Kim Annink

106 Chapter 5 on IQ and memory analyzed with multivariable linear regression has not been investigated in HIE before, but has been tested in other neonatal populations. In congenital heart diseases, smaller hippocampal volumes were strongly associated with impaired IQ, verbal and working memory (29) and in ECMO survivors with verbal long-term memory which is a subfield of long-term episodic memory (32). It is of interest that there seems to be an association between hippocampal volumes and memory in different neonatal groups experiencing hypoxia, but that the affected subfields differ. Some limitations need to be addressed. Although this is the largest study investigating the effect of HIE on hippocampal volumes, the sample size was too small to perform multivariable linear regression in HIE1 and HIE2 separately. In addition, no severely affected children were included, because they either died in the neonatal period or were too severely impaired to be part of the study. The association between hippocampal damage, HIE and memory might be even stronger including this subgroup. Further, segmentation with Freesurfer has some limitations that might influence the quality of the segmentation: Freesurfer uses T1-weighted images that have less contrast between grey and white matter than T2-weighted images and the automated segmentation method is based on the resolution of 3.0 Tesla images instead of the 1.5 Tesla images that were used (39). Segmentation of images with less contrast or a lower resolution might influence the quality of the segmentation. Based on the quality of the scans it was not feasible to measure the volumes of specific subregions of the hippocampus and to relate these to the different memory fields. The segmentation of subregions might have given additional information, since the posterior subregion of the hippocampus might be more important for episodic memory than the anterior subregion (40). Furthermore, previous studies have shown that hippocampal volumes segmented by Freesurfer are larger than manual segmentations (41). However, automatic segmentation with Freesurfer is better reproducible and if the volume of the hippocampus is overestimated, this applies to all three groups so that it remains feasible to compare the groups. This study shows that children with mild and moderate HIE can experience long- term episodic memory problems, which is associated with hippocampal damage. If hippocampal volumes can be measured in infancy, we may be able to use these measurements to predict memory problems, and intervene at a younger