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BackTable / OBGYN / Podcast / Transcript #20
Podcast Transcript: Uterine Transplant
with Dr. Elliott Richards
In this episode, Dr. Elliot Richards, a true physician-scientist and Director of Research in the Department of Reproductive Endocrinology and Infertility at the Cleveland Clinic, shares about his experience and studies regarding uterine transplant. You can read the full transcript below and listen to this episode here on BackTable.com.
Table of Contents
(1) The Evolution of Uterine Transplantation
(2) Recognizing Infertility as a Disease
(3) Patient Selection and Progress Toward Standard Care
(4) The Screening Process for Uterine Transplantation
(5) The Complexities of Uterine Donor Selection
(6) Securing Blood Flow: Techniques in Uterine Transplant Surgery
(7) Immunosuppression in Uterine Transplants: Balancing Graft Survival and Pregnancy
(8) The Promise of Uterine Transplants: IVF, Embryo Implantation & Beyond
(9) Defining Success in Uterine Transplants
(10) Exploring the Future of Uterine Transplants
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[Dr. Mark Hoffman]
Welcome back to another episode of BackTable OBGYN. This is your host, Mark Hoffman, and I've got my co-host today, Amy Park. Dr. Amy Park from Cleveland, how are you?
[Dr. Amy Park]
Good. How are you?
[Dr. Mark Hoffman]
Good. I was worried you had forgotten about us completely, but you're just doing other work. Important stuff, I assume.
[Dr. Amy Park]
You know me, yes, I'm busy.
[Dr. Mark Hoffman]
Everybody's good, though. Family is good.
[Dr. Amy Park]
Yes, how are you?
[Dr. Mark Hoffman]
Awesome. Everybody's Good.
[Dr. Amy Park]
Good.
[Dr. Mark Hoffman]
Busy, like you said, but, well, awesome, awesome guest today. I'm excited to learn about what he does. We have Dr. Elliott Richards, Director of Research for the Division of Reproductive Endocrinology and Infertility at the Cleveland Clinic. He is here to talk about uterine transplant. He is written quite a lot on uterine transplant, and he's developed the uterine Transplant Program, which is part of the first trial in the US for uterine transplant. Second program with a successful live birth, and he also is an active surgeon operating on patients with endometriosis and fibroids. Dr. Richards, welcome to the show.
[Dr. Elliott Richards]
Thank you for having me.
[Dr. Amy Park]
Elliott also has his own lab, basic science lab, and learner.
[Dr. Mark Hoffman]
An actual physician-scientist. How do you do it?
[Dr. Amy Park]
He's a multi-hyphenate, too.
[Dr. Mark Hoffman]
I don't think I'm a multi-hyphenate. I think this is all I do. This is all I got.
[Dr. Amy Park]
He's a clinician, surgeon, scientist, educator.
[Dr. Mark Hoffman]
My imposter syndrome is raging right now to be honest. Welcome to the show. We're very excited to have you. It's a big topic, but we'll try to do our best, in the name of time, to get to the meat here, which is uterine transplant. Talk to us a little bit about how you got interested in uterine transplant, about your career, and how you ended up doing what you're doing now.
[Dr. Elliott Richards]
Thank you for that wonderful introduction. For myself and my place and uterus transplant, it really was something that fell into, right place, right time, amazing mentors when I came to Cleveland Clinic who were involved. I was not here at the clinic for the first transplant, but then every subsequent one, I was able to scrub in and be part of, and really was excited, couldn't get enough.
As there was shifting of different roles and turnover over the years, just suddenly found myself leading the GYN efforts in the program, and really had some huge shoes to fill following Dr. Rebecca Flyckt, who was one of the pioneers here at the Cleveland Clinic and turned over a lot of this to me just a couple of years back.
[Dr. Mark Hoffman]
Wow. Not something you were doing, something that was being done when you got there, and really just it became a passion of yours.
[Dr. Elliott Richards]
Absolutely. In fact, to be honest, before I got here, it really didn't exist in the United States. Just really in two centers at that time, Cleveland Clinic and at Baylor Dallas. I remember when I did some of my training at Mayo Clinic, and we were visited by Mats Brännström and his team from Sweden, and telling his story, and I remember just, "This is so amazing." I had no idea at that moment that just a couple of years later, I would be part of one of their American teams.
[Dr. Mark Hoffman]
It's so funny how that works.
[Dr. Elliott Richards]
I tell my trainees that, honestly, that quarter, that 80% is just showing up. That's really what it was for me is that I showed enthusiasm, I scrubbed in I came to the-- none of these required things, but just showing that interest. As you show interest and you get on papers, and you say hey, "Let's do this, let's do this idea." Suddenly, you get more and more responsibility and more collaborations. It's a great example of being in the right place the right time, but also having that enthusiasm and interest. I'm very fortunate to be part of this program.
(1) The Evolution of Uterine Transplantation
[Dr. Mark Hoffman]
You mentioned Mats Brännström. I remember I went to AGL one year. I think he was one of the keynote speakers. I remember being, honestly, a little confused, like, why do we need uterine transplant? At Mayo, it was obviously not part of my practice as a mix surgeon. Talk to us first about the history of uterine transplant and with that, maybe a touch on why it was started, why it's being done.
[Dr. Elliott Richards]
It's really fascinating. When you talk with the early pioneers including Mats, they had the same reaction and actually, like, why uterus transplant? That's crazy. Mats, he could certainly should speak for himself, and if you ever had the opportunity to chat with him, but my impressions from conversations with him, I got to hang out with him actually at the international conference just last fall, and was able to get the story again from him. It really was uterus transplantation in the modern era has been patient-driven and patient demand.
His story, as I understand it, truly was a patient saying, "Why can't we do this? Why can't we do uterus transplant for me?" His reaction first was like, "That's crazy." Then, as he thought about it more-- and it's been a similar story, I think, for all the early pioneers. First time hearing it being like, "This seems absolutely ridiculous," but as you learn more about the patients, and also the process, it begins to make a lot more sense. One of the goals that I have for our talk today is I hope to convince some of your more skeptical listeners that this is actually something that we should take seriously.
[Dr. Mark Hoffman]
I think he also mentioned that where he's from, it's illegal, surrogacy is illegal. I know that in the state of Kentucky, actually, surrogacy is illegal. We always think, "Oh, why don't you just throw that embryo in somebody else's uterus?" If that uterus is still in that person, in many places in the world, that's not an option. Certainly, patients have the opportunity and the autonomy to make decisions for themselves. Uterine transplants, an interesting topic, but it's also the only option for some patients as well. It's not been around very long. This is not something people have been doing for a very long time.
[Dr. Elliott Richards]
Well, and that's actually a really interesting point is, a lot of people don't realize that the first uterus transplant was almost 100 years ago. Did you see the film that came out in 2015, The Danish Girl? Are you familiar with?
[Dr. Mark Hoffman]
No.
[Dr. Elliott Richards]
It's the story of Lili Elbe, who was a transgender woman, and really excellent film. I recommend it very highly. In one of these examples, and I'm disappointed you're not familiar with the film because it'd be a lot easier to explain. In the film during this time in the 1920s, where there wasn't a culture of understanding and acceptance of gender-diverse individuals, this individual underwent a series of, actually four gender-affirming surgeries, and in 1931, eventually succumbed to organ failure, sepsis, and death, secondary to a uterus transplant and vaginoplasty.
What's really fascinating in the film, it actually doesn't even capture the extent of what was done. In the film, it's her second surgery, and they mention, I think, vaginoplasty, but in reality, it was a uterus transplant. That's actually not mentioned in the film, and it was her fourth surgery. Now, this was 20 years before the first successful organ transplant, which was a kidney transplant in the '50s.
[Dr. Mark Hoffman]
There were no other transplants before. That's fascinating.
[Dr. Elliott Richards]
There were no immunosuppressants.
[Dr. Mark Hoffman]
Wow.
[Dr. Elliott Richards]
There was a lot that wasn't known, but this is a great example of patients pushing and saying that I want this. This is part of gender-affirming surgery for me in this case. It's interesting because now we're starting to come full circle because there's a lot of serious discussion now about when are we going to offer uterus transplantation for gender-diverse and transgender individuals. It hasn't happened yet, and I do think that there are still some steps we need to take before we're ready to make that jump, but I do think that it's in the near future. The first year of transplant, technically, was in 1931.
[Dr. Mark Hoffman]
Not successful but attempted.
[Dr. Elliott Richards]
Correct. In the '50s and '60s, there were a series of animal experiments, mostly autotransplantation, first in dogs and then in primates, removing the uterus and putting it back into the same animal. To my knowledge, there was no demonstrated pregnancies at that time. The first in the modern era uterus transplant was actually in 2000. That was in Saudi Arabia. It was a living donor. There's graft failure at about three months attributed to a thromboembolism.
Then in 2011, in Turkey, there was a deceased donor of uterus transplant that was performed by a plastic surgeon. Interestingly enough, that patient delivered just about two years ago, and so she was on immunosuppression for almost a decade. It was actually Mats Brännström who partnered with them to troubleshoot. They did some revisions of the graft, and that's thought to be the reason why they were able to ultimately achieve pregnancy. I think what's important about the Saudi Arabia and the Turkish case is that these were not done in clinical trials. They were one-offs.
The reason that the Swedish group are really considered the pioneers is they really took a systematic approach to uterus transplantation, actually starting with their own animal experiments. The first animal study showing successful pregnancy was actually in a mouse model in 2010 by Mats Brännström's group. I think Mats recognized that a big failure would set back the field, potentially even indefinitely. They were really very careful and approached it very cautiously. Unlike, unfortunately, these two first attempts that were really just, again, one-offs and, "Hey, let's just do it because we can." What I consider the modern era of uterus transplantation truly began with the Swedish group, with their clinical trial in 2013, and then their successful live birth a year later in 2014.
[Dr. Mark Hoffman]
Tom Curry runs research in our labs here at the University of Kentucky and knows Matts, knew him from meetings and stuff. I think I came home and talked to him all about that talk. He was like, "Oh, he would be sitting there chatting with me sewing microsurgery vessels on mice like it was no big deal. He was just reanastomosing all these vessels and doing transplants as he was just chit-chatting."
He did it countless times, and so by the time he got to the OR with a human, I imagine those vessels probably seemed like garden roses. He had done it for so long on these tiny, tiny models for it to work. The dedication and persistence and skill and all of those things that it takes to get to that point is just unimaginable to me, honestly.
[Dr. Elliott Richards]
As he tells me, he was a bit of a, it sounds like a pariah during those years, because at home, I think he was somewhat ridiculed for what he was attempting and trying to do.
[Dr. Mark Hoffman]
Isn't that always the case though? It seems like you have to fight everybody in your own institution to do something that the rest of the world's dying to see. That's an incredible story.
[Dr. Amy Park]
I have to admit, when I first heard about uterine transplant, I was like, "Who would want to do that?" Like, "Just get a surrogate." Obviously, when you're on protocol, there's not as much cost to the patient, but it's a huge surgery. We're talking about grafts, we're talking about immunosuppressants.
Just hearing about it and the sheer technical aspect and psychological aspects. Also, I have to give the pioneering surgeon so much credit because patients try and push us into things all the time. You have to be really open-minded in entertaining these seemingly impossible endeavors and that can-do spirit. Then saying, "Why not," instead of, "Why," or trying to come from a place of, "Yes." I really do have to respect that.
[Dr. Mark Hoffman]
Initially, thinking, "Oh, heart transplant makes sense." You can't live without a heart, lung, kidney, liver. This seems like someone saying, "Oh, we should just do it to see if we can." Hearing it from that perspective, from the patient's perspective, understanding that we have transplants with the eyes and other things, where it's not life and death, but it's absolutely life. If that makes sense. This is life for folks.
(2) Recognizing Infertility as a Disease
[Dr. Elliott Richards]
The first generation of kidney transplant surgeons who worked with Dr. Starzl, a lot of them are around still. It's so interesting. In fact, one of them, Dr. Zahka at Cleveland Clinic, I definitely want to give credit to him. He was really the person who brought it to the clinic. He was involved in Dr. Brännström's some of the uterus transplants in humans that were performed. He was a trainee of Dr. Starzl, really, the pioneer in transplant surgery.
As he tells it, a lot of the same attitudes that are about uterus transplant now were the same things were being said about kidney transplant and liver transplant in those early days. I think, ultimately, because there are a lot of naysayers, and I think that this is not a clear cut issue, there's a lot of complexity here and ethical questions to ask. These ethical questions actually have been debated and talked about for actually decades at this point.
Any concerns or points that people bring up either for or against uterus transplant, I can guarantee you that they've pretty much been talked about in depth. I think the fundamental question for me is, do you consider infertility a disease? That's something that ASRM and RESOLVE, which is advocacy group in the United States for infertility, really, that classification is important, because once we recognize and accept the idea of infertility being a disease and something that warrants treatment, we suddenly have this population who have what before was essentially incurable form of the disease, and now we have a treatment for it. I think, fundamentally, a lot of people who are against uterus transplant, there is, not always, but oftentimes, a resistance to this underlying concept of infertility being a disease.
[Dr. Mark Hoffman]
I've seen that in training along the way. I trained in Illinois, where insurance covers female infertility, and then Ann Arbor, Michigan and back here in Kentucky, where infertility's not, in a sense, treated like a disease. If it's a disease, you would think health insurance should recognize it for that, and there should be a treatment for it, which it is a diagnosis. There is an ICD code and we do have CPT codes for the procedures we do for these things, but it's not considered a disease by the institutions who we've charged, in a sense, for paying for management of those diseases.
[Dr. Elliott Richards]
Absolutely. I think that, as you say, sometimes there's lip service given to it, but absolutely, is not being seen as the disease that it is. One point that I wanted to make is that it's been known ever since the '90s, actually, that a diagnosis of infertility has the same stress and anxiety level on patients who suffer from infertility as a cancer or other diagnosis of a chronic condition. There's a massive impact on a person's wellbeing and mental health by having an infertility diagnosis.
One of the rotations I was able to do as a Mayo Clinic resident was to go to Uganda and work in a Ugandan hospital. It was so fascinating to me because there is amazing amounts of money flowing into Africa to help support family planning, which of course, is a euphemism not for necessarily building families, but for contraception birth control. Those are definitely very important things to give.
So many women who are ostracized, the level of isolation that they felt and the loss of their social status was akin to fistula, which gets a lot of attention in Africa, but yet as I shadowed this brilliant Ugandan gynecologist, his clinic was like, I don't know the exact numbers, but certainly felt like 75% infertility.
Patients coming from all over rural Uganda because there just simply is no money towards family building because the emphasis is so much on contraception. I think we see something similar here that, United States, which has such lip service towards family values and family building. There's gross lack of funding and insurance coverage for fertility and conditions that cause infertility.
(3) Patient Selection and Progress Toward Standard Care
[Dr. Mark Hoffman]
It's hard to explain to patients when they ask why. Trying to explain to a patient why we can't do something when those reasons have nothing to do with medicine, it can be very frustrating for both the patient and the physician. For the societies that are doing their work, it's incredibly important that they do the work. Your advocacy, we're grateful for that.
When it comes to uterine transplant though, and this is something that, again, I think, certainly, in doing some homework for this, it's not something I learned about in residency because it was something that was being done with any regularity when I was in residency. Can you walk us through the process in terms of patient selection? Who is a candidate for uterine transplant? How are we deciding who gets them, et cetera? All the way through a pregnancy. Can you do that in a way that won't waste your whole night with it? I'm sure it's a very simple process.
[Dr. Elliott Richards]
Can I do it in a way that's concise? Yes, absolutely. Let me back up just a second though, and say that uterine transplant is an interesting time, in that, it is beginning to transition from experimental science to really a curative treatment that is on its way to being, potentially, a gold standard care for patients with absolute uterine factor infertility.
In fact, the group in Dallas now has a cash pay uterus transplantation that's outside of a clinical trial. They've had three patients who have paid for uterus transplantation. University of Alabama now, they started a trial of, I believe, they're funded for 25 uterus transplants, and they elected not to do it under a clinical trial. This change is happening. Now, for us at Cleveland Clinic and at Penn, both of our centers are still doing this work through a clinical trial, but this transition is happening. It's happening because the efficacy truly has been established.
[Dr. Amy Park]
By the way, how much is the cost? How much are they charging?
[Dr. Elliott Richards]
It'd be great if we had Lisa Johansen on the call to speak. I believe, it's on the ballpark of around 200,000, might be 250,000. I believe that covers IVF and the pregnancy and delivery, so it's like a full package, but don't quote me. This is my understanding of the rough estimates. I'm not answering the question you first asked, but that's a big thing that our centers are working on.
One thing just as another aside, it's really so wonderful being in uterus transplantation, is that it's incredibly collaborative between us, the Baylor group, the UAB group, and Penn, where we're sharing data, we're sharing things that we've learned. That's one of the things that we're working on now, is cost-effectiveness analysis. We're building some models and we hope to publish in the next year, but there's going to be some arguments that can be made especially for patients who want more than one child.
That even putting aside the lack of access to just, say, for surrogacy for a lot of people in different states, and certainly, European countries, but there may even be some economic arguments for uterus transplantation. That's getting off-topic for what you asked. In terms of walking through the whole process, I also want to say it's important to recognize who this is for.
I was mentioning, setting the stage, talking about it being under the guise first of clinical research because the patients who have gone through and gotten uterus transplant, and I should say, we have over 31 babies born at this point in the United States. The vast majority of patients who have gone through, they have been Mayer-Rokitansky-Küster-Hauser or Mullerian agenesis patients, vast majority.
When we look at the 5,000 people who have contacted our three centers, meaning Penn, Baylor and Cleveland Clinic, that's actually only about 20% of the applicants. Because this has really started out as a clinical research trial, we've really selected the best prognosis patients, but this doesn't reflect the actual true population that suffers from AUFI, Absolute Uterine Factor Infertility.
There's huge problems with disparities that these are most often White women, and that's not a reflection of the patients who are suffering. Particularly when you look at secondary AUFI, hysterectomy. It's estimated that as high as 15% of reproductive-age women have had a hysterectomy. We're talking, potentially, hundreds of thousands of women who might-- Of course, that doesn't mean they're all interested in carrying their own child and taking on the risks of uterus transplantation. Potentially, a huge population in the United States that might be interested
Really, it's been just a very small subset. In terms of our trial and who's selected, they go through an extremely rigorous process. With the thousands of people who have contacted our center, we've really only selected, essentially, a dozen women to be recipient candidates. The hope and goal has always been to expand access to this treatment to more women.
That was a big aside from what you asked. Let me start walking you through. I should say we've done, essentially, no advertising when this was posted on ClinicalTrials.gov, we had people knocking down our door. It's so interesting hearing their stories, how word of mouth, and in many cases, families who said 10 years ago to their child, who in many cases was discovered at age 15, 16, 17, when she wasn't having periods like her friends, and suddenly this life-altering diagnosis. I can think of one in particular, her father telling her one day they're going to be able to give you a uterus. This particular father would send her news clippings of Mats Brännström work. That was just one of many patients who found us and found our trial.
[Dr. Mark Hoffman]
These aren't people who were coming to [unintelligible 00:23:09] clinics 10 years ago. These are people who were silent in the infertility world because there was no discussion. There was no like, "Oh, well let's see if we can do this," because there was nothing to do. The way you've described all the potential patients, it just seems like an overwhelmingly big task, once you open this door, all the people who want to get in. It's interesting. I hadn't thought about it in those terms.
[Dr. Elliott Richards]
Certainly, there was marketing and reaching out to media outlets, and so I'm not going to say there was no-- Definitely, no direct advertising, but there's definitely exposure. Beyond that, we essentially closed off our trial because we found all of our candidates relatively quickly and we still got, again, no advertising, just people finding ClinicalTrials.gov, the email address on there, and just getting hundreds and hundreds of people contacting us.
There is a lot of demand here. I think, while I'm talking about this one particular woman, and she was actually our first successful live birth, her story is, I think, so fascinating because she actually had a child through gestational surrogacy, and it was such an awful experience for her because she had such a loss of control and reproductive autonomy with what the surrogate was doing and all that goes behind that, that she wanted a second child but absolutely did not want to do gestational surrogacy again. Even though it was an option and something that she had tried before, she looked at all the risks and the unknowns, particularly at that time when she was admitted to the trial and said, "This is important enough to me and I don't want to go back to using a surrogate again."
[Dr. Amy Park]
Wow. It's like that movie Baby Mama. Have you guys heard about this movie?
[Dr. Elliott Richards]
I haven't, no.
(4) The Screening Process for Uterine Transplantation
[Dr. Amy Park]
They have this surrogate and she's doing all the things that just make your toes curl. She's drinking, she's smoking, she's partying, she's carrying the fetus. What in particular makes somebody a good candidate to undergo the surgery? I'm assuming there's physical components, there's psychosocial support, there's all sorts of things, stable relationship. I don't know, I'm not sure. Do you say it's okay for a single woman to undergo this? I don't know.
[Dr. Elliott Richards]
Again, I can only speak for our clinical trial in terms of our screening criteria, which, because we really designed our trial as one of the very first in the world, by necessity, it was a lot more stringent inclusion criteria with the hope that we can expand access as efficacy is shown, and moving on to, potentially, more complex presentations in patients.
There's first of all, in the screening process, a lot of experts that they need to meet with. All of our candidates met with ethicists, with social workers, with psychologists. They needed to be willing to undergo anesthesia. IVF, a major surgery, a high-risk pregnancy and really multiple surgeries. They need to be willing to receive the high-dose immunosuppressive therapy, to receive vaccinations, and informed consent.
What is informed consent? How can you truly consent anyone? There needed to be high level of understanding and education for these patients so they knew what they were signing up for, particularly at the beginning when we didn't really know how successful this was going to be, because we really only had the first Swedish trial to go on. Very extensive screening into their medical history.
We had a BMI cutoff. A lot of these patients, again, Mullerian agenesis, and so we would exclude patients if they had a pelvic kidney, for example, if there's any history of cancer for the exception of early-stage cervical cancer, any history of hypertension, diabetes, hepatitis, HIV. With our clinical trial, cisgender women, we did not, and it was actually a big area of discussion at the beginning in terms of will we allow single women versus do they need to be in a relationship.
Ultimately, we decided it was important that they had social supports, but they didn't necessarily need to have a partner or be married. We felt that that was just discriminatory, and obviously, some discrimination on the basis of medical criteria we had to have just because it was early trial, but that social sort of discrimination was deemed to be not a compelling argument to exclude those women.
[Dr. Mark Hoffman]
Interesting. Again, it seems like an incredible amount of work outside of just the technical aspect just to get these things off the ground in any way. Once you selected a candidate, you also have to find a uterus. My understanding is when Brännström was doing his, these were live donors of a family, is that right? Because I think the one he talked about was mother to daughter.
(5) The Complexities of Uterine Donor Selection
[Dr. Elliott Richards]
Well, yes. In Sweden, and my understanding is in really every other European trial that I can think of, the patient essentially has to bring their own directed donor. The vast majority of cases, this was, say, a mother to daughter. That in itself is somewhat problematic because it means it discriminates against people who don't have a willing family member, and family relationships are complex enough.
I can't imagine a daughter-to-mother relationship and then suddenly you're adding in the complexity of a donate uterus, and not even just when things go right, but also when things go wrong. Because now there's a sense of guilt for a mother who's like, "I've now failed my daughter twice. I didn't give her a uterus, then I gave her a uterus transplant failed." There's certainly been some psychological fallout in sequelae from these failed transplants in the Swedish trial and others.
In Dallas, they use actually non-directed donors, I believe, exclusively. These are labor and delivery nurses. Dallas found not only just huge interest in potential recipients, but absolutely massive interest in being a donor actually. I personally feel like the non-directed donor route, it is probably the best way to go.
[Dr. Mark Hoffman]
There was a massive interest in being a donor?
[Dr. Elliott Richards]
Being a donor. Correct.
[Dr. Mark Hoffman]
Wow.
[Dr. Amy Park]
Is it just because hysterectomy, they were going to get their uterus out anyway or they just--
[Dr. Mark Hoffman]
I would think you wouldn't want a uterus that somebody else wants out though, right? If someone's got big fibroids or heavy periods or adenomyosis, these have to be like great shape uteruses?
[Dr. Elliott Richards]
These are multiparous women who felt that their childbearing was done and they wanted to give that gift to another woman, and I think that was something that-- I mean, truly acting from--
[Dr. Amy Park]
Altruism?
[Dr. Elliott Richards]
Yes. Now, at the Cleveland Clinic, we use exclusively a deceased donor model. We decided the ethical complexity of subjecting a living donor to the risk of this procedure because procuring a uterus is not the same even as a radical hysterectomy. In every major series, there's been complications to living donors. We decided early on to pursue a exclusively deceased donor. I do think now that the science as well, that so much more is known, that there's a high likelihood that we will consider having a hybrid approach for our next trial. That was our rationale for being deceased donor only. There's certainly pros and cons of both, and I'm happy to talk about the relative merits because it's not as black-and-white issue there either.
[Dr. Mark Hoffman]
There's a great video, I think it's from your fertility sterility article on YouTube about your program and with the video of the organ procurement of the hysterectomy. It's a fascinating video. It really is an incredible video to show. It's not a simple hysterectomy what you guys are doing.
[Dr. Amy Park]
What are the pros and cons since you alluded to it? I am assuming that tissue is better with a living donor versus the deceased. Deceased, you can get more radical, I guess to the parametrium.
[Dr. Elliott Richards]
First of all, with a deceased donor, you can take the internal iliacs with the uterine artery vein, and so you're just getting much more wide excision than you can with a living donor obviously. There is potentially longer cold ischemia time with the deceased donor, especially if you're procuring. We've altered our radius a couple times in terms of procurement radius, how far out from our institution that we'll go. A further-out procurement means that you have longer cold ischemia time for that organ.
Although our data, especially as we've shared and compared with the Baylor group, we don't see any difference in outcomes. These are still small sample size number. I'd say the biggest disadvantage of using a deceased donor-- Well, there's three actually. One is that we really don't get as much history. We're relying on secondhand information in the medical record. Whether it's a living donor, you can get just such extensive information from that individual. The second thing is that there's really something to be said about a planned surgery. You can put on a date. You can assemble all the teams. Doing a uterus transplantation is an incredibly complex endeavor. Really, you need to have coordination between transplant teams. You have a procurement team, of course, and then you have the transplant team itself. The vaginal anastomosis and the vessel anastomosis, these are done by different teams. If you can do with the living donor and you can set everything up ahead of time, that has great advantages over a deceased donor where the call is always in the middle of the night and it's suddenly, everyone's canceling all their clinic. Transplant surgeons are used to that. Gynecologists, that's not really how we roll. The challenge is there.
[Dr. Mark Hoffman]
Well, you had mentioned on the video, one of the benefits of the deceased donor was that you could take more vagina because you're trying to take a lot less tissue than the living donor, right?
[Dr. Elliott Richards]
Yes. Number one is that you're not putting a living donor at risk. It's not just vagina. Typically, I think it's an interesting question for transgender transplants because now, you're suddenly making a neo vagina and attaching this uterus. Having potentially a bigger donor vagina to add may be an advantage, but really, it's the increased vessels and also time of procurement.
Our first deceased donor procurement, our portion, obviously, it's combined with other transplant groups and they're harvesting lifesaving organs first, and we're doing our first dissection at the beginning and then they harvest and then we're right at the end because we're, of course, doing a vaginotomy and there's a concern for those lifesaving organs potentially seeding bacteria and whatnot.
The uterine veins is what's technically most challenging and why a uterus procurement is not the same as a radical hysterectomy because these uterine veins, they're anomalous, they're different. Oftentimes, they're wrapping around the ureter and it's critical for venous outflow. It's really those veins that are so challenging. When you have a deceased donor that you don't need to preserve the ureter, you can move a lot quicker and faster. The living donor groups have really brought the operative time down. There's been a big push and focus on robotic and minimally evasive surgery. That's why I think that the field is much more mature in terms of using living donors. In the beginning, they were doing 12 plus hours surgeries to procure this uterus, so by no means a radical hysterectomy, much more complex.
(6) Securing Blood Flow: Techniques in Uterine Transplant Surgery
[Dr. Mark Hoffman]
Once you've got a uterus out, I imagine putting it back in looks a little different. What's the major blood supply that you're using on the recipient to attach the uterus to? I guess you've got some collateral blood supply with the utero-ovarians as well. Are you using all four primary blood supplies for the uterus, and where are you attaching them?
[Dr. Elliott Richards]
Inflow is typically just hooking up the uterine arteries to the external iliacs.
[Dr. Mark Hoffman]
External. Okay.
[Dr. Elliott Richards]
There's some variations that have been shown and proposed and I've seen with the internal iliacs before. In terms of outflow, because that really is the biggest challenge, it's typically the uterine vein to the external iliac vein. As you say, the utero variant has been used as an alternate outflow. Our group has actually published a paper using a Y graft. We actually had a intraoperative, the venous outflow completely clotted off. We thought we were done.
We were closing up and just said, oh, let's do Doppler studies, and then it completely clotted off. Our team, brilliant, used a graft of vessel from that same deceased donor and patched in to the external iliac through this patch. The utero-ovarian effect, the United States Uterus Transplant Consortium, that's this group that I mentioned that's highly collaborative. We published a paper really arguing that we should change terminology somewhat.
We've argued for the change in nomenclature for the inferior uterine veins and arteries and the superior uterine veins and arteries to really emphasize that this utero-ovarian calling it the superior uterine veins because they, of course, anastomose with that plexus along the lateral edge of the uterus. A lot of groups will certainly, if they have difficulty, they're not able to get a good outflow or good specimen, inferiorly, they'll use the superior veins for outflow.
There's some then ethically problematic cases in China and India where they did oophorectomy on a living donor to get access to that outflow through the ovaries. That's just simply not acceptable for a living donor. It's really just that short branch that can be used on the superior uterine veins.
[Dr. Mark Hoffman]
Wow. It's incredible. Honestly, I think that we still have so much more to get through with all this stuff too. I'll try to move things along for--
[Dr. Elliott Richards]
I apologize.
(7) Immunosuppression in Uterine Transplants: Balancing Graft Survival and Pregnancy
[Dr. Mark Hoffman]
Listen, this is fascinating, but I also want to be courteous and appreciative of your time, but I do want to get to the other side of it too, which is, once it's in place, we've got two pretty big things to think about, one of which is this is a donor organ, a graft, so patient's immune system has to be managed in a way that will allow that graft not just surgically but also immunologically to be able to survive. You're putting little extra added challenge of having a pregnancy. Obstetricians deal with complicated pregnancies in regular uterus all day. How do you manage the graft versus host, and how do you do that in a way that is safe for pregnancy?
[Dr. Elliott Richards]
We had the advantage of liver-kidney transplantation has been around now for several decades, and those transplant recipients get pregnant. We had a lot of prior data to go on. The advantage that we have with uterus transplant, of course, is that most liver kidney recipients who are pregnant oftentimes have comorbidities that are, again, selected patient population that we're doing for these initial uterus transplant trials are selected because of their lack of comorbidities.
A couple things on that point, another thing that differentiates uterus transplant from other organs is that it's truly the first and only ephemeral transplant, a term coined by Dr. Tzakis at Cleveland Clinic, meaning that this is an organ that's put in with the expectation that it's removed later. This isn't lifelong immunosuppression, it's potentially just a year or two of immunosuppression. Then that immunosuppression is stopped.
Patients who undergo uterus transplantation, first, there's an initial induction therapy. Oftentimes, that's done with MMF, tacrolimus, steroids, and then often switched to azathioprine. Typically, our patients are on just tacrolimus and a low dose of prednisone with levels checked essentially weekly for their tacrolimus levels. We've been monitoring kidney function, and in fact, there's a study hopefully coming out soon from the consortium where we've, again, pooled our data to look at any evidence of renal damage in these patients.
Again, that advantage is is that once they've completed their childbearing, which is typically one or sometimes two live-born children, the graft is removed. Even in those patients where we see increase in their creatinine, we see a recovery.
[Dr. Mark Hoffman]
That's incredible.
[Dr. Elliott Richards]
Absolutely, immunosuppression is not something to be taken lightly. It definitely has its own risks and particularly costs. That's actually where a big portion of the cost of uterus transplant actually comes in because they're not cheap medications.
(8) The Promise of Uterine Transplants: IVF, Embryo Implantation & Beyond
[Dr. Mark Hoffman]
Makes sense. We've had these other organs transplanted for a long time and many of these folks have become pregnant. The other thing is, I guess IVF has to happen. You have a vagina and a cervix and a uterus, but there's probably no fallopian tubes. There's no way for natural insemination to work, correct?
[Dr. Elliott Richards]
That is correct. I do think that it's possible in the future that the fallopian tubes could be preserved. I don't see a reason why we couldn't do this without in vitro fertilization. Currently, the concern about this already being a risky enough procedure, the added risk of ectopic pregnancy, or just infertility in general, other forms of infertility that are now unmasked, is too great. I'm not aware of any protocol currently that retains the fallopian tubes. They're typically removed at time of the procurement of the uterus. IVF is a great question. That goes into-- I kind of just quickly talked a little bit about our screening process. There's a lot of medical exams that we're doing, imaging and serologic testing and other things. One of the things before we actually put someone on the waiting list for an organ is we do IVF.
[Dr. Mark Hoffman]
I was going to ask when that happened in the process, you got to prove you can make an embryo before we give you a uterus.
[Dr. Elliott Richards]
Yes, and that's an interesting question, or an interesting point rather because we think, okay, what is the purpose of this surgery? There's something called the Montreal criteria, which is the first sort of framework, ethical framework. It's been hotly debated, but the essential idea is that the purpose of uterus transplantation is for childbearing and to give the experience of pregnancy. There's been a lot of criticisms of that ethical framework, and it's been revised.
Essentially, because you have patients who like, let's say, have complete androgen insensitivity. These are XY individuals who are phenotypically female but don't have ovaries, also don't have a uterus, are they candidates for uterus transplantation? Of course, we mentioned briefly the transgender woman who would want to bear children, but there are those questions of gametes. Currently, uterus transplantation has only been done for those who have ovaries, who have the potential for eggs.
[Dr. Mark Hoffman]
Then my guess is these conversations happen early in IVF. In the VA, they cover IVF, but you have to be married. There's still some relics of that in current systems too. This seems like inevitably, this will evolve to include a much larger population of individuals who have absolute uterine infertility.
[Dr. Elliott Richards]
Absolutely. To answer your earlier question, in our protocol, we want six cryo-preserved embryos before we put them on the transplant waiting list. University of Alabama I believe is just three, but they use PGTA, so pre-implantation check testing to confirm euploidy. Actually, ASRM has a committee opinion about uterus transplantation that actually is in desperate need of revision. There's some major flaws, it was done pretty early on in the process. Essentially, there isn't a set number for how many embryos you need to cryo-preserve. I've done now two different patients in one patient multiple rounds of post-transplant egg retrievals. Those were a little scary at first because you can see this parametrium in these donated vessels, in some cases, just right in the way of the ovary. It's a situation that we wanted to avoid, but we ran out of embryos without getting her pregnant.
[Dr. Mark Hoffman]
Wow, yes, because the ovary sits right on the external. It's like hanging out over there normal, you're not having to multiply the uterus from that neighborhood actually had done surgery recently on somebody with a uterine anomaly and had just like the left side of the uterus, vaginal agenesis, and the blood supply was primarily off the external iliac. That was definitely a-- I told the resident I'm just going to do this part of the surgery. It was stress-inducing, I was like, "Where in the world?" It was one of those MRI, we looked at a thousand times, and then we did it until, oh, pull the uterus this way and the external goes, whoo, moves over. It's the one part of this I can relate to, which is playing near the external iliacs.
Are you all putting more than one embryo in?
[Dr. Elliott Richards]
Absolutely not.
[Dr. Elliott Richards]
In fact--
[Dr. Amy Park]
Let's not stretch this thing.
[Dr. Elliott Richards]
Yes.
[Dr. Amy Park]
Too much.
[Dr. Mark Hoffman]
Come on.
[Dr. Elliott Richards]
It's interesting because we have one patient who has recurrent implantation failure, where I've met with people all over the world to try to figure out what we can do for this patient. Actually, through that process, we found that almost every major has at least one patient who despite having high-quality embryos, despite having what looks to be a high-quality graft, good lining, everything else, having trouble getting pregnant.
This patient is sort of we've tried almost everything you can think of, and she was really pushing, "Can we just put two embryos in?" The problem is, if we were to have a twin gestation, the media fallout and the pushback we would get. This is such a sensitive time early on in the field. Everyone's very cautious. Anything we can do to reduce risk, we will do.
[Dr. Mark Hoffman]
The risk of twins even with one embryo is higher, I think, in IVF?
[Dr. Elliott Richards]
Yes, to have a splitting of the embryo say that like monozygotic twins, that's pretty rare, pretty on par with nature. Certainly putting two embryos in with a high prognosis patient, you're looking at 25 plus percent chance of twins, which is unacceptably high risk.
[Dr. Mark Hoffman]
The uterus is a dynamic organ, like a nonpregnant uterus, and a uterus at term are two very different looking, acting, functioning organs. To implant a nongravid uterus and sit and wait and watch for it to grow to term, and thinking about all the changes that happen in the uterus, and the blood vessels and all those things, and the thing that an implanted uterus can still do all that, to me, is just miraculous.
It is just an unbelievable-- I can't imagine waiting that first term kid, like waiting for that vessel to tear like for nine months, just like, oh, with every minute of every day waiting, but the fact that they've worked. What are the success rates? Again, the whole thing, we can talk about the miracle of pregnancy, but this is a real miracle. This is something miraculous and a new definition of the word.
[Dr. Elliott Richards]
Absolutely. I think it really just shows that the uterus truly is the most miraculous organ, its plasticity, its regenerative abilities really doesn't exist anywhere else in the human body. Arguably, maybe the ovary has some similar properties.
[Dr. Amy Park]
No, it's the vagina.
[Dr. Elliott Richards]
Yes, okay. We'll say the female reproductive tract is just amazing, its ability to accommodate and to change. I will tell you, the most amazing MRI that I've ever seen in my life was that first MRI from our first successful uterine transplant graft, because it looks so normal. It looked like it had always been there. I had to just say to myself, nope, this did not exist in this person's body one day ago. Then the fact that that patient went on to have a live-born child who, every year at least, we get updates and pictures, and it's just this beautiful child who, it's simply remarkable and amazing.
(9) Defining Success in Uterine Transplants
[Dr. Amy Park]
What is the success rate like? There's two levels of success rates. There's one, the successful uterine transplantation, but then you also have successful pregnancy, live birth.
[Dr. Elliott Richards]
Yes, you've touched on a really important thing that also differentiates uterus transplants from any other type of graft. If you think about it, oftentimes, you can gauge the success almost immediately. In this case, the United States consortium has actually defined five levels or milestones of success. Initially, beginning of menstruation, really fascinating to see a woman so excited to get a period because she really missed out on that life experience. They report that it gets old after a couple of months, but it's very exciting the first couple of months.
[Dr. Mark Hoffman]
How many periods does it take to be asking for a [crosstalk]?
[Dr. Amy Park]
That's hilarious.
[Dr. Elliott Richards]
I can go over all the other milestones, but ultimately, the measure of success is a baby at the end of the day. That isn't determined until potentially years later. Interestingly, with the uterus, we have access to the organ externally through the cervix. These patients will undergo cervical biopsies on a regular basis, and we can monitor for rejection. They're relatively non-invasively, which is pretty remarkable.
What we've seen in our program, and this matches with other programs in the country, is that if we can get the graft to remain viable for two weeks after the surgery, we're going to keep that graft. All of the graft losses that we've had and our other colleagues have had, typically, that happens in the first couple of days, sometimes as late as day 12. Those first two weeks are critical.
Once we can have a one-year graft survival, when we looked at our data, and this is a JAMA paper that we put out our group, Baylor and Penn together sharing our data, we found a 74% pregnancy among those with a viable graph, there's actually an 83% live birth rate, better than IVF. Again, we are sort of cherry-picking patients because we're taking the best patients and we're cryo-preserving embryos, but that's a pretty darn good success rate.
[Dr. Mark Hoffman]
That's incredible.
[Dr. Elliott Richards]
Then those who actually have-- sorry, that was by 74% was the one-year graft survival. 74% have all been successful. As you trend that, the numbers have gone up. Both in our gestational age at delivery and in graft survival at one year, as you look at the different centers, it's been a linear upsloping just as we've gotten more experienced and more comfort.
[Dr. Amy Park]
How many pregnancies do people end up having with their transplanted uterus? So far, is it just one each or how has that worked out?
[Dr. Elliott Richards]
Last September, we just had our first second baby from the same uterus. Prior to that, all of our patients elected for a cesarean hysterectomy. Dallas has delivered-- I can't recall off the top of my head how many double bursts they've had. I believe they even have one patient who, after much back and forth and discussion and counseling, and she's going actually for a third, which was not their original intention but also speaks to the fact that these women have autonomy.
[Dr. Amy Park]
Is the mode of delivery all C-section or can you do vaginal?
[Dr. Elliott Richards]
Yes, cesarean section. No one has, and I don't think will, at least in the foreseeable future, do anything else but a cesarean.
[Dr. Mark Hoffman]
Has anyone gone into spontaneous labor and dilated? It's one of those things you may find out when they show up to the hospital, right?
[Dr. Elliott Richards]
We've certainly had patients where we're picking up uterine contractions. We've had PROM in one patient. She, and actually both of her pregnancies, had premature rupture of membranes and had contractions. She couldn't feel those contractions, but we were picking them up.
[Dr. Amy Park]
How did you know they had PROM because they don't have a vagina, right?
[Dr. Elliott Richards]
Yes, they do. No, they absolutely have to have-- in fact, all of our patients, because they're all MRKH patients, they all had vaginal dilation and then the vaginal anastomosis, because think about it, you still need to have an outflow tract, and so the menstrual effluent has to go out through the vagina, so that's where it was detected.
[Dr. Amy Park]
Wow. See, clearly, I'm not that familiar with the uterine technique, [laughs] but it's pretty amazing.
[Dr. Mark Hoffman]
Every step of it, right? You have to think about every single step of fertility, reproduction, pregnancy, labor, and all of it. In fact, you just said something that-- I wanted to sound like I had done some homework today, but yes, they can't feel contractions. There's no nervous connection. There's no way for patients to know. Are they just like feeling their belly get tight? How do they know they're having contractions?
[Dr. Elliott Richards]
This is where it'd be great to get some of the patients on a future podcast to share some of their experiences from a patient standpoint. Certainly that they're able to still feel baby move, but yes, in terms of innovation of the uterus, the cervical biopsies that we'll take, they sometimes will feel some discomfort, most likely because that point of the anastomosis in the vagina. IT brings up an interesting side note.
I know one of the questions that you were interested in is problems and challenges from a reproductive standpoint. A big proportion of these patients have vaginal strictures and stenosis. In one of the European trials, it was actually quite severe that they actually had to place stents in the vagina because of such severe scarring because once you lose that vaginal access, it's not just for the menstrually effluent but also placing your transfer catheter through. The concern about needing to do a D&C for early loss, how do you get access to the uterus?
Luckily, even in our more severe cases, we've never lost access through the vagina. Our patients have been very good with either vaginal dilation, or in a couple cases, we've had to take them to the OR just for revision surgery or digital dilation, but very interesting doing embryo transfers when you can't see the cervix at all and you're completely reliant on ultrasound guidance just to find the donor cervix because you're beating your little transfer catheter through a three-millimeter hole. On that topic of unforeseen challenges and things that can arise that you take for granted in most patients.
(10) Exploring the Future of Uterine Transplants
[Dr. Amy Park]
Wow. Well, I just wanted to ask, what do you see as the future? You've alluded to it. It sounds like there's some cash-pay programs, multiparous uteri. Do you think it's going to be like more centers doing it?
[Dr. Mark Hoffman]
Are they going to be growing uteruses in a lab?
[Dr. Amy Park]
Yes, Tony Atala's lab.
[Dr. Mark Hoffman]
Yes, Dean Kamen, one of the Segway guy. That was his next big thing, was growing tissue in labs.
[Dr. Elliott Richards]
Yes. No, actually, Mats Brannstrom has some papers of porcine models using bioengineered uterus. I think that, again, the uterus is this kind of magical organ that is able to completely transform itself. I'm a little skeptical that we have anything on the near horizon in terms of bioengineered uterus, but that would certainly sidestep so many of these ethical concerns and with immunosuppression and everything else, if you could just take someone's cells and grow a made-to-order uterus. I think one day, we'll probably get there.
In terms of what I see for the future, so one is, and you touched on this, is cost. We're looking, as I said, cost-effectiveness analysis. I led the effort to get a CPT code and I'm really pleased to say that we were able to get a category three MCPT code. There's a billing code now for transplantation that came into effect about a year and a half ago. We're working to get that to category one status. Really, to be able to convince insurers to pay, there's work with resolve and really saying, okay, we need to treat infertility as a disease and look at the treatments that are required to help patients for their particular diagnosis.
We also need to understand what is the cost. That's a big area of attention and focus. Another thing is the shortage of available donors. We did an analysis of a paper we're hoping to publish, we meaning the consortium, looking at deceased donors. We estimate because if you think about it, for a deceased donor, they need to be a brain-dead donor, they need to be female, they need to have a uterus, so not a prior hysterectomy, and ideally have a prior delivery of that uterus and need to ideally be lower risk.
When you start adding all this criteria, suddenly, our estimates are that it may only be in the range of 300 or 400 potential uteruses in the whole country from deceased donors. That's not even taken into account the fact that we need consent from families and other problems such as that. Really, the living donor route probably is our way to address what we see is what the demand is.
Which is another question, what is the true demand for this? Right now, we know that we've had 5,000 people approach these three centers in the last five years, but what is the true demand? I already mentioned transgender and gender-diverse populations, but disadvantaged groups. It shouldn't be that, but it is a fact that 88% of the patients in the US who've gotten uterus transplants are white. That's certainly not reflective of the AUFI population.
Other things I see in the horizon are really leveraging minimally invasive surgery techniques, robotic surgery, and then considering the fallopian two preservations we talked about. I think that it's a really exciting time. I'm so grateful to be a part of, if not the very ground floor, just shortly after the beginnings of this just truly innovative reproductive technology.
[Dr. Mark Hoffman]
It's incredible. Thank you so much for your time with all the things we listed at the beginning of the show. I know your time is quite valuable, and so it means a great deal to us and to our listener that you were able to come here and share your experience and share the experience of the patients who you've taken care of and what must be an incredible feeling to be doing work that's never been done before. That's truly groundbreaking.
We don't get to do that in medicine very much, and so thank you for not just your time today, but thank you for doing the work you're doing. Again, my wheels are spinning all the things that we joked at the beginning, how are we going to fit this into an hour? I feel like we had to run through this. We've had a number of these shows already and I don't think I've felt as rushed and press for time to get through this just because of the volume of information just to get to the very basic, bare-bones process for uterine transplant. Thank you. Amy, do you have any other thoughts as we finish up here?
[Dr. Amy Park]
I just want to say, world, look out for Elliott Richards. He is coming your way big time, and I am so appreciative that you've made the time for this show. I know the listeners will be super appreciative of all your insights, lots of interesting aspects to it, and we're just looking forward to what the future will bring.
[Dr. Elliott Richards]
If I could add with just a final plug, we've been invited, myself and Kate O'Neal, and Lisa Johansson, so us representing those three centers I mentioned, how we've been invited to sponsor a debate on uterus transplantation at ASRM this year. Please, for those listening, if you're going to be going to ASRM, please check that out. The day and time, I believe to be announced.
[Dr. Mark Hoffman]
That's great. Well, thank you again. Amy, it's always good to work with you. Elliott, thank you so much for your time. That was so much fun. We look forward to chatting with you again at some point soon.
[Dr. Elliott Richards]
Great. Thank you. Take care.
[Dr. Mark Hoffman]
Thank you so much for listening. If you haven't already, make sure to follow the podcast, rate it five stars, and share with a friend. If you have any questions or comments, direct message us @_backtableobgyn on Instagram, Twitter, or LinkedIn. BackTable OBGYN is hosted by myself, Mark Hoffman.
[Dr. Amy Park]
And Amy Park.
[Dr. Mark Hoffman]
The views and opinions expressed by the hosts and guests on BackTable OBGYN are their own and do not reflect the views or positions of their employers or any entities they represent.
Podcast Contributors
Dr. Elliott Richards
Dr. Elliot Richards is the Director of Research in the Department of Reproductive Endocrinology and Infertility at the Cleveland Clinic.
Dr. Amy Park
Dr. Amy Park is the Section Head of Female Pelvic Medicine & Reconstructive Surgery at the Cleveland Clinic, and a co-host of the BackTable OBGYN Podcast.
Dr. Mark Hoffman
Dr. Mark Hoffman is a minimally invasive gynecologic surgeon at the University of Kentucky.
Cite This Podcast
BackTable, LLC (Producer). (2023, April 6). Ep. 20 – Uterine Transplant [Audio podcast]. Retrieved from https://www.backtable.com
Disclaimer: The Materials available on BackTable.com are for informational and educational purposes only and are not a substitute for the professional judgment of a healthcare professional in diagnosing and treating patients. The opinions expressed by participants of the BackTable Podcast belong solely to the participants, and do not necessarily reflect the views of BackTable.
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