Health Economic Evaluation of Non-Invasive Prenatal Exclusion Diagnosis

The study will be proposed to couples undergoing prenatal diagnosis following genetic counseling or during a pregnancy follow-up consultation. The NIPD results obtained via NGS within the PRENATSAFE study will not be disclosed to the couple or their prescribing physician, and they will not impact clinical management. No additional conditions will be diagnosed through NGS-based NIPD. However, the analysis will be conducted under real-life conditions, with a turnaround time of less than ten working days, in order to provide an accurate estimate of NIPD costs. Informed consent will be obtained from the pregnant woman, her partner, and , if applicable both legal guardians by a physician or trained genetic personnel (e.g., a genetic counselor or another investigator). Two additional blood samples (20 ml total, Streck tubes) will be collected from the pregnant woman during routine pregnancy monitoring, prior to any invasive prenatal diagnosis if indicated. These tubes will enable the automated extraction of circulating cell-free fetal DNA (cffDNA). NIPD by NGS will be performed in a trio or quartet format, involving exome sequencing of ccffDNA and genomic DNA from the father, mother and from a previous affected child/fetus, if applicable. Genomic DNA samples will either be collected and stored as part of routine clinical care or transferred to the molecular genetics laboratory at Necker-Enfants Malades Hospital (AP-HP) if necessary. Library preparation for sequencing will be automated using the Magnis Dx system (Agilent Technologies), and data analysis will be conducted using a dedicated bioinformatics algorithm. For the study, results from prenatal diagnoses performed as part of routine care (invasive PND or PCR-based NIPD) and occurrences of fetal loss and pregnancy outcomes will be recorded. Pregnancy will be monitored according to standard clinical practice, with no additional visits required for research purposes. Follow-up for the PRENATSAFE study will conclude one month after the expected end of pregnancy or following the post-termination consultation, which occurs three months after medical termination if applicable.