OC04.01: A prospective cohort study to assess the use of cfDNA in miscarriage to detect chromosomal abnormalities*

Chromosomal abnormalities cause 50-70% of miscarriages and are identified through cytogenetic testing of miscarriage tissue. Cell-free DNA (cfDNA) is widely used for prenatal screening, but there is little research on its use in miscarriage. This study assesses the success rate and accuracy of cfDNA in identifying chromosomal status in miscarriage compared with cytogenetic testing. Prospective cohort study of 299 patients experiencing miscarriage < 20 weeks of gestation, recruited from two London hospitals between Feb 2021-Nov 2022. Blood samples were collected for genome-wide cfDNA testing prior to miscarriage tissue collection for cytogenetic analysis (QF-PCR, SNP microarray or BACs-on-Beads). Tissue cytogenetics and cfDNA results were available in 231 (77%) after 5 (2%) withdrew, no cytogenetic result was available in 54 (18% - 23 no tissue, 29 only maternal tissue collected, 2 microarray failures), and no cfDNA results were available in 9 (3% - no blood drawn in 4, test failure in 5). cfDNA results were available in all 54 cases where tissue cytogenetics were not. Mean clinical and sonographic gestational age was 10 and 7.6 weeks respectively. Chromosomal abnormalities were detected in 161/231 (70%) of tissue analysis. cfDNA correctly identified 106/161(66%) of these aneuploid cases and 67/70 (95.7%) of euploid cases. Overall concordance between cytogenetics and cfDNA results was 74.9% (173/231), with 65.8% sensitivity and 95.7% specificity. Positive predictive value was 97.2%, with a 4.3% false-positive rate. cfDNA offers a faster, more accessible way to identify aneuploidy in clinical and research settings. Furthermore, cfDNA achieved a result where tissue cytogenetics could not and offers a reliable alternative in cases where cytogenetics fails. This data supports the use of cfDNA to detect chromosomal status in miscarriage. The next step is to apply a pregnancy-loss specific threshold to the data to assess if accuracy can be further improved.