 First speakers today, and I will introduce both of them. And that is Dr. Andreas Stzakis, who leads the transplant program at Cleveland Clinic, Florida. Dr. Stzakis is a renowned transplant surgeon. And then Dr. Rick Kodish, who's the chair of the Department of Bioethics at Cleveland Clinic Foundation and Professor of Pediatrics, Lerner College of Medicine at Case Western University. And Dr. Stzakis and Kodish will be speaking on the provocative topic of ethical issues in uterine transplantation. I think Dr. Stzakis is speaking first. Thank you very much. And I want to thank Dr. Siegler for the kind invitation and the McLean's for having made this possible. So the subject is uterus transplants. Why should we talk about uterus transplants? Uterus transplants is intended to be as an option for uterine infertility, which is due to either absence of the uterus congenital, as in the Rokotansky syndrome, or surgical. Usually, hysterectomy is done for bleeding or for cancer, for tumors, or it can be due to dysfunction from infection short abortions. It's a common problem. There are about 50,000 women in the United States alone who have uterine infertility. Now, if they want to have children, at the moment they have two options, adoption and surrogacy. And these have been great options for thousands of women. There are thousands of happy families as a result. But these options are not possible for others. The adoption saves lives. It saves lives because there are more than 20 million children in the world that are orphaned and they need their home. Adoption gives them an opportunity for a life, a new life. It also saves a sick mother from the risk of a pregnancy that could be dangerous for her life. On the downside, there is no genetic relationship of the parents to the child, a fact which is prohibitive for some families. There is a relative shortage of available children. The process of adoption is lengthy and expensive. And families resort to adopting children from other countries. At times, international adoption is subject to diplomatic games between governments. Surrogacy provides parents with a child that's genetically related to one of both parents. It also obviates the need for pregnancy by the mother and spares a sick mother from a dangerous pregnancy. It is an ancient practice. From the Bible, Sarah could not conceive. So she offered her Egyptian slave, Hagar, to Abraham to bear his children. There was a problem, though. As soon as Hagar became pregnant, she became very difficult to live with. So they asked her to leave the house. Indeed, she left. But then the angel told her that her son Ishmael will be a leader of the Jews. And she had to go back. So she went back. But then Sarah miraculously became pregnant. And after Isaac was born, Hagar was sent away for good to the land of Paran. So there were some problems with surrogacy, even in antiquity. Now, in modern times, there are no national policies. Several states expressly prohibit surrogacy. So agreements signed are unenforceable and void simply by crossing state lines. The cost is significant, more than $100,000, today's money. Most insurance policies do not provide coverage for surrogates. So who is responsible for maternity benefits? Who is responsible for complications? What about postpartum depression? Then there is a risk of exploitation of poor women by attracting them to a career in commercial surrogacy. This danger is present and clear. If you have any doubt, just Google career in surrogacy. So although adoption and surrogacy have been great solutions for many women and families, they are not acceptable for others. Utterine transplantation is intended as an option for these situations. So what is so different about this transplant? First, it is not a life-saving procedure. In this way, it is not different than phase or extremity transplants. As a matter of fact, kidney transplants till recently were not thought to be life-saving, just improving quality of life. We now know that they also save lives, prolong lives. But this is the first ephemeral transplant to ever be attempted. A transplant, which is not intended to last for the duration of the patient's life, but only till the goal of successful pregnancies is accomplished. Indeed, support for with immunosuppression will be discontinued, and the uterine graft will be removed or left to atrophy. In uterine transplantation, there are three lives at risk. The mothers, the donors, and the offsprings. And the risks cannot be overemphasized. The risks to the mother are surgical, obstetrical, and the risks of immunosuppression. The surgical risk of the transplant itself is probably equivalent to that of a kidney transplant. Indeed, it has been done safely in many experimental models. The immunosuppression is similar to what we use in other solid organ transplants, like kidney transplants, but it will not be lifelong. It is expected to last no longer than three or four years. The pregnancy will be a high-risk pregnancy, and will have to be followed very carefully by a qualified obstetrical team integrated to the multidisciplinary transplant team. Experienced with well over 1,000 recipients of solid organs who became pregnant and deliver babies have shown that there is a high risk of preeclampsia and eclampsia. They are frequently related to preexisting comorbidities of this patient as diabetes or hypertension. Uterine transplant recipients are expected to be healthy without comorbidities. So this risk should be minimized. The risk to the donor in case of a live donor is equivalent to that of a radical hysterectomy. And then last but not least is the risk to the offspring. The effects of the immunosuppression on the offspring are well known. There has been no teratogenesis with a commonly used immunosuppressants, cyclosporine, entachrolimus, and steroids, and anti-linfocytes globulins. The use of mycophenolate morphetil is associated with teratogenesis as it discontinued during pregnancies. Babies born from transplant recipients are normal, although frequently small forage. Cyclosporine entachrolimus cross the placenta so attention is paid to renal dysfunction and hyperkalemia, which are temporary and resolve within a day or so after delivery. Gestation and delivery are species-specific, although extensive studies have already been performed in small and large animals and demonstrated successful outcomes. The effect of growing in a transplanted uterus in humans is a process we all anticipate in all. In closing, we propose that uterine transplant is a project worth pursuing, because if successful, it'd be a valuable option for women with uterine infertility. Thank you. Again, to talk about the ethics a little bit by referring to something called the Montreal criteria, which were specified about a year or two ago. It's for the ethical feasibility of uterine transplantation and the authors from Montreal talk about recipient criteria, donor criteria and the healthcare team as the three areas to look at. And I'm not gonna go through the whole thing, but I wanna point out that they require that the recipient be a genetic female of reproductive age with no medical contraindications to transplantation. The fact that the first sort of order of business is to specify that the recipient should be a genetic female I think signals to us something that we should be thinking about because part of our job as ethicists is to think about future problems and anticipate them. And certainly the possibility of uterine transplant into a male is something that is proscribed by the Montreal criteria right now. I'm not gonna go into that today, but I think a few years from now we may be talking about that. What I also wanna say is that criteria one C is that the person has either a personal or legal contraindication to surrogacy and adoption measures and desires to have a child or two, the person seeks a uterine transplant solely as a measure to experience gestation with an understanding of the limitations provided by uterine transplant in this respect. They go on to talk about donor in the healthcare team which I'm gonna skip over and would point out that the Montreal criteria don't talk about the fetus or child at all which I think is a gap. As a pediatrician I wanna also acknowledge that this is a little bit out of my comfort zone but I've been studying informed consent for many years and that is a place I'd like to begin. For a uterine transplant to be ethically permissible I think we would all agree that there are important informed consent considerations and there would be four involved parties in my mind. There would be the recipient, there would be the donor, there would be the fetus slash infant and then there would be the father of the fetus slash infant. When it comes to consent for the recipient there would be a number of challenges. I think helping her to understand the very experimental nature of the procedure. The risks, benefits and alternatives which Dr. Tzak is outlined. Consent for the donor would be very different depending on whether the route chosen was a living donor or a cadaveric donor. If it's the former I think the consent process would be a lot like that which we've developed for living kidney donors and living liver donors. A key component of that would be to rule out coercion or financial compensation for the uterus. If the organ is a dead donor I think the consent process needs to go beyond the routine discussion with survivors because of the experimental nature of the transplant. What about the fetus or infant who is gestated as a result of a uterine transplant experiment? We've talked about a separate advocacy team for the fetus infant consisting of a pediatrician, a clinical ethicist, and a pediatric nurse or social worker. A team that would monitor the progress of the pregnancy and follow the infant in the first several years. And we feel this is important because the stakes of a pregnancy in a uterine transplant situation would be very high and the parental decision making could be constrained in a number of ways. And that's a piece to the Montreal criteria that we would add is important I think. And finally, as I said in many cases there will be a father involved in giving the novelty of the procedure and the likely focus on the recipient and the fetus slash infant. I think there's considerable risk that his perspective would be ignored or minimized and I think that would be problematic and should be avoided. So those are some informed consent considerations. Beyond informed consent, I think there are several other important ethical considerations. One is the role of cultural sensitivity and the variety of religious and cultural perspectives that impact attitudes toward the acceptability of this procedure. And I'm gonna do on one hand and on the other hand here. On the one hand, our initial research suggested for many Muslim families, neither surrogacy nor adoption is a viable option if uterine factor infertility is the diagnosis. And we think that that may increase the relative interest in this procedure among the Muslim community. By contrast, the Catholic faith tradition has a prohibition on many forms of reproductive technology and that might be a problem among Catholics for uterine transplant. My purpose here is not to provide an in-depth analysis of these considerations. I have neither the expertise nor enough time to go into it, but only to signal that I think these religious and cultural considerations are really, really important as we tackle this ethical challenge of uterine transplant. Another area of critical importance that was mentioned this morning is moral imagination. And by this, I mean to say that an excellent clinical ethicist must have the ability to think both with a creative and empathic approach. As it relates to uterine transplant, my first reaction was of admittedly narrow moral imagination. I could not imagine why someone would go through something like this to have the experience of pregnancy. Assuming that there were other ways that is adoption of surrogacy to get to that end goal of having a child. I tried my best to use my moral imagination to understand how this could be meaningful and important enough for someone to accept the accompanying risks and uncertainties. As my friend who's a physician in Portland said when I mentioned this whole idea to he said, that's crazy, why would someone want to do that? And I have to admit that was my initial reaction as well. But I remember that God gave us two years in one mouth for a reason, and we should always listen twice as much as we talk. And that helps us to develop our moral imagination. So I talked to my wife first, having never been pregnant. It was the closest I could do. She was pregnant three times and she stated conclusively that the experience of pregnancy, nausea, back pain, labor delivery were difficulties she could have easily done without. It was the pot of gold at the end of the rainbow. It was the three wonderful children we have that are a blessing that made it worth it for her. I spoke to other women who had experienced pregnancy. I think the vast majority, as I listened, felt the same way about this issue as my wife. But several women that I talked to took the opposing view and said the experience of pregnancy itself was wonderful and meaningful. I got the sense from some of them that it was holistic and helpful as a conduit to positive maternal bonding experience. And that this might be lost if an adoption or surrogacy option was taken. So this informal survey is decidedly not rigorous, not scientific, but it allowed me to change my thinking a little bit and hopefully allowed me to cultivate the moral imagination that I think a good ethicist needs to have. Finally, I want to do a little transplant ethics casuistry with you. As some of you know, I had the privilege of being involved with the first North American face transplant. And as we come up on the five-year anniversary of that, I think it's important to reflect on that experience and try to do some comparison in the ethical analysis of uterine transplant, vis-a-vis face transplant. So let's start with the question that Dr. Tsakis mentioned about what's a vital organ. Without going into in-depth, I think we would all agree that the heart and the liver are vital organs. There was some controversy about whether the face counts as a vital organ or not. But I think almost everyone would agree that the uterus is not a vital organ. So we can put that aside. I don't think it counts as a vital organ. It's not to say that we shouldn't transplant non-vital organs. So that's an important difference. An important similarity, I think, relates to progress in surgical innovation, something I know that's of great interest to many of you in this audience. And when it comes to progress in surgical innovation, I think the face and uterine transplant cases both have extensive pre-clinical science and animal experiments that lay the foundation for this first in-human operation. And looking back more generally at surgical progress, we find that this is truly one of the enduring questions in surgical ethics. When is the right time to cross the threshold and try something for the first time in a human being? Dr. Tsakis didn't mention this, but his colleagues in Sweden have answered this question by conducting a series of uterus transplants in the past year. I think they've done eight or nine. And we at the Cleveland Clinic, I think, feel compelled to learn from that experience before we go forward with our first uterus transplant. Finally, I think there's the issue of candidate selection. And we learned something in the face transplant process about that as well. We worked with a remarkable woman named Connie Kulp who was both courageous and generous. She was a victim of facial trauma. And as we spoke with her before she was listed, it became clear that she was motivated both to help herself and to allow us to learn something to help other victims of facial trauma. So she was committed to the scientific project, if you will. With any novel surgical procedure, this is the ideal, I think, because going first with the wrong candidate runs the risk of torpedoing the whole project. And as more cases are done and experience is gained, the issues of generalizability, which are standard for good clinical research, become more important and paradoxically, I think, case selection becomes less tightly controlled. So one final important lesson in this casuistry has to do with a very careful patient selection when it comes to the first North American uterus transplant. In conclusion, I'd like to say that uterus transplant may ultimately offer an approach to uterine factor infertility that is ethically superior to surrogacy. And I'm making a big normative judgment here, I realized, but I feel safe with this crowd. Ethically superior to surrogacy. I think the latter is plagued by concerns about commercialization, potential exploitation, legal uncertainty, psychological challenges, and my gravest concern, the risk of commodification of children. If the surgical technique in immunosuppressive science and the gestational questions of uterine transplant can be safely and effectively mastered, it may one day replace surrogacy and come to be seen as another landmark of improving the lives of people through surgical progress. So with that, we conclude, we look forward to your concerns and your questions and comments. Thanks.