Single and repetitive maternal glucocorticoid exposures reduce fetal growth in sheep

Jobe, Alan H.; Wada, Norihisa; Berry, Lynne M.; Ikegami, Machiko; Ervin, M. Gore

doi:10.1016/s0002-9378(98)70518-6

Cited by 203 publications

(111 citation statements)

References 24 publications

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“…Exposure to glucocorticoid results in reductions in weight at birth (Reinisch et al 1978, Johnson et al 1981, Jobe et al 1998) -a finding that we have substantiated using smaller amounts of steroid in the present study. Organ weights from a larger cohort of animals treated alongside this group have been published elsewhere and showed reductions in liver, brain and kidney weight and a significant increase in the brain:liver weight ratio .…”

Section: Discussionsupporting

confidence: 84%

“…Various studies in animals have shown reductions in weight at birth ( Jobe et al 1998), alterations in organ ( Johnson et al 1981) and neuronal development (Uno et al 1990, 1994, Dunlop et al 1997, and increases in basal and stress-induced plasma cortisol concentrations postnatally (Uno et al 1994) after prenatal glucocorticoids. These last observations suggest that chronic fetal exposure to glucocorticoid may alter the development of the hypothalamo-pituitary-adrenal HPA axis in utero.…”

Section: Introductionmentioning

confidence: 99%

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

Sloboda

Newnham²,

Challis³

2000

Journal of Endocrinology

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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 respiratory distress syndrome. Although previous studies have shown that glucocorticoids have deleterious consequences on fetal development, there is little information regarding the effects of clinically relevant repeated maternal doses of glucocorticoids on fetal growth and hypothalamic-pituitary-adrenal (HPA) function. We hypothesised that repeated prenatal exposure to increased 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 weights were recorded. Maternal and fetal blood samples were gathered and fetal tissue collected. Maternal oestradiol concentrations were significantly greater than those in controls at 125 days of gestation, but were not different at 146 days. Maternal plasma progesterone concentrations were similar between groups at both 125 and 146 days of gestation. Weight at birth was significantly reduced by 23% at 125 days and 19% at 146 days of gestation (P<0·05) after exposure to glucocorticoid. Cord plasma ACTH concentrations were not significantly different between groups at day 125, but were significantly increased in day 146 fetuses of ewes that had received betamethasone (P<0·05). Cord plasma cortisol concentrations followed the same trend, although differences were not statistically significant. Cord plasma corticosteroid binding capacity (CBC) was significantly increased at 125 days of gestation 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 determine the distribution and levels of mRNA encoding key pituitary and hypothalamic neuropeptides of the HPA axis. In pituitaries of 146-day fetuses, there were no significant differences in the regional pattern of distribution or amounts of pro-opiomelanocortin (POMC) mRNA between betamethasone-treated 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, immunoreactive ACTH peptide content in the fetal pars distalis was not different but glucocorticoid receptor (GR) mRNA levels in the pars distalis were increased significantly (P<0·05). No significant difference in distribution pattern or concentrations of corticotrophin-releasing hormone (CRH) mRNA, GR mRNA, oxytocin mRNA and pre-proenkephalin mRNA were found in hypothalami from fetuses at 146 days of gestation after betamethasone treatment. We...

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Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

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

Sloboda

Newnham²,

Challis³

2000

Journal of Endocrinology

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“…These findings were consistent with studies that suggested that PNS effects decreased preterm infant size and subsequent growth (French et al, 1999) and that preterm infant subnormal head size impacts cognitive abilities at school age (Hack et al, 1991). This is also consistent with findings in animal studies that suggested a dose-dependent steroid relationship with decreased fetal growth (Coe & Lubach, 2000;Jobe et al, 1998).…”

Section: Pns Vabs Composite Growth and Crib Score Outcomessupporting

confidence: 90%

Cumulative Perinatal Steroids: Child Development of Preterm Infants

Purdy

Wiley

Smith

et al. 2008

Journal of Pediatric Nursing

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The development of premature infants may be altered due to exposure to high cumulative doses of the perinatal corticosteroid dexamethasone during critical growth periods. To compare child behavioral development of prematurely born infants who were exposed to higher perinatal steroids (PNS; N0.2 mg/kg) with that of infants exposed to lower PNS (≤0.2 mg/kg), we used the Vineland Adaptive Behavioral Scales to assess school-age behavioral outcomes of a historical cohort of 45 prematurely born infants. Children who had received higher PNS treatment were more likely to have lower overall behavioral developmental scores, especially lower social skills (p < .05). Higher PNS plus higher severity of illness during the first day of life based on the Clinical Risk Index for Babies (p = .016) and lower birth head size (p = .015) were linked with poorer behavioral outcomes among participants. Nursing practice includes promotion of quality care and should include closer evaluation of cumulative steroid therapy, severity of illness, and promotion of long-term follow-up support for premature infants. KeywordsPerinatal steroids; Dexamethasone; Preterm infants; Neurodevelopment PRETERM DELIVERY, ESTIMATED to occur in 7-11% of all North American births, is responsible for 75% of neonatal deaths (National Institutes of Health [NIH] Consensus Development Conference Statement, 1994). The outcomes of preterm infant survival are often dependent upon the provision of high-quality perinatal care, prior to 40 weeks' postconceptual age, as this is a vulnerable time in development. Over the past 30 years, synthetic or exogenous steroids have increasingly been prescribed before and after birth with the intent to improve infant lung maturity and outcomes. The 1994 NIH consensus panel recommendation for antenatal steroids (before birth) consisted of two doses of 12 mg of betamethasone given intramuscularly at 24-hour intervals or four doses of 6 mg of dexamethasone given intramuscularly at 12-hour intervals. In 2000, the panel revisited this recommendation and discouraged the use of multiple-course antenatal steroids because studies identified associations between steroids and impaired infant head growth and neurodevelop-mental outcomes (National Institutes of Health, 2000 Although commonly given for a variety of therapeutic reasons in perinatal care, the risks may not outweigh the benefits of either higher antenatal or postnatal steroid exposure. Perinatal steroids (PNS) are primarily administered for the promotion of infant lung maturation and reduction of respiratory distress syndrome and mortality (Huang, Dunlop, & Harper, 1999). Many premature infants have received multiple doses of therapeutic steroid drugs while in utero as well as in the postnatal period.Studies have retrospectively examined either antenatal or postnatal steroid effects . This study was the first to retrospectively identify the precise milligram amount of cumulative PNS dosed prior to 40 weeks and prospectively examine relationships with neurodevelopment of pre...

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“…The concentration range chosen included the range of cortisol levels present in cord blood in in vivo studies (13-23 g/dL) (32). Previous studies in lambs have suggested that application of repetitive maternal glucocorticoid exposure leads to symmetric growth retardation in lambs delivered prematurely and a decreased fetal size persisted to term (33). Furthermore, increased cortisol levels have been noted in SGA fetuses (34).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Placental Growth Hormone Secretion in a Human Trophoblast Model—The Effects of Hormones and Adipokines

et al. 2008

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Placental growth hormone (PGH) is secreted from the human placental syncytiotrophoblast into the maternal circulation. PGH levels in pregnant women correlate with the birth weight of their offspring. We hypothesized that metabolic regulators may alter PGH secretion. BeWo cells as human trophoblast models were treated for 24, 48, and 72 h with insulin, insulin-like growth factor (IGF)-1, cortisol, ghrelin, leptin and visfatin. P lacental growth hormone (PGH) is synthesized in and secreted from the human placental syncytiotrophoblast (1) into the maternal circulation in a nonpulsatile manner, detectable in the maternal circulation from gestational week 5, and gradually increases in concentration throughout pregnancy. It has a short half-life and is undetectable 3 h after parturition (2). It is only found in the maternal, but not fetal circulation. Its maternal levels rise profoundly between weeks 20 and 30 of gestation, thus progressively replacing pituitary growth hormone in the human maternal circulation from midgestation onward (3-5). PGH has somatotropic effects, acting on liver and adipose tissue to influence gluconeogenesis and lipolysis to help ensure an adequate nutrient supply for the fetoplacental unit (6).Previously, our group and others have shown a positive correlation between PGH levels in pregnant women and the birth weight of their offspring, stimulating discussions about its possible impact on fetal growth (2,7). Understanding the regulation of fetal growth is important. According to the "Fetal Origins of Disease" hypothesis, it is well recognized that Type 2 diabetes mellitus (T2DM) and features of the metabolic syndrome are associated with birth weights at the extreme of the growth continuum (either small or large for gestational age) (8). The physiologic role of PGH in pregnancy is not completely understood, but its continuous secretion at high levels during pregnancy sparked speculation that it may be an important placental hormone affecting both mother and, indirectly, fetus (9). In vivo experiments have demonstrated that growth hormone, when infused into pregnant ewes late in gestation, can increase fetal growth (10). Transgenic mice overexpressing the human PGH gene become larger than their normal littermates and are hyperinsulinemic and insulin resistant (11). The relationship between fetal growth and PGH raises the possibility that PGH could be involved in the development of insulin resistance in pregnancy and might play an important role in gestational diabetes mellitus (GDM) and pregestational diabetes (12,13).The regulation of PGH secretion is very different from that of pituitary growth hormone (GH) as growth-hormone-releasing hormone does not modulate PGH in vivo. Furthermore, in vitro and in vivo studies have revealed that alterations in maternal nutrient (glucose) availability may alter PGH secretion (14). However, two decades have passed since the discovery of PGH, and still little is known about the regulation of its secretion.We hypothesized that PGH secretion is regul...

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Single and repetitive maternal glucocorticoid exposures reduce fetal growth in sheep

Cited by 203 publications

References 24 publications

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

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

Cumulative Perinatal Steroids: Child Development of Preterm Infants

Regulation of Placental Growth Hormone Secretion in a Human Trophoblast Model—The Effects of Hormones and Adipokines

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