OC01.03: State‐wide performance of traditional and cell‐free DNA‐based prenatal testing pathways: the Victorian Perinatal Record Linkage (PeRL) study

OBJECTIVES: Women's choices of prenatal screening and diagnostic pathways have increased in complexity since the introduction of cell-free DNA (cfDNA) screening and chromosomal microarrays. We performed individual record-linkage of women undergoing screening with cfDNA, combined first trimester screening (CFTS), second trimester serum screening (STSS), and/or prenatal and postnatal cytogenetic testing to (i) obtain population-based estimates on women's utilization of screening and diagnosis, (ii) analyse the performance of different screening strategies, and (iii) report the residual risks of any major chromosome abnormality following a low risk aneuploidy screen. METHODS: Retrospective study of women resident in Victoria, Australia, undergoing screening or prenatal diagnosis in 2015. Patient-funded cfDNA referrals from multiple providers were merged with state-wide results for government-subsidized CFTS, STSS and invasive diagnostic procedures. Postnatal cytogenetic results from products of conception and infants up to 12 months of age were obtained to ascertain cases of false negative screening results and atypical chromosome abnormalities. Individual record-linkage was performed with LinkageWizTM and statistical analyses with STATA v14.0. RESULTS: There were 79,140 births during the study period; 66,166 women (83.4%) underwent at least one form of aneuploidy screening. Linkage data were complete for 92.4% of women undergoing screening (n=61,911) and of these, 73.1% (n=45,275) used CFTS alone, 20.2% (n=12,520) used cfDNA alone; 5.3% (n=3268) used STSS alone, 1.3% (n=813) used both CFTS and cfDNA, and < 0.1% (n=35) used both STSS and cfDNA. CFTS had a combined sensitivity for trisomies 21, 13 and 18 of 89.57% (95%CI 82.64-93.93) for a screen positive rate (SPR) of 2.94%. There were 12 false negative results in the CFTS pathway (10 trisomy 21, 1 trisomy 18 and 1 trisomy 13). CfDNA had a combined sensitivity of 100% (95% CI 95.0-100.0) for trisomies 21, 13 and 18 for a 1.21% screen positive rate. When high risk cfDNA results for any chromosome, including the sex chromosomes, and failed cfDNA tests were treated as screen positives, the cfDNA SPR increased to 2.42%. The risk of any major chromosome abnormality (including atypical abnormalities) detected on prenatal or postnatal diagnostic testing after a low risk screening result was 1 in 1188 for CFTS (n=37) and 1 in 762 for cfDNA (n=16) (p= 0.13). The range of chromosome abnormalities detected after low risk cfDNA included pathogenic CNVs (n=6), triploidy (n=3), rare autosomal trisomies (n=3) and monosomy X (n=2). CONCLUSIONS: Our state-wide linkage analysis delineated the utilization and clinical performance of the multitude of screening pathways available to pregnant women. The sensitivity of cfDNA for trisomies 21, 13 and 18 was clearly superior to CFTS. While there was no statistically significant difference in the residual risk of any major chromosome abnormality after low risk CFTS or cfDNA result, there were fewer live infants diagnosed with a major chromosome abnormality in the cfDNA cohort. These data provide valuable population-based evidence to inform practice recommendations and health policy. This article is protected by copyright. All rights reserved.