Hello everybody and welcome to another Journal Club Global sponsored by Fertility and Sterility. I'm Kurt Barnhart, the media editor, and it is my privilege to be on another Journal Club Global with you, with my international experts. Good morning, good evening, or good afternoon, depending where you are in the world, for this Journal Club that's meant to be lunchtime in the United States and dinnertime in Europe.
It'll be co-sponsored today by Dominic who will be joining me and introducing our illustrious panelists as well. We have a very important and interesting journal article to describe, Recurrent Implantation Failure in Art, Myth and Reality is the topic, and we have the authors and some internationally renowned discussants to enlighten you all. So again, welcome, and Dominic, please take over and tell us what we have in store for us today.
Thank you, Kurt. It's really a pleasure for me to participate in this European, U.S. and worldwide Journal Club. We indeed have a fantastic topic to discuss and it will be certainly the source of many discussions and many questions.
This actually is a study conducted by Paul Piatel who is going to describe the details of that, but it was inspired by Richard Scott, who actually is the Director of the Lab and Clinical Director at RME New Jersey. He also has a variety of different distinctions and he's known to all of us in the field. Before having Paul describe the study, I thought it was interesting to actually hear the background that led Richard to actually study and design this study.
Richard? Thank you, Dom. Recurrent implantation failure has been a problem that we all have probably dealt with in some way in our patients and within our programs for a long time. People have talked about it since the really inception of IVF, certainly in the 1980s.
But of course, in the 1980s, implantation rates in Norfolk, when I was a fellow there, were four and a half percent. And so everything was recurrent implantation failure. The best we ever did was recurrent implantation failure.
And so over time, things have improved, of course. And with those enhanced outcomes, thank goodness, there still have been confusing outcomes. We had normal appearing embryos and normal appearing endometria, and we put embryos back and we still didn't get babies sometimes over and over.
So that led to many questions about RIF. If you go to the literature, you'll find that there is no consistent definition, some of which depends on what generation the work was done in. There have been papers in the 90s saying you need 12 embryos, a variety saying you need many transfers, some saying you need as many as a few as four embryos.
But the reality is none took into account really optimizing the embryo or really optimizing embryonic endometrial synchrony. And so we had many questions about recurrent implantation failure patients and many of the diagnostics that have been proposed. And so Paul Portea led a significant effort to try to come to identify a group of patients that we might study in many different ways.
The problem was, how would we define? And ultimately, we said to ourselves, if you take a group of patients, a large group of patients, and 60 percent get pregnant the first time, you do another transfer and 60 percent get pregnant, that's really, one wouldn't be a good enough definition for recurrent implantation failure because you do the transfer again and it stayed the same. Same from two to three, three to four and so on. And so we were looking for a place where the outcomes would diminish to say that that residual group would be enriched with people with genuine recurrent implantation failure group to study.
And so with that sort of philosophy and with that need to not only sponsor this study, but to provide opportunity for many studies, Paul Portea began this project, which I think has been fascinating. Paul? Let me just introduce Paul for a couple of seconds. Paul is a talented doctor who actually, I did only one thing good for him, advised that he does a research fellowship at Richard's Place.
And now he's back with us in Paris and Paul is going to talk about the study he conducted while being at New Jersey RME. Paul? So, okay. My name is Paul Portea and I'm, honestly, I'm very happy and thrilled to be here today and to have this opportunity to share with you the work that I have done in Richard Scott's team in New Jersey.
So today I'm going to talk about the issue of recurrent implantation failure and I know it's not a simple one and I know everyone can't wait to talk about it. And if you agree, I can start doing the presentation or we do the introduction of the discussion. Present your work and the discussion will come by itself.
Perfect. So can you see my screen now? Yes. Perfect.
So this topic that we are talking today, the recurrent implantation failure, have inspired lots of discussions and including also the development of several tests. So just one moment because it doesn't work. So recurrent implantation failure has been a definition, has a definition that is fully debated even now and today the most commonly this applies to the failure of three or more embryo transfer or the failure of a total of four blastocysts.
So when implantation failure occurs repeatedly, this provides recurrent implantation failure. So potential causes, yes, can you hear me? Yeah. So the potential causes for recurrent implantation failure in a morphological normal uterus result from factors that either affect embryo competence or endometrial function.
So numerous authors have claimed that functional alteration of the normal endometrium in otherwise morphological uterus can hamper the capacity of embryos to implant. So the range of functional alteration proposed for explaining implantation failures include endometrial receptivity, the timing of progesterone-driven endometrial changes and the embryo development leading to a misalignment of the elective period of window implantation and receptivity, endometriosis associated endometrial impairment of receptivity, and also immunological problems. So, so far what we know is that live births with frozen euploid embryos, given data which are provided by big groups and big studies, are ranging between 43 and 77 percent.
So as you can clearly see, not all embryos implant, even though PGTA allows for the transfer of chromosomally normal euploid embryos, even though it excludes those embryos with genetic abnormalities then prone to neither not implant or miscarriage, and even so you can see that the results are not 100 percent. So this has led to theories that implantation failures following transfers of euploid embryos might result from functional endometrial factors that could at times be persistent and cause recurrent implantation failure. So this is the whole point of our study and our objective was to determine the true prevalence of recurrent implantation failure in women undergoing three successive frozen euploid single embryo transfers in normal morphological uterus from one or several ART cycles.
So for this, as I had the chance to work with Dr. Scott, we provided a retrospective core study from 2006-2018 in Armenia, New Jersey. We have benefited from PGTA platforms that were validated with qPCR and NGIN-based, and we transferred only frozen single euploid embryo transfers. So we really tried to limit and to provide that aligned uterus and correct embryo to see whether this recurrent implantation failure can be defined.
So we excluded all donor egg cycles, all gestational carriers, we excluded all indication for monogenetic diseases, all moth eggs and segmental abnormalities, and we have excluded all patients with an endometrial thickness of less than seven. We have included in the end 4,429 patients, all reproductive ages included, BMI is all included, with euploid embryos, all single euploid single embryo transfers with a morphological normal uterus. So the results are quite, well, surprising for us, and we are happy that we kind of found them, because there is a chance for good hope.
So after we had transferred the first euploid transfer, we've seen that about 70% have implanted. So that's quite corresponds to the data that we have, and I showed before. So of those who did not implant, some dropped out, which is quite normal to just say infertile population.
And for those who had still remaining embryos, and those who did ART, we have transferred a second euploid transfer embryo. And for those, we have seen that 60% of them had just a barely decreased percentage of implantation of 60%. So this clearly indicates that the failed implantation following the first euploid transfer does not select out women with problems of receptivity.
And you can see that when we went to those who did not implant, we had again dropouts, and still we had patients with remaining embryos, but we had other patients that had to have a new IVF cycle to get embryos. And when we transferred the third embryo transfer, a euploid embryo we have transferred, we have seen that the implantation rates were similar to those after the second one of 60%. So when we saw this, we kind of thought that probably that the first embryo transfer has a higher chance of implantation due to the probability of morphological selection, and probably we'll discuss that about studies that have shown that.
So even with all this, we have reported in the end a LIBERT of 64% after the first euploid transfer, 54% after the second one, and 54% after the third one. So when we did the cumulative implantation rate in LIBERT, we have seen that after three successive frozen euploid single-embryo transfer, we have achieved 95.2% of implantation rate, which is quite surprising. And also when we looked at cumulative LIBERT, we have seen that actually we have 92.6% of cumulative LIBERT after three successive euploid single-embryo transfer.
So this was quite surprising for us. When we look at miscarriages, we have seen that even though the miscarriage rate was observed after a positive fetal heart cardiac activity was 7.2% after the first single-embryo transfer, 8.8% after the second one, and 12.7% after the third, respectively, as you see in the image. When we compare the miscarriage rate resulted, no significant difference was observed according to our logistic regression adjusted for age.
So we report now with our data that women who failed to implant following a course of single frozen euploid embryo transfer do not have a marked increased incidence of failing again to implant in a second and third embryo transfer. So we now know that our study reports a rate of recurrent implantation failure following three successive euploid embryo transfers with an incidence of less than 5%. And this is why we kind of think that the origin of true, the initial origin of true recurrent implantation failure when euploid embryos are transferred is very low when we are talking about morphological normal uterus.
So certainly we have the limitation of our retrospective study and another potential limitation of the study could be represented by the fact that some successive embryo transfer came from different ART cycles, but we still have a very large cohort and it's a very extensive nature. And when we, regarding the second limitation, when we calculate the implantation rate of the two subgroups after the second embryo transfer, we notice similar results of 59 for those using remaining embryos and 61 respectively for those using embryos issued from new ART cycles. Furthermore, we can say that this is our, this is the largest study reported of sequentially frozen single embryo transfer.
And I think that with all the weaknesses, still is, has very strong data, which we think that this can reliably point to question the role of the uterine factors in recurrent implantation failure. So as a conclusion, our finding, after performing three successive frozen euploid single embryo transfer indicated endometrial causes of recurrent implantation failure are rare. This therefore questioned the efficacy of endometrial receptivity tests.
In patients with the ability to have euploid embryo, a blastocyst, 95.2% could achieve clinical pregnancy after three frozen euploid single embryo transfer and 92% achieved live birth. And implantation rates declined minimally with increasing transfers. And I think, and we think that additionally, euploid embryo transfer could offer hope for a better outcome.
Thank you for your attention. I think this is truly amazing. I mean, women who have euploid blastocyst become pregnant.
This does not select out women who have lower chances the next time around. And this was the base of the discussion. It's just amazing.
I know that many of you have questions. It's a European, US drawing club, lunch for some, dinner for others. And so I will leave the mic to Kurt to present the discussion of this paper.
Thank you. Thank you, Paul. This was a great presentation.
Thank you. So that's wonderful for as a background. So as always in these journal clubs, it's wonderful to hear from the author, but we hopefully have lots of questions.
I'm already getting some from the audience. And please, those that are listening, log on and ask your questions and I will get them to the authors. But first, let's start with Danilio, who is the science and research manager at General Life IVF centers.
And we welcome his expertise and his take on the paper. So you get first crack at the questions here. So discuss away.
First of all, I want to thank you all for the invitation. It's a great honor for me to be here. And Paul, there was a very nice paper, very nice presentation.
I also went through, obviously, the manuscript. And there was something that was really interesting that kept my attention. When you say in the introduction already that there is yet no universally accepted definition of RIF.
You know, also by looking at the literature and a survey that we recently conducted in the special interest group of the ASHRAE, Implantation and Early Pregnancy, of which I'm part, we noticed that overall in the world, there is a huge variability in the threshold of maternal age to define RIF. The number of transfers, the stage of the embryos and the definition also of good quality embryo when it comes to understanding what a RIF patient is. Now, my question to you all is, which aspect do you think we should consider the most relevant when it comes to a proper definition of RIF? And what are, according to your opinion, the limitation related to the prevalence of RIF of the current definition that we use? So, I think that one of the problems that definition of RIF encounters is the fact that we deal with ages that are very different.
And I think that when we are talking about the patient in front of, we are talking about patients, we have to imagine that age is more important. It's also important also for diploidy, but it's also important for synchrony. So, I think that when we are talking about RIF, we have to take notice of the age of the person because we all know today that some patients and the older they get, the slower their embryos are, which can cause directly this synchrony with the embryo and the endometrium.
So, age, I think it's a very important cofactor and it has to be taken into account whenever we talk about RIF because I think that this study has shown that if we put things in line, meaning that we have a perfect endometrium and we have a good embryo, the chances of success are very high. And I think this situation is not encountered in many, everywhere, like it can differ from place to place. And I think that from our results, I think that when we talk about rare continuation failure, it's very serious.
Richard, what do you think? I have a question for Richard. And really, when PGTA became available and you've been one of the champions in doing this, it led to several things. One of them is to actually use frozen embryo transfer.
And we might say something about this. And I know that Mika has done the study and I will come back to that. But also, it led to transfers of good embryos, genetically normal.
And we thought intuitively that it would also lead to select out women who have an admission problem. And the surprise is we don't find those, do we? Well, we certainly would say that there are very few. I don't think you can say that there are none.
But we went back and looked even at fourth transfers after the study was done. We don't have an enormous number. That was beyond just the population in the study because we've accumulated a few more over time.
And the implant, the sustained implant delivery rate was 56%. And so now with four euploids, the chance of not delivering is between three and 4%. And so there probably are a few patients in that three to 4% that have recurrent implantation failure.
But this concept that it's widespread and that we need to screen everyone in advance for a variety of different things, I think this seriously calls that into question. Even in that three to 4%, we don't know their endometrium. They could still have an embryonic problem as well.
So the good news is that the vast majority of our patients can deliver. And the tough news for us as investigators, we're still searching for a good way to find that RIF. Let me jump in just for a second, Tom.
There are a couple of questions that are kind of clarifying before we can go on to the study. They all have the same theme. I just want to confirm with the authors that there was nothing done to these patients between their second and third transfer.
In other words, explicitly nobody had endometrial receptivity testing. No one had a change in the way they prepared. All the transfers were done the same way.
I think the answer to that is all yes, but people are asking and I just want to clarify that. Yeah, so I certify that all the transfers were done in the clinic by the team of the clinic. KPI is tested for less than 3% difference between them and no additional tests were performed or receptivity tests were performed.
And all of these were medicated cycles. None of them were natural cycles. Exactly.
Okay. I want to go on to let Zev Williams ask a few questions. Zev is the Wendy Havens Associate Professor in Women's Health and the Chief of the Division of Reproductive Endocrinology and Infertility at Columbia University.
Zev, thank you very much for taking the time to review this paper and adding your take on it as well. Oh, really, it's a pleasure and honor to be here and to discuss this with you. Dr. Bertea and Dr. Scott, first of all, thank you as well for presenting and sharing this work.
I think this is really one of those critical papers that's going to be widely cited and has already started to be cited when we counsel patients. I think it's got some tremendous strengths in terms of what it does. And what it does really well is give us a, you know, when we're talking to patients, a ballpark, a guideline to really define the prevalence in a very well-controlled environment.
I think that kind of information is really powerful to let patients know that if they've had a failed implantation rate, you're looking at roughly that same sort of 60% over and over again. I think that's a great strength to the paper. And I think that's, again, it's one of those, this is going to be one of those papers that gets cited over and over again.
And thank you very much for sharing that work. I think it's kind of the whole area of, well, I think the challenge is that the paper sort of ends where recurrent implantation failure begins. And so it sort of gives us a good sense of the prevalence, but in terms of answering the questions, first of all, does this condition exist? And Dr. Scott sort of alluded to that.
You know, one of the ways we sort of talk about it is like, there's no such thing as, you know, when it comes to flipping a coin, there's not like recurrent heads or recurrent tail. If you flip enough coins, you will get some that get heads five times in a row. But the next time you flip that group of coins, you're back to 50-50 ratio.
And I think the challenge we all have is, is that what we're seeing here? Is it that you're sort of left at 60%? And so some people will be very unfortunate and just keep being on the wrong end of that 60-40 split. And so, yes, some people will have three failed transfers and then four. Or at some point where you start to really, as Dr. Scott pointed out, enrich for those who really have the condition.
I think it's very analogous, I think, to recurrent pregnancy loss as well in that sense, that after one loss, most people will go on to do very well. The challenge is trying to being able to identify early on, you know, the person who has one loss and the person who has 10 losses both started off with one loss. And so is there a way to determine which group someone would be on earlier? Or is it really a very, very narrow group of people who may have this a true entity of recurrent implantation failure? It might be even lower than the 5% that we're seeing here.
One question I wanted to follow up with you, Paul, was just you had mentioned the impact of age. I had thought that in your study, those who had success after their first transfer and those who had failed three transfers, there was no difference in age. No.
No, that's correct. No, that's correct. That's correct.
I was just going to ask the general question. Does age matter in terms of success? Yeah, that's my question. I think that our study, as we mentioned before, was very controlled and the setup, like frozen embryo transfer, the same preparation, same team, same platforms of PGTA, I think that really selected out only those who really had a problem.
Because age can impact the synchrony, as we mentioned before. Age can impact euploidy. But in the end, when you have euploid embryos, we see that they have the same implantation rates.
If I could just extend that comment a little bit. What we see is what we have typically seen and reported in the past, which is certainly past the age of 42. There are very small declines in your 30s, but almost negligible.
But after 42, even with euploids, it drops off pretty quickly. I think that the key for this study, and we think that's still embryonic, by the way, but in this study, the implantation rates for 43 and 44-year-olds, while being somewhat lower, were the same in the first, second, and third transfer. So again, it's not that they were more prone to recurrent implantation failure.
They just still own the limit, which comes with being 44 or 45, which is not overcome by doing aneuploidy screening. There's more to reproductive aging than that. So sure, you can have recurrent implantation failure because of aging.
Probably not endometrial, but there is a component. It's just not enriched over time. Still random variation.
And so, it was interesting. Danilo? Yeah, I had a question. I've noticed that you included all BMIs.
I mean, you didn't exclude patients because they were obese. Did you notice any reduction in the implantation rate of euploid embryos when it comes to higher BMIs? Because I'm aware of at least one paper by Cozzolino published this year in Fertility and Serility, who noticed a higher miscarriage rate also when you transfer euploid embryos in obese women. So in our study, BMI didn't have an impact on the outcomes, but I think Dr. Scott recently published a paper on that, following also body fat and proportion of that and BMI.
But in our study, we did not notice any difference in implantation. Sure, we did a 2,000 patient, Julia Kim from our group, did a 2,000 patient prospective study where we not only looked at BMI, but also percent and distribution of body fat. And it's amazingly not predictive of outcome.
We really thought it would be. And we thought maybe that further subdividing the groups would provide further insight in how to counsel patients. And the reality is it's just not very predictive of clinical outcome.
So we did measure it and control for it here, but I'm not sure it's a major thing. I wanted to add a comment that possibly BGTA has provided an unexpected benefit by using frozen embryos. And for example, in the case of endometriosis, there were numerous reports that the receptivity was altered in the fresh cycle, as well as just in doing biopsies and all kinds of parameters were altered in endometriosis.
But when you have a variant suppression with either the agonist or the antagonist, this alteration go away. Now we have the chance to have with us Mika. And Mika just published, it was part of a group that published an article on implantation rates in frozen euproate blastocysts of women with endometriosis.
And there were no differences between endometriosis and control, maybe because of a benefit of the frozen embryo transfer. What do you think, Mika? Yeah, I think that's very possibly that you're right, Dom. The study was by Lauren Bishop looking at surgically proven patients with endometriosis compared to controls that had male factor or were doing PGT for PGTM.
And there was no difference in the implantation rate within those euploid embryo transfers. And Caroline Juno from Richard's group has also shown in the past that there's no difference in aneuploidy in patients with endometriosis. So perhaps showing both to your point that when they're downregulated in a frozen transfer, we're perhaps ameliorating that effect of endometriosis.
And we certainly don't see that there's an effect on aneuploidy. I did want to just share an audience question. So one of the things I think all of us wanted to know was how we define recurrent implantation failure.
And so we asked our audience. And you can see that the audience really is split on how we clinically define this. And I think that's because the research is split and because we don't really have guidance from our societies on how we should define this.
So I'm just curious from Richard and Paul and the other experts on this call, when should we start looking at other things past just the embryo when we've had multiple euploid embryo transfer failures? How should we define this? And do we need a definition from ASRM or another group? So I certainly think that the definition would be extremely important. But as Danilo said, even in ASHRAE group, the opinions are very divided. And I think that we are very far away from having one.
And given that all over the world, they have different techniques and different protocols. And it will be very difficult to impose a definition on those procedures because just consider fresh and frozen PGTA, non-PGTA. I mean, it's highly complex and relative.
I think that on concerning the investigations, I think that we should do validated investigations for clinical use to all our patients from the beginning. But for those those investigation or tests that are not yet clinically validated, I'm not sure whether we should think about them or considering that those patients who really have a record implantation failure, it's a really small population and possibly they have real problems of age or ovarian reserve. If I may enter in the conversation, I'm aware of a paper published recently by Koot and colleagues.
They noticed that if you apply the current definition of RIF to some patients in the follow up, looking at these patients for the three up to five years follow up after the diagnosis of RIF, let's say 50% of them were able to conceive in some cases even spontaneously. So in other terms, that might be the possibility that the current definition that we use raises the risk of false positive diagnosis of RIF. That's something in my view, it's extremely important.
And again, if you look at the literature, if you're able to transfer looking at cumulative data of pregnancy up to 20 cleavage stage embryos, 10 blastocysts, or you showed in your paper three euploid blastocysts, even more than 90% of the patients are able to conceive. So my question is, is it just a matter of keep trying? And how can we avoid patient dropout? Certainly papers like these are extremely important because of counselling. So we can counsel them that it's just a matter of keep trying.
But do you think that the psychological support or something like that might be important to help our patients keep trying and looking for the euploid blastocysts they will implant? Well, I think that that's crucial because I mean, I hope that our results will bring this kind of hope to our patients and to physicians, because I think patients, of course they are exhausted. And if they do incredible amount of tests and so forth, also their optimist goes away with them. Because most of the time they don't find much and they are pushed away from maybe the main important thing, which is the embryo in this case.
So I think counselling them and explaining everything to them and trying to keep them on the track to obtain their objective is very important. I think it's worth noting that while we had significant dropout after the first and the second transfer, some of those people were out of embryos and elected not to cycle again. Some, of course, were people who just gave up because that's always a problem from our poor patients who put up with so much.
Our group has reacted to this by telling patients that you need three euploid embryos to really to get a good crack at this, and that almost two-thirds will deliver after the first one, and almost 95 percent will deliver within three. And I think if we create that expectation with that big number from the beginning, patients go into it sort of with short-term pessimism, it might not be the first transfer, but long-term optimism, and it helps keep them in care. Plus two-thirds of the patients, a little more, have enough embryos even from one retrieval, enough euploids from one retrieval to get to three transfers.
Whether that will become four or not in the future, we need more data, but which maybe gets you to 96 or 97 percent will deliver. So I think if you kind of sit there on the horizon at the beginning, that's part of that counseling you were mentioning, Daniel, which I agree with completely. It helps them get through those intermittent random failures that appear to be random, and hopefully to a good outcome.
If I may, I think, Paul, one point you brought up, which is really worth emphasizing, is the use of, let's say, not clinically validated tests. And where your paper will be coming very useful is that people, and by people I mean patients and also providers, often view these tests as either helpful or neutral. But you've shown, you know, after two failed transfers, you're looking at roughly a 60 percent success rate the next time around, which means if you use one of these interventions and it's actually harmful, let's say it reduces the implantation rate to 50 percent, you'll still have half the patients thinking it helped them, when in fact it was lowering their chances.
So I think having these numbers, this is not to support or condone, you know, or diminish these tests, just to emphasize the fact that with a lot of the interventions that we do, when you have a sizable success rate with no intervention, you want to also be careful that what you're doing, even if you have patients who succeed, that you're not diminishing the number who will be successful. And if I could pick up on that just for a second, there's a lovely reflection on this article that we published, Fertility and Sterility, by Kate Shoyer, that picks up on the point that Zeb just had, and I just want to bring it to attention, that these adjuvants or add-ons can look to, can appear much better than they are because of our desire to recognize a pattern. If 60 percent of people are going to get pregnant with our next transfer and you added something onto it, you're going to believe that that was the reason that they got pregnant.
Most of these adjuvants are not proven and may be harmful, and that's an epidemiologic reason why people grasp at this, saying the test must be good, and we're having so much trouble figuring out whether it actually works or not, and that can include add-ons, endometrial receptivity tests, and they can be expensive and they can be problematic. So I'm sorry, Dom, you were about to pick up on something. Please.
Yeah, I was just wishing that in terms of methodology of assessing intervention that we may make, that Richard might actually just remind us what a non-intervention study trial is, which would apply also for those endometrial receptivity assets. We recently published a non-intervention trial, basically a non-selection trial for PGT, because people had expressed legitimate concern that if we were over-diagnosing abnormal PGT that we might be actually harming patients by discarding competent embryos, and we demonstrated that that's not the case, at least with one assay, and I believe with many assays. So that's thing one.
I think it goes back to speaking to whenever you do any kind of diagnostic validation, you need to look at the predicted value of the test, positive and negative, and in a non-selected way to see whether or not it truly prognosticates outcome. And that step has been skipped for so many of the diagnostics in our field, many, not just the endometrial type tests, although they are really not as well validated. So they need to define this type of population or some other one that they think benefits, and then they need to really go and demonstrate the predicted value of this, not just because someone had one failed cycle, but because of the subsequent cycle, which comes after the diagnostic was done to show that it still prognosticates the difference in outcome.
That would be enormously helpful, at least from our perspective, and I hope that people will do that in the future. It's really just supporting what Zev and Kurt said, which I thought was awesome. Well, can I ask one other question that I think will be helpful with counseling patients? In your study, there was a pretty wide range.
You sort of gave estrogen until you reached a minimum threshold of seven millimeters. Patients who couldn't reach that were excluded, and I think we agree that, you know, there is a role for that. And the range of time it took to reach that seven millimeters ranged from 12 days to 25 days.
And patients often will ask, does that mean my chances are taking longer than normal? Does that diminish my chances? Prior literature has not suggested that it's harmful, and I'm wondering if you look at that and if that sort of supports that kind of counseling, if your data supports that counseling. Well, we, I mean, as I said before, there was no difference for those who had 12 to 25. And I think that this also goes hand in hand with the data that we recently showed on the exposure to estrogen should be safe up to 38 days in euploid embryos.
Even though there are some studies, European studies, with non-tested, non-genetically tested embryos that show the exact opposite. Recent studies have shown that actually estrogen is safe up to 38 days. So in our study, there was no difference between those who had less or more days of estrogen.
I have another curiosity. Were all the patients included in your study naive, or did they already have some experience of FIF previously? I mean, did they already went through? So, you know, from what they said to the clinic, they were naive. So we, from what we know, they didn't do cycles outside the clinic, but you never know that.
I mean, from the interrogation of the patient, you believe what they are saying, you know, like, you know, cannot really be 100% sure, but yeah. No, because something that we have noticed in our own experience is that when the patient has some experience of implantation failures, let's say more than three, much because of the quality of the embryo and the day of full blastulation. If they had more than three previous implantation failures, we have noticed in our case, a reduction in terms of live birth.
So is it plausible in your opinion, according to your opinion, that maybe not that much, but there might be some influence of endometrial receptivity when it comes to euproid embryo transfer with poor prognosis patients that already had some adverse event? Well, it depends. We are talking in a fresh frozen, fresh. I think that the frozen can provide help and synchrony because outcome or poor oocytes or could have a slow development of the embryo.
And that's the thing that if we talk about transfer, as in the cases of endometriosis and also in the case of maybe obesity, it can provide some help and align endometrium with the obtained embryo. But it's very. If I could add one brief comment to answer Danilo's question, our data really only went through three.
And that's really all we have sufficient insight on to comment on. However, we would agree that there must be someone out there with impaired receptivity that's not evident just by endometrial thickness and pattern. So I suspect that there's a group out there.
And they're probably hiding in that last group. Like I said, now we're through four and we're still not seeing them because it hasn't dropped off. But there probably are out there and we don't know exactly where they're coming from.
And we just don't need to seek better ways to find them. But I would certainly not say these data can say that no one has impaired receptivity. That would be too strong and we would not want to imply that.
I think this study also supports very strongly the replacement regimen that has been used for the frozen embryo transfer. There are now lots of discussion as to whether you want to use different approaches, natural cycle, or slightly stimulated cycles for X or Y reasons. But here, the simple estradiol and injectable progesterone doesn't seem to be able to do any better than that.
You want to comment, Richard? We have looked, I think, in three different internal studies over the years at what we call synthetic cycles, estrogen replacement, progesterone replacement versus natural. And we continue to find really no difference. And I mean, it's just shockingly how well aligned they are.
You can always argue a single patient is different than a population, but the reality is we find no advantage. And that means you can use a natural cycle if you were really inclined. But our patients never seem to ovulate on the day they want their transfer, and they always want to negotiate a compromise.
And it is highly problematic for us in terms of logistics on their part, not on our part. So we really prefer replacement cycles and feel that the outcomes are just as good, at a minimum, just as good. Does any of you have further comments? Well, I think one of the things I want to just, two points.
One, we were talking about sort of the definition of recurring implantation failure. And I think it's important to keep in mind when we come up with a definition, what type of a definition we want. If it's descriptive, then by definition, two failures is repetitive, and that's recurring implantation failure.
If we want a definition that's functional, it would sort of be, okay, after how many losses are we worried that we need to start doing a workup? And that's still different from sort of a biological difference, which is sort of saying after how many losses have we pinpointed that now we're in the group that's selecting out for something? So I think you're going to get very wide skews of the definition because there's different ways of coming up with the criteria for how we define it. Is it just based on the language? Is it based on when we would recommend doing some sort of an evaluation? And I think it does beg the question of what sort of evaluation tools do we have? And the last is, at what point are we actually saying, this defines someone who has a biological impairment, it's not just a matter of chance? So I think that I just want to add into the discussion. And the last thing is, when we're talking about the factors, like it's true, we talked about the uterus, we talked about the embryo.
There are other factors, of course, that we're all aware of that play a role in it. And one of the ones I wanted to ask about is every once in a while, you will encounter a cervix or some other issue that makes it much more challenging, much more difficult. I don't know if you were able to pull aside, there's the operator, the person who's doing the transfer, but there's also the environment, the cervix and other situations.
Were you able to pull out those cases where the transfer itself may be more technically challenging and to see if there was a difference? I'll take a crack at that. In this study, we really had no one that, which is a big number to have no one, I want to confess that, but they really fell into the range where we had difficult transfers. So we had to use a stylet or do something else manipulative.
However, we have those patients too, absolutely guilty as charged. And anytime we have something where we have to change our basic approach to transfer, our outcomes diminish. So at least in our hands, if we can't get this done, we can go slow and take our time.
And maybe it's a couple of three passes, but we can't get it done using the basic technique that we probably all use, then our outcomes are impaired. So that certainly could be a cause. And I would hope people would do something after one bad transfer on that one and not wait for next ones.
Thank you. So our audience is very pragmatic. The questions we're receiving are basically in three categories.
One, I'm just going to dismiss off the top. No, this paper has not defined a new definition for recurrent implantation failure at three transfers. So that's as far as the paper could go, but it is not making a new definition.
And I appreciate the comments of other people wanting a definition. The second group of questions is, okay, I've reached three embryos that have transferred three normal embryos and the patient still isn't pregnant. And people are very much wanting to know what I do after that.
So I think that is a good discussion point that I'll let you guys banter around. I'm not sure it's directly related to the paper, but I would certainly love your suggestions and skills. Go ahead.
Who first? Paul, go ahead and I'll answer as well. So I think that maybe in this group, maybe you can have, you can experience chronic endometritis and you have several papers showing that this can impact the, it can be responsible for recurrent implantation failure and maybe do a biopsy with CD138 or have a treatment with antibiotics. And this could be a reasonable attitude for treating that.
But I think that also you can talk about hysteroscopies and to find new things that maybe were were completely outlooked before. But in the end, I think that one way to go is that if you believe you can obtain new embryos, that's the plan to do, even though you have to keep an eye on all the possible cofactors and pathologies that could impact implantation, like hydrosalpinxes and chronic endometritis and so forth. Richard? I think that's a, those are great.
Those are great insights, Paul. You know, we look for everything. We're not different than anyone else in that we're always desperate to find out what to do when our patients are failing.
And it's not, there's no obvious pathology to explain that. We have not been impressed, with an exclamation point after that, with the endometrial timing assays, at least in our hands, they've not been prognostic. The microbiome, we wrote one of the original papers and we're doing a very large, very large prospective study now.
But again, it really has not been prognostic in our hands to date. Beyond that, certainly, Nola Haraghi from our group is doing a big, big study on chronic endometritis now, and we're awaiting those results. I could go through all the different studies that we're doing, and you guys are many also probably doing similar things.
But the frustrating answer is that we do not really have anything yet, or I can say there's strong evidence that it changes the outcome. So I certainly think you make sure the cavity is normal. I think that's fair.
But beyond that, I think all of these other adjuncts and other studies that we do are not really well studied and well validated. And you're kind of using them at your own risk because of, again, you might be, you know, there's a potential to be misleading and misguiding, and we don't want to do that. So I don't have a good direction for these patients.
I think there's no clear answer, not yet. Michael, you want to make comments? What is the incidence of PGTA that you do in your clinic? Oh, I'm sorry. Go ahead, Dan.
In our clinic, we are about 80 percent of application of PGTA. So I would say, well, we have maternal age, they are 39 years old. So, you know, pretty advanced maternal age.
So it's very common. But starting from the age of 35, we are, you know, suggesting PGTA to all patients and still informing about the risk of anelopitis also to women younger than 35. Because, I mean, if we think of PGTA as a diagnostic procedure, well, anyone would go for PGTA as they go through amniocentesis once they conceive.
So it's just a matter of having a technique that is enough predictive in terms of positive and negative predictive values and what Dr. Scott showed with the TXP paper published in 30 and 30 this year. It's saying us that it's a very well-validated technique as soon as we exclude the report of putative mosaic or segmental and everything. That's the point.
I might make a personal comment here. I mean, you all see my gray hair, so I've been around for quite a while. And there were so many years that we spent thinking that the endometrium might play a very important role and that assessing that was crucial.
And now it seems to have gone the full circle. And I've seen this study being conducted and looked at the results. And it's just amazing.
It's just amazing that the embryo actually is responsible for everything. We still have to unveil why some euploid embryos don't implant. We don't know that.
I don't know whether anyone wants to make a comment on possible causes for aneuploid embryos not implanting. Richard? Boy, that's a curveball. For us anyway, we think that's the greatest single question confronting clinical reproductive endocrine today.
We still think it's principally in the embryo. We think it's not mitochondrial density, but we have some evidence to say that it's mitochondrial function and mitophagy and other potential abnormalities there. And I think there's just a lot of work to be done.
But right now, I do not believe we have anything we can definitively say alters embryonic competence beyond the aneuploidy. Xavier, do you want to make a comment? I mean, you came up with interesting questions on what we got with the transposeroid embryos and the success rate and the vanishing role of the endometrium, so to speak, through your study. I'm sorry, were you calling on me? I didn't hear the first part of it.
Yeah, I meant, do you want to make some more comments on the fact that the endometrium appears to be receptive most of the time? And this is quite a surprise from what we were believing before. And all of this through the euploid embryo transfer and also, I believe, the prosembryo transfer. Well, what we... Implantation is occurring 60% of the time.
Yeah. Whether that's because the embryo is competent that time and the endometrium always is, or sometimes things are more aligned the way they're supposed to be, and other times they're not, and it varies from cycle to cycle. I don't think... It's not a criticism of the study.
The intent of the study was not to delve into the cause, the mechanism, but it was to describe a phenomenon that we're seeing. So I don't think we have the data to answer the question that you're addressing. We're seeing that the implantation is occurring 60% of the time.
When you repeat it, it seems to be quite consistent like that. But what's happening in that other 40% is really a big question. And it doesn't necessarily mean the reason an embryo didn't implant one cycle is the same reason implantation wasn't occurring the next.
I think there's a lot of possible explanations, and I think it's helpful for us not to presume the answer. Yeah. What the study has shown is failing to implant a euploid embryo does not select out women whose chances are less.
Correct. But it doesn't say why they're failing to implant. No.
It's just not. It was a great work that Tom. It was fantastic that he could do this at Richard's place.
And I think the accomplishment and the results are... Yeah. This is great. It's one of those studies that immediately becomes very clinically helpful in talking to patients.
I mean, as recently as yesterday. So thank you. So we have a great time having the journal clubs.
I know now there is lots of competition because we cannot go to any meetings, so everything is online. But it's a great pleasure to share that and to share it with the Europeans and the Americans. The Americans are having lunch.
We're having dinner. And for those for whom the holiday starts tonight, happy holiday. And thanks again for joining this, John.
Thanks, Kurt, for organizing all this. And Mika, thanks to all of you. Thank you.
Again, this is a wonderful event. Thank you for the time. We have a minute or two that we can collect our thoughts.
It's really impressive to get a study like this that I think is going to immediately impact the way we think about things. And what I heard here is that the embryo certainly is driving the majority of reasons a woman gets pregnant. But still, we don't understand why they don't get pregnant 30 or 40 percent of the time with a normal embryo.
But what this study is telling us is that whatever that issue is, it does not seem to be specific to women. It seems to be random or common among women and across cycles. So we have to figure out what that is.
So I don't want to say we should stop using all science and say we don't have to look at the endometrium. We do. We just don't have the right tests at the moment.
Why don't we go around? Does anyone have some final words just to say? Again, thank you very much. But why don't I start, Danilo, from final comments, and then we'll go to Zev and Richard and Paul. No, I want just to conclude that if we think that such a thing like an RIF problem exists, maybe the future avant-garde of genomics will help us, you know, outlining a population that might have some issue with it.
The problem, I think, in studies like these are telling us that there is a problem will be to define in which patient study the genome to an RIF. But I think that, you know, there is a lot to study in our field, luckily or unluckily, depending whether you're a basic scientist or clinician, but definitely we're looking forward to it. Yeah, I want to echo that.
I think what would be exciting would be if we have a journal code like this and then 10 years from now, and instead of being 60%, 60%, 60%, it's 80%, 80%, 80%. I think that's a great challenge for our field. It's probably not one factor, it's probably multiple factors, and we just sort of have to chip away at that 40% number, but look forward to continuing to see those numbers improve from, you know, 4% days up to continuing to improve numbers.
However, Zev, if it were to become 100%, we might not be there to talk about it anymore. That's a good problem to have. Richard and Paul, wonderful paper.
Leave us with some of your thoughts. Well, actually, I'm just extremely curious to find out what happens after four successive transfers. So, I hope that someone will find the, I mean, I hope maybe Richard or someone finds the resources to provide that answer, because I think we really need that.
And I think that in order to provide the best definition for REF, it's to know what happens after that fourth EUPLA-DEMU transfer. So, I thank Richard for helping me with this project, because for me, it was mind-blowing, and I think that this will really change the way I will probably practice fertility in the next future. So, thank you.
Thanks, Paul, for this great work. Thanks, Richard, for being a mentor, and thanks Kurt and Mika for setting up this stronghold. Thank you all.
We cut you off. Do you want to close us out with any final thoughts? No, I just wanted to reiterate how much I appreciate that. I think this is an important paper that can be used for clinical counseling, but the insights that Danilo and Zev and Kurt provided about exploring the other causes and that this is just one more piece of this puzzle is really exciting, and I hope everybody will see that value and will continue to pursue it.
So, what wonderful insights. Thank you. Tom, thank you for organizing this breakfast and dinner club.
I hope I will see you all at a future Journal Club Global with Fertility and Serility. Thank you for those that listened, put the questions in, my participants. Have a great day.
Bye-bye. Bye. You too.
Bye-bye. Bye.
