Predictive Accuracy of Serial Transvaginal Cervical Lengths and Quantitative Vaginal Fetal Fibronectin Levels for Spontaneous Preterm Birth Among Nulliparous Women

Abstract

Importance: Spontaneous preterm birth is a leading cause of infant mortality. Prediction, largely based on prior pregnancy outcomes, is not possible in women pregnant for the first time.

Objective: To assess the accuracy of universal screening to predict spontaneous preterm birth in nulliparous women using serial measurements of vaginal fetal fibronectin levels and cervical length.

Design, settings, and participants: A prospective observational cohort study of nulliparous women with singleton pregnancies, from 8 clinical sites across the United States between October 2010 and May 2014. Women and clinicians were blinded to results unless cervical shortening less than 15 mm was identified.

Exposures: Transvaginal cervical length and quantitative vaginal fetal fibronectin levels were reviewed at 2 study visits 4 or more weeks apart.

Main outcomes and measures: Spontaneous preterm birth at less than 37 weeks was the primary outcome. Cervical length and quantitative fetal fibronectin were considered independently and together at each visit. Measurement distributions were compared for spontaneous preterm birth vs all other births. Spontaneous preterm birth before 32 weeks was a secondary outcome.

Results: The study included 9410 women (median age, 27.0 [interquartile range, 9.0] years; 60.7% non-Hispanic white, 13.8% non-Hispanic black, 16.5% Hispanic, 4.0% Asian, and 5.1% other), of whom 474 (5.0%) had spontaneous preterm births, 335 (3.6%) had medically indicated preterm births, and 8601 (91.4%) had term births. Among women with spontaneous preterm birth, cervical length of 25 mm or less occurred in 35 of 439 (8.0%) at 16 to 22 weeks' gestation and in 94 of 403 (23.3%) at 22 to 30 weeks' gestation. Fetal fibronectin levels of 50 ng/mL or greater at 16 to 22 weeks identified 30 of 410 women (7.3%) with spontaneous preterm birth and 31 of 384 (8.1%) at 22 to 30 weeks. The area under the receiver operating characteristic curve for screening between 22 and 30 weeks for fetal fibronectin level alone was 0.59 (95% CI, 0.56-0.62), for transvaginal cervical length alone was 0.67 (95% CI, 0.64-0.70), and for the combination as continuous variables was 0.67 (95% CI, 0.64-0.70).

Conclusions and relevance: Among nulliparous women with singleton pregnancies, quantitative vaginal fetal fibronectin and serial transvaginal ultrasound cervical length had low predictive accuracy for spontaneous preterm birth. These findings do not support routine use of these tests in such women.

Figure 1. Enrollment and Inclusion in Analysis in the Nulliparous Pregnancy Outcome Study: Monitoring Mothers-to-Be (nuMoM2b)

This analysis assessed serial transvaginal ultrasound cervical length and quantitative vaginal fetal fibronectin, alone and in combination, and measured at different points during pregnancy and as rates of change, to detect spontaneous preterm birth in nulliparous women with singleton pregnancies successfully carried 20 weeks or more. Women enrolled in the study who carried their pregnancy to 20 weeks or more were eligible for the analysis. To determine eligibility required collection of the necessary pregnancy outcome data to exclude pregnancy losses at less than 20 weeks. Furthermore, the analysis was only possible among the women with results from at least 1 serial transvaginal ultrasound or 1 sample assayed for fetal fibronectin level. TVCL indicates transvaginal cervical length. ^aElective termination (n = 10), indicated termination (n = 23), and fetal demise at less than 20 weeks’ gestational age (n = 77).

Figure 2. Receiver Operating Characteristic Curves for Visit-3 Measures Predicting Spontaneous Preterm Birth at Less Than 37 Weeks’ Gestation

Receiver operating characteristic (ROC) curves are shown for serial transvaginal ultrasound cervical length (TVCL), quantitative vaginal fetal fibronectin, and their combination through a logistic regression model in predicting spontaneous preterm birth at less than 37 weeks’ gestation. The ultrasound used for the cervical length measurement and the sample required for the fetal fibronectin assay were taken at Nulliparous Pregnancy Outcome Study: Monitoring Mothers-to-Be (nuMoM2b) visit 3, scheduled for 22 to 30 weeks’ gestation. The graph includes all women with the cervical length measurement for the cervical length curve; all women with fetal fibronectin data for the fetal fibronectin curve; and all women with both for the combined curve. Statistics below the graph correspond to the graph (all available data). Area under the ROC curve (AUC) statistics, restricted to the women with both measures (n = 8211), are 0.67 (95% CI, 0.64–0.71) for TVCL at visit 3; 0.58 (95% CI, 0.55–0.62) for vaginal fetal fibronectin level at visit 3; and 0.67 (95% CI, 0.64–0.70) for both TVCL and fetal fibronectin level at visit 3. The AUCs are significantly different for TVCL vs fetal fibronectin level, P < .001. The AUC combining TVCL and fetal fibronectin level is not significantly different from that for TVCL alone (P = .54). Sensitivity plus specificity is maximized at 31.7 mm for TVCL and 7.08 ng/mL for fetal fibronectin.