Effects of repeated maternal betamethasone administration on growth and hypothalamic-pituitary-adrenal function of the ovine fetus at term

Synthetic glucocorticoids have become an important clinical tool with which to advance fetal lung maturation in women at risk of early preterm birth, and this has succeeded in reducing neonatal mortality and morbidity from re spiratory distress syndrome. Although previous studies have shown that gluc ocorticoids have deleterious consequences on fetal development, there is li ttle information regarding the effects of clinically relevant repeated mate rnal doses of glucocorticoids on fetal growth and hypothalamic-pituitary-ad renal (HPA) function. We hypothesised that repeated prenatal exposure to in creased concentrations of glucocorticoids would alter fetal growth and HPA axis development. Pregnant ewes were injected with betamethasone (0.5 mg/kg ) or vehicle at 104, 111 and 118 days of gestation (term 150 days). Animals were sacrificed at 125 and 146 days of gestation, at which time fetal weig hts were recorded. Maternal and fetal blood samples were gathered and fetal tissue collected. Maternal oestradiol concentrations were significantly gr eater than those in controls at 125 days of gestation, but were not differe nt at 146 days. Maternal plasma progesterone concentrations were similar be tween groups at both 125 and 146 days of gestation. Weight at birth was sig nificantly reduced by 23% at 125 days and 19% at 146 days of gestation (P < 0.05) after exposure to glucocorticoid. Cord plasma ACTH concentrations we re not significantly different between groups at day 125, but were signific antly increased in day 146 fetuses of ewes that had received betamethasone (P < 0.05). Cord plasma cortisol concentrations followed the same trend, al though differences were not statistically significant. Cord plasma corticos teroid binding capacity (CBC) was significantly increased at 125 days of ge station in fetuses of betamethasone-treated animals (P < 0.05), but not at 146 days of gestation. To examine the mechanisms regulating the increase in cord plasma ACTH of 146-day fetuses, we used in situ hybridisation to dete rmine the distribution and levels of mRNA encoding key pituitary and hypoth alamic neuropeptides of the HPA axis. In pituitaries of 146-day fetuses, th ere were no significant differences in the regional pattern of distribution or amounts of pro-opiomelanocortin (POMC) mRNA between betamethasone-treat ed animals and controls, in either the pars intermedia or the inferior and superior regions of the pars distalis. Neither prohormone convertase (PC)-1 nor PC-2 mRNA levels in pituitaries of 146-day fetuses were significantly different between treatment groups. After maternal betamethasone, immunorea ctive ACTH peptide content in the fetal pars distalis was not different but glucocorticoid receptor (GR) mRNA levels in the pars distalis were increas ed significantly (P < 0.05). No significant difference in distribution patt ern or concentrations of corticotrophin-releasing hormone (CRH) mRNA, GR mR NA, oxytocin mRNA and pre-proenkephalin mRNA were found in hypothalami from fetuses at 146 days of gestation after betamethasone treatment. We conclud e that antenatal betamethasone given to pregnant sheep in a manner similar to that used in human obstetric practice results in reduced weight at birth at 125 and 146 days, and altered basal cord levels of plasma ACTH and cort icosteroid binding capacity, but these changes are not reflective of change s in steady state: concentrations of POMC and CRH mRNA in the fetal pituita ry or hypothalamus.