mp-063 - mp-063 - Medical Policies
Fetal Fibronectin Enzyme Immunoassay
Policy Number: MP-063
Latest Review Date: June 2019
Policy Grade: Active Policy but no longer scheduled for regular literature reviews and updates.
DESCRIPTION OF PROCEDURE OR SERVICE:
Assessment of fetal fibronectin (FFN) is proposed for use in the diagnosis and management of preterm labor (PTL) and in the management of women at term being considered for induction. A rapid test is available that can provide results within 20 minutes. FFN testing has been considered for several categories of patients including women who are experiencing symptoms of preterm labor, asymptomatic women at increased risk of pre-term labor and asymptomatic women as part of routine pregnancy care.
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 (normally found in cervical secretion until 16-20 weeks of gestation) 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. Originally, immunoassays of FFN were available only at specialized reference laboratories performing the enzyme linked immunoabsorbent assay (ELISA), which produced semi-quantitative results. Because tests had to be sent to a reference lab, there was a minimum 24-hour delay between sampling and receipt of the results. A rapid fetal fibronectin test is now available permitting results within 20 minutes of testing. This assay produces qualitative results, reported as positive, negative, or indeterminate. Generally, a FFN level of 50 ng/mL or higher is considered a positive test.
The clinical importance of measurements of FFN relates to the diagnosis and management of preterm labor. Clinical symptoms of 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, tocolytic drugs, or prostaglandin inhibitors depending upon the symptoms and results of the physical exam, are prescribed. All current tocolytic agents are considered superior to no treatment at delaying delivery for both 48 hours and seven days, however, prostaglandin inhibitors are considered superior to the other agents and may be considered the optimal first-line agent before 32 weeks of gestation to delay delivery. In many cases, the symptoms of PTL subside during the period of observation and prophylactic treatment. However, if the signs and symptoms of PTL are sufficiently advanced or suspicious, delivery within seven 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.
Accurate diagnosis of PTL is extremely difficult; current methods of assessing risk can result in overdiagnoses of PTL. FFN has been investigated as a method to more accurately diagnose PTL and thus eliminate unnecessary hospitalizations, tocolytic therapy, 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 of average risk who are experiencing symptoms suggestive of preterm labor;
- Women with multiple gestations or other high-risk factors for preterm birth who are experiencing symptoms of preterm labor;
- Asymptomatic women with no risk factors for preterm birth; FFN is used in these patients as a screening test at certain intervals during pregnancy;
- 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.
The use of FFN assays may be considered medically necessary for use in women:
- with singleton or twin gestations; and
- with intact membranes; and
- cervical dilation <3 cm; and
- who are experiencing symptoms suggestive of preterm labor between 24 and <35 weeks gestation.
*This population represents women who are most likely to be hospitalized and treated in an attempt to prevent preterm birth.
All other applications of the FFN assay are considered not medically necessary and investigational, including, but not limited to, the following:
- As part of routine pregnancy monitoring in asymptomatic women with singleton gestation and no risk factors for preterm birth;
- As part of clinical monitoring of asymptomatic women at high risk for preterm birth, including, but not limited to:
- those with multiple gestations,
- history of preterm birth,
- uterine malformation,
- cervical incompetence,
- history of two or more spontaneous second trimester abortions;
- As part of clinical monitoring in women with
- triplet or higher-order gestations,
- intact membranes,
- cervical dilation <3 cm,
- who are experiencing symptoms suggestive of preterm labor;
- As a test to identify women at term being considered for induction that are likely to deliver within 24-48 hours and therefore, do not require induction.
Policy was updated with literature review performed on May 24, 2019.
Preterm labor is defined as labor that occurs before the completion of the 37th week of gestation. The incidence of premature birth has not decreased during the past 40 years. In the United States, preterm delivery affects approximately one in 10 births and is the leading cause of neonatal morbidity and mortality. In 25% of preterm births, labor is induced for various maternal and fetal medical indications; approximately 30% of preterm births are associated with premature rupture of the membranes. Preterm birth can potentially be prevented in less than one half of the mothers who present in labor earlier than 37 weeks’ gestation.
The FDA has labeled fetal fibronectin enzyme immunoassay for use as a screening test for preterm labor. In symptomatic patients, FFN has 69% to 93% sensitivity and a negative predictive value as high as 99.7%. The positive predictive value (ability to predict a patient with a positive test result will have a preterm delivery) has been reported as high as 83% in symptomatic patients.
A 2016 study by Berghella and Saccone reported six trials that included 546 singleton gestations with symptoms of preterm labor were included in the metaanalysis. The overall risk of bias of the included trials was low. Women were eligible for the random assignment in case of symptoms that suggested preterm labor at 23-34 weeks of gestation. During admission, before digital examination, a Dacron swab was rotated in the posterior fornix for 10 seconds to absorb cervicovaginal secretions that were then analyzed for the fetal fibronectin qualitative method, with results reported as either positive or negative. Women who were assigned randomly to the fetal fibronectin group had a similar incidence of preterm birth at<37 weeks of gestation (20.7% vs 29.2%; relative risk, 0.72; 95% confidence interval, 0.52-1.01), at<34 weeks of gestation (8.3% vs 7.9%; relative risk, 1.09; 95% confidence interval, 0.54-2.18), at<32 weeks of gestation (3.3% vs 5.6%; relative risk, 0.64; 95% confidence interval, 0.24-1.74), and at<28 weeks of gestation (1.1% vs 1.7%; relative risk, 0.74; 95% confidence interval, 0.15-3.67) compared with the control group. No differences were found in the number of women who delivered within seven days (12.8% vs 14.5%; relative risk, 0.76; 95% confidence interval, 0.47-1.21), in the mean of gestational age at delivery (mean difference, 0.20 week; 95% confidence interval, -0.26 to 0.67), in the rate of maternal hospitalization (27.4% vs 26.9%; relative risk, 1.07; 95% confidence interval, 0.80-1.44), in the use of tocolysis (25.3% vs 28.2%; relative risk, 0.97; 95% confidence interval, 0.75-1.24), antenatal steroids (29.2% vs 29.2%; relative risk, 1.05; 95% confidence interval, 0.79-1.39), in the mean time in the triage unit (mean difference, 0.60 hour; 95% confidence interval, -0.03 to 1.23) and in neonatal outcomes that included respiratory distress syndrome (1.3% vs 1.5%; relative risk, 0.91; 95% confidence interval, 0.06-14.06), and admission to the neonatal intensive care unit (19.4% vs 8.1%; relative risk, 2.48; 95% confidence interval, 0.96-6.46). This study concluded that fetal fibronectin testing in singleton gestations with threatened preterm labor is not associated with the prevention of preterm birth or improvement in perinatal outcome.
Deshpande et al (2013) assessed the clinical effectiveness of rapid FFN testing in predicting preterm birth (PTB) in symptomatic woman and found that fetal fibronectin testing has moderate accuracy for predicting PTL. The main potential role is likely to be identify women not requiring intervention. Evidence from RCTs suggests that FFN does not increase adverse outcomes and may decrease unnecessary hospitalizations and interventions performed. Currently, there are no high-quality studies and the existing trials were generally underpowered. Hence, there is a need for high-quality adequately powered trials using appropriate study designs to confirm the findings presented. Five RCTs and 15 new DTAs were identified. No RCT reported significant effects of FFN testing on maternal or neonatal outcomes. One study reported a subgroup analysis of women with negative FFN test observed> six hours, which showed a reduction in length of hospital stay where results were known to clinicians. Combining data from new studies and the previous systematic review, the pooled estimates of sensitivity and specificity were: 76.7% and 82.7% for delivery within seven to 10 days of testing; 69.1% and 84.4% for delivery< 34 weeks' gestation; and 60.8% and 82.3% for delivery< 37 weeks' gestation. Estimates were similar across all subgroups sensitivity analyses. Sensitivity analyses indicated that admission rate had the largest impact on results.
Two subsequent studies evaluated use of the FFN assay in asymptomatic women at increased risk of PTL. 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. 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 zero, 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 zero 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.
Shennan et al evaluated whether treatment with metronidazole reduces early preterm labor in women with singleton pregnancies who have positive FFN findings in the second trimester of pregnancy. 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. This study did not show that FFN assessment in asymptomatic high-risk women led to an early intervention that improved outcomes.
Summary of Evidence
It is 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 enough to alter management. FFN assessment is considered not medically necessary and investigational in this situation.
It is concluded that there was sufficient evidence to support the use of fetal fibronectin (FFN) measurement in selected women with signs or symptoms of preterm labor. This conclusion was based on the value of a negative test. A more recent Cochrane review of studies with this population of women found that knowledge of FFN level reduced the preterm birth rate before 37 weeks’ gestation, although other outcomes (including material hospitalization) were not affected by FFN knowledge. Another recent meta-analysis found significantly lower diagnostic accuracy in newer versus older studies evaluating fetal fibronectin tests; no studies comparing the accuracy of the newer rapid fetal fibronectin test to the older membrane test were identified.
There is insufficient evidence that FFN testing improves outcomes for asymptomatic women at average risk or at increased risk of preterm labor. No published evidence was identified on FFN assessment in women with triple or higher-order gestations, or in women being considered for induction. FFN assessment may be considered medically necessary in women with singleton or twin gestations who have signs or symptoms of preterm labor since the original premise has not been disproven. However, use of FFN assessment is considered investigational for all other applications.
Practice Guidelines and Position Statements
The 2016 American Congress of Obstetricians and Gynecologists (ACOG) position statement is as follows: “The positive predictive value of a positive fetal fibronectin test redult or a short cervix alone is poor and should not be used exclusively to direct management in the setting of acute symptoms”.
The Society for Maternal Fetal Medicine (SMFM) position statement is as follows: “FFN seems to be most helpful for women with a ‘boarderline’ transvaginal ultrasound cervical length of 20-29 mm”
U.S. Preventative Services Task Force
Fetal fibronectin enzyme immunoassay, fetal fibronectin, FFN, preterm labor testing, premature labor testing, cervicovaginal FFN
APPROVED BY GOVERNING BODIES:
FFN testing is indicated by the FDA for use in risk assessment of spontaneous preterm birth within <7 or <14 days following cervicovaginal sample collection in patients with symptoms of PTL who are between 24 and 34 weeks of gestation with intact membranes and minimal cervical dilation (<3 cm).
Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.
ITS: Home Policy provisions apply
FEP contracts: FEP does not consider investigational if FDA approved and will be reviewed for medical necessity. Special benefit consideration may apply. Refer to member’s benefit plan.
Fetal fibronectin, cervicovaginal secretions, semiquantitative
- American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics. Practice bulletin no. 171: management of preterm labor. Obstet Gynecol. 2016;128(4):e155-e164.
- ACOG Practice Bulletin 277. Clinical management guidelines for obstetrician-gynecologists, No. 31, October 2001 (Reaffirmed 2008).
- Bartnicki J., Casal D., and et al. Fetal fibronectin in vaginal specimens predicts preterm delivery and very-low-birth-weight infants, American Journal of Obstetrics and Gynecology; 174(3): 1996.
- Ben-Haroush A, Poran E, Yogev Y, Glezerman M. Vaginal fetal fibronectin evaluation before and immediately after ultrasonographic vaginal cervical length measurements in symptomatic women at risk of preterm birth: a pilot study. J Matern Fetal Neonatal Med. 2010 Aug;23(8):854-6.
- Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Fetal fibronectin enzyme immunoassay. TEC Assessments 1997; Volume 12, Tab16.
- Berghella V, Hayes E, Visintine J et al. Fetal fibronectin for reducing the risk of preterm birth. Cochran Database Syst Rev 2008;(4):CD006843.
- Berghella V, Saccone G. Fetal fibronectin testing for prevention of preterm birth in singleton pregnancies with threatened preterm labor: a systematic review and metaanalysis of randomized controlled trials. Am J Obstet Gynecol. 2016 Oct;215(4):431-8.
- Chuck AW, Thanh NX, Chari RS, Wilson RD, Janes-Kelley S, Wesenberg JC. Post-Policy Implementation Review of Rapid Fetal Fibronectin (fFN) Testing for Preterm Labour in Alberta. J Obstet Gynaecol Can. 2016;38(7):659. Epub 2016 May 12.
- Deshpande SN, van Asselt AD, Tomini F, Armstrong N, Allen A, Noake C, Khan K, Severens JL, Kleijnen J, Westwood ME. Rapid fetal fibronectin testing to predict preterm birth in women with symptoms of premature labour: a systematic review and cost analysis. Health Technol Assess. 2013 Sep;17(40):1-138.
- Goldenberg R.L., Mercer B.M., and et al. The preterm prediction study: patterns of cervicovaginal fetal fibronectin as predictors of spontaneous preterm delivery, American Journal of Obstetrics and Gynecology; 177(1): 1997.
- Goldenberg R.L., Thom E., and et al. The preterm prediction study: fetal fibronectin, bacterial vaginosis, and peripartum infection, Obstetrics and Gynecology; 87(5): 199
- Grobman WA, Welshman EE, Calhoun EA. 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.
- Haas DM, Imperiale TF, Kirkpatrick PR, Klein RW, Zollinger TW, Golichowski AM. Tocolytic therapy: a meta-analysis and decision analysis. Obstet Gynecol. 2009;113(3):585.
- Iams J.D., Casal D., and et al. Fetal fibronectin improves the accuracy of diagnosis of preterm labor, American Journal of Obstetrics and Gynecology; 173(1): 1995.
- Joffe G.M., Jacques D., and et al. Impact of the fetal fibronectin assay on admission for preterm labor, American Journal of Obstetrics and Gynecology; 180(3): 199
- 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. Aj J Obstet Gynecol 2009;200(3):263.e1-6.
- Lockwood C.J., Senyei A.E., and et al. Fetal fibronectin in cervical and vaginal secretions as a predictor of preterm delivery, The New Engl. J. of Med.; 325(10): 1991.
- McKenna DS, Chung K, Iams JD. Effect of digital cervical examination on the expression of fetal fibronectin. J Reprod Med. 1999;44(9):796.
- McLaren JS, Hezelgrave NL, Ayubi H, Seed PT, Shennan AH. Prediction of spontaneous preterm birth using quantitative fetal fibronectin after recent sexual intercourse. Am J Obstet Gynecol. 2015 Jan;212(1):89.e1-5. Epub 2014 Jun 30.
- Medical Policy Reference Manual. 2.04.03 Fetal Fibronectin Enzyme Immunoassay; 2010.
- Mercer, B.M., Goldenberg R.L., and et al. The preterm prediction study: a clinical risk assessment system, American Journal of Obstetrics and Gynecology; 174(6): 1996.
- Ness A, Visitine J, Ricci E et al. 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.
- Peaceman A.M., Andrews W.W., and et al. Fetal fibronectin as a predictor of preterm birth in patients with symptoms: a multicenter trial, American Journal of Obstetrics and Gynecology; 177(1): 1997.
- Plaut MM, Smith W, Kennedy K. Fetal fibronectin: the impact of a rapid test on the treatment of women with preterm labor symptoms. Am J Obstet Gynecol 2003;188(6):1588-965.
- Roberts WE, Morrison JC. 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. 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. A randomized controlled trial of metronidazole for the prevention of preterm birth in women positive for cervicovaginal fetal fibronectin: the PREMET study. BJOG 2006;113(1):65-74.
- Shimoya K, Hashimoto K, Shimizu T, Koyama M, Azuma C, Murata Y. Cervical fluid oncofetal fibronectin as a predictor of early ectopic pregnancy. Is it affected by blood contamination? J Reprod Med. 2002 Aug;47(8):640-4.
- Terrone DA, Rinehart BK, Kraeden U et al. Fetal fibronectin in symptomatic twin gestations. Prim Care Update Ob Gyns 1998;5(4):179.
- Von Der Pool B.A. Preterm labor: diagnosis and treatment, American Family Physician; 57(10): 1998.
Medical Policy Group, May 1996
Medical Policy Group, December 1996
TEC, November 1997
TEC, August 2000
Medical Policy Group, July 2002
Medical Policy Administration Committee, August 2002
Available for comment August 26-October 9, 2002
Medical Policy Group, February 2003 (2)
Medical Policy Administration Committee, March 2003
Available for comment April 1-May 16, 2003
Medical Policy Group, August 2004
Medical Policy Group, August 2006 (1)
Medical Policy Group, August 2009 (1)
Medical Policy Panel, September 2010
Medical Policy Group, October 2010 (2)
Medical Policy Administration Committee, November 2010
Available for comment November 4 - December 20, 2010
Medical Policy Group, September 2012 (3): Active Policy but no longer scheduled for regular literature reviews and updates.
Medical Policy Group, June 2019 (9): Updates to Description, Key Points, References. Added key words: cervicovaginal FFN. No change to policy statement.
This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.
This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.
The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.
As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.
The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:
1. The technology must have final approval from the appropriate government regulatory bodies;
2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;
3. The technology must improve the net health outcome;
4. The technology must be as beneficial as any established alternatives;
5. The improvement must be attainable outside the investigational setting.
Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:
1. In accordance with generally accepted standards of medical practice; and
2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and
3. Not primarily for the convenience of the patient, physician or other health care provider; and
4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.