Fetal cardiovascular, metabolic and endocrine responses to acute hypoxaemia during and following maternal treatment with dexamethasone in sheep

Abstract

In sheep, direct fetal treatment with dexamethasone alters basal cardiovascular function and the cardiovascular response to acute hypoxaemia. However, in human clinical practice, dexamethasone is administered to the mother, not to the fetus. Hence, this study investigated physiological responses to acute hypoxaemia in fetal sheep during and following maternal treatment with dexamethasone in doses and at dose intervals used in human clinical practice. Under anaesthesia, 18 fetal sheep were instrumented with vascular and amniotic catheters, a carotid flow probe and a femoral flow probe at 118 days gestation (term ca 145 days). Following 6 days recovery at 124 days gestation, 10 ewes received dexamethasone (2 x 12 mg daily i.m. injections in saline). The remaining animals were saline-injected as age-matched controls. Two episodes of hypoxaemia (H) were induced in all animals by reducing the maternal F(IO2)for 1 h (H1, 8 h after the second injection; H2, 3 days after the second injection). In fetuses whose mothers received saline, hypoxaemia induced significant increases in fetal arterial blood pressure, carotid blood flow and carotid vascular conductance and femoral vascular resistance, significant falls in femoral blood flow and femoral vascular conductance and transient bradycardia. These cardiovascular responses were accompanied by a fall in arterial pH, increases in blood glucose and blood lactate concentrations and increased plasma concentrations of catecholamines. In fetuses whose mothers were treated with dexamethasone, bradycardia persisted throughout hypoxaemia, the magnitude of the femoral vasoconstriction, the glycaemic, lactacidaemic and acidaemic responses and the plasma concentration of neuropeptide Y (NPY) were all enhanced during H1. However, during H2, all of these physiological responses were similar to saline controls. In dexamethasone fetuses, the increase in plasma adrenaline was attenuated during H1 and the increase in carotid vascular conductance during hypoxaemia failed to reach statistical significance both during H1 and during H2. These data show that maternal treatment with dexamethasone in doses and intervals used in human obstetric practice modified the fetal cardiovascular, metabolic and endocrine defence responses to acute hypoxaemia. Furthermore, dexamethasone-induced alterations to these defences depended on whether the hypoxaemic challenge occurred during or following maternal dexamethasone treatment.

Figure 1. Fetal: maternal blood glucose ratio during H1 and H2 in saline- and dexamethasone-treated animals

Arterial blood samples were collected at 15 (N15) and 45 min (N45) of normoxia (baseline), at 15 (H15) and 45 min (H45) of hypoxaemia, and at 15 (R15) and 45 min (R45) of recovery during H1 and H2. Values are means ± s.e.m. for saline- (□, n = 8) and dexamethasone- (▪, n = 10) treated ewes and their fetuses. Statistical differences are P < 0.05: a, normoxia versus hypoxaemia or recovery; b, saline versus dexamethasone ewes (two way RM ANOVA with Tukey's test).

Figure 2. Cardiovascular responses during H1 in the carotid and femoral vascular beds in saline and dexamethasone fetuses

Fetal ascending aortic blood pressure, descending aortic blood pressure, heart rate, carotid blood flow, carotid vascular conductance, femoral blood flow and femoral vascular resistance during acute hypoxaemia (H1) during maternal dexamethasone treatment. Values represent either mean changes from baseline ± s.e.m. calculated every minute during 1 h of normoxia, 1 h of hypoxaemia and 1 h of recovery (line graph) or the mean ± area under the curve for each hour of the experimental protocol (bar graphs) in saline (○; H1: n = 6, H2, n = 5) or dexamethasone (•; H1: n = 6, H2: n = 6) fetuses. Statistical differences are P < 0.05: a, normoxia versus hypoxaemia or recovery; b, saline versus dexamethasone ewes (area under the curve; two way RM ANOVA with Tukey's test).

Figure 3. Cardiovascular responses during H2 in the carotid and femoral vascular beds in saline and dexamethasone fetuses

Fetal ascending aortic blood pressure, descending aortic blood pressure, heart rate, carotid blood flow, carotid vascular conductance, femoral blood flow and femoral vascular resistance during acute hypoxaemia (H2) following maternal dexamethasone treatment. Values represent either mean changes from baseline ± s.e.m. calculated every minute during 1 h of normoxia, 1 h of hypoxaemia and 1 h of recovery (line graph) or the mean ± s.e.m. area under the curve for each hour of the experimental protocol (bar graphs) in saline (○; H1: n = 6, H2, n = 5) or dexamethasone (•; H1: n = 6, H2: n = 6) fetuses. Statistical differences are P < 0.05: a, normoxia versus hypoxaemia or recovery (area under the curve; two way RM ANOVA with Tukey's test).

Figure 4. Plasma concentrations of adrenaline, noradrenaline and NPY during H1 and H2 in saline and dexamethasone fetuses

Arterial blood samples were collected at 15 (N15) and 45 min (N45) of normoxia (baseline), at 15 (H15) and 45 min (H45) of hypoxaemia, and at 45 min (R45) of recovery during H1 and H2. Values are means ± s.e.m. for fetuses of saline- (○; n = 6) and dexamethasone- (•; n = 6) treated ewes. Statistical differences are P < 0.05: a, normoxia versus hypoxaemia or recovery; b, saline versus dexamethasone ewes (two Way RM ANOVA and Tukey's test).