1. Academic Validation
  2. Low-dose betamethasone-acetate for fetal lung maturation in preterm sheep

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

  • Am J Obstet Gynecol. 2018 Jan;218(1):132.e1-132.e9. doi: 10.1016/j.ajog.2017.11.560.
Augusto F Schmidt 1 Matthew W Kemp 2 Judith Rittenschober-Böhm 3 Paranthaman S Kannan 1 Haruo Usuda 2 Masatoshi Saito 4 Lucy Furfaro 2 Shimpei Watanabe 4 Sarah Stock 5 Boris W Kramer 6 John P Newnham 2 Suhas G Kallapur 1 Alan H Jobe 7
Affiliations

Affiliations

  • 1 Division of Neonatology and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
  • 2 School Women's and Infants' Health, University of Western Australia, Perth, Australia.
  • 3 Division of Neonatology, Pediatric Intensive Care and Neuropediatrics, Medical University Vienna, Vienna, Austria.
  • 4 Department of Obstetrics and Gynecology, Tohoku University, Sendai, Japan.
  • 5 MRC Centre for Reproductive Health, University of Edinburgh Queen's Medical Research Institute, Edinburgh, United Kingdom.
  • 6 Maastricht University Medical Center, Maastricht, Netherlands.
  • 7 Division of Neonatology and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. Electronic address: alan.jobe@cchmc.org.
Abstract

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.

Keywords

antenatal corticosteroids; betamethasone; fetal lung maturation; prematurity.

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