Yearly Archives: 2017

New Guidelines from the American Thyroid Association on Thyroid Disease During Pregnancy

Thyroid tests
Early in 2017, the American Thyroid Association (ATA) issued new guidelines for the diagnosis and management of thyroid diseases during pregnancy and the postpartum.   This 74 page document covers everything from thyroid function testing during pregnancy, to thyroid autoantibodies and pregnancy complications and thyroid disease and lactation. It is a comprehensive and well written document that is a must-read for anyone interested in thyroid function and laboratory testing during pregnancy.  There is no way I can summarize the whole document here, but I did want to highlight what I think are some important take-home points for laboratorians.

 Normal Reference Intervals for TSH During Pregnancy

In 2011 the ATA guidelines suggested the upper reference limit for serum TSH be set at 2.5 mU/L during the first trimester and 3.0 mU/L in the second and third trimesters. The 2017 guidelines point out that there are now studies demonstrating substantial variation between populations.  The ATA recommended that when possible, population-based trimester-specific reference intervals for serum TSH should be defined and utilized. This is excellent advice, but very difficult for laboratories to establish. When local assessments are not available, the panel now recommends that in the first trimester the non-pregnant reference interval be lowered by 0.4 mU/L at the low end and 0.5 mU/L at the high end (which equates to an upper reference limit of around 4.0 mU/L). This is a significant change from their previous recommendation.

T4 Assessment During Pregnancy

There have been publications which raise uncertainty about free T4 (fT4) measurements using immunoassays in pregnancy. The ATA again recommends that when possible, population-based trimester-specific reference intervals for fT4 should be defined and utilized. Again, such intervals are very difficult for laboratories to establish. When this is not possible, in lieu of measuring fT4, total T4 measurement can be used with the upper reference interval increased by 50% to account for the increased thyroid binding globulin present during pregnancy. They also indicate that free thyroid hormones can be assessed using equilibrium dialysis LC/MS/MS. This method is considered the gold standard, but it is more expensive. They also suggest use of the fT4 index, but I personally think that whenever possible, fT4 by equilibrium LC/MS/MS or total T4 should be used whenever possible rather than this antiquated method. I recently wrote an opinion piece about on this topic. fT4 index should not be used as a substitute for trimester-specific reference intervals. The guideline suggests that isolated hypothyroxinemia (low fT4 with normal TSH), should not be treated.

Iodine Assessment During Pregnancy

There is substantial day-to-day variation in urinary iodine intake and excretion. As such, urinary iodine concentrations cannot be used to identify patients with iodine deficiency. They suggest that all pregnant women should ingest ~250 ug of iodine daily and that excessive doses of iodine should be avoided.

Patients with Thyroid Autoantibodies     

There are increasing data indicating that there appears to be a greater risk for adverse events such as preterm delivery in pregnant women with thyroid autoantibodies compared to those who are thyroid antibody negative. The guidelines suggest that euthyroid pregnant women who are TPOAb or TgAb positive have TSH measured at the time of pregnancy confirmation and every 4 weeks throughout pregnancy in order to monitor them for the development of hypothyroidism.

Hypothyroidism During Pregnancy

Overt hypothyroidism during pregnancy is well known to be associated with adverse pregnancy complications (such as premature birth, low birth weight and pregnancy loss) and detrimental effects on fetal neurocognitive development (such as low IQ). For this reason, treatment of overt hypothyroidism is recommended during pregnancy. However, as we blogged about recently,  screening for and treatment of subclinical hypothyroidism is still being debated. Because of the averse outcomes associated with elevated TPO antibodies (mentioned above) the panel does have specific recommendations with regard to the screening and approach to subclinical hypothyroidism.  First, pregnant women with TSH concentrations >2.5 mU/L should be evaluated for TPO status. Second, subclinical hypothyroidism should be approached as follows:

T4 therapy is recommended for:

  • TPO positive and TSH greater than pregnancy specific reference interval
  • TPO negative and TSH greater than 10 mU/L

T4 therapy is considered for:

  • TPO positive and TSH greater than 2.5 mU/L and less than upper limit of pregnancy specific reference interval
  • TPO negative and TSH greater than pregnancy specific reference interval but less than 10 mU/L

T4 therapy is NOT recommended for:

  • TPO negative and TSH within pregnancy specific reference intervals

The panel suggests that thyroid hormone replacement therapy should target a treatment goal of maternal TSH concentrations below 2.5 mU/L.

Anti-Mullerian Hormone: The Blood-Based Biological Clock?

Many women choose to delay starting a family for various reasons, but how long is too long to wait? Is there some way to determine the time remaining on a woman’s “biological clock” to help guide family planning? A new biomarker measured in blood, anti-Müllerian hormone (AMH), has been proposed to do exactly that but there are some important limitations that must be considered before rushing out to the closest doctor’s office to request an AMH measurement.

First, some background. Women are born with approximately one million primordial ovarian follicles and only about one thousand of these remain when a woman reaches menopause. Over the course of a woman’s reproductive years, these primordial follicles come out of hibernation and develop into immature follicles by accumulating theca cells that produce testosterone and granulosa cells that convert testosterone to estradiol. Each cycle, in response to follicle-stimulating hormone (FSH), one of these immature follicles becomes the dominant, mature follicle that ultimately releases an egg through the process of ovulation. Some immature follicles exit the development pathway and become nonviable while others continue to develop for possible selection as the dominant follicle in a subsequent cycle. The key point is that the granulosa cells of these immature follicles produce AMH, which can be measured in serum or plasma as a direct reflection of the number of immature follicles. If more immature follicles are present, the serum/plasma AMH concentration will be higher. If fewer immature follicles are present, the AMH concentration will be lower. At first glance, measuring AMH would seem to be the ideal way to determine a woman’s reproductive lifespan – if AMH is high, many immature follicles remain and menopause is years away.

Unfortunately, it’s not quite that simple. While elevated AMH concentrations do reflect a large number of immature follicles, this doesn’t necessarily guarantee fertility. Polycystic ovary syndrome (PCOS) is a condition marked by the presence of many immature AMH-secreting follicles and women with PCOS typically have elevated serum/plasma AMH concentrations. AMH has been shown to inhibit the effects of FSH and AMH excess prevents immature follicles from reaching the final stages of development, resulting in impaired fertility for many women with PCOS. While an AMH concentration within the age-appropriate reference interval is a favorable indicator of fertility, higher is not necessarily better as very high AMH concentrations may indicate an underlying anovulatory condition.

At the other extreme, low age-specific serum/plasma AMH concentrations have been associated with impaired fertility in women in their 30s and may predict earlier menopause but low AMH concentrations are substantially harder to interpret in girls and younger women – precisely the population for whom an early estimate of reproductive lifespan would be most valuable. Low AMH concentrations in healthy women in their teens and 20s have not been associated with impaired fertility and survivors of childhood cancers with low AMH concentrations have achieved pregnancy. Furthermore, circulating AMH concentrations are reduced by lifestyle factors like oral contraceptive use and smoking, complicating the connection between AMH concentration and reproductive lifespan.

While studies of large numbers of women show that a low age-specific AMH concentration is associated with earlier menopause, it’s difficult to predict the age at menopause for an individual woman using a serum/plasma AMH concentration. The rate of decline in serum/plasma AMH concentrations varies from woman to woman, meaning that two women with identical AMH concentrations one year may have very different AMH concentrations the following year. Furthermore, the onset of menopause is a complex trait determined by genetic factors, environmental exposures and other influences like smoking, alcohol consumption and previous pregnancies. Ultimately, while AMH does reflect the number of immature follicles, its ability to predict onset of menopause and guide family planning decisions is questionable at the present time.

Currently, the most appropriate clinical use of AMH measurement is to predict response to ovarian stimulation in women undergoing in vitro fertilization (IVF). Women with a high AMH concentration (and a large number of immature follicles) who undergo IVF are at increased risk of ovarian hyperstimulation syndrome (OHSS), a potentially fatal condition marked by abdominal fluid retention, blood clots, altered electrolyte concentrations and kidney failure. Using a moderate ovarian stimulation protocol in women with a high AMH concentration has been shown to reduce the risk of OHSS while increasing the number of pregnancies and live births per IVF cycle started. At the other end of the spectrum, women with a low AMH concentration are enrolled in a more intensive stimulation protocol to maximize egg retrieval while those with undetectable AMH are offered alternate treatment options as the chance of IVF success is low.

It’s possible that one day AMH may be routinely measured to predict the onset of menopause but for now, its most promising uses are limited to PCOS diagnosis (still some kinks to be worked out there too) and customization of ovarian stimulation protocols to improve IVF outcomes while minimizing the occurrence of OHSS.

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
https://www.surveymonkey.com/r/DTCtestingSurvey 
to learn more or contact Dr. Ann Gronowski at 314-362-0194.

Zika Virus Testing in Pregnant Women: New CDC Recommendations

Zika3 figureWe have previously blogged about testing for Zika virus in pregnant women here and here. But testing recommendations continue to evolve.

As a result of increasing knowledge about the Zika virus, the CDC updated their recommendations.   The changes are based on declining trends in the number of reported cases of Zika virus infection in the Americas, emerging evidence on prolonged detection of Zika IgM antibodies, and new limitations for interpreting serologic tests during pregnancy. IgM is most likely to be detected in the first 12 weeks after infection but may persist beyond 12 weeks in some infected individuals, limiting the ability of testing to determine whether an infection occurred during or prior to pregnancy. False positive results and cross-reactivity with other flaviviruses can occur with IgM assays. Therefore, it is important to ascertain whether a woman had exposure to flaviviruses other than Zika virus before the current pregnancy because a positive IgM result might have been caused by cross-reactivity from a previous flavivirus exposure. Given the possibility of a false positive result, laboratory test results should not be released until all testing is complete.

Zika virus tests should be performed in:

  • Symptomatic pregnant women with possible exposure to Zika virus
  • Asymptomatic pregnant women with ongoing possible exposure to Zika virus
  • Pregnant women with possible exposure to Zika virus who have a fetus with prenatal ultrasound findings consistent with congenital Zika virus infection
  • Non-pregnant symptomatic individuals with possible exposure to areas with risk of Zika virus transmission

Zika virus testing may be considered for:

  • Asymptomatic pregnant women with recent possible but no ongoing exposure to Zika virus (i.e., travelers). Although not routinely recommended, testing may be considered on a case-by-case basis and in line with jurisdictional recommendations.

Zika virus testing is not recommended for:

  • Non-pregnant asymptomatic individuals
  • Pre-conception screening

The primary specimens for Zika virus testing should be paired serum and urine samples. Some emergency authorization tests may require other samples types. However, serum should always be obtained in case nucleic acid testing (NAT) testing is indicated after initial test results. NAT (on serum and urine) and IgM serological testing should be performed concurrently when testing symptomatic pregnant women. Specific guidance for laboratories is given by the CDC.

Another Update on Subclinical Hypothyroidism in Pregnancy

Thyroid DiseaseWe have blogged previously about the ongoing debate regarding the treatment of subclinical hypothyroidism in pregnancy (here and here).  In brief, there was a study published in 1999 that demonstrated that 7-9 year old children, from women with abnormal thyroid measurements during pregnancy, performed slightly less well than the control children on 15 IQ tests. Of the 62 women with thyroid disease who were not treated for their hypothyroidism 48 had children who had significantly lower IQ scores than the control children. This report led to a number of follow-up studies to support or refute this study.

Another one of the follow-up studies was recently published in the New England Journal of Medicine.  The authors screened women <20 weeks gestation for: subclinical hypothyroidism TSH ≥4 IU/L with normal fT4 (n=677); and women with hypothyroxinemia normal TSH with fT4 <0.86 ng/dL (n=526). Women in those two groups were then randomly assigned to receive levothyroxine or placebo. The dosage was adjusted each month to maintain normal TSH or normal fT4 (depending on which arm of the study they were in). The children were then followed for 5 years. The authors found that in the subclinical hypothyroidism group, the median IQ in the treated group was 97 and 94 in the untreated group.  In the hypothyroxinemia group, the median IQ was 94 in the treated group and 91 in the untreated group. There were no significant differences between groups in either arm of the study suggesting that there was no benefit to treating.

This study is consistent with the findings in the CATS trial which we have discussed previously. However, as discussed in an editorial about this article, both this study and the CATS trial are limited by the late initiation of treatment (17 weeks in this study). This is important because the fetal thyroid becomes active at 16-20 weeks of gestation, therefore the fetus relies on maternal T4 prior to that time.

The authors of the editorial concluded that because early intervention is feasible and may be beneficial, they still endorse the American Thyroid Association recommendations that suggest screening of certain high risk women and early treatment as indicated.  I suspect we will be blogging about this topic again in the future.

What is Oncofertility?

IVF_2Last week, at the annual meeting of the American Association for Clinical Chemistry (AACC) we heard an impressive presentation by Dr. Teresa Woodruff PhD on “Oncofertility.” Although the topic is a bit removed from laboratory testing, I thought it was still an important topic for this blog.

So what is oncofertility?  The term was coined by Dr. Woodruff to describe the merging of the fields of oncology and fertility. Its focus is to preserve the reproductive capabilities of women after undergoing treatment for cancer.

Every year 1.6 million people are diagnosed with cancer in the US. Most people associate cancer with old age, but 10% of those diagnosed are <45 years old. Due to more advanced and aggressive treatments, an increasing number of people are surviving cancer. Unfortunately, these cancer treatments can also cause infertility, sterility or early menopause. Men have the ability to freeze semen before undergoing treatment that may affect their fertility. But for women it is not that easy. They need to undergo ovarian stimulation to harvest mature eggs to be frozen for later use or for in vitro fertilization in which the embryo can be frozen for later use. Unfortunately, this process of ovarian stimulation may return only a handful of eggs and takes over a month which can delay life-saving treatment.

Now, there are also alternative experimental techniques that involve ovarian tissue banking.  In one method, a part or all of an ovary is removed and cryopreserved. Strips of ovarian tissue are then thawed and transplanted into the patient with the hope that immature follicles within the transplanted strips will begin to develop as they would in a normal ovary. To date, this has resulted in about 15 live births around the United States.

In her lecture, Dr. Woodruff also discussed in vitro follicle maturation. This technique is being investigated currently and involves taking ovarian tissue and, with the help of biomedical engineering, allowing the eggs to grow and mature outside of the body. This method is not yet available for patients, but is promising because it would not delay treatment for the patient and because potentially more eggs could be harvested.

The Oncofertility Consortium is a national group of interdisciplinary scientists, doctors and scholars that work to help women preserve their fertility. This is an important resource for women who plan to undergo treatment for cancer and want to preserve their reproductive capacity.

Predicting Preeclampsia using sFlt-1:PlGF Ratio in Symptomatic Women

High blood pressurePreeclampsia occurs in 5 to 8% of pregnancies and is a major contributor of premature deliveries and neonatal morbidity in the U.S. and worldwide. It is characterized by new onset hypertension and proteinuria after 20 weeks of gestation and delivery is currently the only treatment. Because the etiology of preeclampsia is poorly understood, our ability to distinguish between different hypertensive disorders of pregnancy remains limited.  In addition, our ability to predict and prevent preeclampsia continues to be poor. We have previously blogged about the use of circulating angiogenic factors such as soluble fms-like tyrosine 1 (sFLT-1) and placental growth factor (PlGF) as early predictors of preeclampsia.

In January 2016 study (funded by Roche Diagnostics), Zeisler, et. al. examined the predictive value of the sFlt-1:PlGF ratio to predict the absence or presence of preeclampsia in women with suspected preeclampsia. The study included two groups of pregnant women with elevated blood pressure and suspected preeclampsia: a development cohort with 500 women (101 had preeclampsia or HELLP syndrome) and a validation cohort with 550 women (98 had preeclampsia).

Using the development cohort, the authors established an sFlt-1:PlGF ratio of 38 as a cutoff for predicting preeclampsia. Using the validation cohort, the authors used the sFlt-1:PlGF ratio of 38 to determine the ability to rule out preeclampsia within 1 week of presenting with symptoms and the ability to rule in preeclampsia within 4 weeks of presenting with symptoms. In the validation cohort, 15 women developed preeclampsia within 1 week (prevalence = 15/550= 2.7%) and the sFlt-1:PlGF ratio of 38 demonstrated a negative predictive value of 99.3% to rule out preeclampsia within one week of presenting with symptoms. In the validation cohort, 71 women developed preeclampsia within 4 weeks (prevalence = 71/550= 13%) and they reported a positive predictive value of 36.7% to predict preeclampsia within 4 weeks.  The authors conclude that an sFlt-1:PlGF ratio of 38 or lower can be used to predict the short term absence of preeclampsia in women who are suspected of having preeclampsia.

I have depicted their data below in a familiar 2×2 format.

 

 

 

Rule out preeclampsia within 1 week

sFlt-1:PlGF ratio

Preeclampsia +

Preeclampsia –

Total

 

>38

12

118

130

+ PV 9.2%

≤38

3

417

420

– PV 99.3%

Total

15

535

   
 

Sensitivity 80%

Specificity 78%

   

Rule in preeclampsia within 4 weeks

sFlt-1:PlGF ratio

Preeclampsia +

Preeclampsia –

Total

 

>38

47

82

129

+ PV 36.7%

≤38

24

397

421

– PV 94%

Total

24

479

   
 

Sensitivity 66%

Specificity 83%

   

One can conclude that the sFlt-1:PlGF ratio has an excellent negative predictive value to rule out preeclampsia in both 1 week and 4 weeks (99.3 and 94% respectively), but the positive predictive value is poor for both (9.2 and 36.7% respectively). However, one needs to think critically about the data. In both populations, despite the fact that the women have symptoms of preeclampsia, the prevalence of preeclampsia is still low (2.7% within 1 week and 13% within 4 weeks). Therefore, a marker with high positive predictive value is needed.

If we take the data from the within 1 week population in the table above and instead of using the sFlt-1:PlGF ratio, we flip a coin such that we get a sensitivity of 50% and specificity of 50% the negative predictive value is still 97% (see table below). The sFlt-1:PlGF ratio improves the negative predictive value by 3% over the flip of a coin. Why is this? This is because the pretest probability of not developing preeclampsia within one week, in these symptomatic women, is already 97.3%. The sFlt-1:PlGF ratio adds little to the negative predictive value.

Rule out preeclampsia within 1 week

Coin Flip

Preeclampsia +

Preeclampsia –

Total

 

+

7.5

267.5

275

+ PV  2.7%

7.5

267.5

275

– PV 97%

Total

15

535

   
 

Sensitivity 50%

Specificity 50%

   

In summary, it is clear that markers with a better positive predictive value are still needed to accurately predict women who are likely to develop preeclampsia even in a population of pregnant women with signs and symptoms.

Cell-free DNA screening tests in the general obstetrical population

DNAIt has been several years since cell-free DNA (cfDNA) tests for the detection of fetal aneuploidies became available. The first clinical studies of these tests were reported in women who, because of age or other reasons, were already at increased risk of having an affected pregnancy (i.e. “high risk” women). While these studies demonstrated the superior performance of cfDNA tests compared to traditional biochemical tests, their application to women at low risk was not encouraged because of lack of evidence regarding how well they would work in that population. A recent report on cfDNA screening tests in the general obstetrical population now provides much needed evidence.

Investigators at Brown University described several clinical utility aspects of cfDNA screening for common aneuploidies through the implementation of a statewide program called DNAFirst that offered cfDNA screening tests to the general pregnancy population in the state of Rhode Island. The clinical utility aspects that were investigated were a comparison of screening uptake rates before and after the DNAFirst program, an evaluation of a reflexive serum testing protocol for cfDNA tests that failed to produce a result, and explored women’s decision-making.

Over 11 months, 2,681 women agreed to undergo screening through 72 providers. Prior to undergoing testing, the women received information about cfDNA testing by primary obstetrical care providers. The median maternal age was 31 years and 79% of the women were younger than 35 years of age. There were 16 positive (i.e. abnormal for trisomy 21, 18, or 13) cfDNA results, 12 of which were confirmed as true positive and 4 of which were false-positive. 2,515 women had a negative screening result and all were true-negatives. 150 tests failed to produce a result (none of which were known to have trisomy). Collectively, these data produced a sensitivity of 100%, a positive predictive value of 75% and a false-positive rate of 0.15%. By comparison, the most effective biochemical screening test (the Integrated test) has a 90% detection rate, a 3% false-positive rate, and a positive predictive value of only 6%.

A small number of women who participated in the study (113) completed a survey asking them about their understanding of cfDNA testing. Women reported receiving information from their care provider in 9 minutes or less. While 85% understood that the test identified Down syndrome, 15% incorrectly thought it identified all genetic problems. 79% understood that a negative result did not rule out Down syndrome but 13% thought it did. These survey results suggest that most women do understand the basic concepts of cfDNA screening.

The study’s authors concluded that cfDNA screening tests perform very well in the general pregnancy population and that women understand the basic concepts of screening. Further, the tests were easily incorporated into routine practices. They encouraged clinical laboratories to offer cfDNA screening tests to improve access to better aneuploidy screening for the more than 2 million pregnant women in the United States who choose to undergo such testing each year.

An Update on Zika Virus Testing in Pregnant Women

We have previously blogged about Zika virus   during pregnancy.That post was in February of 2016 and a lot has changed since then.

Zika

For one thing, Zika has been shown to be transmitted via sexual contact from an infected individual (even if he or she does not have symptoms) to a non-infected individual.  The use of condoms can help, and there are guidelines for the pre-conception prevention of sexual transmission. 

In addition, scientists at the CDC have concluded that Zika virus infection does cause microcephaly and other brain defects. This means that women who are infected with Zika virus during pregnancy are at increased risk of having a baby with these problems, but it does not mean that all women with Zika virus infection during pregnancy will have these problems.

Other changes that have occurred since last year include the FDA's Emergency Use Authorization (EUA) for several diagnostic tools for Zika virus, including the Trioplex Real-Time RT-PCR (rRT-PCR) assay and the Zika MAC-ELISA. 

The Trioplex assay is for the detection of RNA from dengue, chikungunya and Zika viruses in serum, whole blood (EDTA), and cerebrospinal fluid (CSF). This is important since dengue and chikungunya are often in the same differential diagnosis with Zika virus. The assay can also be used to detect Zika virus RNA in urine & amniotic fluid.

The Zika MAC-ELISA is intended for the qualitative detection of Zika virus IgM antibodies in human sera or cerebrospinal fluid (CSF).  however, due to cross-reaction with other flaviviruses and possible nonspecific reactivity, results may be difficult to interpret. Consequently, presumed positive, equivocal, or inconclusive tests must be confirmed by plaque-reduction neutralization testing (PRNT).

According to the CDC, who should be tested?

Asymptomatic Pregnant Women

For asymptomatic pregnant women who have traveled to areas with active Zika virus transmission, RNA nucleic acid testing (NAT) testing is recommended on serum and urine within 2 weeks of the date of last possible exposure. Zika virus-specific IgM testing should be performed on women within 2-12 weeks after travel to an area of active transmission or who have had sexual contact with a man confirmed to have Zika virus infection. In areas with active Zika virus transmission, asymptomatic pregnant women should undergo IgM testing as part of routine obstetric care in the 1st and 2nd trimesters. Presumed positive, equivocal, or inconclusive IgM results must be confirmed by plaque reduction neutralization test (PRNT).

Symptomatic Pregnant Women

For symptomatic pregnant women with exposure to Zika virus, RNA nucleic acid testing (NAT) of serum and urine is recommended up to 2 weeks after symptom onset. Whole blood can also be tested for Zika RNA alongside serum and urine. Urine should always be collected with a patient-matched serum specimen. A positive RNA NAT result on any sample confirms Zika virus infection and no additional testing is indicated. A negative RNA NAT result does not exclude Zika virus infection and serum should be tested for the presence of IgM antibodies. If more than 2 weeks have passed since the onset of Zika virus symptoms, specific IgM testing is recommended. Reflex RNA NAT testing should be performed as a subsequent test for pregnant women who are IgM positive.

For recommendations of testing non-pregnant women, and infants, visit the FDA website.

A second hCG blood test that can be performed at the point-of-care

Finger Stick

We have blogged previously about the limitations of urine hCG tests to detect pregnancy in a hospital setting and about the Abbott iSTAT, the first FDA approved device for detection of hCG in whole blood at the point-of-care.

Recently, Nerenz et al evaluated the NOWDiagnostics ADEXUSDx hCG test, a qualitative immunoassay device for the detection of hCG in anticoagulant-free whole blood, heparinized whole blood, or heparinized plasma.  This device is read visually, like the urine/serum POC devices, but it is FDA approved for the use of whole blood samples.

 

Overall, the device performed very well for the detection of hCG using capillary fingerstick samples.

The device has several limitations.

  1. The ADEXUSDx product is a qualitative, not quantitative device. This is different than the iSTAT device, that we reported on previously, as the iSTAT is quantitative with a range of 5-2000 IU/L. However, since hCG concentrations in women rise so rapidly in early pregnancy, and with such a narrow dynamic range some would argue that the iSTAT device is almost a qualitative device.
  2. The authors reported that the device recognized 100% of samples at a concentration of 27 IU/L and approximately 50% of samples at a concentration around 10 IU/L. This analytical sensitivity is similar to the POC serum devices currently used in hospitals.
  3. Finally, the ADEXUSDx device showed susceptibility to the high-dose hook effect, as decreasing test line intensity was observed at concentrations ≥600,000 IU/L, but all devices were interpreted as positive. This limitation is similar to that seen with the iSTAT device.

Overall, this is a nice addition to the available POC hCG devices currently on the market. It should be pointed out that the Abbott iSTAT and the NOWDiagnostics ADEXUSDx are the only two devices currently available for the diagnosis of pregnancy using whole blood at the point of care.

Whole blood should not be used on devices that are only FDA approved for urine and/or serum, as we have pointed out in previous publications.