1,000 U/kg) or matched saline placebo once within 26 hours of birth, and again at 2, 3, 4, and 7 days of age.

Neurodevelopmental impairment outcomes included cerebral palsy, impaired gross motor function, and developmental delay.

Study authors acknowledged that a major limitation of the study was their inability to evaluate the usefulness of erythropoietin without therapeutic hypothermia.

"Because both hypothermia and erythropoietin may initiate similar neuroprotective pathways during the acute phase of hypoxic-ischemic injury, including reduction of apoptotic, inflammatory, and excitotoxic injury, the use of hypothermia in our trial may have reduced any potential for additional benefit from erythropoietin," Wu's team wrote.

Furthermore, they cautioned that trial data came from 17 sites in the U.S. and may not be generalizable to other parts of the world.

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