Before we can talk about the mosaic embryo, we must understand more about genetics and embryos…
Humans have 23 pairs of chromosomes, 22 chromosomes labelled 1-22 in descending order of size and a pair of sometimes matched (XX) in women and sometimes mismatched (XY) in man, sex chromosomes.
In general, when an embryo becomes an embryo, it has a perfectly matched set of 23 chromosome pairs adding up to 46 total chromosomes, one chromosome set inherited from the mother (maternal) and one set from the father (paternal).
An embryo with an unmatched set of chromosomes is aneuploid. Most known syndromes that are created when an embryo has an uneven count of chromosomes is Down syndrome (trisomy 21), or Klinefelter syndrome (XXY). Less known is that many embryos can have an extra or missing chromosome of any number, and that the vast majority of these embryos will not implant or will end in miscarriage.
The hypothesis for PGT-A is simple: if humans create large numbers of embryos with aneuploidy and aneuploid embryos are rarely destined to become live birth, then screening for aneuploidy in embryos during IVF cycles with selective transfer of only embryos deemed to be euploid (having the correct number of chromosomes) should result in better outcomes for patients. When we do PGT-A, only a very small part of the cells is used for testing, obviously, the rest of the embryo must remain untouched so that it can possibly be transferred back into the mother’s uterus later. Today, most PGT-A testing occurs at an advanced stage of embryo development, blastocyst, where cells have differentiated into those that will become the fetus (inner mass cells) and those that will make up the placenta (trophoblast cells). The biopsy for the genetic test is done from the trophoblast cells to avoid damage of the inner mass.
We certainly have a great technique; however, the reality is that although we have been able to test embryos for genetic disease since 1991, genetic testing is still a debated topic and things are getting more and more complex.
We have a technology that sounds awesome and have large numbers of peer-reviewed manuscripts published in well-respected scientific journals showing that it works as expected, so why there is still debate? That debate has recently been given new life with reports of embryos diagnosed during PGT-A as aneuploid that, however, after transfer resulted in a “normal’ live birth. How can this be possible?
And here we enter a new reality of embryos; the mosaic embryos. Before we had two types of embryos, euploid (correct set of chromosomes) and aneuploid (wrong set) embryos. Now, to make things even more complicated, we have a third type of embryo in between these 2 groups, which is mosaic (not necessarily good, but also not necessarily bad at the same time). To simplify, when you think of a mosaic embryo, you can think of a puzzle with several small pieces that when put together in the right order make a larger image. Now imagine that some of these pieces may be of slightly different color, or slightly bigger or smaller. At the end, you still see the full image and these differences may be more, or less visible. Recently, it has become clear that some embryos are like this, it seems that embryos can have cells with one chromosome count (euploid) and other cells with a different chromosome count (aneuploid). This third category of result has created a lot of attention in the field and a lot more concerns for the patients, and the clinicians that take care of them. The truth is that we don’t really understand that much about mosaic embryos currently and that when we find a mosaic embryo, it is very hard to know exactly what to do about it.
What we know is that a mosaic embryo is not definitely equivalent to a mosaic baby, we know that few hundred embryos that have been diagnosed as mosaic through PGT-A testing have been willingly transferred and resulted in a live birth. We know that the risk of miscarriage is much higher when transferring mosaic embryos. We also know that of all of the embryos reported so far resulted in a live birth, the oldest children born are under 2-3 years of age, so we do not have data on long term effects. Lastly, we know that most IVF cycles performed in the world do NOT include PGT-A testing, so there are potentially thousands of embryos transferred each year around the world that are mosaic. And to make things even more difficult, we now know that mosaic embryos can have a different level of mosaicism.
So, mosaic embryos exist and a subset of mosaic embryos, if transferred, can and do end in normal live births. Ultimately, all the data shows that the majority of embryos tested as euploid and aneuploid are truly diagnosed correctly, and that embryos diagnosed as mosaic are a small minority of all embryos tested.
The main question is what to do with mosaic embryos, transfer or not? And if we transfer is there a way to choose the best ones? Many laboratories report results with the different percentage of mosaicism per mosaic embryo and/or information about the different kind of genetic anomaly. Data seems to support that the lower the percentage of mosaicism the better is the chance of having a live birth. Nevertheless, different laboratories have different thresholds, a percentage of mosaicism do not equal to the same percentage in the born baby and babies with different grade of mosaicism can express the same exact phenotype.
In conclusion, at this stage, we do not have enough data to draw any conclusion. Certainly, transfer of a mosaic embryo should be considered only when there are no other options and it requires a special attention. We at BFC refer all couples to a mandatory genetic counseling before taking any decision to transfer mosaic embryos.
– Dr Corona