Hello, everybody. I understand we're live, so excellent. Good morning, good afternoon, good evening, depending on where you are in the world.
Welcome to another Journal Club Global sponsored by Fertility and Sterility. We're here at the Park City Fellows Retreat, and we have a lively performance and discussion for you. We are going to talk about revisiting the STAR trial, and it's going to be in the format of a debate about PGTA.
So I have next to me wonderful teams of fellows who are going to take the pro and the con side. And you in the audience and online are going to be the, I guess, the scorekeepers. We're trying to convince you.
So we're going to use the STAR trial, which is entitled Preimplantation Genetic Testing for Aneuploidy versus Morphology as Selection Criteria for Single Frozen-Thawed Embryo Transfer in Good Prognosis Patient, a Multi-Center Randomized Clinical Trial published in Fertility and Sterility a few years ago. It's now a classic article. Let's just call it the STAR trial.
It's easier. And in a true debate format, we're going to take turns trying to convince you of it after we give a brief synopsis of this article and another similar article in some inferior journal that also regarded PGTA. But to make this a debate format, I'm going to do a quick poll, and we're going to what your position is today or right now.
And then after the debate, we're going to do a re-poll. And the winner is not which side you take, but who had most people switch sides. So the question is, and we'll do it by a raise of hands, and hopefully we can all kind of take a straw poll.
The question is, does PGTA improve patient outcomes? So who votes right now? Yes. It's me. It's me.
Let me say this again. Hang on a second. Hang on a second.
This is a straw poll. I'm not going to remember what your vote was. So I need you to raise your hand high to answer this question, and we're going to see if you're convinced otherwise.
So does PGTA improve patient outcomes? That's the question. Just put your hands up. I'm not going to remember.
I get 27. Does anyone get a different number? I was guesstimating. OK, 27.
At the end of the debate, we're going to find out. I'm assuming the others of you, you can't abstain. So the others of you say it does not improve patient outcomes.
At the end of the debate, we'll decide whether we've switched or not. All right, so let's start with who's presenting the STAR trial briefly, and we'll go with there. All right, so my name is Dr. Ali Bazi.
I'm a third year fellow at the University of Michigan. So with regards to the STAR trial study design, this RCT recruited patients from 34 clinics and testing in nine laboratories across the US, Canada, Australia, and the UK. Females ages 25 to 40 years old undergoing IVF with autologous oocytes with at least two blastocysts of sufficient quality for biopsy and vitrification by day six were included.
And the primary exclusion criteria included diminished ovarian reserve, more than two previous failed IVF embryo transfers, more than one miscarriage, azoospermia, or severe oligospermia. The intention to treat population was defined as patients undergoing randomization. The patients, physicians, and IVF staff, but not the embryologists, were blinded to the randomization.
Patients were stratified by three female age groups less than 35 years old. 35 to 37, and then 38 to 40 years of age. Individual patients were randomized to PGTA or control group, but not randomized by clinic of origin.
Morphologic assessment was performed in all patients prior to vitrification, and the remainder of the embryos were biopsied and vitrified. The embryos transferred in the control arm was the one with the most favorable morphologic assessment, while in the PGTA arm it was the embryo that was euploid as well as the one that was most favorable from a morphologic assessment as well. PGTA for aneuploidy of all samples was performed using a standardized PGS assay.
Only those that were euploid were eligible for transfer. The pregnancy outcomes per intention to treat at randomization and per transfer were reported. Primary outcome was the ongoing pregnancy rate at 20-week gestation, which was reflective of the live birth rate.
It was determined that 300 patients in each arm would provide 85% power. So the study population included 984 consented patients from October 2014 to January 2016. 661 were eligible, with 331 to the control arm, of which 313 ended up receiving the embryo transfer, and then 330 to the PGTA arm, of which 274 received the embryo transfer.
Overall, the demographic characteristics for the two arms were similar. An average of 7.4 day five or six blastocysts were obtained per patient in both arms. Of the 2,178 blastocysts in the PGTA arm, 939, or about 43%, were reported as euploid, and the percent of euploid decreased with increasing maternal age, from 48% for women less than 35 years of age to 35.5% in women 35 to 40 years of age.
So with regards to the clinical outcomes, the ongoing pregnancy rate, or OPR, per transfer at 20 weeks gestation was not significantly different between the PGTA and the control arms for either embryo transfer population or the intention to treat population. Similarly, the rates of negative results, such as miscarriage, biochemical pregnancy, elective termination, were not significant. A post hoc subgroup analysis did reveal a higher ongoing pregnancy rate per transfer in women aged 35 to 40 years of age after PGTA, 50.8% to 37.2%, but not in women aged 25 to 34 years of age.
The ongoing pregnancy rates were not significantly different between arms for these two age groups when analyzed per intention to treat. Miscarriage rates per transfer were 10% regardless of maternal age in both the PGTA and control arms. So to evaluate whether individual lab practices may have contributed to the lack of significance in primary outcomes, variability relating to morphologic classification as well as variability at the level of the clinic sites and genetic testing laboratories was evaluated.
Embryos with a broad range of Gartner scores were transferred, but the overall pattern was found to be similar between the two groups. But when the Gartner scores were mapped to a good, fair, or poor quality score, it appeared that more poor quality embryos and fewer good quality embryos were transferred in the PGTA arm than in the control arm. Additionally, the number of samples in the PGTA arm analyzed at each genetics lab varied and so did the sample size at the clinical sites.
So overall in conclusion, the STAR study showed no overall improvement in ongoing pregnancy rate and live birth rate in women age 25 to 40 years, but does support the use of PGTA for women age 35 years to 40 to improve outcomes for frozen-felled embryo transfer. Okay, we're gonna go with brief kenopsis of the second paper just for the sake of discussion and then we'll go back to the pros and cons. Excellent.
Thank you, Dr. Barnhart. I'm Meg Sachs. I'm a third year fellow at the University of Cincinnati.
The next article we wanted to include for discussion is Live Birth With or Without Preimplantation Genetic Testing for Aneuploidy by Yann et al. published in the New England Journal in 2021. In this multicenter non-inferiority RCT, oh, thank you, non-inferiority RCT subfertile women 20 to 37 years old with three or more good quality blastocysts were assigned a PGTA or conventional IVF.
Patients were recruited at 14 academic fertility centers throughout China from July 2017 through June 2018. Blasts were screened by next-gen sequencing in the PGTA group are chosen by morphologic criteria in the conventional IVF group. The primary outcome was cumulative live birth rates.
You might notice this is different from the STAR trial after up to three embryo transfers within one year of randomization. The authors set the non-inferiority margin at 7%. They enrolled a total of 1,212 patients with live birth occurring in 77.2% of the PGTA group and 81.8% of the conventional IVF group.
So again, the live birth rate was actually higher in the conventional IVF group. They also examined clinical pregnancy loss and found that clinical first trimester pregnancy loss was slightly higher in the conventional group at 10.5% versus 7% in the PGT group. Overall, the authors concluded that conventional IVF is not only non-inferior to PGT, the live birth rate was numerically higher.
As part of the Khan team, we do wanna highlight this article and I do wanna give some credit to Dr. Jing who has affectionately coined us the PGT-nay team. With that, let's start our opening arguments. Dr. Jing.
Hi, I'm Katie Coyne. I'm the third year fellow at University Hospitals in Cleveland, Ohio and I will start the arguments for the pro side. We believe that PGTA should be offered to patients and particularly recommended in certain clinical situations such as advanced maternal age, recurrent pregnancy loss, recurrent implantation failure and with high responders.
This is because PGTA may not only improve the live birth rate but may also reduce the miscarriage rate, time to pregnancy and overall cost. In terms of patients with advanced age, the STAR trial did demonstrate an increased ongoing pregnancy and live birth rate with PGTA in the 35 to 40 year old group when analyzed per embryo transfer. Although this trend did not persist when analyzed per intention to treat, the study had several limitations such as eligibility criteria biased towards good prognosis patients and being underpowered that likely prevented a true effect from being demonstrated.
Similarly, the YAN trial did not demonstrate a significant difference, however, they also only enrolled good prognosis patients and only up to age 37. Additionally, several more recent studies such as by Hipp et al in JAMA 2022 showed that in older women, cumulative live birth rates were higher in cycles that used PGTA compared with cycles that did not. And this logically makes sense as we know that there's an increased aneuploidy rate with increasing maternal age.
Neither the STAR trial nor the YAN study demonstrated significant reduction in frequency of miscarriage with PGTA, but this is again likely not generalizable as those with recurrent losses were excluded from the studies and other newer trials such as by Bott et al in Human Reproduction in 2022 demonstrated improved live birth rate with PGTA specifically in RPL patients. Lastly, with high responders and therefore those with likely a surplus of embryos, PGTA is extremely useful for prioritization of embryos selected for transfer, especially as our political climate changes and access to reproductive care is limited in many states. Diagnosis of early aneuploidy can help reduce the number of terminations for prenatally diagnosed trisomies.
The technology used for PGTA has improved significantly over the years and now with the use of next gen sequencing and SNPs, we can feel confident with euploid results and thus this assist with selecting a single embryo for transfer and in reducing the number of transfers needed to achieve a live birth. Good morning everyone, I'm David Huang and I'm the fellow at University of California, San Francisco. As the person doing the opening statement for our team, I'd like to present our point of view using one of the Hippocratic oaths, do no harm.
So PGT is a procedure and like all other procedures and surgeries, the expertise of the procedural list is highly important and that's hard to control or standardize across all nations. In 2017, there's a study showing that from trophectoderm biopsies where you have relatively higher DNA content that there's a lower life birth rate after transfer which signals that the PGT process likely has a mechanical impact and potentially harm the viability of these embryos. In addition, PGT like any other clinical test is definitely not perfect.
There's nothing that's 100% and in our field, I think even 1% for some patients is what they're striving for. So for that, I think it's important to realize that and now we know that complex mosaics depending on the degree of mosaicism, the chromosomes that are involved potentially could still yield life birth and many of these complex mosaics in the past are traditionally discarded. Furthermore, in basic science findings, I always say mother nature is way smarter than all of us.
We are increasingly recognized that chromosomal errors are likely physiologic events that are present in pre-implantation embryos and the fate of these chromosomal errors and after post-implantation is unclear and there's some evidence suggesting that mother nature has corrective mechanisms in place and to me, that's extremely important because the only thing I know for sure is the embryo that's not gonna give you a life birth is the one that you didn't transfer or the one that you threw away and for our patients, especially the poor prognosis patients, this is so important and these are also the ones that are excluded from both of these trials in these high-impact journals so I think it's important to recognize that and lastly, as REIs, I think our responsibility to our patients and to society doesn't end at a successful pregnancy scan. Anything we do has potential implications and long-term health effects of children conceived via IVF are still pending and I think for anyone who's observed a PGT, it's not hard to imagine that it could potentially induce epigenetic changes to these embryos that are only 60 to 100 cells and we already have evidence that PGT are associated with increased obstetric outcomes for both the moms and the babies so in conclusion, from our opening standpoint, I don't think that we should advocate for routine use of PGTA because there's no strong, clear, conclusive clinical evidence that it helps. It's not a perfect test that could potentially harm many of our patients.
Hello everyone, I'm Victoria Jang. I'm the third year fellow at Massachusetts General Hospital in Boston. That is a very strong opening statement, Dr. Huang and I have many thoughts on how we can also do no harm by having lots of options available from a reproductive autonomy standpoint and that the evidence is inconclusive in both directions and so I want to really build off of Dr. Coyne's leading points.
It's important to consider the unique benefits of PGTA, particularly in embryo selection. To date, we have very limited tools to be able to assist with embryo selection and embryo morphology has always been kind of the mainstay before we really started expanding the utilization of PGTA. While there are some noninvasive techniques in the pipeline, some of which my team has worked on at MGH, there are none of these methods have come to reality for reproducibility, reliability, or accuracy.
One huge benefit of PGTA would be optimizing embryo selection to prioritize single embryo transfer, further reducing multiple gestation pregnancies. I don't need to remind anybody in this room that back in the mid-1990s, more than 30% of IVF cycles resulted in twin or higher order pregnancies. But in 2019, this rate has remarkably dropped to less than 7% with increasing focus on single embryo transfer and partially in due to the use of PGTA.
While there are pitfalls, as you have mentioned, to PGTA, it has still played a critical role in the success and the utilization of single embryo transfers and their improved outcomes throughout the years. Emphasizing Dr. Coyne's message further, while PGTA is not appropriate for every population, it still can be helpful for specific populations. We are not saying that PGTA should be offered to every single person and routinely used, but for specific vulnerable populations, it can provide clinical benefit and information that we otherwise would not have, specifically the populations that are advanced maternal age, recurrent pregnancy loss, and recurrent implantation failure.
Additionally, I posit there is important value for PGTA in gestational carrier cycles. A SARTCORS analysis of nearly 4,800 GC cycles from 2014 to 2016 analyzed birth outcomes following either single or multiple embryo transfers with and without the use of PGTA. And they saw that the live birth rate among these patients went from 42 to 45% with the multiple gestational, multiple embryo transfer group to 1.4% of multiple gestations in the PGTA single embryo transfer group.
This study is strongly aligned with the continued focus and emphasis of ASRM for continued use and utilization of single embryo transfers, particularly in GC cycles, where even the ASRM practice committee opinion strongly suggests considering PGTA in these cycles if you're prioritizing single embryo transfer. From a cost perspective, selecting euploid embryos in these cycles may decrease the time to pregnancy and total number of transfer cycles that GC needs to undergo and achieve pregnancy, helping with the burden among intended parents. While it isn't the perfect tool, if you can have a technique that can select implantation and live birth potential up to and sometimes exceeding 50% independent of age, can you say it has no value and can you conscionably not offer it to your patients? We'll get back to you.
All right, hi, everyone, my name is Zachary Walker. I'm a third year fellow at Brigham and Women's Hospital. So following my colleague from Boston, it's nice to be on the opposite side so we can argue a little bit.
But so I have been hearing all the statements from the PGT pro side as far as the populations that you believe PGTA is useful for and you guys have talked about it. You guys have talked about advanced maternal age, recurring pregnancy loss, recurring implantation failure, gestational carriers, and from our standpoint, we agree with you on some of those populations that PGTA would be useful for, such as recurring pregnancy loss because as we all know, we take care of patients who have the emotional burden of going through multiple miscarriages and giving them this additional information is something that is probably higher precedent in their kind of emotion going forward with another IVF cycle and having this information would be very, very important even if the patient is younger of age and not necessarily have benefit from the STAR trial or from the ANN study, but having them feel comfortable moving forward is very important. However, I would counter about the points about advanced maternal age and those with diminished ovarian reserve.
There have been several papers published about those, one particularly is the Gordon et al study that showed that if patients have less than three 2PNs, they never have an embryo to biopsy. Also, if you have diminished ovarian reserve, you're most likely not gonna make a blastocyst if your clinic is only doing day five transfers, it's not open to doing day three transfers, so you already are discriminating a certain patient population as well to try to get to this tool that you're having everyone do potentially. So there's been a recent study by Karaman et al who showed, was looking at what to do in patients with only one blastocyst which is a situation that many of us have been in after IVF cycle, only having one frozen, whether to do a PGTA biopsy versus moving forward with a transfer.
And something that we have come to find out in most studies looking at PGTA, they like to report per embryo transfer outcomes which, when you look at those stats, they look very nice because the numbers are high versus per cycle start which is what SART reports on and the numbers are more accurate in my mindset of how you counsel a patient coming into your clinic of what the likelihood will be from start to finish. And when you look at per cycle start, especially with the Karaman et al study, the live birth rates were higher in those who did not do PGTA versus those who did. So when you are dealing with this vulnerable patient population which you guys are reporting to use it for and you're giving these numbers, what is the actual starting line that you're reporting to these patients and are you ethically satisfied with giving those numbers knowing that it may not lead to somebody putting all this money into an IVF cycle, especially most of our states don't cover IVF and you're having them do multiple biopsies or pay for a whole cycle and never have an embryo transfer, is that the premise that we want to put out into the world as RAF physicians that, yes, pay all this money up front and we may never end up with a transfer.
And then where do we go from there? So I do want to put out that from the con side, we understand that PGTA is useful, but we need to kind of going off of Dr. Jiang, not have it as a requirement for every clinic or every patient population, but try to revisit the usefulness of the tool and find the perfect or best population that will be useful for. Did we get through all arguments? I think so. Okay, so you've heard both sides and I've heard a couple of the themes.
There seems to be some question, there seems to be pros, like there's reasons to do it and there's reasons not to do it. But let's focus on the question just for a second. Did we think that PGTA actually increases efficacy of an IVF cycle or are we just arguing that it's not a good idea? That it should only be used in subpopulations? I'll ask the pro-con first.
Yeah, I think that some of the things we talked about in certain populations, looking at things globally, depending on the patient diagnosis, that overall it could improve the efficacy of the IVF cycle, shorten the time to live birth rate, especially patients with certain medical conditions who are focused on making embryos can give them that rest assurance that what they have and what they're banking are euploid embryos and thereby allowing them to focus on other issues and other health concerns. What's your reply to that? Yeah, I think that's a great overall question but I think what we really need to examine here is if this biopsy truly is representative of the developing fetus, if we can assume that that trabectoderm biopsy is representative of that intercell mass, shouldn't we see a stark difference, not only negative findings which we're seeing in these trials but actually a really significant finding which leads me to believe we're either getting false positives, false negatives, or we're actually harming the embryo. I do wanna draw attention to one other trial.
There's a study, well, it's not a trial but a study by Gradi et al in 2018 where they looked at amniocentesis and chorionic villus sampling for mosaic PGT resulting pregnancies and they found that 86.7% of these pregnancies on follow-up amniocentesis had no sign of aneuploidy. So this to me is very significant. We need to not determine that these PGT biopsies really are 100% representative because again, wouldn't we find these stark differences in these randomized control trials that we've done? Can I ask a quick question about that? Do you think it's more so the PGTA technique or it's just not standardized that could potentially improve and that we have to work on standardizing how to do so across the country? Yeah, I think that's, oh, I'm sorry, Zach, did you? I was gonna say, I didn't mean to interrupt.
We'll go right to Zach after this. But I think it's important, that's an important question because we don't at this time have a standardized option for how we train for HCLD is my understanding. I know there's some recommendations from ASHRAE on how many biopsies you should have but do we hold everyone to the same exact standard and aren't those higher yield practices in clinics biopsying more frequently and perhaps having different outcomes that we can't generalize to our patient population if we're at a smaller practice? The other point I wanted to draw attention to is with not only the way that we conduct the biopsy and standardizing that but just like Dr. Walker said, how we report that is so significant and we as an overall society have to make sure that are we gonna report by transfer? Are we gonna report by cycle? Are we looking at live birth rate? Are we looking at ongoing pregnancy rate? And once we can come to a general consensus that we can get some really meaningful data.
Zach, take it away. Is that okay? I also wanna say I think this is a lot of what we're seeing in reproductive medicine is so many of the things that logically make sense have not been proven helpful and in all other fields of medicine, they go through rigorous scientific process before introducing it to patient care and there are many reasons why we all know that that is hard to do in REI. But again, there's no strong conclusive clinical evidence of benefit and the purported benefit is all done on post hoc analysis in these RCT trials which is hard to interpret.
And again, kind of what Dr. Sachs was saying, these discrepancies, I don't think it's purely because we are biopsying the wrong place. I do think Mother Nature has a corrective mechanism to correct itself during this periconception window and also the fact that these mosaic embryos, we know and actually from a recent study done at Penn where they imaged live embryos, we know that doing PGT induces nuclear shedding and that gets amplified. Is that the reason for mosaics? Because you're just inducing nuclear shedding.
So I think all of this again just goes back to the whole concept that you need to prove clinical benefit first before introducing it and then you can choose to, you can do further studies to see what is the right population to do them in and really introducing it to the market. I was gonna say one last comment to just kind of put things in perspective in our current field of me being a 30-year fellow, like I know everything about IVF, I don't, but I think we are in a situation in our field where we have academic practices versus private practices and different rigors on when to introduce new technology into our clinics versus what patients would want from what they're reading online versus what is offered at our clinics based off of the people above us. We all are scientists coming from very well-trained fellowship programs but when you get out into the actual world and you're having these patients come to see you about these different techniques such as ERA, PGTA, all these different biopsies, there is maybe somewhat of a difference in how quickly you may be interested in starting these things without having the potential barriers to doing that based on the setting that you're in.
So I feel like PGTA, since we don't really know its validation just yet, I would say it's the rigor of testing that Dr. Huang was telling us about that we are competing amongst ourselves to kind of have patients be seen as quickly as possible, go through the IVF process and trust us. And sometimes the data that we're telling them in the clinic may not be the one that you hear down the street. So I think that's also another conversation we need to bring into the fold about PGTA use.
I just have a quick comment too. I just want to reiterate that it's not a perfect tool but our job as physicians is to counsel patients on the most up-to-date evidence that we have to facilitate them making the best decision for themselves with what we have. So not a perfect tool but we're using it, it's out there so we should be offering it to our patients and counseling them for them to make that decision.
That's a good segue. So I'm gonna change this a little bit and ask you guys both questions. What is the reason to do a randomized trial? Anybody? It's a rhetorical question.
Is the most standard for bias and confounding? So it does. So it is what we consider the most powerful method to control for bias and confounding and get a true measure of the efficacy of an intervention. In this case we've decided is PGTA more effective than non-PGTA, right? So we have two randomized clinical trials.
We very quickly devolve into when we should use in the specifics and the pros and cons of it and into situations and I will agree with you that's outside the scope of a randomized trial because you can't take an individual patient, you have to look overall. I just want to read the conclusions of the STAR trial and let's talk about it for a second because we're doing a journal club on this trial. The conclusion, PGTA did not improve overall pregnancy outcomes in all women as analyzed per embryo transfer or per intention to treat.
There was a significant increase in ongoing pregnancy rate per embryo transfer with the use of PGTA in a subgroup of women aged 35 to 40 with two or more embryos that could be biopsied but that was not significant when analyzed by intention to treat. What does that mean? Sorry. So what does that, in other words, do you dispute that? What does that conclusion mean and do you dispute it? So when we were analyzing this trial and really reading and preparing for this journal club, what was actually striking to me is that this is a study that is commonly quoted by many REIs to be able to justify the utilization of PGTA, particularly among the women that are 35 to 40.
But I think that this trial also shows us the real challenges of being able to conduct a randomized control trial, particularly in a multi-center, multinational way and being able to really standardize the ways that we practice as a field. And so the way that I perceived this conclusion was was that so there is not a completely clear answer in whether or not PGTA is gonna be able to be effectively utilized for clinical efficiency, specifically among all women that were recruited in this. But there may be some value among some women with certain populations, particularly between the ages of 35 and 40.
And when you exclude women that are in the intention to treat analysis, particularly in this study, they were excluding women that did not have either, they decided that they wanted to pull out of the trial because they didn't want to be randomized, which is always a predilection that any person can have in a trial, in a fair conducted RCT. But they also excluded women that did not have more than one blastocyst, or more than two blastocysts that were able, so the choice of a blastocyst to transfer. Also, if you think about the women that were excluded in this trial, there were about 42 women that were excluded that really helped, really deterred us from being able to get that power that we needed to in that PGTA arm, so be able to get that number above 300.
And 65% of those women, or 25 women in that group, had at least one embryo that was PGTA tested that showed that they had a low level of mosaicism, or only one chromosome that was affected from a mosaic standpoint. And if you're thinking about the impact and birth potential of low mosaics, you may have actually confounded the impact or effect within this intention to treat population that could have not necessarily translated that effect when we're doing that intention to treat. Okay, that was a long answer for your, let's go to the other side.
What do you think of that conclusion, and what do you think? Yeah, I think, just being blunt about it, is that the study did not work. There was no difference. I mean, as you look through the stats of the study, when you read the methods, the study was underpowered.
Even looking at a 80% power, it was lower than that. And then also, they did not find a difference. And then, I've always been taught that a post-hoc analysis is not useful.
It's something that many studies may do to the case their primary objective was not significant. You do a post-hoc analysis to see if there is a difference in somewhere else, which is somewhat backtracking, which I found a little bit problematic with the study. And to quote some of these results from the study to lead people to do PGTA, I feel it's misleading.
But from my standpoint of the conclusion is that there is no difference, and PGTA did not significantly benefit patients overall, compared to conventional IVF. I'm gonna ask a loaded question, then we'll get to some questions. So the overall study said it didn't help, right? And that was the finding of the study.
Then we went and said, well, let's look at only the people that had biopsies. That's called per protocol, as opposed to intention to treat, right? They only made it to the biopsy. So it doesn't help all women, but maybe it helps women with a lot of embryos.
Well, it seems to help people only with people, I'm sorry, it only helps people in a higher age group. What does that mean about the lower age group? There's no answer overall. This group is higher.
What does that mean to the lower age group? To get back to the middle? Lower, yeah, it's lower. So it harmed people in the younger age group to get the middle. So that's an interesting question.
So back to you guys. Does that mean PGTA helps or hurts? I still think there are some limitations from the study to be really truly come to that finding. Most of the patients were, I think the average age was 33, and they only went up to 40.
So we're excluding some patients that we'd be seeing in our clinics older than 40. And again, all good prognosis patients. And then the other issue comes to not transferring mosaic embryos, which we are, I think most of us are at least transferring the low-level mosaics, and that can result in a normal live birth.
So I think that by excluding transfer of mosaic embryos in this study, the results are skewed. Okay, and what do you think that conclusion is that I just described? I think, well, one, it says that routine use definitely is not supported by this trial because depending on the way you look at the data at the age group, some may potentially benefit, but some may potentially harm, which brings, again, into the question of whether or not this test has a true, is a gold standard for whatever it's supposed to be doing. And there's a false positive, false negative rate, either through the biopsy result or the way that we're using and the way we're applying these results to our patients.
But then the question is, you mentioned a little bit earlier, Mother Nature, correct yourself, how do we measure that objectively? So when you have patients who come to you and sometimes their end goal, if they can just get the answers objectively, that's reassuring in itself. And the best we have right now may be PGT. So if we're not able to objectively measure the opposite side, Mother Nature correcting itself, maybe offering this by providing the risks and benefits and giving them those extra data points really helps overall manage their care and brings fulfillment to the patients.
I think our objective measurement would be looking at pregnancy rate or live birth pregnancy rate or however we want to define that in our conventional IVF group. Just because we can't see it developing or biopsy or have quantifiable data doesn't mean that we don't have the outcome that we're looking for. Let's open it up to outside.
I don't mean to dominate this and frame the issue, but what do you guys think to help you make your decision? And while I'm... I just have a question for both sides. Who bears the... You're talking about both of you counseling to some degree. Both of you guys agreed to offer counseling.
Who bears the burden of the recommendation and the ultimate decision? Is it the physician or the patient? I think that is an exceedingly complex question, particularly in the field of reproductive medicine. I think that we as the physicians have the burden to make the recommendations that we feel are a compilation of the education that we've received and the current data that's available through us, through our governing organizations and through the high-impact journals that are being published. But I think that ultimately being able to offer patients reproductive autonomies to a certain degree to things that we may not necessarily think cause harm.
I think one thing that was really challenging for me to really interpret in the STAR trial is that I don't necessarily interpret not improving as causing harm. I think that there's a difference between significantly reduced pregnancy rates versus did not improve or was non-inferior, essentially. And I think that that's what effectively the conclusion was within the STAR trial.
And I think what can be really challenging is as our reproductive field becomes filled with lots of different and varying opinions of the people that are kind of ancillary and also involved in patient advocacy groups, I think we have to really understand where the evidence is and really empower the patient to be able to make the best decision that they can, knowing that at the end of the day, there's also a lot of opportunities for patients to be able to seek care and get second opinions and be able to pursue that autonomy that they're looking for. Do you wanna tackle that? I'd love to connect Dr. Omertag's question back to Dr. Coyne's point about the current political climate. I think first and foremost, shared decision-making, patient autonomy.
We're here to be a patient liaison and help them sift through this remarkable amount of literature that we have and data, some better than others, but also we're there to be their support system. And when it comes down to it, we leave it at their decision whether they wanna do the PGT testing. But when it comes down to those further down the road implications like politics, I think it's really important to make sure that you're counseling your patient that if there is an aneuploidy finding, if there is a mosaic finding, if you wanna do a transfer of a mosaic or aneuploid, most offices are not going to allow that.
And what that means with this current political climate may have implications that we haven't even considered yet. All right, we have a question here and we do have our online audience. We already have multiple comments.
I just wanna say that David Ball, a PhD expert, asked the same question you did, Kurt, and cited a recent jarg study this year using SART data that suggested maybe there actually is harm in the younger patients, but you guys addressed that, but David Ball had that same question. Yeah, so I just want to answer Dr. Banhar's question regarding the conclusion from epidemiology standpoint. If you see a discrepancy between the intention to treat and basically put protocol, result that always should raise a red flag of potential confounding and unbalanced dropout.
That's first. Second is, my question for both sides is there have been basic science studies, one from Dr. Diana Bianchi in 1993 showing that the cells from trophectoderm derive, they belong to completely different lineages because there's a lineage split after the embryo is fertilized. They belong to different lineage from the parts that will become the embryo, the endoderm, the mesoderm.
And subsequently, more than 10 years ago, around 2010 to 2012, there are three studies that are showing if you take cells from unemployed embryos, you can derive euploid embryonic stem cells. So in the face of these basic science evidence, how do you justify to say there's even biological possibility that this is going to improve the outcome? I think that's a question for the pro side, as I've said that before. And thank you for that.
When you're thinking about it right now, at this moment, the best we have is the PGTA. Eventually, when we start looking at things like copy number variance of the inner cell mass, that could potentially change things. But I beg the question, if we start, we no longer offer this and we give a kind of a negative connotation, is the research gonna be further propelled to look at these other ways of accurately depicting the genetic makeup of the embryo? Thank you for that.
Any other questions from out? Hi, thank you so much. It's been great. My name is Eileen.
She, her pronouns, WashU first year fellow. My question is, I have a background in biotech and used to work for a company. And the next neighbor, my neighbor company was Illumina.
And Illumina is one of the next generation sequencing instruments. And I kind of have an experience with these equipment and how humans run it. There's always also error in that.
And I wonder if, and maybe how you guys calculate in this like potential false positive, false negative, are, we talked about the biopser, the embryologist taking the biopsy, but what about the equipment that we're using? Is that, how are we validating that, I guess? Are we looking at that? Thank you. I would say that is definitely an interesting question, interesting point to even all research about kind of validation tools and stuff, even for basic science, like is the equipment up to date? Are you using the correct protocols? Are the people, the technicians in the lab trained to do this? So I think these are kind of inherent flaws to any research design that is, that you can't catch or capture in anything, but would hope that they will be all like standardized in any project that you do, because I don't see how else you will be able to control for that in the studies that we've reviewed today. I think that, you know, from my own personal experience at MGH, the way that we do QIQC at our clinic, as well as considering the research that I've personally done in trying to better understand like genetic sequencing platforms, I think there's a twofold way that I would go about doing it, not knowing that this is necessarily the right way about going about doing it.
I know that for our clinic, for example, we do rigorous QIQC on any of the PGT cases at least quarterly throughout the year, and try to really flag any concerns for PGT errors. So like for example, one of the examples that we had was like if you were to hypothetically have a patient who had an XY embryo that was transferred, and then they ended up doing a prenatal anatomy scan and showed that it was an XX embryo, or an XX fetus that was developing, right? And so that would be a classic example of somewhere along the pipeline there was some sort of error, particularly in the sampling, in the processing, in the shipping, or the testing, or the results reporting, or even the embryo transfer and the embryo thawing process that you were trying to isolate where that error is. And so I think rigorous QIQC, would you work with your embryology lab to make sure that if you have a patient with one of these errors or any of these concerns and really trying to do root cause analysis is important to identify whether or not you need to switch labs.
I think also any kind of representative from the lab that you're going to, you should be empowered to be able to talk to the genetic counselors, as well as the technicians that are the known people that are running the machines, that know the quality assurance processes within the machines that they're doing at these companies to be able to know that the lab that your clinic has chosen is a reputable lab that is offering reliable results. I think one thing you should really consider is how do they report aneuploidy? I think every lab has a different threshold for which aneuploidy is reported. So is it a 50% threshold? Is it a 70% threshold? Are you having your clinic report mosaicism? These are all really important questions to ask your embryology lab.
Just like a one sentence about that. So, you know, are we doing our patients that just discuss it by saying PGT is good or bad, or should we first standardize all the things we just discussed right now? The machinery, the person doing the biopsy, the lab itself, and then make that conclusion. I think it's a little bit too early to say, well, definitely, it's not proving outcomes, so, you know, let's stay away from that.
Or should we work on standardizing and then really test it and see the clinical utility of it? I'm gonna jump in with a Kurt Barnhart-ism and then we'll get back to the questions. I'd like to clarify things from a methodologic point of view. This is a test to try to diagnose the embryo.
There's four phases to making this work out. The first is, does your test do what it does? Technical validation. Does my biopsy read the right thing? Am I reading the right genetic code? Do I get the same thing again and again? And that has to do with machine and error.
The second question is, is the result I get predictive of what I think it is? We have very little information on that. In other words, this embryo says it's aneuploid. This embryo says it's mosaic.
This embryo says it's normal. Is that true? And we're just starting to learn that now with some of these, it's a kind of strange terminology called non-selective studies, but you have to put the embryo in to find out if the prediction was true or not. The third stage of the development is, does the technique as a whole improve outcomes? And that's what the STAR trial was.
That's a randomized trial. Does technique A result in improvement than technique B? And then the fourth phase is actually post-marketing or basically, now that I'm using it, what are the metrics that have to be reported to ensure I'm doing it properly? So there's four phases here. We jumped right to phase three in the STAR trial, and I'm not trying to give my opinion here, but whenever a randomized trial doesn't show the answer you want, you find reasons to find out why the trial wasn't done right.
And people go back to say, well, it was a subgroup, or well, the test wasn't a good test, or now I have a better platform. May or may not be true, but we've done the phase three trial to say, does it work or not work? And the answer is no. And now we're jumping to different situations about yeah, but.
So anyway, that was my pontificating. There were some other questions I saw, yeah. Yeah, we'll get to that in just a second.
And we did have Dom DeZiegler in Paris, one of our associate editors, had a question that you guys essentially just answered, but the follow-on to that is, do you think, based upon the discussion we just had in the lab methodology, that that was more likely to bias the STAR trial towards the null or towards a significant finding? And then we'll get to our question. Anyone wanna take a stab at that? The question's about lab error. I think I'm gonna paraphrase Dom's question.
If the test was not perfect, the test itself, does that, how does that affect the randomized clinical trial? I think it would bias against the null. I think it would bias to the null, right? If your test was really not showing what you thought it showed, then how is it going to improve anything, right? So in other words, if it had an efficacy, it would not show it, and if it showed a harm, it would not show it, because the test wasn't what you thought. So I think as a general epidemiologic point of view, if your methodology is not doing what you think it does, you're gonna bias your study to the null, and that's one of the strongest arguments I've heard in this field, is that the STAR trial failed because we weren't very good at doing PGTA yet, right? Now, take that as you will, but again, improving the genetic assay to saying now I can do next-generation sequencing or now I can do SNP arrays is still not, is only at phase one.
It's the technical validation. We still don't know whether your test answer predicts the truth, and then we don't know if when you use that test in a population, whether it actually does benefit or harm. So the question is, can we really say that it's beneficial at this point right now and make a decision one way or the other? Right, and the other question, again, is in perfect hands, you might get one answer, but in universal use, you're gonna get a different answer, right, and that's, again, what a randomized trial does, and that's why sometimes methodology fails because in all hands, it's not as good as the perfect hands.
I think this is something that's really important to highlight for our field uniquely and especially to all the fellows listening today is that perhaps we're one field that's gonna get, I hate to use the word manipulated, but into hopping on new technology sooner because we have those patients who want everything. They wanna do anything possible, and we want that for them, but we need to be cautious and not jump to introducing things that we don't have the supportive data yet. All right, we have another audience question here, and then I'll get to the middle.
Hi, this is Gratia. I'm one of the REI fellows at Stanford. Previously to be a fellow now was a geneticist in an IVF clinic, and I was part of these discussions from the post-discounseling.
So going back to the question of Dr. Omertag, so we ultimately decide it's a complex discussion, especially when you have a lot of abnormal embryos, and I wanna highlight one of the few points. One, the pre-test counseling, we need to do better at that because definitely patients have different expectations of what we, of the test, and then when we go back and discuss the results, it's sort of there. They thought when I screened for autism, congenital heart defects and others thing that definitely are not part of these tests, and also mentioning that it's a screening tool, right? So post-test testing during the pregnancy is strongly recommended, and I will argue for more abnormal than CVS.
And then the other important piece is sort of that discussion. Ultimately, the patient really asks you, you are the geneticist, what is your decision? Which embryo would transfer? You have seen babies born with these anomalies or these chromosomal abnormalities, and it's still complex, right? Because we don't know how to truly extrapolate that from the newborn, right, or the infants, or even younger people that may explain, express something as they grow. So my question to you guys is more in terms, and I wanna hear both sides.
What are, now based on what we read in these two articles, how that pre-test counseling will change based on expectations? What are some of the key points that you will discuss with your patients based on these articles, and then set up that expectations? Any time, so I think one of the great parts of having a continuity clinic is you really start having these conversations. And any time that I talk to any patient that comes into the door that says, I really wanna get PGTA immediately, 32-year-old coming in with her partner, they can't get pregnant, it's been a year, they're like, my friend got this test, and I wanna be able to get it because you're gonna tell me that it's gonna reduce my risk of miscarriage. What I tell her is exactly what you said.
This is a screening test, it does not have a diagnostic test to be able to confirm this information, and you still need to do prenatal genetic testing to be able to verify that this is gonna be a healthy pregnancy as far as any employee. I always say that there are certain populations that this can benefit, and that the evidence is not completely supported, 100% use in every single person, and it's not a routine tool that we can use reliably. But the technology's continuing to improve, and we're continuing to do studies as a field to be able to better understand the best utilization of this technique.
And so I think that at the end of the day, this may not necessarily help you in your journey to get pregnant, but this is going to be something that can be a tool that if you wanted to be able to use this, then these are the caveats and the pitfalls of the technology that exists. But there are limited benefits for somebody between the ages of 35 to 40. I think we would agree with a lot of what Dr. Jing has said in terms of risk-benefit counseling, but one thing that I think is really important to include is the mosaic counseling, and that just as you had mentioned out in the crowd, that there are a lot of different chromosomes that can be affected, there are multiple at once, and that we might not know what that means for a developing fetus, or if that's gonna be representative.
There are some great studies out there. We did some deep dives in our research into mosaics in preparation for this journal club, and they do characterize some of these mosaicisms, but at the same time, making sure that the patient knows this is not 100%. In fact, there is possible harm.
In fact, there is misleading reporting, and that ultimately we might not know what it means, and that might prohibit a transfer. I would also add a little tidbit, because we all practice in different states with different insurance coverages, and PGTA is not covered by insurance in any state that I'm aware of, but practicing in Boston, mostly everything is covered, so when patients are adding on this simple test, it seems very not expensive compared to another state where they're paying everything out of pocket, so I would say the counter argument is that if you're working at a clinic where every patient's coming in to do PGTA, counseling against, if a patient comes to you and say, I wanna go against what your practice does and not do PGTA, how do we counsel that? Or have that patient come through and your partners may not agree with that, or how do you do that kind of conversation? I've never been in that situation, so I'm curious to know if there are any physicians out here or somebody who wants to kind of comment on going against the grain to your practice and not doing PGTA when routinely everybody else does. Maybe there was a question over here, go ahead.
Yeah, I had two questions, but one of them kind of goes along with insurance coverage, so I'm Lisa Shanley, I am from Emory University in Georgia. We do not have coverage for IVF, so most patients are paying out of pocket. For the PGTA team, how do you justify having patients pay for a test that has no proven benefit to them? And for the PGTA team, how do you justify making patients pay for one or two failed transfers when having done PGTA may have got them to a baby faster? I can start with the pro side.
So when we think about costs overall, there is a cost of PGTA, but then you also have to think about the cost of embryo transfers, because that's not cheap either, and not just the cost, but the time. So I do think you have to kind of weigh out what the costs are gonna be, and it's specific to each patient, and you can counsel them appropriately again, but I wouldn't say that it's significantly causing a burden more than multiple transfers would have, and then of course we all need to advocate for increased insurance coverage to include PGT. And for me, I think the cost is defined so differently for so many of our patients, and truly all our patients are different in terms of their circumstances, where they are mentally and psychologically, so I think my counseling, I would probably have a general counseling like what we've discussed, but depending on the patient's circumstance, it changes how I think.
Is the cost of a failed transfer more than you having thrown away a potentially viable embryo? And for me, if I'm a 43-year-old with an AFC of five, you are telling me that this test is not perfect, I'd rather have a failed transfer than you throwing away anything that can give me a small chance of giving myself an autologous, oocyte-generated pregnancy. I'm gonna take the prerogative now and see if we can wrap this up, because about four minutes. I'm gonna re-ask the question, but before I do, remember the question, the question isn't, is it a good tool? Are there patients to use it in? Should we offer it? That's not the question.
We can get to that in a second. The question was, does PGTA improve patient outcomes? So let's re-take the vote. I asked that question on purpose for this moment.
So who believes that PGTA, based on this discussion, improves patient outcomes? Oh my god. We had a 27 versus 68. We had 30% of people before, so now we have one, two, wow, three, four, five.
You're all safe, and no one's, you know, five. This is a safe space. This is a safe space.
We're just tracking which programs they're coming from. So we went from about 25% thinking it was to around 5%. So if I had an award, I would give it to the con side.
So we've actually switched people's minds on that specific question, right? So congratulations. But now I'm gonna ask you the other question, because I think it's different. How many think PGTA is a useful tool? And I can't count, because it looks like everybody.
So the output of this isn't that not, that to discard the baby with the bathwater. The object of this journal club was to improve us, because I like Kenan's question, because on the boards, and not to get too personal about this, when someone kept telling me on the boards, it's the patient's choice, it's the patient's choice, it's not the patient's choice. The patient is not the educated REI fellow.
You need to give good credence and good counseling to your patients to help them make the choice. You just can't say, I got two choices, which do you want? It's not ordering an appetizer at a restaurant. So that's my take on it.
So I will give the pros and the cons, a final statement on this. Why don't you guys think of what you want to say? Again, now you can open it up, not just efficacy. Go ahead.
So I know that we've heard a lot of data today, a lot of different opinions, and a lot of really interesting, thoughtful comments on the utilization of PGTA, particularly in the context of clinical efficacy. I think that the answer is still not there, and I think that that's what the important aspect of it is, is that, as you can see, it is still a useful clinical tool that we have to be able to assist with embryo selection, and it definitely has played a big role in the evolution of REI as a field, as well as the efficacy and efficiency of single embryo transfers. I think at the end of the day, we still need to have significantly larger, more rigorous clinical studies in larger populations, or maybe even in these subgroup populations to really understand exactly the role of what PGTA will play in its utilization within the REI field.
I think at the end of the day, there are a lot of different things that will be political, social, psychological, physiological, even scientific, that we're gonna be able to gain and understand over the next 10 years in the same way that we've gained and understand over the last 25 as we've been trying to grow as a very young field. I would agree with Dr. Barnhart in a way, in two ways, that the, as he said yesterday, the absence of evidence is not the evidence of absence, and I also say it's not time to throw the embryo out with the media, and so I think at the end of the day, we may not be PGTA, we may not be PGTNA, but we should be PGTOK. Okay.
I agree with you now that we've won already. I wish we could end on that, because that was just such a great final message. Fantastic.
But I do just wanna encourage everybody one more time, we're living in this age of big data, with data-driven patients, data-driven providers, don't get swept up, and there was an RCT, that's the bottom line, that's it. We have to be thinking critically about this, what were the methods, what's the primary outcome that we're looking at? And additionally, I think we've made it clear that PGTA is not the ultimate marker of embryonic competence, so keep that in mind, it's not representing or replacing that prenatal testing, just like we've covered here. And obviously, current evidence is not suggestive of this.
But the most important thing, I think, to take away, too, is what Dr. Walker made a point about in access to care, and that is this gonna actually be detrimental to patients accessing IVF, and also to patients getting to that transfer point. So until we have a validated platform to account for inconsistencies across labs and further prospective follow-up studies on the actual transfer of mosaic embryos, we'll continue to unjustifiably discard and underprioritize embryos. So that's just kind of the caution point that we wanted to tie up from the PGTA side.
And I'll add my last comment, which is, as an epidemiologist and as a clinician, sometimes we have different perspectives. I'm sure you've heard this cliche before, but are you talking about looking at the denominator or the numerator? If you're looking at helping the most people, the denominator of this, there is no evidence that PGA is increasing efficacy. In fact, there's papers coming out again and again that pregnancy rates on a population level are lower.
If you're looking to maximize that patient in front of you, the numerator, there are plenty of reasons that PGTA might be good for that particular patient. But my take-home message to you is, you have to be the experts. You have to understand this really complex situation and come to that conclusion yourself.
So don't be misled, don't be swayed, don't misinterpret the trial. Just put this all into your very smart brain and figure out what's best for the person in front of you. So we'll leave it right there.
So thank you again for another Journal Club program. You guys did a great job. That was fun.
