Preimplantation genetic screening (PGS) is a genetic test designed to improve in vitro fertilization (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 PGS technology have uncovered a third class of PGS results that lie somewhere in between. This new class, deemed mosaic embryos, contain a mix of normal and abnormal cells. Euploid embryos are obviously your best shot at success, yet our data suggest that mosaics account for 10 – 20% of all PGS-tested embryos. That being the case, I find that the most common question asked by patients when reviewing their PGS 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, CoGEN updated a position statement on the matter following their annual meeting in Barcelona in 2017.
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 Grati et al study considered four parameters to determine a “scoring system” for embryos based on chromosome change, including (1) the likelihood that a mosaic aneuploidy detected in CVS samples will impact the fetus, (2) 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), (3) miscarriage, and (4) 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 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|
|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 PGS.” 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. So, what other things should you take into account?
1. What does your personal fertility journey look like?
- What have you been through and where has your journey brought you? Have you experienced multiple pregnancy losses, the loss of a child with disabilities, or no pregnancy to date?
- What is your current financial situation and what are your IVF coverage options? Is another egg retrieval doable – physically, emotionally, and financially?
- What is your comfort level with various risks – the risk of non-implantation, miscarriage, stillbirth, and the birth of a child with disabilities? Where you’ve been and what you’ve been through can have an enormous impact on where you 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 & 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 you work through many of these issues so that you understand your results and your options.
It’s 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 in the next 40 years.