Last updated on March 2020

RCT Study to Validate niPGT-A Clinical Benefit.


Brief description of study

The study and selection of embryos before transfer is a key step for the success of infertility treatments in assisted reproduction. Embryo selection based on morphology is the most common method used for evaluating embryo quality in vitro. However, it performs poorly in identifying the embryo with the highest implantation potential because of its weak association with embryo ploidy status, which is the most critical factor for implantation in IVF (In Vitro Fertilization). Chromosomal aneuploidies are highly associated with spontaneous miscarriages in human pregnancies and some specific abnormal chromosome patterns are not lethal but can result in abnormal offspring. In addition, some types of aneuploidy are reported to prevent implantation.

At present, trophectoderm biopsy plus Next-Generation Sequencing (NGS) is the most common approach to determine the embryo chromosomal status. This technique is called Preimplantation Genetic Testing for Aneuploidy (PGT-A). Although shown to be efficient, the technique suffers from some limitations. It can be considered invasive, it requires specific technical skills, and it still remains expensive. Therefore, the development of a non-invasive, rapid, and cheaper method for assessing embryo ploidy status would represent a progress in the field of IVF.

The non-invasive approach has been evaluated in some studies analyzing the spent culture medium where the embryo was incubated up to the time of transfer or freezing. In daily routine, this media is discarded after the embryo culture. This media may have traces of embryonic cell-free DNA (cfDNA) that would represent the genetic load of the embryo.

Thus, the main objective of this project is to evaluate the potential clinical benefits of a new non-invasive method for PGT-A (ni-PGT-A), based on the analysis of the embryonic cfDNA released into the embryo culture media.

Detailed Study Description

The goal of assisted reproductive technology (ART) is to optimise the chances of conception and the delivery of healthy babies. The study and selection of embryos before transfer is a key step for the success of infertility treatments in assisted reproduction. Chromosomal abnormalities lead to implantation failure, early pregnancy loss or severe chromosomal diseases. Recent studies suggest that transfer of euploid embryos, significantly improves implantation and ongoing pregnancy rates, and decreases miscarriage rates. Therefore, assessment of the genetic status of a preimplantation embryo is an important step for selecting the most potent embryos for transfer.

Currently, the most used method for embryo selection is the morphological assessment (following Gardner's criteria). However, it performs poorly in identifying the embryo with the highest implantation potential because of its weak association with embryo ploidy status, which is the most critical factor for implantation in IVF (In Vitro Fertilization). Morphokinetics has also been incorporated in IVF to add the kinetic parameters of the embryo as additional information to improve the embryo selection process for transfer and therefore, the clinical outcome. Although there might be a correlation between kinetic parameters and embryo chromosomal abnormalities, time-lapse systems do not allow clinicians to predict the ploidy status of the embryo. For these reasons, Preimplantation Genetic Testing for Aneuploidy (PGT-A) with trophectoderm biopsy remains the most reliable method to assess chromosomal complement of preimplantation embryos.

Current PGT-A techniques analyze the full chromosome content of a single or few cells with high sensitivity and specificity using Next-Generation Sequencing (NGS). Although shown to be efficient, the technique suffers from some limitations. It requires an embryo biopsy, specific technical skills, and it still remains expensive. Therefore, non-invasive techniques for assessing embryo ploidy status are sought as an alternative. Such non-invasive approaches would have various advantages over current strategies, including the elimination of a costly micromanipulation biopsy procedure and the avoidance of risks associated with cell removal. Futhermore, it would be more advantageous, especially for those patients who undergo IVF treatment but do not have PGT-A indication or they are not willing to have their embryos tested with invasive techniques.

The identification of embryonic cfDNA in spent culture media is one of the main recent advances in the field. The origin of the cfDNA at the blastocyst stage could be attributed to apoptosis, which may occur during normal development. However, studies evaluating the feasibility of spent medium DNA for genetic testing of the embryo have met with conflicting results. The main challenges in the culture medium approach are maternal DNA contamination from granulosa cells (MCC) and the possibility of embryo mosaicism.

In a pilot study conducted by our group, the ploidy concordance rate between blastocyst biopsy and spent culture medium was 84%, with a false-positive rate of 8.6% and a false-negative rate of 2.5%. On the basis of this preliminary study, the investigators carried out this project. niPGT-A for chromosomal abnormalities assessment may have the potential to be an accurate and reliable option for preimplantation genetic testing of human embryos. Moreover, this approach can circumvent the need for an embryo biopsy, avoiding the possible damaging effect of the biopsy on the embryo and decreasing the economic cost.

Clinical Study Identifier: NCT04000152

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