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

• DOI: 10.1016/j.ajog.2017.11.560
• Publication Date: 2017-11-12T13:17:49Z
• Authors: Augusto F. Schmidt; Matthew W. Kemp; Judith Rittenscho...; Paranthaman S. Ka...; Haruo Usuda; Masatoshi Saito; Lucy Furfaro; Shimpei Watanabe; Sarah Stock; Boris W. Kramer; John P. Newnham; Suhas G. Kallapur; Alan H. Jobe
• Keywords: PHARMACOKINETICS; GLUCOCORTICOID TREATMENT; Messenger; Reproductive health and childbirth; fetal lung maturation; Low Birth Weight and Health of the Newborn; Betamethasone; 0302 clinical medicine; Models; Pregnancy; Infant Mortality; GESTATIONAL-AGE; Lung; Pediatric; BORN; NEONATAL-MORTALITY; RANDOMIZED CONTROLLED-TRIAL; 3. Good health; Subfamily A; PREGNANCY; RESPIRATORY-DISTRESS; 6.1 Pharmaceuticals; Models, Animal; TRIAL; Female; Drug; ANTENATAL CORTICOSTEROIDS; Pulmonary Surfactant-Associated Proteins; ATP Binding Cassette Transporter, Subfamily A; BIRTH; ATP Binding Cassette Transporter; 610; betamethasone; TERM; Article; Dose-Response Relationship; Paediatrics and Reproductive Medicine; 03 medical and health sciences; Fetal Organ Maturity; Preterm; Animals; RNA, Messenger; Obstetrics & Reproductive Medicine; Glucocorticoids; MULTIPLE COURSES; Sheep; Biomedical and Clinical Sciences; Dose-Response Relationship, Drug; Animal; prematurity; Evaluation of treatments and therapeutic interventions; Paediatrics; Perinatal Period - Conditions Originating in Perinatal Period; antenatal corticosteroids; Aquaporin 5; Reproductive Medicine; RNA; Reproductive medicine

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.The purpose of this study was to investigate pharmacokinetics and fetal lung maturation of antenatal betamethasone-acetate in preterm fetal sheep.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.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.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.