Kim Annink

134 Chapter 6 Memory and behavioral problems are often not recognized until school-age, emphasizing the need for long-term follow-up. Hayes et al. confirmed that children with HIE show more problems at the age of 42 months and above in domains of attention, memory and behavior than was expected based on the 2 year assessment with the Bayley-III (34). Furthermore, it has been reported that one third of the cooled infants without CP still experienced motor problems at the age of 6 to 8 years that were not recognized during the regular 18 month examination (35). Clinicians should realize, that even with a normal 18-24 month follow-up, deficits can still become apparent at school-age. This study has several limitations. First of all, as mentioned before, the study design is not randomized and does not allow us to draw conclusions about the effect of therapeutic hypothermia at school-age. Also, no data of healthy controls were available for comparison. Secondly, a bias in screening and inclusion criteria might have resulted in slightly different groups. Lactate and Apgar scores suggest that the HT group was more severely affected than the non-HT group. Thompson scores were not conducted in the non-HT group, but the patient files were studied to ascertain that infants would have fulfilled the hypothermia criteria. Furthermore, numbers about neonatal death are difficult to compare, since in the hypothermia era all infants born in level II hospitals that fulfilled hypothermia criteria were transferred to the level III hospitals and before 2008 one cannot exclude that infants who were in a very poor neurological condition were not transferred to the level II hospital and may have died in the level II hospitals. Lastly, the brain volumes were highly correlated. This made it impossible to include different brain volumes in a model and determine which brain volume is most associated with different outcome measures. This may be solved by principal component analysis in future larger studies. This study has multiple implications for clinical care and follow-up of infants with HIE. First of all, therapeutic hypothermia does decrease neonatal death, CP, and epilepsy, but does not sufficiently protect the brain to prevent cognitive and memory problems at school-age. Different add-on therapies are currently being investigated in larger trials (36), which hopefully help to further improve long-term neurodevelopmental outcome. Furthermore, early atrophy of the MB is strongly predictive for long-term outcome and easy to assess. This might be an early indicator for long-term cognitive outcome, also in infants who are treated with therapeutic hypothermia. Finally, this study underlines the importance of long-