During this webinar, Fertility Genetic Counsellor, Claire Bascuñana introduced the world of Preimplantation Genetic Testing for Aneuploidy (PGT-A). Claire explained how the PGT-A tool can be integrated into your IVF journey and its benefits, limitations, and potential impact on your fertility treatment.
To begin, for those who are not aware of what PGT-A is, it’s an add-on for an IVF cycle. PGT-A means pre-implantation genetic testing for aneuploidy. Aneuploidy means there is an abnormal number of chromosomes. We are supposed to have 2 copies of each chromosome, and when there is an extra copy or a missing copy of a chromosome, it can impact development, pregnancy, and health. Having an abnormal number of chromosomes is an important determinant of fertility success. That’s why PGT-A is used to screen for aneuploidy.
Why is PGT-A used? The initial objective is to increase the implantation rate per embryo transfer during an IVF cycle. It means we want to increase the likelihood of an ongoing pregnancy after transferring an embryo. The second goal is to decrease the likelihood of losing the pregnancy due to a miscarriage. We want to reduce the risk that the pregnancy won’t reach full term. It’s also aimed at decreasing the time it takes to achieve an ongoing pregnancy, especially when a large number of aneuploid embryos are produced during the IVF cycle. The more aneuploid embryos you have, the more possibilities you have for transfer. However, if you do not transfer the embryos with the best likelihood of resulting in an ongoing pregnancy first, it may take more time to become pregnant. PGT-A aims to reduce this timing by directly selecting the embryos with the best likelihood of achieving an ongoing pregnancy.
All of these objectives are meant to increase the efficiency of IVF when compared to the standard method, which is just looking at the morphology of the embryo for selection. We now know that a good-looking embryo with good morphology is not enough to guarantee its viability. Sometimes, a very good-looking embryo with a high grade can have chromosomal issues that are not compatible with life. That’s the main reason why PGT-A was implemented in fertility clinics during IVF cycles. It’s important to understand the link between aneuploidy or chromosomal issues and maternal age. With an increase in maternal age, there is a higher proportion of abnormal embryos produced.
As a woman’s age increases, the proportion of embryos with abnormal chromosomes also increases. At 36 years old, it’s about half of the embryos produced are aneuploid, and half with chromosomal issues. Maternal age has a significant impact. Aneuploidy is one of the main causes of implantation failure and miscarriages. Understanding this, you can see why PGT-A could be useful in improving outcomes. There is a specific population of patients that can benefit from PGT-A.
Not all patients could benefit from PGT-A; it’s not a one-size-fits-all solution. The first population of patients that could benefit from it is patients with advanced maternal age. As we saw in the graph earlier, patients with advanced maternal age have a higher risk of producing abnormal embryos, which can lead to lower chances of an ongoing pregnancy due to chromosomal issues. For these women, PGT-A would allow the direct selection of embryos that are not affected by chromosomal issues, increasing the likelihood of an ongoing pregnancy.
The other two patient populations that could benefit significantly from PGT-A are patients with recurrent miscarriages or implantation failure. It’s essential to keep in mind that PGT-A won’t help if the miscarriages or implantation failures are not due to chromosomal issues. Sometimes there are other health factors involved, and PGT-A may not be the solution. It’s not a perfect test, and sometimes even with PGT-A, you can still have implantation failure or miscarriages, indicating that the cause might be something other than chromosomal issues.
For women with advanced maternal age, PGT-A seems to eliminate the effect of maternal age on implantation, but it doesn’t significantly influence the outcomes for young patients with good prognoses. If you do not fall into these categories of patients, you may not benefit from PGT-A, and it could sometimes even be harmful.
For fertilization, not all collected eggs will be fertilized. It’s estimated that only 60-70% of eggs will successfully fertilize. So, at each step of the process, there’s some loss of biological material. After fertilization, the embryos are left to develop for several days before the biopsy. The biopsy occurs at the blastocyst stage, which is typically on day five. The blastocyst has an internal cavity, a mass of cells for the future fetus, and a layer of cells for the future placenta. At this stage, about 50% of blastocysts naturally survive, representing a natural selection process. The biopsy of the embryo at day five requires expertise. Studies show that when done by a skilled lab, there is a similar pregnancy rate with or without biopsy. The biopsy itself does not seem to harm the future development of the embryo.
During the biopsy, only 5 to 8 cells are removed, which is a small fraction of the approximately 100 cells an embryo has at this stage. The cells biopsied are not from the inner cell mass, which becomes the future fetus. They come from the trophectoderm, which is the future placenta. This is an important point because it explains why PGT-A cannot be a perfect technique. The cells analyzed for the biopsy are not the ones that will form the future fetus. Most of the time, the cells from the future fetus and the future placenta are the same in terms of chromosomal and genetic content, but sometimes they differ. When there’s a discrepancy between the PGT-A result and the future fetus’s status, we encounter the concept of mosaicism.
After the biopsy, the cells are sent to the PGT-A lab, and the embryos are frozen at the fertility clinic, awaiting the results. The goal is to freeze all embryos, send the biopsy to the lab, and then select the healthiest embryo from this cycle for transfer.
The genetic analysis (PGT-A) is usually performed by a technique called Next Generation sequencing. The objective of the test is simply to determine how many copies of each chromosome the biopsy cells have. We want to see if each chromosome is present in two copies, as we are supposed to have one copy from the biological mother and one from the biological father. When we have more or fewer copies, we call that trisomy or monosomy, and this can impact the development of the embryo and the future pregnancy’s health, if there is a pregnancy.
PGT-A technique can assess a variety of factors, not just major chromosomal abnormalities, but also some smaller segmental anomalies. Segmental anomalies occur when there is only one piece of a chromosome that is missing or duplicated. However, PGT-A cannot detect microduplications or microdeletions, which are small pieces of chromosomes. It can only detect whole chromosomes or large segments.
It’s essential to note that PGT-A is not 100% accurate because it relies on analysing future placental cells, and it doesn’t provide information about future fetal cells. Therefore, even if PGT-A suggests that your embryo doesn’t have any chromosomal issues, prenatal recommendations are still necessary because it’s not a diagnostic test. It’s more like a screening of the embryo.
PGT-A results are not just a simple “yes” or “no” answer. They have various implications. The results determine whether you can transfer the embryo, the priority order for transferring embryos, and the likelihood of success based on the specific result. It’s recommended to discuss your PGT-A results with a genetic counsellor or your doctor to understand the impact of each type of result.
Additionally, it’s important to know that different labs performing PGT-A may have different thresholds for determining whether an embryo is euploid, aneuploid, or mosaic. Therefore, the lab itself can influence the type of result you receive.
Mosaicism, where there is a mix of normal and abnormal cells in the embryo, was not always reported by many labs. However, it’s now advocated that some mosaic embryos can be transferred with proper genetic counseling and prenatal care.
In terms of the outcomes of transferring mosaic embryos, they have a lower implantation rate and a higher rate of miscarriages compared to euploid embryos. However, low-level mosaic embryos can have a similar ongoing pregnancy rate as euploid embryos, depending on the percentage of mosaic cells. The risk of having an affected pregnancy after transferring a mosaic embryo is around 1%, based on recent studies. It’s encouraging that studies have shown no significant differences in pregnancy complications, delivery types, birth age, Apgar scores, congenital anomalies, and chronic illnesses between mosaic embryo transfers and euploid embryos up to 3 years old.
It’s important to know that abnormal PGT-A could mean a lot of different things. Sometimes, you don’t have any results; sometimes, you have a chaotic result with six different types of anomalies. Sometimes, you have a mosaic that is identified, and sometimes you just have what we call a segmental aneuploidy, meaning you have one part of the chromosome missing.
Sometimes, it’s the whole chromosome missing. All these specific situations, I don’t have the time to detail now, but they should be addressed by a genetic counselor if you have hesitations about whether you can transfer those embryos. Of course, it depends on the policy of the clinic you’re working with, but asking these questions can be very helpful for you to feel empowered throughout your fertility journey and to understand what those results mean.
Another thing to think about is that some clinics are very hesitant to transfer, for example, a mosaic embryo. But before PGT-A, if you don’t do PGT-A, you might transfer thousands of embryos blindly that are probably mosaic or aneuploid without knowing it. So, it’s something we need to consider when we restrict patients from using certain embryos.
The next step after receiving the results and deciding which embryos should be transferred is the actual embryo transfer. 99% of embryos survive the thawing process, and then we expect an implantation rate, which depends on the embryo’s status. Depending on the embryo status, we’ll have specific prenatal recommendations. Globally, when you transfer a euploid embryo, or any embryo with a biopsy through PGT-A, it’s recommended to have all the usual ultrasounds, including a first-trimester ultrasound with nuchal translucency measurement and a morphological ultrasound.
Regarding specific prenatal screening, it’s important to know that PGT-A has a similar detection rate as NIPT (non-invasive prenatal testing). So, because of that, serum marker screening is not recommended, as it has a lower detection rate compared to PGT-A. However, if a patient still wants additional screening, they can go privately for non-invasive prenatal testing.
For mosaic embryos that are transferred, ultrasound is still indicated, and it’s possible to go through various types of screening. However, most non-invasive prenatal screenings only look at the main chromosomes 21, 18, and 13, which are possibly viable during pregnancy. Sometimes, the type of mosaic you transfer may affect other chromosomes not included in the screening. Because of this, for all pregnancies resulting from a mosaic embryo transfer, there is a possibility to go through amniocentesis, like invasive prenatal diagnosis, to target the specific chromosome of the mosaic and make sure the fetus is not affected. There’s a 1% risk of having an abnormal prenatal diagnosis following a mosaic embryo transfer.
I would like to emphasize that many patients opt not to go through invasive testing even with the 1% risk, and it’s a personal choice.
PGT-A does not improve the cumulative success of your cycle; it only impacts the success per transfer. It cannot guarantee anything and does not screen for all genetic conditions or congenital defects.
Pregnancy resulting from embryos with a mosaic transfer might be a personal decision, and genetic counseling is essential to make informed choices. PGT-A is a useful tool in specific situations, but it’s important to understand its limits and implications. It’s not a one-size-fits-all approach, and the decision to pursue PGT-A should be based on individual circumstances.
In summary, consider PGT-A if it aligns with your specific situation, but keep in mind that research and knowledge in this field may continue to evolve in the coming years.- Questions and Answers