Tommy's National Centre for Miscarriage Research, Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, United Kingdom.
Tommy's National Centre for Miscarriage Research, Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, United Kingdom.
Am J Obstet Gynecol. 2020 Aug;223(2):167-176. doi: 10.1016/j.ajog.2019.12.006. Epub 2020 Jan 31.
Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone supplementation may reduce the risk of miscarriage in women with recurrent or threatened miscarriage. Cochrane Reviews summarized the evidence and found that the trials were small with substantial methodologic weaknesses. Since then, the effects of first-trimester use of vaginal micronized progesterone have been evaluated in 2 large, high-quality, multicenter placebo-controlled trials, one targeting women with unexplained recurrent miscarriages (the PROMISE [PROgesterone in recurrent MIScarriagE] trial) and the other targeting women with early pregnancy bleeding (the PRISM [PRogesterone In Spontaneous Miscarriage] trial). The PROMISE trial studied 836 women from 45 hospitals in the United Kingdom and the Netherlands and found a 3% greater live birth rate with progesterone but with substantial statistical uncertainty. The PRISM trial studied 4153 women from 48 hospitals in the United Kingdom and found a 3% greater live birth rate with progesterone, but with a P value of .08. A key finding, first observed in the PROMISE trial, and then replicated in the PRISM trial, was that treatment with vaginal micronized progesterone 400 mg twice daily was associated with increasing live birth rates according to the number of previous miscarriages. Prespecified PRISM trial subgroup analysis in women with the dual risk factors of previous miscarriage(s) and current pregnancy bleeding fulfilled all 11 conditions for credible subgroup analysis. For the subgroup of women with a history of 1 or more miscarriage(s) and current pregnancy bleeding, the live birth rate was 75% (689/914) with progesterone vs 70% (619/886) with placebo (rate difference 5%; risk ratio, 1.09, 95% confidence interval, 1.03-1.15; P=.003). The benefit was greater for the subgroup of women with 3 or more previous miscarriages and current pregnancy bleeding; live birth rate was 72% (98/137) with progesterone vs 57% (85/148) with placebo (rate difference 15%; risk ratio, 1.28, 95% confidence interval, 1.08-1.51; P=.004). No short-term safety concerns were identified from the PROMISE and PRISM trials. Therefore, women with a history of miscarriage who present with bleeding in early pregnancy may benefit from the use of vaginal micronized progesterone 400 mg twice daily. Women and their care providers should use the findings for shared decision-making.
孕激素对于维持妊娠至关重要。几项小型试验表明，孕激素补充可能降低复发性或有流产风险的女性的流产风险。 Cochrane 综述总结了证据，发现这些试验规模较小，方法学上存在较大的缺陷。此后，阴道用微粒化黄体酮在早孕期的应用效果已在两项大型、高质量、多中心安慰剂对照试验中进行了评估，一项针对不明原因复发性流产的女性（PROMISE [PROgesterone in recurrent MIScarriagE] 试验），另一项针对早孕期出血的女性（PRISM [PRogesterone In Spontaneous Miscarriage] 试验）。PROMISE 试验纳入了来自英国和荷兰 45 家医院的 836 名女性，结果发现孕激素组活产率增加了 3%，但存在较大的统计学不确定性。PRISM 试验纳入了来自英国 48 家医院的 4153 名女性，结果发现孕激素组活产率增加了 3%，但 P 值为 0.08。一个关键发现是，阴道用微粒化黄体酮 400mg，每日两次，治疗可提高活产率，且这种效果与既往流产次数相关，这一发现最初在 PROMISE 试验中观察到，随后在 PRISM 试验中得到了证实。PRISM 试验预先设定的亚组分析显示，对于既往流产史和当前妊娠出血的双重危险因素的女性，符合所有 11 项可信亚组分析条件。对于有 1 次或多次流产史和当前妊娠出血的女性亚组，孕激素组活产率为 75%（689/914），安慰剂组为 70%（619/886）（差异 5%；风险比，1.09，95%置信区间，1.03-1.15；P=.003）。对于既往有 3 次或以上流产史和当前妊娠出血的女性亚组，获益更大；孕激素组活产率为 72%（98/137），安慰剂组为 57%（85/148）（差异 15%；风险比，1.28，95%置信区间，1.08-1.51；P=.004）。PROMISE 和 PRISM 试验均未发现短期安全性问题。因此，有流产史且早孕期出血的女性可能从阴道用微粒化黄体酮 400mg，每日两次的治疗中获益。女性及其护理人员应根据研究结果进行共同决策。
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