Bibian van der Voorn

123 EARLY LIFE GROWTH ON CORTISOL AFTER PREMATURITY INTRODUCTION In infants born very preterm ,i.e., born at a gestational age ≤32 wks, the HPA axis is not yet fully maturated. Relative adrenal insufficiency is common in this group during the first weeks of life, and is characterized by relatively low basal and stress- induced cortisol levels, and increased risks of hypotension, hypoglycemia and bronchopulmonary dysplasia 2-5 . This is partly attributable to the sudden disruption of the maturation of the fetal HPA axis, which in full-term pregnancies is stimulated in the third trimester by an increase in the secretion of placental CRH and alterations in the expression of 11βHSD type 2 by the placenta 2 . Conversely, there is some evidence suggesting that HPA axis activity is upregulated years after preterm birth 3 , which might contribute to the association between prematurity and long-term sequelae like cardiometabolic diseases and neurodevelopmental impairments. Little is knownabout the impact of intrauterine andearly-postnatal growthpatterns on these associations in preterm infants. Intrauterine growth restriction is accompanied by a reduced expression and activity of the placental barrier enzyme 11Βhsd type 2, which converts cortisol to inert cortisone 6 . The subsequent fetal overexposure to maternal cortisol has been suggested to permanently alter HPA axis settings 7 , initially by suppressing the axis, followed by increased activity later in life. This is strengthened by animal studies suggesting that the presence of abundant glucocorticoids in-utero, could result in a reduced expression of glucocorticoid receptors in tissues, and thereby, a compensatory upregulation of HPA axis activity 8-10 . Moreover, animal studies suggest that fetal growth restriction as well as early- postnatal growth restriction may predispose to cardiometabolic diseases later in life. Also, rapid postnatal growth after being born with a low birth weight has been associated with cardiometabolic disease risk, and alterations in HPA axis functioning have been suggested to explain these associations 10,11 . In term born subjects, there are few studies that have explored whether the HPA axis could explain part of the association between low birth weight and cardiometabolic disease 1,12 . In preterm born infants, rapid early-postnatal and childhood growth have been associated with risks of cardiometabolic diseases 13,14 , but their relation with HPA axis activity throughout the lifespan has never been described. To study the development of HPA axis activity after preterm birth in association with intrauterine and early-postnatal growth, we assessed cortisol levels of infants who were born very preterm and/or with a very low birth weight (≤1,500g), from term age until the age of 8 y.