The Importance of Fetal Fibronectin Testing for Women with Symptomatic Preterm Labor

Thought LeadersMichael S. RumaMaternal-Fetal Medicine Specialist Perinatal Associates of New Mexico An interview with Michael S. Ruma, MD, MPH conducted by Kate Anderton, BSc

Please can you give an overview of the causes of preterm labor.

Preterm birth is the most significant issue facing pregnant women and the clinicians caring for them.  With each preterm delivery, a significant cost is incurred by the infant, the mother and her family and the health system.

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Preterm birth for the clinician caring for the pregnant woman is always an issue on the forefront of his or her mind because ultimately an early delivery leads to significant potential harm to the infant due to outcomes related to prematurity.

Preterm delivery stands as the leading cause of infant morbidity and mortality globally, with short term complications such as respiratory distress and intraventricular hemorrhage, and long-term complications such as chronic lung disease and neurodevelopmental disorders.

In the United States, nearly 10% of infants are born too early (less than 37 weeks of pregnancy).  The majority of these preterm births (70%) are spontaneous related to preterm labor (45%) and preterm premature rupture of membranes (25%) and the remaining (30%) are medically-indicated for reasons related to the health of the mother or her unborn child.

It’s a difficult conversation to have with patients and it's something that clinicians don't enjoy dealing with, so anything that reduces the risks of preterm birth is a step forward.

The outcomes are significantly better for babies born at 32 weeks, compared to say, 24 or 28 weeks. They have significantly lower death and medical complication rates. However, they still spend a prolonged amount of time in the hospital following birth, in most cases three to five weeks, delaying the initiation of normal family life after the child’s birth.

What are the symptoms of preterm labor? Do all women develop symptoms?

Preterm labor typically presents with uterine contractions which are regular in rhythm and often last for hours. Many signs and symptoms of preterm labor are non-specific and include intermittent contractions, cramping (similar to menstrual cramps), low back pain, pelvic pressure in the vagina or pelvis, vaginal discharge and vaginal bleeding. Most women who undergo preterm labor develop symptoms, but they are non-specific so many cases go undiagnosed.

The true definition of preterm labor from a clinical standpoint is painful contractions with cervical change, however identifying this phenomenon in pregnant women remains a challenge in obstetrics as most patients who present with these symptoms at preterm gestational ages ultimately will go on to deliver at term.

Some women can differentiate that these symptoms are not rhythmic, not alarming, not consistent, but to the majority of pregnant women, it is a concerning symptom to have pressure, and pain, and pulling and tugging. The development of contractions that can sometimes last an hour or two in a day is often the reason women visit their obstetric provider for evaluation.

Preterm labor is suspected when patients present with complaints of contraction activity and often they truly believe they are in labor. Clinicians are then faced with having to differentiate between a patient who is at high risk to deliver preterm and those patients who are unlikely to deliver. The problem arises because 50-80% of women with symptoms of preterm labor go on to deliver at full term, making it harder to identify those who are truly in labor based on symptoms alone.

What is fetal fibronectin (fFN) and how is it associated with preterm labor?

The uterus is the cavity in which the pregnancy develops. When a fertilized egg implants into the uterus, multiple cell layers develop. The first is the decidual cell layer, found on the uterine interface, which faces the chorion (the first cell layer of the developing placenta), and then next to that is the amnion, or gestational sac. So, the decidual-chorionic interface is basically the mom’s connection to the baby.

Fetal fibronectin (fFN) is an extracellular matrix glycoprotein which is found between the decidual-chorionic interface.  If this interface deteriorates due to underlying factors such as infection or inflammation, placental abruption or uterine contraction activity, fFN is released through the cervix via cervicovaginal secretions.  It has been shown through a large number of different studies to be a strong and significant biomarker for identifying women at high-risk of spontaneous preterm birth.

fFN can be detected in these secretions using a unique swab and laboratory analyzer and when identified acts as a biomarker for spontaneous preterm birth (sPTB).  Initial research in the late 1990’s, identified that fFN is present early in pregnancy until the beginning weeks of the second trimester, but then is absent until labor presents at the end of the third trimester.

Detection of fFN between these times is abnormal and associated with a significant increase in the rate of sPTB in these patients.  fFN not only is able to predict delivery less then 37 weeks, but also within a 1-2 week time period which is useful for clinicians faced with decision-making on the plan of care for patients presenting with symptoms of preterm labor.

What impact does preterm labor have on the health of the mother and baby?

Preterm labor presents a variety of unique issues and challenges for both the mother and her baby.  Often, preterm labor symptoms lead to a hospital evaluation with the possibility for admission or maternal transport to a facility able to care for preterm infants were an early delivery to occur.

If preterm labor seems imminent, the mother undergoes a variety of medical treatments to prepare the unborn infant for a preterm delivery.  If a preterm delivery occurs, the infant faces a significant hospital stay typically until they demonstrate multiple milestones including feeding and maintaining their body temperature.  For example, if an infant is born at 32 weeks, a neonatal intensive care unit (NICU) stay for that infant may last 4-6 weeks.

Please outline your recent research into this area.

As a maternal-fetal medicine specialist, I maintain a keen interest in the prevention of preterm birth.  Specifically surrounding preterm labor prediction, I have participated as a principal investigator for one of several enrollment sites across the country in a recent industry-sponsored study on the predictive ability of quantitative fetal fibronectin in asymptomatic patients.

I routinely speak on the benefits of standardization and the use of protocols for the evaluation and management of patients with preterm labor.  I also recently published a review article in the American Journal of Managed Care this past year on fetal fibronectin and its role in testing of patients who present with symptoms of preterm labor.

How many women have access to fetal fibronectin (fFN) testing?

fFN testing has been available to clinicians for over 20 years. Despite this, uptake rates are low. Two recent articles have highlighted surprising findings with regards to the utilization of fFN testing in the United States.

Despite fFN’s ability to predict sPTB and assist clinicians in differentiating high and low risk cohorts of patients for preterm birth prevention strategies, a recent article by Blackwell et al., which was recently published in ClinicoEconomics and Outcomes Research, and another by Barner et al., recently published in the American Journal of Managed Care, found that fFN utilization is extremely low in scenarios where it should be used routinely.

The Blackwell study looked at multiple reports from several states, where the Barner study looked simply at Texas patients covered by Medicaid. Medicaid is the US government’s medical insurance for low-income patients, and it covers a large proportion of pregnancies in the United States.

Both researchers found similar utilization rates of fFN in the setting of patients presenting with symptoms of preterm labor at 12% and 14%, respectively.

Blackwell documented that of the 76% of patients discharged home after an evaluation for symptoms of preterm labor, over 20% went on to deliver within 3 days.  In this group of women previously evaluated for preterm labor who ultimately did deliver preterm, only 4% were evaluated with fFN testing. Unfortunately, the studies did not delineate the reasons behind clinician’s decisions to use or not use fFN testing in patients who present with symptoms of preterm labor.

Notably, Barner demonstrated that patients screened with fFN testing remained pregnant longer than patients not undergoing fFN testing.  This result is particularly interesting as it supports prior research by Ness et al., published in the American Journal of Obstetrics and Gynecology in 2007, which also illustrated that patients undergoing a standardized evaluation for preterm labor symptoms not only had a longer interval from evaluation to delivery, but also a reduction in sPTB.

One may surmise some reasoning for the low uptake rates may be attributable to the lack of support of fFN testing by professional agencies such as the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine. Organizations such as these wait for large, randomized, controlled trials, which are often difficult, extremely expensive to conduct, before they put a stamp of approval on any kind of recommendation.

Most clinicians look to their professional organization for guidance, and when they receive mixed messages from research and societal bodies, they lack direction on the use of different tools to help assess their pregnant patients.

Other reasons include the autonomy of providers, the absence of oversight and enforcement from medical licensing boards and hospital medical staff affairs or a simple lack of knowledge about the research supporting fFN use in practice.  Regardless of the cause, it is clear from these recent publications that utilization of fFN testing is low and that implementation of its use may yield a significant benefit to patients.

What options does fetal fibronectin (fFN) testing provide to women who show symptoms of preterm labor?

When fFN testing is performed on patients with symptoms of preterm labor, the test results return as either negative or positive.  The majority of patients will have a negative fFN result and these patients based on the fFN test’s high negative predictive value may be safely discharged home and reassured that they are at low risk for sPTB in the coming weeks.

Patients with a positive test may be identified as being high risk for sPTB and should receive antenatal corticosteroids for the benefit of the preterm fetus reducing the risks of respiratory distress, intraventricular hemorrhage and necrotizing entercolitis if preterm delivery occurs. These patients also should be administered magnesium sulfate if under 32 weeks to assist in the prevention of cerebral palsy, a well-known substantially detrimental neonatal and pediatric outcome.

Are there any limitations to the current method of fetal fibronectin (fFN) testing? Are there any alternative test?

Currently fFN testing is done using a qualitative test i.e. a test that is negative if < 50ng/mL or positive if ≥ 50ng/mL.  Quantitative fFN testing, which has been available in Europe for years, is currently under research in the United States.  Tests with negative and positive results using a single threshold are inherently prone to increased false-positive and false-negative results.

Using a variety of cut-offs, quantitative fFN testing holds the potential to more accurately predict sPTB in the future.  As quantitative fFN testing becomes available in the United States, its use may lead to significant improvement in the prediction of sPTB and more importantly may help clinicians decrease the rates of sPTB which affect so many pregnant women and their preterm infants.

There are alternatives to fFN testing. One mainstay evaluation tool for patients with symptomatic preterm labor is transvaginal cervical length evaluation. This method has similar predictability rates to fetal fibronectin. However, all tools have limitations, and many hospitals lack access to trained professionals who are able to provide 24 hour access to complete the transvaginal ultrasound to assess the cervical length.  Also, there are a number of studies looking at cervical length and its variability, which may be as high as 20% depending on whether or not the measurement is done correctly.

Fetal fibronectin also has limitations, for example, sensitivity is reduced if a patient has gross vaginal bleeding. In addition, if a patient has had intercourse or a digital cervical exam, this may manipulate the cervix and release some fibronectin, leading to a false positive.

Nevertheless, it is important to always objectively evaluate patients with subjective symptoms and ideally that would include both a fibronectin and a cervical length by ultrasound. But if a facility does not have trained individuals with the proper ability to assess a transvaginal ultrasound, fetal fibronectin should be used given its reliability and high negative predictive value.

What does the future hold for research into preterm labor?

We need to look at why pregnant woman are not being tested appropriately with preterm labor prediction tests, be it fibronectin or cervical length. When a patient comes to the emergency room in the United States with chest pain, it is standard of care that those individuals get two tests; an EKG and a test for a cardiac enzyme called troponin, which determine whether the patient is at high or low risk for having a heart attack. This needs to be the case for preterm labor, as we make guesses far too often, and that may lead to undesired outcomes.

We need to develop and implement standardized protocols using fetal fibronectin testing so that we can appropriately identify those patients at high risk of sPTB, and administer medications which are protective for their preterm infant.

Reproducibility in research is critically important. A 2007 study showed that if we use standard protocols incorporating fetal fibronectin, as well as cervical length screening and appropriately triage people in the high or low risk categories, women can be triaged appropriately and are more likely to stay pregnant for longer periods of time. No one understands why this is, but potentially if we directed a standard treatment to only individuals at high risk for sPTB, we could save lives. I think our research really needs to focus on that area to help mother’s in preterm labor and their unborn infants.

Where can readers find more information?

About Michael S. Ruma, MD, MPH

Dr. Michael Ruma is a maternal-fetal medicine specialist in Albuquerque, New Mexico.  He joined Perinatal Associates of New Mexico in 2008 after completing a fellowship in Maternal–Fetal Medicine at the University of North Carolina.

He is a board–certified by the American Board of Obstetrics and Gynecology in obstetrics and gynecology and maternal-fetal medicine.  He specializes in the care of medical, surgical and obstetric complications during pregnancy. Dr. Ruma has received numerous awards for excellence in teaching and research.

He also has presented at many national and international conferences on a variety of topics and is the author of peer-reviewed manuscripts on maternal red blood cell sensitization, the effects of periodontal disease on pregnancy, efficiency in obstetric ultrasound performance and recently the use of fetal fibronectin in patients with symptoms of preterm labor.

Helping women overcome the issues facing them during their high-risk pregnancies is his greatest achievement.   

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