Hello everybody and welcome to another Journal Club Global sponsored by Fertility and Sterility. I'm Kurt Barnhart, the media editor for the journal, and it is my pleasure to now have an international conference this time in conjunction with our colleagues in India. This is scheduled across the world.
We have participants in I think three, maybe even four continents joining us this time, and we're going to discuss add-ons for assistive reproduction and see how we can use those or perhaps not use them in our practice. As a background for this discussion, we're talking about the December issue of Fertility and Sterility and the views and reviews sections put together by Cindy Farquhar, and I want to thank Cindy for putting it together. There are four papers in this views and reviews, and we're going to discuss two of them, which include the clinical adjuncts and in vitro fertilization growing list, and we have some of the authors with us on this call, as well as add-ons for the endometrium, and we have authors for that paper as well.
So it is my pleasure to turn this over to our co-host, Dr. Guru Shah, who put this together in a wonderful fashion and has a panel of experts which you can introduce, and she can introduce the first article for us. So Dr. Shah, pleasure to work with you. Thank you so much, Kurt, for having invited me to host this wonderful webinar, which is being organized by ASRM through Fertility and Sterility.
Now, we are today going to discuss areas which we commonly see in practice of IVF, and there are so many such incidents in the past, say, for example, when ICSI was introduced. It was introduced so quickly, and we did not have any access to any evidence, etc. Similarly, during IVF, all of us, or many centers, are using so many products which we don't have even gone to date.
So I'm happy that, you know, we have had these wonderful review papers in the Fertility and Sterility issue of December 2019, wherein the authors, Mohan Kamath and his colleagues, Mariano and Sankara, have put together information related to products used during, or even procedures used during IVF. So we have with us today two experts, David Adamson from California, and we have Professor Gamal from Cairo, who's joined us in this discussion. And we have my fellow Vishesh Yadav with me, and we have, of course, Kurt Bernhardt, the media editor, who's also the co-author of the second paper, which will be discussed.
So I'm going to ask Vishesh to put across the first paper, what exactly it included, and then we follow it up with the authors of that paper. So Vishesh, over to you, please put forward the first paper. Thank you, ma'am.
Good evening, everyone, or good morning. So before we move on to the discussion with the authors and experts, I'll be giving you a little background on the papers today. The life birth rate initiated per cycle remains at 19 to 22 percent in per IVF cycle.
In spite of various advances made in the stimulation protocols, laboratory techniques, and pre-treatment, we are still struggling with low success rates. Hence, IVF clinics are strongly determined to achieve success for their patients. As a matter of fact, high cost of IVF has always been associated with both financial and emotional burden.
Hence, globally, various add-ons are being offered to infertile couples without any clear evidence of safety and effectiveness and, you know, contributing it to the high cost of treatment. Some of these treatments have been even found to be ineffective and harmful in the randomized control trials. Dr. Vishesh, I'm trying to move on to the next slide.
Please place your cursor in the bottom line. So while we're looking to change the slides, I think this is a, I just want to add a little bit to the introduction. There are many things in medicine that have been really strong contributions with just anecdotes.
Many surgical procedures and ICSI as well. And I think we're continually looking for those kind of interventions to really bolster IVF. However, some of these may or may not work, and that's why we're reviewing these topics.
So I'm going to head it back to Vishesh, who's got the slides working again, and she can give us a more update view of which one of these adjuncts we're talking about. Yes, sorry for the trouble. So the first paper we are going to be discussing is on the clinical adjuncts in in vitro fertilization growing list.
This current review is a summary of common IVF add-ons, and this was made through a PubMed search till June 2019. It included all the Cochrane database reviews, the database of the abstracts of reviews of effects, systematic reviews, randomized control trials, and non-randomized studies if no RCT was available. So we have basically divided the add-ons into two parts, for better understanding, the pre-stimulation and during the stimulation.
During the pre-stimulation, we use screening histroscopy, the DHEA and testosterone, the androgens, and antioxidants for both partners. And during the stimulation and in the luteal phase, we use the growth hormone, aspirin, heparin, seminal plasma application, and platelet-rich plasma PRP. I will now initiate the discussion and tell Dr. Shah and Dr. Kurt to help with the discussion with the authors and the experts.
I would like to take forward the discussion on this paper and will request Dr. Mohan Kamath to start with, you know, talking about at least four of the adjuncts which they have reviewed in their paper and the results of that analysis. Okay. Good evening, all.
Thank you for having me over here. Dr. Rusha, Fertility Sterility, the journal club over here. So, we looked at 10 clinical adjuncts, the add-ons, during reviewing this paper.
That's what we did for this paper. Of course, that was mainly restricted to the clinical application. The other papers looked at the lab and the endometrium.
That's been covered by other authors. So, I am going to summarize the evidence for four of these. That's screening astroscopy, antioxidants for male and the female, and, of course, aspirin.
So, the first one was screening astroscopy, which was the only surgical add-on in IVF, which is quite commonly used. It's a routine procedure. But the difference here is that we are doing a pre-IVF astroscopy in women who had a normal pelvic ultrasound.
We did not find any pathology, but we still offer a routine astroscopy just to make sure that we don't miss out any pathology, intracavitary pathology, which probably might affect the IVF. So, we used the Cochrane Review, which was published in 2019, pulled in 10 trials. The Cochrane Review pulled in 10 trials, and there was low-quality evidence of improvement in live birth rate.
Now, this was a conflicting evidence to, if you actually summarize, because what happened was out of the 10 trials, only two trials were high-quality trials, and when we pulled only the high-quality trials, we found no improvement in live birth rate following screening astroscopy. So, that's where the evidence stands. It is conflicting in nature, and as we know, it's a fairly invasive procedure, and it does raise the cost and so on.
There is probably some set of women, like in the review, we did subgroup analysis of two or more IVF failures, and it appeared that it helped them, the screening astroscopy helped these women, this particular group, more than unselected or the ones with first IVF failure. So, that's where the screening astroscopy evidence stood. And then, of course, it was the antioxidants in the mail, where we found that there is a Cochrane Review published, but this Cochrane Review actually focused on mainly use of antioxidant in non-IVF setting, that is for natural conception.
So, there were only two trials in this Cochrane Review, which when the pooled estimate was found to be showing improvement in live birth rate following antioxidant. The problem with this evidence was that the whole sample size after pooling the two trials was 90. So, you had a very less sample size for making any broad conclusions about benefits of these antioxidants.
The second issue was that there's far too many agents, antioxidants, you know, that we had vitamin E, vitamin C, then CoQ, carnitine, and so on and so forth. There's just a plethora of antioxidants being used in the men, and these two trials did show some improvement. But, of course, the Cochrane did not grade the evidence for this particular subset of population.
I would like to add that the largest trial for antioxidant usage in male factor infertility prior to ARTxE was published last month by our own group in Human Reproduction Open, and it kind of mirrors the conclusions in the sense in the intention to treat analysis did not show any improvement in live birth rate after giving antioxidant to the men. So, that's where the evidence stood for in the male partner, and then, of course, use of antioxidant in female as well. We had a Cochrane review, again, a subgroup of women who were undergoing IVF.
We had four trials, and they did not grade the evidence for this particular population, but we found there's no improvement in live birth rate after giving antioxidants. Now, again, there were so many of them. It was vitamin D, inositol, vitamin C, and so on.
So, that's where the evidence for antioxidant for the female partner prior to IVF. And the last one I want to summarize is aspirin, which has been used very commonly, and it's used sometimes pre-stimulation, goes on till stimulation, and subsequently following the embryo transfer. So, we looked at the Cochrane, which was published in 2016, 10 trials, and the quality of evidence was moderate for this, and they did not show any improvement in live birth rate as well.
And, of course, because of some association of higher miscarriage in patients who are getting aspirin in non-IVF setting, there have been concerns of using aspirin as well. So, on the whole, all four of them actually had either low quality evidence or no clear evidence of benefit. Yeah, that's all I would say.
So, I think there's been quite a bit of review of literature, Dan. The fact is that it has helped certain areas. Would anyone of our experts like to talk about, you know, say, David, if you would like to add on anything to what is done in practice besides what has come out in the review paper? Well, I think the whole issue of the add-ons is obviously very, very complicated.
Kurt mentioned earlier that I think one of the special issues in our field is that it has really developed without a lot of randomized control trials, and there are a number of reasons for this. One of the big reasons, which I think is important to note, is that because of the, you know, societal differences in perspective about reproductive medicine and women's rights, gender equality in particular, national policies on a global basis often do not really address research in this area appropriately. So, for example, in the United States, you have very serious restrictions on the types of studies that can be done.
And as a result of this, without, you know, federal funding or large funding, without universities being involved early on because the areas are not supported, you know, by funding frequently, what happens is that practitioners try things because they hear about them and they think of them, and we start to develop a whole culture around trying new things on people. And I think another fact that is really unique to our specialty is that when you're talking about IVF, you do an intervention during the ovarian stimulation or egg retrieval or in the lab, and within two weeks, you know the outcome basically, they get pregnant or not. And so I think there's a huge propensity to say there's cause effect involved here because I just did this and look at the outcome, whereas if you were treating chronic back pain or something, it might take a year to know if you had a benefit.
So, I think there are some special areas, and of course, our patients are very emotionally challenged by this, and they also are spending a lot of their own money. So, there's a lot of pressure on the doctors, a lot of pressure on the patients, and I think there are structural issues which have caused add-ons to be used much more than would be justified by this, you know, honest appraisal which these papers have done. Yeah.
So, the thing is that, you know, probably after this review, would you be able to identify, Mohan, any specific group whom you would say that it's worth going ahead with, you know, like the screening histoscopy, whether you would want to do an advanced reproductive imaging. Yeah. So, the interesting thing is that we've seen this in a couple of more Cochrane reviews as well, is that any intervention, when it starts being looked at in two or more failures, everything seems to be working in them.
You know, it's the GCSF, it's the endometrial scratch, the same thing we found. So, there's something called performance bias. I think that's what's happening here, but there could be a subset of women who probably would be benefited, I would say, the ones who had difficult cervical, difficult embryo transfer, you know.
You kind of struggle, but these things don't get documented or it doesn't get picked up in the baseline of any trial, okay. The clinicians know that sometimes things just don't work out, and these are the cases where you put good embryos, everything worked fine, but you kind of didn't get it right in the embryo transfer stage. This, and because of the anatomy, you probably would offer them, that's one case, and of course, that's for the screening histoscopy.
The antioxidant male, I would say the problem is that it's, again, unselected population. Most of the time, the two trials, only one of them did a DNA fragmentation and kind of tried to get, you know, who had higher DNA fragmentation, the antioxidant was offered to them. So, probably there is a subgroup, there could be, we need more evidence on this, but in unselected population, just giving antioxidant for all the men with male factor subfertility is not the right approach.
We need to identify that subset, probably the ones with higher DNA fragmentation, and then probably have those trials and may find a benefit out there. So, these are probably my suggestions on these two interventions, at least. The antioxidant in female is just too vast, there's just too many of them, and we need to really look at them separately, the indication-wise, and so on.
Right. So, I think, thank you, Mohan, for that. I would like to request Sej, if she's coming in now and talking about the next three adjuvants.
Thank you, Dr. Shah, and thank you, Ehsan, for this very interesting journal club. What I looked at within this paper, or what I will be covering is the adjuvants which are very specific to ovarian stimulation, and these are very tropical, and these are androgen supplementation and pro-tumor supplementation. So, what is the rationale behind giving androgens, adjuvant androgens, during ovarian stimulation, either before or during ovarian stimulation? This is based on climate studies, which show that androgens enhance SSH receptors in the granulosa cells, and also studies in primates show that androgens significantly increase the primary pre-antral and antral follicles.
And based on this, we moved on to clinical application, i.e. introducing androgens during ovarian stimulation to enhance ovarian response, and mostly in the context of per-ovarian response. So, the androgen adjuvants, which we commonly use, or we commonly come across, are DHEA, dehydroepiandrosterone, and testosterone. So, let me start off with DHEA.
So, what is the evidence for the use or not use of DHEA during ovarian stimulation? So, I'll start off with the Cochrane Review. The Cochrane Review was published in 2015, and was starting off with DHEA. There were about eight randomized controlled trials that looked at the composite outcome of ongoing pregnancy rate and live birth rate.
And pooling of these studies showed that there was an improvement in live birth rate for the use of DHEA. However, when studies which had high risk of performance bias were removed, and only good quality studies, higher quality studies were pooled together, there was no significant difference in the ongoing pregnancy or live birth rate, whether you use DHEA or not use DHEA, i.e. in the control group, which some of them had no placebo, some of them had placebo. So, that was what the Cochrane Review showed.
That was in 2015. Subsequent to the Cochrane Review, there have been other randomized controlled trials on this topic. This is, you know, always in the limelight.
DHEA is always in the limelight. It sounds, at one point, used to sound very fashionable. But these randomized controlled trials which came out subsequently showed very inconsistent results.
Some of them showed that there was a benefit, and not all studies were powered to detect an outcome of live birth, which would be an outcome of interest. Some of them looked into suicide as the primary outcome, and the results from the randomized controlled trials that were published subsequently were quite inconsistent. Based on this, in the review, we said that, you know, DHEA, current evidence with regards to DHEA is inconsistent and conflicting, and therefore should not be used in routine clinical practice.
And what I am pleased to say is that what we said in the review very much compares with the HRA guideline on awareness stimulation. The HRA guideline on awareness stimulation was released late last year, and that's quite an extensive and comprehensive guideline. And I'm a co-author on that, and I worked on this section too.
And again, the HRA recommendation very much mirrors what we said here, in that DHEA cannot be recommended for routine clinical use before or during awareness stimulation. The other problem we faced when we looked at the studies is that, you know, studies have different duration for which they get the DHEA, and there was no long-term safety data. When there is so much of, so many unanswered questions, I think at the current moment, we cannot say that DHEA will improve awareness responsiveness or outcomes, whether it is in the context of co-responders or in any responder in the context of awareness stimulation.
So that's DHEA. So the next, let's move on to the next androgen pretreatment, which is testosterone. So again, with testosterone, the Cochrane review looked at, in 2015, looked at testosterone pretreatment in co-responders, and pooling of these studies showed that testosterone could improve the ongoing pregnancy, live birth rate, composite outcome together.
But again, there were four randomized controlled trials. But again, when we only, when they only looked at the study, which did not have a high bias, that means removed all the studies, which all three studies, which had a high risk of performance bias, there was no significant difference in the ongoing pregnancy and live birth rate. And again, if you look at that, if you're looking at evidence that has, that we are looking at applying across the globe to different, in different continents, different groups of patients, you're just looking at four randomized controlled trials published so far.
So again, this evidence is too insufficient, it's inconsistent, and therefore we cannot recommend the use of testosterone pretreatment. The other problem we are faced with, again, with similar to the DHEA is what is the right dose? How long do we give it for? Again, are there any longer term, is there any longer term safety data? We're lacking in all that. So again, what we said in this review very much compares to the ASHRAE recommendation, that is, testosterone pretreatment cannot be recommended for routine clinical use.
And the justification is what I alluded to before. So then the next one is growth hormone, growth hormone supplementation. Again, very topical.
I'm sure there'll be a lot of questions about testosterone and growth hormone. I'm sure, you know, there are quite a few people who are using it and I hope they will not use it after this webinar or probably discuss. Growth hormone, again, you know, all of us who are in this webinar probably are quite well read.
You know, if you look at publications, there's so many systematic reviews, systematic review after systematic review after systematic review on the use of growth hormone in the context of ovarian stimulation. And what are the results? The results are more sort of concurrent in the sense that they show that there could be an improvement in live birth rate with the use of growth hormone. But again, systematic review after systematic review after systematic review.
If you look at the sample size of the RCP so far pooled together, the maximum sample size, if you look at the most recent systematic review, is coming close to 600 patients. But can you apply the evidence on 600 patients to everyone across the globe, across all centers? And again, there is, you know, there is doubt about the quality of the evidence and the, you know, whether there is performance bias in some of the studies that were included. Again, the same problem as with the same issue as with the other adjuvants or supplements, what is the right dose of growth hormone do you give and how long do you give it for? Again, growth hormone is not something cheap.
You know, you give it if you really think it is beneficial. So, and again, no long-term safety data. So, with very little data around, no concrete evidence, the recommendation, you know, or the way we discussed in the review is that growth hormone in routine clinical use, you know, cannot be suggested.
And that again, very much concurs to the ASHRAE guideline, which is a conditional guideline saying that growth hormone cannot be recommended during ovarian stimulation in clinical practice. If somebody was to do something, probably do it in the context of clinical research. And I want to, in that context, I want to refer to a very recent paper.
Most of us would be aware of the LIFE study, which came from Australia, whereby they had a sample size of 195 women where they had to, wanted to recruit previous co-responders to growth hormone or no growth hormone. But unfortunately, the paper was published in RBM online. They had to terminate the study before they could reach full sample size.
And probably one of the reasons is, yes, co-responders is a very niche group of women. It's very difficult to get the population to recruit into the study. But also the problem is that sometimes, you know, as clinicians, as Professor Adamson said, as clinicians or as practitioners in this field, because of the pressures or because of the competition or because we want to do what we want to do, we might be, you know, we might, clinicians might have a bias and there might not be clinical equipoise.
And therefore, when we are in a situation when we are no more in clinical equipoise, the randomized controlled trials recruitment suffer. So if I have to conclude on the three adjuvants, it is very, pretty much similar. The evidence there is quite inconsistent.
And therefore, in the current context, we cannot recommend in clinical use, for routine clinical use. Dr. Shah, you're on mute. One more time, Dr. Shah.
Kurt, you can take over. So Dr. Shah is having a little trouble with the technical aspects of the mute here. We'll get that fixed shortly.
But what I hear, Sesh, is that most of the things, most of the adjuvants we've looked at haven't worked. So we haven't found the home run that people are looking for. However, have any of these been found to be harmful? And is this, should we, in other words, should we never use them? Or is there a time that we should try because nothing else is working? Yeah, that's a very good question.
I mean, looking at harm in a randomized controlled trial is very difficult, because you would need a very large sample size. But nevertheless, there is very little reporting on any harmful effects. So either there were, and it's difficult to say whether there were no harmful effects, or the authors simply didn't look at the harmful effects.
So, you know, and hence, what we can say is that there is a serious lack of long-term safety data. And yeah. So I was going to ask Mohan and Sesh, the ESHRA guidelines and what we've talked about often say there's no evidence of support.
But do they often say or do they ever say there's evidence that you should not use? There's a distinction here that I want our audience to understand, right? Yeah, yeah. If I can come on that, that is a position we take when we say that it should not be used. Because, for example, when, because you're referring to the ESHRA guideline, if aspirin, it was one of the adjuvants we looked into.
And then we saw aspirin in the context of ovarian stimulation, was there any benefit? And we found that there was no benefit, even in terms of reduction of ovarian hyperstimulation. So our outcomes when looking at adjuvants and looking at outcomes were live birth, cumulative live birth, adverse effects such as ovarian hyperstimulation. So in the context of aspirin, we said very strong recommendation that it is not recommended to use aspirin during or before stimulation to improve any outcome.
So there are instances where we say should not be recommended. OK, thank you. Since Professor Gamal has joined in and he's chaired an ethics committee at FIGO, would you say it's ethical for us to use products which have not yet been completely found to be safe in terms of effects on the fetus? Dhruv, for this very important question, the problem is when you look at the fact of the matter that most IVF cycles around the globe are being performed in the private sector and the patients are paying out of their pocket.
And in many countries, particularly the developing countries, the cost of a single IVF cycle is almost half of the annual income of the family. So if you consider three cycles to a live birth, then it is almost equal to the income for one and a half years. So on what evidence can we offer procedures which would cost money, as well as some of the procedures are involving some risks, as was clearly said by the presenters, when you don't have really solid evidence to use this? I think this becomes unethical.
And the problem is because many of the IVF centers are private centers and the information is being disseminated over all the communication media, website, the social media, etc. And then the patient comes and asks you to have these procedures. And if you don't do this procedure, because you don't have evidence-based support of the procedure, and if the patient doesn't get pregnant, which is likely to happen, then the patient comes back to you, blaming you that the procedure did not succeed because he did not do the histroscopy before the procedure or because he did not give them uterine vasodilators or because he did not do intravenous lipids or immunoglobulin, etc.
This is the problem. So I think, you know, when you talk about ethics, I think we should not provide patients a procedure unless it is proved useful. And I fully agree with the last presenter that, you know, some harms also are included in this procedure.
Thank you, Dhruv. Over to you. Thank you, Kamal.
So, Marianne, I would like you to complete the rest of the adjuvants from your paper and talk about them. Thank you, Dr. Shah. It's great to be able to share some of our thoughts to an international audience.
And thank you very much for putting this program together. The first adjuvant I'm going to talk about is heparin. Now, heparin and IVF can be used in different circumstances.
You can use it in situations where someone develops hyperstimulation syndrome to reduce the risk of blood clots. That is completely justified. You can use it to reduce the risk of blood clots during pregnancy.
That is also completely justified. What we looked at here was the use of heparin specifically as a means to improve the life-birth rate. So why has heparin been used in this context? It was historically thought that disturbances in blood supply to the growing embryo may cause problems in implantation.
And microthrombi were considered as one of the causes. And so it logically came to affect that if you use heparin, it should reduce, it should improve implantation. And in certain circumstances, it certainly does.
For example, in women with antiphospholipid antibody syndrome, using heparin does seem to improve the life-birth rate. However, when used in IVF generally, even in women who have had multiple failed IVF cycles, the evidence is not reassuring. So the Cochrane review was the last in 2013, included three RCTs with 386 sample size, and did not show any difference in the, it did show a difference in the life-birth rate, but it was sensitive to the choice of the model used.
So they used a fixed effect model. There was a small difference in life-birth rate. They used a random effects model.
There wasn't any difference. A further more recent meta-analysis in 2018 included only women without a known clotting disorder, without thrombophilia, and they found no differences in the life-birth rate. This was a bit larger with four trials and 776 sample size, so a bit more robust in its conclusion.
The findings appear to be different depending on whether the meta-analysis included studies which included women with thrombophilia or not. And one study, which was quite elegantly conducted and meta-analysis conducted in 2013, separated out these two subgroups. And what they found is if you lump all studies together with or without thrombophilias, there was an improvement in the life-birth rate.
But if you take out these studies with thrombophilia, there doesn't appear to be an improvement in the life-birth rate. And that's, that seems to be the thrust of most of the research studies on the topic. Now, question may come as to whether everyone needs to be screened for thrombophilias.
The trouble is these studies, which have specifically looked at inherited thrombophilias and early pregnancy heparin, have not really shown a huge benefit. There is a large multi-center trial going on in the UK, the ALI-2 study, specifically looking at that topic. Now, you may ask, why is it only working in antiphospholipid antibody syndrome? It's not working in other thrombophilias.
The reason is supposed to be the heparin has some sort of immunomodulatory effect on antiphospholipid antibody syndrome associated antibodies. So it doesn't seem to be a microthromboid busting issue here at work. It's more of an immunomodulatory effect on specifically on antiphospholipid antibody syndrome.
More so now that we know that the early embryo development doesn't really depend on much vasculature. Most of the energy it gets is from diffusion. So a microthrombus or no microthrombus shouldn't theoretically make any difference to at least early implantation.
And that also feeds in with why aspirin is given after heart betacine and so on. So that's one. I promise I'll be short for the other two because there's not much data on the other two.
Seminal plasma. So there have been quite a few studies which have looked at application of seminal plasma. Either one applying the purified seminal plasma after the spermal extractor pharynx at the day of aggregate will inject it into the posterior pharynx applied to the cervix.
The other is just ask the couple to have sex at home. So those are the two different methods in which these trials have been conducted. The hypothesis is that seminal plasma contains substances which makes the uterus more immune tolerant to the fetus.
The old theory of how first primiparas have more risk of preeclampsia. It's a corollary of that. The Cochrane review did not show any difference in the live birth rate, but only three studies had reported live birth rate with a total sample size of close to 1000.
If you look at the clinical pregnancy, there were more studies. There were 10 RCTs with around 2500 people and there was a slight improvement in the clinical pregnancy rates. But if you take out the studies at high risk of bias, there's again no difference.
So at this stage, all we can say is it doesn't seem to make a huge difference to the pregnancy rates. But on the other hand, if someone were to ask, can I have sex when I'm having IVF? We can definitely say it's not harmful. So that's the only takeaway I would take from that.
And if you're having sex, basically there's no extra expenditure involved. So that's from a cost effectiveness point of view, it doesn't make a huge difference. The last thing is platelet-rich plasma.
Platelet-rich plasma is to take whole blood and centrifuge out the red blood cells and what you're left with is a high concentration of platelets and plasma. It is supposed to have a high degree of growth factors and it's been used in different specialties as sort of a anti-aging anesthesia. People have tried it either injecting it intrauterine into the endometrium and also into the ovaries.
There is a bit more data on endometrial application, but even that data is limited. It's only, at least they have RCTs in that topic and it's been used in thin endometrium. The RCT has not shown any difference.
In recurrent implantation failure, there is an RCT, but it's only been published as a conference abstract. The full paper has not been peer reviewed, so we don't know. It might show an improvement, but at this stage we have to say we do not know.
And I think I would be hard-pressed to justify it to a patient, say there's one RCT which has not been published and I'm going to use it for you, especially because you are instilling into the uterus around the stage of embryo transfer. What are the consequences of that on the growing embryo is something that we're definitely not sure about. The other thing about ovarian injection of PRP is something which has been coming into practice in the past decade, but there appear to be no published randomized control trials.
There are only case series and I have significant misgivings about advocating a technique for which there may not be enough data, especially you're injecting into the ovaries and we do not know the impact of that on the oocyte. We do know that PRP is supposed to increase the vascular flow, but whether that's a good thing, we don't know because the early primordial follicles do need to be in a hypoxic environment. Too much oxygen actually causes oxidative stress to the mitochondria.
So again, PRP is something I wouldn't say is something I would advise someone personally, if someone asked me, a patient in the clinic asked if I could have PRP. And again, it's not approved by the FDA. I do not think it is approved anywhere.
It's mainly used off-license and it is an invasive procedure. So that needs to be taken into consideration by anyone considering using this technique. Thank you.
Thank you, Mariano. I like the way you have concluded what you think and your opinion on it. So in short, PRP in India has been used for everything I will believe.
They've been using it on the skin for hair growth. They've been using it in the ovaries, inside the uterus and everywhere possible to even in the thyroid, I've seen it being injected. So we have got all kinds of situations without any evidence on it at the moment.
So this is something which we have now covered and I will go back to the questions later related to all these adjuvants. I would request Dr. Vishesha to put forward the second paper so that we could have some information on that too. And go ahead, Vishesha.
Yes, ma'am. So moving on to the second paper, the in-vitro fertilization add-ons for the endometrium, it doesn't add up. So this article focuses on the value of add-ons to improve the endometrial reflectivity and thus the implantation rates.
The methods used for this paper are similar to the first one. All the cochrane reviews, systematic reviews, randomized control trials and all the relevant search from PubMed was included till June 2019. The current rating for each add-on as assigned by the HFA was captured, that is the Human Fertilization and Embryology Authority UK and the cost of each add-on was obtained.
Now the add-ons reviewed in this paper include immune therapies consisting of corticosteroids, intravenous immunoglobulin, GCSF and intralipids. It also includes the endometrial scratching, the endometrial receptivity array, uterine artery vasodilatation and intrauterine HCG installation. I now request Dr. Shah and Dr. Kurt to initiate the discussion with our authors and experts, post which we will have the question-answer session.
Thank you, Vishesha. I think Kurt is one of the co-authors of this paper and since he's here on the media, I mean I would like him to talk something about the paper before we start the discussion. So I'll take the opportunity to cover a couple of points.
First of all, the paper in brief cannot find strong evidence for any of these adjuvants and I think we know that, that's been the theme of this. But there's three themes I'd like to bring out in this one, is that how much evidence do we need to actually use something and can we use it without evidence? So we can be fooled in two ways. We could be fooled that something really works and the evidence isn't getting out there.
We could be fooled that it appears to work but then later we test it and find out it doesn't. Or we could decide that we're just going to use it because we think it's the right thing to do medically and we're all smart people and we know better. So it's almost as if you've got the proverbial half-full, half-empty glass sitting on your counter.
There's some people that would say that glass is only half-full or that glass is half-full. If there's any evidence that it works and there's no harm, I should be using this adjuvant. There's a whole other group of people that says it's half-empty and that if I don't have evidence for it and I don't have a randomized trial and a meta-analysis, you should never be able to use it.
I would argue that the glass is simply the wrong size, that we're doing this the wrong way, that we have to be very careful in the way we approach our patients and how we present the literature. And I'll use an example with endometrial scratching for example. Endometrial scratching in this paper was originally shown to be effective in some small clinical trials and in fact there was a Cochrane review that summarized these trials and demonstrated that in aggregate there was an effect.
The reason I'm using endometrial scratching is because it's an invasive procedure and potentially could have had side effects. It's not simply giving aspirin. When a very large-scale study was done by Sarah Lenson, who actually is the primary author on this paper and a primary author on the endometrial scratching published in the New England Journal, she found that there was no evidence, absolutely no evidence.
To my surprise, there was also no harm, which was also very good. But it led me to think of why did we get misled by this adjunct? And it is probably because the trials underlying it were not very good, were bias in themselves. People wanted it to work and therefore published trials that were positive.
There's even question that the data underlying some of these trials is not genuine and people are publishing because they want to become famous and get published. And that led us to an invasive procedure that actually could have done harm. So I'm not advocating that no adjuvant should ever be studied.
I'm advocating that adjuvant should be studied very well and exhaustively. And the other example in this paper that's not written explicitly is the colony simulating factor. There were some papers about a decade ago that showed some promise in certain clinics across the country, anecdotal, if you will.
And then actually a company randomized, I mean, ran a very large trial because they wanted to market this as a product and actually found out it didn't work. And now it's fallen off the radar. So that was studied appropriately and saved a lot of costs and money.
So I don't have an answer for you on how to, when to use an adjuvant and why not to, but I'm giving you two case studies saying that we have to be careful that we're not fooled by false positives. And I recognize that not every adjuvant can be studied in a randomized trial. There's simply just not enough money and enough time.
So with that, I'm going to bring it back to my esteemed colleagues here to see if I can pick up on some of those themes and give our listeners some solace of when should you use this? When should you use your clinical judgment as a physician and when should you actually wait for a randomized trial? Anybody answer that loaded question? I'll take a shot at it, Kurt. I think you brought up excellent points and so did Gamal. And I'd just like to further those before giving a specific answer.
And that is that when we look at most of these studies, it's do they work or don't they work and is there harm? But there's much more harm than the medical harm that's looked at in these studies. And Gamal addressed the financial impact on an individual patient, but there's obviously also the psychological impact on them and their family. There's the loss of time that comes out of their life when they're doing this.
But I would argue, especially in lower middle income countries, but even in the wealthy countries, because there's only half a dozen countries at the most in the world where everybody who needs IVF can get it. In almost every country in the world, when we're using a lot of adjuvants that are not proven add-ons, what's happening is we're wasting healthcare system resources. We're wasting the time, the mind share, and the opportunity cost of the doctors, the nurses, the IVF coordinators, the clinics, and all the rest doing things that don't work.
They cost money. They don't improve the number of babies. If you took all that effort and that money and that time from the system and you focused it on treatments that we know are effective, then you'd get more babies at less cost for more people.
So I think it is a real ethical issue. That said, I think we need to be very careful about assessing the studies that come out. As you said, Kurt, the problem is a lot of the studies have a lot of bias.
They're biased on the doctor side, on the patient side, on small number side, on poor methodology. I think our role as physicians and for our listeners is to be really critical about the data and look at whether it's a good study or not. Go to the Cochrane reviews.
Once something gets to the point where maybe there's clinical equipoise, we're not really sure, then I think it's reasonable to have the conversation with the patient when they're in a situation that might be applicable, which is going to be different for every patient. You owe it to yourself and your patients to know the literature enough to have that conversation and make a decision on that one person whether it's worth it. That's why we're clinicians and physicians.
These are very difficult decisions, but the burden, the barrier to use, I think should be far higher than it is now. It is not going to be very often that the benefit outweighs the cost when you look at the global benefit and cost as well as the one for the individual patient. It's a very complicated situation for physicians, but we need to rise to the challenge.
Absolutely, David. That is very well said. Gamal, you want to add anything to that? His audio is not OK.
Can you. Can you unmute yourself, please? Yes. Yeah.
Yeah. I fully endorse. Thank you.
I fully endorse what David said, actually, because this is not only ethical, it is also social, it is psychological and it is giving high hopes for the patients who are desperate. Unless we have robust evidence for the use of a certain ads, I don't think we should use it on the assumption that it doesn't do harm. And some of them, they do harm because certainly it gives you expectation, unnecessary expectation.
When you have a patient with repeated failure and then you tell her I'm going to do such and such without evidence and then she puts a lot of hope on the new additions, which you are doing, and then she gets disappointed after, you know, she had all the hopes and etc. And this is a problem. And, you know, I think here there is an obligation of the editors of the journal.
I think when papers are published, because we know how, you know, the researchers would like to publish papers for their own sake and also for their reputation and for their promotion, etc. But I think it would be good if the editor of the journal would put down his conclusion of the paper, because I think this would help. JAMA is doing this, actually.
It goes through the papers and then the editor puts his comment, because sometimes you look at a randomized control trial and wonderful. I mean, one of the trials which came from Egypt here, you know, showing a difference between 65 live birth rate to a 25 birth rate, you know, and the number of cases is not that, you know, that is allow you to drive such conclusion. Anyone, anyone would read this paper and say, oh, wonderful, you know, that's 65 live birth rate compared to 25.
I would go and follow this procedure or this adds on. Well, it is not so, you know, so I think here there is a duty and obligation of the editors of the journals. And if we have this, I think we will really save our patients a lot of unnecessary procedure and save them unnecessary sufferings as well.
Thank you, Gamal. Kurt, do we have any questions from the audience? We do not at the moment. I would encourage people, if they'd like to send in questions, we would certainly like to entertain them.
But I would love to make a comment on this. I think another analogy I've often used in this dilemma, and there clearly is a dilemma between the academicians who want evidence and the private practitioners who just want to treat their patients. It's almost as if you're a numerator or denominator person, right? In the public health, you want to help as many people as possible.
You want to expand the denominator. And I've done cost effective analysis that said money would be better spent in improving IVF for good prognosis patients. You would help more people than spending the money to try to find the cure for the decreased ovarian reserve, that problem patient.
That's a denominator approach. But most clinicians I know are focused on the numerator, the patient in front of them. What can I do to this particular patient at this particular time? And why can't I use X, Y, and Z to help them? So it's hard to tell a private practitioner not to focus on the numerator.
And it's hard to tell a public health official not to focus on the denominator. So I would love to see other people's perspective. As a matter of fact, in our country too, when we speak to the Ministry of Health and talk about putting in some funding for fertility treatment, because women in our country, it's a cultural, it's a social and a cultural issue with infertility being a sort of a look down upon situation.
And the government believes that yes, we have many more things to spend the money on. We have to take care of maternal mortality, we have to take care of newborns. And we don't have the money just now for infertility treatment.
Though in India, infertility is considered as a, it's a real social taboo. So when we look at patients who come to us for infertility, and we are trying to treat them, those who are coming into the private sector have a lot of money to spend. But when we want to use these adjuvants, I think we need to step back and think, is it really going to help the lady? And if at all, we are in a dilemma, we are in a situation where we really don't know which way to go, at least what I like to follow is talk to the patient, tell her what the facts are about any new protocol which has come in, what I've read about, what I've read in journals.
And I tell them that this is something which is new, this is something which is available, it costs a lot of money, it has no evidence to show that it really helps, would you like to try? As long as I know that it's not going to harm her, then it's fine. But thinking about situations as we talked about, where in rejuvenation, sticking a needle into the ovaries and ultrasound control, talking about putting in something inside the uterine, into the uterine cavity, and things like that, I think we need to really think and then start working with our patients on that. And I thank all the authors, and if there's one last one-one statement which each one would like to make, I think we could close with that.
I agree. Let's go around the table and give everyone a chance. So why don't we start with Shash, what do you think your final thoughts are on this topic? I like very much the numerator-denominator comparisons, but I think, and a very valid question for many of the audience that are joining us would be, yes, you talk about evidence, but I'm talking about my patient, what should I do with my patient? That's a conversation I have with many not-so-sticklers of evidence-based medicine.
But then I say to them, have an honest conversation with your patient. It has to be very honest. You can't really bring in something which has not been proven.
You have to look at what is there critically. As Professor Adamson said, don't believe everything that is published. There could be a lot of bias there.
Look at things critically and have an honest conversation with your patient, as Dr. Shah mentioned, that there is no evidence, but if you want to try this, you don't know what the benefits are, there could be harms. So we can't just be giving things emphatically. Most of the time, I'm a clinician, I'm a clinical academic, so if I speak to a patient and explain to her, most of the time they listen to us, and I'm sure that will be the same if you're in a private setup too.
And if you all do the same thing, then as a fraternity, we'll be together. Thank you. Yes, Mohan? Yeah, two points, quick points.
One is we need to re-look at the evidence synthesis part. We've worked on so many Cochrane reviews, and what we figured out, just take the example of screening histroscopy. We have these 10 trials, but basically what happens is you have so many suboptimal trials, pooled in with two high-quality trials, and we did not really know how to put the conclusion, because the pooled trials from all the suboptimal ones took the estimate towards benefit, whereas the high-quality trials actually showed no benefit.
So we had to convey this to the clinician and the patient, so that was a challenge for us, because most of them will go through the abstract and move on. So we are kind of working on this. The second thing is, of course, yes, be honest to the patient, and I use this word like I don't know.
We don't know whether this really works. Be honest, that we don't know thing needs to come in our counselling when it comes to add-ons, you know. That's the key message here, yeah.
Thank you. Mariano? Full disclosure, I work in a private IVF clinic, so all my patients are self-funding. How I would approach this is, if there's a clear evidence of benefit from good-quality randomized controlled trials, then minor evidences of potential risks can be justified.
But if the data is uncertain as to whether there's benefit or not, every possible harm, even though theoretical, has to be carefully scrutinized and expected, especially when we are dealing with things which can go through multiple generations. And I'd like to, you know, specifically reiterate and reinforce the point that you made about injecting the ovaries with medications, which we do not know what it does. And sometimes the theoretical background on which we work may be flawed.
For example, increasing ovarian blood supply to the ovaries may be a good thing, or it might be a bad thing because it might increase oxidative damage. We don't know. And when I was a postgraduate, my consultant told me, when you practice, you should approach everything with a zen-like state.
So don't change with every new paper which comes. Wait two years, wait for the third or fourth paper to come, and then change your practice, and that way you'll not go wrong. Absolutely.
Thank you. Thank you so much. I think we are approaching the end of our session, and I would like to take this opportunity to thank everyone for being with us.
All of you, Mohan Kamat, Sesh Sankara, Mariano Mascarenas, our experts, David Adamson and Gamal Saroor, and Vishesh, my fellow, for joining us in and helping us with the whole program. And third, for giving me the opportunity to be the host for this session. Thank you so much.
Thank you, Joru. Again, good evening, good afternoon, or good morning, depending on where you are in the world. This was another wonderful Journal Club Global.
It will be online, so you can share with your friends and colleagues, and I hope I will see you at another Journal Club Global in the near future. Thank you, participants and audience, and I hope this was helpful. Thank you.
Thank you. A big thank you to Jessica. Yeah, Jessica.
Yes, bye.
