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Low-dose betamethasone-acetate for fetal lung maturation in preterm sheep

BACKGROUND: Antenatal steroids are standard of care for women who are at risk of preterm delivery; however, antenatal steroid dosing and formulation have not been evaluated adequately. The standard clinical 2-dose treatment with betamethasone-acetate+betamethasone-phosphate is more effective than 2...

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Autores principales: Schmidt, Augusto F., Kemp, Matthew W., Rittenschober-Böhm, Judith, Kannan, Paranthaman S., Usuda, Haruo, Saito, Masatoshi, Furfaro, Lucy, Watanabe, Shimpei, Stock, Sarah, Kramer, Boris W., Newnham, John P., Kallapur, Suhas G., Jobe, Alan H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5759749/
https://www.ncbi.nlm.nih.gov/pubmed/29138038
http://dx.doi.org/10.1016/j.ajog.2017.11.560
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author Schmidt, Augusto F.
Kemp, Matthew W.
Rittenschober-Böhm, Judith
Kannan, Paranthaman S.
Usuda, Haruo
Saito, Masatoshi
Furfaro, Lucy
Watanabe, Shimpei
Stock, Sarah
Kramer, Boris W.
Newnham, John P.
Kallapur, Suhas G.
Jobe, Alan H.
author_facet Schmidt, Augusto F.
Kemp, Matthew W.
Rittenschober-Böhm, Judith
Kannan, Paranthaman S.
Usuda, Haruo
Saito, Masatoshi
Furfaro, Lucy
Watanabe, Shimpei
Stock, Sarah
Kramer, Boris W.
Newnham, John P.
Kallapur, Suhas G.
Jobe, Alan H.
author_sort Schmidt, Augusto F.
collection PubMed
description BACKGROUND: Antenatal steroids are standard of care for women who are at risk of preterm delivery; however, antenatal steroid dosing and formulation have not been evaluated adequately. The standard clinical 2-dose treatment with betamethasone-acetate+betamethasone-phosphate is more effective than 2 doses of betamethasone-phosphate for the induction of lung maturation in preterm fetal sheep. We hypothesized that the slowly released betamethasone-acetate component induces similar lung maturation to betamethasone-phosphate+betamethasone-acetate with decreased dose and fetal exposure. OBJECTIVE: The purpose of this study was to investigate pharmacokinetics and fetal lung maturation of antenatal betamethasone-acetate in preterm fetal sheep. STUDY DESIGN: Groups of 10 singleton-pregnant ewes received 1 or 2 intramuscular doses 24 hours apart of 0.25 mg/kg/dose of betamethasone-phosphate+betamethasone-acetate (the standard of care dose) or 1 intramuscular dose of 0.5 mg/kg, 0.25 mg/kg, or 0.125 mg/kg of betamethasone-acetate. Fetuses were delivered 48 hours after the first injection at 122 days of gestation (80% of term) and ventilated for 30 minutes, with ventilator settings, compliance, vital signs, and blood gas measurements recorded every 10 minutes. After ventilation, we measured static lung pressure-volume curves and sampled the lungs for messenger RNA measurements. Other groups of pregnant ewes and fetuses were catheterized and treated with intramuscular injections of betamethasone-phosphate 0.125 mg/kg, betamethasone-acetate 0.125 mg/kg, or betamethasone-acetate 0.5 mg/kg. Maternal and fetal betamethasone concentrations in plasma were measured for 24 hours. RESULTS: All betamethasone-treated groups had increased messenger RNA expression of surfactant proteins A, B, and C, ATP-binding cassette subfamily A member 3, and aquaporin-5 compared with control animals. Treatment with 1 dose of intramuscular betamethasone-acetate 0.125mg/kg improved dynamic and static lung compliance, gas exchange, and ventilation efficiency similarly to the standard treatment of 2 doses of 0.25 m/kg of betamethasone-acetate+betamethasone-phosphate. Betamethasone-acetate 0.125 mg/kg resulted in lower maternal and fetal peak plasma concentrations and decreased fetal exposure to betamethasone compared with betamethasone-phosphate 0.125 mg/kg. CONCLUSION: A single dose of betamethasone-acetate results in similar fetal lung maturation as the 2-dose clinical formulation of betamethasone-phosphate+betamethasone-acetate with decreased fetal exposure to betamethasone. A lower dose of betamethasone-acetate may be an effective alternative to induce fetal lung maturation with less risk to the fetus.
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spelling pubmed-57597492018-01-11 Low-dose betamethasone-acetate for fetal lung maturation in preterm sheep Schmidt, Augusto F. Kemp, Matthew W. Rittenschober-Böhm, Judith Kannan, Paranthaman S. Usuda, Haruo Saito, Masatoshi Furfaro, Lucy Watanabe, Shimpei Stock, Sarah Kramer, Boris W. Newnham, John P. Kallapur, Suhas G. Jobe, Alan H. Am J Obstet Gynecol Article BACKGROUND: Antenatal steroids are standard of care for women who are at risk of preterm delivery; however, antenatal steroid dosing and formulation have not been evaluated adequately. The standard clinical 2-dose treatment with betamethasone-acetate+betamethasone-phosphate is more effective than 2 doses of betamethasone-phosphate for the induction of lung maturation in preterm fetal sheep. We hypothesized that the slowly released betamethasone-acetate component induces similar lung maturation to betamethasone-phosphate+betamethasone-acetate with decreased dose and fetal exposure. OBJECTIVE: The purpose of this study was to investigate pharmacokinetics and fetal lung maturation of antenatal betamethasone-acetate in preterm fetal sheep. STUDY DESIGN: Groups of 10 singleton-pregnant ewes received 1 or 2 intramuscular doses 24 hours apart of 0.25 mg/kg/dose of betamethasone-phosphate+betamethasone-acetate (the standard of care dose) or 1 intramuscular dose of 0.5 mg/kg, 0.25 mg/kg, or 0.125 mg/kg of betamethasone-acetate. Fetuses were delivered 48 hours after the first injection at 122 days of gestation (80% of term) and ventilated for 30 minutes, with ventilator settings, compliance, vital signs, and blood gas measurements recorded every 10 minutes. After ventilation, we measured static lung pressure-volume curves and sampled the lungs for messenger RNA measurements. Other groups of pregnant ewes and fetuses were catheterized and treated with intramuscular injections of betamethasone-phosphate 0.125 mg/kg, betamethasone-acetate 0.125 mg/kg, or betamethasone-acetate 0.5 mg/kg. Maternal and fetal betamethasone concentrations in plasma were measured for 24 hours. RESULTS: All betamethasone-treated groups had increased messenger RNA expression of surfactant proteins A, B, and C, ATP-binding cassette subfamily A member 3, and aquaporin-5 compared with control animals. Treatment with 1 dose of intramuscular betamethasone-acetate 0.125mg/kg improved dynamic and static lung compliance, gas exchange, and ventilation efficiency similarly to the standard treatment of 2 doses of 0.25 m/kg of betamethasone-acetate+betamethasone-phosphate. Betamethasone-acetate 0.125 mg/kg resulted in lower maternal and fetal peak plasma concentrations and decreased fetal exposure to betamethasone compared with betamethasone-phosphate 0.125 mg/kg. CONCLUSION: A single dose of betamethasone-acetate results in similar fetal lung maturation as the 2-dose clinical formulation of betamethasone-phosphate+betamethasone-acetate with decreased fetal exposure to betamethasone. A lower dose of betamethasone-acetate may be an effective alternative to induce fetal lung maturation with less risk to the fetus. Elsevier 2018-01 /pmc/articles/PMC5759749/ /pubmed/29138038 http://dx.doi.org/10.1016/j.ajog.2017.11.560 Text en © 2017 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Schmidt, Augusto F.
Kemp, Matthew W.
Rittenschober-Böhm, Judith
Kannan, Paranthaman S.
Usuda, Haruo
Saito, Masatoshi
Furfaro, Lucy
Watanabe, Shimpei
Stock, Sarah
Kramer, Boris W.
Newnham, John P.
Kallapur, Suhas G.
Jobe, Alan H.
Low-dose betamethasone-acetate for fetal lung maturation in preterm sheep
title Low-dose betamethasone-acetate for fetal lung maturation in preterm sheep
title_full Low-dose betamethasone-acetate for fetal lung maturation in preterm sheep
title_fullStr Low-dose betamethasone-acetate for fetal lung maturation in preterm sheep
title_full_unstemmed Low-dose betamethasone-acetate for fetal lung maturation in preterm sheep
title_short Low-dose betamethasone-acetate for fetal lung maturation in preterm sheep
title_sort low-dose betamethasone-acetate for fetal lung maturation in preterm sheep
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5759749/
https://www.ncbi.nlm.nih.gov/pubmed/29138038
http://dx.doi.org/10.1016/j.ajog.2017.11.560
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