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

Abstract

; for the SAFE 21 Study Group 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 ϱ; 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.

Risk of miscarriage following amniocentesis or chorionic villus sampling: systematic review of literature and updated meta‐analysis

“…The electronic search yielded 2943 potentially eligible citations, of which 2911 were excluded because they were a duplicate, case report or letter or they did not meet the inclusion criteria following review of the title or abstract, leaving 32 studies for full-text review. After the full-manuscript review, we finally considered 12 studies for amniocentesis 6,7,[9][10][11][19][20][21][22][23][24][25] and eight studies for CVS [6][7][8]10,11,[26][27][28] (four studies 6,7,10,11 reported on both procedures). Of those, one study 26 was eventually excluded, as it reported cumulative data for miscarriage and stillbirth, leaving 12 studies for amniocentesis and seven for CVS ( Figure 1).…”

“…The raw data for the study of Wulff et al 6 were calculated from the published adjusted estimates and were complemented with additional information provided by the authors. Similarly, additional data for amniocentesis and CVS were obtained for the study of Malan et al 10 by contacting the authors. Characteristics of the included studies are presented in Table 1.…”

“…Overall (I 2 = 70.1%; P < 0.0001) Corrado (2012) 25 Beta (2019) 11 Odibo (2008) 23 Muller (2002) 19 Bakker (2017) 7 Wulff (2016) 6 Kong (2006) 21 Theodora (2015) 9 Malan (2018) 10 Towner (2007) 22 Eddleman (2006) Malan (2018) 10 Akolekar (2011) 27 Wah (2017) 8 Beta (2019) 11 Odibo (2008) 28 Bakker (2017) for chromosomal abnormalities ( Table 1). The pooled risk RD (i.e.…”

“…When studies with similar risk levels between the amniocentesis and control groups were analyzed, there was no significant procedure-related risk (pooled RD, 0.12% (95% CI, −0.05 to 0.30%; I 2 = 44.1%)) following amniocentesis (Figure 3a). The procedure-related risk following CVS was non-significant when studies with similar level of risk 20 Malan (2018) 10 Wulff (2016) 6 Theodora (2015) 9 Muller (2002) 19 Beta (2019) 11 Subtotal (I 2 = 38.1%; P = 0.152) Kong (2006) 21 Towner (2007) 22 Bakker (2017) 7 Pitukkijronnakorn (2011) Subtotal (I 2 = 0.0%; P = 0.743) Subtotal (I 2 = 0.0%; P = 0.605) Wulff (2016) 6 Beta (2019) 11 Akolekar (2011) 27 Odibo (2008) 28 Wah (2017) between the CVS and the control groups were compared (pooled RD, −0.11% (95% CI, −0.29 to 0.08%); I 2 = 0%). In contrast, CVS was associated with a pooled procedure-related risk of 0.48% (95% CI, 0.17-0.78; I 2 = 0%) when studies with dissimilar level of risk between the intervention and control groups were analyzed (Figure 3b).…”

Impact of ultrasonography on identifying noninvasive prenatal screening false-negative aneuploidy

“…That is, 90.5% of the cases with ultrasound information (19 out of 21) and at least 27.5% of the total cohort (19 out of 69) were NIPS false-negative cases that could potentially be avoided by means of a combination of NIPS and an US examination, followed by G-banded karyotyping or CMA diagnosis, which would probably not increase the risk of fetal loss. 14 It did not escape our notice that 6 out of 7 born cases had abnormal ultrasound findings during pregnancy; that is, 6 out of 7 born NIPS false-negative cases could have potentially been identified by means of the US examination ( Figure 1, Table 1 ). The abnormal ultrasound findings for the 6 born cases included small head circumference, lateral ventriculomegaly (11.2/10.2 mm), ventricular septal defect, aortarctia, tricuspid moderate regurgitation, nasal bones dysplasia, short femora, short humeri, bilateral renal pelvis separation (4.9/4.0 mm), polyhydramnios, and single umbilical artery ( Table 1 ).…”