Investigating the outcomes of pregnancies with atypical results following SNP-based cfDNA screening: a population-based cohort study

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BACKGROUND: Cell-free DNA (cfDNA) screening has transformed prenatal screening by offering superior performance for detecting common aneuploidies, though it occasionally yields nonreportable or uninterpretable results. In 2020, a SNP-based cfDNA platform introduced a new category of nonreportable results termed "atypical," indicating additional or unexpected findings during DNA analysis. The clinical significance of these atypical results remains unclear, leaving clinicians without evidence-based guidance for counseling of pregnant individuals in the context of such results. OBJECTIVES: This study aimed to evaluate the association between atypical results and fetal chromosomal abnormalities. Our objectives were to estimate the incidence of atypical results, describe the characteristics of pregnancies with such results, and report on fetal/neonatal chromosomal abnormalities and pregnancy outcomes. STUDY DESIGN: This was a population-based cohort study of all singleton pregnancies in Ontario with an estimated date of delivery from October 1, 2020, to December 31, 2023, with SNP-based cfDNA screening. The study was conducted using data from Ontario's prescribed perinatal registry, Better Outcomes Registry & Network. Pregnancies with atypical cfDNA results were compared to those with low-risk results for chromosomal abnormalities and pregnancy outcomes. Additionally, subgroups of atypical results were identified and analyzed separately: (1) origin reported as fetal, (2) origin reported as maternal, (3) origin unspecified, and (4) atypical results reported alongside a high-risk result for a common aneuploidy. Associations were evaluated using a modified Poisson regression model, with adjustments for maternal age, gestational age, and conception type. RESULTS: The study included 53,283 singleton pregnancies with SNP-based cfDNA screening, among which 415 (0.8%) had an atypical result. Among the pregnancies with atypical results in which cytogenetic testing was performed, or for those in which a live birth was recorded, 18.2% were found to have a fetal chromosomal abnormality, ranging from 2.9% in the maternal atypical result group, 15.2% in the unspecified atypical result group, 24.2% for fetal atypical results and up to 100.0% for atypical results that were reported along with a high-risk result for a common aneuploidy. The risk of chromosomal abnormalities in a pregnancy with an atypical result was 36.3 times higher (adjusted relative risk 36.3, 95% confidence interval 28.1-47.0), compared to a pregnancy with low-risk results. CONCLUSIONS: Pregnancies with atypical cfDNA results showed an increased risk of chromosomal abnormalities, which varied by result subtype. This study is the first to report on the incidence of atypical results in the SNP-based cfDNA screening platform, and their association with chromosomal abnormalities on a population-level, thereby providing a foundation for evidence-based counseling and future research.

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