New Recommendations for Prenatal Genetic Testing

By: David Shifrin, PhD
Life Science Consultant and Freelance Writer

The European Society of Human Genetics (ESHG) and the American Society of Human Genetics (ASHG) have released new recommendations for prenatal testing. At the center of the discussion and recommendations is the use of non-invasive prenatal testing (NIPT) as a complement or alternative to procedures such as amniocentesis. The work was published on March 18 in the European Journal of Human Genetics in a paper titled “Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening.”

For the most part, particularly in this paper, NIPT refers to sequencing cell-free (i.e. “free-floating,” not contained within an intact nucleus) fetal DNA isolated from maternal plasma. In the case of this discussion, the testing looks for fetal aneuploidy. Specifically, NIPT can be employed to look for trisomy 21 (Down syndrome), 18 (Edwards’ syndrome) and 13 (Patau syndrome).

While amniocentesis is quite safe, there are still risks associated with the procedure. Risks associated with NIPT, in contrast, are negligible. At the same time, there are concerns about occasional false results returned from NIPT. For this reason, it has not become the primary first-tier test for expectant mothers. However, the authors point out, NIPT is now often offered as an option for women with greater risk factors. Use in high-risk populations has begun to trickle down, and NIPT is being offered to women at lower risk for fetal aneuploidy in some facilities.

Traditional prenatal screening has included a combined first-trimester screening (cFTS, which is made up of several non-invasive tests) followed by amniocentesis if a risk cutoff is reached. With this background, the authors point to three ways in which NIPT may be incorporated: 1) subsequent to cFTS in at-risk women based on current cutoffs, 2) instead of cFTS, and 3) subsequent to cFTS with a lower cutoff. Like most situations where a new technology is being introduced into a workflow, each of these three scenarios is limited in some way by questions about the effectiveness and cost of NIPT.

There are other concerns, as well. Worry caused by a false positive, the rate of which is likely to increase slightly, is one. Additionally, the authors express concern that increasing use of NIPT could lead to its “routinisation,” where women assume it’s just part of the process and therefore don’t make informed decisions about declining the screen. “However, the screening would still have the same consequences in case of a positive final diagnosis. Preparing women for this would require giving all relevant information to all of them already at the pre-screening stage, whereas the present two-step approach (ideally) allows for further moments of (additional) information and reflection for those with a positive initial screen.” A last concern is that increased use of NIPT could potentially reduce the discovery of “clinically relevant conditions that the screening may bring to light.” If NIPT is targeted only to trisomy 13, 18, and 21, other rare aneuplodies that may have otherwise been discovered will likely remain hidden. In other cases, the opposite issue may arise where additional unexpected findings may be discovered. This can lead to additional emotional burden and difficult decisions regarding followup testing.

With these (and other) issues as background, the authors state that the primary goal is to create a system that best allows for informed and autonomous decision making:

“In order to avoid these ethical pitfalls, relevant policy documents stress that prenatal screening for fetal abnormalities is aimed, not at preventing the birth of children with specific abnormalities, but at enabling autonomous reproductive choices by pregnant women and their partners. This may need to be qualified as referring to meaningful choices related to serious health problems, as maximizing reproductive autonomy as such cannot possibly be a justified public health aim.”

The challenge will continue, as NIPT expands to detect additional abnormalities and becomes less expensive. Therefore, ASHG and ESHG included ten recommendations for NIPT. These include the need to recommend follow up testing after a positive NIPT result, the importance of maintaining “standards for pretest information and counseling” in the face of more effective screening, and informing women/couples about the possibility of finding additional abnormalities before the test is performed. Similarly, providers should be careful about combining too many prenatal genetic screens to avoid confusion and “sending mixed messages” about what is being done and what potential outcomes could be.

In light of those last two points (which encompass recommendations 3 and 5), it is important to note recommendation 4. Even though additional findings may be unavoidable, “Expanding NIPT-based prenatal screening to also report on sex chromosomal abnormalities and microdeletions not only raises ethical concerns related to information and counseling challenges but also risks reversing the important reduction in invasive testing achieved with implementation of NIPT for aneuploidy, and is therefore currently not recommended.”

Most of the remaining recommendations deal with the need to keep debate open and study the issues further as prenatal genetic screening technology advances. This will be critical to maintaining an effective and widely acceptable screening process in the face of an issue fraught with such ethical and medical challenges.