At what cost experimentation…?

A new opportunity in reproductive technology has recently appeared in the news: uterine transplantation—referred to in the lay press as “womb transplants.” The experimental procedure was performed on 9 Swedish women in 2012 using live donors; they will soon be trying to conceive. The UK is preparing to follow suit using cadaveric donors. And not to be outdone, the Cleveland Clinic recently announced in a physician newsletter that one of their transplant surgeons is hoping to do the same, if the “ethical, procedural, and financial hurdles can be overcome.”

The accepted indications for uterine transplantation are loss of a uterus due to cervical cancer or Mayer-Rokitansky-Kuster-Hauser syndrome. MRKH is a congenital condition in which the uterus, cervix, and/or vagina are congenitally absent or underdeveloped and is commonly associated with renal abnormalities. It affects approximately 1 in 4500 female infants in the US who have a normal 46XX chromosomal complement and, as adults, have normally functioning ovaries. No definitive genetic cause has been identified.

On the surface, uterine transplantation appears to be a beneficial and hopeful procedure, one that would allow women to bear children who could not do so otherwise; and it would do so without the depersonalized use of artificial wombs (still on the drawing board) or the legal conundrum of surrogacy. It has, no doubt, raised the hopes of many women. But there are ethical concerns surrounding the current experimental risks of the procedure as well as looming issues with regard to costs and resource allocation.

Of primary concern is the ethic of human experimentation for a non-life-threatening condition (Jon Holmlund may have to weigh in here). Despite years of animal experimentation, to date there have been no successful pregnancies in primate models. In light of this fact, the first human uterine transplant was attempted in Saudi Arabia in 2000, but ended in a hysterectomy within 3 months due to thrombosis of the anastomosis. Turkey has also attempted one cadaveric transplant; the woman later conceived but miscarried. As one surgeon from Sweden stated, “This is a new kind of surgery. We have no text books to look at.” The transplant surgeon from the Cleveland Clinic concurred noting that they are “patching” together information from each animal trial in order to proceed with human clinical trials. Is such human experimentation legitimate? While human experimentation may be a necessary evil when life-threatening conditions are involved, it seems difficult to justify when the issue being addressed is not a “life-threatening” but a “life-enhancing” one.

According to the U.S. Dept. of Health and Human Services, in order to approve research on human subjects, Institutional Review Boards that oversee research protocols must determine that “risks to subjects are minimized by using procedures already being performed for diagnostic or therapeutic purposes,” and that “risks are reasonable in relations to the anticipated benefits.” But the question remains: who decides?

For the risks are not insignificant. Unlike most transplantation cases which involve sterile organs, this is a “clean-contaminated” case involving an elevated risk of infection due to the need to reconnect the uterus to the vagina. Using an organ from a live donor where the cervix and vagina cannot be sterilized exacerbates this risk of infection, as does required immunosuppression. The risk of clot formation in the anastomosis is real—as evidenced in the Saudi case–necessitating additional surgery to remove the transplanted organ. And even if the transplant is successful, further surgery is required to later remove the transplanted uterus, for this is considered a “new” kind of transplant—an “ephemeral transplant:” it is not intended to be permanent. After 2 pregnancies the uterus would be removed so that the need for immunosuppression would be eliminated.

But calculation of risk cannot stop with the recipient, for it involves two other lives: the donor and the fetus. The procedure needed to remove the uterus for transplantation is much more complicated than a normal hysterectomy entailing a laparotomy and greater risk to the donor’s renal system.

Finally, there are the significant risks to the fetus, whose survival is speculative at best. In order for these women to bear children of their own, in-vitro fertilization, with its attendant risks to the embryos, would be required since the fallopian tubes would not be anastomosed in the transplantation. It appears that the endometrium in these transplants is responding normally to the hormonal milieu, since some of the women have had menses, but what about the myometrium—the muscle wall: will it function properly, expanding and contracting, if a pregnancy occurs? Will there be greater risk for uterine rupture due to damaged myometrium—a life-threatening situation for mother and baby?

There is the additional risk of immunosuppressive drugs on the fetus. A British physician stated that the data from renal transplants “didn’t suggest” that the babies are at increased risk from the drugs. It is curious that in all other circumstances we are to practice only according to valid and reliable evidence, not suggestions. Human research should not be exempt; the risks of immunosuppression should rightly be proven before intentionally subjecting a fetus to those risks for the sake of another.

The greatest concern, however, is that of uterine circulation. The uterus has tremendous collateral circulation that is required for placentation and nourishment of the fetus; yet during transplantation, only the major uterine artery and vein are anastomosed. Will collateral circulation develop, and if so, how long will it take? Is one year adequate? How will one know—only when it fails? Abnormal placentation or vascular abnormalities place the fetus at great risk for miscarriage or growth retardation—essentially, intrauterine starvation. This is the greatest concern of the British researchers: yet having no answers, they move ahead, driven by the technological imperative—and competition.

Given the significant attendant risks, are there some hurdles that should not be attempted? Prudence would require that some level of success be achieved in animal or primate models before forging ahead in human clinical trials. In our obsession to attain one more technological milestone—an ephemeral uterine transplant–we have minimized or ignored the risks to all involved, and especially to the fetus who has become a disposable pawn in the desire for another’s self-fulfillment—an issue to be continued…

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Susan HaackChristian VerclerJon Holmlund Recent comment authors
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Jon Holmlund
Jon Holmlund

Susan, you ask me to weigh in but I have little to add to an excellent discussion. Your review of the relevant IRB issues is accurate and you appear to have done a comprehensive job of identifying and addressing the risks. Do you know if this topic has been addressed in the ethics literature? I think that with a few more nods to the human subjects research regulations, this discussion would be good to submit to the Hasting’s Center’s journal IRB, for publication. Because, as you ask, “who decides” whether risks are commensurate with the benefits of research? The IRB… Read more »

Christian Vercler
Christian Vercler

If you look at the situation with hand and face transplantation (vascularized composite allotransplantation, VCA), many of the questions you raise (which are all valid) were the ones raised before we started doing these. Some of the technical questions are partially answered: we have evidence in face transplant that significant collateral circulation develops rapidly. (I am not sure if they have published that yet, but we did studies at the Brigham that showed that.) Hands and faces are not sterile and that has not really been be a problem. Also, VCA largely has charged ahead before animal models have proven… Read more »