Residual Risks of Fetal Chromosome Aberrations When Cell-Free DNA Prenatal Screening Is Normal: A Retrospective Study.

Objectives: To estimate the residual risk of fetal chromosomal aberrations in pregnant women with normal cell-free DNA (cfDNA) screening results to refine prenatal counseling.

Methods: A retrospective single-center study was conducted between April-2017 and March-2021. In total, 46,007 women received a normal cfDNA screening result. The cohort was subdivided into women receiving normal results for only chromosomes 13/18/21 (targeted cfDNA) and all autosomes (genome-wide cfDNA with a test resolution ∼10-20 Mb). Cytogenomic follow-up included prenatal or postnatal chromosomal microarray (CMA) data.

Results: Out of 46,007 women with normal cfDNA results, 806 (1.8%) were referred for CMA testing; the majority (511/806) were referred due to ultrasound anomalies. The residual risk for a pathogenic chromosomal aberration in the entire targeted cfDNA cohort was 1:641 (0.15%); in the genome-wide cfDNA group, it was 1:699 (0.14%). For fetuses with ultrasound anomalies, the residual risk for a pathogenic chromosomal aberration in the targeted-cfDNA group was 1:8 (13.3%), and 1:12 (8.1%) in the genome-wide cfDNA group.

Conclusions: The residual risk of a pathogenic CNV after a normal cfDNA result is low in women who opt for screening. However, when ultrasound anomalies are detected, this risk is severely increased, justifying the use of invasive testing even with normal cfDNA results. These figures can be used for pre-and-post-test counseling.