Among pregnant women at high risk for trisomy 21, performing cell-free DNA (cfDNA) screening tests followed by invasive testing when warranted did not yield statistically significant reductions in miscarriage rates when compared with invasive testing procedures alone, according to a study published in JAMA.

A group of French researchers conducted a 2-year, nationwide, 1:1 randomized trial (NCT Identifier: NCT02127515) to compare rates of miscarriage after either cfDNA testing with invasive procedures performed after yielding a positive test result vs immediate invasive testing procedures. Women included in the study (n= 2111) had a risk for trisomy 21 between 1 in 5 and 1 in 250; women with a risk greater than 1 in 250 were automatically considered screen positive. Additional inclusion criteria were maternal age ≥18 years, singleton pregnancy, medical coverage by the national healthcare system of France, and gestation between 11 and 18 weeks.

Women assigned to undergo cfDNA testing provided blood samples; women in the invasive prenatal diagnosis group underwent karyotyping performed at a cytogenetic laboratory. Genomic DNA was extracted from 5mL of plasma; sequencing of a control sample of 11 patients with trisomy 21 was performed using an in-house validated method.

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The primary outcome was miscarriage before 24 weeks’ gestation; secondary outcomes included number and percentage of invasive procedures performed in both treatment groups, performance characteristics of cfDNA testing, time interval between blood sample receipt and result availability, and diagnosis of chromosomal abnormalities in each group.

No significant miscarriage rates were identified between the groups (8 [0.8%] vs 8 [0.8%] miscarriages; risk difference, −0.03%). Miscarriages occurred at a median of 19.9 weeks’ gestation and 19.9 weeks’ gestation for both groups, as well. No significant differences were found in miscarriage rates in either cfDNA testing (n=1103) and invasive testing (n = 733) (8 [0.7%] vs 7 [1%] miscarriages; risk difference, −0.23%). No patient had a miscarriage following invasive testing performed after a positive cfDNA result.

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Detection of trisomy 21 was 100% in the cfDNA group, with a false-positive rate of 5.6%. Mean interval time between receipt of blood sample and test result availability was 13 days and <3 weeks, respectively, for 88% of women who underwent cfDNA testing. Overall, 28 (2.8%) and 49 (5%) chromosomal abnormalities were diagnosed in the cfDNA and invasive testing groups, respectively, with 1 (0.1%) and 11 (1.1%) found to be other than trisomy 21.

“In this randomized clinical trial, there was no significant decrease in the risk of miscarriage before 24 weeks in high-risk pregnancies after cfDNA testing followed by invasive testing only in women with a positive cfDNA test result vs immediate invasive testing,” the authors concluded.”


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 21: a randomized clinical trial [published online August 14, 2018]. JAMA. doi:10.1001/jama.2018.9396