“Confined Placental Mosaicism: More common than you might think” – with Tamar Goldwaser

Dr. Tamar Goldwaser joins Dr. Fox to discuss confined placental mosaicism, a condition in which the DNA makeup of the baby does not match the DNA makeup of the placenta. They cover what this means for DNA testing results, how it could affect the baby, and more.

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Dr. Fox: Welcome to today’s episode of “Healthful Woman,” a podcast designed to explore topics in women’s health at all stages of life. I’m your host, Dr. Nathan Fox, an OB-GYN and maternal-fetal medicine specialist practicing in New York City. At “Healthful Woman,” I speak with leaders in the field to help you learn more about women’s health, pregnancy, and wellness. All right, Dr. Tamar Goldwaser, welcome back to the podcast. How goes it?
Dr. Goldwaser: Hi. Well, thanks for having me back. Everything’s good.
Dr. Fox: How’s the world of genetics?
Dr. Goldwaser: Always exciting. I love it. Always something new.
Dr. Fox: Oh my god, there’s always something new with genetics. As I said, the course me and you and Andre gave together, when I got to speak, I said, “I’m intellectually outmatched,” it’s just there’s so much to know and there’s so much that’s evolving and so much is being discovered. And the people who are doing this every day, it’s crazy how advanced it is. Crazy in a good way.
Dr. Goldwaser: Yeah. I mean I feel the same way, it’s kind of like every day you learn something new, every day we learn something new, which is why I think genetic testing can be more complex to interpret and why it’s good that we’re doing this podcast.
Dr. Fox: We’re gonna be talking today about…I’m gonna call it a condition, although “condition” isn’t really the right word, maybe the situation, it’s confined placental mosaicism. And, you know, in our line of work, this does come up. You know, for those of us who see pregnant patients, for those of us particularly who do CVS and screening and testing for genetic conditions, we do see this. And the reason it came up is because I was doing one of the high-risk birth-story podcasts, which actually we’re gonna drop later this week. And it just became evident to me that, first of all, for our listeners of both podcasts, it’ll be helpful to get this review before hearing that, to sort of understand her story and empathize a little bit more exactly what she was going through. But also, when I was talking to her, it became really apparent to me how little people know about this, even though it’s been known for a long time. And it’s not a new diagnosis, it’s just being made more and more nowadays.
Dr. Goldwaser: Yeah, definitely. I think it’s, you know, a combination of the fact that many people are using cell-free DNA to screen for conditions like Down syndrome and other chromosome abnormalities. And that test is based on DNA that comes from the placenta. So, I think that’s where we’re learning a lot more about it and seeing it a lot more.
Dr. Fox: The way I explain it to people in the simplest form, and we’ll get into how this can possibly happen, is confined placental mosaicism is essentially when the DNA makeup of the placenta is not the same as the DNA makeup of the baby. So, it is true that about 99% of the time they’re the same. And we’ll explain why that is, but 99% of the time the DNA of the baby and the DNA the placenta are the same. Meaning, if you do any sort of genetic test on the baby or the placenta, you’ll get the same results. And confined placental mosaicism is a situation where that’s not the case. And that’s sort of what is going on but it wreaks havoc when you’re doing testing on the placenta in some form to learn about the baby.
Dr. Goldwaser: Right. Yeah. And I think the concept of mosaicism is also just interesting. If we picture a tile mosaic, it means that not all the cells or not all the tiles are the same. And, so, when we use the term “mosaicism,” we mean that for this organ, so, in this case the placenta, not all the cells are the same. And they’re not all the same because some might have a genetic imbalance and some might be balanced. So, some might have a problem and some of the cells don’t have a problem. And then we use the word “confined,” meaning this whole situation is confined to the placenta and the fetus is actually spared or healthy.
Dr. Fox: That sort of makes it unique in two aspects, like you said. Number one, there is this concept of mosaicism, which itself means that not all the cells are the same. And then there’s this sort of second layer that, not only does that exist, but it doesn’t exist uniformly, it only exists in the placenta, it does not exist in the baby. So, let’s start, I guess, with that. Let’s start with mosaicism in general. So, conceptually, how do you explain mosaicism to people? Because it could be true in an adult, an adult can have a mosaicism, it could be true in a child, it could be true in a fetus. So, what does that mean that not all the cells are the same?
Dr. Goldwaser: When you’re talking about genetics, when you say that there is mosaicism, a grown-up person can be mosaic for a certain genetic mutation, meaning that some or most of the cells in that person’s body have, let’s say, 46 chromosomes, which is the typical dosage of chromosomes, but there is a smaller percentage of cells mixed in to that person’s body that actually don’t have 46 chromosomes. Maybe they’re missing, in a female, they could be missing one of their X chromosomes and you can also see lots of other variations.
And, so, generally, when we do a blood test to check somebody’s chromosomes, we are looking at one part of their body, we’re looking at their blood and checking the chromosomes. And then we use that to represent the whole person. But, in the back of our minds, in the genetics world, we know there could be a smaller group of cells somewhere in this body that actually doesn’t have 46 chromosomes, but we may not be powered to detect it. But sometimes we do see two different groups of cells even in someone’s blood. Even in a grown-up adult person we might get a result that says, “90% of the cells are showing that they have 46 chromosomes with two X chromosomes,” so, that would be a typical female, and then, “10% of the cells show 45 chromosomes with only 1 X,” so, that’s an example of monosomy X mosaicism. So, you could be a mosaic for lots of different conditions, it just means that, if you take the whole person’s body and all the cells, they’re not all exhibiting the same thing or they don’t all have the same genetic makeup.
Dr. Fox: Right. And I’m not sure if everybody remembers from, you know, high-school biology, or whatever it is, that one of the tenets of sort of genetics and DNA is that every cell in our body is the same. Which is conceptually why, you know, let’s say you’re, you know, if you’re watching like “CSI” or something, they can take a hair sample and get someone’s DNA or they can take a saliva sample or they could take a skin sample or a blood sample. Or anything because any part of the body, the DNA should be the same across. And when people have mosaicism, that would not be the case. And based on just either by chance, which cell you happen to pick up it’s gonna tell you one thing versus another, or if you pick up a bunch of cells, you may get different results from them. How common would you say this is? Let’s talk about, you know, in children and adults, forget…let’s not talk about fetuses yet. Is it a very common thing or it’s a pretty uncommon thing?
Dr. Goldwaser: It’s hard to say because most people never had their chromosomes checked. It’s usually uncommon to find it. But generally, if you check a healthy person’s chromosome, they’re not gonna have a split. But it is hard to say. And usually you don’t find it. But, you know, I like what you said because, basically, yeah, every cell of your body is supposed to really have all of the same exact DNA code and different cells express different parts. But the reason that this is highlighted is because it’s a deviation from that initial rule that we learn when we start studying the biology of humans. So, it’s different that you should find mosaicism.
Dr. Fox: And the reason it would matter in terms of a fetus to determine does the fetus have this or not is, based on the mosaicism, the prognosis, you know, how important is this, how significant is it, depends. So, for example, if you’re mosaic for something like, what you were mentioning before, monosomy X, or also called Turner syndrome, most of those children tend to be healthy. There might be some issues related to fertility or, potentially, you know, with how their heart was formed and there are things that go along with that, but most of…first of all, most people with full Turner’s are healthy but certainly people with mosaic. Whereas, if it’s mosaic for something like trisomy 13, which is a much more severe genetic abnormality, those children will, on average, have more complications than, let’s say, mosaic for Turner’s. So, one of the sort of variables and how much it means is which chromosome is mosaic, and the second is how much. Right? So, if your mosaic where 99% of your cells are normal and 1% are abnormal, probably you’re better off than if it’s 50/50.
Now, we can’t tell you exactly what that means because a lot of it depends on where the cell’s abnormal, is it in an important place, you know, not an important place, so, you can’t sort of map it out and say exactly what a child is gonna be like based on the percentages. But conceptually, it makes sense that, the more normal percentage versus abnormal percentage, the better off they’re likely to be. And, so, there are these variables that come in when trying to determine if you knew, let’s say, the fetus has a mosaic condition, or a mosaic genotype, how severe is it gonna be, you have to try to sort that out as best as you can.
Dr. Goldwaser: And then, it’s complicated because, when we’re looking at the placenta to represent the fetus, you might get one result and then you might end up needing to check the fetus in another way, like an amniocentesis, to see, “Well, what’s a better representation of what this baby really has?”
Dr. Fox: What you’re describing is how do we even find out if the baby has it. But if we know the baby has it, that itself has a lot of uncertainty. I mean, even if you knew 100% the baby has a mosaic condition, it’s hard to say with certainty what that’s gonna turn into…
Dr. Goldwaser: What that’s gonna look like. Right. My pediatric genetics colleagues will usually say, “With a mosaic, it’s all bets are off,” so, you can have a completely apparently unaffected child or baby or you can have a baby that can really more likely more closely represent the full condition, you know. So, it’s really hard, the counseling and the prediction of those outcomes are really difficult when you know a fetus or a baby has mosaicism.
Dr. Fox: That’s when the baby has it. And, so, when we’re talking about confined placental mosaicism, what we’re referring to is a situation, assuming confined placental mosaicism is the diagnosis, where the baby does not have that, the baby has a totally normal karyotype, you know, a number of chromosomes, there’s no mosaicism in the baby but there is mosaicism in the placenta. So, that is the condition we’re talking about. And again, part of the reason it’s complicated is because the actual mosaicism, it’s hard to say exactly what that would mean for the baby. And number two, it’s complicated because we first have to figure out, and how do we figure out, that it’s just the placenta and not the baby.
Dr. Goldwaser: I just remembered that one of the things that first turned me on to genetics was a project I did in college, and I learned about X-inactivation mosaicism where, basically, every female, even if she has balanced chromosomes, is a mosaic because every cell of her body is not expressing the same X chromosome. And this is just a normal healthy way that women develop. So, all females or all people with 45,X as their chromosome complement are actually mosaics because in half the cells of their body they’re expressing the X chromosome from their father and in the other half of the X chromosomes of their body they’re expressing their X chromosome from their mother. So, I thought that was just so fascinating. And this is actually kind of what got me interested in genetics, so…
Dr. Fox: We’re get a vignette into Tamar’s past and her road to where she is now. Love it. Let’s do a brief review of sort of the genetics of the baby and the placenta. And then we’ll talk about how it could happen that you would get different DNA, like mosaicism in the placenta and not in the baby. And then we’ll talk about sort of practically how does it play out sort of from a clinical sense with women who are pregnant. So, in terms of the genetics of the embryo in the placenta, it starts with one egg and one sperm. Right? So, the egg is 23 chromosomes ideally and the sperm has 23 chromosomes ideally. And when they come together and fertilize that zygote, which is 2 cells, it has 46 chromosomes in those two cells, each of those 2 cells, and then they start to divide, right, 2 cells, 4 cells, 8 cells. And this is what we call in biology what people remember with [inaudible 00:12:45] mitosis. Right? Where these cells split into two cells that look like the prior cell. So, one cell with 46 chromosomes becomes 2 cells, each with 46, and so forth and so forth. And then, at what point does the baby divide from the placenta? Because that clump of cells that’s created, this blastocyst, eventually splits and part of those cells end up creating the placenta and part of those cells create the baby.
Dr. Goldwaser: Right. So, it actually happens pretty early on, I’m not exactly sure of the day, but it’s in the realm of days. So, within single-digit days of after conception, you’ll have some cells that become what’s called the trophectoderm, which is just like this outer layer that will then, ultimately, become the placenta. And another group of cells become what’s called the inner cell mass, and that then stays as the inside of this sphere. And that clump of cells called the inner cell mass ultimately is what becomes the fetus.
Dr. Fox: Right. I think that’s the coolest part that not everyone realizes, that the placenta and the baby started from the same cell, and then the same two cells, and four cells, until they split into just two piles. Right? They just divided the groups in two but they came from the exact same precursor, which is why, normally, the DNA in the placenta, if you test the DNA in the cell of a placenta, it’s gonna be the exact same as the baby. So, knowing that, how is it possible that a placenta would end up with different DNA from the baby, with mosaicism that the baby does not have? What could happen? There’s basically two ways it could happen, what are the two ways?
Dr. Goldwaser: Either you start off like you described where you have the initial conception with 46 chromosomes balanced and then, somewhere along the road in those multiple cell divisions, a accident occurs where the chromosomes don’t divide evenly. And where you start off with a parent cell with 46 chromosomes, then the 2 daughter cells, 1 may both be unbalanced. So, one cell line might have an extra chromosome and the other daughter cell might be missing a chromosome. In the meantime, the rest of those cells that we’re actively dividing are still doing a good job and still making daughter cells with 46 chromosomes. And, so, now somewhere along the line a new cell line develops that’s unbalanced and some might die off soon but some may persist. And, so, now amongst the whole group of cells that are actively dividing, you have a smaller group that is perpetuating this mistake or this imbalance. And, so, now you have a smaller group of cells within the pool that either have something like an extra chromosome, so, it could be called a trisomy, or missing a chromosome, like a monosomy.
Dr. Fox: Right. And, so, if that happens at the very beginning, from conception, then everything’s gonna be abnormal usually. The baby’s gonna be abnormal, the placenta’s gonna be abnormal. If it happened after the split and it only happened in the baby, right, that’s not so usual because they tend to miscarry. But if it happened and the cells that are abnormal are only on the placenta side of the split, then you’ll see this abnormal cell line, like you said, in the placenta. And it’s not that every cell is abnormal, it’s that, you know, let’s say, four out of the five cells, whatever, were normal and then one of the five split and was abnormal. So, let’s say, 20% end up being abnormal, something like that. So, you have that mosaicism in the placenta. But the baby was already separated off before that happened, so, the baby doesn’t see any of that. So, that’s one way you can get this mosaicism in the placenta that’s not present in the baby. So, what’s the other way? And this is the one that’s really the wild one.
Dr. Goldwaser: So, the other way is if, let’s say, at conception, there was an imbalance, maybe an extra chromosome. There’s something called trisomy rescue where sort of like life finds a way as the developing embryo continues to have cell division, within a new cell division you can end up with a balanced daughter cell sort of by design. Then you can sort of rescue that embryo, or rescue that conception, and now you have a new healthy cell line that grows and might even become the predominant cell line. So, you kick out the one extra chromosome that you started with and now, instead of having 3 chromosome 13, you now just have 2 chromosome 13. And that’s what the typical human has. So, you might end up with a mix of cells that way where some still have trisomy 13 but some have 46 chromosomes with just 2 copies of that chromosome 13.
Dr. Fox: The way I sort of explain it to people, if I have to explain it to people, if they ask, is just like, in the first example where everything’s normal and sort of randomly you end up with a bad split, and then, from that point on, you get a cell line that’s, quote unquote, “bad,” you can start out with sort of bad chromosomes and kind of randomly get a split that leads to a good one. Right? So, it sort of becomes it…so, it starts in balance and then, if it imbalances in the other direction, you’ll have a good cell line. And then it can either just randomly end up being good or there’s also this concept that cells with normal DNA are gonna divide better and live longer than cells with abnormal DNA. So, the good ones will sort of outlast the bad ones.
And, so, if you have an abnormal clump of cells and then they divide into two, you can have the placenta remain sort of abnormal. But then the baby, if there’s a rescue, all the good cells can win out. And, so, you can have a normal baby and an abnormal placenta. But in this situation, everything started abnormal, whereas in the first situation everything started normal. Now, in terms of like how it ends up, you know, abnormal placenta, normal baby, it doesn’t really matter which way it got there. But there are, and we’ll talk about it in the end, some unique situations where it would matter which of the two ways it got there. But from the initial diagnosis, you wouldn’t know and you usually wouldn’t care but then you would try to figure out, and we’ll talk about when that nuance exists.
So, that’s how it happens. Right? And the way someone even finds out about this is you would have to do something that tests the DNA of the placenta. So, if someone goes about a pregnancy and has no genetic screen that involves anything related to the placenta, they would never find this out. Right? So, if they just do, let’s say, their genetic screen is an ultrasound at 12 weeks and the baby’s gonna look normal and then they do an amniocentesis, let’s say, at 16 weeks, so, in that case, the cells from the amniocentesis come from the baby, their skin cells. It’s gonna be normal, normal, normal, they’ll never know this exists ever. And that’s really how things were done for ever. Right? That they either had no genetic screening or the genetic screening they had involved just ultrasound. Or, potentially, if there was an invasive test, it was usually an amniocentesis. I think where this started to get discovered first was when we started doing CVS, chorionic villus sampling. Which, as you know from our prior podcast, is, essentially, a test like an amniocentesis where we stick a needle inside the pregnancy but we guide the needle into the placenta and test the DNA in the placenta again under the assumption it’s gonna be the same as the baby. And then, about 1% to 2% of the time, you get this wacky mosaic result and you have to decide, “Well, is this the baby or is it just the placenta?” And, so, those of us who do CVS have known about this for a long time.
Dr. Goldwaser: Right. And then the newer thing, which you’ll probably want to talk about, is the fact that we’re screening with cell-free DNA. So, now more people know about this.
Dr. Fox: Right. So, explain what that…so, this is something we discussed in our prior podcast, this concept is cell-free fetal DNA or non-invasive prenatal testing NIPT, it’s sometimes called that, but it’s basically a blood test. It’s newer, meaning the past several years, which is looking for fetal DNA in the mother’s blood. But as you said, where does that DNA actually come from? It doesn’t come from the fetus, it comes from where?
Dr. Goldwaser: Right, it’s coming from the placenta. It’s so cool, the placenta is constantly shedding fragments of its own DNA into the mother’s bloodstream. So, there are these just little short pieces of the DNA from the placenta that are detectable with a blood test that you can perform on the mother. So, again, it’s sort of like using the placenta as the fill-in or the representer of the fetus. And, so, this is a really good tool to screen for Down syndrome or other chromosome abnormalities in the fetus without doing any invasive tests.
Dr. Fox: Exactly. And, so, when it comes back normal and all the DNA that’s in the maternal circulation that came from the placenta is normal, it’s very very very highly suggestive that the baby is gonna have a normal…at least for the things that they’re testing for, like Down syndrome, trisomy 18, trisomy 13. Not the exact same as doing a CVS, it’s not quite as high, it’s not 100% like a CVS might be, but it’s in the high 90s. It’s really really very good.
But one of the interesting things is, and this is something we know, if that blood test comes back abnormal, one of the reasons when we counsel women about that test, we don’t tell them, “This means your baby’s abnormal,” is because we know that there’s a lot of reasons this test can give you a false positive. And one of those reasons is your baby’s normal but your placenta is not. There’s other reasons it could be falsely abnormal but this is one of the big ones and we have to tell people, “Because of this we really have to do further testing,” and we don’t make any decisions or any conclusions about abnormal babies with just this blood test. That would be a big mistake.
Dr. Goldwaser: Absolutely. Right. So, I think what confuses people is that it is accepted that NIPT, which is non-invasive prenatal testing, or NIPS, non-invasive prenatal screening, it’s all the same thing, it’s a blood test on the mother looking at the circulating placental DNA. This is the test we’re talking about right now. It is accepted that it picks up 99 out of 100 cases of Down syndrome. And, so, we hear a lot of people saying, “This test is 99% accurate.” So, it’s true because it does take up 99 out of 100 cases of Down syndrome, which is, when there’s an extra chromosome 21 or even when there’s a problem with chromosome 18 or 13, but once you have an abnormal test, we have to think about it in a little bit of a different way. We don’t say, “There’s a 99% chance that your baby has a problem with this chromosome 18.” In fact, depending on which chromosome is called out as abnormal, there’s gonna be a different likelihood that, in fact, this is gonna be found in the fetus versus maybe this is just gonna be found in the placenta as confined placental mosaicism. The numbers are different when you have an abnormal test result. So, I think that’s where a lot of confusion comes. And that’s why you and I would never call someone and say, “There’s a 99% chance that your baby has this chromosome problem,” we would just say, “your test results came back high-risk and we need to do a workup.”
Dr. Fox: Yeah. And I think that part of it is, unfortunately, these tests are marketed. The people who market them first are people who are selling it to you. And it’s not that they’re bad people, they have a really good test but they’re gonna look at a number like 99% accuracy and say, “Oh, it’s 99% accurate.” So, what does that mean? Right, when someone says a test is 99% accurate, right, what that means sort of from like a statistical standpoint? That means, if they run 1,000 tests, 990 of them will give the correct result and 10 will give the incorrect results. Or, if they run 100 tests, 99 will give the correct result and 1 will give the incorrect result. And that can be a true fact, right, but the accuracy depends on a lot of things.
But that’s not what people wanna know. What people wanna know is, “If I have an abnormal test, what is the likelihood that it’s real, that it means something?” And that’s what we call in statistics the positive predictive value. If your test is positive, positive is bad, negative is good, that’s one way we confuse people, but if the test is positive or abnormal, what is the likelihood my baby’s actually abnormal? And, so, if that number is 5%, all right, 5% is probably higher than we’d like it to be but it’s still only one 1 of 20. Whereas, if it’s 95%, then it’s 19 out of 20.
And, so, like you said, it depends on which result you get. It’s different based on which chromosome. So, for some of them it’s…all right, if it’s abnormal, you have a 20% chance of the baby having this. And for others it is closer to a 90% chance of the baby having this. And, so, it has to be nuanced. And when we just say “accuracy,” it gets more confusing, I would say, than helpful.
Dr. Goldwaser: Yeah, agree. So, that’s really…you know, it depends on which chromosome. And actually I always like to use a tool because different labs offer these tests. And there are tools that we could use to find out the positive predictive values. So, some patients will come and talk to us about an abnormal NIPT result and they’ll say, “Well, what are the chances that it’s really gonna be found in my fetus?” And, so, you can actually give these calculations. But, at the end of the day, those are all predictions, you’re never gonna know the actual answer until you do a diagnostic test. So, either CVS, which is a placenta biopsy, which will just give you a better more accurate representation of the chromosome complement, like what are the chromosomes doing in the placenta, or amniocentesis, which is gonna tell you what are the chromosomes doing in the fetus and the fetal skin cells.
Dr. Fox: Right. So, if someone goes through and the way they enter this sort of situation is through a blood test, sometimes the blood test itself, when you get the results, were already suspicious that it’s confined placental mosaicism. Because it comes back as, you know, atypical and mosaic. And you sort of look at this, you know, “This kind of,” you know, “the baby looks normal, that doesn’t make a lot of sense.” And sometimes we’ll tell them, “You know what? Just skip the CVS because the likelihood is it’s gonna come back as mosaic.” And then we’re gonna end up having to do an amnio anyways, so, “Just skip it and we’ll do the amnio.” Or sometimes we’ll say, “All right, let’s do the CVS. If it comes back totally normal, we know that the blood test was abnormal for another reason. Or, if it comes back mosaic, fine, at least you know that,” you know, “we’re sort of heading down the right road, if you don’t mind having two procedures.” I don’t feel too strongly about those two options. Do you generally counsel people to just wait and do an amnio or do you give them the option to do the CVS first? Again, if, from the blood test, you’re suspicious it might be this situation.
Dr. Goldwaser: So, it depends. So, if it’s positive for, let’s say, trisomy 21, which is an extra chromosome 21, we just know it’s less likely to be just attributable to a mosaic cell line in the placenta. I might say that that scenario where you need a CVS and then an amnio is gonna be less likely so I might fall for that…also trisomy 21, or Down syndrome, often times, in the first trimester when we’re dealing with these test results, they can have a normal ultrasound and look really good. And, so, we can’t rely as heavily on our ultrasound. So, I might say, “You really have the two options, you could do a CVS or you could do an amniocentesis with a chance that you might have a,” you know, “need…” “you might find mosaicism and then need an amnio but less likely with trisomy 21.”
But if I had a case where the NIPT showed a high risk for trisomy 13 or monosomy X, with trisomy 13 in particular, oftentimes, we do see some significant abnormalities in the first trimester. And if we’re looking at a beautiful ultrasound at the time, I already start to be a little suspicious that maybe the fetus is gonna be okay. But also, with trisomy 13, it is more common to find a mosaic cell line in the placenta with a normal baby. So, in that case, I might explain I have a higher level of suspicion that this is a placental issue, and, “If you have a normal ultrasound, you may just wanna wait for your amniocentesis to do that procedure.”
Part of the discussion is also just about the safety of invasive testing, which I think is very important to explain to our patients because there is a fear of miscarriage. Obviously, people are here with concern because this was a desired pregnancy and people don’t wanna do anything that might risk the pregnancy. But, once we explain that, in experienced hands, the risk of a miscarriage after CVS or amniocentesis is very low, maybe 1 in 500 to 1 in 1000 risk, people feel more comfortable doing it. So, it’s nuanced. But if the scan looks beautiful and the NIPT shows trisomy 13, I will be encouraging. I will say, you know, “If you just wait and do an amniocentesis, we also have a chance at the amniocentesis appointment to look at the baby’s anatomy, at that initial look.” You know, at 16 weeks, you can get a very good look at the brain, the spine, the heart, you know, the full anatomy, kidneys, hands. And, so, you can look on the ultrasound for any signs of trisomy 13, you can get more reassurance there, do an amniocentesis, and likely to get a good result.
Dr. Fox: Yeah. And I think that…totally true with the blood test, but a lot of times people enter this diagnosis who didn’t have the blood test and they say, “You know what, I’m just gonna do a CVS test. I wanna get as much testing as possible early in pregnancy. No need to do the blood tests, I’m doing a CVS anyways.” And they do a CVS and the results come back as mosaic and the baby looks normal. And, so, in that situation, we say, “All right, the placenta DNA is mosaic, the baby looks normal. So, we’re left with really one of two options, either in fact the baby has a mosaicism…again, the significance of that is hard to predict, we do our best but it’s hard to predict accurately…or it’s just confined to the placenta and the baby’s fine.”
And really, the only way to know that for sure is to then do the second test, which is the amnio, about a month later, at 16 weeks, because you’re not testing cells from the placenta anymore, you’re testing cells that came directly from the baby. Now, if the baby’s truly mosaic, almost always when you do the amnio, you get a bunch of cells there…right, because you’re taking fluid and there’s many many cells floating around in there, if it’s mosaic truly and the lab looks at a bunch of those cells, they’ll see, again, some percentage normal, some percentage abnormal. Whereas, if all of them are normal, it almost always means in fact the baby has no mosaicism or you’re just really really unlucky enough that the baby’s truly mosaic but none of the abnormal cells got caught up in the fluid because maybe they’re confined to an organ or maybe they just weren’t there by chance. But it’s always a possibility and we tell people that, basically, if the amnio is normal, particularly if the baby looks normal, they can, you know, pretty high confidence rest assured the baby’s not gonna have mosaicism.
Dr. Goldwaser: Yeah, very reassuring.
Dr. Fox: When that happens, we generally get people…it’s kind of a roller coaster. And I think one of the important lessons is, at the outset, like we’re talking about, it’s very important with counseling these test results to sort of be very precise about what they mean. And to just tell someone, “Your test is abnormal, you need a CVS, you need an amnio,” is a lot different from saying, “your test came back abnormal. It does not diagnose anything in the baby, it just means we need to do further investigation, further testing. If you want to know your odds of a normal CVS versus abnormal CVS, we can tell you those percentages but, ultimately, we’re gonna do the test and find out.” I think what ends up happening in the second situation is, assuming the testing comes out normal, people’s anxiety is a lot lowered because they were never freaked out to the nth degree. But if you sort of drop a bomb on them and say, “Your baby is abnormal,” you can never undo that. There’s almost nothing you can do to undo that statement. I mean they’ll be thinking about it when the kid is 8, right, and doesn’t do great on their first, you know, spelling test. They’d be like, “Ah, it was that damn test. I knew it, I know there’s something in there,” and they’ll never forget it.
Dr. Goldwaser: “I need to go back and do an amnio.”
Dr. Fox: Yeah. But it’s true, people are like, “Ah, yeah, there was something there, I remember that test, there was something wrong.” And it’s so important with these tests for those of us who offer them and do them to know how to counsel the results. And it’s also important, I would say, for people listening who may be undergoing these tests to make sure you’re getting good information about what it means. And if it’s not clear, try to speak to either a genetic counselor or geneticist, a maternal-fetal medicine specialist, whether it’s…or an obstetrician who does a lot of this and understands it. And rather than just going online and saying, “Abnormal, normal,” you have to be very careful because the information you get, A, may not be right, it might just be wrong, and also it may do serious psychological harm for a long time if you’re told something that’s not accurate.
Dr. Goldwaser: Yeah. I think we all hold that responsibility. You know, even if you’re told that it’s just a high chance, I think sometimes you could walk away as a patient hearing that the baby has this condition. But I think we, as practitioners, have to be careful and and say, “This is just a red flag and we have to work it up,” because this test, it’s not diagnostic, it’s just a screening test, it’s just a way for us to determine who should be referred for diagnostic testing.
Dr. Fox: That was the first thing. The second thing is that, for the vast majority of people, if they go through this process and they find out in fact there is confined placental mosaicism, whether they first had an abnormal blood test or they had a CVS and they were, “Okay, after all the test [inaudible 00:34:43] amnio. The baby’s fine, genetics of the baby seem fine, genetics of the placenta seem a little screwy,” and we’re saying, “all right, everything’s good,” but there are a couple of nuances. Right? If we know someone has this condition, we do follow the pregnancies a little bit differently. And one of those things is related to genetics and the other thing is related to how the placenta is gonna function. With the placenta part, you know, there is this concept, and it makes a lot of sense, if the placenta has some percentage of abnormal DNA, it may not be a healthy placenta. It may not work as well as it’s supposed to. So, in these pregnancies, there is an increased risk of things related to the placenta. Like fetal growth restriction, is the baby gonna get enough nutrients through the placenta? Or maybe something called preeclampsia where the placenta can sort of cause the mom’s body to react in a way with high blood pressure. Or as the placenta gonna separate early. Things of that…so, we do follow these pregnancies a little bit closer knowing that there’s confined placental mosaicism. Which is one of the reasons some people believe you should do that CVS and then the amnio because you’d like to know if the placenta’s abnormal, meaning there’s some value in knowing that other than just the genetic part. So, that’s one nuance, that we do follow these pregnancies a little bit closer because the placenta itself might have a problem.
The second one is the complicated genetic one. And this goes back to what we said earlier in the podcast, that other root that you can get a placenta that’s abnormal in a baby that’s normal, which is the trisomic rescue where you start with abnormal and then the baby converts to normal through some sort of, you know, change. Why is that something that’s relevant here and why is it something we need to think about in this situation?
Dr. Goldwaser: Okay. So, it’s due to a very interesting phenomenon where, in certain genes that live on certain chromosomes, it’s not just important that you have two copies of each gene, meaning one from your mother, one from your father, but it’s also important that those two copies come from different parents. So, there’s this idea called imprinting where for some genes, depending on if you inherited it from your mother or your father, one copy might be imprinted, which means that there are some carbons put on top of it and it’s turned off. And, so, you really need to be able to use the copy that you got from your mother. And for some genes, you really need to use the copy you got from your father. And sometimes you end up, if you started off with a trisomy, when the sperm and the egg first got together and they came together to create that first cell, if there was an extra chromosome but only some are subject to this nuance…so, if, let’s say, you had an extra chromosome 15. So, you were trisomy 15 for a little bit, then you undergo some rescue event where now you’re back to having just 2 copies of chromosome 15, if you end up with 2 copies of chromosome 15 but both from your father or both from your mother, either one of those scenarios can actually cause different genetic syndromes that are due to the fact that you don’t have the copy from your mother or don’t have a copy from your father.
So, for instance, there’s a genetic syndrome called Prader-Willi syndrome that leads to cardiac or heart defects and other medical conditions and intellectual disability of varying degrees. It can happen when you don’t have both copies of your 5th chromosome 15 from different parents. And, so, this phenomenon is called “imprinting” and certain chromosomes are subject or more likely to cause imprinting disorders if you don’t have one copy from each parent.
Dr. Fox: This is tough stuff. Another way think about it is, if you started out as a cell, like you said, we’ll use the 15th chromosome, because that’s a classic example that they use in genetics, because of, you know, Prader-Willi, for example, and you have three chromosomes. So, it’s gonna be either mom-mom-dad or mom-dad-dad. Right? That’s how it’s gonna be. It’s not gonna be…you can’t have mom-mom-mom, right, or dad-dad-dad. If you have three, it means you got one from one parent and two from the other. So, if it gets rescued, so to speak, and one of those three chromosomes sort of gets weeded out and you end up with two, that’s great, now you have two, which you’re supposed to have. But if you were mom-mom-dad and you dropped the dad, now your 15th chromosome is mom-mom.
And, in that situation, for that chromosome, you can have one of those conditions. And like you said, it’s unique to certain chromosomes. So, one of the nuances is, if we know there is confined placental mosaicism and it’s mosaic for one of the chromosomes that have this problem, there’s additional testing that the lab is gonna do on the amniotic fluid to not only tell you, “Is the baby normal?” another two copies of the, let’s say, the 15th chromosome, but, “do they come from the same parent or different parents?” And that’s an important nuance that the geneticist and the genetics lab needs to know to test and which chromosomes require that testing, which chromosomes don’t require that testing. And another term that people use for that is UPD or uniparental disomy. “Disomy” means two copies of a chromosome and “uniparental” means you got it from one parent. And, so, that’s like a really fascinating genetic nuance that gets like added on.
But, fortunately, that’s, you know, not always relevant and, typically, that’s something that just the lab is gonna know to test for. But I mean this just gets really fascinating because you can have a situation you have two normal chromosomes, there’s no mutation on it, the 15th chromosomes, they’re both normal. But since they came from the same parent, it behaves as if someone had a mutation on the other’s chromosome. If you have 2 mom 15s, the baby’s gonna be the exact same way as if that a mom 15 and a mutated dad 15. And, so, it’s just wild. Crazy stuff.
Dr. Goldwaser: Right. Right. And we could rely on most of the labs that do prenatal genetic testing to cue us into that. But, if you have any abnormal test result that indicates mosaicism, we would encourage you to seek out a genetics professional to kind of flesh that out. And we don’t expect every practitioner to know all of these types of details just to know this requires genetic counseling, there’s more that we can learn here, there’s more that the lab can do to help us to understand what other risks the patient might be facing.
Dr. Fox: Right. And that’s really critical because, let’s say, we didn’t know about the confined placental mosaicism and this baby, you know, is born and goes on and, at age 3, gets a blood test for genetics. They would just say 2 copies of the 15th chromosome, they wouldn’t know to start testing for this, you know, uniparental disomy in the 15th chromosome. Unless someone told them either the baby presents with this, you know, Prader-Willi syndrome or someone said, “oh yeah, there was confined placental mosaicism.” When we do the amnio, they sort of know that that’s going on so they’re gonna test for it. But, you know, it’s not like because of a skill set of the lab, they just need to know that that’s on the table, that that’s a possibility, to go into that testing.
So, for those of us who made it to the end of this podcast without their heads exploding from DNA and biology and high school and whatnot, just as like a simple review, I think the takeaway point is confined placental mosaicism is, number one, where the placenta has abnormal mosaic cell line and the baby does not, number two, this actually happens 1% to 2% at a time. And it normally was only known about when people had a CVS but now that we’re doing these blood tests to check the DNA in the mother’s blood, which comes from the placenta, it’s gonna be picked up a lot more. And, so, you know, almost universally, anyone who has his blood tests we’re probably gonna find this. And, so, about 1% to 2% of people who are pregnant and having this blood tests might be dealing with this. And because of that, it’s important people know about it to sort of help put into context, quote unquote, “abnormal results” on that blood test, that this is one of the reasons it might not be reflecting the baby. And once you go through this sort of like roller coaster of testing and you get to the end of the line, you’ll, fortunately, find out your baby’s okay, they’ll do the extra genetic testing to make sure your baby’s okay, and then we just have to watch the placenta, you know, the pregnancy because of this placenta to make sure everything works out all right. And usually everything works out all right. Is that a good summary for you, my genetics friend?
Dr. Goldwaser: Yes. And I would also say, if you get a mosaic result on the placenta, there’s a really good chance that the baby, when you do an amnio, is gonna be normal. It’s actually in your favor. So, I think that’s another good take home, I don’t know if I actually said it or if you said it, but, once you find mosaicism in the placenta on the CVS, you have a lot of room to be hopeful that, once you do the amnio, it’s gonna actually be normal. Because the odds are then in your favor.
Dr. Fox: Right, if you did the CVS and everything’s abnormal in the placenta, that’s generally not a good sign.
Dr. Goldwaser: Right.
Dr. Fox: Tamar, thank you for getting on the podcast to talk about this complicated topic. I love talking these genetics’ issues out with you because you know a lot and you explain things well. And it’s just really cool to be able to work in this world, I would say, and to continue to feel like I don’t know what I’m talking about all the time but at least with people who can help me feel like I know more by teaching me.
Dr. Goldwaser: Yeah. So, it was a pleasure. I love talking about genetics, I think it’s so interesting. And I love that you think it’s interesting too, so, thank you. And I hope it’s helpful.
Dr. Fox: Thank you for listening to the “Healthful Woman Podcast.” To learn more about our podcast, please visit our website at www.healthfulwoman.com. That’s H-E-A-L-T-H-F-U-L-W-O-M-A-N .com. If you have any questions about this podcast or any other topic you would like us to address, please feel free to email us at HW@healthfulwoman.com. Have a great day.
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