The uterine transplant is the surgical procedure (under research) whereby a healthy uterus is transplanted into an organism of which the uterus is absent or diseased. A diseased or absent uterus does not allow normal embryonic implantation whereby leads to infertility in females. This phenomenon is known as absolute uterine factor infertility (AUFI). Uterine transplant is an experimental treatment for this form of infertility.
A transplantation of a uterus, unlike any other organ transplantation, involves no less than four parties – recipient, donor, partner of the recipient, and the possible future child. All of them are exposed to potential risks if the surgery has to be performed. Uterus transplantation is a complex procedure and is surrounded by not only medical and psychological implications but also ethical, moral, and cultural concerns and expectations.
Uterine factor infertility can be present due to congenital, disease-related, or iatrogenic causes that are inadvertent by a physician or surgeon or by medical treatment or diagnostic procedures. For example, a woman can be born without a uterus (Mayer-Rokitansky-Kuster-Hauser syndrome), the uterus may have been removed as a component of surgical staging and treatment for cervical cancer, or an emergency hysterectomy (surgical removal of the uterus) may have been completed during a postpartum hemorrhage (loss of more than 500 ml or 1,000 ml of blood within the first 24 hours following childbirth) after delivery or after a trauma. Prior to uterus transplantation, patients with UFI don´t have clinical interventions available that made pregnancy possible, leaving surrogacy and adoption as the only options for family-building.
Uterus transplantation offers a novel treatment option for women with uterine factor infertility. It uniquely allows for women to experience the gestational component of motherhood and also to potentially share a genetic link with the offspring. While both adoption and gestational surrogacy allow women to parent a child, adoption does not allow for a genetic link to the future child, and neither option allows for the experience of the gestational component of motherhood. Furthermore, in many countries, surrogacy is legally banned (France and Italy for altruistic surrogacy, and Australia, France, Italy, New Zealand, South Africa, and the UK for commercial surrogacy). Some parts of the world discourage surrogacy for religious reasons or place bans on surrogacy contracts or surrogacy brokerage (e.g., Hong Kong). Women with UFI in these places do not have any opportunities to have a genetic link to their children as the only currently available option is adoption.
While the transplanted uterus is not connected to fallopian tubes, women is not able to become pregnant through natural fertilization, but only with fertility treatment (in vitro fertilization (IVF) followed by embryo transfer). The process starts with IVF stimulation of patient´s ovaries, within which patient´s eggs are removed and fertilized in lab dish and subsequently 6-10 embryos are frozen and stored. Afterwards, donated uterus is transplanted into patient. She is put on immunosuppresant drugs treatment to prevent rejection of uterus and it is need throughout the process. In a few months, menstrual periods begin to occur. In a year later, uterus is healed after the surgery and thus IVF process continues through transfer of the previously frozen embryos. The uterus is highly monitored by biopsies to check for rejection every month throughout pregnancy. Following childbirth is delivered by Caesarean section and women will have the option to keep the transplanted uterus and try to have another baby. Finally, the women will need to undergo the surgery to remove the uterus (hysterectomy) after 1-2 deliveries whereas she can stop taking anti-rejection drugs.
Live uterus donation
When procuring a uterus from a live donor, it is possible to set the time for transplantation to a convenient date and the recipient can receive the transplant at a time when both parties are in an optimized and thoroughly prepared condition, thus increasing the odds of graft survival. This possibility to schedule the surgery also gives ample time to evaluate the donor and the organ prior to the transplantation.
Exclusion of unsuitable donor candidates and organs of inferior quality is crucial to the outcome. Using patient´s mother or close relative as donors are preferred in order to reduce the risk that woman´s immune system would attack the organ and reject it. Other criteria are just to have a healthy uterus and ideally the age of 18-40, regardless of whether it was pregnant or not.
Deceased uterus donation
The overshadowing benefit associated with deceased uterus donation is that there is no donor risk associated with surgery. Other potential benefits might be that the surgical dissection procedure is easier and takes a shorter time and that the vessels of larger diameter can be used for the anastomoses (communication between neighboring blood vessels), also simplifying the transplantation procedure.
In deceased donation, the ischemic time (the time that an organ is outside the body) is generally longer than in live donation. A prolonged ischemic time is known to reduce graft function and increase the incidence of postoperative rejection, both acute and chronic. The tolerable ischemic time differs between organs and is not yet defined in a human uterus.
Uterus transplantation and immunology
Since the induction of tolerance, precluding the need for maintenance immunosuppression, has proven to be elusive, immunosuppressive drugs are still used to minimize graft rejection, following organ transplantation. Finding the most favorable level of immunosuppression in solid organ transplantation is a balancing act between preventing rejection and the adverse effects of immunosuppressive drugs causing morbidity. The need for immunosuppressive medications is not constant, and the required initial high blood levels of immunosuppression can shortly be reduced to a lower maintenance blood level after transplantation. Induction therapy, i.e., perioperative prophylactic immunosuppression, is commonly used to prevent acute rejection (from one week to three months after transplantation) in the first month after transplantation. The maintenance therapy is normally given as a combination of drugs with different pharmacokinetic mechanisms (metabolic changes of the substance in the body) in order to minimize potential side effects.
The major issues of uterus transplantation regarding immunosuppression and rejection can be summarized in three different areas of concern: the effect of pregnancy on graft rejection, the effect of the transplanted graft on pregnancy, and the effect of immunosuppression on both the fertility and the pregnancy outcome.
Following transplantation, the surveillance of organ functionality, particularly to detect the onset of rejection, is a crucial task for the long-term viability of the graft. Usually, diagnosis of acute rejection relies on clinical signs, but laboratory data such as blood markers (lipase/amylase in pancreas transplantation, creatinine in kidney transplantation, and liver enzymes in liver transplantation) are invaluable tools to monitor graft function. There is no specific blood marker for the uterus that reveals a decline in uterine function or rejection, and rejection might thus not be clinically detected until significant graft damage has occurred. As subclinical rejection episodes may occur, a noninvasive graft monitoring is desirable in all organ transplantation. These subclinical episodes of uterus rejection can only be detected with acute or protocol biopsies. The uterine graft is, unlike other solid organs, easily accessible from the vagina, and cervical tissue biopsies are, if not noninvasive, at least minimally invasive and provide an ample surveillance option of rejection. Unlike an endometrial biopsy, the cervical biopsy does not interfere with the cavity of the uterus and can therefore also function as surveillance of rejection during pregnancy.
Throughout pregnancy, intake of immunosuppressive agents is vital to prevent organ rejection. All common medications used to avoid episodes of rejection cross the placenta barrier and subsequently reach the fetal circulation, thus exposing the child to potentially teratogenic agents during important developmental phases. Three large registers offer data about the outcome of pregnancies in transplant recipients, and all of these indicate similar trends of an increased incidence of obstetric complications, including ectopic pregnancy, hypertension (high blood pressure) and preeclampsia (high blood pressure during pregnancy), miscarriage, premature delivery, low birth weight, stillbirth, and neonatal death (death within the first seven days of life).
Pregnancies and live births
The potential adverse effects of immunosuppressive drugs are of a broad spectrum, ranging from severe malformations to delicate hardly detectable neurocognitive defects. The US Food and Drug Administration (FDA) has categorized immunosuppressive medications, and based on its recommendation, a ceased intake of some drugs is recommended prior to attempt of pregnancy. Using only the immunosuppressive drugs approved by the FDA during pregnancy, the risk of congenital malformations or anomalies in a pregnancy exposed to immunosuppression is comparable to the risk in a normal pregnancy.
During pregnancy, uterine and placental physiologic and changes in blood flow occur, inducing changes in the plasma concentrations of drugs; hence, these need to be monitored thoroughly.
Immunosuppressive doses often need to be increased during pregnancy and decreased in the postpartum period to achieve constant trough levels. Some studies report pregnant recipients requiring an almost twofold increase in doses compared with pre-pregnancy doses in order to keep trough level in a therapeutic window (the range of drug dosages which can treat disease effectively without having toxic effects).
Uterus transplantation raises questions not only of medical character but also of psychological aspects (Pic. 1). Well-being among the participants is of great importance considering that uterus transplantation is a new type of a major experimental surgical procedure and infertility treatment. Regardless of the outcome of the transplant, it is important to recognize the impairment in quality of life of each individual and to offer support during these periods of need.
Improving the quality of a patient’s life, rather than saving life itself, is a more recent goal and achievement of organ transplant (eg, hand, corneal, and face transplants) that presents further ethical considerations. For example, it is unclear how much risk is justified in the face of interventions aimed at improving quality of life rather than saving life. Uterus transplantation raises these same issues along with novel ones. For example, it is the first organ transplant with the goal being reproduction. Also, uterus transplantation is the first ephemeral organ transplant, or a transplant designed specifically for a short term, rather than the anticipated long-term nature of a transplanted liver or kidney, for example.
As a transplant with reproduction as its goal, it necessarily raises ethical questions about technological aid of reproduction, including the rights of any reproductive donors, the interests of the child, commodification of women’s bodies, the interests and goals of the mother, and the role of the state in regulating women’s bodies and reproduction. To women with uterine factor infertility (UFI) or infertility due to an anatomic issue specifically surrounding the uterus, uterus transplantation offers a novel treatment approach in addition to the currently available options of adoption and gestational surrogacy. However, transplantation for the goal of reproduction steps beyond the ethical debate in both assisted reproduction and transplantation, making it important to analyze the ethical, legal, and social implications of uterus transplantation prior to moving from the research phase to clinical practice.
The potential patients undergoing uterus transplantation have to be of childbearing age (21-39) with uterine factor infertility (UFI).
A common side-effect of many long-term used immunosuppressive drugs is immunodeficiency, because the majority of them act non-selectively, resulting in increased susceptibility to infections and decreased cancer immunosurveillance. There are also other side-effects, such as hypertension, dyslipidemia (abnormal amount of blood lipids), hyperglycemia (high blood sugar), stomach ulcers, lipodystrophy (selective loss of body fat), moon face (rounded appearance due to fat deposits on the sides of the face), liver and kidney injury. The immunosuppressive drugs also interact with other medicines and affect their metabolism and action.
If utilizing living donors, the concern surrounding medical safety is paramount. While hysterectomies are performed daily around the world for many reasons, hysterectomies are not without risk to the patient, including major blood loss, injury to bowel or bladder, thrombosis, adverse anesthetic reactions, and death. While these hysterectomies are medically indicated for a variety of reasons and thus offer benefit to the patient, there is no such medical benefit to a hysterectomy to serve as a uterus donor. Furthermore, due to the need to preserve vascular pedicles, the length of procurement surgery was 10 hours and 7 minutes, which far exceeds the typical length of surgery for most hysterectomies for clinical indications (Pic. 2).
After the initial transplant surgery, at least two additional major surgeries would be required in the event if the transplant is successful and the recipient is able to carry a pregnancy: a Cesarean section for delivery and a postpartum hysterectomy to prevent necessity for lifelong immunosuppressive therapy. The purpose of this medical risk is to experience the gestational component of motherhood, and possibly the genetic if gestational surrogacy is not available. Yet, given the inability to anastomosis nerves (nervous connection), it is unclear how the sensation of pregnancy will vary for patients of uterus transplantation versus women who naturally conceive. For example, while the patient will experience morning sickness and experience swelling and an enlarging uterus, it is unclear whether the sensation of contractions or fetal movement will be the same. Thus, the experience of pregnancy, the very goal of uterus transplantation versus surrogacy or adoption, will differ for recipients than for those who spontaneously conceive and carry a pregnancy. Additionally, the transplant will bring first periods thus some women may experience new hormonal fluctuations that they had not experienced never before.
Unique to uterus transplantation versus other transplanted organs is the need to consider the well-being of the future intended child, the goal of the transplant. Safety remains a key concern. While the immunosuppressive regimen is not teratogenic, high-quality data do not exist. Furthermore, there remains a risk of premature delivery and low birth weight, though it is unclear whether this is due to the mother’s underlying medical comorbidities. Second, in the case of acute vascular thrombosis (the formation of a blood clot), it is unclear what the impact of hypoxia (reduced oxygen supply) would be on the developing fetus. Due to these concerns, it is imperative that patients account for risks to the future child in their decision-making processes and that physicians recognize their double responsibility – both to the intended mother and to the future child.
Over the last decade, there has been dramatic success with uterus transplantation rapidly moving from the preclinical to the clinical research stage. While the report of the first successful live birth following uterus transplantation in 2014 marked a potential new beginning for women and couples with UFI, there remain clinical, ethical, and regulatory challenges. The medical safety for the donor, recipient, and future child remains an area of active research interest. The ethical implications for all three parties should continue to be discussed, and the eventual uptake into clinical practice will require deliberation and modifications regarding regulatory process. However, as both adoption and gestational surrogacy do not potentially allow for a genetic and/or gestational link, uterus transplantation is a novel treatment option for women with UFI.
It is important for the transplant team to be clear that, as of yet, uterus transplantation remains research and that guarantee of outcome (i.e., a child) cannot be made. As research continues, the results of these studies should continue to guide and inform future research direction and the consent process for future patients; for example, a careful examination of how these patients experience pregnancy so that future patients can consider this in their risk/benefit analysis and their goals for the procedure.
The future of uterus transplantation is prone to hold modifications of the procedure. New methods to evaluate the recipients, donors, and organs, like angiographic mapping of vessels, preoperative or even perioperative, will possibly simplify the procedure and improve the outcome. There will certainly also be other surgical options, such as laparoscopic and robotic-assisted methods, giving the possibility to reduce the surgical duration and concurrent risks for both recipients and live donors. Extensive efforts are currently made in the area of bioengineered organs (produced from patient´s stem cells) for transplantation purpose, the uterus not being an exception. The organ-engineering technology, being still in its infancy, pursues two ways of solution: the first involves donated organs, not suitable for transplantation, that is decellularized and the second alternative involves a synthetic matrix. The two different types of matrices would then after a recellularization process by the recipients own stem cells to be transplanted and in theory, function as good as any transplanted organ with the major benefit that no immunosuppression would be needed. At the time when uterus transplantation will enter the clinical arena in a wider perspective, the participants will express a broader diversity, both medically and psychologically. It will be of utmost importance to continue to develop and improve protocols for psychology with thorough assessment and support in a systematic and structured way.