Today, I’m excited to talk to Dr. Eric Forman today about PGT-A.
Dr. Forman is one of the most respected fertility doctors in our country. Not only that, the research he does sets the standard for all of us.
He’s the medical and lab director at Columbia University Fertility Center, and he oversees the medical practice as well as the IVF embryology and andrology labs. He actively sees patients in his practice with infertility and those seeking to preserve their fertility. He’s published more than 40 articles in peer reviewed journals on a wide range of topics.
For patients who are out there who know about elective single embryo transfers, eSETs, he’s the one who basically set that as a standard in most clinics, not just in this country but in the world. He revolutionized how we freeze eggs, and his research proved that the rapid vitrification technology, which is the standard now, does not increase the risk of genetic abnormalities in resulting embryos.
Here we are today to discuss the hot topic in fertility medicine, which is PGT-A.
Dr. Aimee: Welcome Eric. Thank you for joining us today.
Dr. Eric Forman: Thanks again for having me and for that really nice introduction. As you know, there is a team of doctors, nurses, researchers, and patients. I couldn’t have done all of that without all of the great people that I’ve worked with over the years. But I am excited to talk to you specifically about PGT-A.
Dr. Aimee: There’s a recent Chinese study published in The New England Journal of Medicine about PGT-A titled Live Birth With or Without Preimplantation Genetic Testing for Aneuploidy. First off, for our listeners who don’t necessarily know what PGT is, can you give me a one-minute definition? Whatever you’d say to your patients.
Dr. Eric Forman: PGT-A is a test that is performed on embryos in an IVF lab. Basically, we know that to make a healthy baby an embryo has to have the correct number of chromosomes. That’s one of the key building blocks. Not the only thing, but it is important. We know that sometimes when egg and sperm combine, they contribute an incorrect number of chromosomes. That can result in embryos that don’t implant or that can result in miscarriages or even ongoing trisomy type syndrome.
What PGT-A is, it gives us the ability to take a few cells from an embryo and be able to analyze the DNA from those cells, make a very accurate, although not perfect, nothing is perfect, but a very accurate prediction of the chromosome status of those cells, which correlates with the chromosome status of the embryo. The goal is to selectively transfer an embryo with the correct number of chromosomes that has a better chance, although not 100% chance, but a better chance of being able to result in a healthy ongoing pregnancy and live birth. Also, to eliminate the ones that we think result in a lot of the failed transfers, miscarriages and sometimes even termination.
In a nutshell, basically, it’s a selection tool to help us identify chromosomally normal embryos and try to transfer those one at a time. That’s really what my prior research focused on. When we know the embryo is normal, they do really well one at a time. That also has dramatically lowered the multiple pregnancy rates and a lot of the complications that went along with that.
Dr. Aimee: I love that, it’s a selection tool and it’s not perfect, but it is helpful. And I agree with you. Why is this study getting a lot of attention right now?
Dr. Eric Forman: Well, The New England Journal of Medicine is a very prestigious journal, so I’m actually very happy to see PGT-A in maybe the most prestigious journal. Every trial in The New England Journal of Medicine gets circulated, I think, in the media. So, that’s one thing.
But this was a large multi-center trial. Although I have concerns about some of the design and the conclusions that we’ll get to, I think it was well done. I think the PGT-A analysis seems to be done very well. The aneuploidy rates in this population are consistent with what we see in our clinic and the labs that we work with. They got very good results with the normal embryos that were transferred. So, I think it was a well designed trial.
It’s getting a lot of attention. For whatever reason, I think there are a lot of naysayers out there and detractors or skeptics. I tend to be skeptical and wait until there is good evidence before adopting things. There’s definitely a community that is anti-PGT-A and anti-“add-ons.”
The final conclusion of this trial was that PGT-A did not improve accumulative live births from an IVF cycle. Those who want to detract from PGT-A say this doesn’t help, it’s expensive, and it’s a way that maybe patients are being taken advantage of. But we dig a little deeper into the details, which we will, I come out with a different conclusion from the same data.
Dr. Aimee: You had concerns about the study design. I imagine that has something to do with your different conclusions. Talk to us about the study design and what your concerns are.
Dr. Eric Forman: My main concern is that this was a young population. I offer PGT-A to every patient doing IVF because you can have a trisomy miscarriage even in your 20s, but I strongly recommend in that age group. I do more strongly offer or even recommend in the later 30s and early 40s age group where we know there becomes even a greater than 50% chance of aneuploidy in even good quality blastocysts. I really want to transfer one embryo at a time, but it gets really difficult in that age group.
In this study, it was limited to women aged 20 to 37. For the women that had the highest rates of aneuploidy babies, studies needed to still prove this baby had the most benefit from PGT-A were not included. Also, though these patients were good responders, they produced 20 eggs, and on average seven good quality blastocysts, which is great. But when we practice PGT-A, usually we biopsy all of the good quality embryos because we want to be able to select from all of them.
If it was always the case that the best looking embryo was normal, we really wouldn’t need to do PGT-A, we could just transfer the best looking embryo. Sometimes it’s the fourth or fifth best looking embryo that may be normal or may be some combination therein. There are sometimes patients who produce a very high number of blastocysts and choose to only test a portion of them, but even then it’s usually six or eight. In this study, they limited the PGT-A group to biopsy only their three best quality embryos.
This study was different from typical studies were they look at only one transfer of an untested or tested embryo. In this study, the control group that did not do PGT-A had the opportunity to transfer three times and it was not clear if they just required a single transfer.
I think on average there were 1.3 embryos transferred, so sometimes they must have transferred two. But in the PGT-A group, they could only choose from those three embryos biopsied, and so many of those patients didn’t have an opportunity to even have three transfers. We don’t have all of this data, but I think it’s reasonable to assume some of those patients had four, five, six embryos, but maybe only one out of three was normal and it didn’t implant, and that was it, they didn’t have another chance. But they might have if their fourth, fifth, or sixth embryo was normal.
That’s my concern. I think it was a good outcome to look at, but I think a better design would have been the way we practice. Biopsing all of the embryos, no matter the number of euploid embryos the patient has. I think revealing mosaicism is also crucial, now we do have a lot of data about mosaic embryos and how well they perform resulting in healthy babies. If the PGT-A patients had abnormal or mosaic embryos, those were not transferred, but again, if they had been able to biopsy all of their embryos, more of them might have been able to have two or three transfers.
Again, if we’re looking at all of the embryos and eventually you transfer all of them, PGT-A does not make the embryo better. We just hope that it doesn’t harm the embryo by biopsying it. I think this study even goes a long way towards supporting the safety of it. We can talk about that in a bit. But it’s not going to make more babies out of the same group of embryos. It just hopefully gets us there in fewer transfers and fewer miscarriages. Again, if we just looked at the first three transfers, it’s even possible that there might have been more live births if that PGT-A group had an opportunity to work with all of their embryos.
Dr. Aimee: What you’re basically saying is what we do in the real world isn’t how this study was designed. Can you just share with our listeners what we do in the real world compared to how this was, just one more time for the people who are listening?
Dr. Eric Forman: Yes. Typically, in the real world, all of the good quality blastocysts are biopsied and tested, and then we select amongst all of them. Especially for couples who want more than one child, or maybe are in their later 30s, that’s a big advantage that’s often overlooked from PGT-A, because it’s nice and helpful to know if some of those other frozen embryos, even if the first transfer works, how many of the other ones are normal and would it be beneficial to consider another retrieval “banking” if maybe none of them or only one of them are normal.
We do usually test the whole cohort and then select amongst them, but here the PGT-A group had sort of a limitation that they only tested three of them. Then they were looking at up to three transfers, but many of those patients weren’t able to transfer three normal embryos, but they may have had other embryos frozen. If you look at some of the supplementary outcomes, it wasn’t statistically significant, but there actually was a numerically higher live birth rate if you looked at all of the outcomes. We don’t know all of the details, but maybe they transferred some of those untested embryos, some of them got pregnant on their own, but basically within a year, having done PGT-A, there were actually more babies born.
Again, not statistically significant, but I think again it points to the safety of this approach that it’s not “throwing away” lots of potential live births, which is an argument that has been debated for years amongst those who are skeptical of PGT-A. They think that the biopsy is harming a lot of embryos, that technology is overcalling them abnormal so we’re losing a lot of live births. Those are definitely valid concerns. I think it is a risk and it could be done incorrectly, but when done well, which it appears like it was in this trial, that’s one of the take home messages for me that there weren’t fewer even with these limitations and the PGT-A group did really well.
Dr. Aimee: I love that you brought that up, because in this patient population being under the age of 30, you would imagine that they would probably go back in two years to try to conceive again, on average, with another embryo that’s frozen. You and I make projections for patients every single day about what their fertility will be like in two years, so we’re not just thinking about a patient’s first baby, we’re thinking about their family size goals when we’re trying to use a selection tool in their particular case. Do you agree?
Dr. Eric Forman: Yes. Exactly. I think this field is moving forward and the research is getting better, so it’s not just looking at pregnancy rates, it’s not just getting pregnant, you want to have a baby, so now you look at live birth rate, but even that maybe if you have other embryos frozen, it’s cumulative live birth rate. Even beyond that, it’s the desired family size. The research hasn’t gone there yet.
But yes, I think one of the major benefits of PGT-A is for those who want two or three children, it helps them plan and see if they are likely to achieve that from one egg retrieval when they’re as young as they’ll ever be, or should they try to get more embryos while they’re still in that age group, depending on the potential of the embryos that they have frozen.
That does bring up another point that there are a lot of additional benefits that although live birth is important, it’s not, in my view, the only thing. I think our goal as reproductive endocrinologists, fertility specialists, and the ultimate goal of IVF is to help couples achieve their desired family size, one healthy baby at a time, while minimizing the burdens that go along with it, which include cost, disappointment, miscarriage.
You see a lot of comments in the media that say PGT-A isn’t necessary, but if you start talking to patients, which I have and you do every single day, and if you said, “You could do three transfers and you won’t get pregnant, you’ll have a miscarriage, but then you’ll have a baby, or do a transfer, get pregnant, have a baby,” what are they going to choose?
I was involved in randomized trials and I know in that setting there are research nurses and coordinators and patients agree to follow the protocol, but in the real world it’s very difficult to say we’ll just transfer one embryo at a time and eventually one will take. That may be true, but people drop out, they get discouraged, they insist on transferring multiple embryos. So, PGT-A really has, I think, made single embryo transfer, at least for the first couple or few tries, the standard and everyone has been able to buy into that.
Dr. Aimee: I agree. Thank you for this incredible summary. I will include this in my IVF course that I have online for folks as they’re preparing for their IVF cycle. I think that not everyone gets as adequate informed consent as they could or should when it comes to PGT-A, so I feel like no matter what your age is this would be a really important show for people to listen to.
Is there anything else you want to share with our listeners today?
Dr. Eric Forman: I think just digging into the details a little bit more of this trial that were somewhat glossed over was that there was a higher live birth per transfer. Both groups did really well. I forget the exact numbers. I think it was 65%. If you look at the number of transfers performed to achieve these babies…
Dr. Aimee: You’re right, it was 65.4%.
Dr. Eric Forman: Versus 59%, so not a huge difference. This kind of shows that in a young population you don’t “need” to do PGT-A. They did really well, 59% live birth per transfer is great, but it was significantly higher. Again, I don’t think the biopsy is significantly harming the embryo if done safely and well.
The miscarriage risk is relatively low in this young average age 29 population, but it’s not zero, and not all miscarriages are due to chromosomal aneuploidy, but a lot of them are. There was roughly 12%, 8-something-percent was over a 40% higher risk of miscarriage. Although, it still was only 12%. As you know, each clinical miscarriage is devastating. It takes months to recover from. Again, patients get discouraged and maybe don’t come back for a while. Preventing that is glossed over by, again, critics who say what doesn’t improve live birth rates, you get the same number of, or you get a not inferior number of babies. Yes, but getting fewer miscarriages is a big deal.
Again, my take home is that even though this was a study done in a young population, that’s not the population that probably benefits most from PGT-A, results still ended up with about the same number of live births with fewer transfers, so fewer failed transfers, and fewer miscarriages. So, I think this is more evidence that PGT-A actually does work.
I think if done appropriately, there is a role for PGT-A, it can work. It’s not required or mandatory, everyone doesn’t have to do it. Young patients can do well if they’re willing to transfer one embryo at a time. Even older patients, because it’s not perfect. If they really wouldn’t terminate a trisomy 21 pregnancy, not everybody would, or they would be uncomfortable not transferring that embryo, then it’s reasonable not to do PGT-A. If they’re willing to go through a failed transfer or miscarriage and ultimately they want to give every embryo a chance, I think that’s reasonable too. But I think there is a role, it can be done effectively, and it can really help enhance selection for single embryo transfer.
Dr. Aimee: Right. As a patient, you should be able to describe to your doctor what your priorities are so that you can figure out what the right IVF plan is for you.
Eric, thank you so much for coming on today’s Egg Whisperer Show. For people who want to follow you or see you as a patient, can you tell us where they can find you?
Dr. Eric Forman: My handle would be @EricFormanMD. I’m on Twitter, Instagram, and Facebook. I really enjoy following you and your posts and your podcast, so keep up the great work. I look forward to speaking to you again. Thanks, Aimee.
Dr. Aimee: Thank you, Eric.
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