Does performing cell-free DNA testing on women with pregnancies at high risk of trisomy 21, followed by invasive testing only if cell-free DNA test results are positive, reduce the rate of miscarriage compared with immediate invasive testing?
In this randomized clinical trial that included 2111 women with pregnancies with a risk of trisomy 21 greater than 1 in 250 following combined first-trimester screening, the miscarriage rate was 0.8% in the cell-free DNA group and 0.8% in the invasive procedures group, a difference that was not statistically significant.
Using cell-free DNA to stratify individuals for invasive testing compared with direct invasive testing was not associated with a significant reduction in the rate of miscarriage in women with pregnancies at high risk of trisomy 21.
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.
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.
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.
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.
ClinicalTrials.gov Identifier: NCT02127515
Malan V, Bussières L, Winer N, et al. Effect of Cell-Free DNA Screening vs Direct Invasive Diagnosis on Miscarriage Rates in Women With Pregnancies at High Risk of Trisomy 21A Randomized Clinical Trial. JAMA. 2018;320(6):557–565. doi:10.1001/jama.2018.9396
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