Fertility and Sterility On Air - TOC: August 2025

Take a sneak peek at this month's Fertility & Sterility! Articles discussed this month are:  

08:57 Trends in Use of Preimplantation Genetic Testing for Aneuploidy Before Dobbs, After Dobbs Leak, and After Dobbs Final Ruling

20:12 The impact of PGT-A on time to live birth in IVF.

32:02 A Nationwide Analysis of the Trends in Permanent Contraception Utilization Before and After the Dobbs Ruling  

37:28 Use of assisted reproductive technologies for male and female infertility and perinatal outcomes 

50:50 Assisted hatching decreases pregnancy outcomes in vitrified donor oocytes

56:42 Use of medically assisted reproduction and the risk of multiple live birth across sexual orientation groups—results from a national longitudinal cohort  

View the August 2025 issue, Vol 124: Issue 2 - https://www.fertstert.org/issue/S0015-0282(25)X0008-X

View Fertility and Sterility at https://www.fertstert.org/

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 discussions with authors and other special features. F&S On Air is brought to you by the 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, Dr. Pietro Bortoletto, Interactive Associate-in-Chief, and Dr. Kate Devine.

Hello everybody and welcome to Fertility and Sterility On Air. I get the privilege of hosting today as our strong and fearless co-presenters are missing this session or are out of town this session. So, we're going to describe the table of contents for Fertility and Sterility in August 2025, if you're keeping track at home, volume 124, number 2. It's a pleasure to be here with Eve Feinberg and Kate Devine.

Hello guys, how are you? Good morning. I'm great. I'm great.

Excellent. Well, I'm going to jump right in because it's a privilege to host this session, mostly because it's one of the celebratory sessions or celebratory volumes for F&S. Did you all know that 75 years is the birth date we're celebrating for Fertility and Sterility right now? Yes, Fertility and Sterility has been around for 75 years.

History is sometimes lost on us and we don't realize that how much we discuss as fact and banter about was really unknown not that long ago. 75 years ago represents not only the birth of the journal, but I would argue probably the birth of our profession as at that time it really was just a small group of scientists forming a specialty. They were understanding and developing the science and the pathophysiology and the physiology of human reproduction, and they realized, as they should, that the best way to promote a new subspecialty in medicine is to really do it academically and with a journal.

And hence, Fertility and Sterility was born and 75 years later here we are. It's been really quite an expansion of the journal and it's really telling the story of our field. I hope that you all read this editorial that leads the journal written co-authored by myself and Allison Eubanks and it is simply entitled a journal that built the subspecialty.

So for those of you who can't do the math like me, Fertility and Sterility first came out in 1950 and it really was a reflection on the field, but since then we have really published much of what we consider fact and guidelines and protocols and definitions that we use today. It was the first journal where embryo morphology was used to predict implantation, which we now call secondhand with the Gardner criteria, and it also has had great association with ASRM. Perhaps ASRM is similarly aged, but it also allows ASRM to publish and disseminate what we all consider to be great guidelines, including the definition of infertility, the transition from egg cryopreservation from experimental to clinical care, guidelines on transfers, the birth of SART as an organization, and then ultimately the use of their data from multiple publications in our journal.

And the journal has really moved from simply a journal on reproductive medicine to now we include andrology, embryology, assisted reproduction. So it's still the cornerstone of fibroids and endometriosis, family planning and medicine, but now we've expanded that journal to really what drives our science and our clinical practice today. I'm very proud of the 50 years, I'm sorry, the 75 years of Fertility and Sterility, and I look forward to many more years of, again, where we as scientists and clinicians can offer new ideas, have them assessed by others, our peers, and really disseminate rigorous, wonderful science that allows us to be evidence-based in practice in the field that we are today.

Eve and Kate, do you have any reflections on what you thought really Fertility and Sterility meant to you or some of the history as you went through it or reflected upon it? Yeah, I mean, first of all, kudos to you as our fearless editor-in-chief. I think it's a monumental job that you've taken on, and I think one that's really important, and I just want to say I'm honored and thrilled to be one of the editorial editors. It's truly, I think, one of the joys and privileges of my career.

I've been involved with Fertility and Sterility since I was a fellow, and Alan DeCherney was the editor-in-chief, and so I've seen the evolution of the journal from the very first paper that I published with Eddie Confino back in 2001 when we submitted our manuscript in paper to the transition to online submissions and have really watched this journal grow and evolve from really an editor-in-chief who made many of the decisions solo to being part of an incredibly robust team with multiple layers of editorial editors, associate editors who we all know are the powerhouse of this journal, to the editorial editors who drive a lot of the editorial content. And so I've really, it's been a joy to watch the evolution of the journal and to be a part of it. So I think it's been incredible, and reading it every month and feeling very on top of the science and ahead of the curve, I think has really helped my practice tremendously.

Yeah, I couldn't agree more, even. I feel similarly privileged to be able to participate in what I think this journal provides, which is a vital function for our field to be able to assess new technologies as they emerge, new therapies, new insights, and adjustments to existing ones. And so I think of it in large part the way I think about the field of journalism and its role in terms of history and government and public policy and what a vital service that provides to the public.

And so I think that a peer-reviewed journal of high quality such as this is so important to any field. And I just feel so fortunate that we have this one to help us assess innovation as it happens and to use that information to advance the field further and better serve our patients. So thanks to all of our readership and thanks to all of our authors who contribute on a regular basis.

And I look forward to 75 more years of Fertility and Sterility. Great. I can't help but add one more comment on this.

We all commented on the cornerstone of Fertility and Sterility, which is really rigorous peer review and outstanding science. At a time in this world where that trusted science is really important, having a journal that's increased in impact factor over the years and really does publish the best science is critical. But Fertility and Sterility has also advanced in many, many other opportunities I want you all to take care of and consider.

We're the first journal that published video articles and they're in the journal as well. We have a separate section called Consider This for opinion pieces that are online that maybe not are full scientific papers but can really express your opinion and get huge likes and impact on social media. We also have a lot of editorial comments, I mean content including reviews and reviews and fertile battles.

So the cornerstone is the science, but there's lots of ways to get involved in Fertility and Sterility. And lest I forget, there's also a family of journals now. It's not just Fertility and Sterility and congratulations to F&S Science and F&S Reports, both of which have impact factors and are robust and leading the way and close behind it will be F&S Reviews that also will be a great opportunity.

So thank you for all your kind words, but it's up to you guys for the next 75 years and let's just make it even stronger. Staying true to what I said, before we dive into the science, we want to consider a little bit of some of the important timely editorial content in the journal. And we're going to start with Eve as she talks a little bit about some very important issues.

Yeah, this first paper is called Trends in the Use of Preimplantation Genetic Testing for Antipoiety Before Dobbs, After the Dobbs Leak, and After the Dobbs Final Ruling. And the first author was Kiley Hunkler with senior author Trimble Spitzer and Kate, our very own Kate Devine, is a collaborator. The objective of this study was to determine if PGT-A increased after the Dobbs decision leak on May 2, 2022, and after the Dobbs final ruling June 24 compared with before the decision.

The main outcome measure was the percentage of cycles using PGT-A defined as the number of IVF cycles using PGT-A divided by the total number of cycles during the study period. This was a retrospective cohort study. They used data from a large network practice, U.S. fertility across six states in the U.S. Pennsylvania, Virginia, Florida, Maryland, New York, and Georgia.

The IVF cycles were grouped into three periods. So pre-Dobbs was June 1, 2021 to May 2, 2022. Post-Dobbs leak was May 3, 2022 to June 4, 2022.

And then post-Dobbs final ruling was June 25, 2022 to June 30, 2023. And you guys chose to use the Dobbs leak as a separate time point given that many patients likely discovered the outcome in advance of the final decision. So patients were stratified as to those less than 35 and greater than 35.

Race and ethnicity were evaluated as was socioeconomic status based on zip code median income. And then state abortion legislation was classified as restrictive or protective using the Guttmacher Institute criteria. And I also want to call out the excellent inkling written by Heather Hipp and Allie Herwick from Emory in Georgia, a state with an extremely restrictive ban on their thoughts about the classification used in this manuscript.

A little bit more on this later. So looking at the total number of IVF cycles, there were over 22,000 IVF cycles that were included. And of these, 6,600 were in restrictive states and close to 16,000 in protective states.

The key findings were that there were no significant changes in PGT-A used across time periods. Pre-Dobbs, about 57% of cycles used PGT-A. Post-leak, close to 57% at 56.8. And post-ruling, 56.2. And so when looking at adjusted risk ratios for post-leak versus pre-Dobbs and post-ruling versus pre-Dobbs, there were no significant differences between groups.

Looking at specifically at state legislation, interestingly, PGT-A use was consistently higher in restrictive states versus protective states, but that didn't change. And there was a slight decrease in PGT-A use in protective states post-Dobbs ruling, but again, it was very small. And there were no changes in restrictive states.

I want to call out what I alluded to earlier, that these findings may be influenced by how the authors chose to categorize abortion restrictive versus protective as a binary outcome. The Guttmacher Institute actually categorizes U.S. on the basis of restrictiveness and places states into seven tiers on the basis of criteria, things like gestational limits, procedural requirements, and presence or absence of constitutional protections. Let's take Kurt's state, Pennsylvania, considered to be restrictive because they ban abortion at 24 weeks and the state limits Medicaid coverage for abortion.

Georgia, where Emory is at, is considered very restrictive because the abortion ban is at six weeks, there's an imposed 24-hour waiting period, and Medicaid also limits funding. So in this particular study, these two states were placed in the same category of restrictive. And the points that were brought up in the reflections are excellent, and I wholeheartedly agree that a 24-week ban would likely not influence someone's decision to do PGT because of the ability to do NIPS and have a confirmatory CVS or amnio or even wait for your anatomy scan before making a decision about termination.

And so I think that by lumping restrictive altogether, we may have blunted the effect of PGT-A decisions. And so I think this point is truly key in understanding the limitations of the study and perhaps why no differences were truly found. And I wonder how much of this is because it was a network study and not a SART database study, that there may not have been enough numbers, even though we had 22,000 cycles.

If you were to group that into seven categories, it would really diminish the power of this study. And so I think that more data is needed, and I am going to challenge the authors to consider perhaps redoing this study using a larger database and maybe less of a binary categorization. But I think overall, it's interesting.

We're going to touch upon another study looking at contraception post-Dobbs, but I think that the intersection of policy and politics with reproductive medicine is fascinating and timely. So I think I want to congratulate these authors on a timely piece, but challenge them to perhaps think about it a little bit differently. Yeah, thanks, Eve.

I want to congratulate Dr. Hunkler for this well-conducted study that said, yes, being limited as a network to not all 50 states and needing to analyze these data relatively close to the event that occurred, being the Dobbs leak, was somewhat limiting in terms of the granularity of the exposure, with the exposure being the restrictiveness, not just the time point of Dobbs, but the restrictiveness of what Dobbs would entail, or the state of abortion access in the states that pre-existed. As a medical director of this network, I've always been very impressed by the differences in terms of PGT utilization that did seem to be quite closely linked to abortion access. And we certainly see in our clinics in Texas and Florida, a very, very high rate of PGT utilization, and that was true both pre- and post-Dobbs.

So 100% challenge accepted. Once SART data catches up, which will be in a couple of years, we will absolutely analyze those data according to all seven Guttmacher categories, and also the challenge posed by Heather Hipp's great editorial. So I think this is a start, and I think it is really telling that people are afraid that they won't be able to make reproductive decisions, even in the setting of pregnancies that would have very significant chromosomal disorders in their states, and that they may take it upon themselves to test embryos more so in states where they're concerned about their reproductive decision-making.

So again, more to come, and thanks for the great summary. So I'm going to challenge you guys with a thought that just popped into my head, listening to this excellent paper. This is an F&S because of the timeliness and how much that politics and lifestyle can really affect what we do in medicine.

That's why it's here. But I want to push a little bit on the hypothesis. There's a big debate about PGT-A on whether it should solely be used to enhance the live birth of your first embryo transfer versus whether it actually diagnoses the embryo or not.

So are people using PGT-A improperly? Because there's a school of people out there that says that PGT-A is not a diagnostic test, and it is not diagnosing trisomy. So therefore, why are we using it to lower the risk of a trisomy in a birth later? Is that just misinformation or is that wrong? I think it's a great point and certainly calls for heightened counseling when patients are thinking about using it in this way. That said, when we look at the PGT non-selection studies, there's essentially 100% positive predictive value for whole chromosome aneuploidies, right? So while it's certainly not 100% accurate, nor is any test and shouldn't be used as a diagnostic test overall, I would be hard-pressed to counsel patients who say that they would never want to, for example, have to care for a child with a significant illness like a trisomy 13, 18, or 21, that they shouldn't do PGT-A if they were in a state where they couldn't terminate.

Eve, you were about to say something. No, I mean that was exactly the point that I was going to make is while I think that PGT-A is certainly not perfect, I do think that it has good clinical utility for ruling out whole chromosome trisomies. Yeah, it's interesting that we clearly adopted this, and it makes sense to me too that, you know, whatever you can do to enhance your reproductive choice and better your risks for minimizing an undesired outcome, I'm all for it, but the debate really is, is this really the right test to do that? I think it lives because it's the only test to do it, but I think we have a lot more to figure out on whether it really is an efficient way of getting people to where they want to go in terms of diagnosing their embryo.

Yeah, and I think, spoiler alert, we have two papers in this journal that really look at the time to conception with PGT, and then another one that digs a little bit further into whether or not mosaic embryos are mitotic or meiotic, and I think that as the technology evolves, we are getting better. We're not there yet. It still has an error rate.

I still don't think PGT-A is the right tool for younger patients, but I do think that it has utility, and I think that especially in the setting of restricted reproductive choice, intellectually, it makes a lot of sense to use that as one layer of protection, but it certainly should not be the only layer of protection. So Eve, that's a really great point. Why don't we segue to some other articles you mentioned in the journal this month to talk a little bit about more PGT-A.

Again, I want to make the point that what we just talked about with the Dobbs is just a very specific indication for PGT-A, not why most people choose it, so let's talk a little bit more about the technology in general and what we're learning this month. Thanks, Kurt. That is a great segue.

So there's actually been quite a theme, I think, in the journal recently, and I think with some more articles to come, looking at appropriate cohort in whom to use PGT and what might it be able to do for our patients versus who might it not be helping. We looked recently at the paper that was out of China that evaluated and found a benefit among patients greater than 35, and now we have another very good paper with first author Yael Elinor and authors from Boston IVF, including senior author Denis Vaughan. So this paper, entitled The Impact of PGT-A on Time to Live Birth, is a retrospective cohort of a propensity score matched group of patients who underwent their first egg retrieval between 2014 and 2022, and they used seven criteria for propensity score matching.

So they looked first at their group of patients who underwent PGT-A, and they analyzed separately, and I believe appropriately, those that were younger than 38 years old versus those that were 38 and older, and then chose a group without PGT-A that was propensity score matched for gravidity, parity, BMI, age at first retrieval, infertility diagnosis, date of first retrieval, and the number of oocytes retrieved at first retrieval, whether ICSI was used, and gonadotropin dosing. And so this matching resulted in 2,158 patients in each arm who were younger than 38 years old, so again the arms being with or without PGT in their first egg retrieval, and 1,343 patients in each arm in the greater than or equal to 38 year old group. The primary outcome they assessed was the probability of attaining a pregnancy that would ultimately lead to live birth occurring within a year of the first egg retrieval, and they did exclude patients who elected to forego embryo transfer for a period of greater than three months.

It wasn't clear to me whether they excluded patients that had any gap of greater than three months between retrieval and transfer or between transfers, but at least between the first egg retrieval and the first transfer, those patients were excluded. So they conducted their analysis using Kaplan-Meier curves compared using the log-rank test, and hazard ratios were calculated for the full 12-month period using the Cox proportional hazard model primarily. And I'm interested in, as Micah would say, fireside stats with Kurt Barnhart coming up next year as we discuss this, but essentially the proportional hazards assumption was not maintained.

It was violated over the full 12-month period, and therefore they conducted a piecewise hazard model separately analyzing by quarter of the year following the first egg retrieval. And so again, just to geek out a little bit here, the proportional hazards assumption dates that the hazard ratio between any two individuals remains constant over time. And so that means that if one group has a higher hazard rate than another, the difference in hazard rates is consistent throughout the study period.

And so we saw here with PGT, and it follows, I think, intuitively that this wasn't maintained for this particular group in terms of the exposure and outcome. And we can see how that would be the case, right? Because in the first three months following an egg retrieval, the group of patients who did not undergo PGT-A had the opportunity for a fresh embryo transfer and have an opportunity to achieve a pregnancy that could lead to a live birth sooner. And really, that's right to the crux of the question here in terms of does PGT-A increase, or I should say, decrease the time to live birth? And if so, in whom does it do so? And so to return back to the paper and their results, they found no difference in this primary outcome of the attainment of pregnancy resulting in live birth within one year following retrieval in the younger cohort.

So again, fairly intuitive and as expected. But in the older group, they found a hazard ratio of 1.46 in favor of PGT-A with a 95% confidence interval of 1.3 to 1.64. So I think that this is a paper that really nicely illustrates for whom PGT-A might benefit. On the other hand, as with any retrospective study, it has significant limitations.

The authors are unable or did not assess whether there was crossover between the groups in terms of moving from PGT-A to no PGT-A or vice versa over the study period. And of course, there may be unidentified confounding variables in terms of the patients for whom the patient and the provider elect to do PGT-A at the beginning. Certainly, and very nicely, the authors did give a fairly comprehensive description of the baseline characteristics in the patient populations prior to propensity score matching.

And certainly, the group of patients who underwent PGT-A had significant advantages in terms of their ovarian reserve, et cetera. That said, the propensity score matching should and does in terms of looking at the differences between the groups in the seven variables that were matched correct for that. And so I think that it points to something that I believe to be true, which is that probably in older patients due to miscarriage, and we see that in their reporting of their secondary outcomes, we see a shorter time to pregnancy among patients who have a higher rate of aneuploidy among their embryos.

So I think a very nice study by the group at Boston IVF. I think it does provide helpful data for counseling patients and for decision-making. What did the two of you think? So I think you hit the nail on the head earlier, though, when you talked a little bit about the three-month gap.

And I feel like that really skewed the data that they only included patients who had less than a three-month gap from the time of their first egg retrieval until the time of their first transfer, and all other patients were excluded. And so it's not surprising to me that they saw a faster time to pregnancy in that particular scenario. Why I'm really bothered with that is there are so many patients who don't have any euploids, and it takes them five, six cycles to get a euploid embryo, and PGT may actually be lengthening the time, not shortening the time, because theoretically, if those patients had transferred embryos in that interval, they may have achieved a pregnancy.

And so I think that the design of the study was very much set up to show these results. I will say intuitively, I do counsel patients that once you go to embryo transfer, your time to pregnancy is faster, but I'm not convinced that from the day of your first egg retrieval to embryo transfer, it's faster if you exclude the patients who take more than three months. So I think that it's kind of the fatal flaw of the study in its design, but I think that the intent is good, and I think that it does do a nice job of showing that once you're transferring, your time to live birth is faster.

But I think it's exaggerated by the bias in the study design. Eve, I tend to agree with you. I think this and many papers in fertility and medical literature have a bias.

Can you say that again? We agree. We agree. But I don't think a bias is necessarily a fatal flaw.

I think that's why it deserves to be published and we discuss it. But I would argue from a slightly different perspective that I'm still not convinced why we consider time to pregnancy that strong an outcome. Like how much time did they actually save, Kate? I know the relative risk was 1.45, but they saved months, right? So again, this is another flaw of the paper.

I would have really liked to see that outcome analyzed. And because they looked only over the course of a year, they really didn't analyze the data in that way. I would have liked to see the time period following the first retrieval go out farther.

Yeah, they censored their limitations. So the point I was going to make there is I don't want people to take this paper as proof that there's benefit of PGT-A. We can have a legitimate argument about whether it actually legitimately reduces your time to pregnancy, but that shouldn't take your counseling to everybody says, see there's this benefit to this technology.

It really requires a more subtle discussion. Would you rather perhaps give up the chance that you might not get pregnant at all for having a pregnancy a few months earlier? And if you say it like that, I think patients might have a very different reaction than saying, oh, I have a test that will help you get pregnant faster. So it's it's it's really subtle here when you're talking about, of course, it's faster if you have a euploid embryo.

But if you look at the cumulative pregnancy rates, number of cycles, time to take, who gets a transfer, who doesn't, it's really a complex issue. And I'm not I'm not sure I really am totally not sure whether I told a lot of women, would you take a risk of not getting pregnant at all for getting pregnant faster? Would they take that risk? Some would, especially as we talked about for Dobbs, that they're willing to sacrifice embryos to have a normal one, but not everybody would. So it's it's more complex than the paper says, is what I'm trying to say.

Without question, it's very complex. That said, again, I think what's hard to analyze, and I would love to kind of apply a similar analysis looking out further at some of the other data sets that we've reviewed recently, you know, in this journal, that the issue in the older cohort, and this is, again, not a perfect analysis, as you both highlighted very well, to address this, but is if you wind up having a miscarriage from an an embryo that is abnormal, that you could have prevented transferring, such that you don't do another retrieval for enough time that your outcomes have changed significantly, you know, is that going to be the difference between having a baby or not having a baby as well? So again, this paper doesn't answer that super complex question and counseling of patients, but good to have the opportunity to reflect on it here with this. Yeah, but that was a great discussion.

So we just had a real long discussion about why people might choose or not choose existed technology. Let's go a little off target from embryology and IVF and talk about how in the same vein, the Dobbs decision might affect contraceptive choice. Yeah, this next study is also looking at the Dobbs decision from the opposite lens, and I know we talk a lot about the title of the journal, Fertility and Sterility, for better or worse, but we just talked about a fertility article, and this is actually a sterility article.

The title of this is a nationwide analysis of the trends in permanent contraception utilization before and after the Dobbs ruling, and so the objective of this study was to look at national trends in the use of vasectomy and tubal ligation before and after the Dobbs decision. The data source for this was the Epic Cosmos database, and it was a retrospective review of individuals age 18 and older who underwent vasectomy or tubal ligation, and they looked just at two time points, pre-Dobbs, post-Dobbs, not taking into consideration the Dobbs leak, and they looked at incidence rate ratios were calculated and then stratified by demographics and state abortion laws, and they stratified state abortion laws into non-hostile, hostile, and illegal, so three different categories. When we looked at vasectomy trends, these increased from 18,000 pre-Dobbs in the year pre-Dobbs to 26,000, 26,500 post-Dobbs, and there was a significant increase among patients less than age 30 and a significant increase among single individuals, which I thought was actually really interesting, so those patients who are at that time 100% sure that they don't want to have kids or that they are done having kids started having vasectomies at younger ages.

When they looked at by state legal status, it was increased across all categories in all states, but there was highest state-specific increases much more in restrictive states, so Tennessee, Missouri, Virginia had state-specific increases, as did Florida and Nevada and Vermont, and so I thought that was not surprising but really interesting, and similarly, same thing was seen in tubal ligation trends, so increased from close to 18,000 pre-Dobbs to just over 18,000 post-Dobbs, so a little bit more of a modest increase, but there was no change by legal status, so non-hostile versus illegal did not have increases in tubal ligation trends, and there were some more restrictive states that had high state-specific increases, but it really was across the board in both hostile states as well as permissive states, and I think that the biggest takeaway that I saw from this is that there's a rise in vasectomies, and I think that may reflect a shift towards more shared reproductive responsibility. The legal climate is absolutely influencing reproductive decisions on the sterility side of things, and I think it's emphasizing the importance of patient education, shared decision-making, and access to all contraceptive options, so I really liked this study. I thought it was a really nice national overview, and again, at that intersection of reproductive choice and political climate, and I like that the male partners are stepping up and sharing in reproductive decision-making.

I agree. I think that this speaks to a trend that is positive in terms of the way Americans are controlling their reproduction. I do think that in terms of looking at it geographically, in addition to abortion access in these states, there may also be differences in terms of comfort level with things like hormonal contraception, et cetera, and I also was thinking about this paper and their findings in terms of some of the things that we've been discussing recently, and I think we'll be discussing more and more about population replacement and people's decision-making in terms of wanting to really kind of definitively limit their family sizes more than we may have seen in the past.

So, interesting trends. I love the research letters. We have another one we're going to be discussing in this paper, but it's awesome to have these kind of hard-hitting findings, but delivered in really kind of digestible packets of information and data.

Thanks for commenting on the research letter, Kate. I agree. Research letters, I think, are a great addition to the journal where you really can get concise messages out there, and this is a good one.

I mean, this trend might not be the same in 10 years. I understand that. That's the problem of assessing any trend, but it really is important to show that actions in life affect behavior in our field in particular, and that's why this, I think, is important information to get out and discuss.

Well, I'm going to make a bad segue back to ART, and we talked about the history of the journal, but one question that's been vexing me, not for 75 years, but for perhaps the last 30 or so, has been, you know, we're very successful at ART, but the question still remains, is the health of children conceived with assistive reproductive technologies different from those conceived without? And there's a nice paper, even though this question has been answered and addressed many times, there's a nice paper in the journal and this paper is the use of assistive reproductive male and female infertility and perinatal outcomes by Maria Magnus is the first author, by a long list of authors, mostly in Europe, as this was a registry study done in Norway. Let me just set the stage for you. We all understand that no one wants to go through ART.

It's a treatment for infertility, but it is a long process, and we've always questioned if there's an effect on the children, at least the perinatal outcomes, after they're conceived and born. And I think this is just a very one-sentence summary, is I think we've demonstrated that there really is. We could argue how, what's the order of magnitude of that change, but children conceived with ART do tend to be smaller, increased risk of perinatal outcomes, such as preeclampsia, increased risk of C-section, increased risk of diabetes and some other things as well.

But the question, even if we accept that, the question has always been, why are these women at an increased risk? Is it due to their underlying fertility issues, which might make the pregnancy more complicated, or is it due to the actual procedures of ART itself? Hard to tease that out, but that's essentially what this paper is doing. And let me go through the methods real quickly. They're basically saying, I wish I had this luxury, but they're taking a registry for almost 12 years in Norway that captures pretty much all of the births.

We can argue a little bit later on how accurate that is, but I think it is very accurate. And they're comparing children conceived with ART to those conceived without. But importantly, they have a distinction where they could divide their patients that did conceive with ART into why they had ART.

And they have a pretty good discrimination of female factor only, male factor only, which, interestingly, they call sperm factor or sperm abnormality, which brought a smile to my face because they're just saying it's the sperm. They're not saying it's the man, which is interesting. But anyway, and then there's those people that are mixed, and they looked at the differences between these perinatal outcomes that I just rattled off, and if they're different between those that have a male factor, theoretically, the female partner is normal and has normal reproductive function versus somebody that might have infertility due to an abnormal female reproductive track or hormonal milieu or something which might contribute to its own morbidity.

So, it's not a small study. There's more than a million children conceived without ART and about 30,500 with ART. And it's about 30% that are male only, 30% female only, and then a mixture.

And the main finding is that there is increased risk of all these perinatal morbidities that I mentioned, kind of across the board, preeclampsia, diabetes, cesarean section, small for gestational age, etc. That's not news. We know that.

But what they're trying to demonstrate is that the magnitude of that difference seems to be smaller for women that have male factor infertility compared to women that had female factor infertility, therefore suggesting that there is some innate risk due to abnormality in pathophysiology for a female reproductive track, but also problem or additional risk due to the ART procedures themselves. So, let me be a little more specific, because I actually thought about this and published a long time. There's lots of reasons to think that women that have infertility might have abnormal pregnancies.

And as I said years ago, health affects reproduction, which affects health, meaning if your uterus is full of fibroids, you're not necessarily going to have the most uneventful pregnancy, and you certainly might have perinatal morbidity. That one's obvious. We don't even think about that.

But you could say the same for endometriosis with inflammation and altered hormonal milieu. You could certainly say the same for PCOS for different mechanisms with, you know, hyperandrogenism and altered metabolisms, adenomyosis. So, there's lots of reasons to think that the reason a woman has trouble getting pregnant is going to affect the pregnancy itself.

Now, unexplained is a tough one because it shows that as best we can tell, we can't find anything abnormal. But there's lots of studies, including some of my former fellows, who have suggested that there's alterations in genetics and epigenetics and telomere lengths and lots of other reasons to suspect that, you know, unexplained infertility might be the, quote-unquote, canary in the coal mine. There might be something wrong.

So, that's a strong argument. But there's also a very strong argument to say, let's look at the ART process for a second. Superphysiologic hormones, you know, removed by definition in vitro handling of the gametes and fertilizations, culture with media that sometimes we, as much as good as it is, we can't say it's perfect because we don't know.

Lots of studies, including some of my colleagues, Christos Coutifaris and Monica Mainigi, have shown that there are epigenetic changes based on how you culture embryos. Now, how much that matters is still a question, but there's, you can't say it's a normal process. So, both of these have, you know, reasons to contribute.

So, the take-home message, which I want to be reassuring, even though I just gave that entire diatribe on reasons, is that it doesn't surprise me in a good way that we do have some morbidity associated with fertility as a disease. And I wish this paper could be more granular to say, you know, what's the risk for endometriosis versus PCOS versus fibroids versus adenomyosis if it doesn't do that. But it does pretty convincingly, well, somewhat convincingly, to use Micah's favorite word, when you let the data flow over you, show that it looks like the risk might be slightly different in male factor infertility, meaning there's two risks factors here, both the procedure itself and the underlying disease.

It's not apparent when you look at all the tables, which you should look at the tables. It's a great paper about, you know, with the forest plots all lined up, and you can see that there's, you know, the forest plots are closer to the line for male fertility than female infertility. By the way, mixed is closer to female, which I also would expect.

But there are risks there. And, you know, when you go down the list, looking at small for gestational age and abnormal APGARs and things like that, it's real. And we as professionals can't forget the fact that our patients, when we discharge them to obstetrical care, do have more complications than we think.

And sometimes I think we forget that. So I don't think this paper is astoundingly novel, but it kind of puts it into a nice package for you to reread this issue and have a very good argument for both of these are competing risks. Now, what we do about that is hard.

We can't just accept that there's risk for women with infertility. We need to do our best to minimize the risk. We also add on due to our procedures.

And I think that the last 10 years, there's been a lot of research on what aspects, particular aspects of ART could potentially be changed. And I hope we continue to do that rather than just focus on efficiency. I hope we don't just become complacent that said our pregnancy rates are great and we don't focus on this issue anymore.

So I would recommend you guys, listeners, take a look at this paper because it really brings this whole very important topic back to the forefront. And I think the authors did a nice job and it was a wonderful reflection that describes much of this as well. It's worth your time to reading.

Do you guys think of anything new about this paper? Does that strike you as different than what you was already in your minds? I had the same reaction that you did, Kurt, in terms of intense curiosity about the specific female infertility diagnoses and the strength of association for each one. And there's also a very nice reflection on this paper, which delves into what you had mentioned that both exposures, the exposure of infertility and exposure to ART have biologic plausibility in terms of how they might induce adverse perinatal outcomes. And so I'm still waiting and hoping that somebody with a really granular data set and a large one at that, because this one to have 30,000 ART births is nothing to scoff at, we'll be able to do that analysis.

And even one further down on the wishlist is to look at the specific adverse perinatal outcomes as well and which ones are associated with which diagnoses. That would really kind of be the holy grail. Yeah, so I echo those sentiments wholeheartedly.

Where I struggle a little bit with it is twofold. First is we're assuming that patients who have male factor infertility, that that's a comparison group. And I don't think that that's accurate.

And I don't think that that's fair. I think the best comparison group should be gestational carriers. So take a normal pregnancy, somebody without infertility and use the embryos there.

It still doesn't mitigate the risk of male factor though. And so how much of adverse outcome has to do with the male genome and possibly DNA fragmentation or all of the other epigenetic changes that may happen in the setting of male infertility. And so I still don't think that we can separate out the infertility from the technology.

I think the group does a really nice job in trying to do that. But I think it's naive to think that male factor infertility is completely normal. And so I think it's just hard.

The second point is if you look at what are the actual outcomes, the gestational age, it's by a couple of days. The birth weight is by 50 ounces. I think many of the outcomes are statistically significant because of the very large sample size.

But I don't think that most of these were clinically meaningful. I mean, I certainly don't want to undermine the risks that are associated with ART. But when you look at the absolute risk, not the relative risk, I think that most of these outcomes are not terrible.

And I do think that we need to counsel our patients that ART has risk and we use it with caution. And we strive to improve it to try to make it as safe as medically unassisted conception. But I looked at this and I was like, huh, not so bad.

Without getting statistically geeky here, the small risks in the continuous outcomes are because you're using registry database and there's such variation and that there's people that have delivered post-gestation, there's people that have delivered pre-gestation. So when you look at this in a linear model, finding differences are usually not that impressive. But they are impressive because they've translated to categorical increased risk for things like small for gestational age and preterm delivery.

So it really depends on how you look at your data. So I just wanted to say, be careful looking at continuous data because it looks less impressive than it can be. Really what might be more important is looking at the tables that show that really every perinatal risk that we can measure is elevated in children conceived with ART.

So it just depends how you look at it. Now there's another thing, since I'm getting geeky on statistics, this paper only starts with people starting at 12 weeks or 20 weeks, depending on how you read this paper and which data they put in. So there's something called a survivorship bias here innately, right, that only gestations that made it to 20 weeks are included in this, which are relatively healthy.

So you're only looking at the survivor best of the ART pregnancies in this group. You're not looking at what it might do epigenetically or genetically or other reasons to people that miscarriage or have problems before that. So the epi is really hard to be granular, is my point.

And, you know, everyone is free to interpret this data where they want, but I think to me, it confirmed that there is a risk with ART, but we just can't figure a way yet to mitigate that risk, except perhaps looking at the paper that Kate is about to talk about, or maybe, yeah, I think it was Kate, on assisted hatching. You know, that's a technology that's falling out of favor, and maybe that did have some risk. Maybe by continually looking at the process of ART, we can make it safer.

Great with the segues today, Kurt. So, yes, I'll be talking about a paper by my fellow, Dr. Amalia Namath, entitled Assisted Hatching Decreases Pregnancy Outcomes in Vitrified Donor Oocytes. So this was a retrospective cohort of single fresh embryo transfers of unbiopsied embryos from frozen donor eggs occurring between 2015 and 2020 at 29 different fertility clinics.

So frozen eggs were derived from a single egg bank, and all transferred blastocysts, again, were in a single embryo transfer and had a start grade or modified Gardner score, however you want to call it, of grade BB or better. So the exposure was whether assisted hatching was done, and in this cohort, 1,668 embryos were hatched, 949 were not, and the outcomes assessed were implantation, clinical pregnancy, miscarriage, and ongoing pregnancy. Hatching was performed on the day of transfer according to the center's protocols, which were buried.

92% of them were hatched using laser photoablation, so that was the vast majority. The author's analysis was adjusted for age and BMI of the donor only, and so this is like the big Achilles heel of this paper, is that there's just a lot of data that were not available to be able to do the adjusted analyses that we probably all would have liked to see. The BMI and age of the donor, by the way, were similar between the two groups.

A sub-analysis of cycles was done with data available on the recipient, and those adjustments were made for the age and BMI of the recipient only. In their primary adjusted analysis, and again, just adjusted for the age and BMI of the donor, they found implantation, clinical pregnancy, and ongoing pregnancy were all slightly but statistically significantly decreased in the hatching group. The authors defined ongoing pregnancy as fetal cardiac activity at the eight to ten week follow-up ultrasound, and the absolute numbers in terms of ongoing pregnancy were 57% in the group that had hatching versus 62% in the unhatched group.

Miscarriage was not statistically different. Interestingly, and importantly given the historical context for assisted hatching, there was no difference in the rate of monozygotic twinning, although the study was almost certainly not powered to assess this rare outcome. It was rare in both groups, and in the overall cohort, the rate of monozygotic twinning was approximately 1%.

The sub-analysis that controlled for recipient age and BMI, so again, they only conducted this analysis for transfers that had these data available, contained only 80 transfers, 75 of which were hatched. So I think this probably was something that was asked for by an editor or reviewer, but doesn't really contribute much to the overall analysis. Only five patients in the group that had recipient age and BMI had hatching, and my strong suspicion is that they all came from the same center, or largely from the same center for whom they were able to get this data.

An analysis of 856 transfers from sibling oocytes, so one lot of eggs from the donor that had hatching versus another egg that did not, showed no difference in any of the outcomes assessed, which I think is telling. And so a couple of things that I wonder about here is the interaction between the center and hatching. Almost certainly there were centers that do hatch embryos derived from frozen donor oocytes versus those that don't, and certainly centers have differential success rates.

That's something that I would have liked to see controlled for in the analysis. I don't take these data on my read to really indicate that hatching, quote-unquote, has decreased the probability of success because of some of the confounders that probably existed and could not be or were not analyzed. That said, I think it's very likely not helping, and in terms of add-ons to ART that add cost and possibly risk, you know, looking back at the last paper that we just talked about, I certainly would advocate for leaving it out in this particular clinical setting.

What did the two of you think? I'd like this paper for the very reason you said. If we can find things that aren't working, why are we doing them, right? I mean, when we, we, the Royal We just worked on IVF, we've made some decisions that we think this is better, and not all of them end up to be correct. So I'm a firm believer in less manipulation to better.

So this is a nice evidence to show if it's not helping, don't use it because you're right, it could be harmful. Yeah, and I thought it was a really elegant study design. So I love how you partnered with Donor Egg Bank to get these data and to really analyze them with sibling oocytes, which I thought was really, really great.

So I wholeheartedly agree. I would take this to say it's not helping, probably is not hurting much, but it's certainly not helping. And so why do it? We've had a great conversation with some really heavy articles.

Why don't we end on one more research letter that I think addresses a pertinent question in a concise way. Kate, I think that's yours as well, talking about live births across different groups that are using ART that perhaps are not always infertile. Yeah.

So this is a paper by Dr. Brent Monseur at Stanford. He's doing a lot of really great work looking at, you know, sexual orientation and gender identity in ART and in medically assisted reproduction in general. In this particular research letter, he and colleagues looked at data derived from Nurses Health Study 2. The data set contained 100 plus thousand participants that were aged 24 to 44 years old in 1989 and completed a baseline questionnaire at that time, and then submitted follow-up responses through 2009, self-categorizing sexual orientation as heterosexual, bisexual, or lesbian, providing pregnancy outcomes, and noting whether or not they had ever used medically assisted reproduction.

Medically assisted reproduction was defined as clomiphene and or gonadotropin exposure. Age-adjusted Poisson models and weighted generalized estimated equations were used to estimate prevalence ratios and 95 percent confidence intervals. There were 75,000 plus respondents among the original 116,000 who reported at least one pregnancy.

Interestingly, and I think somewhat surprisingly, perhaps maybe even not true, 99 percent, 99.3 percent of these patients stated that they were heterosexual, so does not represent, you know, the true population. That said, these were the patients that reported a birth, so I suppose it's possible. 0.3 percent of them identified as bisexual or self-reported bisexual orientation, and 0.4 percent self-reported lesbian sexual orientation.

Of note, this corresponds to only 213 bisexual individuals and 274 lesbian individuals in the analyzed data set, and to me, we'll circle back to this, this is really perhaps the most interesting finding of the paper. The incidence of medically assisted reproduction was similar among groups. However, multiple birth and multiple birth among medically assisted reproduction users was higher in lesbians, with a prevalence ratio of 3.43 and a 95 percent confidence interval that was wide at 1.59 to 7.4. Of note, this represented only 10 multiple births among the 274 lesbians.

So, you know, I think this is a really important paper. I think the reason that it is so important mostly is just the extreme paucity of data that we have in this population and the very askant number of analyses we have looking at this. I wholeheartedly agree with the conclusion, and it was an excellent analysis, by the way, well worth the read and very concisely stated again in this research letter format.

I agree with the conclusion that likely same-sex female couples or just lesbians in general have been treated over time with ovulation induction, even if not infertile, and that this likely puts them at risk for multiple birth. My fellow Olivia, well, no longer a fellow, but at the time Olivia Carpinello, also did an analysis of our data that showed a similar finding, that essentially when we treat non-infertile women using donor sperm via IUI with ovulation induction, we are increasing the risk of multiple birth without really truly increasing their chances of having a baby. So, this is nice data that finds a similar outcome, but I think what's really important here is how important Brent Monseur's work is, because we know so little in this population and in this tragic time, there was a paper or a posting on the ASRM website about how he unfortunately lost his funding and all that's going on at the NIH, and it's tragic, truly, and ASRM was able to help preserve some of the work he's doing in the form of a research grant, and we all really do need to pull together and support research at this time.

So, a bit of a meandering discussion there, but I think this paper is a nice jumping off point to look at some important issues in the field of research in sexual minority groups, and then also to look at the importance of the environment of research funding at this time as well. Yeah, I'm going to put a plug in for ASRM's Fighting for Our Future research bridge funding, and would encourage everybody in the field to donate, and as a board member, we have each contributed a significant amount to help bridge that gap in funding for our colleagues who have lost funding. So, I want to encourage everyone to attend the gala this year and to make an additional donation to this special fund to help support our colleagues whose research is being funded.

But I couldn't agree more, and I think that oftentimes what I think these data don't capture is many times I have patients, same-sex female couples who are coming in, who have tried insemination at home for 12 months through various mechanisms. And so, by the time they come to us, some of them do have a diagnosis of infertility, but I do think that the point of trying ovulation induction for many more months on your own before adding in Clomid is worthwhile. I do think that there is a real risk of OI agents in multiple pregnancies.

The numbers are small, but they are real. I think that the point that often gets brought up in the office is sperm is so expensive, we're paying so much, can you do anything to increase our chances? And I think we all need to remember that ovulation induction doesn't necessarily increase the chances, but it does increase the risk of multiples. But again, not all these patients are naive to treatment when they come into our office.

Well said, Eve. So we had, I think, a very nice discussion. Thank you, Eve and Kate.

This was terrific. Not to diminish the young men who aren't with us, Pietro and Micah, but I want to remind everybody that not just to listen to this podcast, that there's a lot of content in the journal you should pay attention to, in particular, there are a couple of letters to the editors and exchanges, which I might pique your curiosity about PGT-A and cumulative pregnancy rates, a closer look at the evidence. So take a look at the disagreement that we might have.

There's also some letters on the outcomes post-myomectomy for those of us that are still surgeons. And the video articles look terrific too, in terms of some novel surgical techniques. And finally, to bring this full circle, there's one retraction notice in the journal.

And I just wanted to make one comment on that. I just, we all just espouse the quality of science in Fertility and Sterility and how important the medical literature is. Having said that, we do have an underlying battle that there is some fraud in the medical literature and ASRM and Fertility and Sterility continue to work very hard at ferreting out those papers, which are not scientifically correct.

And there's one that's being retracted in the journal this month, even though the paper is from the year 2000, I still think it's very important to correct the medical literature when corrections need to be made. But my point is, that doesn't mean we can't trust the medical literature. It just means that there's a small percentage of it that needs to be corrected.

And this corrective process should make you even more confident in what is in literature. So the theme I'm promoting is medical literature is the best literature that we have, and we should do our best to make sure it's in good standing, but we should be standing on it and using it in our daily lives and not be dissuaded by misinformation. So great podcast.

Any final comments, Kate or Eva? I like that full circle as well. Here's to another 75 years of Fertility and Sterility. Yeah, I agree.

I think it's a beautiful way to start and a beautiful way to end. Perfect. So we'll see you all, quote unquote, next month on the podcast.

Thank you very much. This concludes our episode of

Fertility and Sterility On Air brought to you by Fertility and Sterility in conjunction with the American Society for Reproductive Medicine. This podcast is produced by Dr. Molly Kornfield, Dr. Adriana Wong, and Dr. Elena Huganesh.