VANCOUVER—Erythropoietin (EPO) plus therapeutic hypothermia may reduce brain injury and improve one-year motor outcomes in neonates with hypoxic-ischemic encephalopathy (HIE), according to phase II trial results presented at the 45th Annual Meeting of the Child Neurology Society.
A large number of in vitro and in vivo studies have shown that EPO has neuroprotective effects after neonatal HIE. “Acutely, it reduces inflammation and apoptosis and improves cell survival. In the long term, it enhances brain repair through a number of mechanisms,” said Yvonne Wu, MD, MPH, Professor of Neurology and Pediatrics at the University of California, San Francisco.
Hypothermia reduces the risk of death and moderate to severe disability, including cerebral palsy; however, about 40% of infants who are cooled still have adverse outcomes, said Dr. Wu. Studies suggest that multiple doses of EPO provide optimal neuroprotection. In addition, studies in animals have shown that EPO can be neuroprotective even when given up to seven days after the hypoxic-ischemic insult.
To study the effect of EPO and hypothermia combined in neonates with moderate to severe HIE, Dr. Wu and colleagues conducted a randomized, double-blind, placebo-controlled multicenter trial. They evaluated safety, feasibility, and biomarkers of brain injury.
Researchers randomized 50 patients at seven sites to receive either 1,000 U/kg of EPO plus hypothermia or placebo plus hypothermia. Twenty-four babies were randomized to receive EPO and 26 were randomized to receive placebo. Babies received the study drug on five days during the first week of age. Investigators performed MRI on days 4 through 7. They assessed patients’ outcomes at six months and 12 months.
Babies included in the study met standard cooling criteria, including evidence of perinatal distress (eg, Apgar score of less than 5 at 10 minutes). Investigators excluded babies with a genetic disorder, congenital malformation, birth weight less than 1,800 g, microcephaly, or no indwelling line, as well as babies for whom withdrawal of care was considered or who were unlikely to be followed up at 12 months.
To assess neurodevelopmental outcomes at 12 months, researchers administered the Warner Initial Developmental Evaluation (WIDEA), a parental questionnaire that assesses four domains of infant development. In addition, they rated motor function using the Alberta Infant Motor Scale (AIMS). At 12 months, the EPOgroup had a significantly higher AIMS score and a trend toward improvement on the WIDEA score, compared with the placebo group.
Out of 24 infants receiving EPO, 23 had MRI and received three or more doses of treatment. About half of the babies received four to five doses of EPO prior to the MRI.
Researchers scored eight regions of the brain based on the extent of abnormal signal intensity. They found that the babies in the EPO-treated group had a lower median global injury score than those in the placebo group (2 vs 11). In addition, the number of patients with moderate or severe brain MRI abnormalities was lower in the EPO group (one out of 24) versus the placebo group (11 out of 26).
Researchers also noted that EPO appeared to protect the subcortical region of the brain; fewer babies in the EPO-treated group had injury to the deep gray nuclei, compared with babies who received placebo. Two babies died before hospital discharge in the EPO plus hypothermia group, and five died in the hypothermia-alone group. One baby in each group was lost to follow-up at 12 months. No adverse events were considered related to EPO treatment.
“These are small numbers, but our findings raise the possibility that EPO is really doing what we see in animals, which is reducing injury and enhancing repair, so that outcomes are better than expected hypoxic-ischemic encephalopathy,” said Dr. Wu.
Rogers EE, Bonifacio Sl, Glass HC, et al. Erythropoieten and hypothermia for hypoxic-ischemic encephalopathy. Pediatr Neurol. 2014 Aug 24 [Epub ahead of print].
Wu YW, Bauer LA, Ballard RA, et al. Erythropoietin for neuroprotection in neonatal encephalopathy: safety and pharmacokinetics. Pediatrics. 2012 Sep 24 [Epub ahead of print].
Wu YW, Mathur AM, Chang T, et al. High-dose erythropoietin and hypothermia for hypoxic-ischemic encephalopathy: a phase II trial. Pediatrics. 2016;137(6).