Danish Prognostic Research on Embryonic Diagnostics Involving Chromosomal Testing.

Assessment if Predictive Values of Preimplantation Genetic Testing for Aneuploidy (PGT.A). A Prospective, Blinded, Prognostic Cohort Study With the Aim of Determining if Preimplantation Genetic Testing for Aneuploidy Can be Used to Predict Clinical Outcomes.

The study aim is to evaluate whether testing embryos for chromosomal abnormalities (known as aneuploidy) can aid in embryo selection.

If so, transfer of embryos that will fail to implant, miscarry or lead to birth of affected children, can be reduces. This would reduce the risk of miscarriage and increase the chance of healthy live birth per embryo transfer, which in turn would reduce the time and economical, physical and psychological cost associated with fertility treatment.

The method of genetically testing embryos for aneuploidy is know as preimplantation genetic testing for aneuploidy (PGT-A). It entails testing a biopsy from preimplantation embryos generated from assisted reproductive technology (ART) from which DNA can be analyzed. Another potential source of embryonic DNA is the spent culture media, the media in which the embryo has grown since the egg was fertilized with the sperm. Previous research suggest that the media contains DNA shed from the embryo during development. Hence, this a potential non-invasive way of obtaining DNA for PGT-A. Both embryo biopsy and spent culture media will be assessed in the study.

The study will be conducted as a prospective, blinded, prognostic cohort study in a cohort receiving preimplantation genetic testing for monogenic disorders (PGT-M). Hence, the study does not include an intervention, as data on aneuploidy is collected but not used to guide embryo selections and embryos are biopsied as part of standard care (PGT-M). Once clinical outcomes from embryo transfers has been collected from the study, the aneuploidy data will be assessed. Blinded towards the actual clinical outcome, predictions on whether each embryo would result in live birth or not will be made based on the aneuploidy results. Following prediction, actual clinical outcomes are revealed allowing calculation of predictive values. Predictive values will be calculated for PGT-A on embryos biopsies and spent culture media.

Two predictive values will be assessed. The positive predictive value (PPV) and the negative predictive value (NPV).

The PPV states how often an embryo predicted to result in live birth upon transfer actually did so. Numerous factors affect the chance of live birth besides aneuploidy, so while the PPV will never reach 100%, it should increase compared to the PPV of standard care (without testing for aneuploidy.

The NPV states how often an embryo predicted not to result in live birth upon transfer actually also failed to do so. The NPV should be near 100 %, which would mean that all or almost all embryos that would have been deselected did not result in live birth. If the NPV is too low, it means that too many embryos capable of resulting in live birth are being discarded, disqualifying PGT-A for clinical use.

With the predictive values assessed a proper evaluation of whether PGT-A should be used clinically can be made.

A number of pre- and postnatal samples will be collected in the study to further validate PGT-A results. These include chorionic villus sampling, amniocentesis, Fetal cells isolated from maternal blood, products of conception and a DNA sample from the newborn. All of these samples can be consented to individually and as such are not required for participation in the study. Chorionic villus sampling and amniocenteses are only acquired if performed as part of routine care.

The study is expected to include 540 transfers requiring the recruitment of approximately 220 patients. Recruitment is expected to take two years combined at the two centers in Denmark participating in the study.

Inclusion Criteria:

• Undergoing preimplantation genetic testing for monogenic disorders (PGT-M)

Exclusion Criteria:

• None