State-wide performance of traditional and cell-free DNA based prenatal testing pathways: The Victorian Perinatal Record Linkage (PeRL) study.

Abstract

Objectives: To perform individual record-linkage of women undergoing prenatal screening and/or prenatal and postnatal diagnosis to analyse the performance of different screening strategies, and report the residual risks of any major chromosome abnormality following a low risk result. Method(s): Retrospective study of women resident in Victoria, Australia, undergoing screening or prenatal diagnosis in 2015. Patientfunded cell-free (cf) DNA referrals from multiple providers were merged with statewide results for combined first trimester screening (CFTS), second trimester serum screening (STSS) and invasive diagnostic procedures. Postnatal cytogenetic results from products of conception and infants up to 12 months of age were used to ascertain cases of false negative screening results. Individual record-linkage was performed with LinkageWizTM and statistical analyses with STATA v14.0. Result(s): In 2015, 66,146 women (83.6% total births) accessed at least one form of aneuploidy screening. Of the 61,810 (94.6%) women with complete linkage data, 20.1% used cfDNA as their primary screen; 73.2% used CFTS alone; 5.3% had STSS, and 1.3% used both CFTS and cfDNA. Of women with a high risk CFTS result (>1 in 300), 11.6% (178) had additional screening with cfDNA and of these, 10 had fetal aneuploidy confirmed on prenatal diagnosis. CFTS had a combined sensitivity for trisomies 21/13/18 of 87.95% (95% CI 79.22-93.32) for a screen positive rate (SPR) of 2.94%; cfDNA screening had 100% (95% CI 93.47-100.0) sensitivity and a 1.21% SPR for trisomies 21/13/18. When high risk cfDNA results for any chromosome abnormality and failed cfDNA tests were treated as screen positives, the SPR increased to 2.42%. The risk of any major chromosome abnormality after a low risk screening result was 1 in 1188 for CFTS and 1 in 717 for cfDNA (p = 0.08). Conclusion(s): In a population with primary screening with government-subsidized CFTS or self-funded cfDNA available, approximately 1 in 5 women chose self-funded cfDNA as a first line test. The SPR of cfDNA screening approached that of CFTS when failed cfDNA results were treated as a high risk result. While the sensitivity of cfDNA for the trisomy 21/18/13 was superior to CFTS, there was no statistically significant difference in the risk of any major chromosome abnormality after low risk CFTS or cfDNA result.