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Current Perspectives on the Use of Fetal Fibronectin Testing in Preterm Labor Diagnosis and Management
Michael S. Ruma, MD, MPH; Katie C. Bittner, PhD; and Clara B. Soh, MPA
Management of Preterm Birth: Current Practices, Challenges, and Opportunities Participating Faculty

Current Perspectives on the Use of Fetal Fibronectin Testing in Preterm Labor Diagnosis and Management

Michael S. Ruma, MD, MPH; Katie C. Bittner, PhD; and Clara B. Soh, MPA
Similar to the professional society recommendations, all of the algorithms examined here are consistent in their recommendations on the use of fFN testing in conjunction with TVU and with other clinical signs of PTL. The various algorithms differ in the specific parameters for using fFN in assessing risk for spontaneous preterm birth, and this variance primarily revolves around the cervical length measurement determined to indicate the need for fFN testing13-17 (Table). For example, the algorithm published by Rose et al recommends using fFN for women with a cervical length between 16 and 29 mm and cervical dilation of <2 cm.13 In contrast, the Ohio State Algorithm by Iams et al recommends the use of fFN testing when the clinical and sonography data are equivocal (<2 cm dilation and 20-30 mm cervical length) or in contrast (<3 cm dilation, having changed by digital exam, and 35 mm cervical length measurement). Although the algorithms differ in the specific clinical characteristics of women who are candidates for fFN testing, they maintain a commonality regarding the utility of a standardized protocol-based approach, supporting the use of fFN testing coupled with TVU as the best diagnostic manner to evaluate a woman’s risk of spontaneous preterm birth when she presents with symptoms of PTL.

Review of Recent Studies on fFN Testing to Assess Risk of Preterm Birth

While multiple guidelines recommend the use of fFN testing under certain conditions, there remains a true lack of clear direction regarding when to use fFN testing in the diagnosis of PTL. This discrepancy may be due in part to the available medical literature presenting conflicting results regarding the utility of fFN testing.21,30-32 A detailed review of these studies reveals that the disparate results are largely due to inconsistent application of fFN testing, lack of adherence to standard protocols for management based on fFN results, and inappropriate use of the test to positively identify women at risk of spontaneous preterm birth. fFN testing is most valuable as a tool to help identify which women are at low risk for spontaneous preterm birth among those that present with symptoms of PTL. Unfortunately, much of the recent literature seeks to expand the use of fFN testing to identify which women will ultimately deliver preterm (at less than 37 weeks’ gestation) as a primary outcome, an outcome the fFN test was not designed to assess under its FDA indications.14,20,21,26,27,33-36 Thus, the lack of strict adherence to diagnostic and treatment protocols, as well as the expansion of the use of fFN beyond its core assessment strength, has resulted in literature-based evidence that has confounded our understanding of the proper role of fFN testing. This likely has diminished use of this diagnostic tool in clinical settings.

Several randomized trials, and a recent meta-analysis collating them, report that fFN testing had a limited impact on reducing the spontaneous preterm birth rate, a major outcome of interest.31,32,37-39 Nonetheless, although the result of the meta-analysis was not statistically significant, the relative risk for spontaneous preterm birth at <37 weeks of gestation was 0.72 (95% CI, 0.52-1.01) when the fFN test was randomly used to assess patients with symptoms of PTL. This relative risk determination demonstrates a directionality toward favoring fFN testing, even for an outcome that is not its original indication, nor the primary strength of the fFN test. Ideally, this phenomenon, where use of fFN may lead to a reduction in spontaneous preterm birth, would be further borne out in additional randomized controlled studies. In addition, several studies included in the meta-analysis lacked clearly defined protocols for treatment of women who were identified as high risk and left treatment options to physician discretion in all groups (fFN positive, fFN negative, and fFN result blinded), which may confound any of the results presented in these studies and the final results reported in the meta-analysis.32

The lack of guidance for clinicians treating patients with symptoms of PTL could easily contribute to the variability in the outcomes in these studies. A recent study examining the use of fFN to triage women with symptoms of PTL found that “practitioners either ignored the fFN result[s] or did not clearly understand them.”38 The inherent advantage of using a standardized decision algorithm in any scenario is that it eliminates variability in management at the end of each arm in the evaluation and management pathways. Implementation of a standardized decision algorithm in future studies, in which clinician management is directed by the results of fFN testing in combination with TVU cervical length, could potentially minimize this variability and more accurately determine whether fFN testing leads to reduced rates of spontaneous preterm birth or other major outcomes of interest, such as improved neonatal outcomes.

Assessing Risk for Spontaneous Preterm Birth: Underutilization of fFN Testing

The lack of consensus on when to use fFN testing may impact the use of this tool, and 2 recent analyses of administrative claims data support a low utilization of fFN testing in obstetric care today.11,12,27 A recent retrospective claims analysis covering more than 23,000 women presenting with symptoms of PTL in LD settings across the United States found that fFN testing was performed in only 14%, while 21.5% underwent evaluation by TVU.11,12 The same study found that 20.1% of patients discharged from LD settings delivered within 3 days and only 4.2% of these women were evaluated by an fFN test. As described in the study by Barner et al,40 a sizeable review of nearly 30,000 patients in the Texas Medicaid population found that of patients with 1 hospital or ED visit for symptoms of PTL, only 12% were evaluated with fFN testing.40

Need for Standardized Protocols Incorporating fFN Testing

The aforementioned lack of clear consensus among published clinical guidelines and algorithms, as well as the heterogeneity of outcomes examined and reported in the literature, may contribute to the underutility of fFN testing as observed in real-world data. Consensus may be difficult to achieve, but consistent implementation of a standardized protocol alone has been previously demonstrated to positively influence patient care.14,41-43 Further support of standardization comes from a recently presented research project conducted in northern Michigan (see Case Study 44). In addition to improving outcomes for patients, implementation of standardized protocols can positively affect healthcare expenditures. For example, a study performed by Rose et al demonstrated that implementation of an evidence-based protocol for PTL assessment reduced the rate of maternal hospital admission by 56% and resulted in an annual cost savings of $39,900.13 In assessing a variety of published data, there appears to be a clear role for fFN in combination with TVU to assess, identify, and potentially appropriately intervene among patients with symptoms of PTL to determine those at high risk of spontaneous preterm birth.

Conclusions

Although the ability to diminish the progression of PTL is limited, evaluating patients with symptoms of PTL through the use of standardized protocols is critical so clinicians can deliver therapies to those patients at greatest risk of spontaneous preterm birth, thereby promoting fetal maturation and reducing the risk of adverse perinatal outcomes.1,35,36,45 Conversely, accurately triaging women who present with suspected PTL, but are actually at low risk for spontaneous preterm birth, may reduce the use of unnecessary interventions and the expense incurred with such treatment.13-16,27

fFN testing has been shown to be effective in identifying patients at low and high risk of spontaneous preterm birth within 1 to 2 weeks in patients with symptoms of PTL.27 The use of this test in standardized algorithms can reduce disposition times and hasten treatment decisions in situations where timely intervention is crucial to the unborn neonate.13,30,46-49 To date, there remains a lack of true consensus in our field around when fFN testing should be used in the diagnostic pathway and how it should be coupled with other tests, such as TVU cervical length measurement. This disparity creates inconsistent assessment pathways and causes confusion; it may also diminish the use of fFN testing because clinicians may be unsure when fFN testing is appropriate.

Ultimately, healthcare providers and institutions should look to areas of agreement within the data published on this topic and adopt a standardized approach to PTL assessment. Implementing standardized algorithms based on this evidence will help ensure that testing occurs at the appropriate point in the diagnostic pathway in order to optimize patient care and improve the identification and management of women at high risk of delivering preterm.44,50 Tools such as fFN testing, which improve outcomes and meaningfully guide decision making, should be incorporated into these clinical decision pathways. Clinicians should be encouraged to follow standardized algorithms in order to fully realize their potential to reduce the impact of PTL and spontaneous preterm birth on patients and the healthcare system.

Author affiliations: Avalere Health, LLC (CBS, KCB); Perinatal Associates of New Mexico, Albuquerque, NM (MSR).
Funding source: Hologic, Inc, manufacturer of the Fetal Fibronectin Enzyme Immunoassay and Rapid fFN Test for the TLiIQ® System, provided funding for this analysis.
Author disclosures: Dr Bittner has disclosed that she is an employee of Avalere Health, LLC, which received funding from Hologic, Inc for the preparation of this manuscript; Dr Ruma has disclosed that he is a consulting physician for Hologic, Inc, that he has received honoraria and lecture fees at the invitation of a commercial sponsor, and that he received payment for his involvement in the preparation of this manuscript. Ms Soh has disclosed that she is an employee of Avalere Health, LLC, which received funding for this study.
Authorship information: Acquisition of data (KCB, MSR); analysis and interpretation of data (CBS, KCB, MSR); concept and design (CBS, KCB, MSR); critical revision of the manuscript for important intellectual content (CBS, KCB, MSR); drafting of the manuscript (CBS, KCB, MSR); supervision (KCB).
Address correspondence to: Michael S. Ruma, MD, MPH, Perinatal Associates of New Mexico, Suite 405, 201 Cedar SE, Albuquerque, NM 87106. E-mail: mruma@panm.com.
 
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