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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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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:Background: Retinopathy of prematurity (ROP) is a major cause of childhood blindness. Antenatal corticosteroids (ACS) exposure is known to ameliorate the risk of and mortality of neonatal morbidities. However, the effect of ACS on ROP development is currently unknown. We conducted a meta-analysis with up-to-date evidence to assess the association between ACS exposure and the development of ROP in at-risk preterm infants. Methods: PubMed, EMBASE, Scopus, Web of Science, and the Cochrane Library were systematically searched from inception to May 2021, supplemented with manual search from reference lists. Studies with a control group reporting ROP rate in ACS-exposed infants were included. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated utilizing a random-effects model. The Newcastle-Ottawa Scale was used for assessment of risk of bias in the included studies. Meta-regressions were performed to explore the predictive role of confounders for between-study variance. Results: A total of 63 studies, involving 196,264 infants, were included. Meta-analysis showed ACS exposure was not associated with ROP occurrence (uOR 0.92, 95% CI 0.80-1.07; aOR 0.87, 95% CI 0.7-1.08). Results from extremely immature subgroups revealed significant reduced risks of ROP occurrence in ACS-exposed infants. ACS exposure was associated with significantly lower odds of ROP progression in adjusted analysis (aOR 0.48, 95% CI 0.26-0.89) instead of unadjusted analysis (uOR 0.86, 95% CI 0.68-1.08). Meta-regression showed birth weight and patent ductus arteriosus of the cohort were associated with ROP occurrence, sample size and study design strongly associated with ROP progression in ACS-exposed infants. Conclusion: ACS treatment may decrease, but not prevent, the severity of ROP. Findings from severe ROP should be interpreted with caution owing to limited studies and the possibility of false-positive results. Considering the particular benefits in extremely immature infants, we recommend routine usage of ACS in mothers with threatened delivery to this particular birth cohort to prevent ROP occurrence. Future studies adjusting for major confounders are warranted to mitigate risk of bias in such observational evidence.

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Oral antenatal corticosteroids evaluated in fetal sheep.

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Oral antenatal corticosteroids evaluated in fetal sheep.

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