Ch. 2, Part 10: A “serious concern” about cell free DNA screening

And so we have arrived at the final section of Chapter Two’s disquisition on prenatal genetic testing for Down syndrome. It covers how once cell free DNA screening entered the marketplace, professional medical organizations and researchers expressed “serious concern” about its misleading marketing and rapid adoption in clinical practice. But, in just a few years, the professional medical organizations all fell in line with recommending offering cell free DNA screening to all expectant mothers. So, it seems, they weren’t that seriously concerned after all.

After these tests had been on the market, and practitioners and researchers began to see the effects it was having, concerns began to be expressed.

• In its statement on NIPS, the ACMG voiced concern over the lack of transparency in the labs actual performance and their results, making it impossible for practitioners and patients to know which test was most accurate for which tested-for condition.
• Professors with Harvard’s Department of Health Policy and Public Health co-authored an article in the New England Journal of Medicine. They reported how obstetricians at Massachusetts General Hospital, cautioning that “the diffusion of [cell free DNA screening] into routine prenatal care may be occurring too quickly. … [The] testing seems to be drifting into routine practice ahead of the evidence.”
• The Society for Maternal-Fetal Medicine (“SMFM”) felt compelled to issue a statement reminding physicians that cell free DNA screening was not diagnostic, lamenting that “[u]nfortunately, in part because of the high stakes in this very competitive market, the tests are being presented as having >99% accuracy, the same accuracy as is used to describe amniocentesis and CVS.”
• The ISPD, in its initial statement, stated that it had a “serious concern” due to “[t]he current absence of specific guidelines for quality control and quality assurance for cfDNA screening”.

One of the reasons for the lack of this quality control is that all of the cell free DNA laboratories are what are known as “Laboratory Developed Tests” or “LDTs.” LDTs are outside the regulatory scope of the Food & Drug Administration and only have to comply with the Centers for Medicare & Medicaid Services’ Clinical Laboratory Improvement Amendments or “CLIA.” CLIA does not require clinical validation that the tests detect and predict the tested for condition at an appropriate rate. The FDA regulations require truth in marketing materials, adverse event reporting, and informed consent for patients participating in clinical studies. But, Sequenom et al. are not required to comply with FDA regulation.

When cell free DNA screening commercially launched, all of the studies were based on what were termed “high risk” pregnancies for the tested-for conditions: the mothers were 35 or older or had another factor that increased their chances for having a child with a tested for condition, like an elevated conventional screen result. For this reason, with ACMG proving the exception to the rule, all other professional medical organizations, ACOG, SMFM, NSGC, ISPD, recommended cell free DNA screening only to high risk pregnancies.

The marketing goal for the labs was to get their tests offered to all expectant mothers, the far greater number than the minority of pregnancies that would be considered “high risk.” In less than three years, the labs achieved their goals, with all major medical organizations removing the “high risk” restriction.

While the ISPD had voiced a “serious concern” in its 2013 statement, just two years later, it changed its recommendations so that cell free DNA screening was to be offered to all expectant mothers. Nevermind that the laboratories had not addressed ISPD’s concerns or were reporting their test results in line with the ISPD’s recommendations. But, what had changed was that the membership of the committee issuing the statements had gained a super-majority of members with disclosed conflicts of interest for having worked for or accepted funding from the cell free DNA screening laboratories.

Initially, ACOG did not go as far as the ACMG or ISPD in recommending offering cell free DNA screening to all women. Instead, in an almost shoulder shrug of acknowledging how actual clinical practice was disregarding its previous recommendation to only offer cell free DNA screening to high risk pregnancies, ACOG said in 2015 that low risk expectant mothers could choose to have cell free DNA screening, but that conventional screening was more appropriate for these pregnancies. This is because, in part, cell free DNA screening was only recognized by ACOG for testing for a very limited number of conditions: Down syndrome, Trisomy 18 and 13, and the sex of the baby. Conventional screening had been shown in multiple studies to instead identify several more genetic conditions than that of cell free DNA screening. But, with the guidelines now lifting the restriction to just high risk, cell free DNA screening increasingly became the prenatal screening of choice for both physicians and patients.

In 2020, ACOG would revise its recommendations again to fall in line with the other medical societies’ recommending cell free DNA screening to all expectant mothers. Surely by pure coincidence, several of the cfDNA screening labs had created in the intervening years a lobbying organization advocating for insurance coverage, both public and private, for their laboratories’ tests.

In the five decades that have elapsed since amnio and CVS ushered in prenatal genetic testing, it has grown exponentially in just my daughter’s lifetime. The risk of miscarriage and the relative newness of invasive diagnostic testing caused it to have a slow growth in patients undergoing the procedure for the first couple of decades. The introduction of AFP and then Quad testing made prenatal testing something more mothers were willing to do, since screening posed no risk of harm to the pregnancy. Still, until 2007, prenatal genetic testing was something largely associated with those “AMA moms,” moms 35 and older, and therefore a minority of pregnancies.

With the introduction of the NT-combined screen and then with cell free DNA screening, it is now estimated that 70% of all pregnancies in the United States undergo some form of prenatal genetic testing. Having become the rule and no longer the exception, the decisions that follow its results, how it is administered, and how it is funded will have a societal impact on future generations. These are the subjects of the next few chapters.