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.
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.