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Cell-free DNA vs sequential screening for the detection of fetal chromosomal abnormalities

American Journal of Obstetrics and Gynecology, Volume 214, Issue 6, June 2016, Pages 727.e1 - 727.e6

Background

Sequential and cell-free DNA (cfDNA) screening are both tests for the common aneuploidies. Although cfDNA has a greater detection rate (DR) for trisomy 21, sequential screening also can identify risk for other aneuploidies. The comparative DR for all chromosomal abnormalities is unknown.

Objective

To compare sequential and cfDNA screening for detection of fetal chromosomal abnormalities in a general prenatal cohort.

Study Design

The performance of sequential screening for the detection of chromosome abnormalities in a cohort of patients screened through the California Prenatal Screening Program with estimated due dates between August 2009 and December 2012 was compared with the estimated DRs and false-positive rates (FPRs) of cfDNA screening if used as primary screening in this same cohort. DR and FPR for cfDNA screening were abstracted from the published literature, as were the rates of “no results” in euploid and aneuploid cases. Chromosome abnormalities in the entire cohort were categorized as detectable (trisomies 13, 18, and 21, and sex chromosome aneuploidy), or not detectable (other chromosome abnormalities) by cfDNA screening. DR and FPR were compared for individual and all chromosome abnormalities. DR and FPR for the cohort were compared if “no results” cases were considered “screen negative” or “screen positive” for aneuploidy. DR and FPR rates were compared by use of the Fisher exact test.

Results

Of 452,901 women who underwent sequential screening during the time period of the study, 2575 (0.57%) had a fetal chromosomal abnormality; 2101 were detected for a DR of 81.6%, and 19,929 euploid fetuses had positive sequential screening for an FPR rate of 4.5%. If no results cases were presumed normal, cfDNA screening would have detected 1820 chromosome abnormalities (70.7%) with an FPR of 0.7%. If no results cases were considered screen positive, 1985 (77.1%) cases would be detected at a total screen positive rate of 3.7%. In either case, the detection rate of sequential screening for all aneuploidies in the cohort was greater than cfDNA (P<.0001).

Conclusion

For primary population screening, cfDNA provides lower DR than sequential screening if considering detection of all chromosomal abnormalities. Assuming that no results cfDNA cases are high-risk improves cfDNA detection but with a greater FPR. cfDNA should not be adopted as primary screening without further evaluation of the implications for detection of all chromosomal abnormalities and how to best evaluate no results cases.

Key words: aneuploidy screening, cell-free DNA screening, noninvasive prenatal screening, noninvasive prenatal testing, sequential screening.

Footnotes

a Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA

b Genetic Disease Screening Program, California Department of Public Health, Richmond, CA

c University of California San Diego, Department of Pediatrics, La Jolla, CA

d Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY

e Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA

Corresponding author: Mary E. Norton, MD.

Disclosures: M.E.N. has received research funding from Ariosa Diagnostics and Natera; R.J.W. has received research funding from Ariosa Diagnostics, Natera, Sequenom, and Illumina; M.K. has received unrestricted research funding from Illumina; the other authors declare no conflicts of interest.

Cite this article as: Norton ME, Baer RJ, Wapner RJ, et al. Cell-free DNA vs sequential screening for the detection of fetal chromosomal abnormalities. Am J Obstet Gynecol 2016;214:727.e1-6.