Kim Annink

16 Chapter 1 reduces apoptosis and necrosis, leads to a lower metabolism in the brain and reduces the production and uptake of glutamate, NO and free radicals (31,32). Multiple clinical trials have demonstrated that therapeutic hypothermia is neuroprotective in HIE by further reducing the incidence of death and neurodevelopmental disabilities at 18-24 months of age, e.g. Azzopardi et al. showed that cooling improved survival without neurodevelopmental problems from ~30% to ~45% (1,33–37). Jacobs et al. conducted a systematic Cochrane review including 11 RCT’s investigating the neuroprotective effect of therapeutic hypothermia in 1505 infants with HIE with a gestational age of 35 weeks and more (31). Therapeutic hypothermia reduced the composite outcome of mortality and severe neurodevelopmental problems at 18 months of age with a relative risk of 0.75 and a number needed to treat of 7 (31). Mortality alone was also decreased in the hypothermia group with a number needed to treat of 11 and a relative risk of 0.75 (31). There was also less CP in the infants with HIE in the hypothermia group that survived with a relative risk of 0.66 and number needed to treat of 8 (31). There are possible risks of therapeutic hypothermia, such as subcutaneous fat necrosis, bradycardia, hypotension, thrombocytopenia and possibly pulmonary hypertension (31,38,39). However, the benefits on neurocognitive outcome outweigh these risks (30,31). Long-term neurodevelopmental prognosis While 18 to 24 month outcome improved since the introduction of therapeutic hypothermia, less is known about the neurodevelopment of infants with HIE at school-age. Even though infants seem to be developing well at two years of age, children might still evolve problems at school-age (40). Therefore, long-term follow- up is essential in children with HIE. Our research group reported earlier that before therapeutic hypothermia became standard of care, children with HIE without CP that survived also showed significantly more memory and behavioral problems at ten years of age than healthy controls (41,42). Even children with mild HIE had more memory problems at school-age compared to controls (41). So far, it was unclear what type of brain injury led to these memory problems. Gadian et al. showed that the hippocampus is an important brain structure for memory and cognition and is also very vulnerable to hypoxic-ischemia