Moving forward rapidly in the clinical research phase, uterus transplantation may be a future treatment option for women with uterine factor infertility, which accounts for three per cent of all infertility in women. This new method of treatment would allow women, who currently rely on gestational surrogacy or adoption, to gestate and birth their own genetic offspring. Since uterus transplantation carries significant risk when compared with surrogacy and adoption as well as when compared with other organ transplants, it requires greater justification because its goals are quality of life, not life-saving, in their scope. It is important to address questions regarding the physical, psychosocial and ethical risks and benefits of uterus transplantation for all three parties involved—the patient, the donor and the potential child—as well as discuss the regulatory implications as research on uterus transplantations moves forward.
- Reproductive Medicine
- Obstetrics and Gynaecology
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The experimental technique of uterus transplantation is moving forward into the clinical research phase and would represent a new level of collaboration between transplant medicine and assisted reproductive technology (ART). Currently in animal and early human studies, uterus transplantation may someday be a treatment option for the three per cent of infertile women with uterine factor infertility (UFI).1 UFI can be congenital, disease-related or iatrogenic and studies approximate that of the 62 million women of reproductive age in the USA, 9.5 million have some form of UFI.2–4
While gestational surrogacy and adoption are the current reproductive options for women with UFI, uterus transplantation offers several advantages compared with both currently available options. The primary benefits of uterus transplantation are the potential for a genetic link between mother and child (possible in surrogacy but not possible in the alternative of adoption) as well as the ability of the recipient to experience some of the physical and emotional aspects of pregnancy (distinct from the alternative of gestational surrogacy). Uterus transplantation may also be a legal alternative in countries where altruistic (France, Greece, Italy) or commercial surrogacy (Australia, France, Greece, Italy, New Zealand, South Africa, UK) is banned, the practice is religiously discouraged or where the practice is made more difficult by bans on brokers, contracts etc (Hong Kong).5
Throughout its development, scholars have legitimately raised concerns about the safety of uterus transplantation, as well as the ethical, psychological, legal, and societal risks and benefits of the technique.6–8 Since uterus transplantation carries significant risk when compared with surrogacy and adoption as well as when compared with other organ transplants, it requires greater justification because its goals are quality of life, not life-saving, in their scope.9 Despite these concerns, studies on uterus transplantation have moved forward in animals and humans, most likely because of the immense benefits it may bring—women previously unable to would be able to experience the joy of pregnancy, have increased control over lifestyle influences on the fetus, and avoid the legal and religious stipulations surrounding gestational surrogacy in some cultures. Other non-vital organ transplants span the gamut from being widely performed (corneal transplant) to also being in the clinical research stages at a few, select institutions (hand and face transplants). While authors have debated the risk/benefit ratio for these other non-vital organs as well, it is important to remember that the function being restored by uterus transplantation is fundamentally different in that it is a reproductive function being restored. The intent, then, is not simply to see or feel or smile, but to produce a child—a difference that surely has ethical import.10
Given that nationally and internationally, research has moved forward rapidly into the clinical phase, it is important to address questions regarding the physical, psychosocial, and ethical risks and benefits of uterus transplantation for all three parties involved—the donor, recipient and potential child—as well as discuss the regulatory implications. While previous research into this risk/benefit ratio from an ethics perspective has largely been from a theoretical perspective, it is important to transition to a clinical perspective in order to provide guidance that is useful and much needed by the physicians moving forward with uterus transplantation clinical research.
The state of uterus transplantation
The state of the science for uterus transplantation has been rapidly moving forward with significant progress in the last several years with animal and human studies. In animal models, scientists have achieved successful menses and births in several animal models including mammals.11 The first human uterus transplant was performed on 6 April 2000 on a 62-year-old woman in Saudi Arabia with UFI due to a prior hysterectomy after postpartum haemorrhage.4 While the transplant was technically successful because the participant experienced two cycles of menses, a hysterectomy was necessary 99 days post-transplant after development of an acute vascular thrombosis. It is hypothesised that this clot formed secondary to kinking of the arterial supply due to poor positioning of the uterus by the transplant team and not because of rejection of the organ itself.2 ,8 ,12 In the USA, some researchers have received institutional review board approval to recruit female subjects for transplant with cadaver uteri and have received over 500 applicants.7 ,13 In Sweden, researchers have performed four uterus transplants, including a transplant between mother and daughter.14 ,15 A successful transplant occurred in Turkey in August 2011, and the woman is reportedly several weeks pregnant after in vitro fertilisation.15 ,16 If the trial in Turkey is successful, British physicians intend to attempt the first transplant in the UK in 2014. These doctors also predict that uterus transplantation could be streamlined and affordable enough to be available on the National Health Service by 2020.16
Risks to donors
As clinical research begins, it is important for the risks to donors to be discussed and viewed from a clinical lens. Deceased and living uterus donors are being used in these early-phase clinical trials. For deceased donations, Agich argues that traditional transplantation and retrieval of organs from a corpse was based on rescue ethics theory—only a strongly valued social goal like restoring basic physiological function necessary for life would justify ‘the desecration of a corpse and the removal of organs’.9 Using rescue ethics, ethical mores can be more easily trumped because of the urgency of the need. This is distinct from non-vital organ transplantation, raising the question of whether we should consider harvesting uteri from the deceased at all or whether the quality of life improvement rendered to the recipient does not rise to the level of that of a life-saving transplant.
Hand, corneal and face transplants have moved forward with deceased donation, even though they are non-vital, based on the recipients’ quality of life improvement. However, hand and face transplants are still rare and hospitals have taken special care when seeking donors, particularly in face candidates. When the first partial face transplant in the USA occurred at the Cleveland Clinic, donor specialists called the family to discuss the face separately, after the decision to donate other vital organs had already been made. The family's choice was driven by the similarities between their loved one and the recipient, as well as their impression of the donor's spirit in giving.17 Transplantation of cadaver uteri would likely be similar, at least early in the course of this treatment, until such transplant became more socially and ethically acceptable. Physicians, hospitals and donor experts should communicate with the family about special risks and concerns (or preferably use donors who have specified this interest while living) prior to seeking cadaver uteri donation.
What would or what should constitute consent by the dead donor of a uterus and should the uterus be treated differently than other organs in this regard? This depends greatly on the country where donation is occurring and how uteri are classified. The USA has a Uniform Anatomical Gift Act (UAGA) to regulate the donation of tissue from the deceased which allows the next of kin to donate organs even where the individual did not elect to do so when alive.18 In contrast, the UK's Human Fertilization and Embryology Act only permits donation of certain reproductive tissues (embryos and gametes) with the individual's consent.19 While such rules do not apply to uteri (likely because they do not have genetic potential), they are a reproductive organ and it is unclear whether individuals would be willing to donate such an organ or whether they would distinguish it from other organs, like livers and kidneys. Such a question is ripe for empirical review of social perspectives.
For living donors, like the mother of the recipient in Sweden, the risks can be more tangibly characterised and parallel those of women undergoing hysterectomies. These include blood clots, infection, bleeding, damage to other bodily systems like the urinary tract or bowel, reactions to anaesthesia and rarely death.20 Hysterectomies are medically indicated for a variety of conditions including cancer, endometriosis and fibroids but donation for uterus transplantation offers no medical benefit to the recipient and could potentially have more risk than a standard hysterectomy given the need to preserve extensive vascular support to the transplanted uterus.8
In the USA, there is extensive regulation of informed consent by living organ donors. The transplant team should be divided between the donor and the recipient with an independent specialist assigned to be the advocate for the donor and her interests,21 and there are specifications about what constitutes consent. The donor must have decision-making capacity, be free from coercion and be willing to donate. Donors are tested for medical and psychosocial suitability, and must be fully informed of the risks and benefits to the donor as well as the risks, benefits and alternatives for the recipient.22 Specifically, the Centers for Medicare and Medicaid Services also requires disclosure of the medical outcomes of donation, possibility of future health problems, and potential implications for insurance coverage.21 Donor advocates also give donors the right to opt out at any time without disclosing the reason to the recipient. Donation may be from a loved one, or an individual who has never met the recipient, and both types of donations have occurred in experimental uterus transplantation. Countries vary on whether living organ donation is illegal and, if so, how it is regulated, which will have implications for uterus transplantation and may alter favorability for cadaverous or living donation in certain jurisdictions.
Risks to recipients
While infertility treatments in general are burdensome on emotional and physical health, finances and time, uterus transplantation carries considerably greater risk than other forms of ART. The uterus donor and recipient must undergo major abdominal surgery that, in the USA, would likely not be covered by insurance. The recipient would also be required to undergo a second major abdominal operation, a caesarean section followed by immediate postpartum hysterectomy if she had completed childbearing, to prevent the need for lifelong immunosuppressive therapy. Like any early human experimentation, there needs to be a reasonable expectation of a benefit that warrants the risk and there should be a justification for the research (that it improves upon or creates a new option for patient care). While current teams conducting clinical research on uterus transplantation have deemed these significant risks to be outweighed by the benefits of experiencing some of the sensations of pregnancy and have therefore proceeded, it cannot be said that the calculus will remain the same as we gain more information on the technique and its outcomes as data is gathered. Clinical teams and ethicists must remain open-minded and discuss this delicate balance as we gain more information.
Other non-life-saving transplants have been justified on the basis of quality of life improvements. While hand, cornea and face transplants do not require major abdominal surgery, they do carry the greater risk of requiring lifelong immunosuppression, while recipients of uterus transplantation are able to stop immunosuppressive therapy after they have completed childbearing and a hysterectomy is performed of the donor uterus. Hand transplantation, much like uterus transplantation, also has low-risk alternatives such as hand prostheses. The cost of the hand transplant compared with that of a prosthesis in terms of quality of life years (which is greater in prosthetics given the complications of immunosuppressive therapy) makes hand transplant difficult to justify in a national healthcare system such as the UK's. Prosthetics, however, may not offer the same technical manoeuvrability and cosmetic appearance as a hand transplant.23 It is ultimately the patient who has the right to choose between these two alternatives knowing the risks and benefits in a free-market healthcare system such as ours in the USA.
Likewise, cornea and face transplants require lifelong courses of immunosuppression presenting similar risks in that respect to hand transplants. Proponents of face transplant believe that such risks are justified by relief to the intense psychological suffering which a disfigured person might feel as well as the practical consideration of improved ability to eat and speak, while others disagree based on a lack of evidence to date to suggest that such efforts really minimise suffering (eg, quality of life does not appear greater in hand transplants generally because of the offsetting harms from immunosuppression).7 ,24 Similarily, the importance of sight to basic human functioning is used to justify corneal transplantation. Notably, however, there are no prosthetic equivalents for face or cornea transplants as there are in hand or adoption/surrogacy substitutes in uterus transplantation.
Currently, we have no empirical evidence comparing the difference in quality of life between recipients of uterus transplantation versus women with UFI employing surrogacy or adoption. We do not know yet the psychological and societal factors that would influence uterus transplantation as we do in face transplantation. Likewise, we have ample data on public perspectives about risk related to a number of transplants and rejection, but we do not know this data for the uterus.25 The exit plans for uterus transplantation are also more ethically and clinically complicated than those of hand or face transplant given the potential addition of the fetus gestating inside the transplanted uterus. The decision to increase immunosuppressive therapy versus remove the uterus if rejection occurs is certainly made more complex if the recipient is pregnant.
As Orentlicher suggests, we must be careful about being overly sceptical of uterus transplantation. In the USA, at least, infertile couples often feel that their infertility is minimised or disregarded. In one study infertility was the most upsetting experience for 50% of women, while many women with cancer state loss of fertility is as emotionally disturbing as having cancer itself. Moreover, the alternatives of adoption and gestational surrogacy carry risks and burdens as well. Neither allows the woman to experience carrying the child to term and birth, experiences which may be an important aspect of motherhood for some women. Adoption remains an expensive alternative and does not provide genetic relationships which some families want, and gestational surrogacy is illegal in some countries and may be burdensome for the surrogate who becomes emotionally involved in the gestating child.26
However, it is important to remember that recipients of transplanted uteri will experience a distinct gestational experience from that of unassisted reproduction. Given that it is not feasible to anastomose the pelvic nerves during uterus transplantation, many of the normal sensations of pregnancy and labour may be perceived differently by the recipient.1 Of course, the gestational component is not fully lost for the uterus transplant patient. Just as not every woman experiences morning sickness, round ligament pain, or Braxton-Hicks contractions, the entire physiology and psychology of the pregnancy experience is unique from woman-to-woman, pregnancy-to-pregnancy, regardless of how the pregnancy was achieved. She may not experience uterine sensations, but she will suffer through morning sickness, be unable to fit into her prepregnancy clothes as her belly grows, and watch her ankles swell. In our pronatalist society, many of these experiences are valued socially and by the individual infertile couple and the importance of these should not be minimised. Researchers must be careful to inform subjects that because the nerves will be severed, they will not experience the complete experience of pregnancy. However, they will be visibly pregnant, emotionally pregnant and seen as pregnant by society—important considerations as they are the ultimate goals of uterus transplantation.
Another element to ethical exploration of uterus transplant is informed consent by the recipient. Like consent by the donor, this concept will evolve with time as clinicians receive improved information to help inform the decisions of their patients. In these early stages, though, physicians and researchers must consider and uphold the standards of informed consent that we expect in other types of research. Like many forms of developing research, long-term safety profiles are still unknown and informed consent would need to emphasise to participants that uterus transplant is not an established clinical practice like gestational surrogacy or in vitro fertilisation.7 This potential for the therapeutic misconception is only heightened due to the psychology of infertility that Orentlicher describes.8 Women enrolled in uterus transplant studies must also have the ability to refuse to participate in the study or to withdraw, and must enter into the process voluntarily. As in other maternal-fetal type research, the mother is consenting to the study for the potential fetus as well and should consider the well-being of any resulting child in her consent process.
Uterus transplantation also carries risks to any resulting children. While as of yet clinical research has not yet resulted in a child born of uterus transplantation, that day is surely in the near and coming future. The fetus would be subjected to immunosuppressive therapy which may have the potential for teratogenesis as well as other adverse effects such as preterm delivery.1 If an acute vascular thrombosis were to occur, as did in the trial in Saudi Arabia, fetal development could be negatively impacted by hypoxia or stillbirth could result.7 However data on greater than 15 000 births following kidney, liver and other solid organ transplant recipients is available since the 1950s and is reassuring. While fetuses tend to have lower birth weights and premature births, there are no known malformations or other serious risks.10
Another ethical argument that is often used in discussions of ART is also less compelling for uterus transplantation, that being the question of whether the child is worse off than if he or she had never been born.10 ,27 While it is certainly true that the same child could be born without the risks of immunosuppressive therapy in the alternative method of gestational surrogacy, this is not an available option for all women with UFI. In countries where surrogacy is illegal or not available or if surrogacy is not a welcome option personally, the scenario is quite different. The same child is either not born or must be born with the risks of immunosuppression, raising the question about how to characterise such harm. It is difficult therefore to argue that this child has been harmed and should not have been created.
Certainly the well-being and interests of the resulting child must be considered, particularly because the child is the only party unable to represent his or her own wishes in this process. It is important to recognise the tension that may exist between the parent and the resulting child in uterus transplantation. Using fertility services to allow pregnancies that increase the risk to the child have frequently caused ethical controversy including pregnancies in women with HIV, parents with inadequate parenting skills and lifestyle factors of the parent. The European Society of Human Reproduction and Embryology states that fertility doctors ‘have a double responsibility: to the patient and the child’.28 ,29 It is certainly true that physicians and society allow and encourage reproduction in other potentially high-risk scenarios to the fetus, for example, in cases of HIV-positive mothers and couples with genetic disorders. Importantly, the harms to the potential child can be actively minimised in these scenarios, unlike the potential harms of immunosuppression in uterus transplantation.26 However, the right or the interest in being a parent is a specially protected interest and physicians should carefully consider whether the risks to the child are significant enough to counterbalance the reproductive interests of the parent.
The interest of the patient's partner (if involved) can be discussed in this light as having the same reproductive right to parent as the patient. The currently available options of surrogacy or adoption for UFI limit the partner's involvement in the process. While the patient and partner can certainly make a mutual decision on which child to adopt or the partner's genetic material (whether sperm or ovum) can be implanted into the surrogate, the gestational component of parenthood and possibly the genetic is not realised. Uterus transplantation allows for the partner to participate in the experience of pregnancy in a more active manner.
Regulation: is uterus transplant an organ or an ART?
As research moves forward and uterus transplantation moves from the realm of clinical research to being a clinically-available treatment, it is important to consider how the transplanted uteri will be regulated. Uterus transplantation does not neatly fit the free market regulation of other ARTs but is also outside the current scope of the Uniform Network for Organ Sharing (UNOS) which is the current system used to regulate transplant organ distribution. While ARTs are commonly bought and sold in the free market, uterus transplant presents a problem distinct from gestational surrogacy or egg donation because of its involvement of human organs. The UAGA specifically prohibits the sale of transplant organs and a uterus qualifies under its statutory definition.18 Thus uterus transplant is likely precluded from being regulated in the manner of other ARTs. Even if uterus transplantation itself is regulated as an ART, it would also have the inherent problems present in the regulation of other ARTs, like distributive justice. ART is already expensive, but uterus transplantation would have by far the highest price tag and it is problematic that only those with the funds and access to individual clinics providing the technology would be able to treat their UFI.
UNOS seems more promising in that it is specifically designed to allocate scarce resources (such as uteri) and the concern of distributive justice is much less than in a free market scheme. However, the current model of UNOS distribution would have to be reformulated for use for uterus transplantation since it is a reproductive, non-life-saving organ unlike the other organs currently under UNOS’ purview. While UNOS favours clinical variables in determining who receives an organ first (issues like sickest first, best prognosis or quality of life assessments) it is unclear how to prioritise in uterus transplant where all patients would only need to maintain the organ for an equal length of time (through gestation) and nobody is more or less infertile than the next.30 ,31 Because uterus transplant would be a means to the end of a live birth, a woman's reproductive history could possibly be taken into account. However, does prognosis mean medical prognosis (who is more likely to have a pregnancy that carries to term), psychosocial impact on the woman (who is going to benefit the most psychologically by having a functioning uterus) or future success at motherhood (who is most likely to be a good mother)? For each of these possible definitions of prognosis, the allocation could be substantially different.32
The free market regulation of ART is a less ideal structure for regulating uterus transplant, but still provides some important considerations. On one hand, the UAGA specifically prohibits the sale of transplant organs (and uterus transplant will likely be regulated by the UAGA). Yet, underground markets exist for trafficking of kidneys, liver and other non-essential body parts.33 In contrast, the sale of other reproductive tissues is legal and commonplace. Oocyte donors do not face the risks of major surgery as abdominal organ donors do, but they must take powerful hormone medications to induce superovulation which can cause significant risks to their health.34 As reproductive tissue donations, ova and sperm are essential components in a successful pregnancy. While a transplanted uterus would not change the genetic makeup of the infant it gestated, it too is a necessary component in a future birth. The dilemma of whether life, or the components of life, can be bought or sold is troublesome.
As a reproductive organ, the uterus and its products are already functionally traded in the free market. Surrogacy can cost an extraordinary sum of money, a problem that has infertile couples travelling to other parts of the world in search of a cheaper surrogate.35 Finally, in our society, cost is unfortunately equated many times with value. If it costs 10 times more to have a child via uterus transplant than adoption or surrogacy, does that pregnancy have 10 times the value? While we would never put a price on the mother-child bond, surely there is a higher opportunity cost with achieving a pregnancy with uterus transplantation than other ARTs. Such discussions touch on the commodification concerns which have previously been raised in egg donation and commercial surrogacy and are only amplified by uterus transplantation.36
As the technology of uterus transplant advances from the research to clinical phases, it will be ever more important for lawmakers, physicians and the public to carefully consider the implications and safety of this new and unique technique for donors, recipients and resulting children alike as well as the regulatory difficulties. Uterus transplantation poses novel challenges in the worlds of ART and transplant medicine. While the potential benefits are enormous, the risks are also unprecedented. It is imperative that the ethical and legal challenges are addressed and discussed prior to further clinical and research implementation, particularly with attention to risks to living or deceased donors, recipients, and resulting children and regulatory implications.
Contributors KSA and VB are responsible for the planning, conduct and reporting of the research presented in the manuscript. KS is responsible for the overall content of the manuscript.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.