Tests based on cell-free DNA in the context of screening for trisomy 21: appropriateness of detecting other chromosomal abnormalities

The prenatal screening strategy for trisomy 21 changed in France in 2018 following the public health guideline issued by the French National Authority for Health (HAS). It is now recommended that all pregnant women whose first-trimester combined screening test indicates a trisomy 21 risk of between 1/1,000 and 1/51 be systematically offered a cell-free DNA (cfDNA) test, instead of immediate karyotype for women whose first-trimester combined screening test risk was above 1/250, the aim being to limit the number of invasive procedures (amniocentesis, chorionic villus sampling) required for karyotyping. It had been pointed by the HAS in 2017 that the introduction of cfDNA testing may result in the lower detection of chromosomal abnormalities other than T21 (due to the decreased number of karyotypes).

Hence, in line with the HAS recommendations issued in 2017, and in response to a new referral by the French Ministry of Health, the HAS assessed the benefit and impact of detecting other chromosomal abnormalities by cell-free DNA testing in maternal blood performed in the context of screening for T21.

At the end of its assessment, having taken into consideration the data in the literature relating to the frequency of chromosomal abnormalities and the clinical features, the performance of the cfDNA tests, current practices in France and other countries, discussions with the working group and contributions from stakeholders, the HAS recommends:

• Offering women who meet the conditions of the order of 14 December 2018 testing for chromosomal abnormalities compatible with an ongoing pregnancy and liable to have particularly serious foetal or obstetric consequences. As knowledge currently stands and in view of the prevalence of foetal involvement and the known consequences of placental involvement, the abnormalities meeting these criteria are trisomies 2, 8, 9, 13, 14, 15, 16, 18, 21 and 22 and noncryptic segmental abnormalities. 
• Extending the indications for cfDNA testing to the following situations:
  • in the event of a history of pregnancy with aneuploidy,
  • if one of the parents is a carrier of a Robertsonian translocation involving chromosome 13,
  • in the event of a first-trimester maternal serum marker profile suggestive of trisomy 13 or 18. This recommendation implies that a probability of T13 or T18 be indicated by the laboratories following first-trimester combined screening;
• That pregnant women be provided with information that they can easily understand so that they can make an informed decision with respect to the performance of screening and diagnostic tests;
• That prescriber training be scheduled in order to guarantee the quality of the information provided and women's autonomy in terms of decision-making, particularly in the context of an increase in the number of abnormalities screened for;
• That a dedicated time slot for providing screening information be scheduled in the care pathway for pregnant women, prior to prescription of the test, with fair remuneration of practitioners. The methods for informing pregnant women will be defined by the French Biomedicine Agency (ABM). This implies appropriate human and financial resources dedicated to implementing and monitoring the extension of screening for chromosomal abnormalities.

The list of Rare Autosomal Trisomies (RAT) for which screening is recommended will need to be reviewed based on the data that becomes available relating to the consequences of the various chromosomal abnormalities and the performance of the cfDNA tests.

The consent methods will be defined by the French Biomedicine Agency, which was consulted in parallel by the French Ministry of Health to define the methods for informing women and professionals, the consent process and the informed consent form. Uncertainties related to the results of cfDNA tests will have to be included in this information.