Deborah Howell (Host): If you're undergoing in vitro fertilization or IVF, you may have heard about pre-implementation, genetic testing, or PGT as a way to improve your chances of a successful pregnancy. But how does it work and is it right for you? Dr. Jane Nani, a Reproductive Endocrinologist and Medical Director of Third Party Reproduction joins the podcast to explain the different types of PGT, debunk common misconceptions, and discuss how this technology has advanced in recent years. Whether you're exploring genetic testing, or just curious about its benefits, this episode will provide the insights you need to make an informed decision on your fertility journey.

This is the Time to talk Fertility podcast. I'm your host, Deborah Howell. Welcome back Dr. Nani.

Jane Nani, MD: Thank you so much for having me today. I'm happy to speak with you. 

Deborah Howell (Host): The pleasure is all ours. Right off the bat I have to ask you, what is pre-implementation genetic testing or PGT and what is the test for?

Jane Nani, MD: Pre-implantation genetic testing is pretty much exactly what it refers to. It talks about testing embryos prior to their being implanted in the uterus andin particular, pre-implantation genetic testing looks for, there's an A that we primarily do, and this means it looks for normal chromosomes. When they're abnormal, we call that aneuploidy, but when they're normal, we call that euploidy.

So really it can discern among a certain couple, which of the embryos are that, whether they're aneuploid not eligible for embryo transfer, or whether they're euploid or normal and eligible for transfer. So that's the specifics of the PGTA.

Host: Very useful information. So who would you recommend genetic testing for during fertility treatments? 

Jane Nani, MD: One might think that all couples should seek it, but in particular we recommend it for women who are of advanced maternal age. Now, that usually refers to women older than 35. But for this particular kind of testing, it's even perhaps a little bit more narrow.

Women older than 37, 38 as they get, beyond age 35, 36; this is generally where we see higher rates of abnormal chromosomes in the early embryos. So this is when we recommend women of advanced maternal age and the other large category, we often recommend it for women who have experienced what we think of as recurrent pregnancy loss.

Now, not all pregnancy loss is genetic, but it's one of the most common reasons that people experience pregnancy loss or miscarriage. One of the highest diagnoses at miscarriage is something chromosomally abnormal in the early embryos. So women who have had recurrence and usually the recurrent pregnancy losses after two or three, then we would recommend that we want to make sure when the embryos get transferred, that we have a genetically normal embryo for transfer. And usually that does minimize miscarriage rates. So that group of people. The other group, so there's three, the one who you know, advanced maternal age, someone with recurrent loss.

And then also there are certain women, even though they may not be so much of advanced maternal age, but some of the testing we do for women tell us that perhaps their ovarian potential is not so strong, even though they might be in their early thirties. So we call that women with diminished poor ovarian potential. 

Again, they might be the candidates to go through something like this where we create embryos, look at the genetics of the embryo and make sure that we have at least one genetically normal embryo to transfer. And it is true whether women are in their twenties, in their thirties, or even their forties.

Our professional society has come out and said all these age groups, when we have genetically normal embryos transfer only one in all of these age groups, 'cause you do tend to end up with a live birth. 

Host: What are some of the common misconceptions about PGT testing with fertility treatments?

Jane Nani, MD: Yeah, I think the major ones is people think thatanybody should do it. And again, we've done it enough over the last 15 years or so. It really is not overall recommended for everyone, but for those groups I've spoken about, we don't see a lot of difference with younger age population, whether they do it or not, so it's not really considered to be across the board recommended for all comers.

The other thing I think is a misconception is that it can potentially damage the embryo. And even though theoretically that is true, when we, you work with laboratories that are doing this kind of thing over and over again, in particular, they're so adept at doing this kind of technique that the damage or potential damage to the embryo is quite minimal or negligible even. So those are the major things. 

Host: And what about the differences between PGTA, PGTM and PGT SR? 

Jane Nani, MD: Very good because these are very, very interesting categories. So the aneuploidy is the A, aneuploidy versus euploidy. And again, the aneuploidy could be anything like what we think of as a trisomy, or a monosomy or something called a polyploidy or even a mosaic. But the normal chromosomes, the euploid are either 46 xx. We find this the entire genome of the early embryo. A 46 xx, that's a girl embryo. A 46 XY, that's a boy embryo. Those are the ones that are eligible to be transferred. That's aneuploidy. The PGTM, those are for people that may carry a genetic disorder on a specific chromosome. The typical ones are cystic fibrosis for example. Both members of the couple may be carriers of cystic fibrosis or any other of these single gene disorders, sickle cell or Tay Sachs. We can go right into these embryos and make sure that they don't have affected embryos for those particular diseases. So this is what we think of as monogenetic disorders.

M is for monogenetic disorders, meaning it could be looking for any particular genetic disease that the couple might be at risk of carrying in their embryos. And then the SR. This is another broad category, but it's not as common as the others. SR is structural rearrangements. It happens that there are certain individuals that have all the normal chromosomes that we all have, but sometimes they have what we think of as structural rearrangements in the early embryo.

So these are what we call a balanced translocation. And if either of the couple carries this balanced translocation, this is considered to be a structural rearrangement, then the embryos might be at risk of having something like this. So we can screen for the embryos for structural rearrangements That's a SR, for monogenetic disorders, or aneuploidy. And sometimes we do two of these in the same group of embryos. Somebody might be advanced maternal age and looking for aneuploidy, but they both might carry cystic fibrosis, for example. We can do both of those at the same time, in the same embryo.  

Host: So how accurate is PGT in detecting chromosomal abnormalities?

Jane Nani, MD: Well, interesting Deborah, this whole ability to look and to discern the chromosomes in the early embryo have evolved over time. At the early stages of genetic testing, we were only looking at a group of embryos, and this was an early technology called Fish or fluorescent in situ hybridization.

We don't need to remember all these terms 'cause we have evolved quite a bit from those early days. And now we look at the entire genetic makeup of the embryo. This is called Next Generation Sequencing. And we get it quickly. It's something that results in the entire genetic makeup.

The error rate we like to say is a hundred percent, but it really isn't. We do have studies that have looked at these. The error rate is generally in all these potential studies are less than 2%. So it's quite low. 

Host: Now can you explain how genetic testing in IVF is actually performed? 

Jane Nani, MD: This has evolved a long way over the course of our doing in vitro fertilization over many, many years. And it's true, 'cause now the embryos are growing from the early cellular stage to the next stage of development. We call that the blastocyst stage. So it's a funny word.

The blastocyst. But the blastocyst does refer to the idea that the embryo has evolved from just a few cells, eight cells, for example. We start to see that the embryo has already voluntarily or spontaneously differentiated into two distinct populations of cells. Now, one of the populations happens to be something that's called the trophectoderm, one's called the Inner Cell Mass, but in pregnancy, we understand that it's the inner cell mass that makes up the cell lines of the human fetus. However, the trophectoderm makes up the cell lines of the placenta. The point I'm trying to make is that we biopsy trophectoderm five days in the culture. So the five days of life of this early embryo, there's a little biopsy that gets done of the trophectoderm.

We don't really touch the inner cell mass. The, the trophectoderm gets biopsied. It gets created on a slide, and this is what gets transferred into a little aliquot of cells. Actually, not a slide, but it's aliquot of cells that then get sent off for next generation sequencing. So the whole idea here is we don't do cleavage stave biopsies on day three that we might have done in the past. Now we grow the embryos for day five and do trophectoderm biopsy. However, this means that the embryos do have to advance to a blastocyst stage, or where we start to see these two populations of cells. So this is an important step.

Because on certain groups of embryos, sometimes the embryos don't seem to progress very well out that blastocyst stage and we can't do a biopsy. There's a certain integrity of the embryo that can, has to continue to advance. And then they grow to a certain number of days, usually five days in culture or six days in culture.

And then we can do the biopsy of the trophectoderm. And this is the cellular material of the trophectoderm that gets sent for this genetic screening.

Host: I'm wondering, can PGT improve the success rates of IVF? 

Jane Nani, MD: That's a very burning question, Deborah, that's, we are looking at this data continually because really these techniques have evolved over the last 12 to 15 years and we have larger and larger sets of data to be analyzed. The American Society for Reproductive Medicine has come out just last year in fact, and we do tend to see that it does improve pregnancy success, particularly in the older age populations, women older than 37. We tend to see higher implantation rates and lower miscarriage rates, particularly in this older population for sure. So when we transfer to these ladies, particularly we mentioned that sometimes the indication is they've had pregnancy losses.

Now when we transfer a genetically normal embryo, they tend to go to have a live birth. So that's where the successhas come in particularly in women who are perhaps on the older gae spectrum.

Host: Such good news. How do you handle situations where all embryos in a cycle do test abnormal?

Jane Nani, MD: Well, this does happen, particularly when there are only a few embryos to consider. So the goal with all of this, is really to have a number of embryos to test. How do we get that? This requires a woman to stimulate and to produce a number of eggs to start with.

Now, every individual woman would produce a variable amount. Younger women produce more eggs, older women, fewer eggs, and it all depends on how many eggs get retrieved, how many eggs get fertilized. Once fertilization occurs, these are now early embryos, and then the embryos do have to grow, we think to day five.

Now, if all we have in a certain cohort are two embryos, it's not unusual for both of those embryos to be abnormal and not to have anyone to transfer. The larger number of embryos that get biopsied, most likely if there are four or more embryos to biopsy, chances are there'll be at least one that's genetically normal.

Not a hundred percent, but the more embryos there are to biopsy and consider, the more likely that they will end up with at least one. And sometimes we end up quite a number of them. So somebody who's going through and has a nice response to the stimulation, a nice number of embryos created, a nice number of embryos that we were able to do the biopsy; we'll see sometimes 5 out of 10 that are good, 50% or 60%, that will be genetically normal. It depends on how many there are to test. 

Host: Okay. Now, are there any risks associated with performing PGT on embryos?

Jane Nani, MD: Well, as I mentioned before, that's one of the misconceptions that there could be trauma to their early embryo. And there was trauma when they were doing biopsies in the cleavage stage. But now we do grow them out to this blastocyst stage to day five in culture, or day six in culture with a biopsy of the trophectoderm.

So, and we're experienced so that the risk to the embryo itself is, actually minimal. So it is less impact we think on the viability of that embryo. The other thing that has evolved is when the embryos get frozen, we do, not the old fashioned freeze, but something called vitrification, and the embryos seem to respond so much more favorably to not only the freezing, but to thawing process with the vitrification process so that they do much better in terms of their ability to implant as opposed to that older style of freezing. 

Host: Which brings me to my next question. You've tapped into a couple of these things already, but how has pre-implementation genetic testing evolved in the field of reproductive medicine over the last decade?

Jane Nani, MD: Well, that's an excellent question because we are seeing more and more of it. In fact, this is what the American Society of Reproductive medicine has come out with, quite recently. We've seen increase in numbers of couples choosing this kind of technology. In fact, the data that they presented recently was only about 14% of all couples seeking IVF were doing pre-implantation genetic testing in 2014, for example. But in 2019, so just not five years ago, it went from 14% to roughly 44%. So many, many more people are choosing this. And that's one of the most remarkable stories that is increasingly utilized by couples. We say the vast majority of people get pregnant spontaneously.

So the couples that come to see us, we see more and more people that are inclined to pursue this. Sometimes I think Deborah, we see these people that do get pregnant on their first IVF cycle, but have embryos that are gonna make it to the freezer. And if they are gonna have embryos that make it to the freezer, well why not do a biopsy and find out that they have genetically normals?

'cause they may have a live birth and then they come back in two or three years and they wanna choose the opposite gender. We always get the entire genetic makeup as I say, which are the female embryos or the male embryos, which are the trisomy, which are, we will know what they are.

Some people don't wanna know gender, but certainly we'll have that information. And often if one couple gets pregnant initially on their first IVF cycle and they come back, let's say two or three years later for the sibling, they may choose the opposite gender. And that's quite possible that they can do that. 

Host: Final question for you, Doctor. What advice do you have for couples considering genetic testing as part of their fertility journey?

Jane Nani, MD: I think the first thing is to ascertain particularly for women, but for men too, to understand what the potential is in terms of their fertility. And that largely comes down to what is the ovarian potential. So there's ovarian testing that all women can do and even women who freeze their eggs, we recommend they do assessment of their ovarian potential. And normally this is very easy to do. It's a simple blood test and a simple ultrasound, and we can get a lot of information in terms of the ovarian potential in women by just during those two things. The blood test looks at the hormone that regulates the cycle and the ultrasound looks at the ovaries, and we can count the potential eggs that are there.

So this is the place to start, with good, healthy, young individual women, they're gonna get pregnant spontaneously, but if they are gonna be choosing something like this, the more potential they have, they're gonna be in a better situation in terms of pursuing this kind of technology. 

Host: Well, that's excellent advice and insight. Um, we want to thank you so much Dr. Nani, for being with us today. We really appreciate your expertise. You can schedule an appointment to talk to a fertility specialist at 877-324-4483 or visit fcionline.com for more information. If you enjoyed this podcast, you can find more like it in our podcast library and be sure to give us a like and a follow if you do.

That's all for this time. I'm Deborah Howell. Have yourself a terrific day.