
Transcript
Join the SART Fertility Experts as they discuss Preimplantation Genetic Testing for Aneuploidy (PGT-A) for chromosome abnormalities, mosaicism, and IVF considerations, addressing patient age, testing accuracy, outcomes, and future use. Hosted by Dr. Timothy Hickman with special guest and Genetic Counselor, Amber Kaplun.
This is Timothy Hickman, past president of SART, the Society for Assisted Repair of Technology. Thrilled to have you here today on SART Fertility Experts Podcast. Today we're very fortunate to have Amber Kaplun with us.
Amber is the lead genetic counselor for IVI RMA North America. And today our topic is PGT-A, or pre-implantation genetic testing for aneuploidy. So let's start out.
Amber, if you can kind of tell us what is PGT-A? PGT-A is a screening test, first and foremost, and it's looking for chromosome abnormalities within a biopsy that comes from the trophectoderm, or the part of the embryo that will create the placenta. Primarily, we're looking for chromosome abnormalities that can affect an embryo's chance to develop into a later pregnancy. But a secondary piece of the testing is we can get information on conditions such as Down syndrome that we do find in living humans as well.
How would one's age, the age of the female, matter as far as the results you might find in this test? Most cases of whole chromosome abnormalities do originate from the egg, and that is mostly a process of aging. Women are born with all of the eggs that they will ever have, and as they get older, every month as those eggs start to develop, there is a little bit higher chance that there could be a chromosome separation error as the eggs develop. So because there is an extra or missing whole chromosome in those eggs, that is then found later on in the embryo that is generated from the egg.
And what would you say is the accuracy of this type of test? It is quoted as greater than 97% by a lot of the labs in the commercial space. When you think about PGT test validation, there's really two ways that you can think about it, analytical validation and clinical validation. Analytical validation really means that you're testing a result on a biopsy to a whole embryo that is donated for research.
Clinical validation really being transfer of embryos with all different types of PGT-A results and looking to see what the outcome is in a later pregnancy or a child that's born from that embryo. So a lot of the labs have devoted a lot of effort to analytical validation, but I think clinical validation is still an area that we have a lot of growth opportunity for. Excellent.
Well, let's go back a little bit and talk about the process of IVF, each step, and then where this PGT-A would fit in this process. So I think really the first step is where physicians such as yourself come in and really the patient taking the medications, the eggs developing, the egg retrieval, those eggs are then combined with sperm in the lab, the embryo is created. And the first five to seven days, the embryologists are just working to nurture that embryo and help it grow.
And then once it reaches a certain phase, they do a biopsy that's usually between day five and day seven. And that biopsy is sent to a lab for testing and the embryo itself is frozen. Would it be fair to say that there's a significant drop-off from eggs to fertilized eggs to eggs that make it to the blastocyst stage and then to those that are chromosomally normal? Yes.
And I think that is one of the least understood aspects of IVF in the general population. Attrition is something that is very normal through this process. I guess just like in natural reproduction, at our peak fertility, we're just not that efficient.
Yes. Does a woman in her 20s ever have a chromosomal abnormality or is it simply reserved for those that are in their late 30s and 40s? It can happen in younger populations as well. The chance of it happening is a lot less, but we do expect to see that there are embryos with whole chromosome abnormalities no matter what the age of our patient is.
It's really the proportion of embryos that we're expecting to come back with an abnormality that can change. Let's talk a little bit about who would be a good candidate for doing PGT-A. Who would be an ideal candidate? Who would be somebody where maybe it's not recommended or not strongly recommended? What would you say in that regard? Your ideal candidate is really going to be a patient that is 35 and older because if we're talking about whole chromosome abnormalities, that's really the population where we know that that can come up more frequently.
Some patients may choose to undergo the testing if they've had recurrent pregnancy losses. I think that when you look at the data on that, it is most compelling for that indication if we have seen that there are whole chromosome abnormalities in those previous pregnancies. For patients for whom it's maybe a little less strongly recommended are going to be younger patients where just the risk that you're starting off with to find a whole chromosome abnormality is going to be lower than some of the other populations.
Are there any other side benefits that you might see? It was very common years ago to have twins and triplets. What would you say about number of embryos you should transfer and how that relates to PGT-A? The greatest benefit of PGT-A I feel like that has happened is that it has really driven the uptake of single embryo transfer. Before the days of routine PGT-A, multiple embryos may be transferred and that can be risky because if we're talking about a multiple pregnancy, there's higher chances for complications.
Being able to get some information on the chromosome status of the embryo before it is implanted in order to try and increase chance for a successful pregnancy with that transfer has really driven the rise of single embryo transfer. Let's talk a little bit about some of the results we get occasionally with PGT-A. One is something called mosaicism.
What is mosaicism? Mosaicism is a result where when the scientist at the lab is looking at the data, it suggests that some cells of the embryo's biopsy are normal and some cells of that biopsy have a chromosome abnormality. Two cell lines. Yes, exactly.
It's tricky because when you look at the discourse around mosaicism, there's a lot of terms like low level, high level, a percentage of mosaicism. It's not always necessarily that easy to take that information and apply it directly back to the biopsy. For example, two out of five cells are abnormal.
It's also not always that easy to say that what we're seeing in the biopsy is going to be reflective of the entire embryo. We already know that there are two cell lines within the biopsy and what that proportion of normal to abnormal may be is not always clear when we're talking about the entire embryo. So the placental cells may not represent the actual fetus itself.
Correct. So that's kind of a tricky subject then. Yes.
So if somebody has a mosaic embryo, let's say that's the only embryo they have, I guess they would transfer ideally their euploid embryos first before they go on to considering transferring a mosaic embryo. As a counselor, genetic counselor, what would you counsel them about? When we look at the data on mosaic embryo transfer, we've accumulated a lot over the last decade. And I think the one consistent thing that's coming out in that data is that the chance for a baby to be born with some evidence of that same chromosome abnormality is low.
And I think that also goes for when you're talking about prenatal testing. There's generally two camps when it comes to other types of data like pregnancy rates, miscarriage rates. There are a number of studies that do show things like lower chances for pregnancy, higher chances for miscarriage.
And then there are some newer studies that are coming out where patients and providers are almost blinded to the mosaic results at the time that the embryo is transferred. So you're really making a decision just based on the grade of the embryo, which one to transfer. And those studies are suggesting that there may not be that much of a difference in pregnancy rates and miscarriage rates.
But there's really only been a couple studies in that design so far. So there's still a lot more research that is needed through that study design before we can say with confidence. And every PGT lab is a little bit different.
Their protocols are going to be different. So it's not always easy to take data from one lab and apply it directly to another lab. So how would you explain that, though, if you have two cell lines and the baby comes out completely normal? What actually is happening then if the biopsy result is correct? Let's just make that assumption.
What's happening? The way I always phrase it to patients is we have to go from one cell a day zero to hundreds of cells by the time that the embryo is biopsied. And so the growth of those cells has to happen very quickly. So it's almost like the quality control and the chromosome separation is a little bit more relaxed for that to happen.
But we do have good evidence at this point that there is some sort of mechanism where these abnormal cells either completely disappear with further development or that they grow much slower than the normal cells within the embryo and they are pushed to the outside of the embryo. So one of the biggest challenges with this topic is there's a very big swath of time between when we transfer an embryo and prenatal testing is done where we can't necessarily access what's happening from a research perspective. But we do have some studies of the early embryo that are suggesting these mechanisms exist.
So I've heard some people say self-correction. Is that kind of what's going on? In other words, the good cell line is growing well, the poor cell line, abnormal cell line is not proliferating as much, and therefore, in the end, you end up with almost always, if not complete, chromosome normality? Yeah, I think that's the easiest way to think about it. Does percentage of an abnormal cell line matter? Let's say this is a low mosaic versus a high mosaic.
Can you talk about that a little bit? It can. I think really depending on the lab that you're using. Some labs have consistent data that suggests that if you have an embryo with a high-level mosaic biopsy that the pregnancy rate may be lower than a low-level mosaic or a euploid.
Some other labs have studies suggesting that low-level, high-level, it may not make that much of a difference. So I think generally for most labs, yes, low-level, high-level, the data is telling us there is a difference. In our program, when we have a mosaic embryo, which is rare, it's only about 2% of the time, but when we have one, if we're going to transfer that embryo, usually we would preferentially use a euploid embryo.
And if we don't have any of those left, that's where we go to the mosaics. And before that, we would have them talk with a genetic counselor to go over the risk, because I heard there have been some reported abnormalities with some of these children. That is correct.
And I think more often we're seeing that in losses as well. So I think it is very important for a patient to have a good understanding about what is being seen in the biopsy and the possible outcomes so that they can make the most informed decision with their physician about if they want to move forward with transfer or not. Perfect.
Let's talk a little bit about reference labs. We've seen that some reference labs that do the actual testing for PGT-A come back with a mosaicism rate of sometimes as high as 30 to 40%. Others are as low as 2%.
Can you kind of comment on that? Yeah, every PGT-A lab is a little bit different. It's going to be a little bit different in the technology that they use, the way they handle the samples. So I think it's very important for patients to have a very upfront discussion with their physician and ask about their lab.
I think that also kind of comes back to my point about clinical validation, right? I think if we had more study on this type of topic, we'd be able to better understand what's driving these differences, because beyond just being able to say that there are differences in lab platforms and analytics and data handling and stuff like that, we don't really have much more than that. Well, we've talked a lot about PGT-A, and we know that a very high percentage of cycles now in the United States are using this. Give us some thoughts about what you see as what's the future going to look like for us with PGT-A.
I think it probably is going to be used more and more as time goes on, for better or for worse. For many people, they see it as an opportunity to get some information about risk in a pregnancy and kind of be able to target embryo transfer. That being said, it's still not going to be right for all patients, and that's why it does have to be an individualized discussion.
I'm also seeing patients that start off doing PGT-A, but they may decide not to do it in a subsequent cycle for whatever reason. So I think even though I am expecting for the percentage to go up, I think it's never going to reach 100% for sure. So I know we're focused on PGT-A for aneuploidy here, but there are other types of tests that can be done with this trophactoderm tissue.
Can you kind of go over maybe SR and M and other types of PGT? Yeah. So PGT-M and PGT-SR have been the other historic layers under the PGT umbrella. So PGT-M is used where we know that a patient or their reproductive partner has a genetic condition where we've identified the causative DNA variant.
We know there is a chance for it to be passed on to the embryo, and that testing is trying to identify if an embryo inherits that DNA variant or not. PGT-SR is used in cases where X source or sperm source has a chromosome abnormality, like a translocation, and a translocation is where pieces of two chromosomes break off and switch places. So for that individual, there is a higher chance than the general population for there to be extra or missing chromosome material in their embryos, and so PGT-SR allows us to understand if there are unbalanced forms of that chromosome abnormality and reduce the risk for an unbalanced form in a child.
Well, this has been excellent. Are there any other things you'd like to add for our listening audience about PGT-A? I mean, I think I would just say that patients are increasingly becoming more savvy about PGT-A and learning a lot about it, and, you know, there are lots of communities online, and in some respects, that's very good, right, because patients are kind of connecting and information, but I think at the end of the day, it is very important to check understanding with your provider so that we can make sure that patients are working with the correct information. Excellent.
Well, thank you so much. Well, we certainly appreciate Amber Kaplun, lead geneticist at IVI RMA North America, and we appreciate your time and hope you've all learned something. Thank you for having me.
My pleasure. The information and opinions expressed in this podcast do not necessarily reflect those of ASRM and its affiliates. These are provided as a source of general information and are not a substitute for consultation with a physician.
For more information about the Society for Assisted Reproductive Technology, visit our website at https://www.sart.org
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