Predictive value of quantitative fetal fibronectin for spontaneous preterm birth in asymptomatic pregnancies: a systematic literature review and meta-analysis

Figures & data

Figure 1. (a) Risk of sPTB before 34 weeks based on fFN concentration. This figure does not present data for all thresholds reported because of the substantial heterogeneity observed. The figure presents thresholds that facilitate an assessment of the trend in sPTB based on the incremental fFN thresholds reported. Outcomes for the other thresholds, not shown here, are reported in Table 1. Data presented here are reported for the overall cohort enrolled in each study; subgroup data are not presented. fFN: fetal fibronectin; sPTB: spontaneous preterm birth. (b). Risk of sPTB before 37 weeks based on fFN concentration. This figure does not present data for all thresholds reported because of the substantial heterogeneity observed. The figure presents thresholds that facilitate an assessment of the trend in sPTB based on the incremental fFN thresholds reported. Outcomes for the other thresholds, not shown here, are reported in Table 1. Data presented here are reported for the overall cohort enrolled in each study; subgroup data are not presented. NuMoM2b collected fFN specimens at three timepoints; data are presented for the final follow-up visit (22–30 weeks). fFN: fetal fibronectin; sPTB: spontaneous preterm birth.

Table 1. Summary of included studies and sPTB rates by fFN levels.

Study Name, Country	Study design	Study Population	Gestational age at testing	fFN (ng/ml)	Sample size (n)	sPTB by week of gestation and fFN level (%)
						<28 w	<30 w	<32 w	<34 w	<35 w	<37 w
EQUATE [26] US	Prospective observational study	Asymptomatic high-risk women	Range: 16 weeks and 0 days to 21 weeks and 6 days	<10	921	NR	NR	3.9	NR	10.4	NR
				10-199	532			8.1		16.2
				200-499	72			15.3		23.6
				≥500	21			28.6		38.1
EQUIPP [11] US and UK	Prospective observational study	Asymptomatic high-risk women with singleton pregnancies	Median: 22 weeks 6 days Range: 22 weeks − 27 weeks 6 days	<10	1000	NR	1	NR	2.7	NR	8.1
				10-49	249		3.2		11		20.1
				50-199	121		5		14.9		26.4
				200-499	57		22.8		33.9		45.6
				≥500	21		38.1		47.6		52.4
Goldenberg 2000 [14] US	Prospective observational study	Women with singleton pregnancies^A	Range: 13 weeks − 22 weeks	0	2253	1.2	NR	2.3	NR	4.1	8.9
				1-24	3341	2.3		3.6		6.3	12.4
				25-49	378	4.8		5.8		7.7	15.9
				≥50	536	7.8		9.1		14.7	22
Jwala 2016 [24] US	Prospective observational study	Asymptomatic low-risk women with singleton pregnancies	Range: 18 weeks − 23 weeks 6 days	<5	288	1.04	NR	1.39	NR	3.13	5.21
				≥5	240	2.5		3.75		7.08	8.75
Kurtzman 2014 [25] UK	Prospective observational study	Asymptomatic patients with twin gestations	Mean: 24 weeks Range: 22 weeks − 27 weeks 6 days	0-9	NR	NR	NR	NR	4.1	NR	NR
				10-49					13.3
				50-199					33.3
				≥200					66.7
Muzaffar 2013 [28] UK	Retrospective study	Women who underwent a fFN test^A	NR	<50	NR	NR	NR	NR	NR	NR	3^B
				≥50							64^B
nuMom2b [23] US	Prospective observational study	Nulliparous women with singleton pregnancies^A	Median: 28.0 weeks Range: 22–30 weeks 6 days^C	<10	7727	NR	NR	0.2	NR	NR	3.9
				≥10	749			1.9			11.2
				<50	8187			0.2			4.3
				≥50	289			3.1			10.7
				<200	8369			0.3			4.4
				≥200	107			5.6			14.0
PREMET [16] UK	Post-hoc analysis of randomized prospective multicenter trial	Asymptomatic high-risk women with singleton pregnancies, history of PTB, and no other PTB risk factors	Range: 23 weeks − 24 weeks 6 days	0	497	0.6	0.6	2	5	7.5	18.1
				1-49	41	0	2.5	2.4	12.2	15.1	22
				50-199	17	5.9	11.8	17.7	23.5	29.4	41.2
				≥200	8	25	37.5	37.5	50	50	62.5
Preterm Prediction Study US [14]	Prospective observational study	Asymptomatic women with average risk of sPTB without multiple gestation, cervical cerclage, placenta previa, or major fetal anomaly	24 weeks	0-<20	2596	NR	NR	NR	NR	3	NR
				20-<40	187					6
				40-<60	40					8
				60-<90	17					19
				90-<150	21					19
				150-<300	31					34
				≥300	34					34
Ramsey 2004 [17] US	Post-hoc analysis of prospective randomized trial	Asymptomatic women with fFN ≥50 ng/mL	Range: 21 weeks − 25 weeks	50-99	NR	NR	NR	NR	NR	NR	12
				100-149							13
				150-199							27
				≥200							23
Tran 2019 [27] US	Prospective observational study	Asymptomatic high-risk women with singleton pregnancies with prior sPTB	Range: 18 weeks 0 days − 23 weeks 6 days	<10	65	4.6	NR	4.6	NR	6.2	18.5
				≥10	40	10.0		10.0		17.5	17.5
				<50	85	4.7		4.7		5.9	15.3
				≥50	20	15.0		15.0		30.0	30.0
				10-199	32	3.1		3.1		12.5	12.5
				≥200	8	37.5		37.5		37.5	37.5

fFN: fetal fibronectin; NR: not reported; PTB: preterm birth; fFN: fetal fibronectin; sPTB: spontaneous preterm birth; US: United States; w: week.

A. The publication did not report that women were experiencing symptoms of sPTB. Therefore, these populations were assumed to be asymptomatic women.

B. Study simply reported the proportion of patients delivering “preterm” without specifying the gestational age cutoff its assumed that data reported are sPTB rates before 37 weeks completed gestation.

C. Fetal fibronectin testing was performed at three different study visits, and the data reported here are for the final follow-up visit (between 22 weeks, 0 days and 30 weeks, 6 days).

Cells shaded in grey indicate that data were included in the meta-analysis. The nuMom2b study which investigated women with unspecified sPTB risk, who were assumed to be asymptomatic, was included in a sensitivity analyses.

Figure 2. Meta-analysis results: sPTB risk for women with high vs low fFN concentrations. Forest plot showing the results of the random-effects meta-analyses. Results show the likelihood (odds ratio) that patients with higher fFN concentrations will experience sPTB relative to patients with lower fFN concentrations. The higher the odds ratio, the greater risk of sPTB among patients with the higher fFN concentrations relative to the reference group. The 28-week analysis pooled data reported by PREMET and Tran 2019. The 30- and 34-week analysis pooled data reported by EQUIPP and PREMET. The base case 37-week analyses pooled data reported EQUIPP, PREMET and Tran 2019; the sensitivity analysis also adds data from the nuMoM2b study. CI: confidence interval; fFN: fetal fibronectin; sPTB: spontaneous preterm birth

Norwitz E, Blackwell SC, Adair CD, et al. 545: quantitative fFN for prediction of spontaneous PTB in a high-risk asymptomatic population: the equate trial. Am J Obstet Gynecol. 2019;220(1):S365. doi: 10.1016/j.ajog.2018.11.567.

 Web of Science ®Google Scholar

Abbott DS, Hezelgrave NL, Seed PT, et al. Quantitative fetal fibronectin to predict preterm birth in asymptomatic women at high risk. Obstet Gynecol. 2015;125(5):1168–1176. Maydoi: 10.1097/AOG.0000000000000754.

 PubMed Web of Science ®Google Scholar

Goepfert AR, Goldenberg RL, Mercer B, et al. The preterm prediction study: quantitative fetal fibronectin values and the prediction of spontaneous preterm birth. The national institute of child health and human development maternal-fetal medicine units network. Am J Obstet Gynecol. 2000;183(6):1480–1483. doi: 10.1067/mob.[phone].

 PubMed Web of Science ®Google Scholar

Jwala S, Tran TL, Terenna C, et al. Evaluation of additive effect of quantitative fetal fibronectin to cervical length for prediction of spontaneous preterm birth among asymptomatic low-risk women. Acta Obstet Gynecol Scand. 2016;95(8):948–955. doi: 10.1111/aogs.12907.

 PubMed Web of Science ®Google Scholar

Kurtzman J, Hezelgrave N, Abbott D, et al. 790: prediction of preterm birth in asymptomatic patients with twin gestations using a single quantitative fetal fibronectin screen. Am J Obstet Gynecol. 2014;210(1):S386–S387. doi: 10.1016/j.ajog.2013.10.823.

 Web of Science ®Google Scholar

Muzaffar S, Behrens R, Barns F, et al. editors. Quantitative fetal fibronectin and preterm delivery: BJOG-an international journal of obstetrics and gynaecology. Hoboken: Wiley-Blackwell; 2013.

 Google Scholar

Esplin MS, Elovitz MA, Iams JD, et al. Predictive accuracy of serial transvaginal cervical lengths and quantitative vaginal fetal fibronectin levels for spontaneous preterm birth among nulliparous women. JAMA. 2017;317(10):1047–1056. Mar 14doi: 10.1001/jama.2017.1373.

 PubMed Web of Science ®Google Scholar

Kurtzman J, Chandiramani M, Briley A, et al. Quantitative fetal fibronectin screening in asymptomatic high-risk patients and the spectrum of risk for recurrent preterm delivery. Am J Obstet Gynecol. 2009;200(3):263 e1–6. doi: 10.1016/j.ajog.2009.01.018.

 PubMed Web of Science ®Google Scholar

Ramsey P. Relationship of midtrimester fetal fibronectin (FFN) concentration to antibiotic efficacy for the prevention of spontaneous preterm birth in asymptomatic FFN positive women. Am J Obstet Gynecol. 2004;191(6):S11. doi: 10.1016/j.ajog.2004.09.059.

 PubMed Web of Science ®Google Scholar

Tran TL, Jwala S, Terenna C, et al. Evaluation of additive effect of quantitative fetal fibronectin to cervical length for prediction of spontaneous preterm birth among asymptomatic high-risk women. J Matern Fetal Neonatal Med. 2020;33(15):2628–2634. Aug

 PubMed Web of Science ®Google Scholar

Data availability statement

Study protocol available upon request. The data used in the analyses are presented in Table 1.