Performance of the cervical shortening for prediction of spontaneous preterm birth in uncomplicated twins

There is a lack of consensus about the management of twins with significant cervical length (CL) shortening, especially if CL is above 25 mm. Therefore, it is important to define “abnormal” CL change over time, and to compare the performance of different strategies. The aim of this study was twofold, to describe the performance of the cervical shortening and that of an integrated strategy that includes both the cervical shortening and a fixed CL cutoff <25 mm in any measurement as predictor of spontaneous PTB (sPTB) < 34 weeks in uncomplicated twin pregnancies.
Retrospective cohort study of twins followed in our Twins Clinic at Hospital Italiano de Buenos Aires from 2013 to 2017. Inclusion criteria were dichorionic or monochorionic diamniotic twins with CL measurement between 18 and 33 + 6 weeks with available data of the delivery. Exclusion criteria included any of the following complications: iatrogenic preterm delivery <34 weeks, cerclage, fetal growth restriction, fetal death, structural anomalies, polyhydramnios, twin–twin transfusion syndrome, selective fetal growth restriction, twin anemia–polycythemia sequence, and twin reversed arterial perfusion sequence. Spontaneous preterm birth was defined as spontaneous delivery <34 weeks. Cervical shortening was analyzed in the following periods: 20–24 weeks, 20–28 weeks, 24–28 weeks, 24–32 weeks and 28–32 weeks. Cervical changes were analyzed as velocity of shortening over time (mm/week) and as the ratio of shortening over time (%/week). ROC curves for each period were constructed and two different cutoffs were used to classify changes of the CL as positive or negative screening: a) the shortening of CL associated to the highest value of the Youden Index and b) fixing a 10% false positive rate (FPR). For the second objective, we analyzed an integrated strategy considering a fixed cutoff of 25 mm at any GA and/or a significant shortening. The screening was considered positive if any CL measurement was <25 mm at any GA or there was a shortening of the CL ≥ the cutoff obtained for each period. We report sensitivity, specificity, positive and negative predictive value, positive and negative likelihood ratio and area under the ROC curve.
We included 378 patients and 1417 measurements, 284 (75%) dichorionic and 94 (25%) monochorionic. Between 20 and 28 weeks, with a change in CL cutoff = 1.6 mm/week or 4.1%/week the detection rate was 54.2% (32.8–74.4%) and the specificity 80.5% (75.1–85.1%) and 83.5% (78.5–87.8%) respectively. In the integrated strategy, the detection rate was 65.7% (47.8–80.9%) and the specificity 69 (63.7–74). All the ROC curves of the periods studied showed an AUC < 0.7. In the group of patients that delivered preterm the initial mean CL was shorter than in the term group, 39 (±12) mm vs. 43 (± 7.7) mm (p = .02) and the most important change in CL was at 20–24 weeks both in the velocity and in the ratio of shortening over time. Conversely, patients that delivered at term showed a higher change in CL in the third trimester.
The performance of all the strategies analyzed as a predictor of sPTB <34 weeks was moderate. The period 20–28 weeks detected half of the patients at risk with a FPR around 10–20% and the integrated strategy increased the sensitivity up to a detection of two thirds of the patients at risk but with a FPR of ∼30%. Future analyses need to explore other strategies to improve the performance and to really identify the patients at higher risk.

目前针对伴显著宫颈长度（cervical length, CL）缩短的双胎妊娠的管理方案尚未达成共识，尤其是当CL高于25mm时。因此，明确随时间变化的“异常”CL变化模式，并比较不同筛查策略的效能具有重要意义。本研究旨在达成双重目标：一是描述宫颈缩短的预测效能，以及同时纳入宫颈缩短与任意孕周（gestational age, GA）测量值<25mm这一固定CL截断值的整合策略，对无并发症双胎妊娠的<34周自发性早产（spontaneous PTB, sPTB）的预测价值。

本研究为回顾性队列研究，纳入2013年至2017年于布宜诺斯艾利斯意大利医院双胎门诊随访的双胎妊娠患者。纳入标准为：双绒毛膜或单绒毛膜双羊膜双胎，在孕18~33+6周期间完成CL测量且具备分娩相关完整数据。排除标准包括以下任意一种并发症：医源性<34周早产、宫颈环扎术、胎儿生长受限、胎儿死亡、结构畸形、羊水过多、双胎输血综合征、选择性胎儿生长受限、双胎贫血-红细胞增多序列征以及双胎反向动脉灌注序列征。自发性早产定义为孕周<34周的自发分娩。

宫颈缩短的分析时段设定为20~24周、20~28周、24~28周、24~32周及28~32周。宫颈变化以随时间缩短的速率（mm/周）以及缩短比例（%/周）进行分析。针对每个时段构建受试者工作特征（ROC）曲线，并采用两种不同截断值将CL变化划分为筛查阳性或阴性：a) 对应尤登指数（Youden Index）最高值的CL缩短截断值；b) 设定10%假阳性率（false positive rate, FPR）的截断值。针对第二项研究目标，本研究分析了整合策略：纳入任意孕周下CL<25mm的固定截断值，以及/或显著宫颈缩短。当任意孕周的CL测量值<25mm，或CL缩短幅度≥各时段对应截断值时，判定为筛查阳性。本研究报告了灵敏度、特异度、阳性预测值、阴性预测值、阳性似然比、阴性似然比以及ROC曲线下面积（AUC）。

本研究共纳入378例患者，累计1417次CL测量数据，其中284例（75%）为双绒毛膜双胎，94例（25%）为单绒毛膜双胎。在20~28周时段，当CL缩短截断值为1.6mm/周或4.1%/周时，检出率分别为54.2%（95%置信区间：32.8%~74.4%），特异度分别为80.5%（95%置信区间：75.1%~85.1%）与83.5%（95%置信区间：78.5%~87.8%）。在整合策略下，检出率为65.7%（95%置信区间：47.8%~80.9%），特异度为69%（95%置信区间：63.7%~74%）。所有研究时段的ROC曲线AUC均<0.7。在早产分娩组中，初始平均CL长度显著低于足月分娩组：39mm（±12）vs 43mm（±7.7），p=0.02；且无论是缩短速率还是缩短比例，最显著的CL变化均出现于20~24周时段。与之相反，足月分娩患者的CL变化在妊娠晚期更为显著。

所有分析策略对<34周sPTB的预测效能均为中等。20~28周时段可在10%~20%的假阳性率下检出半数高危患者；而整合策略可将灵敏度提升至约三分之二的高危患者检出率，但假阳性率约为30%。未来的研究需探索其他优化策略，以进一步提升筛查效能，精准识别更高危的双胎妊娠患者。