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Prediction of preterm delivery by fetal fibronectin: A meta-analysis
Review Prediction of preterm delivery by fetal fibronectin: A meta-analysis Gilles Faron, MD, Michel Boulvain, MD, PhD, Olivier Irion, MD, Paul-Marie Bernard, MSc, and William D. Fraser, MD, MSc Objective: To assess the cervicovaginal fetal fibronectin test to predict preterm delivery. Data Sources: We searched MEDLINE, Current Contents, Index Medicus, and proceedings of meetings for studies published between 1991 and June 1997. Methods of Study Selection: Inclusion criteria were prospective cohort study; test performed between 20 and 36 weeks’ gestation; fetal fibronectin measured by a previously described assay, with a cutoff level set at 50 ng/mL; test results not disclosed to women or physicians; and fewer than 20% of study participants excluded from the analysis. Tabulation, Integration, and Results: Twenty-nine relevant studies were stratified according to the prevalence of preterm delivery, the number of tests performed, and delivery before 34, 35, or 37 weeks. Sensitivities, specificities, and likelihood ratios were calculated in each study. The summary estimates of the likelihood ratio for tests yielding positive results or tests yielding negative results along with their 95% confidence intervals (CIs) were computed in each stratum according to a random-effects model. All summary likelihood ratios for a test yielding positive results indicated a significant association with preterm delivery. The strongest association was found between a single test with positive results and delivery before 37 weeks in a low-risk From the Department of Obstetrics and Gynecology, Pavillon SaintFranc¸ois d’Assise, Centre Hospitalier Universitaire de Que´bec, Universite´ Laval, Que´bec, Canada; the Department of Obstetrics and Gynecology, Hoˆpital Universitaire Brugmann, Universite´ Libre de Bruxelles, Brussels, Belgium; the Unite´ de De´veloppement en Obste´trique, Hoˆpitaux Universitaires de Gene`ve, Geneva, Switzerland; and the Department of Social and Preventive Medicine, Universite´ Laval, Que´bec, Canada. The following investigators answered our questions and provided us with additional data: S. Brennecke, B. R. Burrus, J. I. French, P. Gaucherand, F. Goffinet, R. L. Goldenberg, C. A. Grandi, P. Hellemans, G. Jimenez, B. Langer, C. J. Lockwood, J. M. O’Brien, P. Owen, F. Quintieri, P. Rozenberg, C. Salafia, M. Sebastiani, L. Vercoustre, and Y. Vial.
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population (likelihood ratio 7.5; 95% CI 4.6, 12.3). This association also was found in high-risk women (likelihood ratio 3.5; 95% CI 2.6, 4.6). In high-risk women, a test yielding negative results was associated with a reduction in risk of preterm delivery (likelihood ratio 0.4; 95% CI 0.3, 0.5). Conclusion: Fetal fibronectin in cervicovaginal secretions is associated with preterm delivery in both high-risk and low-risk women. (Obstet Gynecol 1998;92:153– 8. © 1998 by The American College of Obstetricians and Gynecologists.)
Determination of the presence of cervicovaginal fetal fibronectin has been proposed as a diagnostic test for women presenting with preterm labor1 as well as a screening test for asymptomatic women.2 Numerous studies,1–31 conducted in various clinical contexts and performed with single or serial testing, have been published recently. To summarize the information provided by these studies and to compare different testing policies, we conducted a meta-analysis of prospective cohort studies of this test.
Data Sources A computerized search was conducted to identify relevant studies published in any language. MEDLINE, Current Contents, and Index Medicus were searched for studies published between 1991 and June 1997. This search was supplemented by a manual search of proceedings of perinatal meetings and of bibliographies of articles and textbooks and by personal communications.
Study Selection To be included, studies had to fulfill the following criteria: prospective cohort study; women tested between 20 and 36 weeks’ gestation; cervicovaginal fetal fibronectin measured by a kit using a previously described enzyme-linked immunosorbant assay1; cutoff level for a test yielding positive results set at 50 ng/mL; test results not disclosed to either women or physicians before delivery; and fewer than 20% of study participants excluded from the analysis.
Tabulation and Integration Because definitions of high-risk and low-risk populations varied across studies, we assessed the risk status of the population based on its overall preterm birth rate. The prevalence levels above which studies were considered as having been conducted in high-risk populations were set before data extraction at 15%, 8%, and 5% for delivery before 37, 35, and 34 completed weeks, respectively. Studies also were stratified according to
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Table 1. Characteristics and Results of Studies Performed in Low-Risk Populations for Assessing the Prediction of Delivery Before 37 Weeks’ Gestation
First author Single test Faron4 Rozenberg10† Goldenberg18† Vercoustre21† Summary likelihood ratio x2 Heterogeneity Multiple tests Lockwood2† Hellemans17† Goldenberg20† Greenhagen‡ Langer†§ Summary likelihood ratio x2 Heterogeneity
Likelihood ratio for positive test result*
Likelihood ratio for negative test result*
95 (92, 99) 96 (92, 99) 98 (97, 99) 89 (81, 97)
6.5 (2.3, 18.2) 14.5 (5.7, 36.8) 5.0 (3.2, 7.7) 9.5 (4.5, 20.3) 7.5 (4.6, 12.3) 5.4 (P 5 .15)
0.7 (0.5, 1.0) 0.4 (0.2, 0.7) 0.9 (0.9, 1.0) 0.3 (0.0, 3.1) 0.7 (0.4, 1.0) 15.0 (P 5 .002)
72 (67, 76) 85 (79, 92) 90 (89, 92) 85 (79, 92) 89 (85, 94)
2.2 (1.6, 2.8) 3.7 (1.9, 7.1) 2.6 (1.9, 3.5) 4.2 (2.2, 8.1) 5.4 (2.5, 11.6) 3.0 (2.2, 4.1) 8.7 (P 5 .07)
0.5 (0.4, 0.8) 0.5 (0.3, 1.0) 0.8 (0.8, 0.9) 0.4 (0.2, 0.9) 0.5 (0.2, 1.1) 0.6 (0.4, 0.9) 13.4 (P 5 .01)
Sampling interval (wk)
Preterm delivery proportion (%)
No. of women included in analysis
Sensitivity (%)*
Specificity (%)*
24 –36 24 –34 24 26 –35
9.9 14.2 10.3 1.7
162 141 2929 58
31 (9, 54) 60 (39, 81) 10 (7, 13) 100
24 –37 26 –36 24 –30 24 –34 24 –34
11.4 9.6 9.0 9.9 3.4
429 136 1870 111 206
61 (48, 75) 54 (27, 81) 25 (18, 31) 64 (35, 92) 57 (20, 94)
* 95% Confidence interval given in parentheses. † Data completed by correspondence with authors. ‡ Greenhagen JB, Van Wagoner J, Dudley D, Hunter C, Mitchell M, Casal D, et al. The value of fetal fibronectin as a predictor of preterm delivery in low risk women [abstract]. Am J Obstet Gynecol 1996;176:471S. § Langer B, Boudier E, Schlaeder G. Prediction of preterm delivery by fetal fibronectin in an asymptomatic population [abstract]. Proceedings of the 15th European Congress of Perinatal Medicine; 1996 Sept 10 –13; Glasgow (UK).
the number of fetal fibronectin tests performed per pregnancy (one and more than one). In studies in which multiple tests were performed, women with at least one positive result were considered to have positive test results. If additional information was necessary, authors were contacted. Sensitivities, specificities, and likelihood ratios for positive and negative test results were computed in each study, along with their 95% confidence intervals (CIs).32 For each stratum, a x2 test of heterogeneity was computed before the summary likelihood ratio was calculated. In accordance with the limited power of this test, P , .1 was considered statistically significant. A random-effects model was used to generate a summary estimate of the likelihood ratio.33
Results Thirty-one articles1–31 and 13 abstracts and letters were identified. Twenty-one articles1–21 and eight abstracts were included (see Tables 1–3 for references). Among them, five articles16 –20 and six abstracts were included after additional information was obtained from the authors. Ten articles were excluded because of an uninterpretable 2 3 2 table,22,23 because fibronectin measurements had been carried out with a different assay,24 –26 because less than 80% of enrolled women had been accounted for in the analysis,27–30 or because a large proportion of subjects had been tested before 20 weeks.31 The studies reported in five abstracts or letters
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did not meet our inclusion criteria (Salafia C, Hardy G, Wahl E, Foye GJ, Kamens C, Vintzileos A. Cervicovaginal fibronectin levels: Clinical and pathologic correlations [abstract]. Am J Obstet Gynecol 1993;168:372S; Gebhardt S, Odendaal HJ. Fetal fibronectin in vaginal secretions—a predictor of preterm delivery? [letter]. S Afr Med J 1995;85:188; Owen P. Fetal fibronectin detection for prediction of preterm birth in low risk women [letter]. Br J Obstet Gynaecol 1995;102:1019; Jimenez G, Garcia A, Casal D, Ayala A, Tena G, Martinez R, et al. Fetal fibronectin as an aid for prediction of preterm delivery [abstract]. Int J Gynecol Obstet 1994;46:145S; Quintieri F, Paternoster D, Plebani M, Grella PV. Fetal fibronectin as a predictor of preterm delivery [abstract]. Int J Gynecol Obstet 1994;46:145S). Twenty-four studies evaluated the fetal fibronectin test to predict preterm delivery (delivery before 37 completed weeks) (Tables 1 and 2). A total of 3290 low-risk women who had a single test were included in four studies (Table 1). The summary likelihood ratio for a positive test result was 7.5 (95% CI 4.6, 12.3). The summary likelihood ratio for a negative test result was 0.7 (95% CI 0.4, 1.0). Five studies, involving 2752 low-risk women, evaluated a multiple-test policy. The summary likelihood ratios for a positive test result and for a negative test result were 3.0 (95% CI 2.2, 4.1) and 0.6 (95% CI 0.4, 0.9), respectively. In high-risk populations, 12 reports involved a total of 1591 symptomatic women who had single tests (risk of preterm delivery 19.1– 67.0%) (Table 2). The sum-
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Table 2. Characteristics and Results of Studies Performed in High-Risk Populations for Assessing the Prediction of Delivery Before 37 Weeks’ Gestation
First author Single test Lockwood1 Morrison3 Irion6 Calda7 Bartnicki9 Rozenberg11† Malak12 Rizzo14 Langer†‡ Peaceman†§ O’Brien†\ Grandi†¶ Summary likelihood ratio x2 Heterogeneity Multiple tests Leeson8 Tolino13 Vercoustre21† Vial†** Krems† †† Summary likelihood ratio x2 Heterogeneity
Sampling interval (wk)
Preterm delivery proportion (%)
No. of women included in analysis
Sensitivity (%)*
Specificity (%)*
21–37 24 –34 25–35 24 –34 22–35 24 –34 24 –37 24 –36 24 –34 24 –35 24 –33 25–36
51.3 35.7 34.0 25.0 35.7 26.3 19.1 43.5 29.5 19.2 67.0 31.0
117 28 64 84 112 76 141 108 61 725 49 26
82 (72, 91) 90 (71, 100) 68 (49, 88) 90 (78, 100) 68 (53, 82) 70 (50, 90) 63 (45, 81) 88 (72, 94) 56 (33, 79) 44 (36, 52) 67 (51, 83) 50 (15, 85)
24 –34 24 –34 26 –35 27–35 24 –36
40.0 48.5 20.9 63.8 38.5
40 68 86 47 26
38 (14, 61) 91 (81, 100) 78 (59, 97) 80 (66, 94) 50 (19, 81)
Likelihood ratio for positive test result*
Likelihood ratio for negative test result*
82 (73, 92) 72 (52, 93) 74 (61, 87) 79 (69, 89) 90 (83, 97) 70 (58, 82) 96 (92, 99) 74 (63, 85) 81 (70, 93) 86 (83, 89) 81 (62, 100) 50 (27, 73)
4.7 (2.6, 8.3) 3.2 (1.5, 7.0) 2.6 (1.5, 4.7) 4.4 (2.6, 7.3) 6.9 (3.3, 14.5) 2.3 (1.4, 3.8) 14.4 (5.8, 35.5) 3.2 (2.0, 4.9) 3.0 (1.4, 6.3) 3.2 (2.4, 4.2) 3.6 (1.2, 10.1) 1.0 (0.4, 2.3) 3.5 (2.6, 4.6) 28.1 (P 5 .003)
0.2 (0.1, 0.4) 0.1 (0.0, 0.9) 0.4 (0.2, 0.8) 0.1 (0.0, 0.5) 0.4 (0.2, 0.6) 0.4 (0.2, 0.9) 0.4 (0.2, 0.6) 0.2 (0.1, 0.4) 0.6 (0.3, 0.9) 0.7 (0.6, 0.8) 0.4 (0.2, 0.7) 1.0 (0.4, 2.3) 0.4 (0.3, 0.5) 42.7 (P , .001)
88 (74, 100) 69 (53, 84) 68 (57, 79) 71 (49, 92) 88 (71, 100)
3.0 (0.9, 10.3) 2.9 (1.8, 4.8) 2.4 (1.6, 3.7) 2.7 (1.3, 5.8) 4.0 (1.0, 16.8) 2.7 (2.1, 3.6) 0.7 (P 5 .950)
0.7 (0.5, 1.1) 0.1 (0.0, 0.4) 0.3 (0.1, 0.8) 0.3 (0.1, 0.6) 0.6 (0.3, 1.1) 0.4 (0.2, 0.7) 15.3 (P 5 .004)
95% Confidence interval given in parentheses. † Data completed by correspondence with authors. ‡ Langer B, Boudier E, Schlaeder G. Prediction of preterm delivery by fetal fibronectin in an asymptomatic population [abstract]. Proceedings of the 15th European Congress of Perinatal Medicine; 1996 Sept 10 –13, Glasgow (UK). § Peaceman AM, Andrews WW, Thorp JM, Cliver SP, Lukes A. Fetal fibronectin as a predictor of preterm birth in symptomatic patients: A multicenter trial [abstract]. Am J Obstet Gynecol 1996;176:303S. \ O’Brien JM, Mercer B, Pitts DW, Sibai BM. A comparison of fetal fibronectin, prolactin and cervical examination for the prediction of preterm delivery in symtomatic patients [abstract]. Am J Obstet Gynecol 1995;172:406S. ¶ Grandi CA, Illia RH, Perego M, Briozzo G, Cassini A, DiMarco I. Fetal fibronectin in prediction of preterm or imminent delivery [abstract]. Proceedings of the 3rd World Congress of Perinatal Medicine; 1996 Oct 20 –24; San Francisco (CA). ** Vial Y, Irion G, Hohlfeld P, Matute J, Magnanelli L, Bischof P, et al. Oncofetal fibronectin in prediction of preterm or imminent delivery [abstract]. Proceedings of the 14th European Congress of Perinatal Medicine; 1994 June 5– 8; Helsinki (Finland). †† Krems J, McGregor J, Hastings C, Hanson J. Fetal fibronectin in cervical secretions: An aid for predicting delivery in women at high risk for preterm delivery [abstract]. Am J Obstet Gynecol 1995;172:406S.
mary likelihood ratios for a positive test result and for a negative test result were 3.5 (95% CI 2.6, 4.6) and 0.4 (95% CI 0.3, 0.5), respectively. In one additional study,15 conducted in 54 asymptomatic high-risk women, a likelihood ratio for a positive test result of 2.3 (95% CI 0.7, 8.3) was found. Five studies involved a total of 267 high-risk women who had more than one test (risk of preterm delivery 20.9 – 63.8%). The summary likelihood ratios for a positive test result and for a negative test result were 2.7 (95% CI 2.1, 3.6) and 0.4 (95% CI 0.2, 0.7), respectively (Table 2). Prediction of delivery before 35 or 34 weeks’ gestation also was calculated from the data of nine studies. These results are presented in Table 3. The x2 test indicated significant heterogeneity between studies in some strata (Tables 1–3).
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Discussion To avoid the problem of publication bias, we made efforts to identify all relevant studies, reported in any language.34 We increased the validity of this metaanalysis by including both published and unpublished data, after submitting them to preset inclusion and exclusion criteria.35 To ensure completeness and quality of the data, we obtained additional information from several authors.16 –20 Data were stratified according to the risk of preterm delivery and the number of tests performed. The classification of high- or low-risk populations according to the prevalence of preterm delivery has the advantage of being independent of other methods of classifying patient risk. The risk status reported by the authors was
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Table 3. Characteristics and Results of Studies Assessing the Prediction of Delivery Before 34 or 35 Weeks’ Gestation
First author Low-risk population, single test, delivery before 35 weeks Faron4† Goldenberg18† Cox‡ Summary likelihood ratio x2 Heterogeneity Low-risk population, multiple tests, delivery before 35 weeks Goldenberg20† High-risk population, single test, delivery before 34 weeks Irion6† Burrus16† O’Brien†§ Summary likelihood ratio x2 Heterogeneity High-risk population, multiple tests, delivery before 34 weeks Morrison5 Tolino13 Summary likelihood ratio x2 Heterogeneity
Sampling interval (wk)
Preterm delivery proportion (%)
No. of women included in analysis
24 –34 24 24 –34
0.7 4.3 8.0
155 2929 175
100 20 (13, 27) 21 (0, 43)
24 –30
2.5
1870
25–33 24 –33 24 –33
20.3 70.3 39.6
26 –27 24 –33
16.5 22.1
Likelihood ratio for positive test result*
Likelihood ratio for negative test result*
94 (90, 98) 97 (97, 98) 86 (81, 92)
17.1 (9.1, 32.3) 7.4 (4.9, 11.2) 1.6 (0.5, 4.6) 6.3 (1.9, 20.7) 19.6 (P , .001)
0.3 (0.0, 2.9) 0.8 (0.8, 0.9) 0.9 (0.7, 1.2) 0.8 (0.8, 0.9) 1.3 (P 5 .53)
46 (31, 60)
90 (88, 91)
4.5 (3.2, 6.3)
0.6 (0.5, 0.8)
64 37 48
77 (54, 100) 88 (76, 100) 79 (61, 97)
69 (56, 81) 45 (16, 75) 69 (52, 86)
2.5 (1.5, 4.1) 1.6 (0.9, 2.8) 2.5 (1.4, 4.6) 2.2 (1.6, 3.0) 1.6 (P 5 .46)
0.3 (0.1, 0.9) 0.3 (0.1, 0.9) 0.3 (0.1, 0.8) 0.3 (0.2, 0.6) 0.1 (P 5 .94)
85 68
43 (17, 69) 93 (81, 100)
89 (81, 96) 66 (53, 79)
3.8 (1.6, 9.3) 2.7 (1.8, 4.1) 2.9 (2.0, 4.2) 0.5 (P 5 .49)
0.6 (0.4, 1.0) 0.1 (0.0, 0.7) 0.3 (0.0, 3.0) 5.7 (P 5 .02)
Sensitivity (%)*
Specificity (%)*
* 95% Confidence interval given in parentheses. † Data completed by correspondence with authors. ‡ Cox S, Little B, Dax J, Leveno K. Fetal fibronectin and preterm delivery [abstract]. Am J Obstet Gynecol 1996;176:306S. § O’Brien JM, Mercer B, Pitts DW, Sibai BM. A comparison of fetal fibronectin, prolactin and cervical examination for the prediction of preterm delivery in symptomatic patients [abstract]. Am J Obstet Gynecol 1995;172:406S.
in agreement with our classification according to the prevalence of preterm delivery in all but one study.15 Our results confirm that the presence of fetal fibronectin in cervicovaginal secretions is associated with delivery before 34, 35, or 37 weeks, in both high- and low-risk populations. A negative test result predicts a favorable outcome. These associations were observed with both single- and multiple-test strategies. Serialtesting strategies have been proposed as a means of improving sensitivity in the context of screening. However, multiple testing did not improve the overall performance of the test. Specificity and sensitivity are given equal weight in the calculation of the likelihood ratio, and, in this situation, the loss in specificity was not compensated for by a similar gain in sensitivity. The higher summary estimate of the likelihood ratio for a positive test result in the two low-risk population strata suggests that a single test discriminates better in this setting. Significant heterogeneity in sensitivity and specificity
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was detected between studies, as noted in a metaanalysis previously published.36 Thus, we calculated the summary likelihood ratio, because this measure varied less between studies. The likelihood ratio is useful for the comparison of test performance and for the computation of predictive values in populations with varying prevalence of the disease. As an example, in a population with a baseline risk of 5%, an asymptomatic woman with a positive fetal fibronectin test result (likelihood ratio 7.5) has a risk of preterm delivery of 28%.32 A negative test result in high-risk women is associated with a reduced risk of preterm delivery. However, in the case of a baseline risk of preterm delivery of 30% and a negative test result (likelihood ratio 0.4), the calculated risk is 15%, which is not completely reassuring. Screening programs are of value only when interventions to modify the natural course of the disorder are available. Fetal fibronectin testing may be useful to identify patient subgroups that are suited for evaluation
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of intervention strategies. Randomized trials assessing both testing and intervention programs must be conducted to determine whether fetal fibronectin screening is beneficial to women and their newborns.
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18.
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Received July 15, 1997. Received in revised form January 12, 1998. Accepted February 5, 1998.
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Gilles Faron, MD Service de gyne´cologie-obste´trique Hoˆpital Universitaire Brugmann 4, place A. Van Gehuchten 1020 Brussels Belgium E-mail: [email protected]
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Copyright © 1998 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc.
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population (likelihood ratio 7.5; 95% CI 4.6, 12.3). This association also was found in high-risk women (likelihood ratio 3.5; 95% CI 2.6, 4.6). In high-risk women, a test yielding negative results was associated with a reduction in risk of preterm delivery (likelihood ratio 0.4; 95% CI 0.3, 0.5). Conclusion: Fetal fibronectin in cervicovaginal secretions is associated with preterm delivery in both high-risk and low-risk women. (Obstet Gynecol 1998;92:153– 8. © 1998 by The American College of Obstetricians and Gynecologists.)
Determination of the presence of cervicovaginal fetal fibronectin has been proposed as a diagnostic test for women presenting with preterm labor1 as well as a screening test for asymptomatic women.2 Numerous studies,1–31 conducted in various clinical contexts and performed with single or serial testing, have been published recently. To summarize the information provided by these studies and to compare different testing policies, we conducted a meta-analysis of prospective cohort studies of this test.
Data Sources A computerized search was conducted to identify relevant studies published in any language. MEDLINE, Current Contents, and Index Medicus were searched for studies published between 1991 and June 1997. This search was supplemented by a manual search of proceedings of perinatal meetings and of bibliographies of articles and textbooks and by personal communications.
Study Selection To be included, studies had to fulfill the following criteria: prospective cohort study; women tested between 20 and 36 weeks’ gestation; cervicovaginal fetal fibronectin measured by a kit using a previously described enzyme-linked immunosorbant assay1; cutoff level for a test yielding positive results set at 50 ng/mL; test results not disclosed to either women or physicians before delivery; and fewer than 20% of study participants excluded from the analysis.
Tabulation and Integration Because definitions of high-risk and low-risk populations varied across studies, we assessed the risk status of the population based on its overall preterm birth rate. The prevalence levels above which studies were considered as having been conducted in high-risk populations were set before data extraction at 15%, 8%, and 5% for delivery before 37, 35, and 34 completed weeks, respectively. Studies also were stratified according to
0029-7844/98/$19.00 PII S0029-7844(98)00067-2
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Table 1. Characteristics and Results of Studies Performed in Low-Risk Populations for Assessing the Prediction of Delivery Before 37 Weeks’ Gestation
First author Single test Faron4 Rozenberg10† Goldenberg18† Vercoustre21† Summary likelihood ratio x2 Heterogeneity Multiple tests Lockwood2† Hellemans17† Goldenberg20† Greenhagen‡ Langer†§ Summary likelihood ratio x2 Heterogeneity
Likelihood ratio for positive test result*
Likelihood ratio for negative test result*
95 (92, 99) 96 (92, 99) 98 (97, 99) 89 (81, 97)
6.5 (2.3, 18.2) 14.5 (5.7, 36.8) 5.0 (3.2, 7.7) 9.5 (4.5, 20.3) 7.5 (4.6, 12.3) 5.4 (P 5 .15)
0.7 (0.5, 1.0) 0.4 (0.2, 0.7) 0.9 (0.9, 1.0) 0.3 (0.0, 3.1) 0.7 (0.4, 1.0) 15.0 (P 5 .002)
72 (67, 76) 85 (79, 92) 90 (89, 92) 85 (79, 92) 89 (85, 94)
2.2 (1.6, 2.8) 3.7 (1.9, 7.1) 2.6 (1.9, 3.5) 4.2 (2.2, 8.1) 5.4 (2.5, 11.6) 3.0 (2.2, 4.1) 8.7 (P 5 .07)
0.5 (0.4, 0.8) 0.5 (0.3, 1.0) 0.8 (0.8, 0.9) 0.4 (0.2, 0.9) 0.5 (0.2, 1.1) 0.6 (0.4, 0.9) 13.4 (P 5 .01)
Sampling interval (wk)
Preterm delivery proportion (%)
No. of women included in analysis
Sensitivity (%)*
Specificity (%)*
24 –36 24 –34 24 26 –35
9.9 14.2 10.3 1.7
162 141 2929 58
31 (9, 54) 60 (39, 81) 10 (7, 13) 100
24 –37 26 –36 24 –30 24 –34 24 –34
11.4 9.6 9.0 9.9 3.4
429 136 1870 111 206
61 (48, 75) 54 (27, 81) 25 (18, 31) 64 (35, 92) 57 (20, 94)
* 95% Confidence interval given in parentheses. † Data completed by correspondence with authors. ‡ Greenhagen JB, Van Wagoner J, Dudley D, Hunter C, Mitchell M, Casal D, et al. The value of fetal fibronectin as a predictor of preterm delivery in low risk women [abstract]. Am J Obstet Gynecol 1996;176:471S. § Langer B, Boudier E, Schlaeder G. Prediction of preterm delivery by fetal fibronectin in an asymptomatic population [abstract]. Proceedings of the 15th European Congress of Perinatal Medicine; 1996 Sept 10 –13; Glasgow (UK).
the number of fetal fibronectin tests performed per pregnancy (one and more than one). In studies in which multiple tests were performed, women with at least one positive result were considered to have positive test results. If additional information was necessary, authors were contacted. Sensitivities, specificities, and likelihood ratios for positive and negative test results were computed in each study, along with their 95% confidence intervals (CIs).32 For each stratum, a x2 test of heterogeneity was computed before the summary likelihood ratio was calculated. In accordance with the limited power of this test, P , .1 was considered statistically significant. A random-effects model was used to generate a summary estimate of the likelihood ratio.33
Results Thirty-one articles1–31 and 13 abstracts and letters were identified. Twenty-one articles1–21 and eight abstracts were included (see Tables 1–3 for references). Among them, five articles16 –20 and six abstracts were included after additional information was obtained from the authors. Ten articles were excluded because of an uninterpretable 2 3 2 table,22,23 because fibronectin measurements had been carried out with a different assay,24 –26 because less than 80% of enrolled women had been accounted for in the analysis,27–30 or because a large proportion of subjects had been tested before 20 weeks.31 The studies reported in five abstracts or letters
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did not meet our inclusion criteria (Salafia C, Hardy G, Wahl E, Foye GJ, Kamens C, Vintzileos A. Cervicovaginal fibronectin levels: Clinical and pathologic correlations [abstract]. Am J Obstet Gynecol 1993;168:372S; Gebhardt S, Odendaal HJ. Fetal fibronectin in vaginal secretions—a predictor of preterm delivery? [letter]. S Afr Med J 1995;85:188; Owen P. Fetal fibronectin detection for prediction of preterm birth in low risk women [letter]. Br J Obstet Gynaecol 1995;102:1019; Jimenez G, Garcia A, Casal D, Ayala A, Tena G, Martinez R, et al. Fetal fibronectin as an aid for prediction of preterm delivery [abstract]. Int J Gynecol Obstet 1994;46:145S; Quintieri F, Paternoster D, Plebani M, Grella PV. Fetal fibronectin as a predictor of preterm delivery [abstract]. Int J Gynecol Obstet 1994;46:145S). Twenty-four studies evaluated the fetal fibronectin test to predict preterm delivery (delivery before 37 completed weeks) (Tables 1 and 2). A total of 3290 low-risk women who had a single test were included in four studies (Table 1). The summary likelihood ratio for a positive test result was 7.5 (95% CI 4.6, 12.3). The summary likelihood ratio for a negative test result was 0.7 (95% CI 0.4, 1.0). Five studies, involving 2752 low-risk women, evaluated a multiple-test policy. The summary likelihood ratios for a positive test result and for a negative test result were 3.0 (95% CI 2.2, 4.1) and 0.6 (95% CI 0.4, 0.9), respectively. In high-risk populations, 12 reports involved a total of 1591 symptomatic women who had single tests (risk of preterm delivery 19.1– 67.0%) (Table 2). The sum-
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Table 2. Characteristics and Results of Studies Performed in High-Risk Populations for Assessing the Prediction of Delivery Before 37 Weeks’ Gestation
First author Single test Lockwood1 Morrison3 Irion6 Calda7 Bartnicki9 Rozenberg11† Malak12 Rizzo14 Langer†‡ Peaceman†§ O’Brien†\ Grandi†¶ Summary likelihood ratio x2 Heterogeneity Multiple tests Leeson8 Tolino13 Vercoustre21† Vial†** Krems† †† Summary likelihood ratio x2 Heterogeneity
Sampling interval (wk)
Preterm delivery proportion (%)
No. of women included in analysis
Sensitivity (%)*
Specificity (%)*
21–37 24 –34 25–35 24 –34 22–35 24 –34 24 –37 24 –36 24 –34 24 –35 24 –33 25–36
51.3 35.7 34.0 25.0 35.7 26.3 19.1 43.5 29.5 19.2 67.0 31.0
117 28 64 84 112 76 141 108 61 725 49 26
82 (72, 91) 90 (71, 100) 68 (49, 88) 90 (78, 100) 68 (53, 82) 70 (50, 90) 63 (45, 81) 88 (72, 94) 56 (33, 79) 44 (36, 52) 67 (51, 83) 50 (15, 85)
24 –34 24 –34 26 –35 27–35 24 –36
40.0 48.5 20.9 63.8 38.5
40 68 86 47 26
38 (14, 61) 91 (81, 100) 78 (59, 97) 80 (66, 94) 50 (19, 81)
Likelihood ratio for positive test result*
Likelihood ratio for negative test result*
82 (73, 92) 72 (52, 93) 74 (61, 87) 79 (69, 89) 90 (83, 97) 70 (58, 82) 96 (92, 99) 74 (63, 85) 81 (70, 93) 86 (83, 89) 81 (62, 100) 50 (27, 73)
4.7 (2.6, 8.3) 3.2 (1.5, 7.0) 2.6 (1.5, 4.7) 4.4 (2.6, 7.3) 6.9 (3.3, 14.5) 2.3 (1.4, 3.8) 14.4 (5.8, 35.5) 3.2 (2.0, 4.9) 3.0 (1.4, 6.3) 3.2 (2.4, 4.2) 3.6 (1.2, 10.1) 1.0 (0.4, 2.3) 3.5 (2.6, 4.6) 28.1 (P 5 .003)
0.2 (0.1, 0.4) 0.1 (0.0, 0.9) 0.4 (0.2, 0.8) 0.1 (0.0, 0.5) 0.4 (0.2, 0.6) 0.4 (0.2, 0.9) 0.4 (0.2, 0.6) 0.2 (0.1, 0.4) 0.6 (0.3, 0.9) 0.7 (0.6, 0.8) 0.4 (0.2, 0.7) 1.0 (0.4, 2.3) 0.4 (0.3, 0.5) 42.7 (P , .001)
88 (74, 100) 69 (53, 84) 68 (57, 79) 71 (49, 92) 88 (71, 100)
3.0 (0.9, 10.3) 2.9 (1.8, 4.8) 2.4 (1.6, 3.7) 2.7 (1.3, 5.8) 4.0 (1.0, 16.8) 2.7 (2.1, 3.6) 0.7 (P 5 .950)
0.7 (0.5, 1.1) 0.1 (0.0, 0.4) 0.3 (0.1, 0.8) 0.3 (0.1, 0.6) 0.6 (0.3, 1.1) 0.4 (0.2, 0.7) 15.3 (P 5 .004)
95% Confidence interval given in parentheses. † Data completed by correspondence with authors. ‡ Langer B, Boudier E, Schlaeder G. Prediction of preterm delivery by fetal fibronectin in an asymptomatic population [abstract]. Proceedings of the 15th European Congress of Perinatal Medicine; 1996 Sept 10 –13, Glasgow (UK). § Peaceman AM, Andrews WW, Thorp JM, Cliver SP, Lukes A. Fetal fibronectin as a predictor of preterm birth in symptomatic patients: A multicenter trial [abstract]. Am J Obstet Gynecol 1996;176:303S. \ O’Brien JM, Mercer B, Pitts DW, Sibai BM. A comparison of fetal fibronectin, prolactin and cervical examination for the prediction of preterm delivery in symtomatic patients [abstract]. Am J Obstet Gynecol 1995;172:406S. ¶ Grandi CA, Illia RH, Perego M, Briozzo G, Cassini A, DiMarco I. Fetal fibronectin in prediction of preterm or imminent delivery [abstract]. Proceedings of the 3rd World Congress of Perinatal Medicine; 1996 Oct 20 –24; San Francisco (CA). ** Vial Y, Irion G, Hohlfeld P, Matute J, Magnanelli L, Bischof P, et al. Oncofetal fibronectin in prediction of preterm or imminent delivery [abstract]. Proceedings of the 14th European Congress of Perinatal Medicine; 1994 June 5– 8; Helsinki (Finland). †† Krems J, McGregor J, Hastings C, Hanson J. Fetal fibronectin in cervical secretions: An aid for predicting delivery in women at high risk for preterm delivery [abstract]. Am J Obstet Gynecol 1995;172:406S.
mary likelihood ratios for a positive test result and for a negative test result were 3.5 (95% CI 2.6, 4.6) and 0.4 (95% CI 0.3, 0.5), respectively. In one additional study,15 conducted in 54 asymptomatic high-risk women, a likelihood ratio for a positive test result of 2.3 (95% CI 0.7, 8.3) was found. Five studies involved a total of 267 high-risk women who had more than one test (risk of preterm delivery 20.9 – 63.8%). The summary likelihood ratios for a positive test result and for a negative test result were 2.7 (95% CI 2.1, 3.6) and 0.4 (95% CI 0.2, 0.7), respectively (Table 2). Prediction of delivery before 35 or 34 weeks’ gestation also was calculated from the data of nine studies. These results are presented in Table 3. The x2 test indicated significant heterogeneity between studies in some strata (Tables 1–3).
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Discussion To avoid the problem of publication bias, we made efforts to identify all relevant studies, reported in any language.34 We increased the validity of this metaanalysis by including both published and unpublished data, after submitting them to preset inclusion and exclusion criteria.35 To ensure completeness and quality of the data, we obtained additional information from several authors.16 –20 Data were stratified according to the risk of preterm delivery and the number of tests performed. The classification of high- or low-risk populations according to the prevalence of preterm delivery has the advantage of being independent of other methods of classifying patient risk. The risk status reported by the authors was
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Table 3. Characteristics and Results of Studies Assessing the Prediction of Delivery Before 34 or 35 Weeks’ Gestation
First author Low-risk population, single test, delivery before 35 weeks Faron4† Goldenberg18† Cox‡ Summary likelihood ratio x2 Heterogeneity Low-risk population, multiple tests, delivery before 35 weeks Goldenberg20† High-risk population, single test, delivery before 34 weeks Irion6† Burrus16† O’Brien†§ Summary likelihood ratio x2 Heterogeneity High-risk population, multiple tests, delivery before 34 weeks Morrison5 Tolino13 Summary likelihood ratio x2 Heterogeneity
Sampling interval (wk)
Preterm delivery proportion (%)
No. of women included in analysis
24 –34 24 24 –34
0.7 4.3 8.0
155 2929 175
100 20 (13, 27) 21 (0, 43)
24 –30
2.5
1870
25–33 24 –33 24 –33
20.3 70.3 39.6
26 –27 24 –33
16.5 22.1
Likelihood ratio for positive test result*
Likelihood ratio for negative test result*
94 (90, 98) 97 (97, 98) 86 (81, 92)
17.1 (9.1, 32.3) 7.4 (4.9, 11.2) 1.6 (0.5, 4.6) 6.3 (1.9, 20.7) 19.6 (P , .001)
0.3 (0.0, 2.9) 0.8 (0.8, 0.9) 0.9 (0.7, 1.2) 0.8 (0.8, 0.9) 1.3 (P 5 .53)
46 (31, 60)
90 (88, 91)
4.5 (3.2, 6.3)
0.6 (0.5, 0.8)
64 37 48
77 (54, 100) 88 (76, 100) 79 (61, 97)
69 (56, 81) 45 (16, 75) 69 (52, 86)
2.5 (1.5, 4.1) 1.6 (0.9, 2.8) 2.5 (1.4, 4.6) 2.2 (1.6, 3.0) 1.6 (P 5 .46)
0.3 (0.1, 0.9) 0.3 (0.1, 0.9) 0.3 (0.1, 0.8) 0.3 (0.2, 0.6) 0.1 (P 5 .94)
85 68
43 (17, 69) 93 (81, 100)
89 (81, 96) 66 (53, 79)
3.8 (1.6, 9.3) 2.7 (1.8, 4.1) 2.9 (2.0, 4.2) 0.5 (P 5 .49)
0.6 (0.4, 1.0) 0.1 (0.0, 0.7) 0.3 (0.0, 3.0) 5.7 (P 5 .02)
Sensitivity (%)*
Specificity (%)*
* 95% Confidence interval given in parentheses. † Data completed by correspondence with authors. ‡ Cox S, Little B, Dax J, Leveno K. Fetal fibronectin and preterm delivery [abstract]. Am J Obstet Gynecol 1996;176:306S. § O’Brien JM, Mercer B, Pitts DW, Sibai BM. A comparison of fetal fibronectin, prolactin and cervical examination for the prediction of preterm delivery in symptomatic patients [abstract]. Am J Obstet Gynecol 1995;172:406S.
in agreement with our classification according to the prevalence of preterm delivery in all but one study.15 Our results confirm that the presence of fetal fibronectin in cervicovaginal secretions is associated with delivery before 34, 35, or 37 weeks, in both high- and low-risk populations. A negative test result predicts a favorable outcome. These associations were observed with both single- and multiple-test strategies. Serialtesting strategies have been proposed as a means of improving sensitivity in the context of screening. However, multiple testing did not improve the overall performance of the test. Specificity and sensitivity are given equal weight in the calculation of the likelihood ratio, and, in this situation, the loss in specificity was not compensated for by a similar gain in sensitivity. The higher summary estimate of the likelihood ratio for a positive test result in the two low-risk population strata suggests that a single test discriminates better in this setting. Significant heterogeneity in sensitivity and specificity
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was detected between studies, as noted in a metaanalysis previously published.36 Thus, we calculated the summary likelihood ratio, because this measure varied less between studies. The likelihood ratio is useful for the comparison of test performance and for the computation of predictive values in populations with varying prevalence of the disease. As an example, in a population with a baseline risk of 5%, an asymptomatic woman with a positive fetal fibronectin test result (likelihood ratio 7.5) has a risk of preterm delivery of 28%.32 A negative test result in high-risk women is associated with a reduced risk of preterm delivery. However, in the case of a baseline risk of preterm delivery of 30% and a negative test result (likelihood ratio 0.4), the calculated risk is 15%, which is not completely reassuring. Screening programs are of value only when interventions to modify the natural course of the disorder are available. Fetal fibronectin testing may be useful to identify patient subgroups that are suited for evaluation
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of intervention strategies. Randomized trials assessing both testing and intervention programs must be conducted to determine whether fetal fibronectin screening is beneficial to women and their newborns.
17.
18.
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et al. Should unpublished data be included in meta-analysis? JAMA 1993;269:2749 –53. 36. Chien PFW, Khan KS, Ogston S, Owen P. The diagnostic accuracy of cervico-vaginal fetal fibronectin in predicting preterm delivery: An overview. Br J Obstet Gynaecol 1997;104:436 – 44.
Received July 15, 1997. Received in revised form January 12, 1998. Accepted February 5, 1998.
Address reprint requests to:
Gilles Faron, MD Service de gyne´cologie-obste´trique Hoˆpital Universitaire Brugmann 4, place A. Van Gehuchten 1020 Brussels Belgium E-mail: [email protected]
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Copyright © 1998 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc.
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