Category Archives: Non-invasive Prenatal Testing

Non-invasive Prenatal Testing

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.

Personalized medicine during pregnancy


Pregnancy dnaPersonalized medicine can be defined as customized disease prevention therapies and drug treatment protocols based on knowledge of an individual’s unique genetic makeup, metabolic profile and clinical presentation. So far, personalized medicine has focused on the prevention and treatment of conditions affecting adults such as cancer and cardiovascular disease.  However pregnancy is a unique situation where the unique characteristics of two individuals are being assessed: mother and infant. Remarkably few studies have addressed the therapeutic implications of recent advances in genetic technologies for the fetus. Focus has been more on prenatal diagnosis than on fetal treatment. As molecular technologies advance and costs decrease, targeted genetic testing and even whole genome sequencing of the fetus are likely to become more available. This brings with it a number of ethical issues especially as it relates to testing of the infant. For instance, there are questions of informed consent, confidentiality of results, the clinical significance of genetic polymorphisms and decisions to terminate pregnancy on the basis of these test results.

Nonetheless, there have been some interesting advances in personalized medicine, for both mother and fetus, during pregnancy. This is the focus of an upcoming symposium at the AACC meeting to be held tomorrow, July 29th, at 10:30 am in Atlanta, Georgia.  

Predicting Response to Drugs:  Sixty-four percent of women in the US are prescribed more than one drug during pregnancy (excluding vitamins). A better understanding of how drugs are metabolized during pregnancy and how they affect the fetus is clearly needed. Cytochrome P450 is the predominant class of oxidative enzymes that catalyze many types of drugs. Interestingly, the expression of a number of P450 genes is altered during pregnancy. Most notably, CYP1A2 has been shown to be decreased by 65% by the 3rd trimester. In the past several years, several studies have examined the ability to predict a woman’s response to drugs used during pregnancy, like tocolytics and anti-emetics, based on their genotype. A study by Haas, et. al. demonstrated that CYP3A5 high-expressing women had lower circulating concentrations of Nifedipine, a common tocolytic. A study by Lehmann, et. al. demonstrated that a genotype for serotonin receptor subunits 5-HT3A and 5-HT3B may play a role in hyperemesis severity and response to anti-emetics. This type of genotyping is not yet ready for prime time, but it holds promise for better utilization of medications during pregnancy.

Assessing the Fetus: We have blogged previously about cell free fetal DNA (cffDNA) in maternal blood and its utility in predicting fetal trisomy. cffDNA can also be used to assess fetal Rhesus D (RhD) status. This method can be used to determine the fetal RhD genotype when the mother has clinically significant alloantibody to the D antigen AND the father is heterozygous for RhD or is not available for testing. Testing such as this is useful because instead of treating all RhD-negative women with RhD immunoglobulin, treatment can be targeted to mothers that carry RhD-positive fetuses. This type of approach can conserve supplies of therapeutic anti-D, prevent unnecessary administration of a human-derived blood product to a vulnerable patient group, and avoid subjecting RhD-positive infants to intensive antenatal monitoring to predict and treat fetal anemia. Interestingly, despite the fact that the American College of Obstetricians and Gynecologists support the use of cffDNA for RhD assessment, it is not a widely used clinical tool in the United States.

Predicting Viability: Not all personalized medicine is genetic. Personalized medicine can also be used to guide treatments. With this in mind, there are several publications that suggest novel uses for hCG testing. The first takes advantage of “semi-quantitative” urine hCG devices. These devices are similar to home pregnancy devices, but they essentially contain multiple detection strips with different cutoffs that can give the reader a rough estimate of the urine hCG concentration (>25, >100, >500, >2000 or >10,000). Several studies have examined the use of these devices in a home setting following medical abortion as a replacement for clinic follow-up. If the woman is able to demonstrate decreasing hCG concentrations at home, she can avoid a return visit to the clinic. This can reduce the burden on the healthcare setting, but it could also help women for whom getting to a clinic is difficult because of work or family commitments or who live in a remote geography. Both studies demonstrate that use of semi-quantitative hCG devices in this setting had 100% sensitivity to detect unsuccessful abortions. The second interesting use for hCG measurement is in the prediction of fetal viability. Several studies have suggested that urine and serum concentrations of hyperglycosylated hCG (hCG-H) are low in women with pregnancy failure. These studies suggest that measurements of serum or urine hCG-H to detect failed pregnancy is 60-70% sensitive and 97-100% specific (links here and here). These studies are small and there is not currently a readily accessible assay for hCG-H, but it is intriguing to think about the possibility of a test that could distinguish viable from non-viable pregnancies especially in an emergency setting when physicians are making treatment decisions and have to take into account potential risks to the fetus.

Conventional aneuploidy screening remains “most appropriate” choice for general population


OpinionThe American Congress of Obstetricians and Gynecologists (ACOG) have updated their guidance on cell-free DNA (cfDNA) screening tests for fetal aneuploidy. In it, they state that any patient (i.e. women at high-risk OR low-risk for having an affected pregnancy) may choose cfDNA testing but they caution that conventional screening tests are more appropriate. This document replaces an earlier opinion, published in 2012, which clearly stated that cfDNA screening tests should not be offered to the general obstetrical population because they are considered to be at low-risk.

So ACOG went from recommending that cfDNA testing not be performed on low-risk women to say that they may choose cfDNA testing. Why the subtle change? Well, as ACOG correctly notes, the landscape of cfDNA is changing rapidly. New studies are published frequently and those that have examined the performance of cfDNA tests in  low-risk women have reported that the test performs just as well in them as it does in high-risk women.

However, they make an important point about a metric that doesn't get the attention it deserves. The positive predictive value (PPV). See here for background. Because the prevalence of fetal aneuploidy in low-risk women is lower than it is in high-risk women, a "positive" or "abnormal" test result in low-risk women is more likely to be a false-positive result. For example, a positive result in a 25-year-old woman gives a 33% chance that the fetus is affected but that chance increases to 87% in a high-risk woman.

The report also calls out the "no result" problem. cfDNA tests fail to produce a result in 1-8% of samples tested, usually due to a low amount of fetal DNA in the blood sample. It's becoming clear that women with samples that fail to produce a result are at increased risk of having an affected fetus. According to ACOG, these women she be offered diagnostic testing such as fetal karyotyping using amniotic fluid obtained by amniocentesis.

Other notable points contained within the updated guidance include:

  • Caution about not routinely performing microdeletion screening (offered by some labs) because it has not been fully validated in clinical studies.
  • Clearly indicating that a negative or normal result does not rule out the possibility of an affected fetus.
  • Providing genetic counseling to patients about test limitations and that decisions such as pregnancy termination should not be based on these screening tests.
  • A reminder that cfDNA tests do not screen for neural tube or ventral wall defects

This certainly won't be the final say that ACOG has on cfDNA aneuploidy screening tests. Indeed, they state that "It will be critical to remain abreast of this rapidly changing technology to provide patients with the most effective, accurate, and cost-conscious methods for aneuploidy screening."

Momentum grows for use of cell-free DNA Down syndrome screening tests in all pregnant women


Low risk

The use of cell-free DNA (cfDNA) testing to screen for fetal aneuploidies has been the topic of several posts on this blog. Large clinical studies that have evaluated the performance of cfDNA tests have all arrived at the same conclusion: cfDNA testing is superior to traditional biochemical screening tests for the detection of trisomy 21 (Down syndrome) and other trisomies. However, most of these studies have tested women who are considered to be at high risk (e.g. over 35 years of age or who have had an abnormal biochemical screening test) of having an affected fetus. Fewer studies have evaluated test performance in women considered to be at low risk. Because of limited data in low-risk women, the majority of professional societies recommend restricting the use of cfDNA screening tests to only high-risk women. 

This is certainly going to change, and sooner rather than later.

The New England Journal of Medicine recently published a very large, well-designed study that compared the performance of a cfDNA screening test to a biochemical screening test (the first trimester combined test) in an unselected population of almost 15,841 women.

The results were rather unsurprising. There were 38 pregnancies affected by Down syndrome. All 38 (100%) were identified by cfDNA testing but only 30 (79%) were identified by biochemical testing. While that was a significant difference in the detection rate there was a greater significant difference in the false-positive rates. There were 854 false-positive results from biochemical screening and only 9 from cfDNA screening. These numbers translate into a false-positive rate of 5.4% and 0.06% for biochemical and cfDNA screening, respectively.

As the proportion of true positive results divided by the number of all positive results, the positive predictive value answers the question: "What is the probability of an affected fetus given a positive result?” In this study, these predictive values were 3.4% for biochemical screening and 80.9% for cfDNA screening. Clearly, cfDNA offers a huge improvement.

I must stress (as I’ve done several times before) that cfDNA tests are screening tests. The better performance of cfDNA tests has, unfortunately, created the perception that cfDNA tests produce conclusive results and, as such, are diagnostic tests. This could not be further from the truth. Just as with a positive biochemical screening test, a positive result from cfDNA testing should be followed by invasive diagnostic testing. Consider, for example, that the positive predictive value of the cfDNA test that was reported in this study for the 14,947 low-risk women was 50%. That’s a coin toss! Without a doubt it is vastly better than biochemical screening but no woman should make a decision to terminate her pregnancy based on cfDNA testing alone.

So is cfDNA testing an appropriate Down syndrome screening strategy for low-risk women? Yes, it is. It’s just a matter of time before professional societies recognize that fact. Indeed, the International Society for Prenatal Diagnosis did just that in their new position statement

Stay tuned…

Confusion over NIPT invites catastrophe


Timing is everything. A week after I wrote about false-positive NIPT results, the Boston Globe published an article titled "Oversold prenatal tests spur some to choose abortions" written by Beth Daley of the New England Center for Investigative Reporting. The article describes non-invasive prenatal testing (NIPT) using relatively new cell free DNA tests with a focus on women who have experienced receiving incorrect results.

The article focuses on one woman who had Sequenom's MaterniT21 PLUS test that indicated her fetus had trisomy 18 or Edwards syndrome. She initially considered immediately terminating the pregnancy and her doctor helped her locate a physician who could perform the procedure the next day. Only hours later did her doctor caution her to consider diagnostic testing which confirmed the fetus did not have trisomy 18. Additional cases in the article tell of one woman who experienced a false-positive result (confirmed by diagnostic testing) but so trusted the results of the DNA test that she aborted her pregnancy anyway and a woman who experience the trauma of a false-negative result.

Stories like this indicate a clear lack of understanding regarding the limitations of NIPT and demonstrate that physicians and consumers don't always appreciate the fact that these are screening tests. In a post on its blog about the Globe article, the Society for Maternal Fetal Medicine emphasizes just that by stating "It is important for providers to remember that cell free DNA is a screening test, and does not have the diagnostic accuracy of amniocentesis." They also point out that doctors who order DNA-based screening tests need to understand the test characteristics and they emphasize the role of genetic counseling for women who undergo screening for aneuploidy. The Society's statement was the focus of a follow-up piece by the New England Center for Investigative Reporting.

Whether aneuploidy screening is performed using DNA-based tests or by traditional biochemical screening, it is a screening test. Neither are diagnostic tests. Abnormal results from any screening test must be followed up by diagnostic testing to confirm (or not) the results of the screening test. To be misinformed on this basic fact of laboratory medicine is to flirt with disaster.

The ugly stepsister: false positive NIPT test results


Positive Negative

© Stuart Miles – Fotolia.com

NIPT (non-invasive prenatal testing) continues to get lots of attention lately. Indeed, we've written about it extensively on this blog. None of this is suprising because NIPT is a new technology that is continually evolving. Two years ago, I wrote about NIPT here and provided information showing it's excellent diagnostic sensitivity and specificity. To be clear: these tests are more accurate than traditional biochemical screening for detecting fetal aneuploides but they are still screening tests, meaning that positive (or abnormal) test results must be confirmed with diagnostic testing.

As is commonplace, with time comes experience and the lens of scruitiny has recently been focused on the positive predicitive value (PPV) of NIPT. What's a PPV? It's the proportion of true positive results divided by the number of all positive results. For NIPT testing, it answers the question: "What is the probability that a positive result means that the fetus is affected?" It is very important to stress that the PPV of any test is not intrinsic to the test. The PPV is also dependent on the prevalence of the condition in the tested population. If the condition is very rare in the tested population, then the PPV will likely be low, meaning that a positive result is more likely to be a false positive. The opposite is also true (positive test results are more likely to be "true" when the condition is highly prevalent).

NIPT is done to screen for fetal aneuploidies (extra copies of specific chromosomes) such as Down syndrome (trisomy 21), Edwards syndrome (trisomy 18), and Patau syndrome (trisomy 13). The prevelance of each of these disorders is influenced by the woman's age. As examples, the prevalence of each in a 35-year-old woman with a fetus at 10 weeks’ gestational age is 1:185, 1:470, and 1:1,500, respectively. As you might expect, the less prevalent a condition is, the more likley a positive result will be falsely positive.

This has been demonstrated for NIPT. A study published earlier this year evaluated the concordance of NIPT and cytogenetic results among cases with positive or negative NIPT results. The study examined test results from 109 consecutive specimens that were either prenatally and/or postnatally studied by fluorescence in situ hybridization, karyotyping, and/or oligo–single-nucleotide polymorphism microarray (as the definitive, or diagnostic, test). NIPT testing was performed with the Panorama (Natera, San Carlos, CA), Harmony (Ariosa Diagnostics, San Jose, CA), MaterniT21 (Sequenom, San Diego, CA), or Verifi (Illumina, Redwood City, CA).

The PPV for T21 was highest at 93% followed by a 64% PPV for T18.  The PPV for T13 was only 44%. Given the prevalence of each of these conditions, these data aren't all that surprising but they are still rather alarming. Why? Because several studies have claimed NIPT tests are >99% specific (e.g. ~1% false-positive rate). As the authors of the study described here state: "To an average clinician, the claim that a test is >99% specific leads him or her to expect that the false-positive rate will be <1%."

As I stated this above and in several other posts on this blog (but is worth emphasizing again): NIPT is a screening test, not a diagnostic test and it cannot be considered a replacement for diagnostic testing.

More on noninvasive prenatal testing for fetal aneuploidy


We have written about nonivasive prenatal testing (NIPT) on this blog several times.  Because they are so new, the landscape around these tests is continually evolving.  The American College of Obstetricians and Gynecologists (ACOG) published guidelines on these tests in December of last year.  Just this week, the American College of Medical Genetics and Genomics (ACMG) released its policy statement on the same topic.  Note that the ACMG refers to these tests as "noninvasive prenatal screening" (NIPS) tests to emphasize that this is what they are: screening, not diagnostic tests.

The ACMG calls for caution before these tests become widely integrated into prenatal care due to the current lack of data obtained from prospective clinical trials.  While they acknowledge that NIPS tests have high sensitivity and specificity there are limitations to the technology and false-positive and false-negative results do occur.

A particular concern, and one that doesn't get as much attention as it should, is that most of the fetal DNA in the mother's blood sample originates from the placenta and not the fetus and it may not accurately reflect the fetal karyotype.  They emphasize (as have others), that abnormal NIPS test results must be confirmed by invasive diagnostic tests such as amniocentesis.

The policy statement also lists several limitations to NIPS tests.  Among them:

  • They only detect aneuploidies (and some detect sex chromosome abnormalities).
  • Certain chromosome abnormalities are not detected.
  • The tests take longer to perform and result than more well-established tests.
  • Data on the performance of the tests in twin and triplet pregnancies is not well established.

A recent paper published in the journal Obstetrics and Gynecology has a similar ring to it.  The authors make several interesting observations:

  • First, they point out that well-established tests were developed in academic settings and came into use gradually and only after independent clinical studies generated data to support their use.  In contrast, NIPT (also developed in academic settings) was quickly licensed to commercial enterprises that have brought them to market without FDA review (as these are "lab-developed tests," FDA appoval is not required).
  • From the analytical perspective, there are currently no guidelines regarding quality control and quality assurance for NIPT; a vital component of any lab test.
  • The performance of NIPT in actual clinical practice settings (i.e. not a clinical study) is currently not well known or documented.  This is especially true for populations of women that have not been represented in the clinical studies (e.g. woman at low risk for having a fetus with an aneuploidy).
  • The more well-established tests are able to detect fetal anomalies besides aneuploidy (e.g. open neural tube defects).

The authors also reflect on how NIPT should be incorporated into clinical care.  They agree with the ACOG recommendations that the tests should not be offered to low-risk women but they go a bit further and state that the most appropriate use of NIPT is as a second screening test used for those who have an abnormal result from convential, more well-established screening tests.  The latter point is something I have commented on before and I could not be in more complete agreement.

    Should DNA-based tests for Down syndrome screening replace biochemical tests?


    In a previous post I described the clinical performance of DNA-based screening tests for fetal aneuploidies like Down syndrome.  Overall, these tests have excellent detection rates (~99%) with very low false-positive rates (~0.2%).  In other words, these tests are about 99.0% sensitive and 99.8% specific.

    With performance like that one might expect these to be considered diagnostic tests.  They are not! Although quite good, test results must not be interpreted as definitive evidence that a fetus does or does not have an aneuploidy.  Recent recommendations from the American College of Obstetricians and Gynecologists (ACOG) are quite clear on that issue.

    In those same recommendations, ACOG also states that DNA-based screening tests may be performed only on women who are at increased risk of having a fetus with aneuloidy.  Among the indications listed for women considered to be at increase risk are:

    • Maternal age 35 years or older at delivery
    • Fetal ultrasound findings suggesting aneuploidy
    • A previous aneuploid pregnancy
    • Abnormal biochemical screening test results
    The ACOG is right to avoid recommending that DNA-based screening tests are acceptable to use regardless of risk factors.  Unfortunately, many women who are not at increased risk are using these new tests as a primary screening test and that's not a good idea.

    To understand why, considered a population of 100,000 pregnant women from the general population and assume that the prevalence of Down syndrome is 1 in 500 pregnancies.  That means that there would be 99,800 unaffected pregnancies and 200 pregnancies with Down syndrome.  The table below compares the results of the most commonly used biochemical screening test (the Quad test) to a DNA-based screening test.

    Quad vs DNA performance
    Clearly, the DNA-based test has several advantages over the Quad test.  Its positive predictive value is nearly 17 times greater than the Quad's and a positive DNA-based test result substantially increases the odds of having an affected fetus.  So why not use the DNA-based test as a primary screening test?  For the following reasons:
    • No studies have been published that have evaluated the performance of DNA-based tests in women who are not at increased risk of having a fetus with an aneuploidy
    • DNA-based tests are not widely available
    • The time it takes to report results of DNA-based testing is about 3 times greater than it is with biochemical testing
    • DNA-based tests are considerably more expensive than biochemical tests
    • Relative lack of insurance coverage for DNA-based tests
    Until these these limitations can be resolved, it makes more sense to use DNA-based testing as a secondary screening test.  In other words, it is only done after one of the risk factors described by ACOG (above) are met.  Doing so greatly improves the performance of both tests (see figure below).  A limitation of this approach is that the detection rate is that of the biochemical test which is not as high as it is with the DNA-based test.  Still, given the current limitations of DNA-based testing, this 2-step testing approach makes the most sense.
    DNA as secondary test

    DNA-based tests for Down syndrome screening show excellent clinical performance


    The use of biochemical screening tests to identify pregnant women who are at high risk of having a fetus with Down syndrome is well established.  Biochemical screening began nearly 30 years ago and, over the years, the tests have evolved and improved.  Now there’s a new kid on the screening test block and it’s name is DNA.

    The discovery of cell-free fetal DNA in maternal plasma in 1997 opened up new possibilities for Down syndrome and other aneuploidy screening protocols.  Rather than rely on biochemical testing to determine a biochemical phenotype, DNA-based tests have been developed that can detect the molecular pathology of aneuploidies (e.g. a fetus that has more than the expected 2 copies of chromosomes 21, 18, or 13; the cause of Down syndrome, Edwards syndrome, and Patau syndrome, respectively).

    We’ve written about DNA-based screening tests before (here and here) and described the clinical performance of the Sequenom test.  Now, other clinical performance studies have been published for 3 of the 4 tests that are (or will be) commercially available.  As expected, all of them show excellent clinical performance.  As shown in the table below, the detection rates for trisomy 21 are greater than or equal to 99% with very low false-positive results.  Similar performance has been reported for trisomy 18 and 13.

    DNA test performance

    Table References: Genet Med 2011;13:913-920Genet Med 2012;14:296-305Obstet Gynecol 2012;119:890-901

    By comparison, the detection rate of the best biochemical Down syndrome screening test (the Integrated test) is very good at 93%.  However, about 5% of all Integrated test results are false-positive.  A 5% false-positive rate may not seem very high but it is.  For example, consider a population of 100,000 pregnant women who choose Integrated testing in the second trimester.  The prevalence of Down syndrome in the second trimester is about 1 in 500 pregnancies so 200 of those 100,000 women will have a fetus with Down syndrome and 99,800 women (100,000 – 200) will have unaffected fetuses.  Of those 99,800 women with unaffected fetuses, 4,900 will have a false-positive Integrated test result.

    Because the false-positive rate of the DNA-based tests is so low (about <0.2%), then if those same 100,000 women were screened there would be only 200 false-positive results, a 96% decrease!

    Does this mean that DNA-based tests should replace biochemical screening tests?  Probably not but I’ll leave the explanation as to why for my next post.

    Molecular testing for Down syndrome: proceed with caution


    Ann recently posted about massively parallel genomic sequencing using maternal blood as a
    screening test for Down syndrome.  In it, she described a recently published, multi-center clinical study that validated this molecular test in just over 1,600 women.  The test detected 98.6% of the Down syndrome fetuses and had a false-positive rate of 0.2%.  Notably, this performance is considerably better than current biochemical marker Down syndrome screening tests.

    Caution
    However, there are some important limitations to this new test.

    1. It’s expensive and available from only one company.  The Sequenom Center for Molecular Medicine, located in Grand Rapids, MI, developed the test and is currently the only place in the US that can do it.  It's marketed as the MaterniT21 test and costs $1,900 for the uninsured and ~$235 for those with insurance.  Biochemical screening tests cost much less.
    2. After the blood sample arrives in the lab, test results are available in about 10 days.  Results for biochemical screening tests take about 1 day.
    3. The test can only be performed in singleton pregnancies (not twins, triplets, etc).  Biochemical screening tests work best in singleton pregnancies, too, although risks can be estimated from a twin pregnancy.
    4. The test fails to work in about 2% of cases, usually as a result of there not being enough fetal DNA detected in the mother's blood.  This is more likely to be the case in overweight women who have a higher blood volume which dilutes the amount of the fetal DNA.  The concentrations of the markers used in biochemical screening tests are also effected by maternal weight but there are effective ways to account for that so that the final result is not affected.
    5. The test is only validated for the detection of Down syndrome and not other fetal aneuploidies such as trisomy 18 or trisomy 13.  The test does have the capability of detecting these disorders and, if they are detected, will be reported.  However, because the test has not been thoroughly investigated for detecting T18 or T13 a negative result doesn't rule out their presence.  Biochemical screening tests can detect these disorders although the detection rates are lower than they are for Down syndrome.
    6. The test does not detect open neural tube defects (e.g. spinal bifida) that are usually screened for using biochemical screening tests.

    I have no doubt that as the technology required to do massively parallel genomic sequencing becomes less expensive, tests like the MaterniT21 will become more affordable and mainstream.  Most of the limitations I described above will also be addressed with time and technological improvements.  As Ann indicated, this is the dawn of a new era in screening for fetal disorders.