Uterine Transplants in Practice: Donor Selection, Procedure Technique & Immunosuppression

[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.

[Dr. Mark Hoffman]
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.