Fetal Corticosteroid Research Articles

Early life corticosteroid overexposure: Epigenetic and fetal origins of adult diseases.

The relationship between events occurring during intrauterine development and later-life predisposition to long-term disease, has been described. The fetus responds to excess intrauterine exposure to high levels of corticosteroids, modifying their physiological development and stopping their growth. Fetal exposure to elevated levels of either endogenous (alterations in fetal hypothalamic-pituitary-adrenal axis) or synthetic corticosteroids, is one model of early-life adversity; to developing adult disease. At the molecular level, there are transcriptional changes in metabolic and growth pathways. Epigenetic mechanisms participate in transgenerational inheritance, not genomic. Exposures that change 11β-hydroxysteroid dehydrogenase type 2 enzyme methylation status in the placenta can result in transcriptional repression of the gene, causing the fetus to be exposed to higher levels of cortisol. More precise diagnosis and management of antenatal corticosteroids for preterm birth, would potentially decrease the risk of long-term adverse outcomes. More studies are needed to understand the potential roles of factors to alter fetal corticosteroid exposure. Long-term infant follow-up is required to determine whether methylation changes in placenta may represent useful biomarkers of later disease risk. This review, summarize recent advances in the programming of fetal effects of corticosteroid exposure, the role of corticosteroids in epigenetic gene regulation of placental 11β-hydroxysteroid dehydrogenase type 2 enzyme expression and transgenerational effects.

Dosing and formulation of antenatal corticosteroids for fetal lung maturation and gene expression in rhesus macaques

Antenatal corticosteroids (ANS) are the major intervention to decrease respiratory distress syndrome and mortality from premature birth and are standard of care. The use of ANS is expanding to include new indications and gestational ages, although the recommended dosing was never optimized. The most widely used treatment is two intramuscular doses of a 1:1 mixture of betamethasone-phosphate (Beta-P) and betamethasone-acetate (Beta-Ac) – the clinical drug. We tested in a primate model the efficacy of the slow release Beta-Ac alone for enhancing fetal lung maturation and to reduce fetal corticosteroid exposure and potential toxic effects. Pregnant rhesus macaques at 127 days of gestation (80% of term) were treated with either the clinical drug (0.25 mg/kg) or Beta-Ac (0.125 mg/kg). Beta-Ac alone increased lung compliance and surfactant concentration in the fetal lung equivalently to the clinical drug. By transcriptome analyses the early suppression of genes associated with immune responses and developmental pathways were less affected by Beta-Ac than the clinical drug. Promoter and regulatory analysis prediction identified differentially expressed genes targeted by the glucocorticoid receptor in the lung. At 5 days the clinical drug suppressed genes associated with neuronal development and differentiation in the fetal hippocampus compared to control, while low dose Beta-Ac alone did not. A low dose ANS treatment with Beta-Ac should be assessed for efficacy in human trials.

483: Antenatal corticosteroids in preterm growth-restricted fetuses: A systematic review and meta- analysis

Prior studies evaluating antenatal corticosteroids (ACS) and preterm birth outcomes have largely excluded patients with fetal growth restriction (FGR), resulting in limited evidence to guide ACS use in these pregnancies. Because growth-restricted fetuses are exposed to higher levels of endogenous steroids, exogenous ACS may not offer additional benefit. We conducted a systematic review and meta-analysis to evaluate the effect of ACS on neonatal outcomes in patients with preterm FGR. We conducted a predefined, systematic search in MEDLINE using relevant search terms. Selected studies were cohort or case-control studies comparing neonatal mortality and morbidity among FGR pregnancies delivered preterm that received ACS to those that did not. The primary outcome was neonatal mortality. Secondary outcomes were composite neonatal morbidity, respiratory distress syndrome (RDS), necrotizing enterocolitis (NEC), intraventricular hemorrhage and/or periventricular leukomalacia (IVH/PVL), bronchopulmonary dysplasia or chronic lung disease of prematurity (BPD/CLD), or neonatal sepsis. We assessed heterogeneity via Higgins I2, and calculated pooled odds ratios (OR) with 95% confidence intervals (CI) using random effects models. Thirteen studies published 1995-2018 met selection criteria including 6,387 FGR pregnancies delivered from 22-35 weeks’ gestational age. Of these, 3,554 (55.6%) received ACS and 2457 (44.4%) did not. Neonatal mortality was significantly lower in patients who received ACS compared to those who did not (12 studies: 12.8% vs. 15.1%, OR 0.63 [95% CI 0.46, 0.86]), with significant heterogeneity between studies (I2=55.1%). There was no significant difference in composite neonatal morbidity (4 studies: OR 0.73 [95% CI 0.53, 1.00]), RDS (12 studies: OR 0.89 [95% CI 0.69, 1.15]), NEC (7 studies: OR 0.93 [95% CI 0.70, 1.22]), IVH/PVL (10 studies: OR 0.82 [95% CI 0.56, 1.19]), BPD/CLD (8 studies: OR 1.11 [95% CI 0.88, 1.41]), or neonatal sepsis (6 studies: OR 1.23 [95% CI 0.94, 1.62]). These data show that ACS reduces neonatal mortality in pregnancies with FGR delivered preterm, with no apparent effect on measures of neonatal morbidity. This supports continued use of ACS for reduction of neonatal mortality in pregnancies with FGR at risk for preterm birth.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Transplacental versus direct fetal corticosteroid treatment for accelerating fetal lung maturation where there is a risk of preterm birth.

Despite major advances in medical technology, the incidence of preterm birth remains high. The use of antenatal corticosteroid administered transplacentally, by intramuscular injection to women at risk of preterm birth, has reduced the incidence of respiratory distress syndrome and increased the survival rates of preterm infants. However, this intervention also comes with its own risks and side effects. Animal studies and early studies in pregnant women at risk of preterm birth have reported the use of an alternative route of administration, by direct intramuscular injection of corticosteroid into the fetus under ultrasound guidance, in an attempt to minimise the side-effect profile. Direct fetal corticosteroid administration may have benefits over maternal administration in terms of safety and efficacy. To assess if different routes of corticosteroid administration (maternal versus direct fetal) have effects on health outcomes for women and their babies. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (25 October 2017), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (25 October 2017) and reference lists of retrieved studies. Randomised controlled trials comparing maternal with direct fetal routes of antenatal corticosteroid administration in women at risk of preterm birth. The two review authors independently assessed study eligibility. In future updates of this review, at least two review authors will extract data and assess the risks of bias in included studies. We will also assess the quality of the evidence using the GRADE approach. We did not identify any eligible randomised controlled trials to include in this review. The available clinical studies carried out so far on animals and human have shown that direct intramuscular injection of corticosteroid into the fetus under ultrasound guidance is feasible, but data on health outcomes are lacking. Uncertainty therefore persists as to which method could provide better efficacy and safety. Randomised controlled trials are required focusing on the benefits and harms of transplacental versus direct fetal corticosteroid treatment. Until the uncertainties have been addressed, it is advisable to stay with the current standard of antenatal transplacental maternally-administered corticosteroid treatment.

The efficacy of antenatal steroid therapy is dependent on the duration of low-concentration fetal exposure: evidence from a sheep model of pregnancy

Antenatal corticosteroids are among the most important and widely used interventions to improve outcomes for preterm infants. Antenatal corticosteroid dosing regimens remain unoptimized and without maternal weight-adjusted dosing. We, and others, have hypothesized that, once a low concentration of maternofetal steroid exposure is achieved and maintained, the duration of the steroid exposure determines treatment efficacy. Using a sheep model of pregnancy, we tested the relationship among steroid dose, duration of exposure, and treatment efficacy. The study was conducted to investigate the relative importance of duration and magnitude of fetal corticosteroid exposure to mature the preterm fetal ovine lung. Ewes with single fetuses at 120 days gestation received an intravenous bolus (loading dose) followed by a maintenance infusion of betamethasone phosphate to target 12-hour fetal plasma betamethasone concentrations of (1) 20 ng/mL, (2) 10 ng/mL, or (3) 2ng/mL. In a subsequent experiment, fetal plasma betamethasone concentrations were targeted at 2 ng/mL for 26 hours. Negative control animals received sterile saline solution. Positive control animals received 2 intramuscular injections of 0.25 mg/kg Celestone Chronodose (betamethasone phosphate+ betamethasone acetate) spaced at 24 hours. Preterm lambs were delivered surgically and ventilated 48 hours after treatment commenced. Maternal and fetal plasma betamethasone concentrations were confirmed by mass spectrometry in a parallel study of chronically catheterized, corticosteroid-treated ewes and fetuses. The loading and maintenance doses were achieved and maintained the desired fetal plasma betamethasone concentrations of approximately 20, 10, and 2 ng/mL for 12 hours. Compared with the 12-hour infusion-treated animals, lambs from the positive control (2intramuscular doses of 0.25 mg/kg Celestone Chronodose) group had the greatest functional lung maturation (compliance, gas exchange, arterial pH) and molecular evidence of maturation (glucocorticoid receptor signaling activation), despite having maximum fetal plasma betamethasone concentrations 2.5 times lower than animals in the 20 ng/mL betamethasone infusion group. Lambs from the 12-hour 2-ng/mL betamethasone infusion group had little functional lung maturation. In contrast, lambs from the 26-hour 2-ng/mL betamethasone infusion group had functional lung maturation equivalent to lambs from the positive control group. In preterm lambs that were exposed to antenatal corticosteroids, high maternofetal plasma betamethasone concentrations did not correlate with improved lung maturation. The largest and most consistent improvements in lung maturation were in animals that were exposed to either the clinical course of Celestone Chronodose or a low-dose betamethasone phosphate infusion to achieve a fetal plasma betamethasone concentration of approximately 2 ng/mL for 26 hours. The duration of low-concentration maternofetal steroid exposure, not total dose or peak drug exposure, is a key determinant for antenatal corticosteroids efficacy. These findings underscore the need to develop an optimized steroid dosing regimen that may improve both the efficacy and safety of antenatal corticosteroids therapy.

The clinical use of corticosteroids in pregnancy.

The use of antenatal steroid therapy is common in pregnancy. In early pregnancy, steroids may be used in women for the treatment of recurrent miscarriage or fetal abnormalities such as congenital adrenal hyperplasia. In mid-late pregnancy, the antenatal administration of corticosteroids to expectant mothers in anticipation of preterm birth is one of the most important advances in perinatal medicine; antenatal corticosteroids are now standard care for pregnancies at risk of premature delivery in high- and middle-income countries. The widespread uptake of this therapy is due to a compelling body of evidence demonstrating improved neonatal outcomes following antenatal corticosteroid exposure, stemming most notably from corticosteroid-driven maturation of fetal pulmonary function. As we approach the 50th anniversary of landmark work in this area by Liggins and Howie, it is apparent that much remains to be understood with regards to how we might best apply antenatal corticosteroid therapy to improve pregnancy outcomes at both early and mid to late gestation. Drawing on advances in laboratory science, pre-clinical and clinical studies, we performed a narrative review of the scientific literature to provide a timely update on the benefits, risks and uncertainties regarding antenatal corticosteroid use in pregnancy. Three, well-established therapeutic uses of antenatal steroids, namely recurrent miscarriage, congenital adrenal hyperplasia and preterm birth, were selected to frame the review. Even the most well-established antenatal steroid therapies lack the comprehensive pharmacokinetic and dose-response data necessary to optimize dosing regimens. New insights into complex, tissue-specific corticosteroid signalling by genomic-dependent and independent mechanisms have not been used to inform corticosteroid treatment strategies. There is growing evidence that some fetal corticosteroid treatments are either ineffective, or may result in adverse outcomes, in addition to lasting epigenetic changes in a variety of homeostatic mechanisms. Nowhere is the need to better understand the intricacies of corticosteroid therapy better conveyed than in the findings of Althabe and colleagues who recently reported an increase in overall neonatal mortality and maternal morbidity in association with antenatal corticosteroid administration in low-resource settings. New research to clarify the benefits and potential risks of antenatal corticosteroid therapy is urgently needed, especially with regard to corticosteroid use in low-resource environments. We conclude that there is both significant scope and an urgent need for further research-informed refinement to the use of antenatal corticosteroids in pregnancy.

Spontaneous resolution of an umbilical cord arteriovenous fistula

AbstractAn umbilical arteriovenous (AV) fistula is an extremely rare anomaly of the umbilical cord, with only one case being documented in the literature. The purpose of this report is to describe the prenatal sonographic characteristics of such a lesion and its potential complications. We report a case of an umbilical cord AV fistula detected at 24 weeks of gestation in one fetus of dichorionic-diamniotic twins. Color flow and spectral Doppler examinations showed a jet originating from one of the umbilical arteries entering the dilated umbilical vein. Serial ultrasounds revealed relative oligohydramnios and deep A waves in the ductus venosus for the affected twin. Upon performing fetal echocardiography assessment, mild cardiomegaly and dilatation of the inferior vena cava were detected. Chromosomal testing revealed a normal karyotype. The patient continued to be followed for close monitoring of fetal well-being and corticosteroids were administered. Cesarean section was planned for 28–30 weeks, but surprisingly, the oligohydramnios resolved, Doppler studies normalized, and no further intra-uterine growth restriction or fetal compromise was observed. Due to the recurrence of abnormal Doppler studies at 36 weeks of gestation, the patient was admitted for an induction of labor followed by a vaginal delivery of two healthy infants. Given the scarcity of reports regarding umbilical cord AV fistula, it is important to perform an extensive investigation of the affected fetus including karyotype and echocardiography. Furthermore, delivery timing should rely on close surveillance of fetal well-being to avoid the risk of fetal demise.

Metyrapone Blocks Maternal Food Restriction-Induced Changes in Female Rat Offspring Lung Development

Maternal food restriction (MFR) during pregnancy affects pulmonary surfactant production in the intrauterine growth-restricted (IUGR) offspring through unknown mechanisms. Since pulmonary surfactant production is regulated by maternal and fetal corticosteroid levels, both known to be increased in IUGR pregnancies, we hypothesized that metyrapone (MTP), a glucocorticoid synthesis inhibitor, would block the effects of MFR on surfactant production in the offspring. Three groups of pregnant rat dams were used (1) control dams fed ad libitum; (2) MFR (50% reduction in calories) from days 10 to 22 of gestation; and (3) MFR + MTP in drinking water (0.5 mg/mL), days 11 to 22 of gestation. At 5 months, the MFR offspring weighed significantly more, had reduced alveolar number, increased septal thickness, and decreased surfactant protein and phospholipid synthesis. These MFR-induced effects were normalized by the antiglucocorticoid MTP, suggesting that the stress of MFR causes hypercorticoidism, altering lung structure and function in adulthood.

Transplacental versus direct fetal corticosteroid treatment for accelerating fetal lung maturation where there is a risk of preterm birth

Despite major advances in medical technology, the incidence of preterm birth remains high. The use of antenatal corticosteroid administered transplacentally, by intramuscular injection to women at risk of preterm birth, has reduced the incidence of respiratory distress syndrome and increased the survival rates of preterm infants. However, this intervention also comes with its own risks and side effects. Animal studies and early studies in pregnant women at risk of preterm birth have reported the use of an alternative route of administration, by direct intramuscular injection of corticosteroid into the fetus under ultrasound guidance, in an attempt to minimise the side effects profile. Direct fetal corticosteroid administration may have benefits over maternal administration in terms of safety and efficacy. To assess if different routes of corticosteroid administration (maternal versus direct fetal) have effects on maternal health, and the risk of stillbirth, neonatal, perinatal, infant and child mortality and morbidity. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (16 June 2011) and the WHO International Clinical Trials Registry Platform (ICTRP) (16 June 2011). Randomised controlled trials comparing maternal with direct fetal routes of antenatal corticosteroid administration in women at risk of preterm birth. We did not perform any data collection or analyses. We did not identify any eligible randomised controlled trials to include in this review. The available clinical studies carried out so far on animals and human have shown that direct intramuscular injection of corticosteroid into the fetus under ultrasound guidance is feasible, but data on health outcomes are lacking. Therefore, uncertainty persists as to which method could provide better efficacy and safety profile. Randomised controlled trials are required focusing on the benefits and harms of transplacental versus direct fetal corticosteroid treatment. Until the uncertainties have been answered, it is advisable to stay with the current standard of antenatal transplacental maternally administered corticosteroid treatment.

Synthesis and Metabolism of 16α-Hydroxy-Steroids and Corticosteroids in Fetuses and Neonates

This study involved the biosynthesis and metabolism of a series of 16α-hydroxy-steroids and gluco- and mineralocorticoids in the fetus and their concentrations in materno-fetal plasma and amniotic fluid. In the biosynthesis of 16α-hydroxy-steroids, 17α-hydroxylase and C17–20-lyase in the adrenals and 16α-hydroxylase in the liver which are distributed in the microsomal fractions, extremely high activities are observed in 16–20 week fetuses. High sulfokinase activity is also found in the 105,000xg supernatant fraction and the activity in decreasing order is adrenal, liver and small intestine. These enzyme activities are affected by some steroids present in the umbilical plasma. In the biosynthesis of gluco- and mineralocorticoids, 17α-, 21-hydroxylase are distributed in the extramitochondrial fraction of the definitive adrenal cortex while 11β-, 18-hydroxylase and 18-dehydrogenase are in the mitochondrial fraction. All of these enzymes show high activities relatively early in gestation and angiotensin-II shows a selective stimulation for 11β-, 18-hydroxylase and potassium together with ACTH for 18-dehydrogenase. All of the 16α-hydroxy-steroids are consistently higher in the fetal plasma than in maternal plasma and show a 2 to 4 fold increase during the 3rd trimester of gestation. All of corticosteroids assayed are also higher in the fetal plasma and increase during this period. It is well established that a portion of cortisol undergoes sulfate conjugation or conversion to tetrahydro-derivative and that aldosterone is largely converted to 3α' 5β-tetrahydro-aldosterone and a portion undergoes glucosiduronation. Thus, in the fetus, some trophic hormones and endogenous steroids become active in the control of 16α-hydroxy-steroid and corticosteroid biosynthesis and metabolism. In conjunction, the presence of protein bound, unbound fractions as well as sulfate or glucuronide conjugated, unconjugated fractions in the blood tends to maintain an equilibrium and control over these systems.

Corticosteroid-induced kidney dysmorphogenesis is associated with deregulated expression of known cystogenic molecules, as well as indian hedgehog

An intact genome is essential for kidney growth and differentiation, but less is known about whether, and how, an altered fetal milieu modifies these processes. Maternal low-protein diets perturb growth of the metanephros, the precursor of the mature kidney. Fetal corticosteroid overexposure may, in part, mediate this, because such diets downregulate placental 11beta-hydroxysteroid dehydrogenase-2, which degrades maternal corticosteroids. We report that glucocorticoid and mineralocorticoid receptors are expressed in mouse metanephric epithelia. Metanephroi maintained in organ culture with hydrocortisone (1.4 or 14 microM) underwent a dose-dependant deceleration of overall growth accompanied by cyst formation. Dexamethasone, a glucocorticoid, reproduced these outcomes, but aldosterone, a mineralocorticoid, did not. Hydrocortisone upregulated transcripts levels of cadherin-11 and downregulated prospero-related homeobox-1, hence mimicking reported effects of maternal low-protein diet. Hydrocortisone also upregulated transcripts encoding Na(+)-K(+)-ATPase subunits and ligands for the epidermal growth factor receptor, all previously implicated in renal cyst growth. The most upregulated transcript, however, was indian hedgehog, and the encoded protein was immunodetected in metanephric cysts. Furthermore, in the presence of hydrocortisone, cystogenesis, but not whole organ growth, was significantly reduced by cyclopamine, a drug downregulating hedgehog signaling. Finally, both glucocorticoid receptor and indian hedgehog proteins were detected by immunohistochemistry in cystic tubules within human dysplastic kidneys, consistent with the hypothesis that these molecules modify the severity of this congenital malformation. Collectively, our observations raise the possibility that enhanced hedgehog signaling is an important stimulus for renal cyst formation. Furthermore, pharmacological inhibition of this pathway should be explored as a potential therapy for renal cystic diseases, starting with relevant animal models.

Intramuscular Fetal Corticosteroid Therapy: Short-Term Effects on the Fetus

Objective: The aim of the study was to assess the short-term effects of direct intramuscular (i.m.) corticosteroid therapy on fetal biophysical profile, baseline fetal heart rate and the nonstress test, which indicate the degree of fetal hypoxia. Method: We evaluated the effect of direct i.m. fetal single-dose dexamethasone (4 mg/kg) on the fetal biophysical profile 2 h before and 2–4 h after corticosteroid therapy in 41 fetuses in the 32nd week of gestation at risk of preterm delivery. Risk factors for preterm delivery included pregnancy-induced hypertension and preeclampsia. Result: There was a statistically significant difference between fetal breathing movements before and after corticosteroid therapy (p = 0.019; 95% confidence interval for difference –11.75, –1.12). No significant changes were observed between baseline fetal heart rate before and after corticosteroid therapy (p = 0.99; 95% confidence interval for difference –4.81, +4.81), biophysical profile before and after fetal corticosteroid therapy, p = 0.235 as well as the nonstress test before and after therapy (p = 0.564). Conclusion: Direct corticosteroid i.m. fetal therapy results in increasing profound short-term fetal breathing movements. There are no changes in baseline fetal heart rate, biophysical profile score, and nonstress test.

Different medicaments in fetus maturation–corticosteroid usage

Objective. The object of work is pointing out the significance of improvement highly risk pregnancies by applying artificial fetal lungs maturation in relation to expected outcomes without adequate therapy.Methods. We analyzed fetal lung maturation by using lecithin and sphingomyelin ratio in embryo fluid received by foam test. We examined successfulness of artificial fetal lungs maturation by applying corticosteroids to the embryo in a group of patients with serious form of growth retardation (group A), then to the mother (group B) and by inducing partial mild form of asphyxia with oxytocin infusion (group C).Results. The success of the method is shown by the success of finished pregnancies. We followed the difference between expected and actual term of delivery.Conclusion. Artificial fetal lungs maturation by applying fetal corticosteroids efficiently increases the creation of lecithin and sphingomyelin and enables life of neonate even in period up to 30th week of gestation.

Cortisol levels as preterms age

Cortisol is a potent developmental regulator that is normally very low in the fetus until just prior to term. Following preterm birth, the newborn must increase plasma cortisol to support multiple physiologic and metabolic adaptations. Cortisol then remains elevated relative to fetal levels until term equivalence. In animal models, fetal corticosteroid exposures can result in altered neuroendocrine regulation and behavior as the newborn grows to become an adult. Grunau et al report the developmental trajectory of salivary cortisol in large cohorts of 23-28 weeks, 28-32 weeks, and term infants at 3, 6, 8, and 18 months corrected age.

The influence of direct intramuscular corticosteroid therapy on parameters of venous circulation in hypoxaemic fetuses

The influence of glucocorticosteroid therapy on foetal lung maturation is evident but little is known about its effects on parameters of foetal venous circulation. The aim of the study was to assess the influence of direct intramuscular (i.m.) foetal corticosteroid therapy (CST) on parameters of foetal venous circulation which indicates a degree of foetal hypoxia. The prospective study was conducted at the Institute of Gynaecology and Obstetrics during 2001. We evaluated the influence of direct i.m. foetal single dose dexamethasone (2 mg/ kg estimated foetal weight by sonographic examination) on foetal ductus venosus (DV) and vena cava inferior (VCI) velocities in 49 foetuses 24 hours before and after therapy. There is positive correlation with the statistical significance in systolic/diastolic ratio (S/D) in DV before and after the corticotherapy r = 0.366; p = 0.018. Reverse flow during contraction of the right atrium in DV was found in 55.6% of foetuses after CST. Reverse flow during the contraction of the right atrium in VCI was found in 3 foetuses before CST and in 4 foetuses after CST. We found positive correlation without statistical significance between the vena cava pre-load indices before and after CST (r = 0.127; p = 0.428). There is positive correlation with the statistical significance between systolic flow in VCI before and after CST (r = 0.478; p = 0.002). Corticosteroid therapy influences parameters of foetal venous circulation. Its influence depends on duration of foetal hypoxia. The parameters of foetal venous circulation can be a predictor of the perinatal outcome.

Effects of Multiple Courses of Antenatal Corticosteroids on Blood-Brain Barrier Permeability in the Ovine Fetus

To test the hypothesis that multiple courses of antenatal corticosteroids accentuate the decreases in blood-brain barrier permeability observed after a single course of corticosteroids in preterm ovine fetuses. Chronically instrumented 106-day gestation ovine fetuses were studied after single and multiple courses of dexamethasone or placebo were given to ewes beginning at 104 to 106 or 76 to 78 days of gestation, respectively. In the single-course groups, the ewes received dexamethasone (6 mg, n = 6) or placebo (n = 6) as four intramuscular injections every 12 hours over 48 hours. In the multiple course groups, the ewes received the same treatment (dexamethasone, n = 9, or placebo, n = 8), once per week for 5 weeks starting at 76 to 78 days of gestation. Blood-brain barrier permeability was quantified with the blood-to-brain transfer constant (K(i)) for alpha-aminoisobutyric acid (AIB) in the brain regions of the fetuses 12 hours after the last injection of dexamethasone was given to the ewes at 106 to 107 days of gestation. Both single (analysis of variance [ANOVA]; main effects for dexamethasone treatment, F = 5.92, P <.04) and multiple (ANOVA; main effects for dexamethasone treatment, F = 4.74, P <.04) courses of antenatal corticosteroids were associated with decreases in blood-brain barrier permeability in the brain regions of the ovine fetus. However, the multiple courses did not accentuate (ANOVA; main effects for single versus multiple courses, F = 1.06, P = .32) the decreases in permeability observed after a single course. Contrary to our hypothesis, antenatal treatment with a 5-week course of corticosteroids did not accentuate the reductions in blood-brain barrier permeability that we observed after a single course of corticosteroids in the fetus.

Repeated ultrasound guided fetal injections of corticosteroid alter nervous system maturation in the ovine fetus.

Recent studies in sheep have shown that repeated maternal injections of betamethasone are associated with adverse effects within the nervous system. Repeated fetal injections of betamethasone achieve serial improvements in preterm lung function in sheep and are a possible alternative to repeated maternal therapy. We have evaluated the effect of repeated fetal administration of betamethasone on nervous system maturation in an ovine model. Date-mated ewes (n = 48) were randomized to receive ultrasound-guided fetal injections of betamethasone or saline between days 104 to 124 of gestation and were delivered by cesarean section on day 125 or 145 (term = 150). Optic and sciatic nerves were prepared for light and electronmicroscopy. Eye diameters were measured and transverse sections of retinae were evaluated. Data were analyzed using a mixed model analysis of variance. Repeated fetal administration of corticosteroid did not significantly affect optic nerve myelination but resulted in significant delays in sciatic axonal growth (p < 0.02) and retinal maturation (p < 0.04). The process of performing repeated fetal injections also significantly affected some retinal parameters. Repeated fetal administration of betamethasone alters some aspects of nervous system maturation in sheep. It is premature to plan trials of repeated fetal corticosteroid therapy in humans.

RDS prevention: Direct fetal versus transplacental corticosteroid therapy

RDS prevention: Direct fetal versus transplacental corticosteroid therapy

Glucocorticoid activity in the fetal spontaneously hypertensive rat.

Fetal exposure to high concentrations of corticosteroids in the rat is associated with elevated blood pressure in postnatal life. In this study we have investigated indicators of corticosteroid activity in fetal spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) in order to determine whether fetal corticosteroid exposure is increased in the SHR. Placental 11beta-hydroxysteroid dehydrogenase (11beta-HSD) activity, which prevents maternal steroids from crossing the placenta, was not impaired in the SHR. Concentrations of amniotic fluid corticosterone were significantly decreased in the SHR compared with the WKY at fetal Day 20, but were not significantly different on fetal Days 16 or 22. This suggests that rather than increased exposure to corticosteroids in the SHR fetus corticosteroid exposure may be reduced. Expression of lung surfactant protein A (Sp-A), a gene induced in late gestation by corticosteroids, was decreased in the SHR. In addition, differences in amniotic fluid electrolyte concentrations were observed which may reflect delayed renal maturation in the fetal SHR. These data suggest that the SHR fetus is exposed to low concentrations of corticosteroids and that the late gestation rise in fetal corticosteroid may be delayed in the SHR.

The placental clock: A review

Summary This review debates the possible existence of a clock within the placenta that might determine the timing of birth, and which may influence the extent to which the fetus becomes programmed by maternal glucocorticoids, and thereby influences the timing of death. Studies in sheep and in monkeys provide evidence against a placental clock per se, and support the role of a clock in the fetus, at the level of the pituitary and/or adrenal which determines gestation length. However, fetal development may be affected by placental influences such as PGE, corticotropin-releasing hormone (CRH) and/or placental adrenocorticotropin (ACTH). During pregnancy, developmental processes are timed precisely. Alteration of those mechanisms by maternally derived glucocorticoids, which escape placental metabolism, or by fetal corticosteroids, produced in response to stress, may have life-long effects on the organism, and contribute to the timing of death. The simplistic view of a single placental clock seems unlikely as a control for these myriad process. Rather, the timing of birth and the onset of adult disease, and in some cases death, may be effected by complex interactions between the placenta and the fetus.