Maternally Administered Dexamethasone at 0.7 of Gestation Suppresses Maternal and Fetal Pituitary and Adrenal Responses to Hypoxemia in Sheep

Abstract

Women who are at risk of preterm delivery are treated with antenatal steroids to facilitate fetal lung maturation. During this period, there is a potential for fetal or maternal hypoxemia to occur. Fetal responses to hypoxemia in sheep are well documented. However, less is known regarding maternal responses to hypoxemia. Therefore, we determined the effects of dexamethasone (DM) on maternal and fetal responses to hypoxemia in sheep. Ewes received four i.m. injections of DM or saline at 12-h intervals beginning at 103 d of gestation. Samples for ACTH, cortisol, and glucose were collected at 0900 h. At 105 d of gestation, hypoxemia was induced for 1 h by maternal nitrogen gas inhalation. Samples for ACTH, cortisol, and glucose were collected at 15-min intervals before, during, and after the hypoxemia challenge. Fluorescent microspheres were administered to the mother and the fetus before and during hypoxemia to measure organ perfusion. DM suppressed basal fetal and maternal cortisol and ACTH concentrations but increased glucose levels. DM also increased fetal but not maternal blood pressure. In control subjects, hypoxemia elevated fetal and maternal cortisol and ACTH concentrations. These responses were obliterated by DM. Hypoxemia increased blood pressure in DM-exposed fetuses but not in control subjects. In addition, hypoxemia decreased fetal adrenal vascular resistance in saline but not DM fetuses or ewes from either treatment group. In summary, maternal administration of a low dose of DM at 0.7 of gestation suppresses maternal and fetal adrenal function and changes fetal responses to hypoxemic stress to resemble those observed later in gestation. Administration of synthetic glucocorticoids, such as betamethasone and dexamethasone (DM), to accelerate fetal lung maturation has become a routine treatment for women who are at risk of preterm labor (1, 2). This treatment is designed to elevate fetal plasma glucocorticoid levels, mimicking the maturational effects that normally occur close to term in humans and other species produced by the endogenous prepartum increases in fetal plasma cortisol (3-6). Prophylactic antenatal glucocorticoid treatment has resulted in a significant decrease in preterm infant morbidity and mortality (1,(7)(8)(9)(10)(11)(12).Despite the clear benefits of antenatal maternal glucocorticoid therapy, unwanted effects on organ systems other than the lung have been identified in both clinical human and research animal studies. For instance, exogenous glucocorticoid use has been associated with reduced weight and head circumference in infants at birth (7,13,14). In addition to the effects on fetal growth, antenatal glucocorticoid treatment administered to fetal sheep in the last third of gestation increases fetal blood pressure (BP) (15)(16)(17)(18)(19). Repeated maternal betamethasone administration in sheep also suppresses neuroendocrine and adrenal responsiveness in the preterm newborn lamb (20,21).Responses to acute hypoxemia in fetal sheep Ͼ120 d of gestation (dGA) are well established (22...

Maternal dexamethasone treatment in late gestation induces precocious fetal maturation and delivery in healthy Thoroughbred mares

“…Dexamethasone, which readily crosses the placenta, binds to glucocorticoid receptors (GR) in the fetal pituitary, hypothalamus and hippocampus, thereby decreasing negative feedback of the HPA pathway leading to low cortisol concentrations (Bertram and Hanson 2002). Suppression of cortisol, or blunted adrenal responses, also occurs in offspring of other species following maternal glucocorticoid treatment (Kutzler et al 2004;Davis et al 2006;Kranendonk et al 2006). In the present study, attenuated adrenocortical function may also have contributed to the lethargy observed in one of the foals and could have implications for the use of dexamethasone in a clinical setting (see below).…”

“…Dexamethasone, which readily crosses the placenta, binds to glucocorticoid receptors (GR) in the fetal pituitary, hypothalamus and hippocampus, thereby decreasing negative feedback of the HPA pathway leading to low cortisol concentrations (Bertram and Hanson 2002). Suppression of cortisol, or blunted adrenal responses, also occurs in offspring of other species following maternal glucocorticoid treatment (Kutzler et al . 2004; Davis et al .…”

Developmental consequences of antenatal dexamethasone treatment in nonhuman primates

“…Because rodents are typically viewed as 'corticoid-sensitive' species, and their newborn pups are extremely immature at birth, the immediate relevance of the rat and mouse models has sometimes been questioned. However, similar types of adverse effects, including an influence of physical growth and suppression of maternal and fetal adrenal activity, have also been observed in sheep [8,39,40]. The alterations in sheep are a little more surprising because high maternal cortisol levels play such an important role in the normal physiology of their pregnancy and parturition.…”

The critical importance of the fetal hypothalamus-pituitary-adrenal axis

“…Circulating concentrations of cortisol in the human and in other species, such as the sheep, are naturally increased in the latter half of pregnancy 65 – 67 . Stress, as previously discussed, further elevates the concentration of cortisol 68 , 69 . But the fact that the normal set point for cortisol is increased in pregnancy raises the question of why this occurs and whether there are species differences with regard to mechanism 68 .…”