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Non-invasive prenatal testing and chromosomal microarray: changing the landscape of prenatal genetic testing


Prenatal testing is a routine part of pregnancy care in much of the world. Every pregnant woman in Canada is offered blood tests and ultrasounds to evaluate the health of her pregnancy. When testing suggests potential genetic abnormalities, doctors offer a further test such as amniocentesis to make a definitive diagnosis. While amniocentesis is very accurate, it also carries a very small risk of miscarriage.

Because of this, scientists have been searching for a “non-invasive” alternative to amniocentesis. In 2013, non-invasive cell-free fetal DNA testing became available in Canada. This development offers pregnant women a safer, more accurate option for screening for the most common chromosome abnormalities, which could dramatically reduce the need for amniocentesis.

However, at the same time another new technology called chromosomal microarray is allowing amniocentesis to detect a much wider array of genetic disorders than ever before – far more than can be currently detected with cell-free fetal DNA testing.

Experts suggest the advent of these two new technologies will create a host of policy challenges and exert pressure on our health care system that will push in opposite directions. As better non-invasive tests reduce the demand for amniocentesis for the most common chromosomal disorders, microarray could have the opposite effect: increasing the number of amniocenteses to diagnose genetic disorders not detectable by non-invasive tests.

The current landscape of prenatal testing in Canada

For several decades, it has been standard practice in Canada to offer all pregnant women the option of prenatal testing. These tests are designed to detect whether a fetus has certain genetic abnormalities, such as an extra copy of chromosome 21, which causes Down Syndrome.

Prenatal testing may be either screening or diagnostic. Screening tests are typically used on people who do not have any symptoms or major risk factors for a particular disease. Screening tests help determine a person’s level of risk, and indicate whether a diagnostic test is needed.

Where screening tests determine whether someone is at risk of a disease, diagnostic tests are designed to give a definitive answer.  Diagnostic tests are used when someone has specific disease symptoms, major risk factors, or a positive screening test. Diagnostic tests are more accurate than screening tests, but are also usually more expensive and often invasive.

Historically, pregnant women were offered diagnostic prenatal testing in the form of amniocentesis beginning at age 35, which was thought to be the age at which the risk of Down syndrome was equal to the chance of miscarriage after amniocentesis. This “advanced maternal age” criteria has since been replaced by several more accurate indicators of chromosome abnormalities.

Pregnant women in Canada are now offered a series of prenatal screening tests – nuchal translucency scan, often combined with various serum “markers”, and a structural review of the fetal anatomy – before 20 to 22 weeks of pregnancy. If these screening tests detect an elevated risk of a genetic disorder, a woman is offered a diagnostic test such as an amniocentesis to confirm or rule out that disorder.

Most of the time, prenatal tests provide reassurance that the fetus is healthy and allow care to continue in the setting of a woman’s choosing.

Non-invasive prenatal testing

Cell-free fetal DNA testing, commonly known as Non-Invasive Prenatal Testing (NIPT), was introduced in Canada in 2013.

NIPT works by taking a sample of a pregnant woman’s blood and isolating freely circulating fragments of placental DNA (usually identical to direct fetal DNA). This DNA is then analyzed for abnormalities of specific chromosomes (13, 18, 21, X, Y) associated with conditions like Down syndrome and Turner syndrome.

Unlike amniocentesis, NIPT carries no risk of miscarriage, because there is no need to pierce the amniotic sac. And because fetal DNA is present early in pregnancy, NIPT can be performed from 9 to 10 weeks in pregnancy, versus 16 weeks for amniocentesis.

Existing evidence indicates that NIPT is very accurate in women at increased risk for the most common chromosomal abnormalities, with a 99% detection rate for Down syndrome, and a very low false positive rate of 0.1% – nearly as accurate as traditional amniocentesis.

Currently, NIPT is available through several US-based companies, each one partnering with a single private laboratory. Blood samples collected in Canada are sent to these labs in the US for analysis.

When first introduced in Canada, NIPT was not covered by any provincial health care system, and so was only available as an out-of-pocket service at a number of private clinics, who charge between $800 and $1000 for the test. The Ontario Ministry of Health and Long Term Care has recently become the first Canadian province to begin funding NIPT for women at increased risk of chromosome abnormalities (to qualify for public funding, a formal request from a health care provider is required).

The limits of non-invasive prenatal testing

NIPT represents a major innovation in prenatal testing, but it does have a number of important limitations. Chief among these is the limited number of chromosomes examined through the test. While the NIPT tests that are available in Canada screen for the most common chromosomal abnormalities, they cannot currently detect genetic conditions caused by abnormalities on smaller segments of a chromosome, some of which can be screened for through standard prenatal screening technologies such as ultrasound.

Francois Rousseau, a medical biochemist at Université Laval who is researching NIPT explains that another important limitation of NIPT is that the strongest evidence for its high detection rate and very low false positive rate is in women at elevated risk, rather than in the general population. Very few studies have looked at the effectiveness of NIPT as a screening test in low risk women, and while Rousseau believes the results are promising, he notes that these studies have been funded by the companies that developed the test, and that independent analysis of NIPT is needed.

Additionally, while the accuracy of the test is vastly better than traditional screening tests for Down syndrome, it is not 100% accurate. For these reason, The Society of Obstetricians and Gynecologists of Canada recommends that any positive result from NIPT be confirmed through amniocentesis before any decision is made about how to proceed.

NIPT may reduce the need for amniocentesis

Despite these limitations, research suggests that the introduction of NIPT could reduce the need for amniocentesis for diagnosing Down syndrome by as much as 80%.

While researchers found that offering NIPT as a screening test for all women would be cost-prohibitive given the current price of the test, they found that using NIPT as a second-tier test could be cost-effective. This approach would involve offering NIPT to women who had tested positive on a nuchal translucency scan or serum tests. Since a negative NIPT result for Down syndrome is so much more accurate, only women who tested positive on NIPT would need to go on to have amniocentesis.

Chromosomal microarray

While the advent of NIPT may substantially reduce the need for amniocentesis to test for some of the most common chromosomal disorders, the introduction of Chromosomal Microarray (CMA) may have the opposite effect, by increasing the number of conditions that can be detected through amniocentesis.

Traditionally, fetal cells acquired through amniocentesis were examined through a technique known as karyotyping, where a geneticist would examine the number, size and appearance of chromosomes under a light microscope.

“Chromosomal microarray offers a much greater resolution than karyotyping,” explains David Chitayat, Head of the Prenatal Diagnosis and Medical Genetics Program at Mt. Sinai Hospital. This means that CMA provides more information about more genetic conditions than previously possible. Some of these conditions, which are undetectable through karyotyping, are associated with significant disorders.

CMA has been shown to be effective in diagnosing previously unexplained developmental disability or birth defects. It is also highly effective in diagnosing genetic conditions following an abnormal result on a screening ultrasound.

CMA has other benefits over karyotyping. Its results are available faster, it involves less subjectivity in the interpretation of results, and the test can be automated.

Together, these factors have led The American College of Obstetricians and Gynecologists Committee on Genetics and the Society for Maternal-Fetal Medicine to recommend that CMA be offered to patients undergoing amniocentesis.

In fact, some believe that CMA should be offered to all women, regardless of age or other risk factors. Chitayat explains that the abnormalities detected by chromosomal microarray “have nothing to do with the age of the mother… every woman has a small risk of having a fetus with a detectable abnormality.” He believes it is important that women have access to this information if they want it.

More choices, more uncertainty

The availability of these two new technologies presents expectant parents with complex choices. Where NIPT presents no risk of pregnancy loss, it only tests for a limited number of conditions, so it may miss a potentially serious genetic disorder. On the other hand, CMA can detect a much a wider range of genetic disorders, but is invasive and carries a very small risk of miscarriage.

In addition, CMA occasionally produces findings where it is not clear how seriously the child we be affected, which can create further challenges for expectant parents. These findings, called variants of unknown significance, were found to occur in up to 1.5% of cases. These variants put patients in a difficult situation, where they must make decisions on how to proceed without definitive information.

Expectant parents and practitioners must also wrestle with whether testing should only cover disorders affecting the newborn/child, or whether testing should include genetic disorders that may not be manifested until adulthood, if at all.

While uncertainty in prenatal testing is not new, these technologies will take uncertainty to a new level. For patients, more choices often mean more stress as they must contemplate difficult and irrevocable decisions.

These issues highlight the need for clear communication between expectant parents and health care providers about the nature of the genetic information relayed by these tests. And since these tests can reveal more information than parents may want to know, clear rules around informed consent will need to be developed.

As technology continues to advance, NIPT and CMA are likely to come together in the form of non-invasive chromosomal microarray testing. When this happens, patients will certainly welcome the elimination of the small risk associated with amniocentesis, but may also be daunted by the sheer volume and uncertainty of genetic information that will become available.

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12 comments

  1. Louise Kinross

    I’d like to hear from the authors what type of counseling is being offered parents who receive CMA findings where there is a wide variation in how children are affected. How is the field improving its ability to counsel parents?

    This article focuses almost exclusively on the testing — on the technical side. It doesn’t provide any information on how parents are counseled after receiving a prenatal diagnosis. THAT is what we should be focused on and spending a great deal of time evaluating.

    As a parent of a child with a rare genetic disorder that is now on the microarray list (but wasn’t able to be detected 20 years ago), I’ve had two prenatal genetic counseling experiences that didn’t involve any “counseling.” They didn’t involve any discussion about what our values as parents were, what parenting meant to us, or how we felt about aborting a child with a genetic diagnosis. We were given the statistics (same risk of losing a child due to miscarriage as having a child with Down syndrome) and when I couldn’t make a decision, an obstetrician was brought in to berate me about the “burden you’ll live with for the rest of your life” if you have a child with Down syndrome.

    That, is not counseling.

    What information, in prenatal counseling, are parents given about real families whose children are living with these conditions? What biases on the part of geneticists and counselors are transmitted? How do parents receiving this counseling evaluate it as helpful or not?

    Why are we devoting so much time to the technical side of prenatal testing when that’s the easy part. The authors note that: “Most of the time, prenatal tests provide reassurance.” But that’s not the point, is it? The point is what happens when a diagnosis is detected. I’d like to know in what way counseling has changed in the last 20 years. Because I’m sad to say that I hear many recent stories of parents who are not provided with any true counseling at all.

    • Jeremy Petch

      Thanks for you suggestion, Louise. We’ll look at doing a story about genetic counselling services.

    • Dr Nan Okun

      Thank you Louise, I couldn’t agree more.
      The technical part is in many ways the easy part of prenatal testing. The discussion around it is much more complex and value laden. Many centres, including ours are working to develop better counseling processes that embed parental values from the beginning of these prenatal testing discussions between them and their care provider. We do need to pay much more attention to this, and part of the rationale for the piece was to increase public awareness of the technologies so that they are better prepared for such discussions.

  2. Jakki Jeffs

    I am also concerned that parents will be literally “swamped” with enormous amounts of information not only regarding the current challenge their child may be facing but those which may or may not occur in the future.
    It is my experience that more choice equals more confusion and in the area of genetics may lead to a lethal choice for the child.
    I have the distinct honour of working with four women, one the mother of a baby girl with Trisomy 18, another of a daughter stillborn, and a son with Autism, another with a daughter struggling to conceive and the last, the adoptive mother of a beautiful boy born with the results of his mother’s drug and alcohol addictions.
    In their eyes and mine every child’s life is precious. Surely we should be testing our hearts in order to love, accept and serve, these tiny ones with challenges, not seeking out less invasive ways to search out and destroy them.

    I would recommend 99 Balloons at http://www.youtube.com/watch?v=th6Njr-qkq0
    and The Dear Future Mum youtube http://www.youtube.com/watch?v=Ju-q4OnBtNU

    How wonderful it would be if instead of changing the landscape of prenatal testing we could change the landscape of our hearts!

  3. mom2six

    I wanted to share the experience we had when I was pregnant with our son. He was diagnosed with hypoplastic left heart syndrome, when I was 22 weeks pregnant. After the echocardiogram, we were led to a private room where we met with one of the cardiologists. He told us what the diagnosis was, drew a rough diagram on a scrap piece of paper he scrambled to find, and gave us a complicated and difficult to understand description of the condition. He then proceeded to tell us that 6 out of 10 babies survive past 5 years of age and that this baby would be a huge burden on our family. He said we needed to consider the fact that we have 3 other children at home. He mentioned that it would cause stress and damage to our marriage if we chose treatment and that we shouldn’t think of termination as being selfish. Treatment is a series of 3 palliative heart surgeries all within the first few years of life. We were told that we needed to make a decision quickly because I was far enough along in the pregnancy that they would soon have to consult with the ethics committee for approval of an abortion. We didn’t have to think about it, we said right away that we had no intention of terminating the pregnancy and wanted full treatment. After we declined termination, comfort care was offered, which meant once the baby was born, he would have been kept “comfortable” without treatment and allowed to die.

    We weren’t given proper information on the condition our son had and no contacts on how we could get proper support. We felt very alone. Thinking back on the experience I should have said much more than I did, but I was in such a state of shock I wasn’t thinking clearly. The doctor did not seem very sympathetic or caring and seemed to have one option in mind, termination, and he tried hard to convince us to choose that.

    Our son is 5 years old now and gone through 4 heart surgeries and numerous catheters. He is a beautiful miracle and brings so much love and happiness to our lives. He’s a happy, healthy, affectionate and energetic boy who loves to play hockey and soccer. He is in kindergarten and thriving. Our marriage if anything grew stronger because of him and the journey we took together. Our other children also have benefited from the experience. What could be better than teaching children to love someone with a disability.

    Since that journey, we had a son who was diagnosed with Trisomy 18. He lived for 6 months with his last week and a half at home. He too was a gift to our family and worth all our efforts to have him treated so he could finally make it home. I’m now 7 weeks pregnant at 40 and just visited my family doctor who spent about 1/2 an hour trying to convince me to get prenatal testing done both screening and diagnostic. She also wanted me to see a genetics counselor. She didn’t figure out my due date or even ask me how I was feeling, she just focused on the risks that were involved with my pregnancy. She proceeded to tell me about other women in her practice that terminated their pregnancies because of chromosomal abnormalities and then went on to have healthy babies. I just declined it all. Why, because it wouldn’t change my decision. I would never terminate the pregnancy no matter what the results were. Every life is a precious gift that is given and people need to realize the benefits of having a child with a disability. Why is society trying to create perfect people? Why are we eliminating all these beautiful children from the world? What does all this prenatal testing do? It creates stress, worry and many needless abortions. Sure it would be informative to know if your baby has any pre-existing condition, you could certainly better prepare yourself for when the baby is born, but that’s not the reality. When an abnormality is detected the parents are being pushed and convinced to abort. Parents aren’t told about the positive side of having a baby with a disability, they aren’t given stories of families that love and care for a child with down syndrome etc., instead they are being told that the baby would be a burden. That’s the problem with prenatal testing it leads the parents down the wrong path. The attitude that exists towards babies with disabilities needs to change.

  4. Karim

    “Traditionally, fetal cells acquired through amniocentesis were examined through a technique known as karyotyping, where a geneticist would examine the number, size and appearance of chromosomes under a light microscope”. In fact, chromosomes are analyzed/examined based on size, centromere position and banding patterns by a Medical Laboratory Technologist (MLT) trained in this field. The results and interpretation are then forwarded to a cytogeneticist for a final check and sign out.

  5. Jennifer Johannesen

    Like some of the other commenters, I am a parent whose child was born with severe anomalies. His diagnosis was never determined but it was accurate enough to just say ‘multiple severe disabilities’. I had plenty of screening in utero (16 years ago) and nothing we learned anticipated the lifelong disabilities he would face. Given he had no diagnosis, I doubt anything would be picked up through screening had it been done with today’s testing technologies.

    I’ve thought long and hard about this question of prenatal diagnosis. Partly because it seems to be a fun party game to ask “what would you have done if you’d known…?” I don’t answer, because I don’t know. I have also come out the ‘other side’ of raising a child with severe disabilities and feel much better off for it. So it’s a ludicrous idea that I might somehow be able to transport myself back in time to speculate on a decision I would have made without the benefit of my current wisdom.

    For those who know they would never abort a fetus for any reason, it’s essentially a pro-life argument, perhaps based in religion or a spiritual belief. I don’t think it’s an easy sell to someone who is either a) pro-choice or b) able to see with their own eyes that indeed, the child in front of them is not actually an angel.

    For those who are pro-choice and troubled by society’s routine tendency to abort a fetus with anomalies – I’m with you. But we can’t blame the technology, and we ought not judge those who would abort for their own personal reasons. Is it somehow less valid to abort for anomalies than it is to abort for convenience (which has been socially sanctioned for decades)?

    Certainly we should be concerned with the quality and breadth of counseling, to expose pregnant women to the idea that there are choices beyond abortion – and that those choices could still lead to a fulfilling life even though ‘that life’ is not the one they first imagined. It’s lamentable indeed that some women might feel coerced or pressured towards termination, especially in such a vulnerable state with immense time pressures.

    But… trying to sell the rewards of parenting a child with severe disabilities using pro-life justifications– it’s not a winning argument.

  6. Wendy Katherine

    Thanks for this great article Nan, and for stimulating the dialogue about what real care in pregnancy, including thorough and compassionate prenatal counselling (which takes time with women and families), screening and options for parents really mean in the age of advancing technology.

  7. mike waddingham

    Based on many of the comments (and my own experience as a parent) the authors appear to be uninformed about the lives of people with disabilities. They use terms like ‘risk of Down syndrome’ instead of ‘chance’. They use the term ‘disorder’ without contrasting what, to them, is ‘in order’. They assume that a pregnancy can’t be healthy unless it results in the delivery of a a ‘typical’ child.

    The authors appear unaware as to the diversity in life, of those that are differently abled and contribute to the world in different ways. Perhaps, over time, they will experience that diversity in positive ways. Perhaps they’ll read a great book and later learn the writer was an alcoholic. Perhaps they’ll use some advanced medical software — designed by a person on the autism spectrum. Or maybe it will be something more normal, more typical and more human: after a pressure-packed day, they encounter a child with Down syndrome who’s smile and laugh lifts their spirits…

    Our human race is imperfect. We are a collection of odd-balls and misfits, with a narrow band of the ‘normal’. Please give parents a real chance — through optional testing and balanced counselling — to keep it that way.

  8. jaytato

    I would like to know how accurate is this non invasive testing to determine paternity? I know some labs say they are 99.99% accurate while others who have had this kind of testing done have had mixed reviews. IF the NON INVASIVE test may not be able to determine ALL of the chromosomal defects in a fetus, how are we so sure that they can establish paternity?
    How can companies stand behind this kind of testing if its not completely accurate?

  9. Not-too-old

    I’m 42 and pregnant after recurrent miscarriages. Earlier testing options would be ideal. I look forward to hearing updates on these new testing options and whether they are offered by MSP especially in BC.

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