The potential of erythropoietin to treat asphyxia in newborns

Abstract

Perinatal asphyxia is a cause of significant neonatal morbidity worldwide. Lack of oxygenation and perfusion to the neonatal brain leads to energy failure and cell death. Currently, therapeutic hypothermia is the standard of care for term infants with hypoxic-ischemic encephalopathy, but as it has shown only modest effects on survival and morbidity, additional neuroprotective agents are needed. Erythropoietin has been extensively studied as a neuroprotective agent for infants who suffer a hypoxic-ischemic brain injury. It has multiple mechanisms of action, in both preventing cell death and promoting tissue repair. Studies have progressed over time from in vitro to in vivo studies, first in animals and now in humans, with several Phase I/II trials completed and Phase III trials underway. As therapeutic hypothermia has become the standard of care in treating term infants with hypoxic-ischemic encephalopathy, studies must now evaluate other neuroprotective agents, including erythropoietin, used in concert with therapeutic hypothermia. Erythropoietin has shown promise as a neuroprotective agent in animal and human models, both alone and together with hypothermia. Perinatal asphyxia Lack of oxygen and tissue perfusion in the perinatal period can lead to neonatal hypoxic-ischemic encephalopathy (HIE), which occurs in one to three/1,000 live births in developed countries. 1 In 2008, it was estimated that birth asphyxia caused between 563,000 and 997,000 deaths worldwide, 9% of all deaths in children younger than 5 years of age. 2 Recently, therapeutic hypothermia has proven to be effective at improving mortality and neurodevelopmental outcomes in infants with moderate-to-severe HIE. 3,4 However, even with therapeutic hypothermia, HIE still causes significant morbidity and mortality, with approximately 48% of infants dying or having major neurodevelopmental disability at 18 months of age. 4 Additional interventions are clearly needed to further improve outcomes, and these must be tested in the context of therapeutic hypothermia. Mechanisms of brain injury Perinatal asphyxia results from disruption in cerebral perfusion and oxygenation, often caused by an interruption in blood flow and gas exchange across the placenta. The resulting brain injury is characterized by an evolving process, which spans the period of initial interruption of blood flow through the period of recovery after reperfusion. The first phase occurs during the period of decreased oxygen delivery to the infant. The body must switch to anaerobic metabolism, resulting in significantly less adenosine