pregnant-dna-tattoo-CTJenny’s sister suffered a stillbirth 6 months ago. Her fetus was found to have trisomy 18 or Edwards syndrome, and Jenny can’t imagine going through the same pain and suffering that her sister did. Jenny is now pregnant and seeing her family doctor for her first prenatal visit. She wonders if there is a way for her to know now, in her first trimester, if her developing baby is healthy and free of any chromosomal anomalies.

The quality and volume of information available to a pregnant woman regarding the health status of her fetus has grown substantially over the last several decades through prenatal screening and diagnosis. Prenatal screening is the use of non-invasive tests to determine high-risk pregnancies that could benefit from diagnostic testing. Prenatal diagnosis is the detection and confirmation of fetal disease prior to birth.

Prenatal diagnostic testing for chromosomal anomalies started in the 1970s in the form of amniocentesis and chorionic villous sampling. A sample of amniotic fluid or chorionic villi is acquired by introducing a needle into the uterine cavity under ultrasound guidance. The sample is then sent for chromosomal analysis. If a chromosomal anomaly is diagnosed, the woman is counseled and given the choice of terminating or continuing with the pregnancy. Initially, testing was offered to women over 35 years old, as the risk of aneuploidy is approximately 1 in 200 compared to 1 in 1500 for a 20 year-old mother. However, the majority of babies with Down syndrome are born to younger mothers due to higher pregnancy rates. Consequently, only 1% of women undergoing these procedures were diagnosed as having a fetus with aneuploidy and only one third of cases of Down syndrome were being detected prenatally. With a 0.5-1% rate of miscarriage with these procedures, many argued that the accuracy of prenatal diagnostic testing was too low to outweigh the inherent risks.

Prenatal screening tests have been developed to better select women who would benefit from invasive testing. The current gold standard is integrated prenatal screening (IPS). For IPS, an algorithm combines the results of ultrasound measurements and maternal blood testing in the first and early second trimester to calculate the odds of the fetus having Down syndrome (trisomy 21), Edward syndrome (trisomy 18) or an open neural tube defect. If a woman screens positive, meaning a risk of Down syndrome of 1/200 or greater, she is referred to a genetic counselor and given the option of invasive diagnostic testing. With IPS, 90% of cases of Down syndrome are being detected prenatally, but 4% of women who are screened are found to have false positive screening results.

More recently, the introduction of cell-free fetal DNA (cffDNA) testing has the potential to revolutionize the field, as it will provide better quality information at an earlier stage of pregnancy with less risk to mother and fetus. However, it comes with ethical, economic and logistical dilemmas to be considered prior to its use in the general population.
cffDNA testing is a novel form of non-invasive prenatal testing (NIPT) first introduced to the public in 2011. Researchers found that fragments of fetal DNA representing the entire genome are present in maternal blood after the fifth week of pregnancy. These fetal DNA fragments are sequenced, and a relative excess or deficit of a particular fetal chromosome can be detected and is indicative of aneuploidy. Fetal DNA from previous pregnancies will not be present to confound the results as the fragments have a very short half life in maternal serum.Using cffDNA testing, a review of high-risk populations reported that Down syndrome or Edwards syndrome can be detected with an average rate of 99.3% and an average false positive rate of 0.16%. The significantly decreased rate of false positive results would lead to less women being subject to the anxiety and risks associated with invasive prenatal diagnostic testing.

Despite the impressive sensitivity and accuracy of cffDNA testing , the Society of Obstetricians and Gynecologists of Canada (SOGC) only recommends cffDNA testing as an adjunct to a positive IPS result. cffDNA testing does not yet match amniocentesis in accuracy and further studies are required on its efficacy in low risk populations. Another barrier to its use as a population-screening tool is the cost: NIPT with cffDNA would cost OHIP $750 compared to $150 per patient for IPS. The difference in price will decrease if and when Canadian labs start doing their own testing as opposed to sending samples to labs in the US. Additional trials and cost analysis studies are underway to determine its utility as a general population screen.

With more information available regarding the health status of fetuses comes more ethically complicated decisions to be made. Non-invasive access to the entire fetal genome facilitates the prenatal diagnosis of a range of genetic disorders, such as cystic fibrosis or Huntington’s chorea. The difficulty will be in deciding which genetic disorders are severe enough to warrant prenatal testing. By including diseases in the prenatal screen, some advocacy groups worry that it delegitimizes people living with that particular disease. Reduced research funding and resource allocation for the population affected by the disease is another fear. On an individual basis, people are often concerned that given more information, women will make the “wrong” decision. This is particularly true in the case of sex-selective abortion, which NIPT could theoretically facilitate. There are many who have strong feelings regarding sex-selective abortion, but restricting women’s access to information is not going to stop it from occuring.

cffDNA testing will provide pregnant women with more information about their fetus that is not only more accurate, but also available at an earlier gestational age than current prenatal screening. With non-invasive access to fetal DNA, the question remains: who has the moral and scientific authority to determine which conditions should be tested for prenatally? In the end, each individual woman should decide what information she desires, and she should have the power to use that information to make decisions regarding her pregnancy.

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Melanie Zimmerman

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2 thoughts on “Advances in Prenatal Screening

  1. Great article Melanie! Unfortunately the first trimester screening test is not statistically valid based on the rate of a true to false positive. In fact, a patient’s score on this test is much more likely to be a false positive than a true positive. As the age of motherhood keeps on increasing, with most first time mothers in Canada now falling within the 30’s years bracket, and thus the probability of a genetic anomaly in the fetus, these tests are sure to be in more demand. That’s why it’s absolutely crucial that they are statistically sound. Otherwise, the false positive result will bring on an unnecessary stress, which has been documented to have a profoundly negative impact on the fetus i.e. in terms of brain development, and highly risky procedures such as amniocentesis to validate the result.

    1. You make an excellent point regarding the issues with the current IPS. The creators of the test sacrificed specificity for sensitivity when determining the threshold for a positive result, as it is felt a false negative is worse than a false positive – but I’m sure if you asked one of the many moms who have had a false positive they may tell you otherwise! Unfortunately, as is the case with lots of obstetrics, we don’t have tests that give definitive answers. When it comes to the health of moms and babies, we often opt to use all the tools at our disposal to give some information as opposed to no information at all. This is part of the reason why I am excited about the possibility of NIPT – more statistically sound information at an earlier gestational age to facilitate decision making would be fantastic!

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