Background

Antenatal betamethasone is recommended before preterm delivery to accelerate fetal lung maturation. However, reports of growth and neurodevelopmental dose-related side-effects suggest that the current dose (12 mg plus 12 mg, 24 h apart) might be too high. We therefore investigated whether a half dose would be non-inferior to the current full dose for preventing respiratory distress syndrome.

Methods

We designed a randomised, multicentre, double-blind, placebo-controlled, non-inferiority trial in 37 level 3 referral perinatal centres in France. Eligible participants were pregnant women aged 18 years or older with a singleton fetus at risk of preterm delivery and already treated with the first injection of antenatal betamethasone (11·4 mg) before 32 weeks’ gestation. We used a computer-generated code producing permuted blocks of varying sizes to randomly assign (1:1) women to receive either a placebo (half-dose group) or a second 11·4 mg betamethasone injection (full-dose group) 24 h later. Randomisation was stratified by gestational age (before or after 28 weeks). Participants, clinicians, and study staff were masked to the treatment allocation. The primary outcome was the need for exogenous intratracheal surfactant within 48 h after birth. Non-inferiority would be shown if the higher limit of the 95% CI for the between-group difference between the half-dose and full-dose groups in the primary endpoint was less than 4 percentage points (corresponding to a maximum relative risk of 1·20). Four interim analyses monitoring the primary and the secondary safety outcomes were done during the study period, using a sequential data analysis method that provided futility and non-inferiority stopping rules and checked for type I and II errors. Interim analyses were done in the intention-to-treat population. This trial was registered with ClinicalTrials.gov, NCT02897076.

Findings

Between Jan 2, 2017, and Oct 9, 2019, 3244 women were randomly assigned to the half-dose (n=1620 [49·9%]) or the full-dose group (n=1624 [50·1%]); 48 women withdrew consent, 30 fetuses were stillborn, 16 neonates were lost to follow-up, and 9 neonates died before evaluation, so that 3141 neonates remained for analysis. In the intention-to-treat analysis, the primary outcome occurred in 313 (20·0%) of 1567 neonates in the half-dose group and 276 (17·5%) of 1574 neonates in the full-dose group (risk difference 2·4%, 95% CI –0·3 to 5·2); thus non-inferiority was not shown. The per-protocol analysis also did not show non-inferiority (risk difference 2·2%, 95% CI –0·6 to 5·1). No between-group differences appeared in the rates of neonatal death, grade 3–4 intraventricular haemorrhage, stage ≥2 necrotising enterocolitis, severe retinopathy of prematurity, or bronchopulmonary dysplasia.

Interpretation

Because non-inferiority of the half-dose compared with the full-dose regimen was not shown, our results do not support practice changes towards antenatal betamethasone dose reduction.

Funding

French Ministry of Health.

中文翻译：

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半剂量与全剂量产前倍他米松相比，有早产风险的妇女的新生儿结局：一项随机、多中心、双盲、安慰剂对照、非劣效性试验

背景

建议在早产前使用产前倍他米松，以加速胎肺成熟。然而，关于生长和神经发育剂量相关副作用的报告表明，当前剂量（12 毫克加 12 毫克，间隔 24 小时）可能过高。因此，我们研究了半剂量是否不劣于当前的全剂量预防呼吸窘迫综合征。

方法

我们在法国 37 个 3 级转诊围产中心设计了一项随机、多中心、双盲、安慰剂对照、非劣效性试验。符合条件的参与者是年龄在 18 岁或以上的孕妇，单胎胎儿有早产风险，并且在妊娠 32 周前已经接受了第一次产前倍他米松（11·4 毫克）的治疗。我们使用计算机生成的代码生成不同大小的置换块，以随机分配 (1:1) 女性在 24 小时内接受安慰剂（半剂量组）或第二次 11·4 mg 倍他米松注射（全剂量组）之后。随机化按胎龄（28 周之前或之后）进行分层。参与者、临床医生和研究人员对治疗分配不知情。主要结果是出生后 48 小时内需要外源性气管内表面活性剂。如果主要终点中半剂量组和全剂量组之间组间差异的 95% CI 上限小于 4 个百分点（对应于最大相对风险 1 ·20)。在研究期间进行了四项监测主要和次要安全性结果的中期分析，使用提供无效和非劣效性停止规则并检查 I 型和 II 型错误的顺序数据分析方法。在意向治疗人群中进行了中期分析。该试验已在 ClinicalTrials.gov 注册，NCT02897076。

发现

2017 年 1 月 2 日至 2019 年 10 月 9 日，3244 名女性被随机分配到半剂量组 (n=1620 [49·9%]) 或全剂量组 (n=1624 [50·1%]) ; 48名妇女撤回同意，30名胎儿死产，16名新生儿失访，9名新生儿在评估前死亡，剩余3141名新生儿进行分析。在意向治疗分析中，主要结局发生在半剂量组 1567 名新生儿中的 313 名（20·0%）和全剂量组 1574 名新生儿中的 276 名（17·5%）（风险差异2·4%, 95% CI –0·3 至 5·2)；因此没有显示出非劣效性。符合方案分析也未显示非劣效性（风险差异 2·2%，95% CI –0·6 至 5·1）。新生儿死亡率、3-4 级脑室内出血、≥2 期坏死性小肠结肠炎、

解释

由于未显示半剂量与全剂量方案相比的非劣效性，我们的结果不支持对产前倍他米松剂量减少的实践改变。

资金

法国卫生部。