Alterations in Fetal Kidney Development and Elevations in Arterial Blood Pressure in Young Adult Sheep after Clinical Doses of Antenatal Glucocorticoids

Abstract

Epidemiologic studies have yielded controversial information regarding an association between antenatal steroid administration and elevations in arterial blood pressure (BP). The aim of the study was to determine whether antenatal administration of a clinically relevant dose of steroids at a time when fetal nephrogenesis is at its highest results in abnormal kidney development and adult hypertension. Pregnant sheep were treated with either vehicle or betamethasone. Maternal injections were given 24 h apart at 80 d of gestational age (dGA; 0.55 of gestation). Animals were studied either as fetuses or as immature adults. Fetuses were delivered by cesarean section at 135 dGA. Adults were studied at 6 mo of age. Betamethasone administration did not induce premature labor or intrauterine growth restriction. In the betamethasone-exposed group, we found at 135 dGA a 25.5% decrease in the number of glomeruli with no differences in fetal kidney weight. In adults, mean, systolic, and diastolic arterial BPs were significantly higher, whereas there were no significant differences in heart rate over the same study period. The major finding of this study is that a single course of antenatal steroids alters renal development and is associated with elevations in arterial BP in lambs at 6 mo of age. We conclude that antenatal glucocorticoid administration under the National Institutes of Health consensus guidelines may alter human fetal renal development. (Pediatr Res 58: 510-515, 2005) Abbreviations AT, angiotensin receptor BP, blood pressure dGA, days of gestational age PAH, para aminohippuric acid RAS, renin-angiotensin systemThe pioneering work of Liggins and Howie (1) resulted in antenatal steroid treatment's becoming standard of care for enhancing fetal lung maturation in pregnancies that are threatened by premature labor between 24 and 34 wk of gestation. Following the National Institutes of Health consensus conference recommendation (2), the use of corticosteroid therapy in the United States has increased from Ͻ15% of individuals who threatened to deliver prematurely in 1990 to Ͼ75% now (3). However, the growing use of glucocorticoids in the perinatal period has become an issue of extreme concern because of the potential for untoward effects found only with long-term outcome studies (3,4). A recent epidemiologic study shows an association between antenatal glucocorticoid administration and elevations in systolic and diastolic blood pressure (BP) at 14 y of age (5). Studies in animals have also associated administration of glucocorticoids during pregnancy with hypertension in the adult offspring (6 -10). However, in these studies, either the dose of glucocorticoids or the developmental stage at which the fetus was exposed does not parallel the clinical use.Fetal exposure to excess glucocorticoids of maternal origin seems to play a central role in the development of hypertension after fetal undernutrition. Maternal adrenalectomy (11) and inhibition of adrenal function with metyrapone (12) negate the effect of protein restr...

Neonatal dexamethasone administration causes progressive renal damage due to induction of an early inflammatory response

“…In rats, the kidney is still immature at birth, and nephrogenesis is not complete until at least 1 wk after birth (25). Although the method of counting nephron numbers in the present study was limited compared with previous methods described (5,12), it is likely that neonatal DEX administration in the first 3 days after birth leads to reduced nephron numbers in adult life by inhibition of nephronegenesis, which has also been found in prenatal studies (14,17). In addition, in our study, DEX-treated rats had increased urinary protein loss from 8 wk onward.…”

“…It has been reported that maternal GC administration may lead to reduced nephron numbers in offspring (17,29). In rats, nephrogenesis is not complete until at least 1 wk after birth (25).…”

“…Data suggest that maternal GC administration, e.g., dexamethasone (DEX) or betamethasone, impairs nephrogenesis and reduces glomeruli numbers, which may contribute to hypertension in late life (17,33). To the best of our knowledge, effects of neonatal GC administration on kidney function have not been studied in animals.…”

Gender differences in the effects of antenatal betamethasone exposure on renal function in adult sheep

“…It is well known that the kidneys play a major role in the long-term regulation of arterial pressure and that change in renal function may lead to alterations in Na ϩ and water balance and blood pressure (19). In a rat model, Ortiz et al (35,36) observed that prenatal exposure to dexamethasone on days 15 and 16 of gestation induced 30 and 20% reductions in glomerular number in offspring compared with controls when assessed at 60 -70 days and 6 -9 mo of age, respectively. This reduction is possibly a consequence of dexamethasone-induced inhibition of ureteric branching morphogenesis (47).…”

Antenatal Betamethasone Administration Has a Dual Effect on Adult Sheep Vascular Reactivity

“…The dose of betamethasone administered to the ewe (0.17 mg/kg body weight) is equivalent to the 12 mg dose recommended by the National Institutes of Health consensus panel to be used in women threatened with premature labor (17). The alterations in vascular reactivity we report suggest that antenatal steroid treatment results in increased smooth muscle responsiveness and also in endothelial dysfunction, thus they could be a contributing factor for the development of hypertension (5). Limited information exists regarding the long-term effects of prenatal glucocorticoids exposure on arterial blood pressure levels in humans.…”