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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, The University of Alabama at Birmingham, Birmingham, Alabama; and Adeza Biomedical, Sunnyvale, California.
Address reprint requests to: George C. Lu, MD Division of Maternal-Fetal Medicine 619 S. 19th Street 451 OHB Birmingham, AL 35249-7333 E-mail: gclu{at}uab.edu
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Abstract |
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Methods: Quantitative fetal fibronectin values were calculated from women who participated in two prospective multicenter trials relating fetal fibronectin to subsequent spontaneous preterm birth. The study populations consisted of women who presented with symptoms of preterm labor between 
and 
weeks, a singleton pregnancy, intact membranes, no prior tocolysis, and cervical dilation less than 3 cm.
Results: The characteristics of the two study populations were similar. In both populations, the rates of delivery within 7, 14, and 21 days after sampling were clustered into three distinct fetal fibronectin groups (less than 40, 40–100, and 100 ng/mL or more). As fetal fibronectin values increased, the risk of subsequent spontaneous preterm birth also increased. Delivery within 7 days of sampling was 0.4%, 3.3%, and 18.2% (trial A) and 1.4%, 8.0%, 30.0% (trial B) as the fetal fibronectin levels increased from less than 40 ng/mL, to 40–100 ng/mL, and to at least 100 ng/mL, respectively.
Conclusion: In women with symptoms of preterm labor, an increase in fetal fibronectin from under 40 ng/mL, to 40–100 ng/mL, to at least 100 ng/mL was associated with a progressive increase in the risk of subsequent spontaneous preterm birth. The use of a single fetal fibronectin cutoff of 50 ng/mL for defining a positive test in women with symptoms of preterm labor should be reevaluated.
Fetal fibronectin, a high-molecular-weight protein produced by the chorioamniotic membranes and trophoblasts, most likely functions as a biologic glue responsible for maintaining the integrity of the chorionic-decidual interface. It is hypothesized that disruption of this interface often precedes the onset of preterm labor and results in the release of fetal fibronectin into the cervicovaginal fluid.1 Several studies have shown a strong statistical association between positive cervicovaginal fetal fibronectin test results and spontaneous preterm birth in both asymptomatic (noncontracting) and symptomatic (contracting) women.2–7 Although quantitative cervicovaginal fetal fibronectin levels are measured by using an enzyme immunoassay, a value of at least 50 ng/mL has been defined as a positive test based on receiver operating characteristic curves from earlier studies.4,7 Therefore, current results are often reported as positive or negative based on that cutoff point.
Data in asymptomatic women from the National Institute of Child Health & Human Development Pre-term Prediction Study indicated that, as fetal fibronectin values increased from 20 ng/mL to 300 ng/mL, so did the risk of subsequent spontaneous preterm birth.8 However, few data were available regarding the relationship between spontaneous preterm birth and values below and above 50 ng/mL in symptomatic women. In this study, we evaluated the relationship between quantitative vaginal fetal fibronectin values and the risk of subsequent spontaneous preterm birth in women with symptoms of preterm labor.
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Materials and Methods |
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The results of the first trial reported tests as positive or negative and have been published.3 The results of the second study, although not published, were similar to those of the first. Both studies recruited women who presented for an unscheduled visit between 24 and weeks gestation at one of the participating centers with intact membranes and with symptoms suggestive of preterm labor, including regular contractions, low abdominal cramping, low back pain, pelvic pressure, vaginal bleeding, or increased vaginal discharge. Women were excluded for any tocolytic before fetal fibronectin sampling, suspected placenta previa, cervical cerclage, trauma precipitating the patient’s symptoms, or cervical dilatation of 3 cm or more.
After recruitment into the trial, a sterile polyester swab was used to obtain the fetal fibronectin sample from the posterior vaginal fornix before digital examination. Specimens were placed in a standard buffer and stored at 2–8C for up to 72 hours. All specimens were assayed on site by a quantitative enzyme-linked immunosorbent assay (ELISA) using a fetal fibronectin–specific monoclonal antibody, FDC-6 (Adeza Biomedical, Sunnyvale, CA), to measure the levels in the vaginal samples. The light absorbances of standard samples and patient samples were determined in duplicate at a wavelength of 550 nm with an automated microtiterplate reader. The calibrators used for determining the concentration were 0, 50, 100, 500, and 1000 ng/mL. The limits of the assay were 0–1000 ng/mL, thus any results at or beyond 1000 ng/mL were coded as 1000 ng/mL. The intraassay coefficient of variation was between 2.9% and 4.2%, whereas the interassay coefficient of variation was between 7.6% and 11.8%. In both studies the results were not available to the managing physicians. Women in both trials received tocolytic therapy or corticosteroid preparations at the discretion of the obstetric care providers once the fetal fibronectin specimen was obtained.
Similar to the original studies, delivery within 7, 14, and 21 days of sampling and delivery at less than 35 and 37 weeks were chosen as the primary outcomes to assess the predictive value of the test. Quantitative values initially were grouped into fetal fibronectin increments of 10 ng/mL for analysis. Chi-square and Fisher exact test were used to compare categoric data. Relative risks and 95% confidence intervals of the delivery outcomes also were calculated. Statistical analysis was done using SAS (SAS Institute, Cary, NC).
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Results |
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. The rate of spontaneous preterm delivery before 37 weeks was 19.0% in trial A and 22.7% in trial B.
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shows the number of women from each trial who delivered within 7, 14, or 21 days after sampling, and before 35 and 37 weeks. In both trials, the outcomes associated with the quantitative fetal fibronectin values clustered into three distinct intervals and so are presented in this manner. The percentage of women who delivered within each time interval and before 35 and 37 weeks increased as the values increased from under 40, to 40–100, and to 100 ng/mL or more (P < .001). However, we were unable to identify significant increases in the rate of preterm delivery among women with values above 100 ng/mL, although 49% and 65% of women had values above 250 ng/mL and 26% and 43% had values above 500 ng/mL (trials A and B, respectively).
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gives the relative risk of preterm birth within 7, 14, and 21 days of sampling and before 35 and 37 weeks for women with fetal fibronectin values of 40 to under 100 ng/mL compared with those with values under 40 ng/mL. A significant increase in the relative risk was noted for many, but not all, of the outcomes. The relative risk for delivery within 7 days of sampling was higher than that for the other outcome measures. Table 4 shows the relative risk of preterm birth within 7, 14, and 21 days of sampling and before 35 and 37 weeks for women with fetal fibronectin values at least 100 ng/mL compared with those whose values were under 40 ng/mL. There was a significant increase in risk in all outcomes. The relative risk of preterm delivery decreased in both trials as the time from sampling to delivery increased from 7 to 21 days.
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Discussion |
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In this analysis of two separate but similar trials of women who presented to the hospital with signs or symptoms potentially consistent with preterm labor, we hypothesized a linear relationship between fetal fibronectin and the risk of spontaneous preterm birth. We therefore evaluated the entire range of fetal fibronectin values to determine its association with subsequent preterm birth within 7, 14, or 21 days after fetal fibronectin sampling and before 35 and 37 weeks. Unlike the asymptomatic women in the Preterm Prediction Study, in which there was higher risk of subsequent preterm birth with quantitative values up to 300 ng/mL, we were unable to identify significant increases in the risk of preterm birth as the fibronectin levels increased above 100 ng/mL, perhaps because of the limited number of women with such high values. Although we could have combined the results of the two trials to better evaluate these higher values, we chose to evaluate the trials separately because of the differences in rates of women with high fetal fibronectin values delivering within specific time intervals (Table 2
). We could not explain these differences on the basis of the available data; however, our results nevertheless demonstrate that higher values were associated with an increase in risk of subsequent preterm delivery. For example, women with values between 40 and 100 ng/mL had at least a five-fold greater risk of delivery within 7 days of sampling compared with women whose values were under 40 ng/mL. By comparison, women with values at least 100 ng/mL had greater than 20-fold increased risk of delivery within 7 days of sampling compared with women whose values were less than 40 ng/mL. That results were similar in two distinct clinical trials strongly supports the conclusion that elevated fetal fibronectin values were associated with increased risk of preterm labor and especially preterm delivery.
The clinical utility of evaluating quantitative fetal fibronectin values is that it will allow the identification of additional cutoff points for predicting subsequent preterm births. It was not our intent to define these specific thresholds to be used in clinical practice; rather, our goal was to confirm the findings from the Preterm Prediction Study in asymptomatic women in a population of symptomatic women. Ideally, such cutoff points could then be used in conjunction with the level of risk or intensity of monitoring involved in preventing pre-term delivery. For example, should effective interventions for preventing preterm delivery be identified, those that involved a greater risk or expense to the mother and fetus could be directed toward women with the greatest risk of subsequent preterm birth, specifically those with the highest fetal fibronectin levels. Conversely, if an effective intervention that entailed less risk or cost were discovered, even some women with values under 50 ng/mL might be appropriate candidates for that treatment. Thus, future studies involving fetal fibronectin in women with symptoms of preterm labor should likewise evaluate the association of quantitative values with the risk of preterm deliveries. This would allow us to identify women with values below 50 ng/mL who are at mildly increased risk of subsequent preterm delivery and those with values above 50 ng/mL who are at even greater risk of spontaneous preterm birth.
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Footnotes |
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Usha S. Kreaden was formerly employed by Adeza Biomedical, which markets materials used in assaying fetal fibronectin. Ms. Kreaden owns stock in Adeza Biomedical.
Received May 18, 2000. Received in revised form September 1, 2000. Accepted October 12, 2000.
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References |
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2. Iams JD, Casal D, McGregor JA, Goodwin TM, Kreaden US, Lowensohn R, et al. Fetal fibronectin improves the accuracy of diagnosis of preterm labor. Am J Obstet Gynecol 1995;173:141–5.[Medline]
3. Peaceman AM, Andrews WW, Thorp JM, Cliver SP, Lukes A, Iams JD, et al. Fetal fibronectin as a predictor of preterm birth in patients with symptoms: A multicenter trial. Am J Obstet Gynecol 1997; 177:13–8.[Medline]
4. Lockwood CJ, Senyei AE, Dische MR, Casal D, Shah KD, Thung SN, et al. Fetal fibronectin in cervical and vaginal secretions as a predictor of preterm delivery. N Engl J Med 1991;325:669–74.[Abstract]
5. Goldenberg RL, Thom E, Moawad AH, Johnson F, Roberts J, Caritis SN. The Preterm Prediction Study: Fetal fibronectin, bacterial vaginosis, and peripartum infection. Obstet Gynecol 1996;87: 656–60.[Abstract]
6. Goldenberg RL, Mercer BM, Meis PJ, Copper RL, Das A, McNellis D. The Preterm Prediction Study: Fetal fibronectin testing and spontaneous preterm birth. Obstet Gynecol 1996;87:643–8.[Abstract]
7. Nageotte MP, Casal D, Senyei AE. Fetal fibronectin in patients at increased risk for premature birth. Am J Obstet Gynecol 1994;170: 20–5.[Medline]
8. Goepfert AR, Goldenberg RL, Mercer BM, Iams JD, Meis PJ, Moawad AH, et al. The Preterm Prediction Study: Quantitative fetal fibronectin values and the prediction of spontaneous preterm birth. Am J Obstet Gynecol (In press).
9. Crane JM, Armson BA, Dodds L, Feinberg RF, Kennedy W, Kirkland SA. Risk scoring, fetal fibronectin, and bacterial vaginosis to predict preterm delivery. Obstet Gynecol 1999;93:517–22.
10. Faron G, Boulvain M, Irion O, Bernard PM, Fraser WD. Prediction of preterm delivery by fetal fibronectin: A meta-analysis. Obstet Gynecol 1998;92:153–8.[Abstract]
11. Goldenberg RL, Mercer BM, Iams JD, Moawad AH, Meis PJ, Das A, et al. The Preterm Prediction Study: Patterns of cervicovaginal fetal fibronectin as predictors of spontaneous preterm delivery. Am J Obstet Gynecol 1997;177:8–12.[Medline]
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