Assessing the risk of preterm birth with fetal fibronectin testing in conjunction with transvaginal ultrasound

A substantial body of evidence suggests the use of fetal fibronectin (fFN) testing can help differentiate between expectant mothers presenting with symptoms of preterm labor who are truly at higher risk of imminent preterm birth from the vast majority whose symptoms will resolve spontaneously without hospitalization and treatment. As the COVID-19 pandemic continues, it is imperative that we are accurate in deciding on when to admit pregnant women to the hospital where resources are overwhelmed and potential risk of exposure to the virus may increase. Laboratories can help by offering fFN testing to aid in the healthcare providers’ decision-making process, improving patient care and reducing unnecessary interventions.

Preterm birth is a global medical problem

Preterm birth, defined as childbirth before 37 weeks of gestation, is a major global healthcare issue. Worldwide, the preterm birth rate is 11 percent, with 15 million preterm children born every year. Most preterm births (84 percent) occur between weeks 32 to 36 of gestation. Unless medically indicated, pregnancy through 39 weeks of gestation is recommended for optimal health of the infant.

In the United States, the preterm birth rate rose for the fourth consecutive year, with 10 percent of infants being born prematurely in 2018. The rates differ between racial and ethnic groups, with a preterm birth rate of 14 percent for black women compared with 9 percent for white women. Preterm birth and low birth weight are the second leading cause of death in infants in the United States, accounting for approximately 17 percent of infant deaths.¹

Preterm birth interrupts growth that would normally be completed in utero and the shorter the gestational age at birth, the greater the risk of long-term disability and/or death of the infant. Infants born preterm experience short-term complications from prematurity that affect most organs and systems, as well as possible intellectual and developmental deficits and other long-term health problems.

Similarly, from an economic standpoint, the earlier the birth occurs, the greater are the costs. The average cost per preterm birth in the United States was $65,000 in 2016, totaling $25.2 billion in societal costs, which include medical costs for the delivery, early intervention and special education services for the preterm child, and lost productivity in the workplace for the parents.²

Due to the overwhelming issues for both mother and child, it is crucial for laboratories to consider offering testing approved by the U.S. Food and Drug Administration (FDA) to rapidly screen all women presenting with symptoms of preterm birth to help reduce the burden on the mother, her unborn child, and the healthcare system overall.

Fetal fibronectin is a biomarker capable of predicting preterm birth

The glycoprotein fFN helps bond the amniotic sac with the chorionic layer of the uterus during gestation.³ fFN is normally not found in vaginal secretions from weeks 16 to 35 during pregnancy.⁴ As the mother prepares to give birth, fFN leaks into the vaginal fluid.5 Testing for fFN can help differentiate between expectant mothers presenting with symptoms of preterm labor at higher risk of imminent preterm birth and the vast majority whose symptoms will resolve spontaneously without hospitalization and treatment, enabling efficient use of healthcare resources, especially during the time of the COVID-19 pandemic, when hospitalization may pose other potential health risks and consume critical resources.

Most women (75 percent to 95 percent) who have preterm labor symptoms before 32 weeks of gestation do not deliver within a week; therefore, prediction of who will actually deliver preterm is important to avoid unnecessary treatment, lower costs, and reduce maternal stress. fFN testing has a high negative predictive value for symptomatic women, meaning a negative fFN test indicates a <1 percent chance of delivery within two weeks.⁵

Numerous studies showing the positive impact of fFN testing have been published for clinical outcomes and cost effectiveness, including preterm birth management algorithms developed by experts that incorporate fFN testing.^6,7 A recent systematic review of clinical trials stated that fFN levels of ≥50 ng/mL at 22 weeks of gestation or later is one of the best predictors of preterm birth in all populations studied and can help select which women are at significant risk for preterm birth.⁸ Another systematic review concluded that fFN testing had the potential to reduce unnecessary use of healthcare resources by identifying women who do not require medical intervention as an inpatient.⁹

Implementation of a standardized preterm labor screening protocol that included fFN testing at three hospitals within the WellStar Health System allowed for more efficient allocation of provider time and hospital resources. After implementation, the proportion of patients who received fFN testing at these hospitals increased from 52 percent to 95 percent.⁷ This increased fFN test uptake was accompanied by a significant reduction in the average time for an assessment by a nurse and led to appropriate and prompt initiation of antenatal corticosteroids and tocolytics as recommended by the American Congress of Obstetricians and Gynecologists. Additionally, cost savings of $264,000 were recognized, stemming from reductions of medical interventions and unnecessary patient hospitalizations.⁷

Fetal fibronectin testing in conjunction with transvaginal ultrasound is the most effective way to assess the risk of preterm birth

The value of fFN testing in assessing preterm birth is already beneficial, but when combined with a transvaginal ultrasound (TVUS) cervical length measurement <30mm, the positive predictive value in determining if a woman is at risk of spontaneous preterm birth is dramatically higher. In fact, in a large study completed in the Netherlands, the combination of a short cervical length with a positive fFN test nearly doubles the risk of preterm birth in seven days.⁶ Preterm birth screening that includes fFN testing with a transvaginal cervical length assessment, when a women presents with symptoms of preterm labor, is the most effective way to determine her risk of an imminent spontaneous preterm delivery, leads to better perinatal outcomes, and reduces health care costs.⁶

In general, fFN testing and TVUS have been underutilized to identify women at risk of preterm delivery. In a retrospective study of more than 23,000 women presenting with symptoms of preterm labor to an emergency department using the Medical Outcomes Research for Effectiveness and Economics Registry, a national multipayer claims database, only 12 percent of patients received an fFN test and only 21.5 percent had a TVUS.¹⁰ The proportion of women who underwent fFN testing was significantly higher for patients discharged home (14.2 percent) versus those admitted to the hospital (5.0 percent; P<0.0001). Overall, accurate assessment of a patient’s risk of imminent preterm delivery was poor, as 76 percent of the women were discharged home, yet 20 percent of these women proceeded to deliver within three days of being discharged. Of the discharged women who suffered a preterm delivery, only 3 percent received fFN testing, only 18 percent received a TVUS, 1 percent received both fFN testing and TVUS, and 78 percent received neither a fFN test, nor a TVUS during their hospital evaluation for symptoms of preterm labor. The overall proportion of women who delivered within three days of assessment in the emergency department was lower among women who only had fFN testing (6.6 percent) compared to those who only had TVUS (21.6 percent), suggesting fFN testing may have provided valuable information for patient care, while TVUS may have provided false reassurance to providers in their decision to discharge the patient. Importantly, preterm delivery was significantly lower among women who had both tests (4.7 percent; P<0.0001).

Given the current strain on the healthcare system due to the COVID-19 pandemic, it is more vital than ever to ensure provider time and system resources are used efficiently and effectively without compromising quality of care. To that end, use of fFN testing with or without TVUS should be incorporated as the standard evaluation to help identify women with symptoms of preterm labor who are at very low risk of imminent preterm birth. Laboratories with fFN testing rapidly available are invaluable in helping healthcare providers make the important decision of whether to admit pregnant women with preterm labor symptoms to the hospital, implement medical interventions beneficial to the infant, or confidently discharge women at low risk of preterm delivery, thereby supporting patient wellbeing and conserving valuable hospital resources.

References

1. Reproductive Health. Premature Birth. Centers for Disease Control and Prevention. https://www.cdc.gov/reproductivehealth/features/premature-birth/index.html. Accessed DECEMBER 19, 2020.
2. Economists tally societal cost of preterm birth UNews. University of Utah. November 4, 2019. https://unews.utah.edu/cost-of-preterm-birth/#:~:text=The%20total%20cost%20in%202016,of%20%2464%2C815%20per%20preterm%20birth. Accessed DECEMBER 19, 2020.
3. Lockwood CJ, Senyei AE, Dische MR, et al. Fetal fibronectin in cervical and vaginal secretions as a predictor of preterm delivery. N Engl J Med. 1991;325(10):669-674. doi: 10.1016/s0002-9378(97)70431-9.
4. Goldenberg, RL et al. The preterm prediction study: the value of new vs standard risk factors in predicting early and all spontaneous preterm births. NICHD MFMU Network. Am J Public Health. 1998 Feb; 88(2): 233-8. doi: 10.2105/ajph.88.2.233.
5. Peaceman AM, Andrews WW, Thorp JM, et al. Fetal fibronectin as a predictor of preterm birth in patients with symptoms: a multicenter trial. Am J Obstet Gynecol. 1997;177:13-18. doi: 10.1016/s0002-9378(97)70431-9.
6. Van Baaren G-J, Vis JY, Wilms FF, et al. Predictive value of cervical length measurement and fibronectin testing in threatened preterm labor. Obstet Gynecol. 2014;123(6):1185-1192. doi: 10.1097/AOG.0000000000000229.
7. Wattie, L. Implementation of PLAT (preterm labor assessment toolkit): a system-wide initiative to improve preterm labor outcomes. Contemporary OB/GYN. January 2017:1-4.
8. Berghella V, Saccone G. Fetal fibronectin testing for reducing the risk of preterm birth. Cochrane Database of Systematic Reviews. 2019;7, Article CD006843, doi: 10.1002/14651858.CD006843.pub3.
9. Deshpande SN, van Asselt ADI, Tomini F, et al. 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;17(40):1-138. doi: 10.3310/hta17400.
10. Blackwell SC, Sullivan EM, Petrilla AA, et al. Utilization of fetal fibronectin testing and pregnancy outcomes among women with symptoms of preterm labor. Clinicoecon Outcomes Res. 2017;9:585-594. doi: 10.2147/CEOR.S141061