Hello and good evening. Welcome to the Global Journal Club of the magazine Fertility and Sterility, Latin American version. My name is Pietro Bortoletto.
I am a chronologist, reproductive in Boston, United States, and also one of the media editors for Fertility and Sterility. It is my pleasure to present one of our many events in Spanish, despite being Brazilian and speaking Portuguese. Our guest tonight is a world-famous doctor, Dr. Ricardo Loret de Mola, who is an endocrinologist and a chief obstetrician and gynecologist at the Faculty of Medicine at the University of Southern Illinois in the United States.
He has brought together a group of experts to discuss the controversial topic of progesterone supplementation during the luteal phase, the cycle for the transfer of frozen embryos. I would like to start with a small introduction by Dr. Gabriel Fitzpum of the Argentine Society of Reproductive Medicine. Dr. Fitzpum, please, take the floor.
Good afternoon, everyone. Welcome. We are going to start with the sixth scientific meeting of SAMER, which is a journal club from research to medical practice.
And we have the great opportunity today to hold this scientific meeting together with Fertility and Sterility. The topics we are going to discuss today are the transfer of frozen embryos, where there is no clear evidence of what protocol to use or what preparation to perform, and the recurrent implantation failure, which is not easy to find a clear definition or indication of this. These topics are central to the daily practice of reproductive scientists, and they come to us every day in the consultancy.
First, I will introduce Secretary Fabián Lorenzo of SAMER, who will make some comments on future SAMER activities. And then I will introduce Ricardo de Mola and I will start this event. Fabi.
Thank you, Gabriel. The truth is that I am very happy to be in this joint meeting. What I have to do is invite you to the next scientific activities.
We have the next one on September 27, attended by clinical classes from the Cuyo region, with the title of Reproductive and Epigenetic Medicine. And next October 6, the AMBA day, where the title is Techniques to Improve Reproductive Results in ART. In addition, next October 19, we have the Scientific Meeting of Immune Hematoma in Reproduction.
And next November 16, a joint meeting between the LARA network, ALMER and SAMER, followed later by the General Assembly of Our Society. So I give way again to Dr. Fitzman to start the meeting. Well, I am going to introduce Dr. Ricardo Lorenz de Mola, who is a graduate of the American Council of Gynecology and Obstetrics in Endocrinology, Reproductive and Infertility, as well as in Gynecological Surgery, Minimally Invasive, and Gynecology and Obstetrics.
Ricardo currently works as a professor and director of the Department of Obstetrics and Gynecology at the University of the South of Illinois, as well as as head and medical director of the Women's Health Service at the St. John's Hospital in Springfield, Illinois. Above all, a great friend of the house. Ricardo, thank you very much for allowing us the possibility of having this scientific meeting together with Fertility Sterility.
Go ahead. Thank you very much, Gabriel. It is a pleasure and how good that we can have these activities, and I hope that it will not be the last one, and that we can always do them.
And God willing, we will be able to have the annual meeting in September of this year, which is coming in Cordoba. Well, let's start with the first article, so as not to have a lot of time in introductions and presentations. And let's talk first about the effect of progesterone on patients who have low levels of progesterone on the day of embryonic transfer.
And let's start with three Argentine doctors, Dr. Marianette Figueraccio, who is a gynecologist specializing in reproductive medicine, affiliated to IFER. Dr. Hernan Elena, who is a gynecologist specializing in human reproduction, certified in biology of reproduction at the Université Française Complète de France, and is also an endoscopic and hysteroscopic surgeon. And Dr. Marisa Geller, who is a gynecologist specializing in reproductive medicine at SAMER.
She is a doctor of in vitro in Buenos Aires, at the Center for Reproductive Medicine, and a professor of the career of a specialist in endocrinology, gynecology and reproduction right there in Argentina. So these are our three speakers. I remind you that you can put in the chat if you have any questions, and we will start the presentation.
Thank you very much. Now, Ricardo, we have a small change. The one who is going to speak is Dr. Cintia Granados, gynecologist specializing in reproductive medicine at SAMER, co-director of the AMBA SAMER region, and a member of the SAMER Directive Commission, and staff at the WeFib fertility center.
And she is going to talk about the effectiveness of progesterone in women presenting low levels of circulating progesterone, around the day of embryonic transfer, a meta-analysis and a systematic review. Thank you very much. First, I would like to thank you for the opportunity to participate in this journal.
We are going to start with the work. Okay. One second, we can't see the presentation.
Yes, it looks perfect. No, sorry. It looks great.
I can't see it. Well, sorry for the imperfections. Well, the title was already given by Fabian, the idea of this publication, which was made in June of this year, in Fertility and Sterility, by a group of Greek authors, in association with authors from the United Kingdom.
As an introduction, in part they mentioned it, that during the last decade, the transfer of frozen embryos has increased, and despite this, there is no optimal protocol for endometrial preparation, and even less so in those patients where the levels of progesterone are reduced. They mention, in principle, a work by Labarta, which was in 2017, the first work that was presented in a prospective way, and Labarta collaborators analyzed the association between the low levels of progesterone and the reproductive results. They concluded that those patients who had low levels of progesterone at the time of the transfer, had 20% less than newborns.
Other authors also found similar results, both in ovulation treatments and in their own treatments. Therefore, these authors, the question that was asked was whether, by rescuing progesterone in those patients where the levels of progesterone were reduced, they could improve the reproductive results. In principle, that was the objective of this systematic meta-analysis and review, using as material and methods six sources, six databases, which were sources for review and meta-analysis search, from the moment 0 to August 2022.
In principle, they obtained in the search 2,737 initial studies, they were left with 2,273 studies, finally 27 studies were chosen, and at the end of all this search they were left with 7 observational studies and a universe of 5,927 patients. The results to be evaluated were primary points, such as the rate of pregnancy in progress, the rate of clinical pregnancy, and other secondary outcomes, such as the rate of spontaneous abortion and the rate of newborns. The seven observational studies were summarized in this picture to try to mention what was used We have the CEDRIN study of 2019, which used as initial preparation 600 milligrams of progesterone vaginal, 600 milligrams of progesterone rescue per day, that is, in total it used 1,200, and the day of rescue, which began the day of the transfer.
The other study was the Spanish Alvarez study of 2021, which is a prospective study, it also used a scheme of 600 milligrams of progesterone vaginal, as a rescue it used a subcutaneous injection of 25 milligrams per day, and it began the day prior to the progesterone. Sorry, there it is. Then the BARTA in 2022, with another work, presented a scheme of 800 milligrams per day of endometrial preparation, and with a rescue of 25 milligrams of subcutaneous per day, which began the day of the transfer.
The Chinese study of 2021, used progesterone vaginal 400 milligrams, combined with vioral, and did as a rescue, intramuscular progesterone, the day of the transfer. Then the other study of 2022, used 800 milligrams per day of vaginal, and the rescue with vioral progesterone, the day prior to the transfer. And then we have two Turkish studies, in 2021 and 2022, one used 200 vaginal, plus intramuscular progesterone, let's say, every two days, and then the rescue was with 25 milligrams of subcutaneous, the day of the transfer.
And the other study that we have left, used crinone as endometrial preparation, rescue with subcutaneous, the day prior to the transfer. These, let's say, the universe of patients, initially we said it was 5,927 women, of which 58% of these women had adequate progesterone, and 41.9% had progesterone at low levels. In the first group, 88.9% were frozen transfusions, and in the second group, 94% were frozen transfusions.
The cut that was used, which is the most accepted, was 10 nanograms per milliliter. They did not find statistical differences in the analyzed groups, with an age of 34 years and a BMI of 24.3. They also did not find significant differences in the tobacco group, which was 14.7 women with low levels of progesterone and 15.4 in those who had adequate progesterone. Ethnicity was not evaluated, the total results of the 5,927 women was a clinical pregnancy rate of 47.5, the newborn rate of 37.5, abortion rate of 15.9, pregnancy rate in course of 42.7, and from here, the analysis of the different, of the seven studies that, well, as we just mentioned, they saw that there were no significant differences in the pregnancy rate in course or in the secondary results, which were the abortion rate and the newborn rate.
They analyzed the different subgroups of, let's say, rescue of progesterone, both subcutaneous, intramuscular, oral or vaginal, and they saw that there was no scheme of progesterone higher than another that was in a significant way. They found comparable results in both groups, let's say, in the group where the rescue dose was made, they were comparable to those who had had adequate levels of progesterone at the time of transfer or peritransfer. At the time of the discussion, well, what I just said, and they evaluate as a favorable action the fact of performing the rescue dose in those patients with low progesterone to try to jump to a higher level of progesterone in those patients They found that the studies based on the administration path of progesterone are contradictory, taking into account that vaginal progesterone would have a better availability and local concentration, that is, at the endometrial level, that the seric concentration would be better in those who have better seric levels, such as intramuscular, oral and subcutaneous, really that availability at the endometrial level would remain.
As for the rescue route at the time of the analysis, the only one who rescued with the same route was the French Drin who used vaginal and rescued him in the endometrial preparation using vaginal progesterone and in the case of the rescue dose using a subcutaneous injection that would be of better acceptance. Regarding the estradiol levels, they did not find that the estradiol levels had a difference in the endometrial preparation and in the endometrial preparation, but in the endometrial preparation they found that The other group that did not receive a rescue dose was the BARTA group that clearly the reproductive results were more negative in those patients whose levels were low and there was no rescue dose, although it mentions that there are ongoing studies that are evaluating that as a strength. It was the first meta-analysis that shows the non-inferiority of the result in those patients that the lutein phase was reinforced with a rescue dose for having low levels of progesterone at the time of peritransference.
As conclusions, the rescue dose with progesterone allowed comparable results with those who had had adequate levels of progesterone at the time of transference. The dosage of progesterone is an opportunity to establish strategies and avoid adverse reproductive results and clearly there is a need for controlled clinical trials for more solid evidence. Well, thank you very much and the floor is open to the speakers.
Thank you, Dr. Granados. Dr. Elena, Dr. Gehlen, the floor is yours. Yes, I think it is a very important job because in the region, practically most of the progesterone intake is done through the vagina.
When vaginal progesterone emerged many years ago, initially we knew that the blood levels were lower than when we used intramuscular, but at that time it was said that the blood levels were not important because the first step through the uterus was very high and that the level at the endometrial level was very low. Also with what happened when the recombinant FSH appeared and the LH was left aside, the use of milk that was not necessary, and then that was changing. Now, perhaps the conclusion happens because the need for the progesterone supply is different in a fresh cycle, in which one simply has to cover a gap that exists between the injection of HSH and the production and support of the luteal body by the embryo.
In cases where it is a treatment of transfer of preserved embryos where there is no luteal body, all the contribution must be given by the progesterone and that is why the level that is controlled well is so important. The evidence is that there is more and more evidence that with low levels of progesterone the results are lower, the birth rate is lower. What level is the one that is taken? It is around 10 nanograms per milliliter, although in the works it varies between 8, 75 and 11 and perhaps a higher level is better, but that is the one that is taken as representative.
How frequent is this low progesterone in patients? And it will depend on the dose of progesterone that is given to the patient. Of the works, when one uses 400 milligrams per vaginal day, there are almost 50% of patients who have less than that level in blood. When we use 600 it is around 37% and when we use 800 it is 30% that remains with low progesterone.
What does that poor absorption depend on, that low blood level? It is not very clear, but it has to do with the weight of the patient, also with age and with the antecedent of having had a previous cycle with low progesterone. It is important to analyze the results according to the time of extraction and the last application, because they have differences. And in the works, only in two works, it is specified at what time the blood was extracted to measure the blood progesterone with respect to the last dose.
Evidently, the work is very clear in demonstrating that a rescue dose is adequate to be able to reestablish the rate of live birth. Now, the works are very heterogeneous, there are different ways of rescue, by subcutaneous, intramuscular, by oral, and what was seen is that the vaginal route, increasing the vaginal dose more, is not enough to restore the results. And finally, I would be interested to know, in no way do they explain why the blood level is so important, let's say, if one has an adequate level at the endometrial level, why the blood level is so important? This is a question that I think is not yet answered in any of the works.
And I think it may have to do with the immune modulation of the pregnancy to make a correct implantation and the development of it. Although I did not find this in any work. And the last question that I would like to present is if it is not convenient to use a combined input scheme in which a vaginal dose is used and some oral route progesterone is added, which we do not have here, or subcutaneous, to achieve perhaps that blood level that has to do with the immune modulation of the pregnancy.
I can't hear you, Ricardo. Thank you very much, Dr. Elena. Dr. Agueler.
Yes, how are you? Good evening, or good afternoon, I don't know for those who are listening. Cindy, the presentation of the article was very clear, and I agree with almost everything that Arnal said. I have some certainties, like him, and a lot of doubts.
We use a lot of progesterone dosage since the work of BARTA appeared and we started to talk about how useful progesterone is. And to do something that is not very expensive, not very cumbersome, and that generates a higher rate of pregnancy, there is no doubt that it must be done. And we do the dosage.
We started to do, as she said, the same day of the transfer, and it ended up being quite cumbersome for the patient who was trying to have the bladder ready to be able to transfer and know if it would not be transferred on that same day. And there we realized that, as the concentrations at 24-48 hours are already stable, we could perfectly do the dosage the day before, or even if the congenital transfer is planned for Monday, we could do the dosage on Saturday. So we started to do the dosages, we started to take the value of 8.8, then we ran it to 9.2, doing what the works say, and now 10.
One of the questions that I have, and that I did not answer in the meta-analysis, and then looking for each of the articles, I did not find the answer, but some of you have it, is, in what cases to cancel? Because we also do rescue progesterone, we do vaginal progesterone, we do 800 milligrams as BARTA does, which is also another of the questions I have, if we would have to go back to, as before, to 600 instead of 800. There was a work that was shown this year in ASHRAE, where they showed that there are the same results with 600 than with 800, and the truth is that for the patient it is quite cumbersome to put so much vaginal progesterone, and apart it is quite expensive, at least in Argentina the progesterone eggs are quite expensive, and then I don't know if we would have to go back to the 600 dosage or not, when in reality BARTA also shows, as BARTA and all the other works, that 30% of the patients have progesterone below 10, so sometimes 800 is not enough, which is one of the questions I ask myself, and the other thing I raised was this, when to cancel it? If the patient instead of 10 has 8, I give him subcutaneous progesterone the day before, but if he gives me 5, what do I do? Do I cancel it and start again with higher doses? And the truth is that I did not see in any of the works, in Materials and Methods, that they tell me what progesterone they had when they were rescued. I don't know if you have the same doubt or if you understand what is the doubt that I have.
The truth is that more and more one transfers frozen eggs, also the good thing is that now we are doing more and more natural cycle, which is not the topic that is discussed in this article, but if we are talking about the transfer of frozen eggs, today we are seeing that there are fewer obstetric complications when there is a luteal body, because of what relaxine generates, which we do not have when we do substitutive treatments. The truth is that if we are doing more natural cycle, we will also have higher progesterone and probably, according to some works, a higher rate of pregnancy. Thank you, Dr. Axgeler.
In fact, I am already receiving questions from the public, I am going to do them, and again I invite everyone, if you have any questions, please, it is an opportunity for discussion. In fact, they ask us here in private, are the levels of progesterone considered when transferring equal in natural cycles? And the public asks us that question. No, well, that's why in natural cycles we generally see much higher values.
The reality is that with more than 10 we are fine and generally we have results of more than 10. That 30% of which speak of progesterone of less than 10 in substitutive treatments, we do not find them in natural cycles. So, in cases of natural cycles, doctor, if you have 10 or more, with that you feel comfortable not to give any rescue hormone or additional to the patient? Yes, we actually do a modified natural cycle, we give HSG, it is not that we measure the peak of LH.
We give HSG and we give a low dose of progesterone. I understand. I don't know what the rest does.
Dr. Helena, what do you do in the center? Yes, I try to do in all patients that I can a natural cycle. The average progesterone in natural cycle patients that I was able to study gives me around 25 nanograms per milliliter, against 14.8 of patients with 800 milligrams per vaginal life. And in patients that I can't do it, I'm doing another branch, in which I give 600 milligrams per vaginal life plus subcutaneous progesterone at the beginning.
And in these patients, the average progesterone is giving me 20 nanograms per milliliter. And with very good results too. So, I'm trying to do everything I can as a modified natural cycle, and if not, at the beginning, do a combined route, lowering a little progesterone to vaginal and adding subcutaneous.
I have another question from the public. The progesterone cut-off point is established at more than 10.6 nanograms per milliliter in blastocyst transference. What is the reference point in the transference of cleavage embryos? Would you change your policy for cleavage against blastocysts? In the works, practically only the French works, Cedrine's and the other French work, are the ones that transfer embryos in second or third day and in blastocysts, and it doesn't make a difference to the cleavage.
Even the other French work, which is Kurt's, they measure it at the first day of progesterone, they measure it the next day of starting progesterone, and they take that value as a cut-off. We only transfer in blastocysts. It is true that the works publish the same values, but if they ask us what we do, we in the clinic only transfer blastocysts, so we don't do measurements at another time.
Another question from the public is, is there a maximum recommended value of progesterone? The reality is that there are works that say that some are more than 20, others more than 30, others more than 40. We don't have a value established by the protocol, but more than 30 in general we don't transfer. Dr. Elena? I don't think there is a maximum level that is negative.
There are some works that say it, but it also depends on the time it is measured. I have patients that post-application of subcutaneous progesterone measured around 60, and that later normalizes. So it is difficult to say a maximum level above which it is not convenient.
I don't think so, but that is something to consider. And it probably also has to do with the time in which the patient applies the progesterone and the injection is done. For pharmacodynamic reasons as well.
But would there be a point, what do you recommend to patients when they do the rescue, that they put the medication immediately, that they put it in the morning, that they put it in the afternoon? I mean, is the injection time important? I think it is necessary to establish well how the function of the last dose is measured. I try to get the patient to measure before placing the egg to have the lowest possible level. Yes, the big jobs that do not pass less than 6 hours, with which I agree, as in general we do 2 eggs in the morning and 2 at night, the idea is that blood is drawn and then the eggs are put.
Dr. Pizma? Is there a maximum level of progesterone to give that one knows can be iatrogenic, for example? 1000, 1200 or more? And the truth is that I was struck by that work of Cedrin, the one that Hernan was talking about, when they give 600 and then rescue with 600 more. It seems a lot to me. But well.
And the waste that that patient is going to have all day is going to be incalculable, poor thing. Yes, that's why I think you also have to think about the discomfort of the patient. And that's why, well, at some point, those of us who do fertilization a lot, before we gave intramuscular daily and one starts to think about that and it seems crazy.
That's why I also celebrate that now there is the option of subcutaneous, so that when one rescues, it is done with vaginal via and then rescues with subcutaneous and the intramuscular is avoided. Of all these jobs, there was only one that gave intramuscular twice a week. But well, at one time we gave it daily.
We in the United States only have vaginal and intramuscular. We don't have subcutaneous. So that changes our perspective a little bit.
And you are quite fans of intramuscular, aren't you? Unfortunately, for patients, yes. And there are data that indicate that intramuscular is a little higher than vaginal, especially in frozen cycles. But well, as Armando says, it also has to do with the fact that, okay, the seric concentrations are going to be higher for intramuscular, but at the local level, the vaginal via is going to be higher.
So, in short, we are also interested in what happens at the uterus level, not just at the blood level. And that has always been the argument. But as we realize in these studies, there doesn't seem to be a number that we can really use as a basis.
And there are also people who use HCG as another alternative, which is something that we have forgotten, but it is something that, historically, has not been used for a long time. I'll ask you another question. Do you do a control measurement after the rescue? No, we don't do that.
It's true that in some jobs they talked about it, but very few actually do it. And we don't do it. And the other thing I wanted to say is, which is not mentioned there, what we do is also the dosage, which probably many of you also do, the dosage of progesterone before giving progesterone.
Another interesting question. In a non-modified natural cycle, after the peak of LH, when to start progesterone? In the natural cycle? In a natural cycle, after a natural transfer with a peak of LH, when to start progesterone? I use it three days before the transfer. 200 mg of LH.
Blastocyst. It would be blastocyst, correct. It's striking the levels of almost 25 ng per ml in a natural cycle, where only the luteal body works and 200 units of progesterone per LH.
I'll ask you another question, and here comes another point. The question is, post-transfer, seven days in preparation, true natural cycle, value of progesterone at 30, and estradiol less than 5. Any conduct for that estradiol so low? Patient of 38 years. I think the question would be, does estradiol have value? The reality is that we don't do that dosage, so we don't know, that's the truth.
We don't do the estradiol dosage. It is true that it is associated that patients who have less estradiol have less progesterone. But that's what literature says, it's not something I see every day.
In ovulatory conditions. But when we are doing a totally artificial cycle, does the level of estradiol have value? No, well, that's why we don't dose it. If it seemed to us that it had some value, we would dose it.
Dr. Elena. You mean an artificial cycle. Normally, I guide myself by the endometrium, I don't measure estradiol.
Because here the question is interesting. If estradiol is low, should we supplement estradiol too? It's an interesting question. But that's a question of a natural cycle.
Correct. But does it have value or not? That analysis is probably wrong, because it is rare that it has such a high progesterone production if they are not adding progesterone in an exogenous way and such a low estradiol, right? It's very rare. We agree.
But the question is interesting. What to do with estradiol? We have focused only on progesterone. Will estradiol also have some value? And the answer I hear from you is probably not.
What is known, in some works that I was reviewing of the meta-analysis, in many patients, the progesterone was also under the absorption of estradiol. So this patient probably has some problem in the absorption. But, well, there were cases where the two French works gave estradiol by vaginal way.
So maybe it's for the same reason why progesterone is not absorbed well. Another question. Does anyone use oral and combined vaginal way? Oral, no.
The problem is that here we don't have dihydrogesterone, which is the progesterone that is being used by oral way, apparently safe and works well. It cannot be measured in blood. When one does the extraction in blood, the level in blood of the progesterone will not increase when one supplements it.
It will only measure the part of the progesterone by vaginal way. And if one gives progesterone micronized by oral way, it metabolizes very quickly and has very little effect. It lasts very little in blood and the metabolites accumulate.
So it would not be a good option. For the sake of time, we are going to move on to the next article, which is the study on recurrent implantation failure, if it is really a reality or is it really a mirage. We have as a presenter Dr. Marianés Vigueracho and the panelists Dr. Horton and Dr. Pesce.
Dr. Vigueracho is a gynecologist, a specialist in reproductive medicine associated with IFER. Dr. Marcos Horton is a gynecologist, also a postgraduate in assisted reproduction in Pasadena, California, and is currently the vice president of the International Federation of Fertility Societies. Dr. Pesce is also a specialist in reproductive medicine and gynecological endocrinology, who is a member of the SAMER Directive Commission, an active member of Cochrane Collaboration, and a postgraduate professor of gynecology at the Italian Hospital University in Buenos Aires.
Thank you very much and welcome everyone. Thank you. I can't hear you well, doctor.
Let's see if you can hear me now. Now yes, now yes. Perfect.
Well, I'm going to tell you about the article on recurrent implantation failure, reality or statistical mirage, and it is the declaration of the Lugano consensus that took place on July 1, 2022, which talked about implantation failure. Well, to date, recurrent implantation failure does not have a clear definition or an accurate diagnosis of its identified cause. If we put in the search engine implantation failure, more than 70 ways to define it appear, and the term is really used randomly and according to the judgment of each doctor.
So this generates a lot of problems for us when it comes to defining it, when it comes to looking for its causes, when it comes to responding to patients who are not getting pregnant with transplants and they ask us what else they can do. So this, the pressure of the patients, makes us do many times unjustified treatments. International experts in reproductive medicine met on July 1 in Lugano, in Switzerland, to review these different facets of the RIF and define the diagnosis and its handling.
They did a systematic review, without meta-analysis, of all studies published in English from January 2015 to May 2022. And really, recurrent implantation failure has been over-evaluated, over-diagnosed and over-treated to a large extent without a critical assessment of its true nature. Currently, implantation failure refers to the sustained failure of the implantation.
And sustained is a word that we are going to evaluate if this is really the case or not, and we are going to try to explain why not. After transferring good quality embryos in a morphologically normal uterus, both by ultrasound, by hysterosome or by hysteroscopy. And the work tells us about several articles that are helping us to think why the recurrent implantation failure is really low.
The first one we have is this work by Paul Pirtea, which is a retrospective cohort study where they included 4,429 patients. It is a retrospective work, but with a very large N, where what they did was to see the result of three successive transferences of euploid embryos, analyzed chromosomally, in the patients. And what did they see? What they saw is that in the first transference the patients achieved almost 70% clinical pregnancy rate, in the second transference 59%, and in the third transference 60%.
So this sustained failure in time is not so sustained if in a second and a third transference the numbers are quite similar. Here what it says is that in the first one, probably in addition to being an euploid embryo, they chose the most beautiful morphologically. So if we do three transferences of euploid embryos, according to Pirtea, a 95.5% clinical pregnancy rate is achieved, which would tell us that the implantation failure would really be close to 4%.
So if the literature said that the implantation failure was between 1, 2 or 5% of the patients, we would have to see that this failure is sustained in time and that in the subsequent transferences we should see a lower implantation rate. And the reality is that what was observed by this group was not like that. It did go down between the first and the second, but then it was sustained.
The same is said by Lassard with the work of 2020 and also in 2021. In women under 35 years of age, in a transference of an euploid blastocyst, in the first transference they had a 62.5% implantation rate and in the second one 55.5%. We see in 2020 and 2021 where the decrease is 6%, less than 7%. So this implantation failure that we believe is sustained we do not know how real it is.
The same with this work, which is a mathematical model of the accumulated probability of implantation based on the euploid, according to the age. And what we see is that if we think that an euploid embryo can implant between 45% and 65%, we, to obtain a 95% of the accumulated rate of implantation, we need between 3 and 5 euploid embryos. Everyone does not make a genetic implantation diagnosis, so how can we estimate what number of embryos or blastocysts we need, unstudied blastocysts, we need to match those 3 euploid embryos.
So if we start from the basis that the estimated neuploidy in patients under 35 years is 20%, we would need 4 unstudied blastocysts, between 35 and 37, 5, between 38 and 47, from 41 to 42, 13, and over 43 years, 27 blastocysts, to be able to say that the patient has a recurrent implantation failure. So this leaves us thinking if the implantation failure really exists as such in such high proportions. And then the work talks about what are the possible underlying causes of this implantation failure.
And it says that without the identification of a true underlying etiology, it is reasonable not to assign this diagnosis to a patient until it has failed at least 3 transferences of euploid blastocysts or an equivalent number of transferences of unselected embryos adjusted according to the patient's age and their corresponding euploidy rate. Now, what do we assign the recurrent implantation failure to when it is not the chromosome? Well, it is really many factors, and all those factors are put into discussion and mentioned one by one. We are going to try to do something fast so as not to tire you.
The effect of the obesity cohort. It says, is it that the cohort of those obese people were responsible? Yes, no. Should we change the cohort? Well, we know that a lower rate of fertilization does show a lower rate of implantation, that a higher rate of triploidies shows a lower rate of implantation.
We know that the uterine factors, obviously an uncommunicating hydrosalp, an anatomical distortion could alter the implantation, but all this must be diagnosed before the first attempt. With echography, with salpingography, with hysterosonography. But they do not recommend the routine use of a previous hysteroscopy.
It talks about asymptomatic adenomyosis, that if it were asymptomatic adenomyosis, its influence on implantation would be doubtful. What about endometrial receptivity tests? Romina, you are going to tell us a little more about this. Well, it mentions LERA, and mentions that the personalized transfer, according to the LERA test, did not show improvements in the results.
The receptive test as an endometriosis marker does not validate its ability to predict endometrial receptivity. The endometrial receptivity factors, which we were just talking about, the transfer factors in natural cycles, in modified natural cycles stimulated with estradiol, give the same rates of implantation, with some benefits for natural cycles at the obstetrical level. The progesterone days, between 3 and 5 days in embryos in clavicle stage and 5 to 7 in blastocysts.
What about thrombophilia? What about immunological tests? Well, acquired thrombophilia or SAF are associated with obstetric complications, but not with alterations in implantation rates. So, it is critical about whether to ask for them or not. The endometrial microbiome, a lot lately about the endometrial microbiome, ends up saying that more studies are necessary to evaluate whether the endometrial microbiome really plays a role in implantation.
The metabolic factors, we know that obesity and the chronic inflammatory state could alter implantation, but more studies are also needed to clarify how. The endometrial thickness mentions a very good work that was published in Fertility and Sterility lately about the endometrial line. And all these studies talk about implantation rates with endometrial lines of more than 7 millimeters.
And there is a work of almost 500 transfers where it is at least in doubt if it would be necessary to cancel the transfers with smaller endometrii. It is said that the endometrii of 4 or 5 millimeters would be enough. The inflammatory factors, the chronic endometritis, it is not shown that it would alter the result of assisted reproduction treatments.
The effect of progesterone, we did say that values of progesterone less than 10 nanograms per milliliter on the day of the transfer are associated with lower rates of implantation and pregnancy evolution. And it is said that intramuscular progesterone would be associated with better rates of birth. The male factor, we need more studies to really evaluate if the fragmentation of the sperm DNA would alter the implantation or not.
Endometrial scratching, which was not proven to be effective, and that there are some studies that suggest that in turn it could be harmful. So all those ads on that we propose to the patient many times for lack of answer, none has really been considered with proven evidence. So the work concludes saying that the true RIF is extremely uncommon and that it occurs in less than 5% of couples with infertility.
That tranquility and conventional continuous treatments are justified in most cases. And that it would seem reasonable not to assign this diagnosis to a patient until it has failed at least three transferences of euploid embryos or the equivalent number of non-selected embryos adjusted to their age. Thank you very much, and we will open the discussion again.
Romina, Marcos. Ricardo is silent. There he is.
Sorry, sorry. What a beautiful presentation. Thank you very much.
Marcos, the floor is yours. Thank you very much, and thanks to Samuel for the invitation. The truth is that it is a pleasure.
These are very interesting topics. I think this presentation was done very well, Inés, in putting all the importance of the work, so you saved me a lot, but I think what we have to focus on, which I think is very important, this work, and there is a practice guideline also very recent, from May, is that they have focused on really making a consensus to define this diagnosis, which per se is a really rare entity, as you said, and also we as clinicians and being all day in the office we make the same mistake of seeing this patient who has already gone through two or three centers, three transplants in each, and we take all as all the same, and there are different oviparous cuts, the patients have different ages, sometimes they come three years after doing all these treatments, and their prognosis is very different, FIVA failures are sometimes very separated in time, and we do not take that into account, so I think the work of the Lugano group focuses mainly on transference of eukloid embryos, which is something we have learned from the experience of that last work of PIRTEA, which also focuses on controlling another factor, which is the support of the luteal phase, to try to prioritize a work that had intramuscular progesterone, maybe there is a North American bias, which is good, because there is evidence that intramuscular progesterone can be, at least, achieve better levels and we can control one more variable, but it is very important for me to take into account that age and eukloid, as they go hand in hand, are very important, and we always have to take it into account when evaluating a patient and want to classify it quickly as a recurrent implantation failure. Another very important topic that the work also mentions are transferences, we all know that embryonic transferences, even in a patient that one already knows, can be different from one transference to the other, despite having done the transference test, that we have everything written down, there are times that it comes with more vehicle, with less vehicle, or do not ask me why, but the same catheter does not work the one you used in the test and does not work on the real day, and there are times that the transferences leave us doubts as operators, sometimes we do not say it because we thought it was fine, but we do not have the true certainty, and that is not written anywhere, sometimes the biologist suspects it, sometimes he says it, sometimes not, we generally have biologists far above the transference and they classify it, but there are times when those things are very difficult to get out of the interrogation when one analyzes and evaluates these patients with previous treatments, not only in our place, but when they come, and it is more difficult than other places, that is not written anywhere.
Also give importance to the issue of the oboe cortis, I think that in the oboe cortis LASAR is recruited, and LASAR has these things, patients who have had very bad cycles, there is low oboe quality, low degree of maturity, or the cortis itself is bad and we do not have ophloid embryos, and many times they do a treatment again and we have ophloid embryos. It is considered, and it is mentioned in the work, that these types of cycles, so dramatically bad, are rare to find that they are repeated, less than 30% are repeated, so there is an effect of the oboe cortis. So I think that the issue of recurrent implantation failure with this work of the Lugano group and with the guidelines of that are making a lot more sense so that we can all speak the same language.
It is the great bias, for me, the mother of the biases of all this, and now I am going to give to Romina, I congratulate you for the work of ERA, that you are co-author and that also evaluate the difficulty of evaluating this group, because in all the meta-analysis and reviews that we read are based on previous work where the definitions of recurrent implantation failure are different. Some may be better than others and more rigorous and with better quality of evidence, but others are really very difficult to standardize. So I think this helps that we all start talking about age, prohibition, and to make a minimum comment on the ERA guideline, what they say is for each patient at their age, when they have already done the sufficient number of cycles that, let's say, for that individual patient would give a cumulative rate of more than 60% and they did not succeed.
And then start studying how recurrent implantation failure, things of another type, such as uterine factors or endometriosis. Dr. Pesce, can you hear us, doctor? You are muted. Perfect.
No, it's still muted. I can't hear you, doctor. Well, I'll tell you the difficulty of dealing with failure.
I think it's the hardest thing for doctors to realize that many of the treatments will fail, especially with the patients we have, at least in Argentina, old people with low barica reserve. That is also what is most difficult for doctors and makes us do things sometimes without scientific certainty. There is information in Argentina about this.
Dr. Pesce, can you hear us? We can't hear you. What a pity. Maybe if you disconnect the microphone, Romina, we can hear you.
No, Romina. While the doctor is looking, is there information or do you have your own information from Argentina regarding the number of transplants that someone would require to get pregnant in the same in the same way in which this analysis was done. I don't know any, and we are seeing this also in our computer system, trying to evaluate this factor.
We have, I think the most important thing in the case of having, obviously, genetic studies, is to evaluate that. Now yes. Now we don't see you, but we hear you.
We hear you. Sorry, I had some topics related to this. Well, short, the same as mine.
The truth is that Inés' presentation was also very well organized. The article is very well organized too. I think it shows all the difficulties we have, the clinicians in the management, and Marcos also made a super summary.
What always happens to me is that, especially the title of this meeting, is how to transfer the part of science and research to clinical practice. As sometimes there are two different needs to cover, then one has a need to give an answer to the patients, and it starts to get confused, it starts to over-diagnose, it starts to over-treat, and we start to move away a little. It is very difficult for us to even do and standardize behaviors that are already tested or that make more sense.
A key example, you mentioned it, was that of ELERA. ELERA, for many, is considered a therapy, if we had to put it in the column, within the therapies, acts on. Later, if you want, I will comment on something related to ELERA, but specifically for when one sees the recurrent implantation rate failures, I think that the great impact that definition has today, we cannot ignore the euploidy.
I believe that the work of PITREA and the mathematical model that Boris Atta does are fundamental when it comes to interpreting and leaving, as they describe, there is a small recalcitrant fraction, describes PITREA, which is around 5%, where the true implantation failure is, and that we cannot have an answer or access, and even marginally, in the work, it is not important to go and discover that, because it can be multi-causal. With respect to the work of PITREA, it is not less than it was done in women under 35 years, that too, right? Although the number is quite impressive, because there are approximately 4,500 patients, and it also uses our most important outcome, which is the cumulative rate of newborns, so it really has a relevance that, for me, necessarily changes the way we have to define, if it is necessary to define the implantation failure. And the same thing that Boris Atta does, but he does it from a mathematical model, and actually what he ends up defining is that there is no implantation failure, what is missing are enough euploid embryos, as to achieve that 95% of the cumulative rate of pregnancy.
It is also important, with respect to... There is a third author, who is a very controversial author, who is an author that is generally published more by Human Reproduction and not by Fertility, which is Ben Rafael. Ben Rafael is an acerbic critic, not only of the era, but everything that has to do with the definitions of the RIF, that is, the implantation failure, and a little mentioning what Marcos said about the transference of the same patient, the same cannula, and so on, he writes and says, well, no man can get into the river twice, because it is not the same man, nor is it the same river, right? So he says, no woman can have the same assisted fertilization treatment cycle twice, because it is not about the same woman, nor the same cycle of FIB, nor the same embryo. So he goes back to, let's say, to deepen that the RIF ends up judging the interpretation of what may be happening, and in that search we begin to look for other therapies, other things that can, let's say, justify the failure that exists in the face of that event.
Yes, I find it interesting, as Marcos said, the effect of progesterone, and what caught my attention is how they hierarchize intramuscular progesterone in this part, saying that there is a slight improvement of intramuscular progesterone with respect, even, to vaginal and subcutaneous supplementation of 25 mg per day. They highlight that. For me, it is something that I underlined to read carefully later, because the truth is that we, I stopped using intramuscular, it is very clear to me that the upper parenteral pathway, that is already proven.
Now, which parenteral pathway is better, if vaginal, rectal, intramuscular or subcutaneous, and in what dose, I think it is still open. From what I understand here, to what dose is better. That is something that was not finished to define either.
And with respect to the era, let's say, we were lucky to participate and we participated in a very arduous job, of a lot of obsession. The truth is that doing a meta-analysis is something that exhausts, to put it simply. Really, more than 2,100 jobs were written, of which only 35 met the inclusion criteria.
But in that reduction work, to see everything that came in to publish and to analyze and to extract data and weigh them, it was really a very arduous job. And a heterogeneity that I thought, I had never seen so much heterogeneity in my life, in jobs, in populations, in interventions, in sub-interventions, in interpretation of what are the definitions of failure of implantation. In this particular case, as it was an endometrial test, in addition to that, the different types of tests that were used were heterogeneous, the different types of genes, because not all tests contain the same genes, to speak.
So it really was a half-titanic job. And to come to a conclusion that I think the conclusion is that the ERA did not show to modify the results in its generalized application. But I don't think it had to do with the idea of the ERA, but rather it has to be related by the enormous heterogeneity that is very difficult to adjust and by the quality of the jobs.
We have only two randomized jobs, of the same author, of the same group, and then we have a lot of cohort studies that are also hyper-heterogeneous. Yes, what we observed, yes, what we observed is that there was an improvement when a personalized transfer was made, adjusted according to the value of the ERA, regardless of the test that has been used, for those patients who had a previous RIF diagnosis. Now, don't ask me what type of RIF was diagnosed, but we polled all those who were RIF, and then we polled everything when a personalized transfer was made and we saw that it improved, that that rate improved with an odds ratio of 2.5, that is, that really the association, although in the quantity we needed, let's say, it was very irregular, the variables that were analyzed, there really was an association and that group was limited to that age group.
So... Because they are paying more attention to more. More attention to what? To this, of course. To that group of patients, who take more time and more concern and more time, and that's why they are doing a little better.
Yes, the truth is that it could be that and it could also be, I don't know, so many things, but it was very, the truth is that with so much heterogeneity, I would not dare to draw conclusions that have an external validity for all cases. That's the conclusion I have, right? That is, when one does a research work and tries to prove that an effect has a certain size in a population group, the second problem arises when you have to be able to extrapolate that value, that conclusion, and be able to represent it and have an external validity in different population groups. And there it seems to me that right in this part it is very difficult, in reproduction in general and with this so heterogeneous in particular.
And then there is another mention, now I go back to the article, related to this too, when one uses definitions based on distributions, to statistical effects. And there, perhaps one can also pifiar it, so to speak, because considering a disease by a population distribution can make the interpretation or be over-diagnosed or the effect is underestimated. So, I'm not going to get too technical, but the reality is that one can be left out of that distribution and not be diagnosed, or, if it is done by the disease, be over-diagnosed and over-treating something that really does not deserve it.
Well, that's it. For me, the implantation failure is still a challenge, something to continue studying, and, as you say, doctor, to pay super attention to patients. But I think I agree with what these three authors say, with Pitréa, Atea and Rafael.
I think this entity does not exist. I think it is something of many variables, but I also have a huge need to be able to give answers to patients. It is also desperate for the doctor and for the patient, to try to give them something that is good for them, that ultimately results in a pregnancy.
I have a couple of questions from the audience. The study includes women under 35 and a more appropriate body mass index, quite far from our patients to achieve that 95%. Interesting comment, which also leads us to the fact that you in Argentina have your own record and that you could potentially contribute a little to literature, talking about what is actually happening in Latin America, because that is another of the problems that we have in world literature, that we talk about European programs, American programs, Canadian, Australian, now Chinese, but what is happening in Latin America? I think that would be something interesting.
Yes, I think that will be there. Maybe people in Samer will correct me, but this is from this year in the record and in Red Lara too. I think that the PGT and the results of PGT, etc.
I think we will have them in about two years. I think, right? At least Red Lara, and maybe Rafa too. They say so.
That's right. Well, I think the other comment that I wanted to make, which I think is also important because both doctors and patients, well, doctors have a little more responsibility not to get so desperate, and I think one thing that is super important that this article also focuses on is that we have to talk about the cumulative pregnancy rate. Because I always remind patients that when they come to the doctor's office with a year or two years of search, they have a cumulative pregnancy rate of zero, but maybe if they leave it for six more months, they could get pregnant and their cumulative rate would be 100 in two and a half years.
Obviously, we always have to establish a point where to start studying them, but it is important to take into account that just as every time one has a relationship and has a percentage of conception, of birth rate, which is very low, and lower in patients with infertility and annuity as we have, the same thing has to be explained about the in vitro fertilization pregnancy rate, which is 30%, 35%, 25%, or less, according to age, and that they will need more than one treatment, and that perhaps the extreme would be the table that Inés showed with the 43-year-old patient, that we will need to transfer her to 27 embryos to see that some, so as not to consider her, she fails to repeat the implantation. And that shows the magnitude of the problem, and sometimes it is very important to give those numbers to the patients too, because even the 39-40-year-old will have to transfer a few embryos to achieve a pregnancy. So I think that this concept of the cumulative rate is what is being imposed in reproductive medicine in general, with the freezol, with the successive transfer of frozen eggs, and so on.
And the last comment, and I wanted to say that recently in the congress that we shared with Ricardo in Athens, a discussion on endometrial receptivity, which was, I participated at the table, Carlos Simon was there, and, let's say, as was led by Olivia Arakis, who has been very critical in general, of LERA and scratching and all the things we want to do. Well, there is a recent review of individual patient data, meta-analysis, that Human just published, in favor of scratching, with which it is quite difficult to establish precisely because the diagnosis, that meta-analysis, looks for patients specifically with recurrent implantation failure and finds very high odds ratio in favor of scratching. But the problem is in the same issue of bias, of how you classified that patient as recurrent implantation failure.
If that is wrong, all the subsequent analysis is wrong. An interesting question from the public. And what happens in patients with ovodonation cycle and euploid embryos? With two or more negative results to classify them as recurrent implantation failure.
Would this apply to ovodonation, in your opinion? The work does not include ovodonation. They were all with their own ovules. Those patients were excluded.
But what is your opinion? Would this apply? In an ovodonation patient, do we apply the same statistics? I think so. It can be applied. When the work shows the data of SART, divided by age, obviously there are not so many patients of 20 or 25 years with infertility that have been registered in SART or in all registries, but that is the age of the donor, where there are still many aneuploidies, even though they are young, they have a level of aneuploidy of 20 or 25 or 30% or 40% and I think it is the same because they are young patients and that percentage is established at the level of each age.
So considering the age for me it is similar. Of course, they are healthier patients who will not have other pathologies, but I think that in general terms it is applicable. I don't know if you can hear me.
Can you hear me? Can you see me? We can hear you. Maybe one of the things that Borizata says when he talks about reflection, he says, well, here, first the aneuploidy and then pay attention and discard all the other factors. If one thinks about ovodonation and assumes that the aneuploidy would not be the effect, well, you have to think, because the ovodonation receptors there are more body mass index, there is more inflammation, there is more masculine factor, there is an advanced age, and it is also seen that as the age increases, it is also light, it is not significant, but it begins to decrease with aneuploidy transfer the implantation.
So maybe there in ovodonation it is to consider it, as Marcos says, within the same definition, but pay more attention more than to the aneuploidy, to all those factors that may also be involved. Because all these jobs are with uterus, with normal cavities, and the receptors, most of them have some huge associated cofactors. Well, we have already spent 17 minutes of time regarding all the attendees and all the attendees.
I thank you infinitely for your participation, and on behalf of Fertility and Sterility, I thank you for honoring us to be present in your congress, in your webinar, and we hope to be able to do this again live next year in Cordoba. Thank you very much to all. Thank you.
Thank you, and excellent. The truth is that I want to congratulate the two speakers. They had a very good presentation.
The excellent four speakers, the truth is that it was a very enriching Journal Club, and to you, Ricardo, I thank you again for allowing us the possibility of doing a Journal Club with Fertility and Sterility. Thank you all. We have to keep doing it.
We have to keep doing it. Of course, we will do it. See you later.
Thank you.
