Maternal cell-free DNA sequencing superior to standard aneuploidy screening [CARE Study]

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1. Maternal plasma cell-free DNA (cfDNA) testing had significantly lower false positive rates and higher positive predictive values for trisomies 21 and 18 than standard screening. 

2. Maternal cfDNA testing also had lower false positive rates for trisomy 13, with borderline statistical significance. 

Evidence Rating Level: 1 (Excellent)       

Study Rundown: Since the introduction of diagnostic obstetrical ultrasound in the 1970s, clinicians and researchers have searched tirelessly for additional noninvasive prenatal screening methods. While amniocentesis and chorionic villus sampling remain the absolute confirmatory diagnostic gold standard, they cannot be used as a screening tool due to invasiveness and small but non-negligible risks for miscarriage (under 1%). In the current study, Bianchi et al. report that maternal cfDNA sequencing detected trisomies 21 and 18 with lower false positive rates and higher positive predictive values than the standard serum biomarker screening in the general obstetrical population. The results suggest that maternal cfDNA sequencing has the potential to become a valuable screening tool in regular clinical practice. Nevertheless, any positive results must be interpreted with caution – any fetus that tests positive must undergo further confirmatory testing. Additionally, the study was not designed to assess sensitivity due to the small number of true positives. The study was blinded and adequately-powered with nearly 2000 enrollees from 21 different US sites.

The study was funded by Illumina. The first author, Dr. Bianchi, has reported receiving fees for serving on an advisory board from Illumina.

Click to read the study, published today in NEJM

Click to read an accompanying editorial in NEJM

Relevant Reading: First-trimester or second-trimester screening, or both, for Down’s syndrome

In-Depth: This study compared maternal plasma cfDNA sequencing to the current standard screening with serum biomarkers in their ability to detect aneuploidy. A total of 2042 women contributed blood samples for sequencing analysis.

The primary outcome compared false positive rates with each method. For trisomies 21 and 18, cfDNA testing had significantly lower false positive rates compared to standard screening. The false positive rates were 0.3% vs. 3.6% (P<0.001) for trisomy 21 and 0.2% vs. 0.6% (P=0.03) for trisomy 18. Both methods detected all cases of true aneuploidy (5 cases of trisomy 21, 2 cases of trisomy 18, and 1 case of trisomy 13), for an overall negative predictive value of 100% (95% confidence interval [CI], 99.8 to 100). The cfDNA method had a much higher positive predictive value than standard screening – 45.5% (95% CI, 16.7 to 76.6) vs. 4.2% (95% CI, 0.9 to 11.7) for trisomy 21, and 40.0% (95% CI, 5.3 to 85.3) vs. 8.3% (95% CI, 0.2 to 38.5) for trisomy 18.

The secondary outcome compared false positive rates for trisomy 13. In this sub-cohort of 899 patients for whom both cfDNA testing and standard screening results were available, there was one false positive with cfDNA and six false positives with standard screening (P=0.059). For the remaining 1015 patients, standard-screening results for trisomy 13 were unavailable.

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