Fertility and Sterility On Air - ANZSREI 2024 Journal Club Global: "Should Unexplained infertility Go Straight to IVF?"

Fertility and Sterility On Air

Presented in partnership with Fertility and Sterility onsite at the 2024 ANZSREI meeting in Sydney, Australia.

The ANZSREI 2024 debate discussed whether patients with unexplained infertility should go straight to IVF. Experts on both sides weighed the effectiveness, cost, and psychological impact of IVF versus alternatives like IUI. The pro side emphasized IVF's high success rates and diagnostic value, while the con side argued for less invasive, cost-effective options. The debate highlighted the need for individualized care, with no clear consensus reached among the audience.

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TRANSCRIPT:

Welcome to Fertility and Sterility On Air, the podcast where you can stay current on the latest global research in the field of reproductive medicine. This podcast brings you an overview of this month's journal, in-depth discussion with authors, and other special features. F&S On Air is brought to you by Fertility and Sterility family of journals in conjunction with the American Society for Reproductive Medicine, and is hosted by Dr. Kurt Barnhart, Editor-in-Chief, Dr. Eve Feinberg, Editorial Editor, Dr. Micah Hill, Media Editor, and Dr. Pietro Bordoletto, Interactive Associate-in-Chief.

I'd just like to say welcome to our third and final day of the ANZSREI conference. We've got our now traditional F&S podcast where we've got an expert panel, we've got our international speaker, Pietro, and we've got a wonderful debate ahead of us. This is all being recorded.

You're welcome, and please think of questions to ask the panel at the end, because it's quite an interactive session, and we're going to get some of the best advice on some of the really controversial areas, like unexplained infertility. Hi, everyone. Welcome to the second annual Fertility and Sterility Journal Club Global, coming to you live from the Australia and New Zealand Society for Reproductive Endocrinology and Infertility meeting.

I think I speak on behalf of everyone at F&S that we are so delighted to be here. Over the last two years, we've really made a concerted effort to take the podcast on the road, and this, I think, is a nice continuation of that. For the folks who are tuning in from home and listening to this podcast after the fact, the Australia and New Zealand Society for Reproductive Endocrinology is a group of over 100 certified reproductive endocrinologists across Australia and New Zealand, and this is their annual meeting live in Sydney, Australia.

Today's debate is a topic that I think has vexed a lot of individuals, a lot of patients, a lot of professional groups. There's a fair amount of disagreement, and today we're going to try to unpack a little bit of unexplained infertility, and the question really is, should we be going straight to IVF? As always, we try to anchor to literature, and there are two wonderful documents in fertility and sterility that we'll be using as our guide for discussion today. The first one is a wonderful series that was published just a few months ago in the May issue, 2024, that is a views and reviews section, which means there's a series of three to five articles that kind of dig into this topic in depth.

And the second article is our professional society guideline, the ASRM Committee Opinion, entitled Evidence-Based Treatments for Couples with Unexplained Infertility, a guideline. The format for today's discussion is debate style. We have a group of six experts, and I've asked them to randomly assign themselves to a pro and a con side.

So I'll make the caveat here that the things that they may be saying, positions they may be trying to influence us on, are not necessarily things that they believe in their academic or clinical life, but for the purposes of a rich debate, they're going to have to be pretty deliberate in convincing us otherwise. I want to introduce my panel for today. We have on my immediate right, Dr. Raewyn Tierney.

She's my co-moderator for tonight, and she's a practicing board-certified fertility specialist at IVF Australia. And on my immediate left, we have the con side. Going from left to right, Dr. Michelle Quick, practicing board-certified fertility specialist at IVF Australia.

Dr. Robert LaHood, board-certified reproductive endocrinologist and clinical director of IVF Australia here in Sydney. And Dr. Clara Bothroyd, medical director at Care Fertility and the current president of the Asia Pacific Initiative in Reproduction. Welcome.

On the pro side, going from right to left, I have Dr. Aurelia Liu. She is a practicing board-certified fertility specialist, medical director of Women's Health Melbourne, and clinical director at Life Fertility in Melbourne. Dr. Marcin Stankiewicz, a practicing board-certified fertility specialist and medical director at Family Fertility Centre in Adelaide.

And finally, but certainly not least, the one who came with a tie this morning, Dr. Roger Hart, who is a professor of reproductive medicine at the University of Western Australia and the national medical director of City Fertility. Welcome, pro side. Thank you.

I feel naked without it. APPLAUSE I've asked both sides to prepare opening arguments. Think of this like a legal case.

We want to hear from the defence, we want to hear from the plaintiffs, and I'm going to start with our pro side. I'd like to give them a few minutes to each kind of introduce their salient points for why we should be starting with IVF for patients with unexplained infertility. Thanks, Pietro.

To provide a diagnosis of unexplained infertility, it's really a reflection of the degree investigation we've undertaken. I believe we all understand that unexplained infertility is diagnosed in the presence of adequate intercourse, normal semen parameters, an absence ovulatory disorder, patent fallopian tubes, and a normal detailed pelvic ultrasound examination. Now, the opposing team will try to convince you that I have not investigated the couple adequately.

Personally, I'm affronted by that suggestion. But what possible causes of infertility have I not investigated? We cannot assess easily sperm fertilising capability, we cannot assess oocyte quality, oocyte fertilisation potential, embryonic development, euploidy rate, and implantation potential. Surely these causes of unexplained fertility will only become evident during an IVF cycle.

As IVF is often diagnostic, it's also a therapeutic intervention. Now, I hear you cry, what about endometriosis? And I agree, what about endometriosis? Remember, we're discussing unexplained infertility here. Yes, there is very good evidence that laparoscopic treatment for symptomatic patients with endometriosis improves pelvic pain, but there is scant evidence that a diagnostic laparoscopy and treating any minor disease in the absence of pain symptoms will improve the chance of natural conception, or to that matter, improve the ultimate success of IVF.

Indeed, in the absence of endometriomas, there is no negative impact on the serum AMH level in women with endometriosis who have not undergone surgery. Furthermore, there is no influence on the number of oocytes collected in an IVF cycle, the rate of embryonic aneuploidy, and the live birth rate after embryo transfer. So why put the woman through a painful, possibly expensive operation with its attendant risks as you're actually delaying her going straight to IVF? What do esteemed societies say about a diagnostic laparoscopy in the setting of unexplained infertility? The ESHRE guidelines state routine diagnostic laparoscopy is not recommended for the diagnosis of unexplained infertility.

Indeed, our own ANZSREI consensus statement says that for a woman with a minimal and mild endometriosis, that the number of women needed to treat for one additional ongoing pregnancy is between 3 and 100 women with endometriosis. Is that reasonable to put an asymptomatic woman through a laparoscopy for that limited potential benefit? Now, regarding the guidelines for unexplained infertility, I agree the ASRM guidelines do not support IVF as a first-line therapy for unexplained infertility for women under 37 years of age. What they should say, and they don't, is that it is assumed that she is trying for her last child.

There's no doubt if this is her last child, if it isn't her last child, sorry, she will be returning, seeking treatment, now over 37 years of age, where the guidelines do state there is good evidence that going straight to IVF may be associated with higher pregnancy rates, a shorter time to pregnancy, as opposed to other strategies. They then state it's important to note that many of these included studies were conducted in an area of low IVF success rates than those currently observed, which may alter this approach, suggesting they do not even endorse their own recommendations. The UK NICE guidelines, what do they say for unexplained infertility? Go straight to IVF.

So while you're listening to my esteemed colleagues on my left speaking against the motion, I'd like to be thinking about other important factors that my colleagues on my right will discuss in more detail. Consider the superior efficacy of IVF versus IUI, the excellent safety profile of IVF and its cost-effectiveness. Further, other factors favouring a direct approach to IVF in the setting of unexplained infertility are what is the woman's desired family? We should not be focusing on her first child, we should be focusing on giving her the family that she desires and how we can minimise her inconvenience during treatment, as this has social, career and financial consequences for those impediments for her while we attempt to help her achieve her desired family.

Thank you. APPLAUSE I think the young crowd would say that that was shots fired. LAUGHTER Con side? We're going to save the rebuttal for the time you've allocated to that, but first I want to put the case about unexplained infertility.

Unexplained infertility in 2024 is very different to what it was 10 and 20 years ago when many of the randomised controlled trials that investigated unexplained infertility were performed. The armamentarium of investigative procedures and options that we have has changed, as indeed has our understanding of the mechanisms of infertility. So much so that that old definition of normal semen analysis, normal pelvis and ovulatory, which I think was in Roy Homburg's day, is now no longer fit for purpose as a definition of unexplained infertility.

And I commend to you ICMART's very long definition of unexplained infertility, which really relies on a whole lot of things, which I'm going to now take you through what we need to do. It is said, or was said, that 30% of infertility was unexplained. I think it's way, way less than that if we actually look at our patients, both of them, carefully with history and examination and directed tests, and you will probably reduce that to about 3%.

Let me take you through female age first. Now, in the old trials, some of the women recruited were as old as 42. That is not unexplained infertility.

We know about oocyte aneuploidy and female ageing. 41, it's not unexplained. 40, it's not unexplained.

39, it's not unexplained. And I would put it to you that the cut-off where you start to see oocyte aneuploidy significantly constraining fertility is probably 35. So unexplained infertility has to, by definition, be a woman who is less than 35.

I put that to you. Now, let's look at the male. Now, what do we know about the male, the effect of male age on fertility? We know that if the woman is over 35, and this is beautiful work that's really done many years ago in Europe, that if the woman is over 35 and the male is five years older than her, her chance of natural conception is reduced by a further 30%.

So I put it to you that, therefore, the male age is relevant. And if she's 35 and has a partner who's 35 years older than her or more, it's not unexplained infertility. It's related to couple age.

Now, we're going to... So that's age. Now, my colleagues are going to take you through a number of treatment interventions other than IVF, which we can do with good effect if we actually make the diagnosis and don't put them into the category of unexplained infertility. You will remember from the old trials that mild or moderate or mild or minimal endometriosis was often included, as was mild male factor or seminal fluid abnormalities.

These were really multifactorial infertility, and I think that's the take-home message, that much of what we call unexplained is multifactorial. You have two minor components that act to reduce natural fecundability. So I now just want to take you through some of the diagnoses that contribute to infertility that we may not, in our routine laparoscopy and workup, we may not pick up and have previously been called unexplained infertility.

For instance, we know that adenomyosis is probably one of the mechanisms by which endometriosis contributes to infertility. Chronic endometritis is now emerging as an operative factor in infertility, and that will not be diagnosed easily. Mild or minimal endometriosis, my colleagues will cover.

The mid-cycle scan will lead you to the thin endometrium, which may be due to unexpected adhesive disease, but also a thin endometrium, which we know has a very adverse prognostic factor, may be due to long-term progestin contraception. We are starting to see this emerge. Secondary infertility after a caesarean section may be due to an isthma seal, and we won't recognise that unless we do mid-cycle scans.

That's the female. Let's look at the male. We know now that seminal fluid analysis is not a good predictor of male fertility, and there is now evidence from Ranjith Ramasamy's work that we are missing clinical varicoceles because we failed to examine the male partner.

My colleagues will talk more about that. We may miss DNA fragmentation, which again may contribute via the basic seminal fluid analysis. Now, most of these diagnoses can be made or sorted out or excluded within one or two months of your detailed assessment of both partners by history and examination.

So it's not straight to IVF, ladies and gentlemen. It's just a little digression, a little lay-by, where you actually assess the patient thoroughly. She did not need a tie for that rebuttal.

LAUGHTER Prasad. Thank you. Well, following from what Professor Hart has said, I'm going to show that IVF should be a go-to option because of its effectiveness, cost-effectiveness and safety.

Now, let me first talk about the effectiveness, and as this is an interaction session, I would like to ask the audience, please, by show of hands, to show me how many of you would accept a medical treatment or buy a new incubator if it had a 94% chance of failure? Well, let the moderator please note that no hands have been raised. Thank you very much. Yet, the chance of live birth in Australian population following IUI is 6%, where, after IVF, the live birth is 40%.

Almost seven times more. Now, why would we subject our patients to something we ourselves would not choose? Similarly, findings were reported from international studies that the hazard ratio of 1.25 favouring immediate IVF, and I will talk later about why it is important from a safety perspective. Cost-effectiveness.

And I quote ESHRE guidelines. The costs, treatment options have not been subject to robust evaluations. Now, again, I would like to ask the audience, this time it's an easy question, how many of you would accept as standard an ongoing pregnancy rate of at least 38% for an average IVF cycle? Yeah, hands up.

All right, I've got three-quarters of the room. OK. Well, I could really rest my case now, as we have good evidence that if a clinic has got an ongoing pregnancy rate of 38% or higher with IVF with single embryo transfer, then it is more effective, more cost-effective, and should be a treatment of choice.

And that evidence comes from the authors that are sitting in this room. Again, what would the patients do? If the patients are paying for the treatment, would they do IUI? Most of them would actually go straight to IVF. And we also have very nice guidelines which advise against IUI based on cost-effectiveness.

Another factor to mention briefly is the multiple births, which cost five to 20 times more than singleton. The neonatal cost of a twin birth costs about five times more than singletons, and pregnancy with delivery of triplets or more costs nearly 20 times. Now, the costs that I'm going to quote are in American dollars and from some time ago, from Fertility and Sterility. However, the total adjusted all healthcare costs for a single-dom delivery is about US$21,000, US$105,000 for twins, and US$400,000 for triplets and more. Then the very, very important is the psychological cost of the high risk of failure with IUI. Now, it is well established that infertility has a psychological impact on our patients.

Studies have shown that prolonged time to conception extends stress, anxiety, and depression, and sexual functioning is significantly negatively impacted. Literature shows that 56% of women and 32% of men undergoing fertility treatment report significant symptoms of depression, and 76% of women and 61% of men report significant symptoms of anxiety. Shockingly, it is reported that 9.4% of women reported having suicidal thoughts or attempts.

The longer the treatment takes, the more our patients display symptoms of distress, depression, and anxiety. Safety. Again, ESHRE guideline says the safety of treatment options have not been subjected to robust evaluation.

But let me talk you through it. In our Australian expert hands, IVF is safe, with the risk of complications of ectopic being about 1 in 1,500 and other risks 1 in 3,000. However, let's think for a moment on impact of multiple births.

A multiple pregnancy has significant psychological, physical, social, and financial consequences, which I can go further into details if required. I just want to mention that the stillbirth rate increases from under 1% for singleton pregnancies to 4.5% for twins and 8.3% for higher-order multiples, and that multiple pregnancies have potential long-term adverse health outcomes for the offspring, such as the increased risk of health issues through their life, increased learning difficulties, language delay, and attention and behavior problems. The lifelong disability is over 25% for babies weighing less than 1 kilogram at delivery.

And please note that the quoted multiple pregnancy rates with IUI can reach up to 33%, although in expert hands it's usually around 15%, which is significantly higher than single embryo transfer. In conclusion, from the mother and child safety perspective, for the reason of medical efficacy and cost effectiveness, we have reasons to believe you should go straight to IVF. We're going to be doing these debates more often from Australia.

This is a great panel. One side, please. Unexplained infertility.

My colleagues were comparing IUI ovulation induction with IVF, but there are other ways of achieving pregnancies with unexplained fertility. I'm going to take the patient's perspective a little bit here. It's all about shared decision-making, so the patient needs to be involved in the decision-making.

And it's quite clear from all the data that many patients with unexplained infertility will fall pregnant naturally by themselves even if you do nothing. So sometimes there's definitely a place in doing nothing, and the patient needs to be aware of that. So it's all about informed consent.

How do we inform the patient? So we've got to make a proper diagnosis, as my colleague Dr. Boothright has already mentioned, and just to jump into IVF because it's cost-effective is not doing our patients a justice. The prognosis is really, really important, and even after 20 years of doing this, it's all about the duration of infertility, the age of the patient, and discussing that prognosis with the patient. We all know that patients who have been trying for longer and who are older do have a worse prognosis, and maybe they do need to look at treatment quicker, but there are many patients that we see that have a good prognosis, and just explaining that to them is all they need to achieve a pregnancy naturally.

And then we're going to talk about other options. It's wrong not to offer those to patients, and my colleague Dr. Quick will talk about that in a moment. Look, we've all had patients that have been scarred by IVF who've spent a lot of money on IVF, did not fall pregnant, and I think the fact that they weren't informed properly, that the diagnosis wasn't made properly, is very frustrating to them.

So to just jump into IVF again is not doing the patients a justice. And look, there are negatives to IVF. There's not just the cost to the patient, the cost to society.

As taxpayers, we all pay for IVF. It's funded here, or sponsored to some degree, and it's also the family and everyone else that's involved in paying for this. So this is not a treatment that is without cost.

There are some harms. We know that ovarian hyperstimulation syndrome still exists, even though it's much less than it used to be. There's a risk of infection and bleeding from the procedures.

And we can look at the baby. The data still suggests that babies born from IVF are smaller and they're born earlier, and monozygotic twinning is more common with IVF, so these are high-risk pregnancies, and all this may have an impact on the long-term health of the babies somewhere down the track at the moment. That is important to still look out for.

But I come back to the emotional toll. Our colleagues were saying that finishing infertility quicker helps to kind of reduce the emotional toll, but the procedure itself does have its own toll if it doesn't work, and so we've got to prepare patients, have them informed. But at the end of the day, it's all about patient choice.

How can a patient make a choice if we don't make a proper diagnosis, give them a prognosis and offer them some other choices that exist? And running the anchor leg of the race for the pro side. IVF in couples with unexplained infertility is the best tool we have in our reproductive medicine toolkit for multiple reasons. Professor Hart has clarified the definition of unexplained infertility.

As a reflection of the degree of investigation we've undertaken. He's explained that IVF is often importantly diagnostic as well as therapeutic, both demonstrating and overcoming barriers to natural conception. Dr Stankiewicz has convinced us that IVF is efficient, safe and cost-effective.

My goal is to show you that IVF is the correct therapy to meet the immediate and big picture family planning goals for our patients with unexplained infertility. More than 80% of couples with defined unexplained infertility who attempt IVF treatment will have a baby. In Australia, ANZSREI data shows us that the average age of the female patients who present with primary unexplained infertility is over 35 years.

And in fact the average is 38 years. We're all aware that the average age of first maternity in Australia has progressively become later over the past two decades. Currently it stands in the mothers and babies report at 32 years.

If the average age of first maternity is 32 years, this means that at least 50% of women attempting their first pregnancy are over 32 years. Research I conducted in Melbourne University with my student Eugenie Pryor asking university students of their family planning intentions and aspirations demonstrated that most people, male and female, want to be parents and most want to have more than one child. However, in Australia, our most recent survey shows that births are at an all-time low, below replacement rate and falling, with an ever greater proportion of our population being unable to have the number of children they aspire to and an ever growing proportion seeking assisted reproductive care.

Fertility declines with age. Factors include egg quality concerns, sperm quality concerns and the accumulation of pathologies over time. Adenomyosis, fibroids, endometriosis are concerns that no person is born with.

They exist on a spectrum and progress over time and may be contributing factors for unexplained infertility. Our patients, when we meet them, are the best IVF candidates that they will ever be. They are the youngest they will ever be and they have the best ovarian reserve they will ever have.

They will generate more euploid embryos now than they will in years to come. The sooner we get our patients pregnant, the sooner they will give birth. It takes nine months to have a baby, 12 months potentially to breastfeed and wean and of course most patients will need time to care for a young infant and recover prior to attempting another pregnancy.

IVF and embryo banking may represent not only their best chance of conception with reduced time to pregnancy but also an opportunity for embryo banking to improve their cumulative live birth rate potential over time. By the time our 38-year-old patient returns to try to conceive for a second child, she will undoubtedly be aged over 40. Her chance of live birth per cycle initiated at IVF at this stage has reduced phenomenally.

The ANZSREI dataset from our most recent report quotes that statistic to be 5%. Her chance of conception with an embryo frozen at 38 years, conversely, is one in three to one in four. There is no room for doubt that IVF gives couples with unexplained infertility not only the most effective treatment we have to help them have a baby, but their best opportunity to have a family.

Last but certainly not least, Dr. Quick, to round out the con sides arguments before we open up for rebuttal. And I'll make a small plea that if you have questions that you'd like to pose directly to the panel, prepare them and we'll make sure we get to them from the audience shortly. Thank you.

So, whilst we have heard that we may be bad doctors because we're delaying our patients' time to pregnancy, I would perhaps put it to you that unexplained infertility is a diagnosis which is made based on exclusion. So perhaps you are the bad doctors because you haven't looked hard enough for the cause of the unexplained infertility. So, in terms of the tests that we all would do, I think, we would all ensure that the woman has an ovarian reserve.

We would all ensure that she has no structural anomaly inside the uterus. We would all ensure that her tubes are patent. We would all ensure that she has regular cycles.

We would ensure that he has a normal semen analysis. I think these are tests that we would all do when trying to evaluate a couple for fertility who are struggling to conceive. And therefore, the chance of them getting pregnant naturally, it's never going to be zero.

And one option therefore, instead of running straight to IVF, would be to say, OK, continue timed intercourse because the chance of you conceiving naturally is not actually zero and this would be the most natural way to conceive, the cheapest way to conceive, the least interventional way to conceive. And whether that be with cycle tracking to ensure appropriate timed intercourse, whether that be with cycle tracking to ensure adequate luteal phase support. When you clear the fallopian tubes, we know that there are studies showing an improvement in natural conception.

Lipidol or oil-based tubal flushing techniques may also help couples to conceive naturally. And then you don't have this multiple pregnancy rate that IVF has. You don't have the cost that you incur with IVF, not just for the couple but to Australian society because IVF is subsidised in this country.

You don't have the risks that the woman goes through to undergo IVF treatment. You don't have the risks that the baby takes on being conceived via IVF. And so conceiving naturally, because it's not going to be zero, is definitely an option for these couples.

In terms of further tests or further investigations that you could do, some people would argue, yes, we haven't looked hard enough for the reason for infertility, therefore we know that ultrasound is notoriously bad at picking up superficial endometriosis. We know that ultrasound cannot pick up subtle changes in the endometrium, as Dr Boothroyd referred to chronic endometritis, for example. So these patients perhaps should undergo a hysteroscopy to see if there is an endometrial issue.

Perhaps these patients should undergo a laparoscopy to see if there is superficial endometriosis. And there are meta-analyses showing that resecting or treating superficial endometriosis may actually help these couples conceive naturally down the track and then therefore they avoid having more interventional treatment in order to conceive. There is also intrauterine insemination with or without ovarian stimulation, which may improve their chances of conceiving naturally.

And that again would be less invasive, less intervention and cheaper for the patient. And we know that therefore there are a lot of other treatment options available to help these couples to conceive. And if it's less invasive, it's more natural, it's cheaper, that ends up being better for the patient.

Psychologically as well, which the other side have brought up, even with Dr Stankiewicz's 38% ongoing pregnancy rate, that also means that 62% of his patients are not going to be pregnant. The psychological impact of that cannot be underestimated because for a lot of patients, IVF is your last resort. And when you don't get pregnant with IVF, that creates an issue too for them.

Embryo banking, which was also brought up, what happens when you create surplus embryos and what's the psychological impact of having to deal with embryos that you are then not going to use in the future? So therefore for those reasons we feel that IVF is not your first line treatment for couples who are diagnosed with unexplained infertility. There are many other ways to help these couples to conceive. We just have a multitude of things to unpack.

And I want to start off by opening up an opportunity for rebuttal. I saw both sides of the panel here taking diligent notes. I think all of us have a full page worth of things that kind of stood out to us.

Since the pro side had an opportunity to begin, I'm actually going to start with the con side and allow the con side to answer specific points made by the pro side and provide just a little bit more detail and clarity for why they think IVF is not the way forward. My learned first speaker, wearing his tie of course, indicated that it was all about laparoscopy and IUI, and it's way more than that. I just want to highlight to you the paper by Dressler in 2017 in the New England Journal of Medicine, a randomised controlled trial of what would be unexplained infertility according to the definition I put out, the less than 35 ovulatory normal semen analysis.

And the intervention was an HSG with either oil-based contrast or water-based contrast. And over the six months, there was clear separation, and this is an effective treatment for unexplained infertility or mild or minimal endometriosis, however it might work. And there's probably separation out to three years.

So as a single intervention, as an alternative to IVF, the use of oil-based contrast is an option. So it's not just about laparoscopy and IUI. I guess the other thing the second speaker did allude to, fairly abysmal success rates with IUI being 6%. That is a problem, and I would like to allude to a very good pragmatic trial conducted by Cindy Farquhar and Emily Lu and their co-workers in New Zealand that really swung the meta-analysis for the use of clomiphene and IUI to clinical efficacy. And they reported a 33% chance of live birth in their IUI and clomiphene arm. I'm going across to Auckland to see what the magic is in that city.

What are they doing? The third speaker did allude to the problem of declining fertility, a global problem, and Australia is not alone. We have solved the problem to date, which we've had for 40 years, with immigration. But Georgina Chambers' work shows beautifully that IVF is not the answer to the falling fertility rates.

It is a way more complex social problem and is probably outside the scope of today's discussion. So those are my three rebuttals to our wonderful team. Thank you very much.

So... You can't bury them. We'll give them an opportunity. Thank you for the opportunity.

So I'd like to address some of the points that my learned debaters on the opposition raised. The first speaker really suggested quite a few things that we probably omitted, like endometritis, failing to examine the male. I think things like that... I think, at a good history, that is essential what we do as part of our investigation.

We're looking for a history of cesarean section, complications subsequent to that. We're doing a detailed scan, and that will exclude the fact that she's got a poor endometrium development, she's got a cesarean scar niche. A good history of a male will allude to the fact that he has some metabolic disorder, degree of hypogonadism.

So we're not delaying anything by these appropriate investigations. Adenomyosis will be raised. I talked about a detailed gynaecological examination.

So I honestly think that a very... As my opening line was, a detailed gynaecological scan, obviously with a very good history taken, is essential. We're not delaying her opportunity to go straight to IVF if we've addressed all these factors. The second speaker talked about shared decision-making, and we'd all completely agree with that.

But we have to be honest and open about the success, which my second speaker talked about, the success of the treatment we're offering. And one thing we should sort of dwell on is it's all... It's a fundamental description of the success of treatment is probably all about prognostic models, and that who not model, that's the original model about the success of conception, is really... Everything flows on from that, which basically talks about a good prognosis patient. 30% chance of live birth after a year.

That's what they talk about, a good prognosis patient. Perhaps the rest of the world is different to your average Australian patient, but if we talked about that being a good prognosis, you've got a one in three chance of being pregnant by a year. I think most of our patients would throttle us.

So that is what all the models are sort of based on, that being a good prognosis patient. So I completely agree with the second speaker that we do have a shared decision. We have to be honest with our patients about the success.

We have to be honest about giving them the prognosis of any treatment that we offer. But really, as my third speaker was talking about, it's about giving the patient the opportunity to have a family, minimal career disruption, minimal life disruption. We have to be honest and talk about the whole picture.

They're focused on the first child because really they can't think beyond that. We're talking about giving them the family that they need. The third speaker spoke very eloquently about the risks associated with the treatment we offer.

I believe we offer a very safe service with our IVF, particularly in Australia, with our 2% twin pregnancy rate. We talk about the higher risk of these pregnancies, but they perhaps don't relate to the treatment we're offering. Perhaps, unfortunately, is the patient, if she's got polycystic ovary syndrome, if she's more likely to have diabetes, premature delivery, preeclampsia.

So I think often the risks associated with IVF and potentially the risks associated to the child born from IVF perhaps don't relate to the treatment of IVF per se. It may well be the woman and perhaps her partner, their underlying medical condition, which lead those risks. So I strongly would encourage you to believe that you take a very good history from your patient, you do a thorough investigation, as I've alluded to, looking for any signs of ovulatory disorder, any gynaecological disorder by a detailed scan, checking tubal patency and a detailed history and the similarities from the man, and then you'll find you're probably going straight to IVF.

APPLAUSE I'd like to talk a bit about the embryo banking and having been in this field for a long time, as a word of caution, we're setting a lot of expectations. I remember going to an ASRM meeting probably 10 years ago where they had this headline, all your embryos in the freezer, your whole family in the freezer, basically expecting that if you get four or five embryos frozen that you'll end up with a family at the end. We all know that for the patient, they're not a percentage, it's either zero or 100%.

And if all the embryos don't work, they don't have a family at the end, you know, it didn't work for them and their expectations haven't been met. And the way we talk about the percentages and that we can solve the patient's problems, that we can make families, it doesn't always happen. So the expectations our position is setting here, we're not always able to meet and so we're going to end up with very unhappy patients.

So this is just a warning to everyone that we need to tell people that this doesn't always work and sometimes they'll end up with no success at all. And from that point of view, I think the way it's presented is way too simplistic and we've got to go back to looking at the other options and not promising things we can't always deliver. So just taking into account all our esteemed interlocutors have said, we don't necessarily disagree with the amount of investigations that they described because nowhere in our argument we said that as soon as the patient registers with the receptionist, they will direct it to an IVF lab.

I think to imply so, we'd be very rich indeed. Maybe there are some clinics that are so efficient. I don't know how it works overseas, but certainly not in Australia.

The other point that was made about the cost of IVF and our, again, esteemed interlocutors are very well aware from the studies done here in Australia that actually every baby that we have to conceive through IVF and create and lives is actually more than 10 to 100 times return on investment because we are creating future taxpayers. We are creating people that will repay the IVF treatment costs over and over and over again. So I'll put to you, Rob, that if you are saying that we can't do IVF because it costs money, you are robbing future treasurers of a huge amount of dollars.

I hope the American audience is listening. In America, we call embryos unborn children in freezers in certain parts and here they're unborn taxpayers. Con side, final opportunity for rebuttal before some audience questions and one more word from the pro side.

Well, actually, Dr Stankiewicz was very happy to hear that you're not going to send your patients straight to the IVF lab because we've managed to convince you that that's not the right thing to do. I clearly have forgotten how to debate because I did all my rebuttals at the end of my presentation but essentially I'll recap because when we're talking about IVF, as we're saying, the chance of pregnancy is not going to be 100% and so there is a psychological impact to IVF not working. There is a psychological impact to banking embryos and creating surplus embryos that eventually may not be used and they were my main rebuttal points in terms of why IVF was not the first-line treatment.

Thank you. So we've heard from the opposition some very valid points of how our patients can be psychologically impacted when fertility treatment is unsuccessful. I will again remind you that IVF is the most successful fertility treatment we have in our treatment armoury.

We are most likely to help our patients have a baby with IVF. The cumulative pregnancy rates for IVF have started back in the late 70s and early 80s in single-digit percentages. We now, with a best prognosis candidate, have at least a one-in-two chance of that patient having a baby per embryo transfer and in our patients with unexplained infertility, the vast majority of our patients will have success.

We also heard from the negative team about the significant chance of pregnancy in patients with expectant management. You're right, there's not a 0% chance of natural conception in patients who have unexplained infertility, but there is a not very good chance. We know from data that we've had for a really long time, going back as far as the Hutterite data, to today's non-contradictory models, which tell us that a couple's chance of conception per month in best prognosis candidates is one in five.

If they've been trying for six months, it's one in ten. If they've been trying for 12 months, it's only 5%, and if they've been trying for 24 months, it's less than 1%. So it may not be zero, but it isn't very good.

In terms of our team reminding us of the extended ICMART definition of unexplained infertility, we don't argue. When we say someone has unexplained infertility, we make the assumption that they have been comprehensively diagnosed by a robust reproductive endocrinologist, as everyone in this room is. And I would say one closing rebuttal.

IUI success rates have been the same for the last 50 years, whereas IVF success rates continue to improve. Why would you offer your patient a treatment from 50 years ago when you can offer them one from today? Thank you. APPLAUSE I'm going to take a personal privilege and ask the first question, in hoping that the microphone makes its way to the second question in the audience.

My colleagues on the pro side have said IVF, IVF, IVF. Can you be a little bit more specific about what kind of IVF? Do you mean IVF with ICSI? Do you mean IVF, ICSI, and PGT? Be a little bit more deliberate for us and tell us exactly how the patient with unexplained infertility should receive IVF. As I said in my statement, I think it's a diagnostic evaluation.

I think there is an argument to consider ICSI, but I think ICSI does have some negative consequences for children born. I think perhaps going straight to ICSI is too much. I think going straight to PGTA perhaps is too much, unless there is something in their history which should indicate that.

But we're talking about unexplained infertility. So I believe a standard IVF cycle, looking at the opportunity to assess embryonic development, is the way to go. I do not think you should be going straight to ICSI.

I think the principle of first do no harm is probably a safe approach. I don't know whether my colleagues have some other comments, but I think that would be the first approach rather than going all guns blazing. I can understand, though, in different settings in the world, there may have... We're very fortunate in Australia, we're very well supported from the government support for IVF, but I think the imperatives in different countries may be different.

But I think that approach would be the right one first. We'll start with a question from the audience. And if you could introduce yourself and have the question allowed for our members in the audience who are not here.

It's Louise Hull here from Adelaide. The question I would like to put to both the pro and con team is that Geeta Mishra from the University of Queensland showed that if you had diagnosed endometriosis before IVF, you were more likely to have a pregnancy and much less likely to have high-order IVF cycles. Given that we now have really good non-invasive diagnostics, we're actually... A lot of the time we can pick up superficial or stage 2 endometriosis if you get the right scan.

We're going to do IVF better if we know about it. Can you comment on that impacting even the diagnosis of unexplained infertility? Thanks. I'd love to take that.

Can I go first, Roger? LAUGHTER Please do. Look, I'd love to take that question. It's a really good question.

And, of course, this is not unexplained infertility, so this is outside the scope here. And I think, really, what we're seeing now, in contrast to where we were at the time of the Markku study, which was all... And the Tulandy study on endometrioma excision, we now see that that is actually damaging to fertility, particularly where there is ovarian endometriosis, and that we compromise their ovarian reserve by doing this surgery before we preserve their fertility, be it oocyte cryopreservation or embryo cryopreservation. So I think it's a bit outside the scope of this talk, but I think the swing of the data now is that we should be doing fertility preservation before we do surgery for deeply infiltrated ovarian endometriosis.

And that would fit with Gita's findings. A brief response. Thanks very much, Louise.

Yeah, we're talking about unexplained infertility here, and my opening line was we need a history, but a detailed gynaecological ultrasound. I think it's important it's a really good ultrasound to exclude that, because the evidence around very minor endometriosis is not there. I agree with significant endometriosis, but that's not the subject of this discussion.

But I do believe with very minimal endometriosis there is really no evidence for that. Janelle MacDonald from Sydney. I'm going to play devil's advocate here.

So everyone is probably aware of the recent government inquiry about obstetric violence. I'm a little concerned that if we are perceived to be encouraging women to IVF first, are we guilty as a profession of performing fertility violence? That's just digressing a little bit, just thinking about how the consumers may perceive this. I think our patients want to have a baby, and that's why they come to see us, and that's what we help them to do through IVF.

I'm not sure the microphone's working. And just introduce yourself. I'm from Sydney, Australia.

Can I disagree with you, Roger, about that question about minimal and mild endometriosis? I'm 68, so I'm old enough to have read a whole lot of papers in the past that are probably seen as relics. But Mark Khoo published an unusual study, because it was actually an RCT. Well, sorry, not an RCT.

It was a study whereby... Well, it was an RCT, and it was randomised really well. It was done in Canada, and there were about 350 subjects, and they were identified to have stage 1 or stage 2 endometriosis at laparoscopy. And the interesting thing is it was seen as an intervention which didn't greatly increase the chance of conception, but it doubled the monthly chance of conception.

So there was clearly a difference between those patients who didn't have endometriosis and those that had stage 1 and stage 2 endometriosis. So the intervention did actually result in an improvement. One of the quotes was, well, I heard since then, well, it didn't make much difference.

But when you realise that infertility is multifactorial, there were probably other factors involved as well. So any increase like that in stage 1 and stage 2 endometriosis sufferers was clearly beneficial for them. So I wouldn't disagree with you completely, but I do think you've got to take it on board that there is some evidence that surgical intervention can help.

And certainly in those patients whereby the financial costs of IVF are still quite, even in Australia, astronomical. Many patients can get this through the public sector or the private sector treatment of their endometriosis laparoscopically very cheaply or at no cost. Thanks, Dr Persson.

So you're right that there was also a counter-randomised controlled trial by the Grupo Italiano which was a counter to that. And actually did not show any benefit. But I believe the Marcu study demonstrated an excess of conception and with treatment of minima and endometriosis of about 4% per month for a few months.

So absolutely, that shared decision-making. Personally, I wouldn't like a laparoscopy to give me an extra 4% chance of a natural conception for four months, which I think the data was. So basically, the basis to my statement that I said without going into great detail was a review article published by Samy Glarner recently in Reproductive Biology and Endocrinology.

And their conclusions were what I basically said, that from looking at all the data, there is no real evidence of intervention for minor endometriosis. We're not talking about pain or significant diagnosed endometriosis on the outcomes of IVF, ovarian reserve, egg quality, embryo development, and euploidy rate. So that was the basis of my... I hate to disagree... I hate to agree with my opponents in a debate, but I'm going to... But there is actually a new network analysis by Rui Wang and some serious heavyweights in evidence-based medicine that pulls together the surgical studies.

And the thing that made the most difference to this of mild and minimal endometriosis from a fertility point of view, not pain, is the use of oil-based uterine contrast. And I commend that paper to you, which fits with exactly what Roger is saying. Hi, my name's Lucy Prentice.

I work in Auckland. And I just wanted to point out the New Zealand perspective a little bit. Where we come from a country with very limited public funding for IVF.

I'm currently running an RCT with Cindy Farquad directly looking at IVF versus IUI for unexplained infertility. And I'd just like to point out that both the ASRM and ESHRE guidelines, which are the most recent ones, both suggest that IUI should be a first-line treatment with oral ovarian stimulation. We have no evidence that IVF is superior based on an IPD meta-analysis published very recently and also a Cochrane review.

And although we would love to be able to complete the family that our patients want from IVF and embryo banking, that option is really not available to a lot of people in New Zealand because of prohibitive costs. We know that IUI with ovarian stimulation is a very effective treatment for people with poor prognosis and unexplained infertility. And I also would just like to add that there's not a cost-effectiveness analysis that shows an improvement in cost-effectiveness for IVF.

There's also never been a study looking at treatment tolerability between the two, so I don't think that you can say that IVF is a treatment that people prefer over IUI. So I may turn around and shoot myself in the foot based on our results that will be coming out next year, but I think at the moment I don't think you can say that IVF is better than IUI with ovarian stimulation for unexplained. We have time for two more questions from the audience, and we have two hands in the back.

Now we can. It's the light green. OK.

Hossam Zini from Melbourne. Thank you very much for the debate. It's very interesting.

The problem is that all of the studies that have been done about comparing IUI to IVF, they are not head-to-head studies. The designs are different. They are having, like, algorithmic approach.

For example, they compare three or four or five cycles of IUI to one cycle of IVF. But about 10 years ago, our group at the Royal Women's Hospital, we have done a study, a randomized control study, to compare IUI to IVF head-to-head, and we randomized the patients at the time of the trigger who only developed, so we did a low stimulation to get two to three follicles only, and that's why it was so hard to recruit lots of patients. So the criticism that was given to the study that it's a small sample size, but we end up with having IVF as a cost-effective treatment.

Our IVF group had a live birth rate about 38%, and on the IUI, 12%. And with our cost calculations, we find out that the IVF is much more cost-effective than the IUI. But I believe that we all now believe in individualized kind of treatment, so patients probably who are younger than 34 years old probably wouldn't go straight to IVF.

Maybe I'll do a laparoscopy and a histroscopy first, okay, and we may give them a chance to achieve a natural conception in the next three months or so. Patients who are older than 35, 37 years old probably will benefit straight from IVF. But again, in day-to-day life cases, we will not force the patient to go straight to IVF.

I will talk to her and I'll tell her, these are your options, expectant treatment. This is the percentage that you would expect. IUI, this is what you expect. IUI with ovulation induction, this is what you expect. IVF, this is what you expect. And then she will discuss that with her partner and come back to me and tell me what she wants to do.

Thanks. I saw a hand show up right next to you, so I'll add one more question given our time limitation. Thanks so much, Kate Stone-Mellon.

I'd like to ask our panel to take themselves out of their role playing and put themselves in another role where they were the head of a very, very well-funded public service, and I'd like to ask the two sides what they really think about what they would do with a patient at the age of 35 with 12 months of unexplained infertility. Well, can I say that? Because that's my role in a different hat. LAUGHTER So, yeah, I run the state facility service in Western Australia.

We looked at the data, because obviously that's what we're doing, IUI, IVF, and unfortunately we stopped doing IUI treatment. The success rate was so low. So we do go straight to IVF with unexplained infertility.

Disappointing, as I'm sure you hear that, Kate, that we do. We looked at the data. Yeah, I think that I would still offer the patients the options, because some people don't want to do IVF.

Even though it's completely free, they may not still want to do the injections and the procedure and take on the risks of the actual egg collection procedure. I don't know, religious issues with creating embryos. Yeah, I would still give patients the option.

We have time for one more question in the back. We'll take the other ones offline afterwards. We'll get you a microphone just to make sure our listeners afterwards can listen.

Following on from the New Zealand experience, which I've experienced... Hello? Yeah. From the New Zealand experience, and having worked here extensively and in New Zealand, you're not comparing apples with apples, Claire. That unexplained couple in New Zealand will wait five years to get funding and currently perhaps another two years to get any treatment.

That's then an apples group compared to the pilot group who may, in fact, walk past the hospital and get treatment. The other thing about this, I think, that we need to forget, or don't forget, is the ethics of things here, two of which is that the whole understanding of unexplained infertility needs research and thinking. And if it wasn't for that understanding of what is the natural history of normal and then the understanding of pathology, we wouldn't do a lot of things in medicine.

So if we have got a subgroup here that's unexplained, it's not just to the patient, we have a responsibility to future patients and ourselves to be honest and do research and learn about these factors. Now, it doesn't answer the debate, but it is something that's what drives the investigation and management of unexplained delay. And, for example, at the moment, there's quite a discussion about two issues of ethics, one about the involuntary childlessness of people that don't get to see us but don't have those children that they wanted to have because they didn't want to undergo treatment, or it was the involuntary childlessness of a second or subsequent child.

And that's quite a big research issue in Europe, I realise, at the moment. And the final thing is about the information giving. The British case Montgomery 2015 has changed consent substantially, for those of you from England, that all information given to patients must include and document the discussion about expectant management versus all the different types of treatment, for and against and risks.

And we're not currently doing that in IVF in this area, but if you read about what's happened in England, it's transformed consent in surgery. And I think a lot of our decision-making isn't in that way. So there are a couple of ethical principles to think about.

Wonderful questions from the audience. Since we're coming up at the end of our time, we typically end the debate with closing remarks, but we'll forego that for this debate. And I'd actually like to just poll the audience.

After hearing both the pro and the con side's arguments, by a show of hands, who in the audience believes that for the patient with unexplained infertility, as defined and detailed here broadly, should we be beginning with IVF? Should we be going straight to IVF? So by a show of hands. And I would say probably 50% of the room raised their hand. And those who think we should not be going straight to IVF? It feels like a little bit more.

40-60, now that I saw the other hands. Well, I'm going to call this a hung jury. I don't know that we have a definitive answer.

Please join me in a round of applause for our panelists. In America, we would call that election interference. I wanted to thank our panelists, our live audience, and the listeners of the podcast.

On behalf of Fertility and Sterility, thank you for the invitation to be here at your meeting and hosting this debate live from the Australian New Zealand Society for Reproductive Endocrinology meeting in Sydney, Australia. Thank you. This concludes our episode of Fertility and Sterility On Air, brought to you by the Fertility and Sterility family of journals in conjunction with the American Society for Reproductive Medicine.

This podcast was developed by Fertility and Sterility and the American Society for Reproductive Medicine as an educational resource and service to its members and other practicing clinicians. While the podcast reflects the views of the authors and the hosts, it is not intended to be the only approved standard of living or to direct an exclusive course of treatment. The opinions expressed are those of the discussants and do not reflect Fertility and Sterility or the American Society for Reproductive Medicine.