Background

Antenatal corticosteroid therapy is a standard of care for women at imminent risk of preterm labor. However, the optimal (maximum benefit and minimal risk of side effects) antenatal corticosteroid dosing strategy remains unclear. Although conveying overall benefit when given to the right patient at the right time, antenatal corticosteroid treatment efficacy is highly variable and is not risk-free. Building on earlier findings, we hypothesized that when administered in combination with slow-release betamethasone acetate, betamethasone phosphate and the high maternal-fetal betamethasone concentrations it generates are redundant for fetal lung maturation.

Objective

Using an established sheep model of prematurity and postnatal ventilation of the preterm lamb, we aimed to compare the pharmacodynamic effects of low-dosage treatment with betamethasone acetate only against a standard dosage of betamethasone phosphate and betamethasone acetate as recommended by the American College of Obstetricians and Gynecologists for women at risk of imminent preterm delivery between 24 0/7 and 35 6/7 weeks’ gestation.

Study Design

Ewes carrying a single fetus at 122±1 days’ gestation (term=150 days) were randomized to receive either (1) maternal intramuscular injections of sterile saline (the saline negative control group, n=12), (2) 2 maternal intramuscular injections of 0.25 mg/kg betamethasone phosphate+betamethasone acetate administered at 24-hour dosing intervals (the betamethasone phosphate+betamethasone acetate group, n=12); or (3) 2 maternal intramuscular injections of 0.125 mg/kg betamethasone acetate administered at 24-hour dosing intervals (the betamethasone acetate group, n=11). The fetuses were surgically delivered 48 hours after treatment initiation and ventilated for 30 minutes to determine functional lung maturation. The fetuses were euthanized after ventilation, and the lungs were collected for analysis using quantitative polymerase chain reaction and Western blot assays. Fetal plasma adrenocorticotropic hormone levels were measured in the cord blood samples taken at delivery.

Results

Preterm lambs were defined as either antenatal corticosteroid treatment responders or nonresponders using an arbitrary cutoff, being a PaCO₂ level at 30 minutes of ventilation being more extreme than 2 standard deviations from the mean value of the normally distributed saline control group values. Compared with the animals in the saline control group, the animals in the antenatal corticosteroid treatment groups showed significantly improved lung physiological responses (blood gas and ventilation data) and had a biochemical signature (messenger RNA and surfactant protein assays) consistent with functional maturation. However, the betamethasone acetate group had a significantly higher treatment response rate than the betamethasone phosphate+betamethasone acetate group. These physiological results were strongly correlated to the amount of surfactant protein A. Birthweight was lower in the betamethasone phosphate+betamethasone acetate group and the fetal hypothalamic-pituitary-adrenal axis was suppressed to a greater extent in the betamethasone phosphate+betamethasone acetate group.

Conclusion

Low-dosage antenatal corticosteroid therapy solely employing betamethasone acetate was sufficient for fetal lung maturation. The elevated maternal-fetal betamethasone concentrations associated with the coadministration of betamethasone phosphate did not in addition improve lung maturation but were associated with greater fetal hypothalamic-pituitary-adrenal axis suppression, a lower antenatal corticosteroid treatment response rate, and lower birthweight—outcomes not desirable in a clinical setting. These data warranted a clinical investigation of sustained low-dosage antenatal corticosteroid treatments that avoid high maternal-fetal betamethasone exposures.

中文翻译：

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磷酸倍他米松与醋酸倍他米松联合使用可降低产前类固醇治疗的疗效，并与较低的出生体重相关

背景

产前皮质类固醇治疗是对即将面临早产风险的妇女的护理标准。然而，最佳（最大益处和最小副作用风险）产前皮质类固醇给药策略仍不清楚。尽管在正确的时间给予正确的患者时会带来整体益处，但产前皮质类固醇治疗的效果是高度可变的，并且并非没有风险。基于早期发现，我们假设当与缓释醋酸倍他米松、磷酸倍他米松及其产生的高母胎倍他米松浓度联合给药时，对于胎儿肺成熟是多余的。

客观的

使用已建立的早产羔羊和产后通气的绵羊模型，我们旨在比较仅使用醋酸倍他米松的低剂量治疗与美国产科医师学会推荐的标准剂量的磷酸倍他米松和醋酸倍他米松治疗的药效学效果。为在妊娠 24 0/7 至 35 6/7 周之间有即将发生早产风险的妇女提供妇科医生。

学习规划

在妊娠 122±1 天（足月 = 150 天）怀有单个胎儿的母羊随机接受（1）母体肌肉注射无菌盐水（盐水阴性对照组，n = 12），（2）2 母体肌肉注射以 24 小时给药间隔注射 0.25 mg/kg 磷酸倍他米松+醋酸倍他米松（磷酸倍他米松+醋酸倍他米松组，n=12）；或 (3) 2 次母体肌肉注射 0.125 mg/kg 醋酸倍他米松，每隔 24 小时给药一次（醋酸倍他米松组，n=11）。胎儿在​​治疗开始后 48 小时通过手术分娩并通气 30 分钟以确定功能性肺成熟。胎儿通气后实施安乐死，收集肺用于使用定量聚合酶链反应和蛋白质印迹分析进行分析。在分娩时采集的脐带血样本中测量胎儿血浆促肾上腺皮质激素水平。

结果

早产羔羊被定义为使用任意截止值的产前皮质类固醇治疗反应者或无反应者，即 PaCO ₂通气 30 分钟时的水平比正态分布盐水对照组值的平均值的 2 个标准差更极端。与盐水对照组的动物相比，产前皮质类固醇治疗组的动物表现出显着改善的肺部生理反应（血气和通气数据），并且具有与功能成熟一致的生化特征（信使 RNA 和表面活性蛋白测定）。然而，醋酸倍他米松组的治疗反应率明显高于磷酸倍他米松+醋酸倍他米松组。这些生理结果与表面活性剂蛋白 A 的量密切相关。

结论

仅使用醋酸倍他米松的低剂量产前皮质类固醇治疗足以使胎儿肺成熟。与联合使用磷酸倍他米松相关的母胎倍他米松浓度升高并没有改善肺成熟，但与更大的胎儿下丘脑-垂体-肾上腺轴抑制、较低的产前皮质类固醇治疗反应率和较低的出生体重相关——结果不可取在临床环境中。这些数据保证了对避免高母胎倍他米松暴露的持续低剂量产前皮质类固醇治疗的临床研究。