What evidence led to cell-free DNA (cfDNA) screening being accepted for the general pregnancy population?

A: Two studies in the New England Journal of Medicine convincingly showed that the performance of cfDNA in average-risk populations is better than first trimester combined serum screening and similar to cfDNA performance in high-risk populations (N Engl J Med 2014;370:799-808 and 2015;372:1589-97). CfDNA screening detected nearly all cases of Down syndrome in these studies with a false positive rate well below 0.5%.

In 2017, our division at Women and Infants Hospital in Providence, Rhode Island, also reported on a clinical utility project that offered cfDNA screening to the general pregnancy population (Genet Med 2017;19:778-86). In addition to confirming excellent test performance, we documented high uptake rates as well as patient and provider satisfaction. We were also able to document good patient understanding of educational materials about the test that was on par with or better than results previously reported for patient understanding of serum screening.

How widespread is cfDNA screening use in general pregnancy populations now?

In our experience, rates of cfDNA use are increasing steadily. From 2011-2016, 30% of our prenatal serum screening tests converted to cfDNA, and our current estimate is that 40%-50% of patients undergoing prenatal screening in the Providence region now choose the cfDNA method. This number will continue to increase as healthcare coverage of this test expands.

What are the advantages and disadvantages of cfDNA screening in a general pregnancy population?

The clear advantage of using cfDNA as a screening test for aneuploidy is its performance. No other screening test provides very high detection (approximately 99%) at a very low false-positive rate. This leads to a very high positive predictive value, meaning that many patients with a screen-positive cfDNA test for the common trisomies will have an affected fetus.

The downside is the test’s cost, which resides mostly in expensive equipment and reagents, as well as in bioinformatics resources required for analysis and interpretation. This is one of the reasons why some health insurance plans still decline to cover testing for average-risk patients. In many cases, patients without insurance coverage can still elect cfDNA testing by paying out of pocket. However, this is creating an inappropriate economic disparity in patient access to cfDNA screening. 

What should labs do to make sure that general pregnancy patients and their providers are able to make informed decisions about cfDNA screening results?

It is imperative that patients understand the implications of their results. Labs should therefore work with the rest of the healthcare team to ensure that patients with screen-positive results are referred for professional genetic counseling. Genetic counselors can also explore the reasons for a test failure and provide expertise on the best next steps for patients in this category.

What aspects of cfDNA use in the general pregnancy population still need to be studied?

Outstanding issues related to cfDNA testing in general pregnancy patients include how best to handle test failures, detection of mosaicism, screening twin gestations, and protocols to address the suspicion of maternal cancers.

Overall, as molecular technologies advance rapidly, it is important to remember basic principles of population screening. CfDNA testing should be reliable, inexpensive, readily accessible to all pregnant patients, and provide screening for relatively common disorders that are both serious and well described.

Geralyn Lambert-Messerlian, PhD, FADLM, is director of medical screening and special testing at Women and Infants Hospital and professor of pathology and laboratory medicine and obstetrics and gynecology at the Alpert Medical School of Brown University in Providence, Rhode Island. +Email: [email protected]