Evaluation of Preterm Labor: A Role for Laboratorians?

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Preterm birth (PTB), the delivery of a baby prior to 37 weeks gestation, is the second most common cause of infant death in the United States and surviving infants are at increased risk of lifelong complications (1). The cost of medical care from delivery through adulthood, as well as diminished workplace productivity in individuals with PTB-associated developmental disabilities is estimated at $26 billion annually (2,3). Clearly, this represents a significant public health issue yet despite substantial effort, the preterm birth rate remains essentially unchanged at 10% (3,4).

Identifying women who will deliver prematurely is difficult as the clinical signs and symptoms are very nonspecific. Complicating matters is the fact that very few women with preterm labor symptoms deliver within seven days. At U.S. medical centers, the typical rate of such deliveries is 2-3%. In other words, 97-98% of women with symptoms of preterm labor will not deliver within one week (5,6).

Given the negative health consequences of PTB, there is a clear need for diagnostic tools that distinguish the small number of women who will deliver preterm from the much larger pool of women who will not. A diagnostic test that identifies the “needle in the haystack” – the 2-3% of women who will deliver, with a high degree of certainty must have a high positive predictive value (PPV: people with a positive test result who have the disease or condition).

Unfortunately, currently available tests for the evaluation of preterm labor have a low PPV and a high negative predictive value (NPV: people with a negative test result who do not have the disease or condition) and they provide limited additional information. Remember that without doing any clinical laboratory testing, prevalence alone provides a NPV of 97-98%. Fetal fibronectin (fFN), the most widely used clinical laboratory test for the evaluation of PTB, consistently demonstrates a NPV of 99% for PTB within seven days. A negative result provides reassurance that delivery within the next week is very unlikely but this doesn’t substantially improve patient management as the same reassurance is provided by prevalence alone. Furthermore, the PPV of fFN for PTB within one week is consistently 15-20% across different patient populations (7–9). As <20% of women with a positive test deliver within one week, this doesn’t substantially change the pre-test probability but may increase stress and prompt unnecessary further evaluation (10). An alternative PTB test, placental alpha microglobulin-1 (PAMG-1), consistently exhibits a higher PPV than fFN but it still falls short of the threshold needed to add value in a population with a low prevalence (11). Limiting testing to those at high risk (and thereby increasing prevalence in the tested population) through ultrasound screening of cervical length increases PPV but this is not routinely performed at most U.S. medical centers (12).

A clinical laboratory test that identifies the minority of women who will deliver prematurely with a high degree of certainty would have immense value. Ultimately, the search continues, as none of the available markers meet the “high PPV” requirement.

References

1. National Vital Statistics Reports Volume 68, Number 9 June 24, 2019 Deaths: Final Data for 2017. :77.
2. Behrman RE, Butler AS, Outcomes I of M (US) C on UPB and AH. Societal Costs of Preterm Birth [Internet]. Preterm Birth: Causes, Consequences, and Prevention. National Academies Press (US); 2007 [cited 2020 Jul 16]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK11358/
3. Prematurity Profile [Internet]. [cited 2020 Aug 5]. Available from: https://www.marchofdimes.org/peristats/tools/prematurityprofile.aspx?reg=99
4. National Vital Statistics Reports Volume 68, Number 13, November 30, 2019, Births: Final Data for 2018. :47.
5. Wing DA, Haeri S, Silber AC, Roth CK, Weiner CP, Echebiri NC, et al. Placental Alpha Microglobulin-1 Compared With Fetal Fibronectin to Predict Preterm Delivery in Symptomatic Women. Obstet Gynecol. 2017;130:1183–91.
6. Melchor JC, Navas H, Marcos M, Iza A, De Diego M, Rando D, et al. Predictive performance of PAMG-1 vs fFN test for risk of spontaneous preterm birth in symptomatic women attending an emergency obstetric unit: retrospective cohort study. Ultrasound Obstet Gynecol. 2018;51:644–9.
7. Iams JD, Casal D, McGregor JA, Goodwin TM, Seshadri Kreaden U, Lowensohn R, et al. Fetal fibronectin improves the accuracy of diagnosis of preterm labor. American Journal of Obstetrics and Gynecology. 1995;173:141–5.
8. Peaceman AM, Andrews WW, Thorp JM, Cliver SP, Lukes A, Iams JD, et al. Fetal fibronectin as a predictor of preterm birth in patients with symptoms: A multicenter trial. American Journal of Obstetrics and Gynecology. 1997;177:13–8.
9. Berghella V, Saccone G. Fetal fibronectin testing for reducing the risk of preterm birth. Cochrane Database Syst Rev. 2019;7:CD006843.
10. 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;38:659-666.e6.
11. Melchor JC, Khalil A, Wing D, Schleussner E, Surbek D. Prediction of preterm delivery in symptomatic women using PAMG-1, fetal fibronectin and phIGFBP-1 tests: systematic review and meta-analysis. Ultrasound in Obstetrics & Gynecology. 2018;52:442–51.
12. Nikolova T, Bayev O, Nikolova N, Di Renzo GC. Comparison of a novel test for placental alpha microglobulin-1 with fetal fibronectin and cervical length measurement for the prediction of imminent spontaneous preterm delivery in patients with threatened preterm labor. J Perinat Med. 2015;43:395–402.