Private prenatal screening: beware of certain tests

A large survey published in the New York Times last January revealed that the genetic tests offered to detect certain rare but non-hereditary diseases gave very many false positive results. Consequence: an increase in the use of costly confirmatory examinations which are not without risk for future mothers and their fetuses, a lot of anxiety and even abortions, all this when the baby was not abnormal. The case caused a stir, leading the Food and Drug Administration (FDA) to issue a warning aimed at expectant parents and healthcare professionals.

“We are not talking about the genomic tests for trisomies which are offered in the public system in Quebec and which are very reliable”, specifies from the outset the D^r Jean-Claude Forest, clinical researcher in medical biochemistry at Laval University and president of the coordinating committee of the Quebec Prenatal Screening Program. In the public system, testing for Down’s syndrome is recommended for women who are at higher risk of having an affected child, because they are over 40 or have already carried a fetus with Down’s syndrome. Others are first offered a blood test and an ultrasound, and if these give ambiguous results, they are given access to the genomic test.

Some future parents then prefer to pay to take this test privately, in order to get the results more quickly. And that’s when they might be suggested the FDA advisory tests that are offered at clinics like Prenato or Dynacare.

Basically, these are the same products used in hospitals to quantify the risks of trisomies 21, 18 and 13. The one from Roche, for example, is called Harmony; it is sold for 499 dollars at Prenato. Added to this, however, for an additional cost of 340 dollars, the possibility of extending the genomic analysis to other anomalies. We then mainly look for microdeletions, in which only a small part of a chromosome is abnormal.

It is from these additional analyzes that the FDA and the D^r Forest call to beware.

Too many false positives

The abnormalities that we try to detect with additional tests can lead to different diseases, such as DiGeorge syndrome, an immune deficiency resulting from the poor development of the thymus, or Prader-Willi syndrome, which generally causes mental retardation, muscle tone problems and morbid obesity.

Most of these abnormalities appear during the first cell divisions that lead to the embryo and are therefore not hereditary. They are rare: while trisomy 21 affects on average 1 in 770 newborns (and up to 1 in 30 when the mother is 45), DiGeorge’s syndrome, the most common anomaly sought in complementary analyzes , affects 1 in 4,000 children.

“It is made clear to expectant mothers that for microdeletions, the reliability of these tests is a little less, around 93% for DiGeorge syndrome for example, and that these data are based on smaller studies than those carried out for the tests of screening for trisomies 21, 18 and 13. They are also explained that this is a screening tool, not a diagnosis, and that it is important not to make a definitive decision on the basis of the test result. says Marie-Ève ​​Lortie, nurse clinician at Prenato.

According to the D^r Forest, however, this reassuring speech is not enough, for various reasons. Firstly because according to the studies carried out on these tests, some would actually give a very large number of false positives.

Let’s look at the numbers: let’s imagine that 80,000 expectant mothers pass the test which aims to detect the 22q11.2 microdeletion, which leads to DiGeorge syndrome. As the latter affects 1 in 4,000 babies, statistically, 20 babies will be carriers of this anomaly. However, the Roche data indicate that the sensitivity of the test (that is to say its ability to identify cases) is around 75% for this anomaly. Only 15 real cases will therefore be detected.

Among the 79,980 mothers-to-be whose babies will not be carriers of this anomaly, 0.5% will have a false positive result (because the specificity of the test, i.e. its ability to clearly distinguish the desired anomaly, is 99.5% according to Roche), which makes about 400 cases (79,980 multiplied by 0.5%).

In total, therefore, in this group of 80,000 future mothers, 415 will test positive; 15 of these results will be true positives and 400 false positives. If you are in this group and your test gives a positive result, then there is a 400 out of 415 chance, or 96% chance, that the result will be a false positive.

“No private clinic details this information in the documentation given to patients”, underlines the D^r forest.

Because of the risk of false positives deemed far too high for the rarer abnormalities, only the genomic tests for the three trisomies are the subject of consensus among experts in the field. They are particularly recommended by the American College of Obstetricians and Gynecologists.

The risks of overscreening

A false positive has serious consequences. “If a future mother obtains a positive result, an amniocentesis or an intravaginal biopsy will have to be performed to confirm or refute the result. However, these two diagnostic tests are not entirely without risk. They are also costly, either for the parents when they are done privately, or for society as a whole if the future parents turn to the public system to validate the result”, explains the D^r forest.

A positive result also causes a lot of anxiety. In the United States, the New York Times found that it sometimes scares future parents so much that they decide to terminate the pregnancy immediately rather than pay for a confirmatory test.

According to Marie-Ève ​​Lortie, from Prenato, out of several thousand expectant mothers purchasing the prenatal genetic test for the three trisomies each year, only a few hundred choose the option including the search for microdeletions. “We see about one positive case per year, and until now it was always a real positive”, she underlines. But these statistics, which are anecdotal, are not enough to disprove what has been established in studies.

A required regulation

In the United States, prenatal genomic tests are considered by the FDA to be laboratory-developed tests that do not require approval. Each company therefore does what it wants.

Health Canada has approved several tests such as the Harmony, for the screening of the three trisomies, on the basis of studies provided by the manufacturers. « We have not issued any warnings because the licensed tests have been reviewed for reliability, and the documentation provided is clear, » Health Canada said by email.

But the analyzes of the microdeletions made in addition by the clinics, they are considered as tests developed in the laboratory. They are the responsibility of the provinces, which do not require studies to prove their reliability.

“Even before the FDA’s opinion, our committee strongly recommended that the Ministry of Health and Social Services better regulate these tests. For example, it could hold clinics accountable for test performance, or encourage them to comply with national recommendations, which are currently limited to testing for the three trisomies,” explains Dr.^r Forest, who expects the Ministry to react quickly.

In Canada, all governments have stuck to genomic testing for the three trisomies in public prenatal screening programs, with the others not deemed relevant. “The techniques are improving, and maybe one day that will change. But for now, these additional analyzes are more harmful than anything else, ”says the specialist.

Jean-Claude Forest also believes that the government should act so that health professionals are more explicit in the prescriptions they write for prenatal tests. “They should specify that they ask for the test for the three trisomies, to avoid abuse. »