Preimplantation genetic testing in IVF can ultimately fulfil the main aim of ART treatment, that is delivering a healthy child, provided no embryos are compromised or discarded due to gaps of scientific knowledge.

It may be well recognised that chromosome abnormalities are the main reason that embryos fail to implant during IVF treatment, however, genetic testing of embryos before embryotransfer for their chromosomes (preimplantation genetic testing for aneuploidies, or PGT-A) remains a controversial issue.

Genetic testing of embryos can either involve specific genes, known to cause single gene-related diseases, (preimplantation genetic testing for single gene defects, or PGT-M), such as cystic fibrosis and thalassemia, or it may involve entire chromosomes, as a screen for the overall integrity of genetic material in embryos.

PGT-M has been widely accepted since the 1990’s as a revolutionary method to select which embryos to transfer, following in vitro fertilization treatment. By the end of 2020 more than 3 million embryos had been tested genetically for over 1200 inherited conditions, including polycystic kidney, retinitis pigmentosa, Duchenne dystrophy and epidermolysis bullosa. Technical platforms and testing methods for PGT-M have been largely shared across the world with similar approaches, addressing high standards of practice in a consistent and effective manner.

However, the same cannot be said about the overall performance of preimplantation genetic testing for chromosomal abnormalities (PGT-A), as controversy still surrounds the wider application of this test.

It all started in the early 1990s, when a clear association was shown between age-related declining fertility and chromosomal abnormalities of embryos. Despite a clear concept behind the introduction of powerful genetic tools to detect chromosomal abnormalities in early stages of embryo development it became clear that many limitations had to be tackled.

PGT-A involves removing a few cells from the developing embryo, while still in the IVF lab, in order to test its chromosomes and provide a diagnosis, that is, whether the embryo has a normal number of chromosomes, (called a “euploid embryo”), or an abnormal number or structure of chromosomes, (called an “aneuploid embryo”). This procedure of removing cells from the developing embryo (known as “embryo biopsy”) is a direct injury to the embryo that may have a negative impact on further development. For quite a while, embryo biopsies were performed at embryos at day three following fertilization in lab culture conditions, only to be shown a few years later, that such a strategy could be compromising with regards to further development of the embryo.

Embryo biopsies, nowadays, are mainly performed at the stage of blastocyst, in other words, five days after fertilisation in lab culture conditions. This has been shown to be less traumatic to the developing embryo and less likely to impact on further development. However, studies have suggested that not all IVF labs perform the same when it comes to successful implantation, following embryo biopsies, implicating staff skills, experience, and methods chosen to carry out the embryo biopsy. Although an embryo biopsy may provide enough material for genetic testing, the embryo might stop developing further and fail to implant, or if implanted, it may miscarry early on in pregnancy.

A crucial issue regarding PGT-A performance is how accurate it is. A large number of studies has been published so far and although an increase in live births may not be consistent in all, it seems that the risk of miscarriage is significantly reduced following IVF and embryotransfer of embryos that have been tested and found to have normal chromosomes.

However, for a genetic test to be accurate at a microscopic level of sampling a few cells only, a vast size of information needs to be generated from a limited source of available genetic material. Recent technological advances in genetics have made it much easier to detect an ever smaller amount of chromosomal errors in developing embryos. Such an increasingly sensitive technology, however, results in the detection of genetic information that cannot always be interpreted with confidence. This is especially the case with embryos diagnosed with a combination of both normal and abnormal chromosomes within the same embryo, a condition also known as “mosaicism”. While the phenomenon of mosaicism is not new in early embryo development, its true importance has only recently started to to become more clear. Interestingly enough, it appears some embryos with mosaicism may be capable to implant and lead to successful pregnancies.

Judging which embryos may be likely to implant and which may not be appropriate to transfer, following IVF, will occasionally be a rather complex issue. Overdetecting chromosomal genetic variation of unknown significance may lead to false positive results and in this way decrease the number of available embryos for embryo transfer.

As knowledge of the early embryo biology is still accumulating it is important to recognise the limits of current technologies in preimplantation genetic testing and make informed decisions following appropriate counseling by fertility specialists with experience in the field. Genetic testing of embryos before embryotransfer can ultimately fullfil the main aim of assisted reproduction treatment, that is delivering a healthy child, provided no embryos are compromised or discarded due to gaps of scientific knowledge.

©2021, Nicholas Christoforidis, Fertility Matters
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