Betamethasone effects on fetal sheep cerebral blood flow are not dependent on maturation of cerebrovascular system and pituitary-adrenal axis

Abstract

Synthetic glucocorticoids are administered to pregnant women in premature labour to accelerate fetal lung maturation at a time when fetal cerebrovascular and endocrine systems are maturing. Exposure to glucocorticoids at 0.8-0.9 of gestation increases peripheral and cerebrovascular resistance (CVR) in fetal sheep. We examined whether the increase of CVR and its adverse effect on cerebral blood flow (CBF) depend on the current level of maturation of the pituitary-adrenal axis and the cerebrovascular system. Using fluorescent microspheres, regional CBF was measured in 11 brain regions before and 24 h and 48 h after the start of 3.3 microg kg(-1) h(-1) betamethasone (n = 8) or vehicle (n = 7) infusions to fetal sheep at 0.73 of gestation. Hypercapnic challenges were performed before and 24 h after the onset of betamethasone exposure to examine betamethasone effects on cerebrovascular reactivity. Betamethasone exposure decreased CBF by approximately 40% in all brain regions after 24 h of infusion (P < 0.05). The decline in CBF was mediated by a CVR increase of 111 +/- 16% in the cerebral cortex and 129 +/- 29% in subcortical regions (P < 0.05). Hypercapnic cerebral vasodilatation and associated increase in CBF were blunted (P < 0.05). Fetal CBF recovered after 48 h of betamethasone administration. There were no differences in glucocorticoid induced CBF and CVR changes compared with our previous findings at 0.87 of gestation. We conclude that the cerebrovascular effects of antenatal glucocorticoids are independent of cerebrovascular maturation and preparturient increase in activity of the fetal pituitary-adrenal axis.

Figure 1. Experimental protocol

Figure 2. Developmental changes of baseline CBF and CVR between 0.73 (white bars) and 0.87 (black bars) of gestation

Values are means ± s.e.m. n = 8 for both groups; ‡P < 0.01, †P < 0.05 in comparison of both groups.

Figure 3. Regional CBF in vehicle and betamethasone treated fetuses at baseline before and 24 and 48 h after the onset of infusion

Values are means ± s.e.m.n = 7 (vehicle) or n = 8 (betamethasone); *P < 0.05 in comparison to baseline values; ‡P < 0.01, †P < 0.05 in comparison to vehicle treated fetuses.

Figure 4. Cerebral vascular resistance (CVR) in vehicle and betamethasone treated fetuses at baseline before and 24 and 48 h after the onset of infusion

Values are means ± s.e.m.n = 7 (vehicle) or n = 8 (betamethasone); *P < 0.05 in comparison to baseline values; ‡P < 0.01, †P < 0.05 in comparison to vehicle treated fetuses.

Figure 5. Regional CBF during theP_a,CO2rise before and 24 h after the onset of vehicle or betamethasone infusion

Values are means ± s.e.m.n = 7 for vehicle treated and n = 8 for betamethasone treated fetuses; *P < 0.05 in comparison to baseline values; ^$P < 0.05 in comparison to hypercapnic flows before betamethasone treatment; †P < 0.05 in comparison to vehicle treated fetuses. Significances in CBF at 24 h of betamethasone infusion are displayed in Fig. 3 and have been omitted for clarity.

Figure 6. Cerebral vascular resistance (CVR) during theP_a,CO2rise before and 24 h after the onset of vehicle or betamethasone infusion

Values are means ± s.e.m.n = 7 for vehicle treated and n = 8 for betamethasone treated fetuses; *P < 0.05 in comparison to baseline values; ^$P < 0.05 in comparison to hypercapnia before betamethasone treatment; ‡P < 0.01, †P < 0.05 in comparison to vehicle treated fetuses. Significances in CVR at 24 h of betamethasone infusion are displayed in Fig. 4 and have been omitted for clarity.

Figure 7. Relative CBF and CVR changes in betamethasone treated fetuses at 0.73 (white bars) and 0.87 (black bars) of gestation

Values are means ± s.e.m.n = 8 for both groups; *P < 0.05 in comparison to baseline values.