Haas David M, Bofill Rodriguez Magdalena, Hathaway Taylor J, Ramsey Patrick S
Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Department of Obstetrics and Gynaecology, University of Auckland, Auckland, New Zealand.
Cochrane Database Syst Rev. 2025 Jun 11;6(6):CD003511. doi: 10.1002/14651858.CD003511.pub6.
RATIONALE: Progesterone, a female sex hormone, is known to induce secretory changes in the lining of the uterus essential for successful implantation of a fertilized egg. Miscarriage is an early pregnancy loss. For women who have recurrent miscarriage, it has been suggested that a causative factor may be inadequate secretion of progesterone. Therefore, clinicians sometimes use progestogens (drugs that interact with the progesterone receptors), beginning in the first trimester of pregnancy, in an attempt to prevent spontaneous miscarriage. It is important to understand if this is beneficial or harmful. This is an update of the review, last published in 2019. Previous versions included two trials that have since been retracted. This update included an updated trial search and evaluation of all trials using the Cochrane Trustworthiness Screening Tool. OBJECTIVES: To assess the benefits and harms of progestogens as a preventative therapy against recurrent miscarriage. SEARCH METHODS: For this update, we searched CENTRAL, MEDLINE, Embase, CINAHL, Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (July 2024). We also searched reference lists from relevant articles, attempted to contact trial authors where necessary, and contacted experts in the field for unpublished works. ELIGIBILITY CRITERIA: We included randomized or quasi-randomized controlled trials in pregnant participants comparing progestogens with placebo or no treatment, given in an effort to prevent miscarriage. We included trials of participants who were diagnosed with recurrent miscarriage (usually of unknown origin) and who began treatment with progestogens in the first trimester of pregnancy. We excluded trials treating participants with threatened miscarriage or who had conceived by in-vitro fertilization. OUTCOMES: The critical outcome was miscarriage. The main important outcomes were live birth rate and preterm birth (< 37 weeks' gestation). Other important outcomes were neonatal death, fetal genital abnormalities, stillbirth, low birthweight (< 2500 g), maternal adverse events and neonatal intensive care unit admission. Other maternal outcomes of interest were severity of 'morning sickness', thromboembolic events, depression, admission to special care unit and subsequent fertility. RISK OF BIAS: Two review authors assessed the studies using the RoB 1 tool for selection, performance, detection, attrition, incomplete outcome data, selective reporting and other bias. SYNTHESIS METHODS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Two reviewers assessed the certainty of the evidence using the GRADE approach. We utilized a random-effects model to synthesize the results. INCLUDED STUDIES: Nine trials with 1426 randomized participants met the inclusion criteria. Eight trials included analyzable data for 1276 participants. Overall, the risk of bias was low for six trials, while three had areas of concern. Because few studies reported on important outcomes, imprecision was high for those outcomes, limiting the certainty of those analyses. SYNTHESIS OF RESULTS: Seven of the included trials compared treatment with placebo and the other two compared progestogen administration with no treatment. The trials were a mix of multicenter and single-center trials, conducted in Jordan, the UK, the Netherlands, and the USA. In three trials, participants had three or more consecutive miscarriages and in six trials, participants had two or more consecutive miscarriages. Route, dosage and duration of progestogen treatment varied across the trials. The majority of trials were at low risk of bias for most domains. Eight trials with 1276 participants contributed data to the analyses. Meta-analysis suggests that there is probably little to no difference in the miscarriage rate for women given progestogen supplementation compared to placebo or no treatment (risk ratio (RR) 0.91, 95% confidence interval (CI) 0.76 to 1.07; I = 0%; 8 studies, 1276 participants; moderate-certainty evidence). Subgroup analyses comparing placebo-controlled versus non-placebo-controlled trials, trials of participants with three or more prior miscarriages compared to women with two or more miscarriages, and different routes of administration showed no clear differences between subgroups for miscarriage. For women with recurrent miscarriage of unclear etiology receiving progestogen, there was probably little to no difference in live birth rate compared to placebo (RR 1.04, 95% CI 0.96 to 1.12; 5 trials, 1063 participants; moderate-certainty evidence). We are uncertain about the effect on the rate of preterm birth; there was probably little to no difference (RR 1.15, 95% CI 0.55 to 2.41; 3 trials, 256 participants; very low-certainty evidence). No clear differences were seen for women receiving progestogen for the other important outcomes, including neonatal death, fetal genital abnormalities, or stillbirth. There was little or no data on other important outcomes of low birth weight, maternal adverse events, teratogenic effects, or admission to a special care unit. None of the trials reported on any other important maternal outcomes, including severity of morning sickness, thromboembolic events, depression, admission to a special care unit, or subsequent fertility. AUTHORS' CONCLUSIONS: For women with unexplained recurrent miscarriage, progestogen supplementation therapy probably results in little to no effect on outcomes in subsequent pregnancies. FUNDING: This Cochrane review had no dedicated funding. REGISTRATION: Previous versions of this review were published in the Cochrane Library, available at doi.org/10.1002/14651858.CD003511.pub5.
理论依据:孕酮是一种女性性激素,已知其可诱导子宫内膜发生分泌期变化,这对受精卵成功着床至关重要。流产是指早期妊娠丢失。对于复发性流产的女性,有人认为其病因可能是孕酮分泌不足。因此,临床医生有时会在妊娠早期开始使用孕激素(与孕酮受体相互作用的药物),试图预防自然流产。了解这种做法是有益还是有害很重要。这是该综述的更新版,上次发表于2019年。之前的版本包括两项后来已被撤回的试验。本次更新包括更新后的试验检索以及使用Cochrane可信度筛查工具对所有试验进行的评估。 目的:评估孕激素作为预防复发性流产的治疗方法的益处和危害。 检索方法:本次更新中,我们检索了CENTRAL、MEDLINE、Embase、CINAHL、Cochrane妊娠与分娩试验注册库、ClinicalTrials.gov以及世界卫生组织国际临床试验注册平台(2024年7月)。我们还检索了相关文章的参考文献列表,必要时尝试联系试验作者,并联系该领域的专家获取未发表的研究成果。 纳入标准:我们纳入了将孕激素与安慰剂或不治疗进行比较的、针对孕妇的随机或半随机对照试验,旨在预防流产。我们纳入了被诊断为复发性流产(通常病因不明)且在妊娠早期开始接受孕激素治疗的参与者的试验。我们排除了治疗有先兆流产的参与者或通过体外受精受孕的参与者的试验。 结局指标:关键结局是流产。主要重要结局是活产率和早产(妊娠<37周)。其他重要结局是新生儿死亡、胎儿生殖器异常、死产、低出生体重(<2500g)、母体不良事件以及新生儿重症监护病房入院情况。其他感兴趣的母体结局是“孕吐”的严重程度、血栓栓塞事件、抑郁症、入住特殊护理病房以及后续生育能力。 偏倚风险:两位综述作者使用RoB 1工具对研究的选择、实施、检测、失访、不完整结局数据、选择性报告以及其他偏倚进行评估。 综合方法:两位综述作者独立评估试验是否纳入以及偏倚风险,提取数据并检查其准确性。两位评价者使用GRADE方法评估证据的确定性。我们采用随机效应模型来综合结果。 纳入研究:9项试验共1426名随机参与者符合纳入标准。8项试验纳入了1276名参与者的可分析数据。总体而言,6项试验的偏倚风险较低,而3项试验存在一些问题。由于很少有研究报告重要结局,这些结局的不精确性较高,限制了这些分析的确定性。 结果综合:纳入的试验中有7项将治疗与安慰剂进行比较,另外2项将孕激素给药与不治疗进行比较。这些试验包括多中心和单中心试验,在约旦、英国、荷兰和美国开展。在3项试验中,参与者有3次或更多次连续流产,在6项试验中,参与者有2次或更多次连续流产。孕激素治疗的途径、剂量和持续时间在各试验中有所不同。大多数试验在大多数领域的偏倚风险较低。8项试验共1276名参与者的数据纳入了分析。荟萃分析表明,与安慰剂或不治疗相比,补充孕激素的女性流产率可能几乎没有差异(风险比(RR)0.91,95%置信区间(CI)0.76至1.07;I² = 0%;8项研究,1276名参与者;中等确定性证据)。比较安慰剂对照试验与非安慰剂对照试验、有3次或更多次既往流产的参与者试验与有2次或更多次流产的女性试验以及不同给药途径的亚组分析显示,各亚组之间流产率无明显差异。对于病因不明的复发性流产且接受孕激素治疗的女性,与安慰剂相比,活产率可能几乎没有差异(RR 1.04,95%CI 0.96至1.12;5项试验,1063名参与者;中等确定性证据)。我们不确定对早产率的影响;可能几乎没有差异(RR 1.15,95%CI 0.55至2.41;3项试验,256名参与者;极低确定性证据)。接受孕激素治疗的女性在其他重要结局方面,包括新生儿死亡、胎儿生殖器异常或死产,未见明显差异。关于低出生体重、母体不良事件、致畸作用或入住特殊护理病房等其他重要结局,几乎没有或没有数据。没有试验报告任何其他重要的母体结局,包括孕吐严重程度、血栓栓塞事件、抑郁症、入住特殊护理病房或后续生育能力。 作者结论:对于不明原因的复发性流产女性,补充孕激素治疗可能对后续妊娠结局几乎没有影响。 资助:本Cochrane综述没有专门的资助。 注册情况:本综述的先前版本发表在Cochrane图书馆,可在doi.org/10.1002/14651858.CD003511.pub5获取。
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