Dr. Zhan Yuan of Beijing Tongren Hospital: Biomarker Testing Significantly Enhances Accuracy and Speed of Preterm Birth Prediction

According to statistics, approximately 15 million preterm infants are born worldwide each year, with a preterm birth rate of about 11.1%. Early prediction and intervention for preterm birth are of significant importance in reducing its incidence and improving the survival and quality of life of neonates and infants. Point-of-care testing (POCT) technologies, represented by biomarker assays, serve as a crucial means for predicting preterm birth and hold substantial application value in centers for critically ill pregnant women.

November 13–14, 2020 — The “2020 China POCT Annual Conference,” co-hosted by the Point-of-Care Testing (POCT) Branch of the China Medical Devices Industry Association and the People’s Government of Jiangbei District, Chongqing, was held in Chongqing. Under the slogan “BeiDou + 5G: Building Dreams for China’s POCT” and the theme “Precision Epidemic Control, Health for All,” the conference covered topics including point-of-care testing applications, nanozymes and POCT, ultrasound testing, POCT and primary healthcare, and POCT and the Six Major Centers. The event featured a plenary session, thirteen specialized academic forums, and an exhibition showcasing corporate products.

On the 14th, at the POCT and Six Major Centers Subforum, Dr. Zhan Yuan, an attending physician in the Department of Obstetrics and Gynecology at Beijing Tongren Hospital, Capital Medical University, delivered a presentation titled “Application of POCT in Critical Maternal Care Centers.” VCBeat has compiled her key insights.

Preterm birth refers to delivery occurring between 28 completed weeks and less than 37 weeks of gestation. In China, its incidence ranges from 5% to 15%. It is a common cause of neonatal morbidity and mortality, with lower gestational age and lower birth weight associated with higher mortality rates. Preterm birth is also the second leading cause of death in children under five years of age, after pneumonia.

Symptoms of preterm labor include irregular uterine contractions, vaginal bleeding, and rupture of membranes (leakage of amniotic fluid) occurring before full term. Identifying individuals at high risk for preterm birth enables timely intervention to reduce its incidence. Meanwhile, it helps minimize overtreatment in low-risk patients, thereby avoiding unnecessary drug side effects and psychological stress.

Zhan Yuan introduced the currently common clinical methods for predicting preterm birth, including transvaginal ultrasound measurement of cervical length and biomarkers, and summarized the advantages and disadvantages of these methods.

Bedside ultrasound plays a pivotal role in the detection of critical obstetric and gynecological conditions, enabling rapid and accurate identification of preterm birth. In 1992, Jackson et al. first proposed the use of transvaginal ultrasound to measure cervical length for predicting preterm birth, with a predictive threshold defined as a cervical length ≤25 mm on transvaginal ultrasound. The measurement is typically recommended at 20 to 23+6 weeks of gestation.

Currently, cervical length measurement remains a relatively accurate and straightforward method for predicting preterm birth. However, it has limitations, including a relatively low positive predictive value and significant susceptibility to individual patient factors. There is currently no clear evidence that measuring cervical length after 24 weeks of gestation can effectively improve clinical outcomes for preterm birth. Therefore, cervical length measurement should not be used in isolation for predicting preterm birth; it must be combined with biochemical test results.

During the first 20 weeks of gestation, the connection between the fetal membranes and the decidua is not yet tightly established, allowing fetal fibronectin (fFN) to be secreted into the posterior vaginal fornix through interstitial spaces. In contrast, during the second and third trimesters, the bond between the fetal membranes and the decidua becomes more robust; fFN is released into the posterior vaginal fornix only when this interface is disrupted by mechanical injury or degradation by proteolytic enzymes. Therefore, measuring fFN levels in vaginal secretions during the second and third trimesters serves as a superior predictor for preterm birth.

In 1991, Lockwood et al. first identified fetal fibronectin (fFN) as a predictor of preterm birth. Point-of-care testing (POCT) methods have greatly promoted the clinical application of fFN testing. Currently, detection of fFN in posterior vaginal fornix secretions is one of the most widely used clinical methods for predicting preterm birth. Its clinical significance lies particularly in its high negative predictive value; specifically, the negative predictive value for non-delivery within one week among patients with a negative fFN result exceeds 97%.

However, this method has low sensitivity, ranging from only 20% to 29%. The 2016 Supplemental Guidance on Preterm Birth issued by the American College of Obstetricians and Gynecologists (ACOG) states that a positive fetal fibronectin (fFN) test alone has a low positive predictive value for preterm birth and should not be used in isolation to guide treatment in emergency cases.

In other words, fFN testing should be used conditionally and is not suitable for predicting preterm birth in all pregnant women; it should be employed based on the results of ultrasound cervical length measurement.

Similar to the principle underlying fetal fibronectin (fFN) testing, insulin-like growth factor-binding protein-1 (IGFBP-1) should not be detectable in cervical secretions after 22 weeks of gestation. However, in cases of threatened preterm labor or preterm labor with uterine contractions, separation of the decidua from the chorion and subsequent disruption of decidual cells cause IGFBP-1 to leak into cervical mucus. Therefore, measurement of IGFBP-1 in cervical mucus can predict preterm birth. Additionally, IGFBP-1 serves as a biomarker for the detection of premature rupture of membranes (PROM).

In pregnant women at 22–36 weeks of gestation, vaginal swabs obtained via speculum examination can yield insulin-like growth factor-binding protein 1 (IGFBP-1) test results within 5 minutes using immunochromatographic strip assays. However, recent systematic reviews have indicated that placental alpha microglobulin-1 (phIGFBP-1) has a sensitivity of only 33% and a specificity of only 79% for predicting preterm birth in asymptomatic women. For symptomatic pregnant women with negative test results, the accuracy in ruling out the risk of delivery within 48 hours is only low to moderate. Therefore, overall, phIGFBP-1 has limited predictive value for the risk of preterm birth in both symptomatic and asymptomatic pregnant women.

PAMG-1 is another glycoprotein synthesized by decidual cells. Its concentration in amniotic fluid is 1,000–10,000 times higher than that in cervicovaginal secretions when the fetal membranes are intact. PAMG-1 was initially used for the diagnosis of premature rupture of membranes (PROM). When the fetal membranes are intact, the concentration of PAMG-1 in cervicovaginal secretions is extremely low, with a cutoff value of 5.0 ng/mL for diagnosing PROM.

In 2012, Mi Lee et al. proposed that in pregnant women with preterm labor and intact fetal membranes, a positive PAMG-1 test has predictive value for preterm birth within 48 hours, 7 days, and 14 days, and is superior to fFN. The PAMG-1 test does not require the use of a speculum; samples are obtained by directly inserting a vaginal swab into the vagina, and results can be available within 5 minutes using an immunochromatographic assay strip.

In 2018, Melchor et al. systematically evaluated the accuracy of PAMG-1, fFN, and phIGFBP-1 tests in predicting spontaneous preterm birth within 7 days among pregnant women with symptoms of preterm labor. Across different risk stratification groups, there were no significant differences in the negative predictive values and negative likelihood ratios among the three biomarker tests; however, the PAMG-1 test demonstrated the highest positive predictive value and positive likelihood ratio (P < 0.05), indicating that PAMG-1 exhibits a higher positive predictive value.

In 2017, the European Association of Perinatal Medicine recommended that PAMG-1 has significant value in predicting spontaneous preterm birth among pregnant women with threatened preterm labor and a cervical length of 15–30 mm.

Zhan Yuan stated that, in addition to the aforementioned methods for predicting preterm birth, other approaches—such as assessing inflammatory mediators, vaginal microecology, and genomics—can also be utilized for preterm birth prediction. In summary, point-of-care testing (POCT) plays a significant role in predicting preterm birth. The use of existing technologies to develop test strips, kits, or assay papers for sampling and detecting various protein biomarkers in cervicovaginal secretions is simple, convenient, and practical. This represents an important application of POCT in the management of critically ill obstetric patients.