Yearly Archives: 2018

Overreliance on Ruptured Membrane Tests Linked to Fetal Deaths

AttentionLaboratory tests are not perfect. I hope this does not come to a surprise to anyone. In a perfect world, a lab test would always identify individuals with a specific condition from those who don’t have that condition. Unfortunately, we don’t live in that world and so lab test results must be interpreted beyond the “negative” or “positive” result or any other way in which a lab test result is reported. Human beings and their health and disease states are complicated and few lab tests can lump people into binary buckets of “yes” or “no.” That’s precisely true for tests of ruptured membranes that might be used during the course of a woman’s pregnancy.

We’ve written about tests for ruptured membranes before here and here. Rupture of membranes (ROM) is the term used to describe the breaking of the amniotic sac, as normally occurs before the onset of labor. If this happens earlier than the 37thweek of pregnancy it is called preterm ROM (PROM).

It’s important to detect women with ruptured membranes, particularly women with PROM, because PROM can lead to complications such as intrauterine infection, umbilical cord compression, and premature birth. Fortunately, there are tests to help identify pregnant women with ROM or PROM. The more reliable of these tests detect substances in amniotic fluid; and amniotic fluid is not normally present in vaginal fluid samples obtained from women with intact membranes. If these substances are detected, then it’s possible the fetal membranes have ruptured. But these tests are not foolproof!

The U.S. FDA recently issued a “letter to healthcare providers” about the risks associate with the use of tests for ruptured membranes. In this letter, FDA reminds providers that over-reliance on tests for ruptured membranes can lead to serious, adverse events. Note the “over-reliance” comment. It echoes what I state above, that lab test results are not perfect tests. FDA confirms that“ 13 fetal deaths and multiple reports of health complications in pregnant women” have been reported because of over-reliance on the accuracy of ruptured membrane tests. In this letter, FDA reminds providers that tests of ruptured membranes should be “part of an overall clinical assessment,”which usually includes physical examinationof the patient as well as tests to detect leaking amniotic fluid.

As laboratory professionals, it is incumbent upon us to continually stress the strengths and limitationsof the tests that are performed in our labs every day.

Thyroid Hormones and the Risk of Gestational Diabetes

Diabetes definitionThyroid hormones play an important role in glucose metabolism and homeostasis. They regulate hepatic gluconeogenesis, intestinal absorption of glucose, and glucose uptake in peripheral tissue. In addition, thyroid hormones modify circulating insulin concentrations. Thyroid function and metabolism undergo significant changes during pregnancy. For these reasons, thyroid hormones have been implicated in the development of gestational diabetes mellitus (GDM).

Published evidence has been conflicting about a possible relationship between overt or subclinical hypothyroidism and development of GDM. Recently, Rawal, et. al. reported an association between elevated concentrations of serum triiodothyronine (T3) and the ratio between elevated free T3 (fT3) and free thyroxine (fT4) ratio. This ratio is a surrogate marker for the body’s conversion of T4 to T3 and has been associated with development of GDM. 

The study was a multicenter and multiracial case-control study nested within the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singleton Cohort.  GDM cases and 214 controls were included in the study. GDM was determined using the Carpenter-Coustan diagnostic criteria.   Blood was collected at four visits across pregnancy (targeted at gestational weeks8-13, 16-22, 24-29, and 34-37), and thyroid stimulating hormone (TSH), fT3, and fT4, were measured using the Roche Cobas e411. TSH concentrations that were ≤4 mIU/L were considered to be normal. Isolated low fT4 (hypothyroxinemia) was defined as having normal TSH with fT4 that was less than the 10th percentile of controls. Overt hypothyroidism was defines as elevated TSH with low or normal fT4 concentrations (less than the 90th percentile of controls).  

The authors reported that increased concentrations of fT3 and increased fT3:fT4 ratio were both associated with a greater risk of developing GDM even after adjusting for the pre-pregnancy body mass index and the family history of diabetes.  The fT3:fT4 ratio was most strongly associated with GDM with women in the highest quartile in the second trimester at a 14-fold increased risk, compared to women at the lowest quartile. Consistent with previous reports, the authors found lower concentrations of fT4 associated with GDM, but the associations were not significant after adjusting for confounders.

The authors suggest that higher fT3 concentrations (perhaps from increased conversion of T4 to T3) may be involved in the pathophysiology of GDM. They also conclude that their finding support the potential importance of thyroid screening for pregnant women. Naturally, these conclusions will need to be validated with a randomized controlled interventional study.

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.

Biodegradable Pregnancy Tests? What’s the big deal?

Recently, there was a buzz in the pregnancy testing world because a company called Lia Diagnostics received pre-market approval from the FDA for the first biodegradable pregnancy test that can be flushed down the toilet. When I excitedly emailed my co-blogger David about this, he said “Is that something that is really important to women?” This is a good question. Today I’d like to discuss why I think this type of product is important and take a look at the 510(K) premarket notification which is publicly available.

First, why is a flushable home pregnancy test important? One of the things that initially made home pregnancy devices attractive when they were first marketed back in the 1970’s is privacy.  They can be used in your own home. No need to go to a doctor or health center to find out if you are pregnant. You are the first to know in the privacy of your own home. However for some women, achieving privacy, even where they live, is difficult. Being able to flush the device down the toilet allows women to truly achieve privacy. No one will know the results or that the testing was even done.

The other reason that a flushable pregnancy device is important is environmental. Pregnancy devices are made from plastic and end up in land-fills. This is a huge burden on our environment and can no longer be ignored in the US or in developing countries, where these devices are also used. Imagine the environmental impact this device could have if it set a trend for other home pregnancy devices and other biomedical products to become biodegradable.  I feel that for this reason alone, this is a major milestone.

One thing that was not talked about in the press (and I could not find on the Lia website) is whether the packaging is also biodegradable & flushable. This will be key to achieve true privacy & environmental friendliness. In my laboratory, we do studies on pregnancy devices. Here I have included some photos of the trash we generated from just one study. As you can see, a great deal of that trash is packing material. This needs to be flushable and biodegradable too in order to achieve the company's goals of privacy & environmental friendliness.

Packaging trash

Six devices
Six devices

Trash generated from one of our home pregnancy device studies (property of Ann M. Gronowski)

Next, let’s take a look at the 510(K) pre-market notification for the Lia Pregnancy test. Lia compared their device to the OSOM hCG urine test. Our lab has studied the OSOM device in the past. In the summary document they show that the device can detect 100% of samples with an hCG concentration of 22 IU/L and 50% of samples at 14 IU/L. This is similar to other over-the counter devices on the market. Using 153 urine samples, the Lia device showed 100% concordance with the OSOM device. The device showed no cross reactivity with LH up to 500 IU/L and FSH & TSH up to 1000 IU/L. They evaluated the hook effect (something that can cause a false-negative result) up to 500 IU/mL (500,000 IU/L) which is good. They also checked for a hook due to hCG β-core fragment and showed no effect up to 500,000 pmol/L, which is a concentration at which we have previously demonstrated the OSOM device to give false negative results.

The Lia pregnancy test is scheduled to be available for purchase in mid-2018. Based on the data submitted to the FDA it sounds very promising. I hope that this novel product will induce other medical device companies take note and start to manufacture more biodegradable products.