Effect of Cell-Free DNA Screening vs Direct Invasive Diagnosis on Miscarriage Rates in Women With Pregnancies at High Risk of Trisomy 21: A Randomized Clinical Trial

Abstract

Importance: Cell-free DNA (cfDNA) tests are increasingly being offered to women in the first trimester of pregnancies at a high risk of trisomy 21 to decrease the number of required invasive fetal karyotyping procedures and their associated miscarriages. The effect of this strategy has not been evaluated.

Objective: To compare the rates of miscarriage following invasive procedures only in the case of positive cfDNA test results vs immediate invasive testing procedures (amniocentesis or chorionic villus sampling) in women with pregnancies at high risk of trisomy 21 as identified by first-trimester combined screening.

Design, setting, and participants: Randomized clinical trial conducted from April 8, 2014, to April 7, 2016, in 57 centers in France among 2111 women with pregnancies with a risk of trisomy 21 between 1 in 5 and 1 in 250 following combined first-trimester screening.

Interventions: Patients were randomized to receive either cfDNA testing followed by invasive testing procedures only when cfDNA tests results were positive (n = 1034) or to receive immediate invasive testing procedures (n = 1017). The cfDNA testing was performed using an in-house validated method based on next-generation sequencing.

Main outcomes and measures: The primary outcome was number of miscarriages before 24 weeks' gestation. Secondary outcomes included cfDNA testing detection rate for trisomy 21. The primary outcome underwent 1-sided testing; secondary outcomes underwent 2-sided testing.

Results: Among 2051 women who were randomized and analyzed (mean age, 36.3 [SD, 5.0] years), 1997 (97.4%) completed the trial. The miscarriage rate was not significantly different between groups at 8 (0.8%) vs 8 (0.8%), for a risk difference of -0.03% (1-sided 95% CI, -0.68% to ∞; P = .47). The cfDNA detection rate for trisomy 21 was 100% (95% CI, 87.2%-100%).

Conclusions and relevance: Among women with pregnancies at high risk of trisomy 21, offering cfDNA screening, followed by invasive testing if cfDNA test results were positive, compared with invasive testing procedures alone, did not result in a significant reduction in miscarriage before 24 weeks. The study may have been underpowered to detect clinically important differences in miscarriage rates.

Trial registration: ClinicalTrials.gov Identifier: NCT02127515.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Figures

Figure.. Participant Flow in the Study of Cell-Free DNA Screening and Miscarriage in High-Risk Pregnancies

cfDNA indicates cell-free DNA. aThe per-protocol analysis analyzed participants according to the first test they received regardless of their initial group randomization. bThe post hoc analysis analyzed participants according to whether they did or did not undergo an invasive procedure (either as a first or second test) regardless of their initial group randomization. Overall, in the invasive group, 745 women underwent invasive testing as a first test and 6 women underwent invasive testing as a second test, while in the cfDNA group, 3 women underwent invasive testing as a first test and 81 women underwent invasive testing as a second test, leading to a post hoc population of 835 women who underwent invasive testing, of whom 16 were excluded because of unknown pregnancy outcomes. Therefore, the post hoc population was 819 women. Reasons for undergoing an invasive test secondarily (n=87) were positive cfDNA test result (n=78), abnormal ultrasound finding (n=5), maternal anxiety (n=2), and no reason recorded (n=2). A total of 1216 women had no invasive test performed, of whom 39 were excluded for unknown pregnancy outcomes. Therefore, the post hoc population with no invasive test performed was 1178 women.