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

Abstract

ObjectiveTo evaluate cell‐free DNA (cfDNA) testing as a non‐invasive approach to detecting aneuploidies in clinical miscarriages.DesignA retrospective cohort study of women with pregnancy loss.SettingHospitals and genetic analysis laboratories.Population or samplePregnancy losses in the period 2021–2022.MethodsResults derived from non‐invasive cfDNA testing (Veriseq NIPT Solution V2) of maternal blood and invasive analysis of products of conception (POC) (Ion ReproSeq) compared in 120 women who suffered a miscarriage.Main outcome measuresConcordance rate results, cfDNA testing performance, non‐informative rate (NIR) and fetal fraction (FF).ResultsWe found no significant differences in the NIR between invasive (iPOC) and non‐invasive (niPOC) analysis of POC (10.0% [12/120] versus 16.7% [20/120]). Of 120 samples, 90 provided an informative result in iPOC and niPOC groups (75%). cfDNA analysis correctly identified 74/87 (85.1%) samples (excluding triploidies). Sensitivity and specificity were 79.4% and 100%, respectively; all discordant cases were female. A binomial logistic model suggested fetal sex as the only variable influencing the concordance rate (P = 0.035). A Y‐chromosome‐based FF estimate allowed the optimal reclassification of cfDNA of non‐informative male fetuses and a more accurate evaluation of cfDNA testing performance. The difference between the two FF estimates (native algorithm and Y‐chromosome‐based) suggests that female non‐concordant cases may represent non‐informative cases.ConclusionsCell‐free DNA‐based testing provides a non‐invasive approach to determining the genetic cause of clinical miscarriage.

What proportion of couples with a history of recurrent pregnancy loss and with a balanced rearrangement in one parent can potentially be identified through cell-free DNA genotyping?

“…Some patients who experience a miscarriage before 8 weeks of gestation may not benefit from the NIPT approach as before 7 weeks of gestation the fetal fraction of cfDNA is more likely to be insufficient [ 16 ]. Although most spontaneous miscarriages are detected between 8 and 13 weeks of gestation, couples with recurrent miscarriages are very aware of becoming pregnant and early monitoring can lead to earlier detection of the miscarriage [ 16 ]; therefore, blood can be drawn at the moment of diagnosis before the products of conception are discharged [ 5 , 26 ]. Colley and colleagues have shown that in 66% of samples before 7 weeks of gestation their cfDNA test provided successful diagnosis [ 16 ].…”