Technical Feasibility of the cfDNA Test for Non-invasive Cytogenetic Analysis of Early Miscarriages Versus the Gold Standard Microarray

Among the 15% of couples who experience a spontaneous early miscarriage (SEM) during their pregnancy, approximately 2 to 5% will suffer from recurrent SEM. It is only after the third SM that they will be offered a workup to look for a predisposition to SEM. This workup does not currently include a search for foetal chromosomal abnormalities that could be considered causal for this event. These anomalies are responsible for approximately 50% of SEM and their detection could lead to an explanation for half of the couples currently without a diagnosis after a standard workup. The diagnosis of chromosomal abnormalities can be made by karyotype analysis or by Cytogenetic Microarray Analysis (CMA) on the product of conception. Unfortunately, karyotyping has a high failure rate due to poor cell culture of samples that are often degraded or of low quantity. The CMA is not always feasible due to the absence of analyzable feto-placental material linked to the use of a drug strategy for its elimination.

The study of cell-free DNA of syncytiotrophoblastic origin (cfDNA) circulating in the maternal plasma could be a solution as it is for non-invasive prenatal screening of trisomy 21. cfDNA is detectable from 6 to 8 weeks of amenorrhea and released in the maternal blood as long as placental tissue is present in the uterus, can be easily obtained by maternal venous sampling. If maternal blood sampling is performed before complete removal of the product of conception, then detection of foetal chromosomal abnormalities would be possible. Thus, if failure rates of CMA and cfDNA techniques are comparable, cfDNA could be preferred as it applies for miscarriages for whom no fetoplacental material can be obtained.

This study therefore proposes to compare the failure rates of the two technologies (CMA and cfDNA) for the detection of chromosomal abnormalities in recurrent SEM.