Kim Annink

10 Chapter 1 GENERAL INTRODUCTION Adverse events around birth can have major life-long consequences. The most important cause of morbidity and mortality in term born neonates is perinatal asphyxia (1,2). Perinatal asphyxia (PA) is defined as an oxygen deprivation around birth and can be caused by several perinatal events, such as placental abruption or umbilical cord prolapse (3). PA can lead to brain injury; hypoxic-ischemic encephalopathy (HIE) refers to early clinical symptoms of impaired neurological functions. PA can also result in hypoxic injury of other organ systems causing cardiac ischemia, hepatic failure or acute tubule necrosis (4). The incidence of HIE varies between 1 to 2 per 1000 term born infants in high income countries and 4 to 26 per 1000 term born infants in middle and low income countries (2). According to the World Health Organization this results in an estimated 1.15 million neonates with newly developed HIE per year and a mortality of 287,000 infants with HIE per year worldwide (2). So, HIE is a major health care problem affecting many neonates and their parents each year. Pathophysiology of HIE Brain injury after acute PA is caused by neuronal and glial cell damage that develops in two stages in infants with HIE: acute injury and reperfusion injury (5,6). The acute period of (fetal) hypoxia around birth may lead to immediate neuronal and glial cell injury by primary energy failure. This primary energy failure increases glutamate release activating the N-methyl D-aspartate (NMDA) receptors which leads to failure of the Na-K-ATPase pump. This results in calcium influx into neuronal cells with subsequent cell death. Next to this immediate cell death, (fetal) hypoxia also leads to lower pH levels in the cell and to the production of pro-radicals such as non- protein-bound iron. Furthermore the hypoxia-induced degradation of adenosine triphosphate (ATP) leads to high levels of adenosine and subsequently to formation of hypoxanthine (5,7,8). See Figure 1. Upon birth reoxygenation and reperfusion of the brain, in combination with accumulation of the pro-radicals and hypoxanthine, results in a second peak of brain injury, the so-called reperfusion injury (5). The reaction between pro-radicals and now sufficiently available oxygen causes activation of different molecular pathways leading to free radical formation. The accumulated hypoxanthine in combination