Cell-Free Fetal DNA Test Cost-effective as a Prenatal Screen

Pam Harrison

November 02, 2016

When a genomic-based, noninvasive prenatal test that uses cell-free fetal DNA in maternal plasma to rule out common aneuploidies, such as Down syndrome, is used in conjunction with current prenatal testing, the need for diagnostic amniocentesis could be reduced by as much as 90%, a cost-effectiveness analysis indicates.

"If you test 1000 women with current approaches, including ultrasound and biochemical tests, 40 of them will be called high-risk," said François Rousseau, MD, PhD, from Laval University in Quebec City, Canada.

"But of these 40 women, you will probably have only two who will have an affected pregnancy. There is a very high false-positive rate with current prenatal screening," he told Medscape Medical News.

In contrast, the cell-free fetal DNA test has a very low false-negative rate (0.5%), which means that only women confirmed to be at high risk for fetal abnormality need to subsequently undergo amniocentesis, Dr Rousseau explained.

Results from this study, which is part of the larger Canadian PEGASUS project, were presented at the American Society of Human Genetics 2016 Annual Meeting in Vancouver, Canada.

Cell-Free Fetal DNA

During pregnancy, 5% to 15% of noncellular — so-called "cell-free" — DNA fragments in the maternal blood are of placental origin.

Researchers isolate these fragments in the plasma of the mother and then perform next-generation sequencing, which allows them to map millions of DNA fragments onto the human genome.

This identifies which chromosomes — including chromosomes 13, 18, and 21 — the fragments come from, Dr Rousseau said.

"If we have a fetus with an extra chromosome, we will see a small increase in the ratio of fragments," he explained. Although the increase is small, it "is still sufficiently important, because it is way outside of the distribution seen in normal pregnancies."

If the results of noninvasive prenatal screening are positive, confirmation with an invasive test, usually amniocentesis, is required. This is because the noninvasive test is indirect and has certain limitations, Dr Rousseau pointed out.

However, when used as a second-tier test, the noninvasive genomics-based test allows researchers to filter out virtually all trisomy 13-, 18-, and 21-negative pregnancies.

"This means that doctors can propose amniocentesis only to women who are at very high risk of having an affected pregnancy," he explained. The great majority of women can be spared the small, but real, risk of losing a fetus as a result of the invasive test.

Cost Analysis

Dr Rousseau and his colleagues set out to determine whether the introduction of this noninvasive prenatal screening, used as either a first- or second-tier test, would be more cost-effective than current screening approaches used in the Quebec healthcare system.

The researchers used a model to simulate the cost-effectiveness of 13 screening strategies. As outcomes, they looked at the total direct costs borne by the Quebec healthcare system, the total number of chromosomal anomalies detected, the number of invasive procedures involved in each screening strategy, and the number of fetal losses related to invasive strategies.

The most cost-effective strategy for women at high risk was serum-integrated screening followed by noninvasive prenatal screening with cell-free fetal DNA. With this combination, each additional case of Down syndrome that was detected cost about $50,000.

Serum-integrated screening involves the analysis of biochemical markers in two separate blood samples taken during the first and second trimesters of pregnancy. Risk is then calculated using a mathematical formula that includes the mother's age.

This formula can be used to predict the risk of a mother having an infant with trisomy 13, 18, or 21 anomalies.

"Current recommendations suggest that if the second-tier test is negative, we shouldn't offer amniocentesis unless there is another good reason to do so," said Dr Rousseau.

"These data will likely convince decision makers that the second-tier test will not cost more than our current screening program," he explained. "And it will bring down the risk of the current screening approach because it will allow many women to avoid amniocentesis."

The problem is that the initial screening doesn't detect all cases of trisomy anomalies Dr Jan Friedman

Amniocentesis itself is quite accurate, said Jan Friedman, MD, PhD, professor of medical genetics at the University of British Columbia. "The problem is that the initial screening doesn't detect all cases of trisomy anomalies," he said.

In British Columbia, women found to be at high risk with conventional screening are offered this noninvasive, genomics-based prenatal testing strategy, Dr Friedman told Medscape Medical News.

"And yes, the test has cut down on amniocentesis rates. That's a good thing because it saves costs, but it also avoids any risk to the pregnancy related to the procedure," he pointed out.

Dr Rousseau and Dr Friedman have disclosed no relevant financial relationships.

American Society of Human Genetics (ASHG) 2016 Annual Meeting: Abstract 28. Presented October 18, 2016.


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