Boelig Rupsa C, Tersigni Chiara, Di Simone Nicoletta, Saccone Gabriele, Facchinetti Fabio, Scambia Giovanni, Berghella Vincenzo
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA (Boelig and Berghella).
Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy (Tersigni and Scambia); Università Cattolica del Sacro Cuore, Rome, Italy (Tersigni and Scambia).
Am J Obstet Gynecol MFM. 2025 Apr;7(4):101602. doi: 10.1016/j.ajogmf.2025.101602. Epub 2025 Jan 27.
Preterm birth remains a leading cause of neonatal morbidity and mortality. Cerclage for short cervical length ≤25 mm in patients with singleton pregnancies with a history of spontaneous preterm birth is associated with decreased neonatal morbidity/mortality. Both vaginal progesterone and cerclage individually have level 1 evidence supporting benefit in the prevention of preterm birth in pregnancies complicated by short cervical length. However, there is a paucity of level 1 evidence regarding the potential benefit of cerclage with progesterone relative to progesterone alone for short cervical length ≤25 mm in patients with singleton pregnancies without a history of spontaneous preterm birth.
This study aimed to conduct a pragmatic randomized controlled trial to evaluate the additional benefit of cerclage with vaginal progesterone relative to vaginal progesterone alone in patients with singleton pregnancies without prior spontaneous preterm birth and with a current midtrimester transvaginal ultrasound cervical length ≤25 mm.
This was a multicenter international randomized controlled trial conducted from September 2017 to September 2023, involving 4 sites in the United States and Italy. Patients with singleton pregnancies without prior spontaneous preterm birth received transvaginal ultrasound cervical length (universal) screening during the midtrimester anatomy ultrasound examination as part of routine care. Inclusion criteria included transvaginal ultrasound cervical length ≤25 mm at 18 0/7 to 23 6/7 weeks. Exclusion criteria included current or planned cerclage, cervical dilation, symptoms of labor, infection, bleeding, and rupture of membranes at screening. Participants were randomized in a 1:1 ratio to cerclage with vaginal progesterone (200-mg vaginal progesterone daily) or vaginal progesterone alone. Randomization was stratified by study site and transvaginal ultrasound cervical length ≤15 mm. The primary outcome was preterm birth <35 weeks, assessed using intention-to-treat analysis. Secondary outcomes included preterm birth <37, 32, 28, and 24 weeks, gestational age at delivery, latency to delivery, and neonatal outcomes. Categorical variables were compared using the Pearson chi-square test and relative risk estimates with 95% confidence intervals. Continuous variables were compared using the Mann-Whitney U test. Latency to delivery and gestational age at delivery were also compared using Kaplan-Meier survival curves. Planned enrollment was set at N=206 on the basis of an estimated 0.54 relative risk with cerclage and a 34% incidence of preterm birth with standard care. The trial was registered on ClinicalTrials.gov (NCT03251729) on June 22, 2017.
Enrollment ran from September 22, 2017 to October 31, 2023, and was halted early because of lagging enrollment. A total of 93 participants were randomized; 3 were excluded because of withdrawal (n=1) and loss to follow-up (n=2). Of the 90 participants included in the intention-to-treat analysis, 43 were assigned to cerclage and progesterone and 47 to progesterone alone. Overall, 40 participants (40.4%) had a transvaginal ultrasound cervical length ≤15 mm. There was no significant difference in the primary outcome of preterm birth <35 weeks between those randomized to cerclage with progesterone vs progesterone alone (16.3% vs 23.4%; relative risk, 0.70 [0.30-1.63]). Those randomized to cerclage with progesterone had significantly increased latency from randomization to delivery (median difference, 13 [5-20] days; P=.01) and a significantly later gestational age at delivery (median difference, 1.0 [0.2-1.7] weeks; P=.035). A Kaplan-Meier survival curve also demonstrated increased latency to delivery and gestational age at delivery for cerclage with progesterone compared with progesterone alone (Mantel-Cox log-rank P<.001 and P=.003, respectively). These findings persisted within both subgroups of cervical length ≤15 mm and 16 to 25 mm.
In singleton gestations without a prior spontaneous preterm birth and a transvaginal ultrasound cervical length ≤25 mm before 24 weeks, cerclage with progesterone was not found to significantly reduce the preterm birth rate compared with progesterone alone. However, cerclage and progesterone did result in a significantly longer latency from randomization to delivery and a significantly later gestational age at delivery, compared to progesterone alone. These results suggest the potential benefit of cerclage and progesterone relative to progesterone alone in patients with singleton pregnancies without a prior spontaneous preterm birth and a short cervical length ≤25 mm before 24 weeks. This trial was halted early, and these findings should be confirmed in a larger trial or meta-analysis. El resumen está disponible en Español al final del artículo.
早产仍然是新生儿发病和死亡的主要原因。对于有自发早产史的单胎妊娠患者，宫颈长度≤25mm时行宫颈环扎术可降低新生儿发病率/死亡率。阴道孕激素和宫颈环扎术单独应用均有1级证据支持其对预防宫颈长度短的妊娠早产有益。然而，对于无自发早产史的单胎妊娠患者，宫颈长度≤25mm时，与单独使用孕激素相比，宫颈环扎术联合孕激素潜在益处的1级证据较少。
本研究旨在进行一项实用的随机对照试验，以评估对于无既往自发早产史且孕中期经阴道超声测量宫颈长度≤25mm的单胎妊娠患者，阴道孕激素联合宫颈环扎术相对于单纯阴道孕激素的额外益处。
这是一项多中心国际随机对照试验，于2017年9月至2023年9月进行，涉及美国和意大利的4个地点。无既往自发早产史的单胎妊娠患者在孕中期解剖超声检查时接受经阴道超声宫颈长度（常规）筛查，作为常规护理的一部分。纳入标准包括孕18 0/7至23 6/7周时经阴道超声宫颈长度≤25mm。排除标准包括当前或计划行宫颈环扎术、宫颈扩张、临产症状、感染、出血以及筛查时胎膜破裂。参与者按1:1比例随机分为阴道孕激素联合宫颈环扎术（每日200mg阴道孕激素）组或单纯阴道孕激素组。随机分组按研究地点和经阴道超声宫颈长度≤15mm进行分层。主要结局为<35周早产，采用意向性分析进行评估。次要结局包括<37、32、28和24周早产、分娩孕周、分娩延迟以及新生儿结局。分类变量采用Pearson卡方检验和95%置信区间的相对风险估计进行比较。连续变量采用Mann-Whitney U检验进行比较。分娩延迟和分娩孕周也采用Kaplan-Meier生存曲线进行比较。根据估计的宫颈环扎术相对风险为0.54以及标准护理下早产发生率为34%，计划入组人数设定为N = 206。该试验于2017年6月22日在ClinicalTrials.gov（NCT03251729）注册。
入组时间为2017年9月22日至2023年10月31日，由于入组滞后提前终止。共有93名参与者被随机分组；3名因退出（n = 1）和失访（n = 2）被排除。在纳入意向性分析的90名参与者中，43名被分配至宫颈环扎术联合孕激素组，47名被分配至单纯孕激素组。总体而言，40名参与者（40.4%）经阴道超声宫颈长度≤15mm。随机分组至阴道孕激素联合宫颈环扎术组与单纯孕激素组的患者，<35周早产这一主要结局无显著差异（16.3%对23.4%；相对风险，0.70 [0.30 - 1.63]）。随机分组至阴道孕激素联合宫颈环扎术组的患者从随机分组到分娩的延迟显著增加（中位数差异，13 [5 - 20]天；P = 0.01）且分娩孕周显著更晚（中位数差异，1.0 [0.2 - 1.7]周；P = 0.035）。Kaplan-Meier生存曲线也显示，与单纯孕激素组相比，阴道孕激素联合宫颈环扎术组的分娩延迟和分娩孕周增加（Mantel-Cox对数秩检验P < 0.001和P = 0.003，分别）。这些发现在宫颈长度≤15mm和16至25mm的两个亚组中均持续存在。
对于无既往自发早产史且孕24周前经阴道超声宫颈长度≤25mm的单胎妊娠，与单纯使用孕激素相比，未发现阴道孕激素联合宫颈环扎术能显著降低早产率。然而，与单纯孕激素相比，阴道孕激素联合宫颈环扎术确实导致从随机分组到分娩的延迟显著延长以及分娩孕周显著更晚。这些结果表明，对于无既往自发早产史且孕24周前宫颈长度短≤25mm的单胎妊娠患者，阴道孕激素联合宫颈环扎术相对于单纯孕激素可能有益。本试验提前终止，这些发现应在更大规模的试验或荟萃分析中得到证实。文章末尾提供了西班牙语摘要。
