Category Archives: Fetal Fibronectin

Fetal Fibronectin

A New FDA-Approved Test for Predicting Preterm Delivery


Preterm baby

According to the March of Dimes, preterm birth occurs in approximately 10% of U.S. pregnancies. Until recently, cervicovaginal fetal fibronectin (fFN) was the only FDA-approved test for predicting preterm delivery in symptomatic women. We have blogged about fFN previously

Despite its FDA approval, fFN has limited clinical value. A condition with low prevalence, such as preterm delivery, has a low pre-test probability of occurring, hence a negative test result adds little to the assessment of the patient. Thus, a screening test for a low prevalence condition must demonstrate high positive predictive value (PPV) to be useful. The negative predictive value (NPV) of fFN is 99.5%, meaning a negative result is highly predictive that a woman will NOT deliver soon. However, PPV of fFN is only ~17%, meaning that less than 1 in 5 women with a positive test result will proceed to delivery with 7-14 days. For comparison, the PPV of flipping a coin in this population is 4%. Meta-analyses have supported the lack of utility for fFN.

In April 2018, the FDA approved cervicovaginal placental alpha macroglobulin-1 (PAMG-1), (brand name Parto Sure from QIAGEN) as a test for assessing the risk of spontaneous preterm birth in patients with symptoms of preterm labor.

Several recent studies have evaluated PAMG-1 for its ability to predict preterm birth.

Wing, et al. conducted a prospective study of pregnant women from 15 US sites, with signs or symptoms of preterm labor between 24 and 35 weeks of gestation with intact membranes and cervical dilations less than 3cm (>3 cm generally indicates active labor). They compared the utility of PAMG-1 to fFN. A summary of their key findings are shown in the table below.

Spontaneous preterm delivery ≤ 7 days

PPV

NPV

PAMG-1

19.0%

99.1%

fFN

6.5%

99.7%

     

Spontaneous preterm delivery ≤ 14 days

   

PAMG-1

25.0%

97.7%

fFN

11.1%

98.7%

Cervicovaginal PAMG-1 demonstrated similar negative predictive value and improved positive predictive value compared to cervicovaginal fFN.

Similarly, Melchor, et al. conducted a retrospective study of women with preterm contractions presenting to a single maternity hospital in Spain. They compared a one year period during which fFN was used to assess risk of pre-term delivery and a one year period where PAMG-1 was used. Similar to the Melchor study, patients were between 24-34 weeks of gestation with signs or symptoms of preterm labor and had intact membranes and a cervical dilation less than 3cm. A summary of their key findings are shown in the table below.

Spontaneous preterm delivery ≤ 7 days

PPV

NPV

PAMG-1

35.3%

98.3%

fFN

7.9%

97.9%

Both studies show improved positive predictive values for PAMG-1 over fFN. However, both studies reported sensitivities for PAMG-1 of 50%.  While this test can certainly be viewed as an improvement over fFN, PAMG-1 will only identify half of the women who will deliver within 7 day. Clearly a better marker to predict pre-term delivery is still needed.

Predicting preterm birth


Preterm baby Preterm birth is a serious problem. Defined as delivery before 37 completed weeks, infants born preterm are at high risk of complications such as respiratory distress syndrome, bleeding into the brain, poor neurological development, and cognitive impairment. Further, preterm birth is responsible for ~75% of death in newborns without genetic anomalies.

Unfortunately, the vast majority of treatments provided to pregnant women with symptoms of preterm labor have done little to prevent preterm birth. About 13% of pregnancies end with preterm delivery and this percentage has increased steadily over the last few decades.

Risk factors for preterm birth include mother's age, socioeconomic status, and being pregnant with more than one fetus. A woman who has had a previous preterm delivery is also at risk of delivering subsequent pregnancies early as well. Preterm birth is also more common among black women compared to other ethnic groups which appears to be unrelated to socioeconomic status or other factors.

Symptoms of preterm labor are just like symptoms of term labor. However, early contractions occur frequently in pregnant women and don't always mean they are in actual preterm labor. In fact, most women with early symptoms go on to delivery term babies. This makes it difficult to diagnose true preterm labor when it occurs. A test that could accurately predict preterm labor would be helpful.

Currently there is only one lab test approved for use to predict preterm labor. Fetal fibronectin (fFN) is a protein produced by the fetal membranes during pregnancy. Although it can be detected in cervicovaginal fluid early in pregnancy it usually becomes undetectable between weeks 25 and 35. After that, it becomes detectable again after 37 weeks. In women with preterm labor, fFN can be detected in cervicovaginal fluid during the time that it is usually not present. This may occur because of a break down of the fetal membranes or in response to inflammation.

A recent study compared the ability of fFN and a interleukin-6 (IL-6), an inflammatory cytokine, to predict preterm birth. The tests were performed in 667 samples collected from 580 women with and without symptoms of preterm labor. About half of the women in the study were black.

In both groups, a positive fFN result was significantly associated with preterm birth occurring within 14 days of testing. However, the actual likelihood of delivery early was still rather low. Like other studies, this one also showed that the strength of the fFN test is it's negative predictive value. That is, the absence of fFN is a much stronger indicator that preterm birth won't occur.

IL-6 was also significantly associated with preterm birth but only in the black women. Like fFN, it also wasn't a strong predictor in this population but it was much better than fFN in either the black or non-black groups.

There's still much to learn. We don't really understand the different processes (which are multifactorial) that lead to preterm delivery. Also, it's clear that the events that lead to preterm delivery are probably not the same between women of different ethnic backgrounds. As such, a single predictor of preterm delivery is probably not going to work well. Combination testing, such as fFN and IL-6 (or other, yet to be discovered markers) may yield more promising results than any one marker alone.