Aetna considers the fetal fibronectin (fFN) immunoassay test medically necessary for evaluating symptomatic pregnant women at high-risk for preterm delivery (see background section for selection criteria).

Aetna considers the fetal fibronectin test experimental and investigational for routine screening of the general obstetric population and for all other indications including high-risk women who are asymptomatic for preterm labor, for identifying optimal candidates for cerclage, and following insertion of a cervical cerclage because its effectiveness for these indications has not been established.

Aetna considers biomarkers of intra-uterine inflammation including angiogenin (in amniotic fluid), cytokines (e.g., interleukin-6, interleukin-8) and maternal matrix metalloproteinase-9 experimental and investigational for evaluating pregnant women at high-risk for preterm delivery because their effectiveness for this indication has not been established.

Aetna considers human chorionic gonadotrophin and phosphorylated insulin-like growth factor binding protein-1 (in cervico-vaginal fluid) experimental and investigational for evaluating pregnant women at high-risk for preterm delivery because their effectiveness for this indication has not been established.

Aetna considers salivary estriol (SalEst) test experimental and investigational because the test results are not available rapidly enough to assist in decisions concerning the immediate care of the member.

This policy is in accordance with the American College of Obstetricians and Gynecologists (ACOG) Committee Opinion on Fetal Fibronectin.

Fetal fibronectin (fFN) assay has recently been approved by the Food and Drug Administration (FDA) for clinical use in identifying patients at risk for preterm delivery.  The fFN immunoassay is a qualitative test for the detection of fFN protein in cervico-vaginal secretions.

A number of studies have examined the value of the fFN test as a predictor of likelihood of preterm delivery in women with symptoms of preterm labor.  The data indicate that a negative test has a maximal negative predictive value of approximately 96 % for not delivering within the next 2 weeks, while a positive test has a 15 to 20 % positive predictive value for preterm delivery.  Despite these data, there have been no prospective interventional studies demonstrating a decrease in preterm deliveries or improved perinatal outcomes based on the knowledge of the results of this test.  No study has examined the efficacy of fFN on the incidence, morbidity, and mortality of preterm delivery.  However, there may be selected cases in which quickly available results may be helpful in assessing the patient's risk of preterm delivery allowing for an impact on clinical decisions.

In a Cochrane review on fFN testing for reducing the risk of preterm birth, Berghella and colleagues (2008) concluded that although fFN is commonly used in labor and delivery units to help in the management of women with symptoms of preterm labor, currently there is not sufficient evidence to recommend its use.  Since this review found an association between knowledge of fFN results and a lower incidence of preterm birth before 37 weeks, further research should be encouraged.

Klebanoff and associates (2008) examined if salivary progesterone (P) or estriol (E3) concentration at 16 to 20 weeks' gestation predicts preterm birth or the response to 17alpha-hydroxyprogesterone caproate (17OHPC) and if 17OHPC treatment affected the trajectory of salivary P and E3 as pregnancy progressed.  This was a secondary analysis of a clinical trial of 17OHPC to prevent preterm birth.  Baseline saliva was assayed for P and E3.  Weekly salivary samples were obtained from 40 women who received 17OHPC and 40 who received placebo in a multi-center randomized study of 17OHPC to prevent recurrent preterm delivery.  Both low and high baseline saliva P and E3 were associated with a slightly increased risk of preterm birth.  However, 17OHPC prevented preterm birth comparably, regardless of baseline salivary concentrations of P and E3.  Moreover, 17OHPC did not alter the trajectory of salivary P over pregnancy, but it significantly blunted the rise in salivary E3 as well as the rise in the E3/P ratio.  The authors concluded that 17OHPC flattened the trajectory of E3 in the second half of pregnancy, suggesting that the drug influences the fetoplacental unit.

Selection Criteria for Fetal Fibronectin (fFN) Immunoassay:

According to the ACOG Committee on Obstetric Practice (1997), the fFN test is only appropriate for use in pregnant women with all of the following characteristics:

• Amniotic membranes intact; and
• Cervical dilatation is minimal (less than 3 cm); and
• Sampling is performed no earlier than 24 weeks, 0 days and no later than 34 weeks, 6 days of gestation.

In addition, the fFN test is only useful if results are available quickly enough (generally considered to be under 4 hours) so that the results can assist in decisions concerning the immediate care of pregnant women.

Although a negative test appears to be useful in ruling out imminent preterm delivery (i.e., within 2 weeks), the clinical implications of a positive result have not been fully evaluated.

If the test is to be clinically useful, the results must be available from the laboratory in a timely manner (generally considered to be under 4 hours) so that the test can effect decisions concerning the immediate care of the patient.  This is in accordance with the ACOG Committee Opinion, which states that “[i]f the test is to be clinically useful, the results must be available from the laboratory in a timely manner.”

ACOG does not recommend the fFN test for screening asymptomatic women to determine risk of preterm delivery.  ACOG's Division of Practice Activities concluded that "this test is not recommended as a routine screening procedure for the general prenatal population".  A recent clinical trial of the fFN test in 108 women at low risk of preterm delivery concluded that bi-weekly fFN determinations in asymptomatic women between 24 and 34 weeks' gestation “are of limited clinical value for the prediction of preterm birth”.

Keeler and colleagues (2009) determined the relationship between fFN testing prior to ultrasound-indicated cerclage and obstetric outcome.  Singleton pregnancies between 18 and 24 weeks' gestation with an ultrasound-diagnosed short cervix (less than 25 mm) and funneling (greater than 25 %) of the chorio-amniotic membranes into the endocervical canal were analyzed.  The fFN testing was performed and patients were randomized to cerclage or no-cerclage.  Groups were stratified by fFN result.  Cerclage patients were compared with no-cerclage patients.  The primary outcome was delivery prior to 35 weeks' gestation.  Spontaneous preterm birth prior to 35 weeks' gestation occurred in 15 (44.1 %) fFN-positive-cerclage patients and 16 (55.2 %) fFN-positive no-cerclage patients (p = 0.45).  Similarly, it occurred in 16 (17.8 %) fFN-negative cerclage patients and 11 (17 %) fFN-no-cerclage patients (p = 0.99).  The authors concluded that fFN testing did not identify optimal candidates for cerclage.

Inflammatory biomarkers are being investigated as predictors of preterm birth.  Gedc and Ford (2010) stated that there is overwhelming evidence that intra-uterine infection and inflammation play an important role in the pathogenesis of spontaneous preterm labor, preterm prelabor rupture of the membranes and fetal injury resulting in long-term sequelae.  Early diagnosis of subclinical infection and inflammation may therefore aid clinicians institute interventions focusing on such adverse outcomes.  Biomarkers of intra-uterine inflammation (e.g., interleukin-6) although sensitive, are not specific.  Thus, decision to deliver remote from term because of intra-uterine infection and/or inflammation should be based on clinical signs and/or bacterial culture or Gram stain of amniotic fluid.  In patients with preterm contractions and intact membranes, the risk of delivery is 1 % within the week following a negative fFN in cervico-vaginal secretions.  This aids to decide if antenatal steroids should be administered to patients presenting with preterm contractions between 24 and 34 weeks' gestation.  Biomarkers in cervical secretions and amniotic fluid identify those who may benefit from cerclage when the cervix is shortened (less than 25 mm) and dilated in the second trimester.  The authors concluded that so far, few interventions utilizing inflammatory biomarkers have shown clinical benefit.  They noted that future efforts should focus on the quest for accurate biomarkers that can be obtained non-invasively and allow early prediction of subclinical disease to initiate appropriate risk-specific intervention.

In a case-control study nested in a large, prospective, multi-center cohort trial (n = 5,337), Kramer and colleagues (2010) examined the role of mid-trimester maternal plasma cytokines and C-reactive protein (CRP) as predictors of spontaneous preterm birth.  Cohort women had an interview, examination, and venipuncture at 24 to 26 weeks.  Frozen plasma samples in women with spontaneous preterm birth (n = 207) and approximately 2 term controls per case (n = 444) were analyzed using Luminex multi-analyte profiling technology.  Fresh placentas were fixed, stained, and blindly assessed for histological evidence of infection/inflammation, decidual vasculopathy, and infarction, and vaginal swabs were analyzed for bacterial vaginosis and fFN concentration.  High maternal matrix metalloproteinase-9 (MMP-9) concentration, but none of the other cytokines or CRP, was significantly associated with spontaneous preterm birth [adjusted odds ratio = 1.7 (1.1 to 2.4)] and showed a dose-response relation across quartiles.  No association was observed, however, between maternal MMP-9 and placental infection/inflammation, bacterial vaginosis, or vaginal fFN concentration.  The authors concluded that these findings require confirmation in future studies, but suggest that a systemic immune response implicating MMP-9 may have an etiologic role in spontaneous preterm birth.

Conde-Agudelo et al (2011) examined the accuracy of novel biomarkers to predict spontaneous preterm birth in women with singleton pregnancies and no symptoms of preterm labor.  Electronic searches in PubMed, Embase, Cinahl, Lilacs, and Medion, references of retrieved articles, and conference proceedings were carried out.  No language restrictions were applied.  Observational studies that evaluated the accuracy of biomarkers proposed in the last decade to predict spontaneous preterm birth in asymptomatic women were selected.  These researchers excluded studies in which biomarkers were evaluated in women with preterm labor.  Two reviewers independently extracted data on study characteristics, quality, and accuracy.  Data were arranged in 2 × 2 contingency tables and synthesised separately for spontaneous preterm birth before 32, 34, and 37 weeks of gestation.  They used bi-variate meta-analysis to estimate pooled sensitivities and specificities, and calculated likelihood ratios (LRs).  A total of 72 studies, including 89,786 women and evaluating 30 novel biomarkers, met the inclusion criteria.  Only 3 biomarkers (proteome profile and prolactin in cervicovaginal fluid, and matrix metalloproteinase-8 in amniotic fluid) had positive LRs greater than 10.  However, each of these biomarkers was evaluated in only 1 small study.  Four biomarkers had a moderate predictive accuracy (interleukin-6 and angiogenin [a potent inducer of neovascularization], in amniotic fluid; human chorionic gonadotrophin and phosphorylated insulin-like growth factor binding protein-1, in cervico-vaginal fluid).  The remaining biomarkers had low predictive accuracies.  The authors concluded that none of the biomarkers evaluated in this review meet the criteria to be considered a clinically useful test to predict spontaneous preterm birth.  They stated that further large, prospective cohort studies are needed to evaluate promising biomarkers such as a proteome profile in cervico-vaginal fluid.

The Royal College of Obstetricians and Gynaecologists’ clinical guideline on “Cervical cerclage” (RCOG, 2011) stated that fetal fibronectin testing following insertion of a cervical cerclage is not recommended.