Cervicovaginal fetal fibronectin for the prediction of spontaneous preterm birth in multiple pregnancies: a systematic review and meta-analysis

Figures & data

Figure 1.  Study selection process.

Table I. Characteristics of studies included in the systematic review.

Study, year, country	No. of women	Inclusion criteria	Exclusion criteria	Gestational age at sampling (weeks)	Sampling frequency	Sampling site	Cut-off value (ng/ml)	Outcome
Asymptomatic women
Tolino et al. [27], 1996, Italy	68	Twins (n = 62) and triplets (n = 6); intact membranes	Not reported	24–34	Serial, weekly	Vaginal fornix and exocervix	50	Preterm birth <34 and <37 weeks
Morrison et al. [28], 1996, United States	29	“Multiples”	Cervical cerclage, preterm labor, uterine irritablity, serious maternal or fetal medical conditions	26–28	Serial, once-twice weekly	Exocervix	50	Preterm birth <34 weeks
Goldenberg et al. [29], 1996, United States	147	Twins	Cervical cerclage, placenta previa, severe fetal anomaly	24–30	Serial, every two weeks	Vaginal fornix and cervix	50	Preterm birth <32, <35, and <37 weeks
Wennerholm et al. [30], 1997, Sweden	101	Twins; intact membranes	Not reported	24–34	Serial, every two weeks	Vaginal fornix and cervix	50	Preterm birth <35 and <37 weeks
Oliveira et al. [31], 1998, Brazil	52	Twins	Not reported	24–34	Serial, every two weeks	Vaginal fornix and cervix	50	Preterm birth <34 and <37 weeks
Ramirez and Turrentine [32], 1999, United States	57	Twins	Not reported	24–34	Serial, every two weeks	Vaginal fornix and cervix	50	Preterm birth <36 weeks
McMahon et al. [33], 2002, United States	109	Twins (n = 85) and triplets (n = 24)	Cervical cerclage, rupture of membranes	20 and 24	Single	Vaginal fornix and cervix	50	Preterm birth <32 weeks
Gibson et al. [34], 2004, United Kingdom	74	Twins	Fetal anomaly, suspected twin-to-twin transfusion	24, 28, and 32	Single	Vaginal fornix	50	Preterm birth <35 weeks
Ruiz et al. [35], 2004, United States	48	Twins	Cervical incompetence, fetal death, uterine malformations	22–34	Serial, weekly	Vaginal fornix and cervix	50	Preterm birth <35 weeks
Roman et al. [36], 2005, United States	169	Twins (n = 140), triplets (n = 27), quadruplets (n = 2)	Not reported	22–32	Serial, every 2–3 weeks	Vaginal fornix	50	Preterm birth <34 weeks
Fox et al. [37], 2009, United States	155	Twins	Monoamniotic twins	22–32	Serial, every 2–3 weeks	Vaginal fornix	50	Preterm birth <32, <34, and <37 weeks
Women with symptoms of preterm labor
Peaceman et al. [38], 1997, United States	38	Twins (n = 37) and triplets (n = 1), intact membranes, symptoms of preterm labor, cervical dilatation <3 cm, no prior tocolysis	Placenta previa, cervical cerclage, trauma, rupture of membranes, cervical dilaltation ≥3 cm	24–34	Single	Vaginal fornix	50	Delivery within 7 and 14 days of sampling, preterm birth <37 weeks
Terrone et al. [39], 1998, United States	43	Twins, intact membranes, symptoms of preterm labor, cervical dilatation <2 cm	Rupture of membranes, cervical dilaltation ≥2 cm, vaginal bleeding, non reassuring fetal assessment	24–35	Single	Vaginal fornix and cervix	50	Delivery within 7 days of sampling
Gonzalez et al. [40], 2004, France	44	Twins, intact membranes, symptoms of preterm labor, cervical dilatation <2 cm	Cervical cerclage,	29.7 ± 2.6	Single	Vaginal fornix	50	Preterm birth <34 and <37 weeks
Singer et al. [41], 2007, United States	87	Twins, intact membranes, symptoms of preterm labor, cervical dilatation <3 cm	Cervical cerclage, and intercourse, a vaginal examination or a vaginal ultrasound within 24 hours of testing,	24–34	Single	Vaginal fornix	50	Delivery within 7, 14, and 21 days of sampling, and preterm birth <34 weeks

Figure 2.  Methodological quality of studies included in the systematic review. Data presented as percentages across all included studies. Figures in the stacks represent number of studies.

Figure 3.  Summary receiver operating characteristic (ROC) curves of cervicovaginal fetal fibronectin for the prediction of spontaneous preterm birth in asymptomatic women with multiple pregnancies. The area of each circle, rectangle and diamond is proportional to study's sample size.

Figure 4.  Summary receiver operating characteristic (ROC) curves of cervicovaginal fetal fibronectin for the prediction of spontaneous preterm birth in asymptomatic women with twin pregnancies. The area of each circle, rectangle and diamond is proportional to study's sample size.

Figure 5.  Summary receiver operating characteristic (ROC) curves of cervicovaginal fetal fibronectin for the prediction of spontaneous preterm birth in women with twin pregnancies and threatened preterm labor. The area of each circle, rectangle and diamond is proportional to study's sample size.

Table II. Pooled estimates for cervicovaginal fetal fibronectin in predicting spontaneous preterm birth in asymptomatic women with multiple pregnancies.

Outcome	No. of studies	No. of women	Pooled sensitivity (%) (95% CI)	Pooled specificity (%) (95% CI)	Positive likelihood ratio (95% CI)	Negative likelihood ratio (95% CI)
Multiple pregnancy (twins, triplets and quadruplets)
Preterm birth <32 weeks	3 [29,33,37]	391	35 (17–59)	94 (86–97)	5.5 (2.8–11.1)	0.69 (0.47–1.06)
Preterm birth <34 weeks	9 [27–31 ,34–37 ]	842	45 (35–57)	81 (76–86)	2.4 (1.6–3.2)	0.68 (0.55–0.85)
Preterm birth <37 weeks	6 [27,29–32 ,37]	588	40 (32–52)	85 (78–93)	2.7 (1.5–4.9)	0.71 (0.55–0.85)
Only twin pregnancy
Preterm birth <32 weeks	2 [29,37]	302	33 (14–60)	94 (85–97)	5.1 (2.7–10.0)	0.71 (0.41–1.27)
Preterm birth <34 weeks	6 [29–31 ,34,35,37]	576	39 (29–51)	80 (74–86)	2.0 (1.2–2.8)	0.76 (0.52–1.06)
Preterm birth <37 weeks	5 [29–32 ,37]	520	33 (25–45)	87 (80–94)	2.6 (1.4–7.1)	0.76 (0.47–0.93)

Table III. Pooled estimates for cervicovaginal fetal fibronectin in predicting spontaneous preterm birth in women with twin pregnancies and threatened preterm labor.

Outcome	No of studies	No of women	Pooled sensitivity (%) (95% CI)	Pooled specificity (%) (95% CI)	Positive likelihood ratio (95% CI)	Negative likelihood ratio (95% CI)
Delivery within 7 days of testing	3 [38,39,41]	168	85 (51–98)	78 (66–90)	3.9 (2.5–5.6)	0.20 (0.05–0.72)
Delivery within 14 days of testing	2 [38,41]	125	64 (27–95)	76 (62–89)	2.7 (1.4–4.7)	0.48 (0.21–1.08)
Preterm birth <34 weeks	2 [40,41]	131	53 (31–76)	71 (55–87)	1.8 (1.2–2.9)	0.67 (0.44–0.97)
Preterm birth <37 weeks	2 [38,40]	82	41 (24–61)	81 (51–97)	2.2 (0.5–5.9)	0.73 (0.54–1.13)

Table IV. Pooled estimates of pre-test probabilities, likelihood ratios, and post-test probabilities for cervicovaginal fetal fibronectin in the prediction of spontaneous preterm birth in women with multiple pregnancies.

Outcome	Pretest probability (%)	Summary likelihood ratio		Post-test probability (%)
		Positive test result	Negative test result	Positive test result	Negative test result
Asymptomatic women with multiple pregnancy
Preterm birth <32 weeks	8.7	5.5	0.69	34.4	6.2
Preterm birth <34 weeks	22.8	2.4	0.68	41.5	16.7
Preterm birth <37 weeks	48.5	2.7	0.71	71.8	40.1
Asymptomatic women with twin pregnancy
Preterm birth <32 weeks	8.9	5.1	0.71	33.3	6.5
Preterm birth <34 weeks	24.7	2.0	0.76	39.6	20.0
Preterm birth <37 weeks	48.5	2.6	0.76	71.0	41.7
Women with twin pregnancy and symptoms of threatened labor
Delivery within 7 days of testing	7.7	3.9	0.20	24.5	1.6
Delivery within 14 days of testing	8.8	2.7	0.48	20.7	4.4
Preterm birth <34 weeks	30.5	1.8	0.67	44.1	22.7
Preterm birth <37 weeks	74.4	2.2	0.73	86.5	68.0

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