Posted on December 9th, 2021by RMANY

Ep 82: Understanding Mosaicism with Teresa Cacchione

Fertility Forward Episode 82:

One of the hottest topics in IVF is mosaic embryos, but not many of us understand what this means, or how mosaic embryos happen. Joining us in conversation is genetic counselor at RMA New York, Teresa Cacchione. Teresa’s position at the junction of science and reproductive medicine gives her unique insight into the latest research and clinical outcomes of mosaic embryos in IVF, and she shares this expertise today. We discuss how mosaic embryos are formed, debunk common myths surrounding them (no, age is not a factor!), and dissect how the testing to identify a mosaic embryo works as well as its shortfalls. Using simple analogies, Teresa brings this hot topic within easy understanding of anyone with a high-school biology background, and shares some comforting statistics on the birth outcomes should you choose to transfer a mosaic embryo. The goal of a genetic counselor is to enable you to make an informed choice, and Teresa certainly provides answers to all sorts of questions in today’s fascinating episode.

Transcript of podcast episode

Rena: Hi, everyone are Rena and Dara and welcome to Fertility Forward. We are part of the wellness team at RMA of New York, a fertility clinic affiliated with Mount Sinai Hospital in New York City. Our Fertility Forward podcast brings together advice from medical professionals, mental health specialists, wellness experts, and patients, because knowledge is power and you are your own best advocate.
Rena:All right. I am so excited to welcome to Fertility Forward today Teresa Cacchione, RMA of New York's Genetics Counselor. We have had you on before and it was fantastic. And I am so excited to have you back to talk about something everyone always asks about, which is mosaics.
Teresa: Yes. Happy to be here. Thanks for having me Rena. It is a tricky topic and yes, this is a really hot topic right now. And there's been so many articles about it. So many patients asking you about it, lots of chatter. I'm happy to kind of shed some light on it.
Rena: Yeah. And I mean, even over the years, you know, since I've been in the field, the data and their research has changed so much. So I love that we're going to present this up-to-date information because people have so many questions and it really, I think is such a hot-button topic.
Teresa: Yeah. I mean, like you said, it's constantly evolving. You know, I have different data now than I did six months ago than I did a year before that. It really is sort of, we're watching science happen on this in real time. Quite literally. So yeah. It's constantly evolving.
Rena: Yeah. So let's get started. I guess maybe the best place to start would be talking just about chromosomes, right?
Teresa: Yeah, no, I, yeah. I think that that's a good place to start for sure. So definitely going to take listeners back to high school bio for a second and remind everybody that, you know, our chromosomes are the structures that hold all of our genetic information. So we have 46 of them total. So 46 chromosomes and they're split up into 23 pairs. So we get one chromosome in each pair from each parent in the egg and the sperm. So 23 chromosomes, one in each pair from the sperm cell. 23 chromosomes one in each pair from the egg cell. The egg and the sperm come together and it goes back up to the normal number that we're supposed to have - 46 chromosomes total. And each chromosome contains hundreds to thousands of genes and they're all mixed up. So every chromosome has got genes that are important in every body system. So it's really important for our overall ability to develop as healthy humans that we have that exact number - 46 total, two of each. The problem is that when our bodies create eggs and sperm, our bodies take the 46 that we have and cut the pairs in half. So again, sort of thinking back to high school bio, that's the process of meiosis for anyone who remembers that. So basically, you know, we go from having the 46 chromosomes in our body cells to 23, 1 from each pair in our egg and sperm cells. And humans in general are honestly pretty terrible at that process and we create egg and sperm cells that have the wrong number of chromosomes as having extra or missing chromosomes all the time. Honestly, we think the baseline for people is for all men and women in their twenties probably is about 20% chance of, of abnormality per egg or sperm cell. And then as we, as women get older and our eggs age with us since we've had all the eggs we're ever going to have from birth or before birth, really, as we get older, that number goes from 20% in our twenties to over 90% by the time we're in our mid forties. So chromosome abnormality is a pretty significant cause of basically just failure to get pregnant. Having extra or missing chromosomes is typically incompatible with life. So it's a big cause of difficulty, you know, conceiving as we get older sort of concurrently running with the decrease in number of eggs that we experience as we get older. And then additionally, it can also it’s the most common cause of early pregnancy loss. So a lot of chromosome abnormalities will result in a positive pregnancy test, but then the body realizes pretty quickly, okay, we don't have the correct number of chromosomes here, this isn't compatible with normal development and the pregnancy doesn't continue. So that's the vast majority of outcomes, is if an egg or a sperm is abnormal and it creates an embryo, we either see no implantation or early loss. But then there are a couple of chromosome abnormalities that can make it to a pregnancy that either makes it much further into pregnancy. So most chromosomally abnormal loss has happened in the first trimester, but some of them can make it further and there are a few that can even make it to live birth. So the most common ones that people have often heard of are down syndrome and Turner syndrome and there's a couple others as well. So what, when your physician recommends pre-implantation genetic testing for aneuploidy or PGT-A (aneuploidy is the fancy word for chromosome abnormalities), essentially what they're thinking about doing is before putting embryos back into the body, screening those embryos to make sure they have the correct number of chromosomes, so that anything that any embryos that we're using for a transfer actually have a legitimate chance of becoming ongoing, healthy pregnancies. So we're reducing the chance of failed implantation or a negative pregnancy test, reducing the chance of first trimester pregnancy loss, and really increasing, you know, sort of the likelihood that a transfer will result in everyone's end goal, which is a healthy, ongoing pregnancy. So that I think it's always good to do a, that was a long-winded way of sort of giving a little baseline here. That's when we're doing PGT-A, the main goal is to try to figure out is an embryo chromosomally normal? So it has 46 chromosomes or is it abnormal? It has extra or missing chromosomes.
Rena: So I think, that was fascinating. I always learn so much from you and I think, okay, so I come away with that sort of thinking, okay. So if I have, you know, an embryo that's missing chromosomes, that doesn't sound like, you know, it would end up being a healthy live birth, or if it was, you know, maybe the child has defects or a syndrome. Is there data though, that shows that embryos, mosaic embryos that are transferred, do result in healthy live births, children that go on to lead remote sort of developmentally, mentally and physically lives?
Teresa: Yeah, there is. And that's really because we're realizing now in the last couple of years that mosaics are kind of like a separate category from normal and abnormal. You know, I think the field, you know, up until a few years ago, we had a very black and white approach: the embryo is normal or it's abnormal. And we're realizing now that a certain percentage of these kind of fall into a gray area in the middle. And so what happened was about four or five years ago, the technology that we use for embryo screening updated, essentially it got much better at predicting normal versus abnormal, which was great, made the technology much more reliable for those diagnoses. But in the process, it started to be able to pick up this, this gray area, this mosaic result. So mosaic essentially means mixture, right? That's what that word means. So when we see a mosaic result, what we think we're seeing in most cases is actually a mixture of normal and abnormal. So an embryo that is somewhere in between those two poles, those two black and white results. And I think in order to understand that we should just do a quick sort of primer or reminder on how we test embryos in IVF. So people listening, especially those who have undergone IVF, you probably took an IVF class at some point where they showed you lots of pictures of embryos. You might remember that when we do PGT-A, when we test the embryos, we're testing them between days five and seven of embryo growth. So that's basically where the embryo has gone from one cell when the egg and the sperm come together to two cells, four cells, eight cells, 16, it's grown bigger and bigger and bigger over the course of five to seven days of growth until it gets to the point between days five and seven, where it's between 80 and 100 cells in size and become something that we call a blastocyst. So that blastocyst essentially means an embryo that's between days five and seven of growth. Now for comparison, at live birth humans have trillions of cells. So it's still a long way off from where it needs to be, but it's a pretty significant stage of a developing embryo because at that point, at that day five to seven point, it starts to split into two different areas. So there's the outside of the embryo. We call that the trophentoderm. That's the part of the embryo that goes on to become the placenta. And then there's the inside of the embryo, the part of the, we call it the inner cell mass or the ICM. That's what becomes the fetus assuming this is a viable embryo. The inner cell mass, that those fetal cells are completely inaccessible. So that's kind of like if you were thinking about an apple, those, the ICM is kind of like the core of the apple. So we can actually get to that when we're looking at the embryos or testing the embryos. But what we can do is we can take a little biopsy of about five cells from that outer part of the embryo, the part that becomes the placenta and because those two, the outer outside and the inside of the embryo started as the same egg and sperm, they theoretically should all be identical, right? So any result we get for the outside should match what's going on, on the fetal cells on the inside. Okay. So it's kind of an indirect measure of what's going on with the fetus's chromosomes. So we take that biopsy that biopsy from each embryo gets set off to the genetics lab for chromosome analysis, and then all the embryos get frozen and stay at the IVF clinic’s embryology lab until there are results. So we know from many years of followup studies that whatever, when we get a result that's either normal or abnormal for the outside of the embryo, we can pretty reliably trust that that is representative of what's going on on the inside of the embryo. So that there's a very high degree of what we call concordance between the two. So if we get abnormal for the outside, we can pretty reliably know that it's abnormal as well on the inside and vice versa. That's with a reliability of about 98 to 99% in the most recent studies, which was one of the reasons why that's the quoted accuracy level in many cases for PGT-A in general. That's one of the factors that goes into that. However, when we get a mosaic result for that outer layer of the embryos. So when we, that mosaic result, essentially when you look at the PGT results in the lab, you're looking at a graph where there's essentially numbers one, two and three for every chromosome that we're testing. all 23 pairs, and they're supposed to be two of each chromosome, right? So we should be seeing two sort of across the graph, the data plot that we have for every chromosome. When we get a mosaic result, it literally comes out in between one and two or in between two and three. So basically an intermediate, we call it an intermediate reading in between the two numbers. So if we were missing a whole chromosome, we would expect one reading. If we had an extra chromosome, we would expect three readings and we're getting results that are in between. So what we believe that's reflective of in most cases is basically in that biopsy sample that we took, there would have been a mixture of some cells that had the correct number of chromosomes and some cells that had the incorrect number of chromosomes. So you mix the DNA from, those cells together, run it through the machine that does the PGT-A analysis and you get an intermediate result. So a mixture of essentially we think it's reflective of a mixture of normal and abnormal cells. Okay. That theoretically, and then we think that's the case then for most embryos, theoretically, that that intermediate number could also just be some errors in the way that we copy the DNA before it gets analyzed. So when you have a really tiny amount of DNA from an embryo, you have to copy it many, many, many times, it's called amplification, before it gets analyzed. And if the chromosome numbers didn't copy equally, it also could result in sort of a similar finding, right? So it's essentially the embryo is actually fully normal or fully abnormal, but it's because of copy errors as part of the test, it results in sort of an intermediate number. So that sort of gives us our first area of unknowns when it comes to mosaicism, is, is this real right? Is it a lab error? Is it an error that's just inherent to this technology or does it truly represent a mixture of normal and abnormal cells? And I think there's probably some of both.
Rena: Can you retest or is that too risky?
Teresa: So we typically don't recommend retesting because A, as you mentioned, that can sometimes be risky for the embryo and B if we do get a different result, it doesn't necessarily mean that the first result we got wasn't accurate, if there's a mixture of normal and abnormal cells and you biopsy from a different area, you could just be getting all the normal cells that time or all the abnormal cells that time. And it doesn't invalidate what you got previously. So we don't typically rebiopsy mosaic embryos, at least not clinically, because we don't know that we would get a meaningful result from that. And rebiopsying embryos does come with some risks to the embryo in terms of chance of surviving thaw if you ever want to use it, et cetera, all that additional manipulation is not great if we can avoid it. So we got sort of this, like I said, this first area of uncertainty with, is it real or not? And sort of the second layer is we've also done a lot of follow-up studies where they have mosaic embryos or embryos that came back as mosaic from testing the outer layer, they've then opened up those embryos and looked at the inside of the embryo, the actual fetal cells. And these are all embryos that were donated and we're not planning to be used for pregnancy, but researchers have looked at the inside and they don't see that same level of concordance or matching that they see when we get a result that's fully normal or fully abnormal. So the biopsy of the outside of the embryo is sort of less predictive of what's really going on on the inside. So when we get that mosaic result for the outside of the embryo, the trophectoderm, we've had studies that show that the inside can either be fully normal, fully abnormal, or truly mosaic, meaning that there's a mixture of cells also on the inside. And as of right now, when we get a mosaic result, there's no way to sort of figure out what's truly going on on the inside of the embryo without opening up that embryo and destroying it. Right? So when we get this result, it kind of leaves us with a question mark as to a, is this real and B if it is real, okay, well, this is the result for the outside of the embryo. What's truly going on the inside inside.
Rena: Is there a stat you would place on a mosaic embryo for resulting in pregnancy?
Teresa: Depends on the type. So yeah, we'll get there in a second for sure. Yeah, they're there, it depends on the type of mosaicism. There's a couple of different types that we typically see. So sort of to circle back on your question from earlier, have we seen live births, healthy life births from the transfer of mosaic embryos? And the question is yes. So as of right now, the pregnancy rate, when we transfer mosaic embryos in general, is about 30 to 40%. Okay. For comparison, when you transfer normal embryos that came back as normal on the PGT analysis, it's more like 60 to 70%, at least at RMA. That number can vary clinic to clinic. So basically I think the first question that I get for most people is sort of how is that possible, right? Those healthy live births that have occurred, what scenarios could have led to that, then there's really three possibilities. So the first is that those are the cases where the inside of the embryo was normal. So the fetal cells were actually normal. The abnormal cells that we were seeing were really limited just to the placental layer and most of the time that doesn't really cause any issues with growth or development or functioning of the placenta. It's something called confined placental mosaicism. We see it in about one to 2% of pregnancies in general. So I think a lot of those cases were probably cases where we were just seeing an issue that was confined to that placental layer and it wasn't a good representation of the actual fetal cells. The second possibility is that it was a test error, right? And that embryo was actually truly normal. And the mosaic result we were seeing wasn't real. Third possibility is the most interesting one. And this is I think the one that's being most heavily researched, and that is a possibility that the embryo was truly mosaic. So there really was a true mixture of normal and abnormal cells on the inside and the outside of the embryo. But it self-corrected. So basically as the embryo continued growing, the normal cells stopped growing. The body realized, okay, we're not going to let these continue. These aren't compatible with healthy cells. And the normal cells kept growing and kind of took over, right? So the embryo becomes normal over time. And there is some evidence that something like that could occur that is really the most heavily area that's being of this whole process that's being most heavily researched right now is to see sort of, is that possible. So we know there are several different avenues that can lead to a healthy live birth as of right now. The problem is we just, when we look, when we get a mosaic result, we don't know which mosaic embryos can lead to that result that everyone wants and which ones can't. So it kind of is still proceeding with a pretty high degree of uncertainty as to outcome, right? In general, when we transfer mosaic embryos, like I said, we're seeing, you know. healthy live births about 30 to 40% of the time. So that is about half what we see for normal embryos. We're also seeing a much higher chance of pregnancy loss in the first trimester with mosaic embryos. So when we transfer a normal embryo, the chance of loss is about five to 10% with mosaic embryos. We're seeing about 20 and some studies as high as 30%. So right now that seems to be sort of the major downside to using these. It's just a much lower chance of the transfer cycle being successful, so much lower chance of even getting a positive pregnancy test and a much higher chance of if there is a positive pregnancy test, it results in a loss. So that seems to be the highest in general, they just seem to have lower reproductive potential. And that makes sense if a significant portion of them are truly abnormal on the inside of the embryo, right? What we haven't seen so far. And this sort of makes sense if, when you think about it overall, we haven't seen an increased rate of birth defects, intellectual disabilities, developmental delays, nothing like that associated with mosaicism and all of the chromosome analysis that's been done. So follow up prenatal testing to look at the actual fetal chromosomes or testing of chromosomes on the baby, after birth, in some cases, all of that, with the exception of one case in Italy, all of those tests have been normal so far. All of the ones that have been done that have been reported back to us in the literature. So it tells us that this seems to be a pretty black or white situation, right? The body seems to catch most of these, if they are real, if there are true abnormalities and we don't see ongoing pregnancies. But we know that it is possible in rare cases for mosaicism to result in problems at live birth. And that's just from natural pregnancies where people are born and have a pretty wide array of birth defects, intellectual disabilities, other health problems. And you look at their blood and their mosaic for normal and abnormal mixture of chromosomes. So we know it is very rare. You know, those are a handful of cases per chromosome. So we're talking one in tens of thousands, in many cases, it's rare, but it's possible sometimes that can escape the body's detection mechanisms. So we are still being really cautious about knowingly transferring these, right? Typically right now we're not transferring a mosaic embryo, at least at RMA. And I know a lot of other clinics are taking a similar approach that we're basically saving these embryos until we have no other option, right? So if someone has no chromosomally normal embryos left and they can't undergo another cycle to create more and that sort of can’t part, you know, honestly, as I'm sure you experience with patients, is really different person to person, right? Everyone has different physical, emotional, financial means for this process. So we don't really put a set most clinics, don't put like a set end point on it, but when a patient and a physician have determined that we're really at the end of the line with more retrievals and end of the line with euploid embryos or normal embryos, then we do at least at RMA do start and in many other clinics now at this point around the country, do start thinking about using the mosaics as your last resort, as long as the patient feels comfortable with a lot of the unknowns that we still have about this process. And related to the fact that we do know that it's, especially that it's theoretically possible in rare cases that this could results in an issue, even though that appears to be pretty unlikely.
Rena: I mean it’s certainly a very, you know, there's so much uncertainty and unknown already with fertility and exactly add this. I think it's very tough.
Teresa: And I think just sort of related to that one other piece that I think ends up being really tricky for patients is that the follow-up for this. So the followup to maybe get some reassurance that everything is okay with the pregnancy, that the fetal chromosomes are truly normal and everything, that follow-up, unfortunately doesn't really come until a later point in pregnancy than most people would like. So what we are recommending currently is that when someone transfers a mosaic embryo, that they undergo what we call invasive prenatal testing during the pregnancy to actually look at the fetal cells, right? And look at the fetal chromosomes and make sure they're there in the appropriate number. There's two ways to do that. There's a test at the very end of the first trimester called a CVS that's at around 11 weeks. And then another test called an amniocentesis in the second trimester of pregnancy around 16 weeks. The CVS, the earlier test, is still just looking at placental tissue. So you still get a possibility of not really, truly getting a good look at actual fetal cells. You're still only looking at placental kind of like the way the PGT is. So really the earliest point in a pregnancy where you can get a direct look at fetal cells is 16 weeks. So that amniocentesis that I mentioned. If you do the amnio at 16 weeks, you usually get an answer by 18 or 19 weeks in terms of what the chromosomes look like. A final answer. You can get preliminary results earlier than that, but the final answer, and that's, you know, that's pretty far along in a pregnancy to get an answer, that’s about halfway through. So I have to say that that has been a pretty significant deciding factor for a lot of my patients is whether or not this is something they feel comfortable proceeding with completely understandably that's a long time to have to wait. And, you know, we've gotten feedback from prenatal colleagues who might, so basically my colleagues who are seeing patients who have done mosaic transfers on the prenatal side after they leave the infertility setting, that it's been a very difficult wait for them, a very anxiety provoking wait for those patients. So I really encourage patients who are thinking about mosaic transfer to think about that. Especially if there's someone who's more prone to anxiety, think about that waiting period and have coping mechanisms, healthy coping mechanisms, set up with their therapist, with their family, you know, with whoever they go to for support to make sure they have a plan for getting through that time, because it has been really difficult for people.
Rena: Absolutely. And so is mosaicism age-related?
Teresa: No! Good question. So that's a common one that I get. It is not. So, as we talked about earlier, when an entire embryo is abnormal, that stems from a fully abnormal egg or sperm. And in the case of eggs, that is age-related. We see eggs become more frequently abnormal as women get older, the egg fertilizes, and then all of the cells that grow from that egg and sperm are abnormal. Mosaicism, actually results from errors that occur after the egg and the sperm come together. So basically those initial cell divisions we were talking about when it goes from being one cell to two cells and then four cells and then eight cells an error occurs during one of those divisions. And you end up with some cells that have divided normally and continue on with the normal number and some that haven't divided normally and have that abnormal number. So we call them mitotic or an error of cell mitosis, which is how our cells grow, not an error with creating eggs or sperm. So that's not age-related. We see it across all age brackets at about the same frequency. The exact number has varied a little bit clinic to clinic and study to study depending on the technology that was being used and the patient population. But I'd say on average, the average number we're coming out with is a risk of about 10% per embryo is what we're seeing with some variation.
Rena: Got it. And what about low versus high mosaicism?
Teresa: Yeah. So there are some, not every lab will report that. So I know you have lots of different listeners that use different IVF clinics. They might use different PGT labs and this isn't always information that's available, but a lot of the labs will report low mosaicism versus high mosaicism. So low basically means that in the biopsy sample that they have, they are seeing more normal chromosome material than abnormal. So essential that we think that reflects basically in that mixture of cells, let's say there were five cells in the embryo biopsy that were probably three or four that were normal and one or two that were abnormal. So that would be low mosaicism and then high would be the opposite. So more abnormal cells than normal. There's a couple of caveats with that information right now. So there's some studies that have shown that the low mosaics might be more likely to result in those healthy, ongoing pregnancies than the high mosaics, but that hasn't been consistent across all studies. We're not a hundred percent certain about that yet, but if I do have multiple embryos to choose from for a patient, and I don't see any other differences or concerns, otherwise I might choose a low versus a high just because there is some data to suggest they might do better. The sort of counter argument is that biopsy is only five cells out of the oval close to in most cases, a hundred cells in the embryo and it's unlikely that the abnormal cells are evenly distributed throughout the embryo. So theoretically you could have biopsied one or two cells to the left and may have gotten an entirely different result that could have been high instead of low or low instead of high. So there's still a lot of research to be done on that front, but there is some evidence to suggest the lowest doing a little bit better.
Rena: So I guess that kind of segues into another question, which is if a patient has multiple mosaics, how do they decide which one to transfer?
Teresa: Yeah, yeah. Another good question. So the most recent study that we have on mosaicism and mosaic outcomes came out a year ago now, and it was a study of the transfer of over a thousand mosaic embryos. And it was an aggregation of data from multiple clinics across the country. And there was a pretty clear findings from that paper that we can stratify the chance of an embryo and mosaic embryo becoming an ongoing pregnancy by different types of mosaicism. So not necessarily low versus high, that does play in a little bit. And we can use that as a factor, but actually looking at the type of chromosome abnormality that's present. So whether or not it's just a segment of a chromosome that's extra or missing instead of the whole chromosome. So they call those segmental aneuploidies versus whole chromosome. So when there's a whole chromosome extra or missing versus multiple abnormalities, so it could be two whole chromosomes or a segmental and a whole, or two segmentals and a whole, there's lots of different combinations. So the segmental versus whole chromosome versus complex, when there's multiple abnormalities and of those we're seeing the segmentals do significantly better than the whole chromosomes and those do significantly better than the complex. So we have kind of a ranking of most likely to least likely to become ongoing pregnancies. And that range is really about 50% to 10% really from segmental to complex. And we can sort of stratify it out within that based on low versus high. So that's essentially what we'll do now, if we have multiple mosaics is look at, okay, the types of mosaicism, we also want to look at the chromosomes that are present, the abnormalities that are present, and we tend to shy away from using understandably using embryos that are mosaic for abnormalities that we know can result in ongoing live birth with chromosome syndrome. So for example, there are a couple of where even if the inside of the embryo was fully abnormal, that could result in an ongoing abnormal pregnancy. So for example, the chromosomes associated with downs syndrome or Turner syndrome, so chromosomes 21 and the X chromosome, we shy away from using those in the mosaic state. Because if that is real, we know it very much can result in an ongoing abnormal pregnancy. So I might want to take those off the table if someone has multiple embryos. And one of those has that abnormality. We also can take into account the morphology of the embryos overall. So not necessarily what's going on genetically, but when the embryology team just looks at the embryo, how healthy it looks to the eye. So which doesn't tell us anything about the genetics, if it did, we wouldn't have to do this whole PGT process, it'd be so much easier, but instead it really just tells us about the strength of that embryo overall. So even if it isn't normal, how likely is it to make it through in terms of its strength, that whole process of implanting in the uterus and becoming an ongoing pregnancy. So if we have embryos that are kind of similar in terms of their types of mosaicism, I might then factor in the morphology in which one looks stronger in that sense as well. So there's multiple different ways we can kind of whittle it down to try to pinpoint one, to prioritize over the other if we're gonna do a transfer.
Rena: And what about keeping mosaics frozen? Would you recommend doing that or no?
Teresa: Yeah. So this is another common question I get. So, you know, we often have scenarios where patients do PGT and they do have euploid embryos for transfer or normal. Euploid is the fancy word for normal. So they do have normal embryos to transfer it, but they also have a bunch of mosaics. So I often get people having, having consults with me, wondering, you know, okay, I have my normal embryos. It's great. I'm excited to use those, but what do I do with all of these mosaics? And, you know, I think at this point we're learning so much, we're still learning a lot about these, the, our approach and our policies and procedures are constantly changing as we get more data. I think that, you know, especially if you have most IVF clinics will start, charge one storage fee, regardless of how many embryos you have frozen. So I think that especially if you have other normal embryos frozen, it certainly makes sense to leave the mosaics for now. If you think there's a possibility that might be something you ever feel comfortable with. You know, as we learn more, you know, this seems to continue to be getting more and more reassuring, and we're just at this point sort of trying to whittle down, okay, how do we figure out which embryos are more likely to result in a pregnancy than others, as opposed to, does this appear to be overall safe because so far does. So I think it's worth it. If you're done family building, or if you don't feel like this is something you would ever feel comfortable with at all, then of course that's a whole different story, but I typically tell patients if you're going to be paying to keep other embryos frozen, anyway, it certainly can't hurt as a backup plan just in case, you know, you ever need these as we find out more and more info. Definitely.
Rena: So, you know, say you're a patient and you have a mosaic to transfer. What are any sort of, kind of reassuring words or kind of final advice you would give them? You know, obviously this is complex and it's not straightforward. You know, I think a lot of things in fertility are complex and not straight forward. I think this is specifically a difficult one. So what would you kind of advise, you know, as a genetics counselor?
Teresa: I mean, first I would definitely meet with a genetics counselor, right? If you're at RMA, I'm here. If you're not, you know, they're most IVF clinics. If they don't have someone in house have a group they work with that they can refer you to, because I think this has to be very personalized. You know, it really depends on, okay, what abnormalities are they seeing in your mosaic embryos and high versus low? What are the gradings? You know, there's so many different factors to take into account. And I think also, you know, a genetic counselor can help you talk through your personal feelings about this. You know, as I said, for example, I've had patients, who've had a lot of experience with pregnancy loss that maybe don't want to be using an embryo that puts them at a greater risk of loss. Even if there is a chance for it to become an ongoing pregnancy or patients who know deep down, they would never feel comfortable with having to wait till 16 makes for an amnio. I think there's so many aspects of this decision that are very personalized and that's why there really is no set guideline on lot of this right now, right? Like the guideline is we'll consider transferring them when we have no other option. But beyond that, we want to make sure you get all the facts that you hear, what we know and what we don't know and decide for yourself, whether or not this is something you feel comfortable with. And I think that's so individualized that I want to make sure people are having that in depth conversation. So a lot of physicians can facilitate that, but I feel like also genetic counselors are pretty great at digging down and getting to those points that are unique to each person. So I would definitely recommend seeing a genetic counselor, but the data at this point does seem pretty hopeful that this could be a good secondary option for some people, if they feel comfortable when they don't have any normal embryos. And honestly, three years ago, I wouldn't have said that. This is a constantly evolving topic. One caveat I would, that I did not mention earlier that I would like to make sure is put out there is that, you know, we've only known this is very reassuring overall in that IVF has been around for over 20 years. And in general, we probably been transferring mosaics for years without knowing it, right, the technology we didn't use to do embryo screening at all. And the technology couldn't pick this up until a couple of years ago, it's definitely always biologically existed. It's not suddenly a new thing that human embryos do, but it's definitely always been there. And we don't see an increased risk of children born from IVF, being born with mosaic chromosome abnormalities, you know, historically over 20 years. So that's pretty reassuring, but we like to work with data that we actually have done with knowing embryo transfers, knowingly transferring mosaic embryos. And I think a big caveat right now that I like, I also like to make sure patients are aware of is that we've only known about this for five years. The outcome data we have on live births is really limited to kids that are under ages three and four, right? And most of the babies that have been bored honestly have been in the last two or three years. So really underage two.
Rena: Is there a number on that?
Teresa: You know, not, there isn't like a central database to report this, that they're working on that and we hopefully will have that soon. But what we do have are various studies from groups that have banded together, the largest study, which was of about a thousand mosaic embryos, as I mentioned earlier, resulted in between 300 and 400 live births, depending on how you count it. There's some overlap between studies as some different groups, sometimes they'll report different studies. So it's, you know, it can be tricky. It's definitely more than several hundred at this point, healthy live births. There's probably been somewhere between one and 2000 transfers in the U S with several hundred healthy life births. The caveat is that a that's as we know of, right, as currently as sort of relying on clinics reporting, if there is an adverse outcome and B all of those kids are under age three, most of them are under age two. So that means that while we haven't seen issues with, you know, major birth defects, that would have been immediately noticeable, you know, major milestone issues in terms of walking, talking, things like that, all of that appears to be going so fine so far, but we're not going to have data on cognitive development, mental health, really autism since that's hard to diagnose before age two, really reliably ages three or four, we don't have long-term outcome data yet on the children born after mosaic embryo transfers. And while the 20 years of IVF data is reassuring, it's not specific to those, you know, mosaic embryo transfers. So I think that that is a piece that I also like to make sure patients feel comfortable with because we just don't have that firm data yet everything is reassuring, but it's, and it's going to be some time before we do. So, you know, I think that that is another, if you're considering the transfer of a mosaic embryo, another factor to take into account as well.
Rena: This has all been amazing. I learned so much from you. I think it's so great to bring because everything changes so quickly.
Teresa: It does, this will probably be different a year from now who knows.
Rena: You know, and I think another really important takeaway that you definitely touched on, you know, for patients is advocacy, ask questions, don't be shy.. You know, schedule an appointment with a genetics counselor or talk to your physician. There is no stupid question it's so important to ask because obviously this is a very big decision. And so it's very, very important to ask questions, get them answered and feel like you are making an informed choice before moving forward.
Teresa: Absolutely. That's. I mean, my genetic counselors in general, our whole goal is informed choice for our patients and patients having the information they need to make whatever choices right for them. And they're really believing that there is no right or wrong answer to a lot of these decisions. So I am, I'm all about that, about giving people the info they need. And it allows me to geek out about genetics in the process. So that's always fun.
Rena: Well, this has been wonderful. Are there any other final thoughts or anything else you think is important to know for anyone listening?
Teresa: I think really just stay tuned for updates, right? This is going to be constantly evolving. That's the nature of science, right? As we're all experiencing in this COVID era, things are, we're constantly getting new info as we get more studies as things change. So stay tuned, I guess, is the final note there.
Rena: Well, thank you so much. If you remember from last time, I like to wrap up each episode with a gratitude. So anything you are grateful for?
Teresa: Oh man. So many, especially going on Thanksgiving. So many things I would say, I mean, honestly, after this year, I'm grateful for science, right? I feel like I am so grateful that we live in the world that we do. And that, you know, things are starting to hopefully get a little bit back to normal and that's all because of the amazing science and everything that's happened in the last two years and how quickly we've figured things out and how quickly we're now looking at vaccines and retroviral treatments and all that kind of stuff. So especially talking about a topic like mosaicism that is really us watching the scientific process in real time makes me very thankful this year, in particular for science.
Rena: I love that. I am going to say that I am just grateful for you. My patients love you. And I think that I love talking to you and having you on because you just so clearly, first of all, I'm so impressed by you. I'm always so blown away. I think it's incredible. And I love to see a woman in science and I just think it's so amazing to have someone who really, I know you so genuinely care about patients in this work. So I think that we are all so lucky to work with you. So yeah. Thank you so much for coming on. We will, of course, have you back to share updates and genetics related stuff. If anyone listening has specific topics about genetics that they want us to cover, you know, definitely reach out, send us a DM or an email and we will definitely cover it. Teresa is such a wealth of knowledge and there's so, so much we could talk about regarding genetics.
Teresa: Always. That's a big topic.
Dara: Thank you so much for listening today and always remember: practice gratitude, give a little love to someone else and yourself and remember - you are not alone. Find us on Instagram at fertility_forward and if you're looking for more support, visit us at www.rmany.com and tune in next week for more Fertility Forward.

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