Thank you for your letter and interest regarding the recent Society for Maternal-Fetal Medicine (SMFM) consult no. 36, Prenatal aneuploidy screening using cell-free DNA (cfDNA). As with all SMFM guidelines, this document was prepared through a standardized, multilevel review process through the SMFM Publications Committee, with additional review and approval by the SMFM Risk Management and Executive Committees.

Whereas we state in the document that cfDNA is highly accurate for Down syndrome detection (Table 2 and discussion page 714, column 1, paragraph 2), the limitations of this technology are often minimized and have led to problematic implementation. Although the document recognizes the positive predictive value (PPV) of cfDNA is far higher than that of traditional screening, it is not 100%. In low-risk women given the prevalence of Down syndrome, an understanding and emphasis on the PPV of the test should be an essential aspect of pretest counseling. This concept has not been well understood by providers who must accurately present positive results to women faced with decisions regarding pregnancy management.

As you note, the SMFM consult compares cfDNA with traditional screening because both are available screening tests for aneuploidy. Several recent studies have indicated that women with screen-positive results for Down syndrome via traditional screening have other significant aneuploidies at a far higher rate than expected by chance.

Additionally, women who receive no results from cfDNA screening appear to be at a higher risk for aneuploidy such that this should prompt such women to consider additional testing, leading to a much higher screen-positive rate than has been reported. These are important differences between these tests, which should be known by obstetric providers.

We were aware of the publication by Norton et al and believe that the findings of that study further support the SMFM consult recommendations. In that large study, cfDNA screening was confirmed to be an excellent test for Down syndrome in those patients with a reported result, regardless of patient age. The PPV was lower in the lowest-risk patients. Furthermore, cfDNA screening would be able to detect only 57 of the 68 aneuploidies present in the cohort (83.8%). Finally, the authors found that in 3% of the patients, the testing had failed, and those pregnancies had a high rate of aneuploidy. In fact, 3 cases of Down syndrome were not detected because of test failure; therefore, the true detection rate was 38 of 41, or 93%.

As the SMFM consult states, cfDNA screening is an important technology that has great benefits in patient care, but the details and complexities of clinical implementation are not clearly understood. It is expected that the existing guidelines will be updated to evaluate the new forthcoming data regarding test performance, expansion of testing for other conditions, and cost-effectiveness. For the question of which strategy of screening performs better in actual practice, comparative effectiveness of randomized controlled trials between cfDNA screening and traditional screening methods is needed. The goal of SMFM documents is to provide clinicians with clear, evidenced-based guidance for clinical care, which includes highlighting benefits as well as complexities and limitations of available alternatives.