Coverage Policy Manual
Policy #: 1998052
Category: Laboratory
Initiated: February 1998
Last Review: October 2018
  Fetal Fibronectin Enzyme Immunoassay

Description:
Fetal fibronectin (FFN) is a high-molecular-weight glycoprotein that can be isolated from fetal connective tissue, placenta, and amniotic fluid. Fetal fibronectin can be measured in cervicovaginal secretions early in pregnancy and at term, but is rarely detectable between 21 and 37 weeks gestation in normal pregnancies that are delivered at term. However, in several studies FFN may also be detected between 21 and 37 weeks in association with preterm delivery. It has been hypothesized that elevation of FFN signals the separation of the placental uterine junction, and thus FFN may be a useful marker in predicting which women will achieve spontaneous labor within a short period of time. At the present time, immunoassays of FFN are available only through the Adeza Biomedical Laboratory.  Samples must be sent by express courier for assay, resulting in a minimum 24-hour delay between sampling and receipt of the result.
 
The clinical importance of measurements of FFN relates to the diagnosis and management of preterm labor. Clinical symptoms of preterm labor (PTL) are nonspecific and include vaginal spotting or bleeding, increased or changed vaginal discharge, intermittent abdominal cramping, backache, and inappropriate uterine contractions. Signs of PTL include cervical effacement and dilation, or a shortened cervix, as assessed by transvaginal ultrasound. When symptoms of PTL develop and the physical exam does not immediately confirm a diagnosis of progressive PTL, the patient is usually hospitalized for an initial period of observation to determine if the symptoms subside or progress. During this time, bed rest and possible treatment in the form of IV hydration, antibiotics, or tocolytic drugs, depending upon the symptoms and results of the physical exam, are prescribed. In many cases, the symptoms of preterm labor subside during the period of observation and prophylactic treatment. However, if the signs and symptoms of PTL are sufficiently advanced or suspicious, delivery within 7 days may be highly likely. In these cases, particularly if gestation is 34 weeks or less, corticosteroid treatment for the induction of fetal lung maturity is indicated.
 
However, accurate diagnosis of PTL is extremely difficult; current methods of assessing risk result in over-diagnosis of PTL. FFN has been investigated as a method to more accurately diagnose PTL and thus eliminate unnecessary hospitalizations, tocolysis, and corticosteroid treatment in women who do not truly have PTL. The use of FFN has been studied in several different categories of patients:
    • Women who are experiencing symptoms suggestive of preterm labor;
    • Asymptomatic women with no risk factors for preterm birth;
    • Asymptomatic women with multiple gestations or other high-risk characteristics of preterm birth;
    • Women at term being considered for induction who are likely to deliver within 24-48 hours and therefore do not require induction;
    • Women with multiple gestations or other high-risk factors for preterm birth who are experiencing symptoms of preterm labor.
 
Regulatory Status
In 1998, a rapid qualitative FFN test (Adeza Fetal Fibronectin Enzyme Immunoassay, Adeza Biomedical, Sunnyvale, CA) was approved by the U.S. Food and Drug Administration (FDA) through the premarket approval process. The test is indicated:
 
  1. As an aid to rapidly assess the risk of preterm delivery in less than 7 or less than 14 days from the time of sample collection in pregnant women with signs and symptoms of early preterm labor, intact amniotic membranes, and minimal cervical dilation (less than 3 cm) sampled between 24 weeks and less than 35 weeks’ gestation;
  2. For use in conjunction with other clinical information to rapidly assess the risk of preterm delivery before 35 weeks in women with singleton pregnancies undergoing a routine prenatal examination between 22 weeks and less than 31 weeks.
 
 

Policy/
Coverage:
The use of FFN assays meets primary coverage criteria for effectiveness and is covered for women with singleton or multiple gestations, intact membranes, cervical dilation less than three cm, and who are experiencing symptoms suggestive of preterm labor. This population represents women who are most likely to be hospitalized and treated in an attempt to prevent preterm birth.
 
All other applications of FFN assays, including, but not limited to, the following:
    • As part of routine pregnancy monitoring in women with singleton gestations, no risk factors for preterm birth, and without symptoms of PTL;
    • As part of clinical monitoring of high-risk women with  other high-risk characteristics for preterm birth (e.g., history of preterm birth, uterine malformation, cervical incompetence, history of two or more spontaneous second trimester abortions) without symptoms of PTL;
    • Women at term being considered for induction who are likely to deliver within 24-48 hours and therefore do not require induction;
    • Women with other high-risk characteristics for preterm birth, with symptoms suggestive of PTL.
are not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For contracts without primary coverage criteria, all other applications of FFN assays, including, but not limited to, the following:
    • As part of routine pregnancy monitoring in women with singleton gestations, no risk factors for preterm birth, and without symptoms of PTL;
    • As part of clinical monitoring of high-risk women with  other high-risk characteristics for preterm birth (e.g., history of preterm birth, uterine malformation, cervical incompetence, history of two or more spontaneous second trimester abortions) without symptoms of PTL;
    • Women at term being considered for induction who are likely to deliver within 24-48 hours and therefore do not require induction;
    • Women with other high-risk characteristics for preterm birth, with symptoms suggestive of PTL.
are considered investigational.  Investigational services are an exclusion in the member certificate of coverage.

Rationale:
The above policy was developed in February 1998, and was based on review of literature available at the time.  Subsequently, the American College of Obstetrics and Gynecology has published similar guidelines, and technology assessment organizations have published reviews supporting the above coverage. (Cochrane Library of Systematic Reviews, 2000; Hayes, Inc, 2006)
 
Non-coverage of FFN for asymptomatic pregnant women is based on a technology assessment by Hayes, Inc, which states, "The available evidence suggests that fFN testing is of limited use in pregnant women without symptoms of PTL. In theory, the high negative predictive value of the fFN test suggests that this test could be used to identify patients at low risk for preterm delivery and therefore might prevent unnecessary treatment in patients unlikely to deliver preterm. However, the impact of fFN testing on clinical decision making or pregnancy outcomes in asymptomatic women has not been evaluated, and the clinical utility of this test remains to be proven. In addition, there is some evidence that a positive test result may increase anxiety in at-risk patients, while a negative result does not appear to reduce anxiety."
 
2010 Update
Fetal fibronectin measurement in women with symptoms of preterm labor.
Sanchez-Ramos and colleagues conducted a meta-analysis of studies on the diagnostic accuracy of fetal fibronectin for predicting preterm birth within 7 days of testing in women with signs or symptoms of preterm labor (Sanchez-Ramos, 2009) In a pooled analysis of data from 32 cohort studies which had a total of 5,355 patients, the pooled estimate of sensitivity was 76.1% (95% confidence interval [CI] =69.1% to 81.9%) and the pooled estimate of specificity was 81.9% (95% CI= 78.9% to 84.5%). The authors conducted a meta-regression analysis to evaluate the impact of different study characteristics on diagnostic accuracy. They found that year of publication was a statistically significant factor, with older studies having findings of higher accuracy than more recent studies (studies in the meta-analysis were published between 1995 and 2008). The authors posited that this may be due to the switch from the membrane immunoassay to the rapid fetal fibronectin test; after 2002, the rapid test was used more commonly. This implies that the rapid test may be less accurate than the membrane test. However, the study did not actually compare the diagnostic accuracy of the two types of fetal fibronectin tests and no other studies comparing test types were identified.
 
A 2008 Cochrane review reviewed the literature on the impact of fetal fibronectin testing on health outcomes in women with signs or symptoms of preterm labor between 22 and 34 weeks’ gestation (Berghella, 2008). Thirteen trials were identified; 7 were excluded because they were limited to women with only positive or only negative FFN tests. Another trial had limited reporting of outcomes, leaving 5 eligible trials. The analyses were based on singleton pregnancies. A pooled analysis of 3 trials found that the rate of preterm birth prior to week 37 was significantly lower when there was knowledge of the FFN level compared to no knowledge of the FFN level; the risk ratio was 0.54. However, other outcomes for which there was sufficient data, including preterm birth at less than 34, 32 or 28 weeks, birthweight less than 2500 grams, maternal hospitalizations and tocolysis did not differ significantly between the groups with and without FFN knowledge. For example, a pooled analysis of 4 studies found a similar rate of tocolysis when there was knowledge of FFN findings and when there was no FFN knowledge; risk ratio=1.01 (95% CI=0.78-1.30).
 
One of the studies included in the Cochrane review was published in 2003 by Plaut and colleagues. They reported on a study that randomized women with symptoms of preterm labor to management either directed or not directed by the results of a fetal fibronectin test. In this study, the length of hospitalization was shorter when physicians knew the results of a negative test (Plaut, 2003). The results of this study contrast with those of Grobman and colleagues, who, in 2004, conducted a randomized trial in women with a singleton pregnancy who were experiencing symptoms of preterm labor (Grobman, 2004). All women underwent a fetal fibronectin test, but the results were only known in one group of women. The women who did not have the fetal fibronectin results available were no different than those women who did with respect to initial length of labor and delivery observation, hospital admission, tocolysis, cessation of work, or total health care-related costs. A third trial in the Cochrane review, published by Ness and colleagues in 2007, was similar in design to the Grobman study (Ness, 2007). One hundred women with symptoms of preterm labor received FFN testing, as well sonographic testing of cervical length, and were randomized to a group that was told the test results (knowledge group) or a group blinded to results. The primary outcome, length of evaluation in triage, did not differ significantly in the two groups. The time from evaluation to discharge was a mean of 2.24 hours in the knowledge group and 2.49 hours in the blinded group. Among the secondary outcomes, groups did not differ in the rate of delivery within 7 days, delivery within 14 days or spontaneous preterm birth before 34 weeks. There was a significantly lower rate of delivery before 37 weeks in the group with knowledge of test results. In addition, the study found that the admission rate for pre-term labor was significantly higher in the knowledge group (19.6%) than in the blinded group (41%).
 
There are limited data specifically addressing the use of FFN in symptomatic patients with additional high-risk factors for preterm birth; these high-risk patients are presumably already undergoing standard aggressive management of symptoms, and there were no data to suggest that the results of FFN would alter management. Some data have since appeared regarding symptomatic patients with twin gestations. One study published in 1998 by Terrone and colleagues calculated a negative predictive value of 94% for delivery within 1 week in 43 patients with twin gestations who presented with symptoms of preterm labor (Terrone, 1998). Negative predictive values between 92% and 99% have been extracted from other studies with small numbers of twins (Roberts, 1998). Although the data are sparse, they suggest that a negative FFN assay may contribute to the decision to withhold or withdraw aggressive treatment for PTL in symptomatic women with twin gestations.
 
There are no data addressing the use of FFN in triplet or higher-order gestations.
 
Fetal fibronectin measurement in asymptomatic women
A 1997 TEC Assessment concluded that, in asymptomatic patients both with and without additional risk factors (including multiple gestations) for preterm birth, the positive predictive value of FFN findings was inadequate to identify women who require preventive treatment based upon the FFN result alone.
 
Since the TEC Assessment, there have been no additional studies that would alter these conclusions. Although the FFN assay is a risk predictor for preterm delivery among asymptomatic women, there is no proven effective treatment for asymptomatic women at risk of preterm birth that is known to improve maternal or fetal outcomes.
 
Two subsequent studies, both from the UK, evaluated use of the FFN assay in asymptomatic women at increased risk of preterm birth. One study reported on a secondary analysis of a prospectively-created database of asymptomatic women with singleton pregnancies who had a history of pre-term delivery and were tested for FFN at 24 weeks’ gestation (Kurtzman, 2009). Data on 563 women were available. A total of 497 (88%) of women had an FFN of 0, 41 (8%) had an FFN between 1-49 ng/mL, 17 (0.3%) had an FFN between 50-199 ng/ML and 7 (0.1%) had an FFN of at least 200 ng/mL. A number of analyses were conducted comparing women with different levels of FFN and calculating the association between FFN level and risk of preterm birth before 28, 32, 34 and 37 weeks. Compared to women with an FFN of 0, those with an FFN above 50 ng/mL had significantly increased risk of spontaneous preterm delivery prior to 32, 34 and 37 weeks’ gestation. For example, 90/497 (18%) women with an FFN of 0 had preterm delivery before 37 weeks, compared to 12/25 (48%) of those with FFN above 50 ng/mL. In addition to multiple statistical comparisons, the study was limited by the small number of women with increased FFN levels which resulted in wide confidence intervals in all analyses.
 
The other study, by Shennan and colleagues in the U.K., evaluated whether treatment with metronidazone reduces early preterm labor in women with singleton pregnancies who have positive FFN findings in the second trimester of pregnancy (Shennan, 2006). One hundred women with positive FFN findings (at least 50 ng/mL) were randomized to receive a week of oral metronidazole 400 mg three times a day or placebo. There was not a statistically significant difference between groups in the primary outcome, delivery before 30 weeks. Rates were 11/53 (21%) in the metronidazole group and 5/46 (11%) in the placebo group. Among the secondary outcomes, there was a significantly higher rate of pre-term delivery before 37 weeks in the group assigned to metronidazole compared to placebo (62% vs. 39%, respectively). The trial was stopped early due to the poorer outcomes in the metronidazole groups. Thus, this study did not show that FFN assessment in asymptomatic high-risk women led to an early intervention that improved outcomes.
 
Fetal fibronectin testing for use in women at term being considered for induction
The 1997 Assessment concluded that the evidence is insufficient to support the use of the FFN assay to identify women at term being considered for induction who are likely to deliver within 24–48 hours and, therefore, do not require induction.  Although many studies show an association between FFN levels and imminent term delivery, there is no evidence that the predictive values are sufficiently high to alter management.
 
 
Technology Assessments, Guidelines and Position Statements
The American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin of October 2001 (reaffirmed 2008) reached the following recommendations regarding FFN testing:
 
FFN or ultrasonography to determine cervical length may be useful in determining women at high risk for preterm labor. However, their clinical usefulness may rest primarily with their negative predictive value given the lack of proven treatment options to prevent preterm birth.
 
FFN testing may be useful in women with symptoms of preterm labor to identify those with negative values and a reduced risk of preterm birth, thereby avoiding unnecessary intervention.
 
2012 Update
A literature search using the MEDLINE database was conducted through September 2012.  There was no new information identified that would prompt a change in the coverage statement.
 
A prospective cohort study published in 2011, evaluated the value of FFN testing and cervical length measurement, alone or combined, for predicting preterm birth in asymptomatic high-risk women with singleton pregnancies (Bolt, 2011). The study included 147 women who had one of the factors indicating increased risk of preterm birth: previous preterm birth, previous preterm rupture of the membranes, previous late miscarriage, extensive cervical surgery, uterine abnormalities or presence of cervical cerclage. At each prenatal care visit (2-6 week intervals) occurring between 22 weeks 0 days and 30 weeks 0 days of gestation, FFN levels were assessed, and cervical length was measured. A total of 34 of 147 (23%) of women tested positive for FFN (at least 50 ng/ml). The mean cervical length was 31 mm (95% CI: 29.4 to 33.4). Eleven of 28 women (39%) with a positive FFN test delivered before 34 weeks compared to 4 of 111 (4%) of women with a negative FFN test. Similarly, 12 of 26 (46%) women with a positive FFN test delivered before 37 weeks compared to 12 of 106 (11%) women with a negative FFN. (Eight women with induction or elective cesarean section were excluded from the 34-week analysis, and 15 were excluded from the 37-week analysis.) The authors did not report statistical significance e.g., p values for the above analyses. FFN status added value to prediction of preterm birth regardless of the cervical length. When hazard ratios were calculated, there was a statistically significant association between a positive FFN test and preterm birth rate both for women with a cervical length 25 mm or less (hazard ratio [HR]: 3.14, 95% CI: 1.34 to 7.38) and for those with a cervical length of more than 25 mm (HR: 2.78, 95% CI: 1.23 to 6.27). This study does not address the issue of whether intervening in women with a high FFN value would reduce the rate of preterm delivery.
 
2013 Update
A search of the MEDLINE database through 2013 did not reveal any new literature that would prompt a change in the coverage statement.
 
2014 Update
A search of the MEDLINE database through March 2014 did not reveal any new literature that would prompt a change in the coverage statement.
 
2016 Update
A literature search conducted through September 2016 did not reveal any new information that would prompt a change in the coverage statement.   
 
2017 Update
A literature search conducted using the MEDLINE database through September 2017 did not reveal any new information that would prompt a change in the coverage statement.
 
2018 Update
A literature search was conducted through September 2018.  There was no new information identified that would prompt a change in the coverage statement.  

CPT/HCPCS:
82731Fetal fibronectin, cervicovaginal secretions, semi-quantitative

References: Blue Shield Association Technology Evaluation Center (TEC).(1997) Fetal fibronectin enzyme immunoassay. TEC Assessments 1997; Volume12, Tab 16.

1997 Blue Cross Blue Shield Association Technology Evaluation Center Assessment; Tab 16.

ACOG Practice Bulletin. Assessment of risk factors for preterm birth. Clinical management guidelines for obstetrician-gynecologists. Number 31, October 2001. Obstet Gynecol 2001; 98(4):709-16. (Reaffirmed 2008)

Ahner R, Kub-Csizi P, Heinzl H, et al.(1997) The fast-reacting fetal fibronectin test: a screening method for better prediction of time of delivery. Am J Ob Gyn 1997; 177:1478-1482.

Assessment of risk factors for preterm birth. Clinical management guidelines for obstetrician-gynecologists. ACOG Practice Bulletin. Obstet Gynecol 2001; 98:709-16.

Benattar C, Taieb J, Fernandez H, et al.(1997) Rapid fetal fibronectin swab-test in preterm labor patients treated by betamimotics. Eur J Ob Gyn Reprod Biol 1997; 72:131-135.

Berghella V, Hayes E, Visintine J et al.(2008) . Fetal fibronectin for reducing the risk of preterm birth. Cochrane Database Syst Rev 2008; (4):CD006843.

Bittar RE, Yamasaki AA, Sasaki S, et al.(1996) Cervical fetal fibronectin in patients at increased risk for preterm delivery. Am J Ob Gyn 1996; 175:178-181.

Bolt LA, Chandiramani M, De Greeff A et al.(2011) The value of combined cervical length measurement and fetal fibronectin testing to predict spontaneous preterm birth in asymptomatic high-risk women. J Matern Fetal Neonatal Med 2011; 24(7):928-32.

Br J Ob Gyn 1997; 104:436-444.

Committee on obstetric practice.(1997) Fetal Fibronectin Preterm Labor Risk Test. ACOG Committee Opinion. Number 187 1997.

Grobman WA, Welshman EE, Calhoun EA.(2004) Does fetal fibronectin use in the diagnosis of preterm labor affect physician behavior and health care costs? A randomized trial. Am J Obstet Gynecol 2004; 191(1):235-40.

Grobman WA, Welshman EE, Calhoun EA.(2004) Does fetal fibronectin use in the diagnosis of preterm labor affect physician behavior and health care costs? A randomized trial. Am J Ob Gyn 2004; 191:235-40.

Joffe GM, Jacques D, Bemis-Heys R et al.(1999) Impact of the fetal fibronectin assay on admissions for preterm labor. Am J Obstet Gynecol 1999; 180(3 pt 1):581-6.

Joffe GM, Jacques D, Bemis-Heys R.(1999) Impact of the fetal fibronectin assay on admissions for preterm labor. Am J Ob Gyn1999; 180:581-6.

Kurtzman J, Chandiramani M, Briley A et al.(2009) 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.

Ness A, Visintine J, Ricci E et al.(2007) Does knowledge of cervical length and fetal fibronectin affect management of women with threatened preterm labor? Am J Obstet Gynecol 2007; 197(4): 426.e1-7.

Plaut MM, Smith W, Kennedy K.(2003) Fetal fibronectin: the impact of a rapid test on the treatment of women with preterm labor symptoms. Am J Obstet Gynecol 2003; 188(6):1588-95.

Roberts WE, Morrison JC.(1998) Has the use of home monitors, fetal fibronectin, and measurement of cervical length helped predict labor and/or prevent preterm delivery in twins. Clin Obstet Gynecol 1998; 41(1):94-102.

Roberts WE, Morrison JC.(1998) Has the use of home monitors, fetal fibronectin, and measurement of cervical length helped predict labor and/or prevent preterm delivery in twins? Clin Obstet Gynecol 1998; 41(1):94-102.

Sanchez-Ramos L, Delke I, Zamora J et al.(2009) Fetal fibronectin as a short-term predictor of preterm birth in symptomatic patients: a meta-analysis. Obstet Gynecol 2009; 114(3): 631-40.

Shennan A, Crawshaw S, Briley A et al.(2006) A randomized controlled trial of metronidazone for the prevention of preterm birth in women positive for cervicovaginal fetal fibronectin: the PREMET study. BJOG 2006; 113(1):65-74.

Terrone DA, Rinehart BK, Kraeden U et al.(1998) Fetal fibronectin in symptomatic twin gestations. Prim Care Update Ob Gyns 1998; 5(4):179.

Terrone DA, Rinehart BK, Kraeden U, et al.(1998) Fetal fibronectin in symptomatic twin gestations. Prim Care Update. Obs Gyns 1998; 5(4):179.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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