Bibian van der Voorn

13 PRETERM GLUCOCORTICOID PROGRAMMING Relative adrenal insufficiency is common among very preterm infants in their first weeks of life and occurs when the HPA axis is unable to produce sufficient cortisol for the degree of illness. However, there is lack of consensus about the definition of a normal cortisol value. A cortisol level ≥15 μg/dL (i.e., ≥414 nmol/L) has been considered adequate for ill very preterm infants 29 . According to this definition, a considerable proportion fail to mount an adequate adrenocortical response to stress ( table 1 ). Still, their cortisol levels are higher than in healthy fetuses of the same postconceptional age 31 . Infants with ELBW who had a cortisol level in the upper quartile at postnatal days 5–7 were found to be at risk of brain damage 32 . Multiple levels along the HPA axis might be affected in infants born preterm ( table 1 ). First, several studies demonstrated that the pituitary response to exogenous CRH was impaired 33-36 when an adrenocorticotropin concentration of 9 pmol/L or more was considered as adequate 37 , although this was not a universal finding 38,39 . Second, many studies showed that adrenal cortex enzymes were immature, and decreased 11β-hydroxylase activity was suggested to be the most important rate-limiting step 28,29,40-42 . Third, one study suggested that the interconversion between cortisol and cortisone favored cortisone with decreasing gestational age 43 . In infants born very preterm or with VLBW who experienced vasopressor-resistant hypotension, hydrocortisone or dexamethasone successfully enabled discontinuation of inotropics 44,45 . Prophylactic glucocorticoids for prevention of hypotension were shown to be effective too in extremely preterm infants (i.e., <28 wks of gestation) 46 . In infants born very preterm or with VLBW who experienced vasopressor-resistant hypotension, hydrocortisone or dexamethasone successfully enabled discontinuation of inotropics 44,45 . Prophylactic glucocorticoids for prevention of hypotension were shown to be effective too in extremely preterm infants (i.e., <28 wks of gestation) 46 . Similarly, extremely preterm infants exposed prenatally to synthetic glucocorticoids for fetal lung maturation had a lower likelihood of becoming hypotensive in the first days after birth 47 . In addition, in a study among preterm infants, proinsulin, insulin and C-peptide levels in cord blood remained elevated up to 48 h after the last steroid dose, in spite of a normal glucose concentration, suggestive of insulin resistance 48 . This might offer protection against neuroglycopenia. Consistent with these observations, the glucocorticoid bioactivity of a single treatment course of betamethasone was found to wear off 1–2 days after the last steroid dose 49 . From these data, it could be inferred that increased glucocorticoid bioactivity offers short-term benefits. Among infants with VLBW, the adrenocortical response to exogenous CRH rose significantly between postnatal days 7 and 14 50 . The improvements were more marked for the group with hypotension necessitating inotropic treatment. The infants within it were also more premature and exhibited greater disease severity scores, suggesting that postnatal adversities could lead to