Literature

Clinical Pearls & Morning Reports


By Carla Rothaus

Published July 13, 2022

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Did the addition of erythropoietin to therapeutic hypothermia reduce the incidence of newborn death or neurodevelopmental impairment in the trial by Wu et al.?

Wu et al. conducted a phase 3 double-blind, randomized, placebo-controlled trial to determine the safety and efficacy of high doses of erythropoietin in conjunction with therapeutic hypothermia for neuroprotection in newborn infants with moderate or severe hypoxic–ischemic encephalopathy. Read the NEJM Original Article here.

Clinical Pearls

Q: How common is neonatal hypoxic–ischemic encephalopathy?  

A: Neonatal hypoxic–ischemic encephalopathy refers to neurologic dysfunction resulting from a reduction of oxygen and blood flow to a fetus’s brain near the time of birth and is an important cause of brain injury in term and near-term infants. Hypoxic–ischemic encephalopathy affects more than 10,000 infants each year in the United States (1 to 3 per 1000 births) and accounts for 22% of neonatal deaths worldwide. Therapeutic hypothermia is the only neuroprotective therapy that improves neurodevelopmental outcomes in large trials involving humans; however, up to 40% of infants who received this therapy during a clinical trial either died or had long-term disabilities, including cerebral palsy and intellectual impairment.

Q: How much evidence to date supports the use of erythropoietin for neonatal hypoxia–ischemia?

A: Recombinant human erythropoietin, a cytokine with neuroprotective and neuroregenerative effects in preclinical models of neonatal hypoxia–ischemia, has been proposed as a potential adjuvant therapy for neonatal hypoxic–ischemic encephalopathy. However, evidence supporting the use of erythropoietin for neonatal neuroprotection is limited by the small size and short follow-up period of previous studies.

Morning Report Questions 

Q: Did the addition of erythropoietin to therapeutic hypothermia reduce the incidence of death or neurodevelopmental impairment in the trial by Wu et al.?

A: The authors found that multiple high doses of erythropoietin given with therapeutic hypothermia to term and near-term newborn infants with moderate or severe hypoxic–ischemic encephalopathy did not significantly affect the incidence of death or neurodevelopmental impairment at 2 to 3 years of age. Death or neurodevelopmental impairment at 22 to 36 months of age occurred in 126 of 240 children (52.5%) in the erythropoietin group and in 110 of 222 children (49.5%) in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P=0.74). Furthermore, infants who received erythropoietin were more likely to have at least one serious adverse event and had a greater number of serious adverse events than those who received placebo. These findings contrast with those of small trials in which erythropoietin appeared both safe and effective. 

Q: Describe some of the limitations of this trial.

A: The authors were unable to address the usefulness of erythropoietin in the absence of therapeutic hypothermia, such as in low- and middle-income countries where hypothermia is unavailable or ineffective, or in infants with milder forms of hypoxic–ischemic encephalopathy. The patient sample was representative of infants with hypoxic–ischemic encephalopathy in the United States, but trial findings are generalizable only to the population of infants with hypoxic–ischemic encephalopathy in this country.

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