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

Abstract

BackgroundAntenatal 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.ObjectiveThe purpose of this study was to investigate pharmacokinetics and fetal lung maturation of antenatal betamethasone-acetate in preterm fetal sheep.Study DesignGroups 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.ResultsAll 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.ConclusionA 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.

Incomplete Antenatal Steroid Therapy Can Enhance Outcomes in Preterm Infants with Emergency Conditions

“…In an animal model with low-dose betamethasone on preterm lambs, the effects of single-dose intramuscular betamethasone therapy were shown to be similar to those of double-dose in terms of significant improvement in dynamic and static lung compliance, gas exchange and ventilation effectiveness (16). It was shown that a single-dose of betamethasone-acetate has an effect on the fetal lung growth with that of the double-dose and the lung function improves 8- 15 hours after the steroid administration (16). Therefore, the efficacy of steroid therapy administered just before birth suggests that the effect will increase even if just a drop with a single-dose administration as it extends over time.…”

Does Prepregnancy Weight or Maternal BMI at Betamethasone Administration Impact Late Preterm Respiratory Morbidity?

“…It is feasible that the current dose of BMZ is sufficiently large to adequately treat women of all BMIs, 12 and sheep models have shown comparable improvement in lung maturation using low-dose steroid regimens. 13,14 The Antenatal Late Preterm Steroids trial, the original trial to our secondary analysis, reported elevated rates of neonatal hypoglycemia in women receiving BMZ compared with placebo. 4 The detailed data regarding hypoglycemia from this trial were not available for review at the time of this publication.…”

Efficacy and safety of antenatal steroids

“…Shorter treatment intervals for the two doses of betamethasone phosphate also were not as effective (97). We now think that the phosphate esters of betamethasone or dexamethasone cause unnecessarily high fetal plasma drug levels for too short an interval to effectively induce lung maturation (54,97,99). In ongoing studies, a single dose of 0.125 mg/kg betamethasone acetate may still be unnecessarily high for adequate lung maturation.…”