Economic impact of using maternal plasma cell‐free DNA testing to guide further workup in recurrent pregnancy loss

Abstract

Objective: We have previously demonstrated that maternal-plasma cell-free DNA (cfDNA)-testing can detect chromosomal anomalies in recurrent pregnancy loss (RPL) with 81.8% sensitivity and 90.3% specificity. Here we assess whether this is cost effective in guiding further workup in RPLs. Method:A decision-analytic model was developed to compare the cost of various RPL management pathways: (1) current American Society for Reproductive Medicine (ASRM) RPL workup; (2) microarray or karyotyping analysis of products of conception (POCs) and RPL workup only for euploid cases; and (3) cfDNA testing and RPL workup only for euploid cases. Sample accessibility, failure rates, and sensitivity were specified for each test. Costs of sample collection, genetic tests, and RPL workup were considered. Analysis outcomes included detection rate of chromosomal anomaly and cost per patient tested. Results:In comparison to existing cytogenetic testing on POCs, cfDNA testing pathway allowed for better sample accessibility with a lower cost per patient. In addition, using cfDNA to guide further workup significantly increases the number of causative fetal chromosome anomalies detected, reducing the number of patients undergoing unnecessary workup resulting in an overall cost savings. Conclusion:Our study showed that inclusion of cfDNA testing is a cost-effective approach to guide RPL workup. Key PointsWhat is already known about this topic? � Chromosomal anomalies account for 50%-70% of early pregnancy loss (EPL) and even in recurrent pregnancy loss (RPL) random aneuploidy is the single most common etiology, accounting for >50% of cases.� In a previous study we have shown that maternal-plasma genome-wide cell-free DNA (cfDNA)-based testing can reliably detect chromosomal anomalies in random EPL and RPL with a sensitivity of 81.8% and a specificity of 90.3%.� We therefore suggested cfDNA-based testing serve to guide further management in cases of RPL: if cfDNA in the second and subsequent RPL demonstrates aneuploidy, no furtherThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Non‐invasive cell‐free DNA‐based approach for the diagnosis of clinical miscarriage: A retrospective study

“…Although cfDNA testing cannot currently replace cytogenetic testing, this approach could improve the diagnostic yields of current approaches. Studies have reported the cost‐effectiveness of cfDNA testing to guide RPL work‐up 56 . In this regard, cfDNA testing represented the second‐highest diagnostic yield pathway for identifying POC aetiology in RPL (ahead of ASRM work‐up and POC karyotyping) and the most cost‐effective system (avoiding costs associated with invasive procedures required for POC collection).…”

A fetal fraction enrichment method reduces false negatives and increases test success rate of fetal chromosome aneuploidy detection in early pregnancy loss

“…Yaron et al [5] revealed an interesting strategy where NIPS can serve as an alternative to cytogenetic analysis in guiding further management of early pregnancy loss; if cfDNA testing demonstrates aneuploidy, no further action is taken and if no abnormality is detected, the recommended early pregnancy loss workup is performed [5]. This strategy reduces the number of patients undergoing unnecessary workups, resulting in overall cost savings [8].…”

“…cfDNA testing had a sensitivity and specificity of 82% (45/55) and 90% (28/31), respectively [5][6][7]. They also performed cost-effective analyses of different testing pathways for early pregnancy loss, which demonstrated that in comparison with existing cytogenetic testing on products of conception, the cfDNA analysis pathway allowed for better sample accessibility at a lower cost per patient [8]. However, even after chromosomespecific standard log likelihood ratio (LLR) threshold corrections, cfDNA testing is unable to detect 18% of aneuploidies; the major reason for this false negative is low fetal fraction (FF).…”

Non‐invasive prenatal testing 10 years on

“…5 Indeed, further applications of cfDNA in reproductive medicine are being proposed with Peng and colleagues suggesting that genome-wide analysis of cfDNA in the maternal plasma of women undergoing recurrent miscarriage may be an economical approach to the investigation of recurrent pregnancy loss. 6 Initially NIPT was only recommended to screen for trisomies 13, 18 and 21 and only in singleton pregnancies, but we now recognise its utility in twin pregnancies with many authorities, including the International Society of Prenatal Diagnosis, 7 recommending NIPT as the preferred aneuploidy screening test in twin pregnancies. It also has utility in establishing zygosity, and potentially for identification of vanishing twins which can be a cause of false positive results making this an exclusion criteria for NIPT.…”

“…Lo also reflects on how applications of cfDNA now go beyond pregnancy screening to cancer detection and treatment monitoring, and transplant monitoring, and whether we will move to cell‐based NIPT—a topic explored in more depth by Vossaert and colleagues in this issue 5 . Indeed, further applications of cfDNA in reproductive medicine are being proposed with Peng and colleagues suggesting that genome‐wide analysis of cfDNA in the maternal plasma of women undergoing recurrent miscarriage may be an economical approach to the investigation of recurrent pregnancy loss 6 …”