Bibian van der Voorn

192 CHAPTER 12 Nowadays in theNetherlands, more than 80%of very preterm(<32wks GA) newborns survive due to large improvements in perinatal care 1 . Very preterm survivors are predisposed to poor growth, unfavorable body composition, cardiovascular diseases, and impaired neurodevelopment. Therefore long-term morbidity after very preterm birth becomes more important. Adaptation of HPA axis settings to very preterm birth is suggested to partly explain these unfavorable disease risks later in life ( Chapter 1 ). Therefore, in this thesis we explored factors relevant to the early life morbidity and mortality of very preterm newborns that could influence permanent adaptation to early life stress: gender, a genetic predisposition to altered glucocorticoid sensitivity, antenatal glucocorticoid treatment, maternal perinatal stress and mother’s milk glucocorticoids. Accordingly, with the data presented in this thesis, we gained some more insights into the consecutive sequelae of person-specific predisposition, early life conditions, and later life challenges that lead to long termrisk for neurodevelopmental impairments and cardiovascular disease. Eventually, by getting a better view on these mechanisms, therapy regimes that are currently adequate for achieving the goal of survival could in the end be translated into appropriate therapy, that is adequate in early life while minimally harming the developmental outcomes in later life. PERSON-SPECIFIC PREDISPOSITION HPA axis functioning includes the maintenance of homeostasis by regulation of basal HPA axis activity, and adaptation to stressors by regulation of HPA axis reactivity. With regard to signal transduction, glucocorticoids have a high affinity for both mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs). MRs are mainly involved in basal HPA axis activity, while GRs, in coordination with MRs, are regulating HPA axis reactivity 2 . Inter-individual variation in the sensitivity of these receptors influences HPA axis functioning, and can thereby result in inter-individual variation in stress vulnerability. In Chapter 7 , we showed that genetic variations in the GR and MR resulted in a person- specific sensitivity towards endogenic glucocorticoids, i.e., reaction to the stressful event of very preterm birth, and exogenic glucocorticoids, antenatally administered. In Chapter 9 and 10 , we assessed the influence of gender on HPA axis functioning during childhood through a systematic review and meta-analysis of published literature, and showed that gender-specific differences in HPA axis activity and reactivity are already present during childhood. Thereafter, during puberty a gender- specific change in HPA axis activitywas seen. This could not be analyzedwith regard to HPA axis reactivity, due to the heterogeneity in stress protocols and the lack of data on