Effects of betamethasone administration to the fetal sheep in late gestation on fetal cerebral blood flow

Abstract

Glucocorticoid administration to women at risk of preterm delivery to accelerate fetal lung maturation has become standard practice. Antenatal glucocorticoids decrease the incidence of intraventricular haemorrhage as well as accelerating fetal lung maturation. Little is known regarding side effects on fetal cerebral function. Cortisol and synthetic glucocorticoids such as betamethasone increase fetal blood pressure and femoral vascular resistance in sheep. We determined the effects of antenatal glucocorticoid administration on cerebral blood flow (CBF) in fetal sheep. Vehicle (n= 8) or betamethasone (n= 8) was infused over 48 h via the jugular vein of chronically instrumented fetal sheep at 128 days gestation (term 146 days). The betamethasone infusion rate was that previously shown to produce fetal plasma betamethasone concentrations similar to human umbilical vein concentrations during antenatal glucocorticoid therapy. Regional CBF was measured in 10 brain regions, using coloured microspheres, before and 24 and 48 h after onset of treatment, and during hypercapnic challenges performed before and 48 h after onset of betamethasone exposure. Betamethasone exposure decreased CBF in all brain regions measured except the hippocampus after 24 h of infusion (P < 0·05). The CBF decrease was most pronounced in the thalamus and hindbrain (45–50 % decrease) and least pronounced in the cortical regions (35–40 % decrease). It was mediated by an increase in cerebral vascular resistance (CVR, P < 0·05) and led to a decrease in oxygen delivery to subcortical and hindbrain structures of 30–40 %, to 8·6 ± 1·1 ml (100 g)−1 min−1, and 40–45 %, to 11·0 ± 1·6 ml 100 g−1 min−1, respectively (P < 0·05). After 48 h of betamethasone treatment, the reduction in CBF was diminished to about 25–30 %, but was still significant in comparison to vehicle‐treated fetuses in all brain regions except three of the five measured cortical regions (P < 0·05). CVR and oxygen delivery were unchanged in comparison to values at 24 h of treatment. The CBF increase in response to hypercapnia was diminished (P < 0·05). These observations demonstrate for the first time that glucocorticoids exert major vasoconstrictor effects on fetal CBF. This mechanism may protect the fetus against intraventricular haemorrhage both at rest and when the fetus is challenged. Betamethasone exposure decreased the hypercapnia‐induced increase in CBF (P < 0·05) due to decreased cerebral vasodilatation (P < 0.05).

6 Intrauterine corticosteroids for lung maturation: Observations of HPA axis function and cardiac autonomic balance in the neonate

“…Adrenergic cardiovascular drive and noradrenergic infl uences play a key role in the development or progression of hypertension and the metabolic syndrome in the adult (Grassi et al, 2009), making this system another key candidate for glucocorticoid induced long-term alterations in system balance. This notion is supported by experiments showing a sustained elevation of blood pressure and altered baroreceptor heart rate response in fetal sheep and the baboon and increased central and peripheral vascular resistance after glucocorticoid administration (Derks et al, 1997;Fletcher et al, 2002;Koenen et al, 2002;Schwab et al, 2000). 6.5 HPA axis functionality in neonates after intrauterine betamethasone treatment Η 53…”

Kinetics of Betamethasone and Fetal Cardiovascular Adverse Effects in Pregnant Sheep After Different Doses

“…Fetal arterial blood pressure changes in their time course are a sensitive measure of the biological activity of glucocorticoids. [7][8][9][10][11] We hypothesized that the clinical doses of betamethasone produce supramaximal effects on the fetal cardiovascular system as an indicator that the doses used clinically may also need evaluation in relation to lung maturation. …”

“…Fetal exposure at critical developmental stages to glucocorticoid concentrations that are inappropriate for that stage has been shown to have acute adverse effects on the central nervous [2][3][4][5][6] and cardiovascular systems in the fetal sheep and baboon. [7][8][9][10][11] In the cardiovascular system of sheep and nonhuman primates, synthetic glucocorticoids increase peripheral [7][8][9]11 and cerebral vascular resistance, 10 leading to increased mean fetal arterial blood pressure and decreased cerebral blood flow. Although the increased blood pressure may have harmful effects, the increase of cerebral vascular resistance may protect the brain from postasphyxic blood pressure peaks and intraventricular hemorrhage (Schwab M Although it has been shown in sheep that repeated treatments may be of benefit for the lung, 12 to our knowledge there has never been a study designed to examine a broad range of doses at the clinical level to determine the dose of maternal glucocorticoid that is optimal for the effects on the fetus in rodents, sheep, nonhuman primates or humans (PubMed, January 1966-January 2006; no language restrictions; search terms: antenatal or prenatal; glucocorticoids, steroids or betamethasone; dose or pharmacokinetics; lung or blood pressure).…”

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

“…DM enhanced the hypoxemiainduced peripheral vasoconstriction, increasing the fetal femoral vascular resistance by 72% as compared with the salinetreated group, in which it increased by 32%. We previously demonstrated that betamethasone given directly to the fetus at 125 dGA decreases fetal cerebral blood flow and blunts hypercapnia-induced vasodilation (15). In contrast, maternal administration at this earlier gestational age seems to provide a slight increase in cortical flow.…”

“…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).…”