Category Archives: Pregnancy Tests

Pregnancy Tests

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.

Direct to Consumer Laboratory Testing Survey

Recruiting Material visit
Direct-to-consumer (DTC) laboratory testing permits consumers to order laboratory tests directly from a clinical laboratory without necessarily having to work with their healthcare provider. Currently nearly 40 states allow consumers to order some or all of their laboratory tests. This model of lab testing is relatively new in the United States and little is known about its impact on consumers.

However, many health care providers are concerned that consumers do not have enough background knowledge and information to make sound decisions based on their test results. Consumers might not understand what tests to order or how to interpret the tests.   It is unclear how often consumers share their results with healthcare providers and what action, if any, is taken based on the results. In addition, frequent test ordering in a normal population increases the chances of false (positive and negative) results. False results may give consumers a false sense of security when tests are normal or result in unnecessary alarm when tests are abnormal.

Recently an article in the medical journal JAMA expressed the opinions of many in the medical field that DTC testing may actually increase the cost of healthcare in the US.

However, many feel that there is value in allowing consumers to order laboratory tests through DTC laboratories and that there is not enough data to conclude that DTC testing adversely affects patient health or healthcare costs. This was expressed in a response to the JAMA article.

In order to gather data on the effects of DTC laboratory testing, a survey is being conducted to identify the reasons American consumers use DTC laboratories. The survey will quantify how frequently consumers of DTC test services order tests, define the most frequently ordered DTC tests, identify resources consumers use to understand DTC test results, and evaluate consumer engagement with health care professionals based on DTC test results.

If you have ever ordered your own lab tests from a direct-to-consumer laboratory, you may be eligible to participate in a research study from Washington University about direct-to-consumer lab testing.

Visit here  or copy this link 
to learn more or contact Dr. Ann Gronowski at 314-362-0194.

How Early Can Pregnancy Be Detected?

Calendar_2“How early can pregnancy be detected?” is a question we are asked all the time. The short answer is, “It depends.” Let’s answer this question one step at a time.

First, the most common way to detect early pregnancy is by measuring the hormone human chorionic gonadotropin (hCG). If an egg is fertilized, the developing embryo will attach to the lining of the uterus around 6-12 days after ovulation. This is called implantation.  The hormone hCG is produced by trophoblastic cells (the outer layer of the embryo) after implantation. It takes several days for hCG to be detectable in blood or urine. hCG production increases very rapidly with serum concentrations doubling every 1-1.5 days in the first 8-10 weeks of pregnancy. So, detecting pregnancy first depends on how quickly implantation occurs.

Second, it depends on the sample in which hCG is measured; blood or urine. Urine concentrations of hCG are almost always lower than serum concentrations. In addition, urine concentrations of hCG can be affected by fluid intake. If large amounts of fluids are ingested (think Big Gulp)  then urine concentrations will be more dilute. This is why first morning urine samples are often recommended because this urine is usually the most concentrated of the day since people don’t tend to drink anything during the sleeping hours. The amount of water in blood is more regulated that that of urine and generally does not change, even after ingesting large amounts of liquid. Therefore, use of a blood sample will generally detect pregnancy earlier than use of urine. 

Third, it depends on the method used to detect hCG; qualitative or quantitative. Qualitative devices are those that can be purchased over-the-counter to detect hCG in urine. They are also used in hospitals and doctor offices. These devices generally have cutoffs for positivity that vary from about 20-50 IU/L. The cutoff varies widely by brand. Interestingly, we have shown that the devices used at home are often more sensitive than the devices used in the hospital!!  We have previously blogged about this topic. Quantitative hCG assays are performed using blood samples in laboratories and are much more analytically sensitive than qualitative assays. Most quantitative hCG assays can detect hCG at concentrations of 2 IU/L and some can go as low as 0.1 IU/L. Therefore, quantitative assays will be able to detect pregnancy earlier than qualitative assays.

Fourth, when the clinical sensitivity of an hCG test for diagnosing pregnancy is determined, it is usually determined as a function of the number of days relative to the expected day of the menstrual period (EMP). How early an hCG test can detect pregnancy depends on how the EMP is estimated. Most women estimate EMP by counting 28 days from the first day of the last menstrual period (LMP). This 28-day cycle includes the approximate 14 days between first day of menses and ovulation (called the follicular phase) and the approximate 14 days between ovulation and the day before the next menstrual period (called the luteal phase). However, the length of menstrual periods varies between women. Studies have shown that most of the variation occurs in the follicular phase.Therefore, the most accurate way to estimate the EMP is by measuring 14 days from ovulation as estimated by detecting a dramatic rise in the concentration of luteinizing hormone (LH), commonly referred to as the LH surge. Using 14 days from the LH surge can detect 100% of pregnancies by the EMP, as opposed to using 28 days from LMP which did not detect 100% of pregnancies until 7 days after EMP.  By measuring serum hCG, 100% of pregnancies can be detected by EMP and nearly all pregnancies can be  detected by 3 days before EMP. 

In summary, how early pregnancy can be detected depends on many factors. In some cases pregnancy can be detected more than 3 days before EMP. Virtually all pregnancies should be detected by one week after EMP.

Finally, an hCG blood test that can be performed at the point-of-care

Testing urine samples for the presence or absence of hCG is commonly performed in hospitals and clinics for the rapid assessment of a woman's pregnancy status. This topic has been discussed several times in this blog (see here and here).

Urine hCG tests are hugely popular because they can be performed near the patient and they are granted waived status by the Clinical Laboratory Improvement Amendments.

However, urine is not a suitable sample type for pregnancy assessment for many reasons, such as:

  • Urine hCG tests are prone to false-negative results.
  • hCG becomes detectable in the urine after it appears in the blood, so urine tests are not as sensitive as blood hCG tests.
  • Urine tests provide a positive/negative results whereas blood tests provide a quantitative concentration.

Because of these limitations, in particular the risk of false negative results, I've often said that urine hCG testing is inappropriate in healthcare delivery settings. Blood tests for hCG are much more reliable but they take longer to produce results because of the time required for sample transport and processing by a centralized laboratory.

Finger StickAt long last, a rapid, quantitative blood test for hCG is finally available in the US from Abbott Point of Care, Inc. on their i-STAT instrument. Naturally, people will want to know how the test performs and we recently published a paper on the analytical performance of the test.

We evaluated the test using whole blood and plasma (the sample types that were cleared for use) as well as serum. Overall, the test works quite well in all sample types and is suitable for use in healthcare settings. It provides the reliability of laboratory blood-based hCG testing but with the convenience of point-of-care testing.

There are two important limitations to note:

  1. The analytical measuring range of the i-STAT hCG test is limited to 5-2,000 IU/L. While this is similar to the measuring ranges of many laboratory hCG tests, the instruments used in labs can automatically dilute and re-test samples that have a high hCG concentration, something that the i-STAT is unable to do. When tested with the i-STAT, a sample with an hCG concentration greater than 2,000 IU/L will be reported as such. While this type of result indicates that hCG is present in the blood, not having an absolute concentration will be insufficiently informative in some clinical situations.
  2. The test is susceptible to the high-dose hook effect at an hCG concentration somewhere between 400,000 and 600,000 IU/L. This means that when a sample with an extremely high hCG concentration is tested, the result can be falsely decreased. However, even though the result is falsely decreased, it is still very likely to be interpreted as "positive" and the risk of a false-negative result is extremely remote.

This type of test is long overdue in the US. The use of urine hCG testing to determine a woman's pregnancy status is fraught with difficulties and is known to cause harm to patients. Despite their problems, urine hCG testing won't be going away any time soon but the availability of a test that performs hCG blood tests close to the patient is a step in the right direction.

False negative pregnancy tests: the story continues

This post was written by Robert D. Nerenz, PhD, an assistant professor at the University of Kentucky, in Lexington.

Neg pregnancy testIn previous posts, we have discussed false negative pregnancy test results caused by hCG beta core fragment (hCGβcf), the predominant form of hCG found in urine after six weeks of pregnancy. False negative pregnancy tests can result in undesirable outcomes (including loss of pregnancy) if inappropriate treatment is given. In a recent study evaluating the performance of devices used in a hospital setting, 9 of 11 devices were found to be susceptible to false negative results when used to test urine solutions containing hCGβcf concentrations observed in normal pregnancy.

After our study was published, we were frequently asked whether these devices actually performed poorly in clinical practice or if the results we observed only occurred in a controlled laboratory environment. To address this question, we searched the database of medical device malfunctions reported to the FDA (Manufacturer and User Facility Device Experience, or MAUDE) to find reports of false negative pregnancy test results in a clinical setting. Using the search term “MAUDE pregnancy false negative” we found 707 reports between 2000 and 2014 that described false negative urine hCG results in women shown to be pregnant at the time of testing. 91 different POC hCG devices were described from 14 manufacturers, including 10 of the 11 devices evaluated in our initial screening study.

Based on the description in the MAUDE report, we subdivided the false negatives by potential cause. In 433 reports the cause of the false negative result was unknown.  132 were likely because the hCG concentration was so low that it was below the limit of detection for the test device. Of these 132, nine were associated with adverse events. We also found 142 reports that were likely due to hCGbcf hook effect and ten (or 7%) of those were associated with adverse events, including delayed prenatal care, delayed treatment of ectopic pregnancy, performance of inappropriate imaging studies and even surgery leading to loss of pregnancy. In addition to the reports documented on the FDA website, it is virtually certain that many more false negative results have occurred and have gone unreported to the FDA.

The fact that false negative pregnancy test results occur relatively frequently in clinical practice was an important finding because it highlighted the limitations of currently available devices and emphasized that this problem is not limited to one or two devices. Rather, the fact that the vast majority of pregnancy test devices performed poorly in our study and were reported to generate false negative results in clinical practice indicates that this is a much larger problem.

To decrease the occurrence of false negative pregnancy test results, contributions from multiple different groups will be required. First, the FDA should insist that device manufacturers market devices that generate positive results in all pregnant women, including those with high urine concentrations of hCGβcf. Second, clinicians at large hospitals should request that pregnancy testing be performed on serum using a quantitative assay, especially in patients with abdominal pain, vaginal bleeding or other symptoms that strongly suggest the patient might be pregnant. Quantitative serum assays can generate results in less than an hour, can detect lower concentrations of hCG than point-of-care test cartridges and are not affected by hCGβcf because hCGβcf is not present in serum. Lastly, laboratorians should work to decrease the time required to generate test results in order to make quantitative testing more appealing to clinicians. At institutions where urine point-of-care testing must be performed, laboratorians should evaluate all available options and select the device that provides an optimal combination of sensitivity and lack of susceptibility to interference caused by elevated concentrations of hCGβcf.

Unfortunately, currently available pregnancy test devices present a risk to patients. It is our hope that a coordinated effort from the FDA, manufacturers, clinicians and laboratorians will eliminate that risk.

Improved Qualitative Pregnancy Devices

In the past, we have blogged about false negative urine qualitative hCG tests in both point-of-care (POC) hospital devices and over-the-counter (OTC) devices due to the presence of high concentrations of hCGbcf. We feel this represents a real problem for patients and clinicians trying to diagnose pregnancy and could results in harm to mother and/or fetus.

It is our understanding that the FDA is requiring device manufacturers to address this problem in any new devices going through the FDA approval process. However, it is up to manufacturers if they want to voluntarily change their existing devices. Hence we have urged manufacturers to modify their devices to eliminate false negatives due to hCGbcf.

Recently, we were made aware of two manufacturers that had apparently modified their qualitative pregnancy devices: The Cen-Med Elite Plus One-Step Pregnancy Test (a hospital POC device) and the First Response Early Result OTC device (an over-the-counter device). In order to evaluate these modifications we compared the old and new devices using the screening test we have developed previously.   Our results demonstrated that indeed, the new version of each device perform better than the previous version.  Both original devices demonstrated significantly diminished signal when 500 pmol/L hCG was tested in the presence of 500,000 pmol/L hCGbcf. However the modified devices gave faint or clear positive signals in the presence of the same hCG concentrations (see figure). Figure for Blog
It is clear that improvement of qualitative urine hCG devices is possible and we encourage all manufacturers to design devices that are not inhibited by hCGbcf. 

The history of pregnancy tests

HCG croppedIf you are interested in hCG, like we are, you might be interested in a recent paper, in Clinical Chemistry, by Dr. Glenn Braunstein entitled "The long gestation of the modern home pregnancy test."

Dr. Braunstein is one of the researchers that helped develop the first radioimmunoassay specific for hCG in the 1970's and is a leader in the field of hCG.

In his paper, Dr. Braunstein reflects on the history of urine pregnancy tests.  He explains that there is actually a description of a pregnancy test in ancient Egyptian papyrus writings. In that test, women urinate on wheat and barley seeds. If neither grows the woman is not pregnant. If the barley grows it will be a male and if the wheat grows it will be a female!

The first bioassay was described in 1927 by the German scientists Ascheim and Zondek who demonstrated ovarian stimulation in mice when they were injected with the urine from pregnant women. After that, there were many bioassays developed to detect pregnancy. Apparently these had analytical sensitivities of between 100-18,000 IU/L and they took 2-9 days to get a result!

The first radioimmunoassay for hCG & LH (leuteinizing hormone) was described in 1966 by Midgley.  Its analytical sensitivity was very high by today’s standards (175 IU/L) but, of course, it recognized both hCG and LH and it took 3 days to perform. The similarity between hCG and LH was a real problem. It was not until Dr. Braunstein, together with Dr. Judith Vaitukaitis, developed new antibodies that were specific to the hCG beta subunit that an hCG-specific assay was developed. With this assay, they were able to detect pregnancy as early as 7.5 days after fertilization and they were able to develop reference intervals for serum during pregnancy.

The first home pregnancy test marketed in the U.S. was the e.p.t.® ("Early pregnancy test") in 1977. It was described as a "private little revolution" because it allowed women to determine if they were pregnant in the privacy of their own home with no one else knowing. Today, pregnancy tests account for $228 million dollars in annual sales and take up considerable shelf space at retail stores with different brands and styles (see photo).  

For further reading, another great reference for the history of the pregnancy test was created by the NIH library and can be found here.

A rapid pregnancy test without using urine? Not so fast.

The rapid assessment of pregnancy status is important in urgent health care settings. Determining if a Tube of blood woman is pregnant or not is necessary to:

  • Determine if symptoms such as abdominal pain, vaginal bleeding, and/or vomiting are due to pregnancy;
  • Prevent fetal exposure to sources of radiation (x-ray, CT, scan, etc);
  • Prevent the administration of teratogenic medication.

In many health care setting, qualitative urine hCG testing is often used to quickly determine a woman's pregnancy status. Several posts on this blog have discussed the limitations of this type of testing (see here and here for some background). We have often advocated for the use of quantitative serum hCG testing over qualitative urine testing for this purpose but there are some logistical challenges with quantitative serum testing:

  • The use of a blood sample requires its collection and transport to a central laboratory.
  • Once received in the lab, a blood sample has to be centrifuged to separate the serum (the liquid part of the blood that is actually tested) from the blood cells.
  • Both of the above steps increase the amount of time needed to perform the test and report the result to the physician.

Although many qualitative hCG tests used in health care settings can be used with either urine or serum, qualitative serum testing is impossible to perform at the point-of-care. This is because obtaining serum requires centrifugation of the whole blood and centrifugation can't practically be done outside of a laboratory.

Recognizing that hCG tests performed on blood samples are generally better than thosed performed on urine, physicians are sometimes tempted to use whole blood (instead of serum) as the sample type for qualitative hCG testing at the point-of-care. An example of this type of use is described here.

That report describes the use of whole blood instead of urine or serum for the qualitative detection of hCG in a patient with a ruptured ectopic pregnancy. This was what I call a VBI: a Very Bad Idea. It is so wrong that two colleagues and I wrote to the journal that published the report to let them know it was a VBI.  Basically, we pointed out that:

  • Using whole blood instead of serum or urine was a modification of the intended use of an FDA-approved test and as such was against the law without appropriate validation experiments.
  • The peer-reviewers and journal editors failed to recognize that their report was in conflict with federal and state regulations and the report's publication essentially recommends the promotion of an unauthorized practice with serious patient safety risks.
  • Involving laboratory professionals to help identify solutions for clinical dilemmas involving laboratory tests is always a smart idea.

In response to our criticism, the authors replied with this:

"Physicians' judgment is relied upon to determine when benefit to the patient outweighs the risk of inaccuracy of unapproved use."

In other words they essentially said "we can do anything we want, regardless of regulations, when we act according to our best judgement."

How convenient. How utterly ignorant. How potentially dangerous.

Sadly, this type of mis-information is widespread. A website called "Emergency Physicians Monthly: The Indpendent Voice for Emergency Physicians" featured an article titled "Stat Pregnancy Test…Without Urine?" in September 2013. This article encourages the use of using whole blood for qualitative hCG testing and even provides a "Quick Trick" section on how to perform the test. This is grossly negligent on their part. I note that under the "Tips" section the author writes:

"Be sure to wait at least 5 minutes when using whole blood in the kit. It sometimes takes a while." (emphasis is mine)

Hmmmm, might someone want to define what "a while" is?

I think my opinion on this matter is evident. If reliable results are to be obtained and utilized for patient care decisions, clinical laboratory tests must be performed using validated methods (including the type of sample tested). To deviate from established protocols without guidance from laboratory professionals is a VBI.

    Pregnancy testing in the Emergency Department: a physician’s perspective

    Today's post is by a guest author, Ian Schwartz, M.D. Dr. Schwartz is an assistant professor of emergency medicine at the Yale University School of Medicine and the former medical director of the adult emergency department at the Yale-New Haven Hospital in New Haven, CT. Here, he provides his perspective on determining a patient’s pregnancy status in an emergency setting and describes the possible consequences of erroneous hCG test results.

    EmergencyThe practice of emergency medicine is a daily challenge for providers in the field. Patient histories are varied and nuanced and no two cases are ever the same.  In the hectic, chaotic and over-flowing hallways of the emergency department (ED), providers (not surprisingly) look to hang on to objective evidence in order to come up with diagnoses and treatment plans.

    Experienced providers realize, of course, that a diagnosis is usually a best guess. For the majority of patients, emergency room doctors are simply synthesizing a few facts and ideas into a coherent explanation for the symptoms that brought the patient to the ED.

    The challenge is that even those elements that we call facts are, themselves, nuanced. Every ED doctor has had the experience of staring at a chest x-ray and debating whether the patient had pneumonia or some fluid in their lungs. X-ray interpretation is literally dealing in shades of grey.

    As opposed to evaluating X-rays, laboratory test results would appear to be much more objective. The lab provides a discrete test result along with a reference interval for defining what is considered to be “normal.” For most health care providers the validity and accuracy of most test results go unquestioned. Yes, that patient absolutely has elevated calcium. Yes, this patient is anemic. Decisions for further testing, treatment and disposition are often made based solely on these test results.

    Emergency providers (and others who practice evidence-based medicine), think in terms of odds and probability. That is, they think about the likelihood of a disease. Some examples: the likelihood of a blood clot in the lungs given a patient’s risk factors or the 30-day likelihood of a heart attack if a patient with chest pain is sent home. Each ED doc has his or her own acceptable “miss rate” for a given condition.

    However, when it comes to pregnancy testing that sort of calculation and prediction simply doesn’t enter the mind of most ED providers. The pregnancy test is often considered to be the one single binary (yes/no) test that they can actually rely on.

    Most emergency departments perform qualitative hCG tests using a urine sample to determine a woman’s pregnancy status. The tests are similar to those that can be purchased over-the-counter and performed at home. The person performing the test will be handed the urine sample, perform the test, and (hopefully) chart that result into the medical record and (hopefully) alert a nurse or other care provider of the result.

    A provider sees this result and takes the appropriate action. There is usually no second thought about the quality of the test result. If it’s negative then the patient with abdominal pain is not pregnant and the physician can get the CT scan of the abdomen instead of the ultrasound. A negative result is also a license to order antibiotics, pain medications, and other drugs without concern for possible fetal harm. The urine hCG test is the standard way we define pregnancy in the emergency department and it gives the green (or red) light to treat the patient as not pregnant (or pregnant).

    There is a problem with this type of reliance: the urine hCG test, itself, is simply not good enough to tell us whether or not a patient is pregnant.

    Here are a few facts that most ED providers are unlikely to know about hCG testing:

    1. hCG appears in blood before urine, sometimes up to 5 days earlier.
    2. The claimed analytical sensitivity of most qualitative urine hCG tests is 25 IU/L whereas the quantitative blood assays are sensitive to 1-2 IU/L (commonly pregnancy is defined by greater than 5 IU/L).
    3. Even though common qualitative urine tests claim 99+% accuracy in determining pregnancy status, a recent study suggests that they are actually only 99% sensitive at an hCG concentration of 150-225 IU/L.
    4. There is a potential window of 3 to 7 days during the first trimester of pregnancy where a quantitative blood test will detect hCG while the qualitative urine test might not.
    5. Ectopic pregnancies can occur at hCG concentrations below what is detectable by current qualitative methods.
    6. In one study of over 11,700 urine samples, 69 (0.5%) of ED hCG test results were erroneous due to documentation errors, inherent deficiencies in qualitative tests or because the hCG concentration was below the level of detection.

    So what are some real-world consequences of not using the most accurate hCG test at our disposal? If we believe a patient with abdominal pain is not pregnant (when in fact they are) we order CT scans of the abdomen looking for appendicitis or other abdominal diseases. That CT scan just delivered 10 mSv of radiation to the mother and fetus and doubled the risk of the fetus developing a childhood cancer (1 in 1,000). Or we just ordered Motrin, a medication known to cause neural tube defects and a variety of heart defects. And we have just increased the risk of miscarriage two and a half fold.

    In a later post, I will address the erroneous belief that qualitative urine hCG tests are quicker to result than quantitative blood tests. However regardless of speed, ED’s across the country are utilizing a test that does not deliver the accuracy that most providers believe they are getting. This is a fact that should be quite troubling to all of us considering the number of urine pregnancy tests that performed each day. How many erroneous results are we are unknowingly receiving and what is the potential harm that is being done to a fetus in its most fragile period of growth?

    False Negative Pregnancy Tests Still a Real Problem in Home and Hospital Devices

    Neg pregnancy testWe have blogged in the past about false negative pregnancy tests due to hCG beta core fragment (hCGbcf).   After about 5 weeks of pregnancy (i.e. 3 weeks after the expected period) concentrations of hCGbcf, in urine, are higher than all other forms of hCG. Our group has shown previously that the concentration of hCGbcf can saturate one of the antibodies used in the point-of-care hospital pregnancy kits. As a result, test shows a negative result. The variant hook effect can be confirmed if testing shows a positive result after diluting the sample. This phenomenon is referred to as the "variant hook effect" and was reported to the FDA in 2009.

    Recently, our group took this observation one step further and examined over-the-counter home pregnancy devices to see if they were subject to the same problem.  We examined six over the counter devices and selected two that seemed to be most affected by the variant hook effect. We then compared those two devices to the hospital device that we had made our original observations in four years ago, and to a hospital device that we thought performs best when compared to various other hospital pregnancy devices. Not surprisingly, we found that the over-the-counter home pregnancy devices are also subject to the variant hook effect. However, what was a surprise was that the hospital pregnancy devices were more affected by hCG beta core fragment than the home pregnancy devices!  Furthermore, despite the fact that the variant hook effect was reported to the FDA in 2009, manufacturers have not changed their devices to avoid this problem. To hear more about this paper you can listen to a podcast describing the findings.

    Our laboratory is currently working to better define how much hCGbcf is required to cause the variant hook effect. We hope that this will help manufacturers to produce devices that avoid false negative results. In the meantime, several things need to be done:

    1. Physicians, nurses, and other health care professionals need to be educated about this problem-especially in the hospital setting.
    2. The variant hook effect should be made clearly visible in pregnancy test package inserts and they need to state that when a false negative is suspected, a simple dilution can yield a positive result if the patient is truly pregnant. This is very important for centers that have no alternative way of testing for pregnancy.
    3. Finally, in my opinion, quantitative serum hCG testing should be the preferred pregnancy test in centers where it is available. Serum testing is not subject to the variant hook effect because hCGbcf is not present in serum. Furthermore, quantitative serum assays are much more sensitive than the qualitative assays.