All right, good afternoon everybody. I'm aware that Friday afternoon in Palm Springs there's starting to be a pull towards the pool, but I'm happy that you're all here. We have another joint session between PCRS and Fertility and Sterility, so essentially a fertility and sterility journal club global that is live streamed from PCRS.
And the debate that we have today is a very exciting topic, the use of ICSI for non-male factor infertility. And we have a fabulous panel to discuss this question, and I will introduce them in just a second. This is the disclosure slide.
So, the expected learning outcomes from this session is to describe the ICSI utilization rates and global variations in usage, to discuss the evidence for and against using ICSI in male factor ART cases, outline the short and long-term risks of ICSI, and compare evidence-based ICSI usage versus it being an ART add-on. So, I'm just the moderator, but I would like to introduce the topic with a few slides. And I would like to start with an audience question, a bit like yesterday in the journal club that we did yesterday.
So, this is a simple question. In your opinion, in the United States, which of the following statements is currently true? ICSI is underutilized, the rate of ICSI use is appropriate, or ICSI is used excessively? So, who, show of hands, who believes that ICSI is underutilized? Nobody. Who believes, B, the rate of ICSI use is appropriate? We have a few.
I would say that was like maybe eight hands. And then the last one, ICSI is used excessively. All right, well, half of our panel is raising their hands.
Okay, good. So, the journal club that we're doing today is based on the Fertile Battle in Fertility and Sterility in February 2022, where other experts also discussed the topic intracytoplasmic sperm injection for all, or for a few. And there was an editorial that went along with it.
This is one of the figures, and I'm not going to sort of go over the information. I'm just going to show you that the topic, the one topic that is obviously clearly obvious from this whole discussion is that the basis for what we're talking about is that ICSI is not only used for male factor indications. It is definitely used for non-male factor indications, as you can see.
So, the cases of male factor IVF or ART have stayed relatively stable, but the ICSI cases have gone up. There are a variety of, oh, there's a controversy regarding the indications for ICSI that we will discuss, and that's one of the tables of this paper. And then there's, as I stated in the learning objectives, there are different research findings regarding ICSI risks.
There is an ASRM committee opinion on this that we will discuss, and I will say I am just the impartial moderator, although I will, for full disclosure, say that I wrote a commentary that says ICSI for non-male factor, do we practice what we preach? And I did that while working at a practice that did 100% ICSI. Around the same time, a little bit embarrassingly, the sort of godfather of ICSI also wrote a commentary, which made me feel sort of a little bit inadequate. But anyway, what he wrote in this, and that's just the introduction for this debate, he wrote, people may have forgotten why ICSI was developed, so maybe we can talk about today why it was developed.
So now, the most important thing is for me to introduce the debate panel, and the exciting part about this today, and the fun part, is that all of these experts are fellows, and so I have the pleasure to introduce them now. So Philip Romanski is an REI fellow at Cornell. He received his medical degree from the University of Central Florida, completed OBGYN residency at Brigham and Women's Hospital, and so he will graduate soon with his REI fellowship, but also with a Master of Science in Clinical and Translational Investigation.
After that, he will join Shady Grove Fertility in New York. He's an active clinical researcher with specific interests in infertile females and males with a poor prognosis. I always have a fun fact for each of these lovely fellows, so his fun fact is that he is a cat person.
If you like cats, go up and speak to him. If you like dogs, do not go to speak to him. He doesn't mind dogs, but he's a cat person.
So anyway, then next one, Dr. Jareen Morris. Dr. Jareen Morris is an REI fellow at UCSF. She completed a Master's of Public Health and Epidemiology at Tulane University.
She has a strong interest in women's health and seeks to serve as an advocate for marginalized women, and so she has already authored multiple publications on this topic and would like to continue this work. As the chair of the ASRM Health Disparity Special Interest Group, she is charged to facilitate programs and opportunities that address reproductive health needs of underrepresented populations. Goes into the sort of direction that Dr. Marsh presented in her fabulous talk this morning.
Her fun fact is that she once went skydiving and closed her eyes the whole time. Dr. I.J. Eco is an REI fellow at the University of Utah. She received her Bachelor's degree from Duke University with a focus in health policy and earned her medical degree from Brown University, completed obstetrics and gynecology residency at the University of California, Davis.
Her clinical interests include infertility, recurrent pregnancy loss, PCOS, research interests, cost-effective care analysis, disparities in infertility diagnosis and treatment outcomes, as well as social and environmental impacts on fertility. Her fun fact is that she is a fanatic Duke fan, and so she's still recovering from last night's game. Dr. Sarah Gavrizi is a third-year REI fellow at the University of Oklahoma.
Unfortunately, she arrived there after I left. I was a faculty just before, I think, you arrived. So she is going to complete a REI fellowship at the University of Oklahoma soon.
She is originally from Texas and completed medical school at McGovern in Houston, followed by obstetrics and gynecology residency at Dell Medical School in Austin, Texas. Her fun fact is that she can learn the lyrics of almost any song within five listens. So if you want to test that out, I would like to, you know, get a demonstration of that.
All right, so Dr. Lauren Virildi is also on the con side, and she is a third-year fellow in REI at the University of Utah also. She received her MD at the University of Washington, completed her OBGYN residency at the University of Wisconsin. Her clinical interests include ovarian aging, primary ovarian insufficiency, and optimizing IVF protocols for porous ponders.
Her fun fact is that she is a Utah trail runner, and so she's looking for somebody else to do a PCR sunset run, and she's actually found somebody because I already said that, you know, we can go tomorrow. Very good. So then last one, Dr. Eduardo Haritan is a fellow at UCSF.
He, I believe, was co-resident with his opponent, Dr. Romanski, at Brigham and Women's Hospital, where he completed his OBGYN residency. He also has an MBA from Harvard Business School. He, as I said, is a fellow of REI at UCSF.
He combines his clinical and business backgrounds to treat patients and think creatively about how to improve the care they receive when seeking fertility services. He's already authored a bunch of publications in high-impact journals, and also already serves as an advisor to early-stage healthcare companies. His fun fact is that he wrote a baby book about IVF that helps parents to explain IVF to their kids.
So anyway, so this is the illustrious panel that we have, and now I will sit down and listen and let these wonderful fellows from all across the country debate the topic whether ICSI should be used for non-male factor indications. So we, there's no slide, but we're gonna go back and forth a couple of times, pro-con, pro-con, pro-con, and then maybe discuss a little bit and open it up for questions. All right, I'm gonna open it up for the pro-non-male infertility indication.
So in support of ICSI for non-male infertility, I'm going to start by offering up a patient-focused framework based on cost and ultimately access to IVF and ICSI care within the United States. According to the 2020 U.S. Census, the median family income is about $68,000. The cost of an IVF cycle in the United States can vary significantly, but can range anywhere between $10,000, excuse me, which is 15 to 30 percent of that median family income that we just quoted.
Furthermore, only 13 of the 50 states, the 26 percent, currently have mandated coverage for IVF, which within those mandated states still leaves gaps in coverage. And then lastly, as we all know, one of the major predictors of success after an IVF cycle, other than age, age, and oh yeah, the age of the person of the oocyte provider, is the number of embryos available for transfer. Now imagine you're a couple with unexplained infertility coming to the provider's office to finalize your IVF cycle plan after taking on a second job, maybe even a second mortgage, to pay for your treatment because unfortunately you live in one of those many states that doesn't have coverage, and your provider tells you, oh actually, there's this really great fertilization technique called endocytopathic sperm injection, ICSI for short, but unfortunately you don't qualify for it because your sperm parameters are normal, which is, you know, good.
And then the provider wanting you to be fully informed goes on to tell you that studies have shown that ICSI is associated with, one, higher rates of fertilization per inseminated oocyte, which then one might logically conclude might mean also more embryos available for transfer, two, decreased fertilization failure, which that just sounds like an absolute nightmare, and then three, provides more accurate information as to the maturity of the oocytes that were fertilized during that cycle. Okay, now imagine again, same couple, you're getting a call from your provider that unfortunately there are no eggs fertilized after using conventional insemination, but good news, next time we'll use ICSI. And then, oh yeah, we weren't really sure about the egg maturity issue, so we'll just kind of throw a couple things in there just in case it was that as well.
And then we can make all these tweaks for that next time, but what if there's not a next time for that couple that had that significant cost burden as well as emotional fatigue of going through that cycle and unexpectedly facing a failed cycle? I would say that unless providers are willing to weigh fees for partial and complete fertilization failure, I would argue that ICSI should be offered for those with unexplained infertility, and if not offer all oocytes, then at least split. But you know what, actually, when I think about it, I change my mind, I take that back, I think that that still isn't enough because studies have also shown that individuals who are going through treatment, even if cost is not their barrier, just the fatigue again of going through treatment leads to higher dropout rates. I think our opponents are going to end up saying that the use of the resources doesn't justify the means, and my rebuttal of that is that I would remind you of the studying by Delmar et al that showed that a diagnosis of infertility carried similar psychological impact to a cancer diagnosis No, it's not life-threatening, but we knew secondhand the effect that it has on our patients.
And so we have to do everything that we can to help decrease that burden on our patients and do the most to get them to that successful end given everything they're putting into the cycle. Okay, transitioning to PGT. Using preamputation genetic testing for monogenomic, monogenic conditions.
I think we can all agree that ixine should be used for PGTM given the concern for erroneous errors from extraneous sperm. So I'm not going to beat that over that. For in vitro maturation, which is going to be the last topic I cover, given the concern for hardening of the zona pellucida and the impairment of sperm penetration and leading to reduced fertilization, I believe it's quite reasonable.
We don't have a lot of evidence, but the evidence that we do have has shown that we have improved fertilization with ixine. So 69% versus 38% and that was in the Saderstrom and Teller et al study. They looked at fertilization rates of mature oocytes from individuals who did not undergo gonadotropin stimulation.
And then, not to beat this over the head, but logical conclusion. If you have better fertilization, you're probably going to have more embryos that are going to be available for future transfer. And with that, I'm going to turn it over to Dr. Varelli, who I know is going to try to undo all that I've just said.
But thank you for allowing me this chance to debate this point. Thank you to my junior fellow. So just a few data points you're all aware of, but as you saw in the graph, we have a very high utilization of ixine, which has become uncoupled from the rates of male factor infertility.
And so really what I'm here to talk about is that these other indications need to be revisited by clinics who are using a blanket statement to employ an ixie-all policy. An ixie-all policy is not fair to your patients. You are the one with extensive training and so you are the one who's capable of deciphering the literature.
Many of these indications have studies with surrogate markers for live birth and differences in live birth and cumulative live birth have not been fully answered. For instance, ixie for unexplained infertility is probably one of the most compelling considerations for an added indication because several studies have demonstrated a decrease in fertilization failure in an ixie-all approach. But most of these studies use sibling oocytes and when it came time for transfer, they didn't pick to transfer who was fertilized with which technique.
This study was also not powered to look at differences in live birth. There was a popular meta-analysis on ixie for unexplained infertility which did find an eight times increased risk of fertilization failure in the conventional insemination group. Unfortunately, this meta-analysis had significant heterogeneity in the studies which really limited the ability to perform a meta-analysis on them.
In addition, this meta-analysis again was not powered to detect a difference in live birth rate which is really the data point we need to be giving our patients. The other point I want to bring up about the unexplained infertility category is several of these studies and the meta-analysis show rates of FERT failure that I think none of your clinics would admit would be your FERT failure rate for conventional insemination. So they're showing rates of 15 to 30 percent.
I'm not aware of anyone who would say that they have a 15 to 30 percent FERT failure rate with their conventional insemination technique in unexplained infertility. So I think this begs the question that many of the patients with unexplained infertility in these studies don't necessarily have unexplained infertility that they may appropriately should have been categorized with male factor infertility and thus would have met the indication for ixie. The other point I want to bring up is using ixie for a PGTA case due to the concern for DNA contamination.
I think this has been refuted over and over again, especially with the use of NextGen, the sequencing platform. In fact, there was a study conducted by several of our conference attendees from Stanford that demonstrated no difference in euploid, aneuploid, or mosaic results among sibling oocytes that were randomized to ixie versus conventional insemination in patients for whom the only indication for ixie was PGTA. And then I want to talk a little bit about ixie for low oocyte yield.
So raise your hand if on the day of trigger for your 39-year-old with an AMH of 0.3, you've got four follicles you're going to aspirate. Raise your hand if you've gone to your lab and said, actually, what's ixie? Oh, one person, two. Okay.
Well, the rest of you are not doing that. So I think ixie for low oocyte yield really pulls at our fear as providers that we have a significant fear of fertilization failure and we're thinking they went through all this, their yield is going to be low. Unfortunately, there has not been a single study that would support that choice.
That is a fear-based choice. I've been in, I felt that way, I know that feeling, but it is not backed by data. There was actually a study in 2014 that showed a lower live birth rate in oocytes that were fertilized with ixie compared with conventional insemination when there was a low oocyte yield.
So I beg you to put your fears aside in that category and actually go back and look at the data. So these scenarios are the ones that I think represent our highest increase in our ixie utilization and I'm sort of here to let you know that the data does not back those decisions. We owe it to our patients to help them make an informed decision and we also owe it to our field to power these studies for taking a baby home.
Maybe a little bit, a little bit better. All right, so switching gears, I wanted to talk about using ixie for cryopreserved oocytes and then also pivot to using ixie for those who have poor quality oocytes and I think I wanted to look at both of them and draw parallels between them, both with limited data. So we all know, first off, who in here uses ixie if oocytes have been cryopreserved? It looks like almost everyone.
Okay, so prior to cryopreservation we know cumulus cells are removed from the surrounding oocyte. This may lead to changes in the zona, namely hardening has been mentioned for a reason or indication to use ixie when you go to thaw and hopefully inseminate the oocytes. A lot of this data represented Gook's work from the 1990s, so specifically in 1995, Gook et al.
went ahead and published a study looking at conventional insemination at one center, followed by ixie use at another center. While fertilization rates were similar, there was a statistically significant difference in cleavage as well as blastocyst rates among the ixie group, so a lot of individuals changed their practice. Moving forward, Porcu et al.
went ahead and detailed in a case report in FNS published in 1997, details about the first live birth of someone who underwent ixie and then an ultimate transfer. Right after that, Gook et al. in 2007 published data looking at human oocyte cryopreservation and really stated, while it's unclear the reasoning behind the increased cleavage as well as blastocyst rates, there's no clear controlled studies that argues for one practice versus another, ixie has pretty much become mainstay and no one would say the dearth of data would be a reason to change your practice back to conventional insemination, or I hope you all don't after today.
When I think about ixie for poor quality oocytes, I think about that same thing. I think about the zona. I think about a lot of the unknowns we had when inseminating oocytes that had been cryopreserved.
So, when you think about oocyte quality, we know thinner zona pellucidas are tending to be associated with higher fertilization rates. It's unclear, however, whether an enlarged perivalent space, enlarged polar body, aggregated smooth endoplasmic reticulum, it's unclear how those aspects of the oocyte will contribute to fertilization and more importantly to pregnancy and live birth rates. However, one study performed by Killani et al.
in 2006 showed that actually the zona between, you know, those who are younger and those who are older are quite different. So, we know that in older patients who, we retrieve their oocytes immediately after retrieval obviously, they tend to have a thicker zona pellucida. We also know that at the day five or the blastocyst stage, they tend to have more dense zona pellucida that's present and that could in theory impact fertilization or excuse me, that could in theory impact pregnancy rates.
So, from there, a lot of the data and a lot of the studies looking at use of ICSI for a non-male factor among those with poor oocyte quality has been focused on the advanced maternal age population. Just to kind of give you some snapshots at what that data looks like, Sundaram et al. recently published a beautiful meta-analysis.
This included seven cohort studies reflecting data from 2001 to 2016. So, a fairly large time period was included. Women included were 38 or greater.
Men had normal semen parameters and there was no difference in the number of oocytes retrieved or fertilization per M2 oocyte that was inseminated. The issue with this meta-analysis is it only included women of advanced maternal age. These women were mostly poor responders and none of the studies were randomized.
None of the studies looked at pregnancy or live birth rate. So, a huge limitation. Haas et al.
then went on to perform an RCT, so stronger quality data and this was a single center looking at randomization of women who were 39 years or greater for conventional insemination or ICSI. I like the way the study was performed. They actually randomized at the level of the ovary.
So, those who underwent a conventional insemination may have the oocytes from one ovary would undergo conventional insemination. The oocytes from another ovary would undergo ICSI. So, it's a fascinating approach and they found that there was no difference in fertilization rate.
The sample size, however, in that study was only 60. So, definitely not enough or powered widely enough to show a difference in pregnancy or live birth rate. And then the way that they generated the embryos, there was no way of even knowing what they transferred.
So, they did not mark from oocyte to embryo where it came from, basically. Interestingly, in 2000, Sato et al. published in FNS a different speculation on how ICSI for non-male factor for poor quality oocytes in particular could be useful.
They focused on the fact that in conventional insemination, you have an oocyte that may be exposed to a lot of the toxic effects of the sperm that they're sitting in, basically. So, if you already have a poorer quality oocyte, they may be more at risk or more stressed to not become fertilized or go into a great blastocyst based on their environment. They showed that there was actually more apoptosis in the granulosa cells and closing the oocytes that were inseminated and fertilized with ICSI compared to those that underwent conventional insemination.
The authors then postulated that the quality of the oocyte, if it's somewhat low, maybe ICSI can be used to overcome the effects that may be seen by conventional insemination. So, in terms of my final thoughts, I think most studies have evaluated fertilization rates and were performed on those who were 38 years or greater, which may be more likely to have, yes, poor oocytes, but what about the patient who comes to see you who has poor quality due to endometriosis? What about the person who comes to you who has poor quality due to obesity and smoking? Yes, we hope our patients don't smoke, but that certainly is also a risk factor for a poor quality oocyte. There have been no prospective cohort studies, no RCTs that I'm aware of that looks at poor quality oocytes undergoing conventional insemination versus ICSI, and using ICSI for cryopreserved oocytes, it was a logical choice.
I would sort of say the same thing for using ICSI for poor quality oocytes also, to me, seems like a logical choice when you think about the parallels between the two as well as the DRFO data. Thank you. So, great points by everybody so far.
As mentioned, there are lots of indications aside from male factor infertility that ICSI may be used, and I think we touched on most of them, so unexplained, poor quality, low yield, et cetera, and while ICSI may provide benefit for some people in those categories, like cryopreserved embryos, the lack of evidence demonstrating improvement in live birth, which is our ultimate goal with ICSI in the majority of these diagnoses, make it difficult to justify the risks of this procedure. So, using ICSI, it bypasses the natural selection barrier to fertilization as well as the normal complex process, including the acrosome reaction, sperm zona binding, and sperm penetration, which you could argue is why it's helpful in male factor, and it does this by injecting a single spermatozoan that's chosen purely by appearance, with the injection itself actually having the potential to disrupt the meiotic spindle of the oocyte. Even the fact that the oocytes are out of the incubator for a longer period of time is a risk that should be considered.
And as far as long-term effects, suggested risks include things like congenital and urogenital malformations, epigenetic disorders, chromosomal abnormalities, delayed psychological and neurological development, things like that, and, you know, there's mixed evidence regarding the risk of congenital malformations in ART, with several studies suggesting that there is an increased risk with IVF. Whether ICSI itself is responsible or changes that risk is still not clearly defined. Widespread use of ICSI for non-male factor infertility is a relatively new thing, and so there's just not a lot of large prospective studies that are looking at this question specifically.
One of the other concerns that I think most people, you know, put in our consents is the increased risk of imprinting disorders. So epigenetic systems include things like DNA methylation, histone modification, et cetera, that can affect phenotypic changes without altering the DNA sequence. And so these imprinting disorders occur when one of the two alleles undergo epigenetic changes, resulting in silencing, leaving expression of only one allele.
So some of these are things like Prader-Willi, Engelman, Beckwith-Wiedemann syndrome, which are rare in the general population but seem to occur more frequently in couples with infertility. And so a 2013 review in FNS included eight epidemiologic studies that were used to calculate the weighted relative risk for the birth of a child with Beckwith-Wiedemann syndrome following IVF or ICSI, and they compared it to the risk of the normal population. This relative risk was 5.2. So in one of the studies, this relative risk was corrected for fertility diagnosis and subsequently no significant association was found.
And while we know imprinting disorders are more prevalent after IVF or ICSI, whether it's ART, the ICSI, or the diagnosis of infertility itself, unfortunately, figuring out what the true culprit is has not been determined. Looking at cognitive impairment, a 2017 systematic review that included 35 studies, seven of which were considered high-quality studies, compared cognitive ability in school-aged children who were conceived using various fertility treatments. Among the high-quality studies, there was no difference in cognitive outcomes among children conceived with conventional IVF and those conceived naturally.
But among the studies of children conceived with ICSI, the findings were inconsistent. So when they were compared to children conceived naturally, one study reported lower intelligence quotient on average, and the other two didn't show a difference. But when they looked at children conceived with ICSI compared with conventional IVF, one reported a significant increase in the risk of mental retardation, another reported a small difference in IQ, and then one found no difference at all.
Lastly, a 2015 human reproduction study, it was a retrospective cohort study that included over 42,000 cases, and they were looking at the prevalence of autism in live-born infants conceived with ART. And they reported that ICSI for non-male factor infertility was associated with an increased risk of autism with an adjusted hazard ratio of 1.57 when compared with conventional IVF. I will freely admit that there are flaws in a lot of these studies, and there's not a lot of data that clearly implicates ICSI itself as the cause of these long-term consequences, but all that means is that there's more work to be done in figuring out the safety of this technique, not that we can just apply it freely without appropriate indication.
You know, medicine is all about the balance of risks and benefits, and in this situation, assuming these risks without any evidence of benefit, especially in our primary outcome, again, live birth, is just not justifiable. All right, so I'm going to touch on the use of ICSI with failed fertilization or to try to prevent failed fertilization. So since the early 1990s, ICSI has dramatically improved our ability to treat patients with male factor infertility by improving the chance for fertilization.
A meta-analysis by Tornay and FNS reported that in male factor cases, ICSI nearly doubles the chance of fertilization, and the number needed to treat to prevent a case of failed fertilization in male factor is 3.1. I know we're not here to talk about male factor. We're here to talk about non-male factor, but I want you to keep that number needed to treat of three cases in mind. In addition to the non-male factor indications already discussed by Jareen and IJ, another very important use of ICSI is for cases of previous failed fertilization, and I don't think there's many providers who would argue against this indication.
In a patient with failed fertilization, the recurrence rate in the subsequent cycle for IVF for insemination has been reported to be as high as 45 to 70 percent. However, in the FNS fertile battle on this topic, the con side argued that it was a myth that ICSI should be offered to patients with previous failed fertilization. ASRM, on the other hand, is on the pro side here, stating that based on current data, ICSI is beneficial in these cases.
In 2005, Vander Westerlaken performed a prospective study in which couples who previously had failed fertilization with IVF had a subsequent cycle with split IVF ICSI on the sibling oocytes. Among 271 total oocytes retrieved, 109 were allocated to IVF again, in which 11 percent of them were fertilized. The other 162 were allocated to ICSI, and 48 percent of these fertilized.
Importantly, what's mentioned less than the ICSI indication for failed fertilization history is the ASRM statement that ICSI can also increase fertilization rates in cases when fertilization with IVF is lower than expected, which is another important cohort to consider. In the same study by Vander Westerlaken, the authors separately enrolled patients with a history of low fertilization rate, less than 25 percent with IVF, to the same split IVF ICSI on sibling oocytes in their subsequent cycle. Among this cohort with low but not failed fertilization, there were a total of 169 oocytes retrieved.
72 were allocated to IVF, of which 22 percent fertilized, and 97 were allocated to ICSI, of which 60 percent fertilized. Therefore, I think it's important to keep in mind that based on the current data, ASRM not only advocates that ICSI can increase fertilization rates after complete failed fertilization, but also after cases of lower than expected fertilization. But should ICSI be used for everyone with non-male factor infertility as a preemptive measure to avoid unexpected cases of failed fertilization or low fertilization? We know that ICSI for all will help to decrease these failed fertilization cases, but at the end of the day, it comes down to the number needed to treat.
The RCT that answered this question was published 20 years ago by Bhattacharya, in which couples with non-male factor infertility were randomized to IVF or ICSI. The pregnancy rate was comparable between groups, and based on a failed fertilization rate of 5 percent in the IVF group and 2 percent in the ICSI group, a number needed to treat was calculated to be 33 cases of ICSI to prevent one failed fertilization case. But is 33 cases too high to recommend ICSI for all? If a number needed to treat of three cases is acceptable for male factor, what number becomes acceptable for non-male factor? One criticism of this study is that the fertilization rate for ICSI cases was only 65 percent, which is lower than what would be expected in this otherwise good prognosis population.
I think another critical limitation of the study is that patients with a history of low fertilization in a previous cycle were excluded. However, that's exactly the population that we're trying to help by utilizing ICSI up front. By removing those who would benefit most from the intervention, the groups were biased.
It's likely that the number needed to treat is actually less than 33. Most other prospective studies designed to evaluate the use of ICSI in non-male cases are of the sibling oocyte design, where the cohort is split between IVF and ICSI. These studies have reported a failed fertilization rate with ICSI between 0 and 3.6 percent and with IVF between 12 and a half to 15 percent, which equates to a number needed to treat somewhere between 5 to 10 patients.
Of course, number needed to treat can't be fairly calculated from a split oocyte cohort because the pool of potential oocytes is split in half. But I do think these studies provide evidence that the number needed to treat is probably somewhere less than 33. At the end of the day, whether that number is 3 or 10 or 30, making a decision about whether the added time and costs of ICSI are worth the potential benefit is a subjective decision.
What is the time cost, financial cost, and emotional cost to a patient that's progressed far enough in their journey to get to a retrieval only to have failed fertilization? When you explain to a non-male factor patient that there's a 5 to 10 percent chance that her oocytes will not fertilize and that the risk can be reduced to 2 percent with ICSI, a shared decision can then be made. Therefore, with the pros and cons presented here, we conclude that while not every patient may decide to utilize ICSI, ICSI should be discussed and offered to all. I have the lovely task of standing between you and the pool bar, so I will try to be very brief.
I've learned in PCRS that you have to side with Rick Paulson in order to have a nice Q&A, so I'll start with that. We have an add-on problem in the U.S., and I think this debate is really important to have. We probably should have had it in 1996 when the rate of ICSI was 36 percent, and we should have debated, do we have enough data to add it on in other indications? And I think my colleagues on both sides have presented really good points of why we should or shouldn't, but we are now well over 70 percent usage, and we're trying to find data to use it less, which is not the right approach.
I think that we need to switch the way we use a lot of these add-ons, and most importantly, we need to not extrapolate the data that we have from male factor infertility into other indications. We need to seek data on their IRBs and study these things before we bring them out and we use them on all our patients. The other thing I want to touch on is we have an access to care crisis in this country.
In 2019, we did about 300,000 cycles or so, and in America, we have one case of IVF for every 1,500 people, much less than in other places like Israel, where it's one in 250, or Japan, where it's one in 400. And if you follow, for example, David Sable, and you look at the size of the IVF market and what should be, it's well over a million cycles. So we need to figure out how, with our capacity, we expand it to take care of people, and doing more things for people who may not need them is probably not the right approach.
I know a lot of you are here, and everybody needs a fellow, and everybody needs a nurse, and everybody needs an embryologist, and that's because we don't have enough capacity in the lab. And I think we would all agree that ICSI increases cost and increases work and increases time in the lab. When you think about it from the embryology side, their time is very valuable.
I asked a couple of embryologists in my lab and throughout, and they say, depending on the number of oocytes, they spend anywhere from 30 to 60 more minutes per cycle when it's an ICSI cycle, and that can be much higher when you have a high responder. If you make the case that half or two-thirds of cases that we do ICSI for do not have an indication for that, then you're spending somewhere between two and six hours per day, depending on the number of cycles that you do in your program, doing ICSI. And when you extrapolate that over the year, that's about half or two-thirds of an employee's full time doing ICSI for cases that you might not need it.
So you can see how that increased strain on your lab can both increase cost but decrease your ability to serve other patients that might need IVF. And then lastly, I think we have to talk about the cost to the patient. I've heard estimates of costs anywhere from $1,000 per cycle to $2,500 per cycle, and this is a cost that is passed through to the patient.
I was having lunch today and talking to someone, and they told me, we don't charge for ICSI. We do it for free. And I said, no, you don't discount it for the ones that you do conventional insemination.
You charge everyone for ICSI. So it's important to understand what it looks like to the patient. Yes, IVF is more expensive, and this may be a dime in the bucket that you throw in at the end, but to Phil's point, it's all about the number needed to treat.
So if that number is 33, it is $46,000 that our patients are spending to prevent one case. And I do not discount that total fertilization failure is an awful thing. It's the call that none of us ever want to make, but we have to think of it at a population level, and we have to apply it to our own clinics.
In our clinic, the total fertilization failure risk is under 5%, so that number needed to treat is higher, and the financial burden that we spread out across a bunch of patients is even more expensive. So when cost is a big driver of our patient's decisions, we need to really be thoughtful about how we spend their dollars and channel it into therapies that have more evidence. And I think we talked a lot about different indications.
I think that if a patient has suboptimal fertilization or failed fertilization or an indication, certainly most of us will go ahead and pursue ICSI. And I think ultimately, I could not agree more with Phil. At the end of the day, we are in a field where we need to practice patient-centered medicine and to share decision-making, but we all know that the way that we counsel patients really drives the decisions that they make.
So I think it's important to follow the data and explain the data that we have, and I think for a lot of the indications that we've talked about today, I don't think that the data bears use of ICSI for non-male factor infertility, at least in unexplained infertility, in the first indication. Thank you. Well, I think I can speak for everybody if I say that was excellent.
Thank you for all these wonderful statements, for all this great information. I think you covered literally almost everything there is to say about this, and a lot of good arguments on both sides, I have to say. A couple of questions and comments.
So the number needed to treat, I think it's important to point out that this is not the number needed to obtain one extra live birth. It's the number needed to prevent one case of fertilization failure, but obviously, who knows if the patients that have fertilization would then also go on to have a live birth, and the people who argue against unnecessary use of ICSI would probably say maybe ICSI wouldn't have helped them obtain a live birth either. So I guess that goes factors into it.
Another point that I would like to make is I think you all did a fabulous job, and I think the side that had to argue that we're doing the right amount of ICSI was up against obviously the fact that there's an ASRM bulletin or ASRM guidelines that sort of have pretty clear statements about what you should or should not do. One question, I guess, before we go to the question and audience and the last audience response question, maybe one member of each team can comment. What do you think about the option of doing split ICSI for, for example, unexplained infertility? You have a patient who has 12 eggs, so you ICSI six of them and do conventional fertilization on the six others.
Is that anything that practices should consider? Yes, no, maybe? Well, you were at OU, so maybe you remember we used to do that routinely for unexplained infertility in particular, but actually, since COVID happened, it was more of a strain on the lab, and they kindly requested that we choose one, and so we have moved towards doing that, but otherwise, it seems like a reasonable option. Arguments against it, maybe? I think it's somewhat, somewhat paradoxical. I think, you know, you either believe in it or not, so I mean, I understand the concept behind it, but I, I, I would, I'd be more for kind of an all or nothing approach.
Yeah, making a, you know, taking a decision, and also, like, for example, the cost issue, I mean, that wouldn't change, and certain of the other arguments that you brought. Who should make the decision whether to do ICSI or not, the lab or the physicians? I think the patient with guidance for the, from the physicians should make that decision. I think it's important to share what you know, and, and everybody comes from a different place, and I think our patients might have had experiences where this is their last cycle, this is all they can afford, and, and they're okay taking on that extra cost burden, and that extra risk, and some patients are not, so I think ultimately, it should be the physician and the patient, not the lab, except in situations where, you know, on the day of retrieval, you have a sperm sample that is suboptimal, and then the lab should be able to let you know to, that they recommend converting to ICSI, and the physician will probably agree.
So you think the patient should make the decision. What if the patient says, well, I'm paying you to make the decisions? Then you can guide them in the direction that you want. Okay.
Okay, yes. No, I do think it should be a shared decision. I have to say, some of the most upset and irate patients that I've ever met in my career were the ones who requested, for example, to have conventional fertilization, and somehow, you know, it wasn't communicated to them that, you know, that wasn't going to be done for whatever reason, and then something else was going to be done.
I, you know, remember some patients who then, you know, had trouble accepting the idea of using the embryos because they felt strongly against ICSI for, for example, you know, epidemiologic considerations, and because it's invasive, and so I do think it's important to have a dialogue with the patient, and for example, I've worked in practices that did very little ICSI, and practices that did all ICSI, and if you have a practice that does all ICSI, I think it's probably important to say that to the patient on the first visit, so that if they don't want to, you know, do ICSI, then they might as well look for another practice at that moment. All right. I think we can go to the next audience response question.
There was already a pretty clear result when we did this question before the, before the debate, so we'll see if it might have changed. So, as a result of this debate in your practice, will you use more, same amount, or less ICSI? So, show of hands, who is going to do more ICSI as a result of this debate? Yeah. Who's going to do the same amount of ICSI? Okay.
Okay. Excellent. And who's going to do less ICSI? At least one person.
So, we have, you know, changed people, and, you know, I always say, you know, I always quote my dad at the end of a debate, and I say, we are still confused, but on a higher level. But anyway, now we have time for questions from the audience for our wonderful panel of experts. Oh, yeah, the mics are here.
Hi. I'm Michael Feinberg from LIG. You were all terrific, really.
I just want to, I'm sad to admit that I'm old enough that I was at the meeting in Venice, Italy, with Porkoo presented the data, and she was adamant, adamant that it was the ICSI that made the difference, because in those days, egg freezing was definitely, you know, it wasn't, it was, and so, she had very elegant data to show that her, and this was slow freezing, too, it wasn't cry, digitification. So, I mean, it doesn't mean it's true because she was adamant. I just think it's historically interesting to hear you wonderful, intelligent people showing that it may not be true, and she was like, I mean, this was it.
We started freezing eggs and using frozen eggs back then because of ICSI. So, it's just kind of interesting. Also, I would argue that failed fertilization is definitely a reasonable indication to do ICSI the next time, because when you're out there finally having your butt on the ground, on the, on the table, if you have a failed fertilization, you sell, you don't do ICSI next game, you're, you get your head chopped off.
You can be as scientific as you want, but it's, it's not so scientific out there. So, thank you for your terrific job, and you'll see it's, it's a rocky road out there. My, my, my master and mentor.
Great job. Quick question. As a male fertility specialist, like, I worry about the cancer-surviving, chemotherapy-laden, azospermic man who you're going to his testicle, and you grab that sperm, and it's, you know, it was never meant maybe to come out, and you have to use ICSI for it, but I think about the implications of that for the health of the child, and I had a, as a, also a statement and a question.
I had a, for Resolve in Northern California, I had a panel of ICSI, an embryologist doing ICSI, and it was for the public, right? So, it was the Resolve patients coming in. It was a couple, 20 years ago, and there's a panel of embryologists, and there's a bunch of patients asking questions, and I, the title of it was, Meet the ICSI Embryologists, and what fascinated me and moderated it was, they didn't ask, all they wanted to know was, who are you, and are you religious or not? Do you have kids or not? You know, they wanted to know what kind of person you were, but all these questions for an hour were just directed like, you know, what do you do when you're, what kind of person is selecting my sperm? And that taught me a lot about, it does matter, so my question is, I don't know if you do it or, but who talks about that part of it, the unknown? Who talks about the unknown of natural selection, breaking down barriers, the epigenetic risk? We know now that, you know, I don't, it's not, it's not out yet, but sperm epigenetics has a huge impact on autism. So, what, what kind of conversations for the risk-benefit analysis are we having with patients about the unknown, the unknown risks of ICSI? By the way, I love Palermo.
I mean, he's like a great friend, okay. I think that's a great question, and I think there's two kinds of unknowns. There's like known unknowns and unknown unknowns, and for the second part, we don't know what we don't know.
I think, I think that's part of being humble, and I think speaking to patients face to face as humans and saying like, you know, I went to school for 16 years, 15 and three quarters, 16 in July, and to be here across from you, I have the pleasure of serving you and helping you build a family, but I don't know everything, and I continue to learn every day, and this is what I know, and this is what I don't know, and I think especially in the cases of total fertilization failure or the cases of, you know, recurrent implantation failure or recurrent pregnancy loss, you say, I'm going to send a bunch of tests. They're probably going to come back, and I'm not going to have an answer, and there's a lot that we don't know, so I think being honest, if you take that approach and speak to patients in that way, they will understand, and some will go get a second opinion. They'll probably hear the same, and they'll add some other tests, but ultimately, when you come from that side, and you're honest, and you say, this is what I know, this is what I don't know, this is what I would do for my family, my sister, my cousin, my best friend, and that's how I aim to treat my patients, that's the best you can hope for.
Yeah, I would also add that keeping in mind that it's a shared decision making sort of process between you and the patient, no matter what's known or what's unknown, that's a global or more population level that doesn't address the person who's in front of you, so I actually had my first case of fertilization failure, and it's tough, because I did not offer that individual ICSI. She had no indication for it, and then none of her oocytes were fertilized, and per the ASRM committee opinion, she had a low oocyte yield. It actually wouldn't recommend that she perform ICSI for that indication, and so having the conversation with her about the fact that we could use ICSI, her question to me was, well, why couldn't we have done this in the first place? I would have paid for it, and that's heartbreaking to know that I didn't even mention it to her.
Now, certainly if she had a child affected by autism, it could have been a really different conversation, so to your point, there's a lot we still don't know, but we have to sort of present all the information, all the data to the patient, and hopefully help them make the best decision for them. Some people are willing to take certain risks that others aren't. You also, just to that point, you also can't judge your actions and your decisions or the quality of your decisions by the outcome when you make the decisions with the best available information at the time that you make it, and also to that question, it's interesting, with the use of ICSI and taking these like handful of sperm and making embryos, we're definitely creating business for ourselves for like centuries to come because apparently this is also going to like keep increasing the rate of infertility in the population.
I've seen lectures about that phenomenon epidemiologically that through the use of assisted reproduction, and especially ICSI, there's going to be more and more infertility in the population going forward. All right, next question. Adams in San Jose, great debate.
Congratulations, everyone. Only a couple of comments and then ask a question. ICSI around the world used in some countries only about 15, 20 percent.
China now it's about 26 percent. Other countries it's 95 percent plus. Just to state that your comments today about difference of opinion about this are global concerns about this, and different countries, different regions, and even doctors in the same country come up with different answers, which means that after 30 years of having this technology, we're still really trying to figure out what to do with it.
The global number though is 65 to 70 percent of all the cycles in the world are done with ICSI today, and interestingly, that number has not changed much in the past 15 years. It stayed about 66 to 69 percent ICSI that's being done, so there's still a huge number of questions about it. The conversation about talking to your patient and do it or not, my question at the end is going to be, I'm really surprised that there was zero comment about ICSI split until the moderator brought it up.
We actually did a fair amount of ICSI split, and I really want to ask the panel, why wouldn't you put ICSI split in one of your three options for the patient for fertilization? Your options are ICSI all, ICSI none, or ICSI split, and since there's so much uncertainty, which we've heard everyone express, I'm not sure why that third option wouldn't be given to the patient, especially, you know, we always required at least, you know, four eggs in a group, so eight total, so you could split them up. You get obviously not a highly statistically significant result, but if you got three out of four in one and one out of four in the other, you figured, you know, it was enough to give you a little clinical indication. Good data, no, but not much worse than all the data that were presented today on many aspects of this, and it's at least data on that one patient that you then can use when you go to your second cycle, if you have to have it, and you've sort of hedged your bet, and you've hedged your bet about the uncertainty that you've discussed, and you have this conversation, and do you recommend it or not? Do you guide the patient or not? One of the techniques I use very commonly was, I always told the patient I thought they needed to have the benefit of my recommendation.
They were paying for my recommendation. They weren't paying for me to tell them and make their own choice, but I could tell them whether I recommended something 95 to 5, I really thought they ought to do it, or I recommended at 51.49, which I did, and said, it's sort of a coin toss. I think it's 51.49. How do you feel? But I think we owe the patient that, especially in something like ICSI, where there's still so much uncertainty, I think we owe them benefit of our estimate.
Is it 70-30? Is it 80-20 that I do it, I wouldn't do it? You do ICSI, not ICSI, and my question is, why not put ICSI split in as your middle option for your patient? So it was brief in my unexplained infertility kind of review, but at the end, when I was going through things that we would talk about the patient for next time, it talked about doing a full ICSI or, at the very least, split. I do think that on the initial encounter, it's something that's reasonable. I know we talked about the time that the lab uses for ICSI, but if you're only for the non-male factors that are separate from PDTM or cryopreservation, those particular cases, I think it would be reasonable.
It would cut down on the lab time, and I know, understand me, still don't have data to support it, but if we're already using it, so considering cutting back full ICSI for the cases that we don't really have great data for, doing split, and then studying things from there. Also, that would give us the ability to study, then, live births, so we were able to then go back and check, okay, we did split ICSI, this embryo took, and as an individual builds their family, we would be able to see the transfers of many embryos, hopefully, and hopefully pregnancies that bear out to live births versus miscarriages, but I think it's, and I'm very early on my career, but looking at the field and looking at the cases that I see in my clinic, I think it's reasonable, and I think it's something that we can gain more data from. I just wanted to add, you know, if, I think if you're worried enough about the adverse effects of ICSI that you split the pool, but you're worried about the risk of failed fertilization as well, I'm just, you know, I'm curious, you know, if anybody who does this regularly could answer, what do you do when you have, let's say, an embryo from each pool, the embryo in the ICSI pool is better quality, is that the one that you transfer, or let's say the patients utilize their inseminated embryos, and they want to transfer another, do they go to the ICSI pool, or do you counsel them to cycle again, because you know they can fertilize, and you're worried about the risks of ICSI, so.
Well, if it's a duoderos patient, then the patient decides, right? I mean, well, one other aspect of this is that I feel like in practices where we did split ICSI, there was a bit of a bias which oocytes would get ICSI, and which ones would get the conventional fertilization, they'd be like sort of take a wild guess whether it was more likely to be mature or not. Well, that's the problem with sibling oocyte studies, you know, which ones will get inseminated and which ones won't, the ones that are more likely to be mature were going to be ICSI-ed. Not a randomization, and then therefore the results, of course, are, you know, a little difficult to interpret.
Yeah, I would argue that that doing like a lot of split cases when, maybe as like the blanket policy for people who don't have a strong indication for ICSI may muddy the waters further with that patient, and then does essentially nothing to increase access, and I think Eduardo's point about we really truly are in a crisis with our access to care, and adding on like a third option that does nothing to, or very little to change access, and then probably confuses our data even further, may make things more challenging. Well, it's hard because how do you explain that to the patient? So if I'm counseling, I would do ICSI, or I'm counseling, I would do IVS, IVF, when they ask, or when I recommend or offer doing split, and they ask, well, what's the benefit? Why not just do one versus another? Then how do you counsel on that? And then what if you get two out of three on one side and one out of three on the other? Like what if the numbers are so small that it's hard to draw any meaningful conclusions to guide you in one direction or another for a large majority of cases? So it's probably a great thing to do under IRB, again probably in 1996, but I don't know, we don't do much of it, and I think it might also have some lab complexity that your embryologists again have to deal with. So I'm going to encourage you all to try it.
You need to select your patients, and you do know how to talk to your patients because you've had this debate today, and you select your patients, and the fact that I really think that you're much better off if the patient has a spectrum of choice, and it's a very reasonable choice, and you're quite right if you get two of one. I mean, we can come up with all the reasons that, you know, well, if you get two of one and one of the other, what's the difference? But if you get four out of four with ICSI and zero to four at the other, and I can do the math on the statistics, you know, and you can do it as well, then you can say what you want, but next time you're going to do ICSI on it, right? And you've also avoided having the problem. So I guess what I'd say is, you know, try it in selected patients.
You might be surprised that it can work out well for you, and of course, it still does cut down the resources because you're doing half as many as you did before, and you choose the one in the conventional insemination unless there's a huge difference in the quality, and if there's a difference, then you use your clinical judgment, which is your 16 years of training, and you talk to your embryologist about what you think, and these are decisions we're all making every five minutes all day long, and I just think you'd find that it's a very reasonable alternative for selected patients. We probably did it in five percent of the patients or ten. You know, it wasn't like everybody got it, but it really, it will help give everybody a little peace of mind, and you won't have to have that really tough decision about, you still get FERT failure, but it's, in our lab, it was about two percent, two and a half percent.
So it does happen, but it's a whole lot less. Can you share what characteristics of patients you thought were the right fits for that approach? Well, it was often, you know, poor male, poor male factor, or, you know, really unexplained infertility. We certainly did it for that once in a while, and obviously, we did it for all the ones.
We basically follow the SRM guidelines for most of things, but as we all know, the SRM guidelines don't address every particular clinical situation. Every patient's different with different, you know, different needs and different concerns about, you know, fertilization happening or not, and the rest of it. So these are, these are clinical choices.
This is why you're having the debate, obviously, and I think you'll, I just think it's an option, given how much uncertainty there is about this, and after, what, 30 years of ICSI now, we're still having this conversation. We're not exactly sure where it should be used. So I just think it's something that should be in your armamentarium to deal with your patients.
It's definitely a great thought, and the one thing it makes me think of is, I sometimes have patients ask me, well, I want to do PGTA, but I still want a fresh transfer, so can I transfer one untested embryo, like the best blastocyst, and then biopsy and freeze the rest? And on principle, that's fine, you know, like if you want to do that, but then basically you haven't really decided whether you would like to have your embryo screened with PGTA or not, because you're happy to transfer one untested embryo, and so actually, I've established a policy where I said, no, you know, this is not like, you know, like, I can't, like, follow every, like, whim, wish. Like, sometimes you have to make a clinical decision, but that's a little bit different, too, because PGTA is something where I feel like you have a long discussion, and then the patient either makes the decision for it or against it, whereas ICSI, maybe it's a bit, the data are a bit more. But I guess I would, my response to that would be, I think it's different, but it's not totally different.
I mean, I think it's interesting. I would put this on first principles. If we're sitting here having debates with really bright people with a lot of training who have totally divergent views of PGT everything or don't, right, or very, very selected, in principle, what's the matter with a compromise? I would look on it that way.
So I'm not sure I'd say no in the situation you've brought up. It's not something that, obviously, would come up very often. I just think in the clinical situation, before we say no to things, we should have some pretty good reasons.
And when we're having debates like this on these issues, it's pretty clear we don't have really solid data, and that's where I think a patient-centric approach, and it's not that we bring all of these things up and say, here's 69 options for what we're going to do, and you don't do that. But when it comes up from the patient, I think it's very reasonable to be flexible if there's still, if there's not unsound principles, you know, treatment principles. And it's almost always possible to be on the same page or to get on the same page.
Yeah, and then they're happier, regardless of what happens. Okay. Real quick, in support of Dr. Adamson's comments, I've found it amusing that much of the time the request for split comes from the patient, not from me.
I tend to be a little more pious, like you, do it this way, that way, and they ask for the split. Right. And I say, okay, that's fine, we're doing a split.
So, I mean, it speaks to all the things that you're all talking about, the patient's input into the decision and so forth, if they're well informed. Absolutely. Great.
I think to conclude, Dr. Verlier had a question to the audience, and then this session will conclude. So. So, I was just curious if anyone who is in a program that employs an ICSI all, like Dr. Kwas, was if they could just offer a little bit about what was their breaking point, and when did you decide to go to ICSI all and stop attempting to use conventional and sanitation? I'm just, I'm curious if anybody could share their insight into that.
I'm not sure we'll get a volunteer for that. I'm not an ICSI all person, so I'm answering, I believe, for the mental state of colleagues I know that do it. They're busy, they're a little older, and they just don't want the aggravation.
I think that's what it is. And I can't remember an ICSI case with failed fertilization in our clinic at all. I was amused by the 2% failed rate in the paper you discussed.
I remember the paper. So, I think that's what it is. You just get, like, enough aggravation already, and I'm just doing ICSI on everybody.
I kind of adopted that approach with overseas patients doing egg donors, because I had someone come from Spain and had a failed fertilization. It's uber painful. So, I think that's the attitude, is just an avoidance of aggravation.
Yeah, excellent. And also maybe logistic factors. Some people like to have the flow, to have standards that are unanimous, so less mistakes when things are standardized.
So, arguments like that, practical arguments. So, I think it's time for, like, huge applause for this wonderful panel. The future of our field.
Okay, thank you very much, and have a lovely afternoon. Oh, yeah, we have to take a picture together.
