Journal Club Global from MEFS 2024

Join Fertility and Sterility to discuss the effectiveness of preconception weight loss interventions in women with obesity and their impact on fertility outcomes.

Article:

• Higher live birth rates are associated with a normal body mass index in preimplantation genetic testing for aneuploidy frozen embryo transfer cycles: a Society for Assisted Reproductive Technology Clinic Outcome Reporting System study

Discussants:

• Mohammed Aboulghar, MD,
• Elizabeth Ginsburg, MD,
• Johnny Awwad, MD,
• Aleya El-Hadi

Moderator: J. Ricardo Loret de Mola, MD

Good afternoon. We welcome you to this Journal Club Global from Fertility and Sterility and American Society of Reproductive Medicine. We are here at the Middle East Fertility Society meeting at the 31st Annual Scientific Meeting of the Society in Qatar, in Doha, Qatar.

We welcome you to this opportunity to share our experiences and our discussion regarding an interesting article that was recently published. Can we have the first slide? So the article we will be discussing today is higher live birth rates are associated with a normal body mass index pre-implantation genetic testing for aneuploidy frozen embryo transfer cycles. A Society for Assisted Reproductive Technology clinic outcome reporting system study from Peterson, Wu, Kappy, Kucherov, Singh, Lieman and Jindal which was published in Fertility and Sterility in February of 2024.

Our distinguished panel today is Dr. Aboulghar who is professor of obstetrics and gynecology, faculty of medicine, Cairo University and clinical director of the Egyptian IVF Center. Dr. Aboulghar is the founder and first president of the Middle East Fertility Society. Dr. Elizabeth Ginsburg who is the fellowship director for reproductive endocrinology and infertility at the Brigham and Women's Hospital in Boston.

And she is professor of Harvard University Medical School and she is current president of the American Society for Reproductive Medicine. Dr. Johnny Awwad is the executive chair of Women's Services and Chief of Reproductive Medicine at Sidra Medicine and Research here in Qatar. And Dr. Aleya El-Hadi who is senior consultant and chairperson of Assisted Reproductive Center, Hamad Medical Corporation and Women's Wellness and Research Center also here in Qatar.

And myself, Ricardo Loret de Mola who is chair of obstetrics and gynecology at Southern Illinois University in the U.S. Thank you very much. Our presentation will be done by Dr. Awwad. Thank you, thank you Ricardo.

So this is great. So this is actually a retrospective cohort study of cycles that were reported to SART between 2014, 2017. These included essentially autologous and donor recipient PGTA tested cycles which were reported to the society.

And the aim of the study was to determine whether there was an association between BMI and reproductive outcome of IVF in these cycles, namely looking at life birth rate per embryo transfer. The investigators looked also at the clinical pregnancy rate and the biochemical miscarriages as well. So essentially all of frozen thought PGT-A tested transfers were included.

There was no confirmation that all of these embryos were euploid, so there was always a possibility some low mosaic system were also included. Patients were not excluded on the basis of the number of blastocysts transferred, so there were lots of cases where more than one embryo were replaced. And in donor recipient cycles, only the BMI of the recipient was recorded.

So in other words, the BMI of the donor was unknown. So these are the World Health Organization guidelines on how to define the BMI categories as you can see them on the screen. But for the sake of the study, the BMI categories were selected to balance the number of patients in each group and to maintain the validity of the grouping on the basis of the observed nonlinear relationship.

So that was a little, it was done for the sake of the study. A total of 77,018 PGT-A cycles from 55,888 patients were analyzed and determined to be eligible. The mean age was 36 years.

The mean BMI was 24.7. A total of 1,734 women were underweight. 33,126 were normal weight. 13,068 were overweight.

And 7,960 were obese. So as you can see on that table, the oocyte source was autologous in 91.9% of the cases and they were donor recipient in 8.8%. 84% had a single embryo transfer, whereas 16% had more than one embryo transferred. Overall, you can see the clinical pregnancy rate was 61.3%. The live birth rate, 52%.

And 0.8% we had missing data. Now if you look at this figure, figure one, it is statistically significant nonlinear relationship was observed between the BMI and live birth rate and clinical pregnancy rate on the right side. The estimated probability of each outcome by BMI when all confounders were taken into account showed that the inverted U-shaped curve had an inflection point at a BMI range of 23 to 24.99 kilograms per square meter.

So that was, because of that, that was taken as the reference group. We lost the slides. Great, I think this is table two that summarizes the main findings of the studies.

You can see that 23, 24.99 was considered to be the reference category. It was associated with the best outcome. As you go upwards, you see how as you go away from that reference group, the live birth rate appears to be compromised, right? So you see in the subgroup of patients with a BMI less than 18.5, if you look at the relative risk, you can see that these patients had a 11% lower risk of live birth.

If you go all the way down to those women above 40, see that 27% lower risk of live birth. So that was significant for both extremes. Now if you look at the biochemical pregnancy, the only subgroup of patients in which the biochemical, the association was significant, essentially those who were underweight with a BMI less than 18.5, which you can see there was a 20% increased risk of biochemical pregnancy in this subgroup.

Now when you look at the donor recipients in the blue shades, they demonstrated a higher live birth rate at a BMI range of 23%, which was similar to autologous. And then you can see the same kind of curve, which kind of led the investigators to conclude that the common thing is really the endometrium and probably the endometrial causes are essential in causing this effect. One major strength of the study was actually the large cohort size.

The inclusion of the frozen thought PGT-A tested blastocyst cycles, minimized the impact of other confounding variables. The limitation, however, remains the retrospective nature of the study and the presumption that all blastocysts transferred were euploid, but there was no confirmation, so some of them could be actually low-level mosaic. And as a conclusion, it was that normal weight BMI range of 23, 24.99 was associated with the highest probability of clinical pregnancy and live birth rate after frozen thought PGT-A blastocyst transfer in both autologous and donor recipient cycles.

Thank you, Dr. Awwad. This is an interesting observation. 40% of the U.S. population is obese.

Do you have a sense of what the population numbers will be in general in the Middle East and perhaps here in Qatar? Actually, yes, assalamu 'aleykum warahmatu 'llahi wabarakatuhu. We do have a high incidence of obesity among women, especially suffering from infertility, especially that what we receive here wouldn't be like completely infertile women. She would be multiparous with previous deliveries of three or four times, and she's coming to have fertility treatment to complete her family size.

So, that will add up to the factors that leads to obesity. In addition to a high incidence of diabetes among our population, and partially it's genetic, the other part is lifestyle, which is maybe in common between us and the Americans, like lifestyle and the type of food that people eat. So, yes, it's very interesting subject, and especially that we are not used, or women in our society, they are not used for the fact that the doctor will oblige them or tell them that it's a condition for them to lose weight.

It's a pretty new in our society. They don't accept it. It's not easy for them to change their lifestyle and modify it.

It's not easy for them to lose weight or to control their diabetes. So, yes, it's a big problem that we are suffering from. Do women here feel offended if you bring up the issue of weight? In a way, yes, partially for some group of them, especially the older ones.

Maybe the new generation will know and will tackle the problem. They know that they are suffering of a problem, but they just can't manage it. And also, maybe it's worth mentioning that currently we have a very, very high incidence of bariatric surgeries among young women and young population, which I don't think that this could be present in any other European or American country, especially that they can get these operations and procedures done free of charge by the governmental hospital for the morbid obesity, and sometimes other people, they will try to get into the system, although they are not morbidly obese.

So, that participates to the factor of malnutrition, and sometimes they go back and they rebound and they gain their weight again. So, they will be with malnutrition and then obesity again, and they go into this cycle. Vicious cycle.

Yes, but yes, there is a big group of women, they will get offended when you tell them that she has to lose weight, especially that her neighbor got pregnant on a BMI of 45. So, it doesn't make sense what you are telling her. It's like you are making things difficult, deliberately.

If her neighbor and her cousin got pregnant with obese weight, then she probably could. Dr. Awwad? Actually, I need to add that it is true, we in Qatar have a high rate of obesity amongst women of reproductive age group. However, I am not sure if that compares to the United States when it comes to probable or possible underlying pathology, right? Because we do have a very high prevalence of polycystic ovary, which can go up to 50% in some families, which is significantly higher than the United States.

So, you would assume in that particular subgroup, patients could be having obesity as a result, maybe. And so, resistance, plus or minus. At the other hand, there's a high genetic background in the population, so we do not know if that genetic causes would compare as well to the U.S. population.

And then when it comes to, if you wanna call it pathological adiposities, those associated with a risk factor, the great majority are associated with diabetes, right? Which may not necessarily be the same elsewhere. I'll give you an example. For example, patients who come to a regular obstetrical service, five, maybe to 7% in the West, will have gestational diabetes, can go up to 25% plus in the community here, right? So, although the numbers may look the same, I think if you drill down into the causes, if at one point of time, we start drilling down into adiposities, we're still looking at the, scorching the external layer of it.

Maybe you'll find a totally different population, even though the numbers could be the same. Do you agree? Dr. Aboulghar, what about in Egypt? Is Egypt any different to Qatar or this side of the Middle East? Unfortunately, we don't have a national figure for the women with high BMI. But in our center, which is 36 years old now, with 5,000 cycles a year, we have a very big number of patients, and we did our own statistics.

The high BMI women are 45%. And the obese women are 20% out of the whole. So, it is a real problem.

The high BMI patients, we advise them to lose weight, but generally, we don't delay, and we start the treatment as soon as possible, particularly if they were above 35 years old. But obese patients, we really insist on losing weight and doing diet, or maybe do bariatric surgery. The only exception is women at the age of 39 or close to 40, where it will be very difficult to lose weight, it will take a longer time.

Then we may start immediately, and we inform them that the live birth rate will not be as good as our general studies. Dr. Ginsburg, it sounds like it's not that different to the patients we treat in the U.S. No, it's, yes, it's working. Yeah, it sounds very similar.

Yeah. They're about 40% also in our program. But I'm surprised that the state covers bariatric surgery.

That's what you said, right? You mean in Qatar? Yes, yes, it can be done in the governmental hospital. The waiting list is getting longer and longer, because it's desirable by many, many, many sectors of the population, but it became more restricted to another group, like morbidly obese. But other people, they can get themselves into the system, yeah.

What of the use of the new medications? Is that something that you see happening here instead of bariatric surgery? Absolutely, it started to be more popular, especially in the younger generation, like teenager, for example, or early 20s, as an alternative to going for bariatric surgeries, or also for people who use the bariatric surgery, and they started to gain weight again. However, if you look at the Saxenda, for example, Mounjaro, all the new injections in the market, it's not recommended to use it soon if you are planning to get pregnant. So, you get stuck again.

I have many patients, they come with having difficulty in losing weight, and sometimes you will keep following up for like two years, coming and going, just checking your BMI, and it's very tricky when she is coming to an age that is very critical. And we do actually have a restriction for performing IVF on obese women. In our unit, we put a cutoff of 30 BMI, and maximum of 35.

We could treat on 35, but not beyond that. Because, of course, the risks of the procedure itself for obese women, difficulty in collecting the eggs, maybe we'll end up with complications, and above all, the lower success rate, or the lower outcome of the pregnancy. So sometimes, also, we tend to do the collection and freeze the embryos and not transferring it back.

Now, if she starts using any of these medications, she won't be able to come for fertility treatment except after three to six months. So that's another challenge. Interesting, Dr. Ginsburg, what's your experience with the GLP ones? Yeah, we have quite a lot of patients on it, although to have insurance cover it, they have to have other core morbidities, so they have to have diabetes or hypertension, and a BMI of over 40, typically.

We only stop the medication for two months before pregnancy, and then from an egg retrieval standpoint, because of the slow gastric emptying, it's two weeks off before our anesthesiologists will give them an elective anesthesia. So most patients, when they stop the medication, they can go ahead and have an egg retrieval after two months. Yeah, yeah, we don't wait that long.

And we have some patients who just take two weeks off to do the egg retrieval and then go back on as well, but with freezing the embryos. And so you freeze the embryos in that scenario, in your center? If it's an older patient, as you were alluding to, you don't really want somebody who's 40 waiting a year to lose weight. So in those patients, if they're motivated, we'll do an egg retrieval, freeze the embryos, and hopefully have them come back at a lower weight.

But we have a BMI cutoff of 60, and that was based on, we're a hospital-based program, so there's really not an anesthetic issue. Our OB anesthesiologists cover the service. We actually haven't seen anybody get a spinal in years, so they generally are pretty comfortable with IV medication.

Propofol primarily, or? Propofol only, yeah. And they'll put the patient on a ramp to elevate their head. I'll be talking a bit about some of our research tomorrow.

But the patients have to go through a lot of hoops when they have a BMI of over 50. All of our patients with BMI of over 40 see MFM before, we'll do IVF treatment, or any fertility treatment, just so they're aware of risks and so on. But especially for the older patients, we just move ahead with IVF.

And the egg retrievals are really tricky, and they are kind of scary. We haven't really had any higher complication rate in them, but sometimes you really don't see the ovaries very well, and it's challenging. Guess a little bit.

Yeah. So, have you noticed any difference in the outcomes of those patients that you end up discontinuing the medication, doing the retrievals, and then transferring at a later date? I don't think we have enough numbers to really even look at yet. I don't think anybody does.

Yeah. And that's part of the problem. Yeah.

Dr. Awwad, what do you do in your center? So, at Sidra Medicine, we do not have a cutoff limit. We take patients any time anesthesiologists are comfortable doing the deep sedation. But again, we are also a hospital-based unit, so we have the luxury of having someone there.

Our operating room can even accommodate an endotracheal general anesthesia, so we're comfortable with that. Dr. Aboulghar, what do you do in your center? Do you have any products? Well, we have an in-house dietician present all the time, every day, because half of the patients are overweight, and we offer them to have the advice, but only 30% of those patients will go to the dietician. The 70% will just say, we want to start, and we start for them the treatment, if they are not obese, but obese patients, we tell them, you have to do something first, because it's very risky.

Do you think that this study actually finally answers the question that obesity does affect fertility, or do you think we need to do more? Well, I think the conclusion of this study, there is something I don't agree on. This study, in the abstract, it clearly says that the reason for lower pregnancy rate, or outcome of IVF, is mainly uterine factors, because of the evidence showed for transferring the donor oocytes and the autologous oocytes, and there was no difference, and that's okay, correct, but they mentioned that this will, in a way, exclude an ovarian course, which I don't agree, because they don't have evidence to exclude another ovarian course. These women are known to use larger doses of gonadotropins, they have a lower number of oocytes, lower number of embryos, possibly embryos are not good.

For all these reasons, there is a possibility also that the study should not exclude ovarian course, should only say the uterine factor that was there, but should not exclude an ovarian course. Ricardo, I think if you look at this study, we're assuming that BMI reflects a homogeneous population of ID positives, but we know that BMI can be high in athletes, so it is affected by the weight irrespective, without discrimination to whether it is muscle or fat, or it is good fat, brown fat, or it is the bad fat, right? And I can recall this study from Mass General Hospital a few years back, the EARTH study, if I remember well, which was a prospective study in women who are overweight, in which they looked at the waist circumference and found out that when the circumference was high, that was associated with significantly lower life-earth rate of the IVF, irrespective of the BMI, and when that circumference was low in those overweight women, the success rate was equivalent to those with a normal weight, right? And that indicates that we need to start digging more in-depth, and is this simply a call for us to maybe include some medical endocrinologists in our research, right, because I think we like statistics, we like correlations as reproductive medicine, or maybe having a medical team with us to start looking a little bit deeper and try to see if we can stratify that group of labeled obese women, maybe by pathology, and then try to see, and this is probably why when we look at all these interventions, we do not come up with a positive outcome, right? You intervene, you drop the weight, but you don't always, it doesn't get you somewhere, right? Maybe if we start looking from a more scientific point of view, right, and maybe this is a call for the scientific community to drill deeper into that. Going back to the egg donors, we also do not know what the BMI of the egg donors was in this group of patients, we don't know what the impact is truly of the BMI on the egg donor group.

It's also interesting that a significant number of people were getting two euploid embryos, which is against the current ASRM guidelines, which were available at the time, and yet it was quite aggressive. No one really talks about the twin rate in the study. I didn't see any data on twins.

Did you? I did not, but I did not look at the supplemental. I could not have access to that. I don't know if you have it.

I have it on my phone, because it wasn't there, but I do have it, if you want to look at it. There was some twin data? I think it's in the supplemental, but I don't know. But also, don't you think that this is a point of bias? Like, if some of them, they had one embryo and the others had two, so regardless of everything else, having two embryos, that might have participated to the better success of certain group of people, which they didn't identify exactly which one had one embryo and which one had two.

Absolutely, I think it's another variable. Bias in the results, yeah. Because it wasn't just single embryo transfers.

They mixed the two groups. I don't think this is like a practice-changing kind of results or study. I wouldn't change my practice according to what came with the results, because it confirmed what we already know about the effect of the BMI on the outcome and the success of the IVF cycle, although it wants us to limit our focus on this BMI that they thought is ideal.

Although the difference in the results between the BMI that is above, a little bit above, like until 30 or 35 or a little bit below until 20, the results are not much different. They are still successful with a good rate. I had a comment sort of following up on Johnny's comment in that, especially if you look at sort of central obesity, that may be a different population of patients.

And I know that our endocrinologists think that metabolic syndrome's an inflammatory state. So whether it's uterus or something else systemically that's making their pregnancy rates lower, I think we don't know. There is a study just talking a little bit about the potential egg factor from RMA where they looked at percent body fat and BMI.

And there was a large population of patients looking at euploidy rates. And their euploidy rates weren't different by BMI, but their blastocyst conversion rate in the high BMI patients was significantly lower. So there's something, I think.

So do you think that, or based on the study that you quoted, as the patient gets older with the additional obesity, that there is a higher aneuploidy rate? Well, they adjusted for that. So I don't think that, well, I think separately from age, I do think that BMI, in that study anyway, contributed to the blastocyst conversion rate, not the aneuploidy rate.

The aneuploidy rates were the same. If anybody from the public has a question or a comment, they're also welcome to make. Yeah, I mean, in the meantime, until we have a question there, I would like to concur, Dr. Aleya, on one thing.

So if you trust these data, I mean, because this is anyway, I would look at it more of an epidemiological rather than something to be applied on an individual level, right? But if we want to say these data, we want to apply them at the individual level. So you're looking, for example, women with a BMI above 40, right, with a 27% less risk of achieving a life or threat. So you're looking at a 40%, say, chance of life or threat that is now compromised to 30%.

So can I tell a patient who has a BMI more than 30, you cannot achieve the 40%, you achieve 30%, I'm gonna decline treatment. Or that would simply be that's good success, except the time to pregnancy is gonna be prolonged, like with several other conditions, right? So I think that's really, we have to not get stuck with the statistics, but maybe look really at real life implications, clinical implications. I think part of the reason our ethics committee decided that we would have this cutoff at 60 was our maternal fetal medicine population was, physicians were fairly comfortable taking care of patients below that, and they had plenty of spontaneously pregnant patients with BMIs in the 50s.

And then the conversation also discussed obesity as potentially kind of a disability, stigma-related condition. The bariatric surgeons were actually at the meeting, they absolutely did not think we should be mandating consultations or weight loss management appointments. We always recommend that they see the weight loss management service at our institution, but they did not think that mandating it was appropriate.

So everybody that's involved with the patient care obviously needs to be on the same page when you're treating these very high BMI patients. Dr. Aboulghar. One thing in this paper, which the authors didn't comment on it, that they mentioned in the results that this doesn't apply to endometriosis.

Right. So it's very strange that no comment, and this is a very important issue, but why endometriosis is not affected, and what is the reason in endometriosis? So endometriosis was linear. Yes.

It was a linear drop, and it wasn't a curve. Yeah. So the BMI did not seem to affect in a similar way.

So this is very, very strange, and I think they should have commented on this, and they didn't. They only mentioned it in the results. Could that speak about something, some type of endometrial factor actually going on in that patient population? Also a volatile factor.

I mean, it could be endometrium or volatile. We don't know. In the supplemental figures also, it looked like there was a difference in the ethnic, in the curve of the ongoing pregnancy live birth rates based on ethnicity, which I thought was interesting.

But I believe the number of patients in those was relatively small, so it was difficult to really mention that. So we also don't know the euploidy of these embryos, right? We don't know if these were mosaics, low-level, high-level, or euploid, and we unfortunately don't have that information. Do you want to comment on that aspect of the study? Yes.

The same group, or the ASRM, the SART published another paper, similar paper a few years ago, and they did not do PGT-A. They just, and exactly similar study. And they found the same results with one exception, that in younger women, the difference was much bigger than elder women.

So I don't know if the PGT-A made any difference in this or not. And it's possible that at the time we were not transferring, at least not the high-level mosaics, or even low-level mosaics at the time, based on the timeframe of the study. I think the older study had very little, very little PGT-A was being done.

Yeah, but I agree with Professor Aboulghar. I think the message is beyond whether all of them were euploid or borderline mosaic, right? I, Ricardo, I would like to have the panel's opinion on whether obesity or adiposity is a disease or not. Because, you know, when you read the literature, it's considered to be the most common non-communicable disease in women of reproductive age group.

I have an issue with that. What do you think? Well, I do think it's a disease, but it is a modifiable disease. And I don't know why it's such an epidemic.

I do think it's the type of food we eat. Certainly in the United States, the portions are enormous. And frankly, if you go to a restaurant and the portion isn't enormous, you feel like you're not getting enough for your money.

So I think culturally, it's really a problem the way we eat. Right, because I think my point is that, you know, this is a condition that may, that is a risk factor for medical problems. But it does not necessarily mean medical problems, right? Many people live their lives, even longer lives, without any risk factors.

And although this is not similar to polycystic ovary, which is inherited congenitally, but polycystic ovary is associated with metabolic disorders. And it's not really a disease, right? It's just a phenotype, right? I mean, this is modifiable phenotype that has potentially can come. I have an issue labeling half of the population of women with reproductive age group as diseased, right? I think it may cause maybe some form of stigmatization, labeling, categorization.

I don't know. If we need to be more sensitive to 50% of our patient population, I don't know. And it's a modifiable disease like hypertension, diabetes.

And we consider those diseases and we can modify them. Why not? What do you think? Well, if there is a big argument about if it is being a disease or not, but certainly it's some kind, maybe it's not a disease, but certainly some kind of disorder. Because there is underlying, most of the time, there is underlying pathology to it, like polycystic ovary, metabolic problems.

And then on the long term, if this disorder continue to be there, then it will lead to certain diseases like hypertension, diabetes. So it's in this corner, like between diseases, like there is a participating factor that is not normal and not physiological or healthy. And there's consequences that, again, they are not healthy or physiological.

And when does it start to become a disease? At 34, at 33, at 32, at 39, right? So where's the definition of disease? Well, the tricky thing is also, if a woman has obesity and she has a baby, that baby's more likely to be obese. And we know that kids that are obese are more likely to have diabetes at young ages. I know our children's hospital is seeing type two diabetics that aren't even 13 years old yet.

Well, the epigenetic factors that affect children. So that's sort of a transmissible disease, if you want to think of it that way. Dr. Aboulghar, you were going to say something? Yeah, no.

Okay. How about if we turn to the other side? How do we explain the fact that the very lean patients, almost in the anorexic scale, had more biochemical pregnancies? Do we have an explanation for that? Because I don't. Yeah, I'm a little bit surprised why clinical pregnancy rate was not included there, right? Because, I mean, there are lots of data to support their clinical pregnancies affected.

But I do not have an explanation for biochemical. Yeah, I don't know why that would be either. Well, their live birth rates are low and we actually had published that older study.

But also in our internal data, our underweight patients actually do, we've seen the same live birth rates in our underweight patients as in our BMI 30 to 35 patients. So it's just as bad. It's about a 20, 30% reduction.

But the lower pregnancy rate in lean women, the underweight, is much, much smaller than obese women. I mean, if there is a difference, it is very small difference not to be compared with overweight women or obese women. And the number also is smaller.

I mean, the number of the obese women and overweight women is very big. So statistically, this will be more significant. So if I wanna stretch my imagination, I'm gonna consider women who are very lean could have a very low LH, prevailing LH serum levels.

And if these women are not properly stimulated, maybe more with recombinant FSH only, would that low FSH prevailing in that follicular phase impact their implantation later on and lead to higher earlier failures of implantation? That's one explanation. Yes. Again, I was puzzled by that data.

I just never expected it. So when do you recommend women to consider bariatric surgery as part of the plan? At what point in time should we put that on the table? Or not at all? Because again, we're not going to deny potentially care in some parts of the world. Well, obese women, they have been trying for years to lose weight by dieting and by exercise and it doesn't work.

So if they really want to lose weight, they have to go to surgery. There is no other option because they have been doing this for years and years and it doesn't work. But overweight women, they can really lose weight by some discipline and it will be okay.

So my advice to the patients, I suggest surgery but I don't condemn myself to saying because this surgery has also its complications. I tell them you have to consult the surgeon and to study the whole thing and find out if you accept the possible complications, that is the best for you. Yeah, I agree.

I think we are not in a position to advise or strongly recommend interventions when we look at the reproductive outcome. I think that should come from a medical doctor because this is related essentially to overall health risks which could translate on a personal level or antenatal level. But I think in relation to the outcome of what we do, I do not think we're in a position to advise.

I think we could refer to the right people to advise. It's interesting, even though there is much bariatric surgery being done around the world, the data available in IVF is very, very limited. There is a couple of studies, there's a Swedish study, a French study that's been published in the past couple of years, mostly retrospective data and there doesn't seem to be a difference in pregnancy rates on patients who underwent bariatric surgery relative to case control studies with up to five times as many normal weight patients and there doesn't seem to be in those studies any difference in pregnancy rates and it's really a shame we don't have more data to be able to be more categorical with patients about the benefits or the harm of bariatric surgery for themselves in pregnancy.

Well, my observation is patients who do surgery who used to have anovulation and long periods of amenorrhea, they immediately menstruate regularly and many of them, they have spontaneous pregnancy but I don't have a study, I don't have real complete figures but this is a clinical observation which needs to be, a good study should be done on this topic. Yeah, I think a case series would support what you said and I don't know of any data showing that if you have bariatric surgery that your ART pregnancy rates are better. Just like there aren't any studies, I don't think showing that acute diet interventions increase ART pregnancy rates.

I think some of them report more spontaneous pregnancies but not ART pregnancies. Should we have national guidelines on weight to move forward with fertility treatments or IVF or should they be done clinic-specific? You know, Ricardo, I go back to the definition of adipositis. I think we ought to look at a different measure than BMI to be able to implement certain cutoffs or policies within the society or within each clinic.

I think based on BMI, it is not fair because you could label people who potentially may not have complications within the whole group and it will not be fair at an individual level. So I think at this stage, the data we have and the measures we use will be very difficult, I mean beyond safety issues, right, to make recommendations. That's why I think we need to drill down in a more scientific way into that population which is becoming now 50% of reproductive-age women.

This should be a primary public health issue and I think lots of funding should be placed there to understand these subcategories and know how to support them and help them. Well, okay, guidelines could be done but not done by gynecologists or IVF people because obesity is a problem which is causing cardiac and diabetes and lots of other major complications, much more than failure of IVF. So it should be done by general medicine or people involved in the management of obesity in general and then we can use these guidelines in IVF but not guidelines for IVF only for obese women.

Yeah, I think practically speaking, I feel also that it has to be looking on the individual level of the patient's health. So certainly if we have a patient whose BMI is only, because it's not that high for our practice, only 40 but she has hypertension and diabetes, that's a different scenario than somebody who's otherwise completely healthy. So I think individualizing the decisions is really important.

I think my opinion will be a bit different. Like we do have guidelines for controlling the obesity or deciding about which weight we could start treatment with especially for infertility, not for general disorders or general problems. And I do support that because it reduces the harm that happens to the patient from the extra costs that will happen when she goes for IVF treatment and she needs, because of her obesity, she will need a higher dose.

So that's affecting the money or the cost that she is paying for her treatment. Then the outcome, if there is studies that proved that there will be a lower outcome for pregnancy and for the IVF cycle if she is above certain weight, then I would rather improve her success and outcome and also take care of her pocket, what she spends on her IVF cycle, and also reduce the risks that will happen to her when she gets pregnant with the obesity and imagine the trouble that the obstetrician will go through, there is no place here to name it because it will take the whole night, all the risks of the obesity in obstetrics. So it's a group of things that makes really having guidelines and being stick to it with the weight of the patients we treat in the IVF is really important.

So you would favor national guidelines, not clinic-specific guidelines? Of course, well, preferably, so it will be more supportive, it will be more powerful to implement if it is national. And I think most of the countries, they do have national guidelines, even in Canada, the Canadian society, they do have a guideline that limits or shows the effect of obesity in the infertility of the male, so the male couple. So not only the wife, also the husband matters.

So I think we need to make a distinction between managed care, government-supported care, like for example, UK, parts of Canada, et cetera, where governments would come up with national guidelines. But it's important as well to hold governments accountable because a lot of the causes of obesity or adiposity is related to things like food at the level of the schools, like accessibility to junk food, like what kinds of food is available to people. And so when a government wants to hold people accountable at the end, they should be accountable from the start.

I think this is where governments fail because they try to hold individuals accountable for failed policies from the start because we know that the great percentage of, I would say the causes of obesity at this stage is believed to be essentially a lifestyle diet much more than it is in relation to inheritance, right? So there's lots of modifiable elements there. But we have to remember also that guidelines are not universally applied, and there are lots of guidelines in America, in ASRM, which nobody follows. And in our area, it's even worse.

So making guidelines will not solve the problem. Guidelines are just like a compass. You should go in this direction, but people sometimes get lost in the process, right? Yeah, because again, when you say we would like to have guidelines, it's important to know what next.

So I'm not gonna allow a patient to get into my practice with a BMI above 40. 40, for example, what next? What is the alternative? Am I going to offer weight loss, and then they would come back? In terms of success rate, that's never been shown to show any improvement there. Am I going to put someone on medicated weight management, and we've seen lots of failures unless you have a whole team around that person, exercise, et cetera, major modifications of behavior, which is not always available, and which is not always successful, and we see the rebound weight gain after six, within the next six months.

So when do you start an IVF? At four months? At six months minus one day? I'm gonna be a little bit cynical here, right? And so it is a little bit impractical to put, and unfair, to put significant pressure, emotional pressure on an individual who could not get rid of the excess weight for a lifetime, especially when they get to 37, and we know that time is key, and any delay of six months or more is detrimental to their overall chance of pregnancy. So I think we have to be a bit more sensitive with these women, unless there's a critical medical issue. Thank you.

Does this article change what you do every day in your clinics? No, I don't think that this article will change much, because what is reported that overweight and obesity has a bad influence on the pregnancy rate is well documented in the literature by tens of studies. The new thing in this is that there is a time factor, which nobody thought about it before, but there is a time factor, but what shall we do? What was this time factor? So I don't think that this study will change anything in our work, but maybe we need further studies to try to find out, can we do something for this time factor? We should also think about ovarian factors, and study it so that we have a complete picture how to solve this problem. Yeah, I still think this is a call for the scientific community to change the way they look at the positives and be more scientific about it.

Dr. Ginsburg? Yeah, I agree with Dr. Awwad that obesity isn't obesity, and there are many different forms and pathologies probably behind it, so I think a multicenter study would be really good. Doctor? Yes, I answered the question earlier about if it will change my practice. As Dr. Aboulghar said, it would rather enforce or document what we are doing already.

So we'll continue to do what we do, and as we agreed, that further studies need to be done, maybe bigger, maybe with the more categorization or the different criteria in a different way, maybe randomized also. It would be very interesting to get some randomization for GLP-1s and see how that really works. I had a conversation with Rick Legro about this, that he's tried for years to get the pharmaceutical company to sponsor a study, and they're just uninterested for PCOS, but there's enough overlap that I think we can make a lot of extrapolations from that.

But they have been completely uninterested in doing that, so this would be also a call for the pharmaceutical industry to help us and help the patients as well. I had a question. What we also have trouble with, not that we have that many underweight patients, very difficult to get them to gain weight.

I don't know if anybody else has experience with that or have found any ways that work better. We have patients on Ensure, seeing dieticians, and they struggle sometimes to get to a BMI of 17.5. Some of them are really little. I think it's also a disease, both extremes.

I mean, I agree for insurance coverage and to label it as a disease, but otherwise. Anorexia is a disease, right? The underweight patients, they get pregnant anyway after a while, even if they don't put on weight. But the obese patients, they have difficulty to become pregnant if they have 35 BMI or something.

Very difficult to become pregnant. It seems like both extremes, as long as they're ovulatory, they tend to do better. Is there an ovulatory ones that don't do as well? Well, thank you so much for your insights on the condition.

And again, thank you for listening to this Journal Club Global today. We appreciate listening to this interesting conversation. And again, we thank you and thank the society, Middle East Fertility Society, for hosting this Journal Club.

Thank you so much. Thank you very much. Thank you.