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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
One in 10 infants in the United States is delivered preterm (ie, before the 37th week of pregnancy), contributing to the significant burden on the national healthcare system. Nevertheless, a lack of agreement continues among obstetric professional societies on guidelines for standardization of the approach to the diagnosis and management of patients with symptoms of preterm labor (PTL). This disparity in consensus has likely resulted in poor identification of women at an increased risk for preterm birth (PTB). This paper presents an overview of several clinical guidelines and recommendations from a variety of studies regarding the use of fetal fibronectin (fFN) testing and transvaginal ultrasound (TVU) cervical length measurement, 2 tools that are used to assess the risk of spontaneous PTB (sPTB) in women with symptoms of PTL. We identify areas of commonality and discord within these publications. Although inconsistencies exist among the published guidelines, algorithms, and studies on how to diagnose and treat women with symptoms of PTL, each of them supports the use of fFN in conjunction with TVU for assessing the risk of sPTB. In addition, we review a case study from a regional hospital system with results demonstrating the benefits to patients and process outcomes when PTL assessment protocols are standardized, incorporating both fFN and TVU test results. In the absence of consensus on this topic, healthcare providers, administrators, and payers must navigate conflicting recommendations and identify areas of agreement for this evaluation within their own local settings.
Am J Manag Care. 2017;23:-S0
Preterm birth, defined as birth before 37 weeks of gestation, is a significant public health issue.1,2 Despite advances in obstetric care, approximately 1 in 10 infants is born preterm.2 About 30% of preterm births are medically indicated or due to maternal or fetal diagnoses, such as preeclampsia and intrauterine fetal growth restriction.3 The remaining 70% are spontaneous preterm births, which are attributed to preterm premature rupture of membranes or spontaneous onset of preterm labor (PTL). Regardless of the cause of preterm birth, complications related to preterm delivery are responsible for more than one-third of infant mortality observed each year in the United States.2 In addition to that significant neonatal death rate, the total annual medical cost associated with preterm birth within the United States, as shown by study results sponsored by the National Academy of Medicine, is estimated to be in excess of $16.9 billion, or more than $33,000 per preterm infant.4 In contrast, the average medical cost associated with a term birth is approximately $3300 per live birth.5

Preterm birth is associated with a wide array of serious health problems and developmental disabilities, including respiratory issues, gastrointestinal complications, central nervous system problems, and long-term cognitive, motor, and behavioral delays.2,4 The rate of spontaneous preterm birth has decreased consistently over the past decade; however, in 2015, a slight increase in the number of infants born before 37 weeks of pregnancy was noted in the United States, indicating that preterm birth continues to be a major public health issue, substantiating the need for prevention and intervention.2

Identifying women with symptoms of PTL, who are at high risk for spontaneous preterm birth and most likely to benefit from treatment, provides an opportunity to utilize appropriate interventions to minimize the potential impact of preterm delivery. At the same time, accurately identifying women who present with symptoms of PTL, but who are at low risk for spontaneous preterm birth, can help reduce overtreatment and misuse of healthcare resources, along with the potential harm that may come with both. The importance of accurate spontaneous preterm birth risk assessment cannot be overstated. This paper examines several clinical guidelines, algorithms, and additional evidence from published studies regarding the assessment of women with symptoms of PTL and summarizes these recommendations in order to identify commonality on how to best utilize available tools for risk assessment of spontaneous preterm birth.

Unmet Need in Assessing Risk for Spontaneous Preterm Birth

Identifying which women are truly at risk for imminent  spontaneous preterm birth is an immediate challenge that confronts any clinician evaluating women with symptoms of PTL. Numerous tools and methods are available to evaluate women with signs of PTL including: observation of clinical symptoms such as cramping, vaginal bleeding, and the frequency of uterine contractions; physical examination to assess cervical dilation; fetal monitoring and tocometry; assessment of cervical length by transvaginal ultrasound (TVU); and laboratory testing to detect the presence of fetal fibronectin (fFN). Despite the availability of these tools, accurately assessing risk for spontaneous preterm birth remains difficult.

The percentage of women admitted with a diagnosis of PTL who end up delivering at term varies widely between studies (15%-70%) and has been shown to vary by gestational age at presentation.6-9 For example, a systematic review found that among women diagnosed with PTL based on clinically observed criteria, more than 70% of these patients ultimately gave birth at term, illustrating that “the classic criteria for the diagnosis of PTL—regular uterine contractions with concomitant cervical change” has limited predictive value.9 Another study found that fewer than 10% of women who were given a clinical diagnosis of PTL gave birth within 7 days.10 Clearly, there is a demonstrated need to supplement the classic clinical examination with additional information to improve the assessment of risk for spontaneous preterm birth in this group of patients.

Although many women presenting with PTL symptoms deliver at term, it is critical to identify the subset of patients who are at greatest risk of preterm delivery. By identifying this high-risk cohort, patients may then be admitted for observation or transferred to a facility with an appropriate-level neonatal intensive care unit, and interventions to prevent spontaneous preterm birth may focus on those who are at greatest risk of delivering preterm. A recent study utilizing administrative claims data demonstrated that more than three-quarters of patients (75.9%) presenting either through an emergency department (ED) or labor and delivery (LD) setting at less than 37 weeks’ gestation with symptoms of PTL were discharged; of those patients, 1 in 5 (20.1%) went on to deliver within the next 3 days.11,12 This analysis of real-world data suggests that patients at imminent risk of spontaneous preterm birth are not being effectively identified or properly managed, indicating a significant need to improve triage and assessment practices.

Despite the availability of a variety of diagnostic tools, it is unclear whether clinicians should use these tools in combination, sequentially, or independently.1,13-18 The lack of consensus on how to systematically assess risk for spontaneous preterm birth results in potentially inappropriate triage of women with symptoms of PTL, contributes to wide practice variation, and highlights the need for a standardized assessment protocol to ensure that all of the available diagnostic and assessment tools are used appropriately—to ensure that patients at low risk of spontaneous preterm birth are not being unnecessarily treated and that patients at high risk are being identified and treated properly.

Review of Clinical Guidelines, Algorithms, and Expert Opinion on the Use of fFN Testing to Assess Risk of Spontaneous Preterm Birth

In order to understand recommendations for assessing risk for spontaneous preterm birth in patients with symptoms of PTL, we reviewed several published guidelines from major obstetric societies, a variety of algorithms from published studies, and expert opinions available online, all of which detail the evaluation and management of these patients. In conducting this review, we found that there is agreement regarding the value of fFN testing, particularly when performed in conjunction with TVU for women with an equivocal cervical length (which varies by study).1,13-19

fFN is an extracellular matrix glycoprotein that is produced by fetal cells and can be detected in cervicovaginal fluid (CVF).20-22 Generally, fFN is detectable from early in gestation until early in the second trimester; it then decreases to undetectable levels in a pregnancy that is at low risk for preterm birth.23-25 The presence of fFN in CVF during or after the second trimester may indicate a disruption of the decidual-chorionic interface of the amniotic membrane and is associated with a significant increased risk of spontaneous preterm birth.20,21,26

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).27 A lack of agreement, however, exists among professional organizations, published algorithms, and expert opinion as to the specific clinical characteristics of women for whom fFN testing should be used (Table).16

Over the past 2 decades, the American Congress of Obstetricians and Gynecologists (ACOG) has provided varied and somewhat conflicting guidance on the assessment of women presenting with symptoms of PTL. In its most recent practice bulletin (171; summarized in the Table), ACOG focuses primarily on the treatment and management of patients at risk of delivery within 7 days, rather than the identification of patients at risk for preterm delivery, and advises against using short cervical length or fFN testing alone in the management of patients with symptoms of PTL.1 However, in an earlier practice bulletin, from 2003, ACOG stated, “fFN testing may be useful in women with symptoms of PTL to identify those with negative values and a reduced risk of preterm birth, thereby avoiding unnecessary interventions.”28 Interestingly, Practice Bulletin 130, “Prediction and Prevention of Preterm Birth,” recommends against the use of fFN testing in asymptomatic women, but never addresses its use in women with symptoms of PTL.29 In contrast, the Society for Maternal Fetal Medicine (SMFM)19 supports fFN use in conjunction with TVU, stating, “fFN seems to be most helpful for women with a ‘borderline’ TVU CL (cervical length) of 20 to 29 mm.” The recommendation from SMFM appears consistent with many other algorithms available in published studies on the topic (Table).

Recently, experts published an evidence-based standardized protocol for diagnosis of PTL.16 The algorithm (Figure16) recommends that fFN be used in women with a cervical length between 20 and 30 mm and cervical dilation <3 cm, similar to an algorithm published by Ness et al in 2007.14 In addition to this protocol available online, other decision algorithms for the diagnosis and management of patients with symptoms of PTL exist.13-17 The diagnosis of PTL and subsequent treatment decisions in these algorithms are based on a combination of factors; they include gestational age, presence of uterine contractions, whether membranes are intact, cervical dilation, fFN testing status, and TVU measured cervical length (Figure).16 Given that no single marker has both high negative and positive predictive values for spontaneous preterm birth, the algorithms rely on multiple factors to guide treatment decisions.

 
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