BACKGROUND AND PURPOSE: 

• Dar et al. (AJOG, 2022) compared the performance of cfDNA screening for T21, T18 and T13 between women at low and high-risk for aneuploidy in a large, prospective cohort with genetic confirmation of results 

METHODS: 

• Multicenter prospective observational study 
• Participants 
  • Women from 6 countries who had SNP-based cfDNA screening for T21, T18, and T13 
• Exposure 
  • Low-risk for aneuploidy 
  • High-risk for aneuploidy 
• Study design 
  • Genetic confirmation of screening results was obtained from prenatal or newborn DNA samples 
  • High-risk for aneuploidy 
    • Prior positive serum-based screen for aneuploidy | NT>3 mm | Ultrasound anomaly | Maternal age ≥35 years at delivery and no other screening results available 
  • The primary outcome was assessed for the full cohort, and based on exposure group (risk of aneuploidy) 
  • The authors also assessed an updated cfDNA algorithm, blinded to pregnancy outcome 
• Primary outcome 
  • Test performance 
  • Test failure (no-call) rates 

RESULTS: 

• 17,851 women with genetic outcomes confirmed 
  • Median (IQR) gestational age: 12.6 (11.6 to 13.9) weeks 
  • Low-risk of aneuploidy: 73.1% 
  • High-risk of aneuploidy: 26.9% 
  • Trisomies diagnosed 
    • T21: 100 
    • T18: 18 
    • T13: 15 
• cfDNA screen positive rate was lower in the low-risk group, compared to those at high-risk (P<0.0001) 
  • Low-risk: 0.27% 
  • High-risk: 2.2% 
• Sensitivity and specificity were similar between groups 
• Positive predictive value  
  • For T21 (P=0.058) 
    • Low-risk: 85.7% 
    • High-risk: 97.5% 
  • For T18 (P=0.283) 
    • Low-risk: 50.0% 
    • High-risk: 81.3% 
  • For T13 (P=0.58) 
    • Low-risk: 62.5% 
    • High-risk: 83.3% 
• No-call results 
  • After the first draw: 3.4% 
  • After including cases with a second draw: 1.61% 
• Trisomy rate was higher in those with no-call results, compared to patients with results on a first draw (P=0.001) 
  • No-call result: 2.8% 
  • Results on first draw: 0.7% 
• Updated algorithm  
  • Similar sensitivity and specificity to the current study algorithm  
  • Lower no-call rate (p<0.001) 
    • After first draw: 1.4% vs. 3.4%  
    • After optional second draw: 0.5% vs. 1.6%   

CONCLUSION: 

• For women with a low risk of aneuploidy, cfDNA screening for trisomies exhibits high sensitivity and specificity, with positive predictive values of 
  • 85.7% for T21  
  • 74.3% for all three common trisomies 
• PPVs were lower among non-risk cohorts as expected, although not statistically significant for T18 and T13, likely due to small sample size  
• Patients who receive a no-call result are at an increased risk of aneuploidy 
• The authors state 

…the findings in this study demonstrate that SNP-based cfDNA screening for the common trisomies performs similarly well in both high- and low-risk groups 

Learn More – Primary Sources: 

Cell-free DNA screening for trisomies 21, 18 and 13 in pregnancies at low and high risk for aneuploidy with genetic confirmation 

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