Glucocorticoid Exposure in Preterm Babies Predicts Saliva Cortisol Response to Immunization at 4 Months

Abstract

Preterm babies are exposed to multiple stressors and this may have long-term effects. In particular, high levels of endogenous cortisol might have a programming effect on the hypothalamicpituitary-adrenal axis as may administered glucocorticoids. In this study, we aimed to test the hypothesis that the level of endogenous and exogenous glucocorticoid exposure during the neonatal period predicts the saliva cortisol response to immunization at 4 mo of age. We followed 45 babies born below 32 wk gestation. We showed that their concentration of plasma cortisol during the first 4 wk was 358, 314, 231, and 195 nmol/L cortisol, respectively (geometric mean). This is four to seven times higher than fetal levels at the same gestational age range. We used routine immunization at 4 mo and 12 mo as a stressor and measured the change in saliva cortisol as the stress response. Mean circulating cortisol in the first 4 wk predicted the cortisol response at 4 but not at 12 mo. Path analysis showed that birthweight for gestational age, therapeutic antenatal steroids, and therapeutic postnatal steroids also contributed to the magnitude of the saliva cortisol response at 4 mo. There is considerable evidence from animal experiments that early exposure to stress, either in the antenatal or in the immediate postnatal periods, can have long term effects on both the function of the HPA axis, and on behavior (1-5). In general, the HPA axis of the offspring becomes hyperresponsive to a novel stressor. These effects are mediated, at least in part, by activation of the maternal HPA axis and the effect of fetal cortisol or corticosterone (in rodents) on the developing brain. These effects can, in some paradigms, be mimicked by synthetic glucocorticoids (6 -8). Until recently, this has been little studied in humans. It does appear that cortisol from the mother crosses the placenta in sufficient amounts to affect the fetus (9,10), although there is so far no direct evidence that maternal cortisol alters infant development. However, there is increasing evidence from epidemiologic studies that maternal stress and anxiety during pregnancy has an adverse effect on the development of the fetus and on the later behavior and cognitive development of the child (11-16).Preterm babies are exposed both to a stressful environment, with concomitant endogenous glucocorticoid release, and may also be exposed, antenatally and postnatally, to exogenous glucocorticoids used therapeutically. If the animal models are relevant, one would predict that these infants would show long-term effects, both in HPA axis response and in behavior. Babies born extremely preterm are at risk of later behavioral problems, most noticeably with attention deficit disorders (17). Recent evidence suggests that antenatal glucocorticoid exposure has long-term effects on brain development (18). Davis et al. (19) have shown preterm babies exposed to antenatal betamethasone had a lower saliva cortisol response to a heel stick than matched controls at 3-6 d after delivery. ABSTRACT1233 c...

Effects of Antenatal Corticosteroids on Cortisol and Heart Rate Reactivity of Preterm Infants

“…Ashwood et al found that 38% of preterm infants receiving a single course of GCs had a suppressed cortisol response, while 68% of infants receiving a repeat course showed suppression. The only other study of which we are aware found that antenatal GCs predicted a suppressed cortisol response at 4 months postnatal in response to immunization (Glover, Miles, Matta, Modi, & Stevenson, 2005). These consistent findings of suppression among GC-exposed preterm infants could stem from enhanced negative feedback on the HPA axis as a result of fetal GC exposure and/or increased tissue sensitivity to GCs (Harris & Seckl, 2011).…”

Cortisol stimulates system A amino acid transport and SNAT2 expression in a human placental cell line (BeWo)

“…Both fetal and maternal serum levels of cortisol increase during gestation and can vary from 20 to 50 nM in the fetal and 200 to 800 nM in the maternal circulations (8,11). Under stress, this can increase two-to threefold (28), and increased cortisol has been associated with problems in fetal growth (7), leading to irreversible reprogramming of the hypothalamic-pituitary-adrenal axis.…”

“…In humans, SNAT1 is expressed predominantly in the brain and the placenta (35). SNAT2 shows ubiquitous tissue expression (11) and is associated with the adaptive regulation seen in system A transport under nutritional challenge (9). SNAT4 is predominantly expressed in liver and skeletal muscle (35), with some expression in the human placenta (5).…”

Prenatal origins of adult disease

“…If exposure to androgen occurred 15 days later, near weaning, there was no persistent effect on reproduction. More recent animal studies have focused on poor nutrition in fetal life (for example, isocaloric low-protein diets [31], global nutrient restriction [32,33], and reduced uterine blood flow [34]), maternal stress (in rhesus monkeys [35,36] and pigs [37]) and exposure to various pharmacological agents (such as antenatal glucocorticoids [38][39][40][41]). Other studies compare outcomes resulting from insults during fetal life with insults occurring during early postnatal life [42,43].…”