Preimplantation genetic testing for aneuploidies (PGT-A, previously referred to as preimplantation genetic screening or PGS) is a genetic test designed to improve IVF success rates by providing information about embryos’ chromosomal health.
Embryos with the correct number of chromosomes (called euploid) have a higher chance of leading to a successful pregnancy than those with the incorrect number of chromosomes (called aneuploid).
However, recent advances in PGT-A technology have uncovered a third class of PGT-A results that lie somewhere in between. This new class, deemed mosaic embryos, contain a mix of normal and abnormal cells.
Euploid embryos are obviously one’s best shot at success, yet data suggest that mosaics account for 10-20% of all PGT-A-tested embryos. That being the case, the most common question asked by patients when reviewing their PGT-A results is, “What would this mosaic result mean for a pregnancy or a baby?”
The answer is complicated. While mosaicism has always existed, it has only been reliably detectable for a couple of years, so research and follow-up studies are still ongoing.
There are some preliminary professional medical society guidelines and recommendations, though.
In 2016, a statement by the Preimplantation Genetic Diagnosis International Society (PGDIS) Position Statement recommended prioritizing mosaic embryos for transfer based on the level of mosaicism and the specific chromosome involved.
Similarly, the Congress on Controversies in Preconception, Preimplantation and Prenatal Genetic Diagnosis (COGEN) updated a position statement on the matter following their annual meeting in Barcelona in 2017.
A Summary and Review of the Grati et al. (2018) Publication
Grati et al. recently published a study in Reproductive BioMedicine Online to help clinicians and patients make sense of mosaic results. Led by scientists out of Italy, this article looked at results on chorionic villi samples (CVS) and products of conception (POC) to help provide guidance around which mosaic embryos may most likely lead to a healthy live birth.
The study considered four parameters to determine a ‘scoring system’ for embryos based on chromosome change, including:
- The likelihood that a mosaic aneuploidy detected in CVS samples will impact the fetus
- The impact of mosaicism on the occurrence of uniparental disomy (i.e., when a fetus has two chromosomes from the same parent instead of one copy from each)
- Whether a live birth with an incorrect number of that specific chromosome has been documented
The following table outlines the recommendations of this study:
|Mosaic Chromosomes Involved||↑ Priority||Reasoning|
|1, 3, 10, 12, and 19||Highest priority for transfer||Very low risk of any aforementioned adverse outcomes|
|4 and 5 and 47, XYY||The second group to be considered for transfer||Slightly increased likelihood of miscarriage or a viable aneuploidy (47, XYY)|
|2, 7, 11, 17, and 22||The third group to be considered for transfer||Slightly higher risk of miscarriage or a relatively low risk for uniparental disomy (UPD) trisomies 7 and 11|
|6, 9, and 15||The possibility for transfer should be considered with caution and only after detailed discussion with the prospective parents||Increased risk of miscarriage, UPD, or viable aneuploidy|
|2, 7, 11, 17, and 22||The third group to be considered for transfer||Slightly higher risk of miscarriage or a relatively low risk for UPD trisomies 7 and 11|
|8, 20, 47, XXX, and 47, XXY||The possibility for transfer could be considered after extensive discussion with prospective parents regarding the possible clinical manifestations||High risk of fetal involvement and a slightly increased risk for miscarriage and viable aneuploidy|
|13, 14, 16, 18, 21, and 45, X||Best avoided||Very high risk of any aforementioned adverse outcomes|
Critics have questioned the recommendations of this study, calling out the potential “emotional rollercoaster for both the patient and the responsible physician” and urging that “explicit counseling regarding the imponderable risk must be provided – most importantly – prior to PGT-A.” Reason being, knowing what chromosome material is extra or missing is only one of many factors to consider when deciding whether or not to transfer a mosaic embryo.
What other factors should you take into account?
1. What does your patient’s personal fertility journey look like?
- What have they been through and where has that journey taken them? Have they experienced multiple pregnancy losses, the loss of a child with disabilities, or no pregnancy to date?
- What is their current financial situation and what are their IVF coverage options? Is another egg retrieval doable – physically, emotionally, and financially?
- What is their comfort level with various risks – the risk of non-implantation, miscarriage, stillbirth, and the birth of a child with disabilities? Where they’ve been and what they’ve been through can have an enormous impact on where they go in the future and ought to be considered.
2. What is the level of mosaicism?
- Depending on the genetic testing laboratory used, the level of mosaicism, i.e., what percentage of cells in the biopsy were found to be abnormal, can be reported. Based on Genoma and CooperGenomics internal data, low-level mosaic embryos (those with 20-40% mosaic cells) implant more and miscarry less than high-level mosaic embryos (those with 40-80% mosaic cells).
3. Is the entire chromosome impacted or only a part of it?
- Grati et al. only discuss the prioritization of mosaic embryos found to have an entire extra or missing chromosome. However mosaic embryos can also have just a part of a given chromosome that is extra or missing in the abnormal cells. These ‘segmental mosaics’ have the same potential range of outcomes as other mosaics: they may result in no implantation, a miscarriage, a child with no health issues, or a child born with physical and/or intellectual disability. As each chromosome contains approximately 1,000 genes, it is often difficult to predict the exact outcome for a specific segmental chromosome result. However, the latest research suggests that segmental mosaics may be associated with better pregnancy outcomes than mosaics in which an entire chromosome is impacted.
Clearly, the short answer to what things should you consider when deciding whether or not to transfer a mosaic embryo is: a lot. Talking with a genetic counselor can help patients work through many of these issues so that they understand their results and options.
It is often said that ‘it takes a village to raise a child’. In today’s ever-changing world of IVF, it can justifiably be said that it takes a village to even have a child, a village made up of reproductive endocrinologists, embryologists, genetic counselors, nurses, and OBGYNs. We are coming up to the 40th anniversary of the first IVF baby, yet in many respects, we are still in this field’s infancy. It will be fascinating to see what new technology and genetic tests we will develop over the next 40 years.
To find out more about mosaicism
download our clinicians’ guide.
Grati FR, et al. An evidence-based scoring system for prioritizing mosaic aneuploid embryos following preimplantation genetic screening. Reproductive BioMedicine Online. 2018;36:442-449.
Murtinger M, et al. Scoring of mosaic embryos after preimplantation genetic testing: a rollercoaster ride between fear, hope and embryo wastage. Reproductive BioMedicine Online. 2018;37:120-121
Further Reading: Expert Article
Co-Founder of CooperGenomics, Santiago Munné PhD, has written an article Mosaicism: The Latest Research in the July edition of our scientific newsletter – ART Scientific.
ART Scientific is a quarterly publication that explores current topics of interest in our industry. It is written by a community of experts in the field and has a science focus at its heart.