Dataset Information

Oral antenatal corticosteroids evaluated in fetal sheep.

ABSTRACT:

Background

The use of antenatal corticosteroids (ACS) in low-resource environments is sporadic. Further, drug choice, dose, and route of ACS are not optimized. We report the pharmacokinetics and pharmacodynamics of oral dosing of ACS using a preterm sheep model.

Methods

We measured pharmacokinetics of oral betamethasone-phosphate (Beta-P) and dexamethasone-phosphate (Dex-P) using catheterized pregnant sheep. We compared fetal lung maturation responses of oral Beta-P and Dex-P to the standard treatment with 2 doses of the i.m. mixture of Beta-P and betamethasone-acetate at 2, 5, and 7 days after initiation of ACS.

Results

Oral Dex-P had lower bioavailability than Beta-P, giving a lower maximum maternal and fetal concentration. A single oral dose of 0.33 mg/kg of Beta-P was equivalent to the standard clinical treatment assessed at 2 days; 2 doses of 0.16 mg/kg of oral Beta-P were equivalent to the standard clinical treatment at 7 days as assessed by lung mechanics and gas exchange after preterm delivery and ventilation. In contrast, oral Dex-P was ineffective because of its decreased bioavailability.

Conclusion

Using a sheep model, we demonstrate the use of pharmacokinetics to develop oral dosing strategies for ACS. Oral dosing is feasible and may facilitate access to ACS in low-resource environments.

SUBMITTER: Schmidt AF

PROVIDER: S-EPMC6848022 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Publications

Oral antenatal corticosteroids evaluated in fetal sheep.

Schmidt Augusto F AF Jobe Alan H AH Kannan Paranthaman S PS Bridges James P JP Newnham John P JP Saito Masatoshi M Usuda Haruo H Kumagai Yusaku Y Fee Erin L EL Clarke Michael M Kemp Matthew W MW

Pediatric research 20190731 5

<h4>Background</h4>The use of antenatal corticosteroids (ACS) in low-resource environments is sporadic. Further, drug choice, dose, and route of ACS are not optimized. We report the pharmacokinetics and pharmacodynamics of oral dosing of ACS using a preterm sheep model.<h4>Methods</h4>We measured pharmacokinetics of oral betamethasone-phosphate (Beta-P) and dexamethasone-phosphate (Dex-P) using catheterized pregnant sheep. We compared fetal lung maturation responses of oral Beta-P and Dex-P to t ...[more]

PMID: 31365919

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Project description:Chorioamnionitis is associated with preterm delivery and involution of the fetal thymus. Women at risk of preterm delivery receive antenatal corticosteroids which accelerate fetal lung maturation and improve neonatal outcome. However, the effects of antenatal corticosteroids on the fetal thymus in the settings of chorioamnionitis are largely unknown. We hypothesized that intra-amniotic exposure to lipopolysaccharide (LPS) causes involution of the fetal thymus resulting in persistent effects on thymic structure and cell populations. We also hypothesized that antenatal corticosteroids may modulate the effects of LPS on thymic development.Time-mated ewes with singleton fetuses received an intra-amniotic injection of LPS 7 or 14 days before preterm delivery at 120 days gestational age (term?=?150 days). LPS and corticosteroid treatment groups received intra-amniotic LPS either preceding or following maternal intra-muscular betamethasone. Gestation matched controls received intra-amniotic and maternal intra-muscular saline. The fetal intra-thoracic thymus was evaluated.Intra-amniotic LPS decreased the cortico-medullary (C/M) ratio of the thymus and increased Toll-like receptor (TLR) 4 mRNA and CD3 expression indicating involution and activation of the fetal thymus. Increased TLR4 and CD3 expression persisted for 14 days but Foxp3 expression decreased suggesting a change in regulatory T-cells. Sonic hedgehog and bone morphogenetic protein 4 mRNA, which are negative regulators of T-cell development, decreased in response to intra-amniotic LPS. Betamethasone treatment before LPS exposure attenuated some of the LPS-induced thymic responses but increased cleaved caspase-3 expression and decreased the C/M ratio. Betamethasone treatment after LPS exposure did not prevent the LPS-induced thymic changes.Intra-amniotic exposure to LPS activated the fetal thymus which was accompanied by structural changes. Treatment with antenatal corticosteroids before LPS partially attenuated the LPS-induced effects but increased apoptosis in the fetal thymus. Corticosteroid administration after the inflammatory stimulus did not inhibit the LPS effects on the fetal thymus.

Project description:ObjectiveTo evaluate the role of antenatal administration of corticosteroids for fetal lung maturation on the short-term perinatal outcome of pregnancy complicated by late fetal growth restriction (FGR).MethodsThis cohort study was a secondary analysis of a multicenter prospective observational study, the TRUFFLE-2 feasibility study, conducted between 2017 and 2018 in 33 European perinatal centers. The study included women with a singleton pregnancy from 32 + 0 to 36 + 6 weeks of gestation with a fetus considered at risk for FGR, defined as estimated fetal weight (EFW) and/or fetal abdominal circumference < 10th percentile, or umbilicocerebral ratio (UCR) ≥ 95th percentile or a drop of more than 40 percentile points in abdominal circumference measurement from the 20-week scan. For the purposes of the current study, we identified women who received a single course of steroids to improve fetal lung maturation before delivery. Each exposed pregnancy was matched with one that did not receive antenatal corticosteroids (ACS) (control), based on gestational age at delivery and birth weight. The primary adverse outcome was a composite of abnormal condition at birth, major neonatal morbidity or perinatal death.ResultsA total of 86 pregnancies that received ACS were matched to 86 controls. The two groups were similar with respect to gestational age (33.1 vs 33.3 weeks), EFW (1673 vs 1634 g) and UCR (0.68 vs 0.62) at inclusion, and gestational age at delivery (35.5 vs 35.9 weeks) and birth weight (1925 vs 1948 g). No significant differences were observed between the exposed and non-exposed groups in the incidence of composite adverse outcome (28% vs 24%; P = 0.73) or any of its elements.ConclusionThe present data do not show a beneficial effect of steroids on short-term outcome of fetuses with late FGR. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Dataset Information

Oral antenatal corticosteroids evaluated in fetal sheep.

Background

Methods

Results

Conclusion

Publications

Oral antenatal corticosteroids evaluated in fetal sheep.

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