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Uterus transplantation for absolute uterine factor infertility: Ethics, patient selection, and consent

Uterus transplantation for absolute uterine factor infertility: Ethics, patient selection, and consent
Literature review current through: Jan 2024.
This topic last updated: Sep 07, 2022.

INTRODUCTION — Historically, no restorative treatment has been available for women with absolute uterine factor infertility (AUFI; ie, uterus absence or non-function). For these women, alternative pathways to parenthood have included adoption or foster parenting and, in countries where available, use of a gestational carrier. However, gestational carrier pregnancy has limited availability worldwide and, for some women, the desire to carry and birth a child make the option of uterus transplantation appealing. This topic will discuss the ethics, indications, and patient selection for uterus transplantation, an experimental approach to restoring fertility in women with AUFI. The purpose of this topic is to provide information on this developing technology for clinicians and patients; the topic is not intended to be used for treatment decisions.

Specific discussion of the procedures for uterus transplantation and general issues related to organ transplantation can be found in the following topics:

(See "Uterus transplantation for absolute uterine factor infertility: Surgery, immunosuppression, and obstetric management".)

(See "Transplantation immunobiology".)

(See "Prevention of graft-versus-host disease", section on 'Introduction'.)

In this topic, when discussing study results, we will use the terms "woman/en" or "patient(s)" as they are used in the studies presented. However, we encourage the reader to consider the specific counseling and treatment needs of transgender and gender diverse individuals.

PROCEDURE OVERVIEW AND HISTORY — Uterus transplantation is an experimental procedure to treat AUFI. Once the intended uterus recipient and organ donor have been identified, the process begins with in vitro fertilization (IVF) to create and freeze embryos for the intended recipient [1]. Next, the organ donor undergoes a radical-type hysterectomy followed by transplantation of the donor organ into the recipient. After at least 6 to 10 months of immunosuppressive treatment, the recipient undergoes embryo transfer, pregnancy, and, if the pregnancy is successful, delivery via cesarean delivery. At the conclusion of childbearing, the transplanted organ is removed to avoid the need for lifelong immunosuppression.

Procedure history

First procedure – The first human uterus transplantation was performed in 2000 in Saudi Arabia, with a uterus from a living donor, and reported to the public in 2002 [2]. This attempt resulted in uterus removal three months after transplantation because of necrosis. Necrosis may have been related to the surgical preparation of the donor uterus; the short pedicles of the uterine arteries and veins were elongated with saphenous vein grafts.

Second procedure – The second human uterus transplantation was performed in September 2011 in Turkey [3]. A 21-year-old women with uterine agenesis received a uterus from a 23-year-old deceased woman. During the organ harvesting surgery, the uterus was prioritized as the first organ to be flushed and removed, with the goal of minimizing damage from warm ischemic time. Embryo transfers started 18 months after transplantation and during the initial period the patient conceived at least two pregnancies, but both ended in early miscarriage [1,4].

Ultimately, the patient delivered a healthy infant nine years after transplant [5]. Prior to this birth, the patient underwent 12 embryo transfers, experienced five pregnancy losses, was diagnosed with partially obstructed blood flow, and underwent a saphenous graft between the utero-ovarian vein of the graft and the left ovarian vein to resolve of venous congestion. The pregnancy was complicated by preterm premature rupture of the membranes at 19 weeks gestation and a live-born infant was delivered at 28 weeks.

Subsequent procedures – Since the initial reports, uterus transplantation has been successfully performed in Sweden, the United States, Brazil, Serbia, India, Czech Republic, China, Lebanon, Germany, Italy, Spain and France. In a review of 33 US uterus transplant recipients, the one-year graft survival rate was 74 percent (23 of 31) [6].

Birth history

First live birth – In 2014, the world's first live birth occurred, from a uterus transplanted by the Swedish team (transplant performed in 2013) [7]. The 35-year-old recipient had congenital absence of the uterus (Mayer-Rokitansky-Küster-Hauser syndrome) and received a uterus from a living, 61-year-old woman who had previously had two live births. The donor had been postmenopausal for seven years prior to donor hysterectomy. Prior to the transplantation, the patient and her male partner underwent IVF to create embryos and also to confirm that conception was possible for the recipient. Approximately one year after the uterus transplantation, the patient then underwent transfer of one previously frozen embryo. The patient developed preeclampsia and a male infant was subsequently born at 31 weeks and 6 days of gestation via cesarean delivery.

Subsequent live births – Additional live births from uteri transplanted by the Swedish team have since occurred, including a birth for a woman who received a uterus from her own mother [8,9]. The first birth from a transplanted uterus in the United States occurred in November 2017 [10]. In December 2018, a team in Brazil reported the first live birth following a deceased-donor uterus transplant performed in a woman with congenital absence of the uterus [11]. The uterus came from a 45-year-old parous three donor who had a subarachnoid hemorrhage and was declared brain dead. In the US, a deceased-donor pregnancy and subsequent birth was achieved despite the patient being initially treated for grade 3 rejection [12].

ABSOLUTE UTERINE FACTOR INFERTILITY

Definition — AUFI refers to infertility that is completely attributable to the uterus because of absence (congenital or surgical) or abnormalities (anatomic or functional) that prevent embryo implantation or completion of a pregnancy to term. AUFI is the primary indication for uterus transplantation.

Prevalence — It is estimated that 1 in 500 women of childbearing age are affected by AUFI, defined as an absent or non-functional uterus [6]. Models predict there are over 12,000 affected women in the United Kingdom and 150,000 women in Europe [13]. While the prevalence of uterine factor infertility can be estimated, the percentage of such women who would desire uterus transplantation to carry a pregnancy is not known.

Absent uterus

Uterine agenesis or Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome – MRKH syndrome is the congenital absence of a uterus or the presence of a rudimentary solid bipartite uterus in combination with absence of the vagina above the hymenal plane. MRKH syndrome accounts for less than 3 percent of all müllerian malformations and has an estimated prevalence of 1:4500 females [14,15]. Females with MRKH syndrome have a normal karyotype, and they can have normal offspring without urogenital malformations when they pursue gestational carrier pregnancy using their own eggs [16]. A study from a United States transplant center reported that, of the 92 percent of recipient candidates who had an anatomical lack of the uterus (from any cause, including hysterectomy), 36 percent had a congenital malformation [17]. (See "Congenital uterine anomalies: Clinical manifestations and diagnosis".)

Women with the typical (ie, type A or women with two kidneys) MRKH syndrome are ideal candidates for uterus transplant, but some programs accept women with a single kidney. Patients with a single kidney may have a higher risk of having obstetric complications such as severe preeclampsia [18]. In the Swedish series, all women who developed preeclampsia had a single kidney, but one of these women with a single kidney did not develop preeclampsia in her second pregnancy, which resulted in a live birth.  

Hysterectomy – Hysterectomy during the reproductive period is the most common cause of acquired AUFI. Approximately 600,000 procedures are performed annually in the United States alone, with more than 40 percent of the surgeries occurring in women under 44 years of age [19]. In one clinical trial in the United States that initially screened 239 women for uterus transplantation, 64 percent had undergone hysterectomy while 32 percent presented with congenital anomalies [20]. Of the women with prior hysterectomy, 50 percent were performed for benign indications, 25 percent for malignancy, and 25 percent for obstetric complications.

Discussion of these common indications for hysterectomy are presented in detail separately:

(See "Management of early-stage cervical cancer", section on 'Type of surgery'.)

(See "Overview of resectable endometrial carcinoma", section on 'Epidemiology'.)

(See "Peripartum hysterectomy for management of hemorrhage".)

(See "Uterine fibroids (leiomyomas): Treatment overview", section on 'Traditional surgery'.)

Transgender women – The role and feasibility of uterus transplantation in transgender women are not yet known [21]. In a survey study of 182 transgender women, 99 percent reported the belief that a uterus transplant would lead to greater happiness [22]. Respondents reported a desire to become pregnant and give birth in the future (94 percent); that the ability to gestate and give birth would enhance perceptions of their femininity (94 percent); and that having a transplanted, functioning vagina would improve their sexual experience (90 percent), improve their quality of life (90 percent), and help them feel more like a female (92 percent). Research into the feasibility of uterus transplant into genetic males, human or animal, has not been done.

Nonfunctional uterus — Women with uterine factors that contribute to, but do not exclusively cause, infertility would not typically be candidates for uterus transplantation because established medical and surgical infertility treatments exist. Uterus transplantation could be considered for these women only when all other therapeutic options have failed.

Müllerian malformations – Congenital uterine malformations occur because of disturbances during fetal life in the formation, development, or fusion of the müllerian (paramesonephric) ducts (figure 1 and figure 2). These malformations can increase the risk of adverse obstetric and perinatal outcomes as well as cause infertility [23]. A summary of the estimated prevalence of the most frequent müllerian malformations and their potential impact on fertility is presented in the table (table 1). Further information and comprehensive reviews of uterus malformations and their management can be found separately. (See "Congenital uterine anomalies: Clinical manifestations and diagnosis" and "Congenital uterine anomalies: Surgical repair".)

Intrauterine adhesions – Intrauterine adhesions, or intrauterine synechiae, result when scar tissue develops within the uterine cavity, typically in response to intrauterine surgery or infection. Intrauterine adhesions accompanied by symptoms (eg, infertility, amenorrhea) are also referred to as Asherman syndrome [24-26]. Asherman syndrome occurs in approximately 1.5 percent of reproductive-age women. Of affected women, approximately 50 percent have infertility and, for those who do conceive, approximately 40 percent miscarry [27,28]. The main treatment is hysteroscopic adhesiolysis, which varies in efficacy from 30 to 90 percent, depending on the severity of the adhesions. Thus, approximately 30 percent of affected women are unable to conceive and could potentially be candidates for hysterectomy followed by uterus transplantation. (See "Intrauterine adhesions: Clinical manifestation and diagnosis".)

Radiation injury – Radiotherapy, given either as total body irradiation or as local irradiation of the pelvis, causes up to a 60 percent reduction in uterine volume that is irreversible [29-31]. This volume reduction, and possible effects on the endometrium, contributes to an inability to conceive, increased rate of early miscarriage, and increased rate of late pregnancy loss [32]. Radiation therapy also causes scarring, adhesions, and impaired healing, which may make these women suboptimal candidates for uterus transplantation [33]. Moreover, the gonadotoxic effects of radiation on the ovaries, and the need for oocyte donation, have to be taken into consideration. (See "Overview of infertility and pregnancy outcome in cancer survivors".)

Repeated unsuccessful implantation – Endometrial receptivity refers to the transient state when the uterine epithelium is suitable for blastocyst attachment and implantation [34]. Endometrial receptivity during the window of implantation (WOI) is crucial for achieving pregnancy. Infertility can result when endometrial receptivity is not synchronized with the WOI. While in vitro fertilization with individually-timed embryo transfer can overcome this discrepancy in most women, approximately 25 percent of women remain infertile, mostly as a result of age and ovarian factors [35]. However, those with infertility related to uterus dysfunction may be candidates for hysterectomy and uterus transplantation.

Myoma not requiring hysterectomy – Uterine leiomyomas (ie, fibroids) are more common in women with infertility than in the general population (27 versus 8 percent) [36]. Submucous and intramural fibroids are associated with decreased implantation and pregnancy rates; the impact of subserosal fibroids on fertility is controversial [34]. One meta-analysis of 11 studies reported a 21 percent relative reduction in live birth rate for women with non-distorting fibroids compared with women without fibroids [37]. While myomectomy is the treatment of choice, women who remain infertile despite myomectomy could be treated with hysterectomy and uterus transplantation.

ETHICAL ISSUES OF UTERUS TRANSPLANTATION — Key ethical points in considering uterus transplantation include the non-life-saving nature of the procedure; existence of proven alternatives to family building; the experimental nature of uterus transplantation; and the risks and benefits to the donor, recipient, developing fetus, and newborn. As gestational carrier pregnancy and adoption both exist as alternative paths to parenthood for women with AUFI, even though they are not available in all regions of the world, the ethics of performing uterine transplantation are often considered in context with these two established options. However, these options differ from uterus transplantation in that adoption does not allow a genetic link between the mother and child and neither adoption nor gestational carrier pregnancy allows the women to have the emotional and physical experiences of pregnancy [38]. In addition, the risks to a gestational carrier must be considered.

The original and revised Montreal Criteria initially provided a theoretical framework to guide uterus transplantation. However, the recommendations were limited because they could not address the practical issues of the still-developing surgery and patient-reported outcomes of uterus transplantation [39,40]. Uterus transplantation is unique in that the rights of multiple parties must be considered and balanced: the living donor or the immediate family of a deceased donor, the recipient, the genetic father (if partnered with the uterus recipient), and the intended child(ren). Major ethical issues specific to uterus transplantation include [41-43]:

Life-enhancing transplant – Uterus transplantation is considered a life-enhancing, rather than life-saving, surgery, similar to transplantation of a face, limb, abdominal wall, trachea, or larynx [44]. Thus, rigorous scientific and ethical justification are required to conduct procedures that are designed to improve life compared with life-saving transplantation procedures. Alternative pathways to parenthood already exist.

The procedure is considered investigational. Thus, informed consent for research participation is required from the living donor and recipient. As with any developing technology, there is a potential for therapeutic misconception during the informed consent process [45]. For this reason, the informed consent process must be conducted by those who are familiar with clinical research.

Deceased-donor consent – Transplantation of deceased-donor organs involves the challenges of consent, procurement, and confidentiality [46]. Some families will consent to donation of all organs except the uterus [41]. As uterus transplantation is new, the patient who consented to traditional organ transplantation may not have considered the implications of uterus transplantation [45]. Thus, additional steps may be needed to assist potential surrogate decision-makers in the decision to consider uterus donation for the deceased patient.

Multiple surgeries for recipient – The organ recipient will undergo, on average, three to four abdominal surgeries, including the transplant itself, cesarean delivery (or deliveries), and hysterectomy once childbearing is complete. Additional surgeries may be needed if complications are encountered. Significant potential complications include bleeding, infection, and venous thromboembolism. The participant must be aware of these risks prior to undertaking uterus transplantation.

Temporary transplant – Uterus transplantation is the first temporary transplant procedure. The reason is that, by removing the transplanted organ after childbearing, the recipient will avoid the needs and risk of lifelong immunosuppression. However, as the organ is part of the recipient once transplantation is complete, removal requires consent of the participant. Allowances must be made for the participant who declines postpregnancy hysterectomy.

Efficacy and outcomes – Procedure efficacy and related outcomes are being elucidated.

Swedish trial of nine uterus transplant procedures – The initial Swedish uterus transplantation trial included nine patients with AUFI [47]. Two patients had their grafts removed within the first six months (one-year graft survival 78 percent); six patients continued through IVF and delivered a total of nine infants (three women gave birth twice) [48]. The cumulative birth rates were 86 percent for surgically successful transplant recipients and 67 percent for all transplant recipients. Mean duration of gestation was 35+3 weeks (range 31+6 to 38+0 weeks) and mean deviation from birth weight by gestational age was -1 percent (range -13 to + 23 percent). Three patients developed preeclampsia and four neonates developed respiratory distress syndrome.

United States trial of 33 uterus transplant recipients – Three US centers performed a total of 33 uterus transplants over five years [6]. One-year graft survival was 74 percent (23 of 31 recipients). Fifty-eight percent (19 of 33 recipients) delivered a live-born infant. Eighty-three percent (19 of 23 patients) with a viable graft at one year had a live birth.  

Potential risks to fetus – There are multiple potential risks for the fetus from uterus transplantation, including exposure to different pharmacologic agents in utero, possible organ rejection, and possible need for organ removal in the setting of viability. In addition, the first live birth from a transplanted uterus occurred at 31 weeks of gestation because of preeclampsia [7]. Thus, the risk and impact of obstetric complications must be considered as well.

Risk of organ rejection – Making the decision to remove the uterus in the setting of rejection that does not respond to conventional treatment becomes much more complicated if that uterus contains a fetus. The patient, family, medical team, and surgical team must be prepared to consider the personal, medical, and ethical issues of pregnancy termination and lose a highly desired pregnancy.

Elective surgery for living donor – Living organ donors will undergo elective surgery that requires extensive surgical dissection, with risk of injury, complication, and implications for future well-being, such as earlier loss of ovarian hormone production and sterilization [38,49,50]. Durations of donor surgery have ranged from 6 to 13.5 hours [10,49,51].

Regulation – It is not yet known how uterus transplantation will be regulated. Regulation is required to ensure that patients can be informed with accurate and up-to-date data about the safety and efficacy of uterus transplantation. Options include regulation as an organ transplantation under the Uniform Network for Organ Sharing or as an assisted reproductive technology, potentially through a free-market system [52]. The International Society of Uterus Transplantation (ISUTx), a section within The Transplantation Society, has created an international internet-based quality registry; the initial report is pending publication [53].

Cost – It is not yet known if and how the medical costs will be covered and by whom. This raises the question of access to uterus transplantation and how to ensure that existing health care disparities and injustices regarding fertility care are not exacerbated with the clinical implementation of the procedure.

In addition, there are important ethical considerations related to the significant cost of the procedure. One study of nine uterus transplantations performed in Sweden reported the total costs for preoperative evaluation, IVF, live donor uterus transplant, and two months of postoperative costs were nearly €75,000 [54]. This raises the question of allocation of medical resources and prioritization of health care needs across the population [55].

SELECTION, EVALUATION, AND SCREENING

Use of living or deceased donor — Live birth has been reported following both living- and deceased-donor uterus transplants [7,11]. Advantages of a living donor include ample time for preoperative testing, screening, imaging of uterus and blood vessels [56], and assembly of a multi-specialty surgical team. Moreover, the donor and recipient have time to minimize the influence of modifiable risk factors such as smoking and excess weight. In the Swedish research protocol, five of the donors were mothers of the recipients, which improves the likelihood of a human leukocyte antigen (HLA) match as well as confirms a reproductively functional uterus [49]. In a review of 33 US transplant recipients, 21 (64 percent) received organs from living donors [6].

The main benefit of deceased-donor transplantation is that the surgical risk for the donor no longer exists [1,41]. In addition, a more radical dissection can be performed on a deceased donor, which allows recovery of larger vessels, especially the veins, and thus potentially reduces the risk of graft thrombosis. The ovaries and ovarian vessels can also be removed.

Disadvantages of a deceased-donor organ include the limited availability of organs, prolonged cold ischemia time during organ procurement, and potential ethical uncertainties regarding consent. It is not possible to know if a deceased donor considered the implications of uterus transplantation while alive because of the experimental nature of the procedure. (See 'Ethical issues of uterus transplantation' above.)

Selection and evaluation of recipient and donor

Selection criteria — As human uterus transplantation is in the beginning stages, the optimal inclusion and exclusion criteria for both donors and recipients are not yet known. Other research groups have developed similar, but not identical, criteria [1]. The inclusion and exclusion criteria used in the Swedish trial are listed in the table (table 2). In addition to meeting medical and psychological requirements, the recipient must have evaluated all other available options for parenthood, including adoption, foster parenting, and gestational carrier pregnancy, before she can be considered for uterus transplantation.

Additional medical issues specific to uterus transplantation include:

Renal anomalies – The authors require that the recipient have dual functioning kidneys or, if a single kidney, a normal glomerular filtration rate (GFR). One major side effect of the calcineurin inhibitors (eg, cyclosporine or tacrolimus) is nephrotoxicity. Pregnancy, especially if preeclampsia develops, is likely to have an additional negative effect on GFR. Around 40 percent of women with Mayer-Rokitansky-Küster-Hauser syndrome have single kidneys with associated upper urinary tract anomalies and thus may have decreased kidney function at baseline [1]. (See "Early pregnancy prediction of preeclampsia".)

Leiomyoma (fibroids) – It is generally accepted that subserosal leiomyomas (fibroids) do not affect pregnancy, while submucosal and intramural leiomyomas protruding into the endometrial cavity are associated with poorer fertility outcomes [34]. The fertility impact of intramural leiomyoma that do not abut or distort the endometrial cavity is less clear [37,57,58]. (See "Uterine fibroids (leiomyomas): Issues in pregnancy".)

Because of the potential effects of leiomyoma in the reproductive outcomes, the authors took the following approach to women with leiomyomas:

Exclusion – Women with submucosal leiomyomas, leiomyomas affecting the endometrial lining, intramural leiomyomas >2 cm, more than one leiomyoma, or subserosal leiomyomas whose location could interfere with the surgical procedure (eg, parametrial fibroids or cervical fibroids) were excluded as uterus donors.

Inclusion – Women with one isolated intramural (not affecting the endometrial cavity) or subserosal fibroid (if the leiomyoma measured <2 cm) were included as uterus donors.

Reproductive history – The authors required uterus donors to have had at least one term vaginal delivery, no history of preterm deliveries, no history of repeated miscarriage, and no history of preeclampsia. The rationale for the first two criteria was that they did not want to transplant a structurally normal uterus that is not fully functional for reproduction. They also limited the number of cesarean deliveries in the donor to one, via transverse lower-uterine segment incision, because of the increased risk of abnormal placentation (placenta previa and accreta) and risk of uterine rupture [59]. (See "Placenta previa: Epidemiology, clinical features, diagnosis, morbidity and mortality", section on 'Epidemiology' and "Uterine rupture: After previous cesarean birth".)

By contrast, the authors did not require uterus donors to be premenopausal. In the trial of nine uterus transplantation procedures, four donor women were premenopausal, two were postmenopausal <5 years, and three were postmenopausal ≥5 years [49]. Postmenopausal uterus donors were treated with estrogen-progestin hormone replacement therapy prior to surgery to ascertain menstrual functionality of the uterus prior to transplantation and to potentially increase the uterine artery blood flow [7]. Aside from the immediate increased risk of venous thromboembolism, the long-term risks of preoperative estrogen therapy in peri- or postmenopausal women are not known. This approach diverges from other programs that required donors to be premenopausal [1].

Evaluation — Living donors and recipients undergo extensive testing to ensure medical and psychological appropriateness [52]. The research protocol included consultation by the following services: gynecology, transplantation surgery, psychology, clinical immunology, anesthesiology, and radiology [49]. Unique to uterus transplantation, the recipient also undergoes a preoperative fertility evaluation and in vitro fertilization (IVF) cycle to create embryos. One protocol for preoperative testing of the organ recipient, by medical specialty, is presented in the table (table 3) [1].

Psychological evaluation is extensive and includes assessment of cognition, social support, mental illness, substance use, and relationship stress [60-62]. In the research trial, the uterus donor and recipient underwent similar testing, but different psychologists evaluated each woman. The organ recipient must have the mental capacity to undergo IVF, multiple surgeries, immunosuppressive treatment, and the challenges of pregnancy, all for a procedure that is not life-saving. In addition, the recipient must be prepared for the possibility that the graft could fail, she could have complications requiring graft removal (including termination of a viable pregnancy), or she could have a successful transplant but still not achieve a live birth. Despite these challenges, preliminary data suggest that patients and their partners remain psychologically stable throughout the process [60,63]. Psychological testing typically occurs as part of the evaluation for IVF and is presented below. (See 'Psychological assessment' below.)

In programs that use deceased donors, the deceased-donor evaluation includes a cervical smear with testing for high-risk human papillomavirus (HPV) infection, a genitourinary medical screen, and a transvaginal ultrasound to evaluate for uterine abnormalities and organ size. (See 'Donor uterus evaluation' below.)

Screening tests — A complete list of the screening studies we use is presented in the table (table 4). Some of the more important screening tests are discussed below:

HLA testing – Both donor and recipient undergo testing to determine compatibility of HLA (human leukocyte antigen), blood group, and donor-specific antibodies in order to provide the best possible match. (See "Kidney transplantation in adults: HLA matching and outcomes".)

Infection – Both recipient and donor are tested for evidence of ongoing or past infection with cytomegalovirus (CMV), Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV), and hepatitis B and C. Serology for toxoplasma is also performed. The role of latent and acquired infections in solid organ transplant recipients is presented in detail separately. (See "Evaluation for infection before solid organ transplantation".)

Infection with HIV, HTLV, and viral hepatitis are contraindications to being either an organ donor or recipient. Previous CMV and EBV infections are, in some programs, relative contraindications, if the donor is positive but the recipient is negative. Transmission of CMV via an infected organ can cause fever, pneumonia, gastrointestinal ulceration, hepatitis, and graft dysfunction. EBV-infected B-cells may proliferate uncontrollably during T-cell immunosuppression, and post-transplant lymphoproliferative disease (PTLD) can result. PTLD can occur when the transplant recipient experiences a primary EBV infection or in reactivated infections. PTLD, itself a serious complication, can also progress to a malignant lymphoma [64,65]. (See "Prevention of cytomegalovirus disease in kidney transplant recipients" and "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders".)

HPV – Both organ donor and recipient must be negative for cervical dysplasia and oncogenic high-risk HPV. Tests that include a large array of high-risk HPVs are preferred. Immunosuppressed women are more likely to have persistent HPV infection, decreased rates of clearance of HPV infection, and increased rates of cervical neoplasia (20- to 100-fold increased risk) [66]. (See "Cervical cancer screening tests: Techniques for cervical cytology and human papillomavirus testing".)

To minimize the risk of HPV infection in the organ recipient after transplantation, the potential donor, recipient, and genetic father are all vaccinated against HPV infection [67]. As immunization after transplantation is less effective, vaccination of the uterus recipient is performed prior to the procedure [68]. The authors use a polyvalent vaccine that covers at least oncogenic HPV types 6, 11, 16, and 18. (See "Human papillomavirus vaccination", section on 'Available vaccines' and "Immunizations in solid organ transplant candidates and recipients", section on 'Human papillomavirus'.)

Donor uterus evaluation — Evaluation of the uterus from a living donor includes investigations by transvaginal ultrasound, colposcopy, hysteroscopy, and magnetic resonance imaging (MRI) prior to uterus removal.

Uterus – The authors use two-dimensional ultrasound to estimate the size of the uterus, rule out uterine pathology, including leiomyomas (fibroids) and polyps, and exclude müllerian anomalies. Three-dimensional ultrasound can be helpful if two-dimensional imaging is unable to exclude müllerian anomalies. Evaluation a deceased-donor uterus can involve ultrasound and MRI.

Uterine arteries and vasculature – MRI, computed tomography angiography (CTA), and contrast angiography have been used to evaluate the uterine vascular supply; the optimal imaging criteria are not fully known. In a study that evaluated 12 potential uterus donors using MRI, CTA, and digital subtraction angiography (DSA), the visualized average uterine artery diameter was similar across modalities and MRI was able to fully evaluate 13 out of 23 (57 percent) uterine arteries [56]. Only one artery was not identified by any of the three methods.

The authors take the following approach [56]:

MRA – MR angiography (MRA) is the initial imaging modality as it can detect adenomyosis [69], is without radiation, and can measure the diameters of the uterine arteries in approximately half of the donors.

CT angiography – When the uterine arteries are not measurable by MRI, the investigation proceeds to CT angiography, which can identify atherosclerotic plaques and has increased sensitivity in measurement of the lumina of the uterine arteries.

Contrast angiography – Contrast angiography, which is the gold standard to assess patency of small vessels, may be used in a small number of cases, and in particular in postmenopausal females, where results of MRI and CT angiography are inconclusive.

Evaluation of genetic father — The goals for the evaluation of the future genetic father are to exclude male-factor causes of infertility, exclude infectious diseases that could be transmitted to the immunosuppressed mother, and identify relationship challenges that could negatively impact the outcome of uterus transplantation [60].

Laboratory evaluation — The main laboratory evaluation of the male partner includes a semen analysis and testing for sexually transmittable infections. This evaluation is ideally performed as close as possible to the IVF procedure and before uterus transplantation. Additional testing may be warranted based on the semen analysis results. (See "Approach to the male with infertility".)

Semen analysis – Any deviation from the standard semen parameters, as defined by the World Health Organization, are regarded with caution because abnormal sperm motility or quality can increase the risk of chromosomally abnormal embryos and decrease implantation rates [70,71]. The authors do not use additional tests of sperm integrity, such as sperm DNA methylation or DNA fragmentation, as there are insufficient data to support routine use [72,73]. IVF cycles that result in normal embryos (blastocyst stage) rule out, as much as possible, the existence of male-factor infertility [74]. However, even with such embryos there remains a small possibility that the embryos will not result in a viable pregnancy. (See "Approach to the male with infertility", section on 'Semen analysis'.)

Sexually transmitted infections – The authors test the genetic father for the following infections:

HIV

HTLV

Hepatitis B

Hepatitis C

Syphilis

Chlamydia and gonorrhea

High-risk human papilloma virus

In contrast to the uterus donor and recipient, HIV, HTLV, and viral hepatitis infections are not contraindications for the genetic father because the recipient must conceive through IVF to conceive. Natural conception or intrauterine insemination between discordant couples is not possible after uterus transplantation because the fallopian tubes are not transplanted. If the genetic father is infected with one of the above viruses, a sero-discordant IVF protocol is used reduce the possibility of viral transmission to the embryo. Additionally, patient education, and medical suppressive therapy, if indicated, are initiated to reduce the risk of viral transmission to the immunosuppressed recipient. (See "Use of assisted reproduction in HIV- and hepatitis-infected couples".)

Psychological assessment — For women with a partner, the relationship between the organ recipient and her partner is of special concern because the organ recipient and her partner are electing to undergo IVF and uterus transplantation to create a family, which impacts them both. Uterus transplantation differs from other non-life-saving transplants in that both members of the couple are directly affected by the transplant because they are future coparents [60]. In the event that the relationship between the uterus recipient and her partner ends during the IVF process, any unfertilized oocytes may be frozen for future use.

The genetic father undergoes psychological evaluation with the intended organ recipient as part of the IVF protocol. A licensed psychologist uses standardized questionnaires that focus on the domains of quality-of-life, mood, relationship, and childlessness. In the Swedish research protocol, the tools used to assess such domains are:

36-Item Short Form Health Survey (SF-36) – The SF-36 is a multipurpose questionnaire that is a generic measure of health (ie, it is not specific to a particular age, disease, or treatment group) that has been validated in multiple populations [75]. The questionnaire consists of 36 questions (representing eight domains) that assess physical and mental health [76]. The physical health summary includes the domains of physical functioning, role-physical, bodily pain, and general health. The mental health summary included vitality, social functioning, role-emotional, and mental health.

Hospital Anxiety and Depression Scale (HADS) – This questionnaire assesses mood in non-psychiatric populations [77].

Dyadic Adjustment Scale (DAS) – The DAS assess concordance within the couple and discriminates between well and poorly adjusted couples [78,79]. The questionnaire is constructed to determine the degree of (a) problematic differences in a couple, (b) interpersonal tension and personal anxiety, (c) dyadic satisfaction, (d) dyadic cohesion, and (e) consensus on matters important to the dyadic interactions.

HPV and vaccination — The authors now test the male partner for evidence of HPV infection in order to minimize the risk of infection of the immunosuppressed transplant recipient. Although HPV testing of the organ donors and recipients was performed in the first clinical trial, the HPV status of the partners was not assessed. One of the women developed a CIN 2 dysplasia from HPV 31 eight months after transplantation and required a cone biopsy [47]. Male partners are advised to undergo HPV vaccination prior to the transplantation.

CONSENT — While the numerous details of research protocol and organ transplantation consent forms are beyond the scope if this review, specific issues regarding consent for uterus transplantation are highlighted here.

Uterus donor — During the consent process, the uterus donor must be free from coercion; be fully informed of the risks, benefits, and alternatives for both the donor and the recipient; and have access to an independent donor advocate [52,80]. In addition, the uterus donor must understand both the immediate surgical risks and potential long-term sequelae of undergoing a radical-type hysterectomy. The issues that the authors discuss include surgical and immediate postsurgical risks such as infection, bleeding, thromboembolism (including pulmonary embolism), injury to the urinary tract (ureter, bladder) or intestines, and dehiscence of the abdominal incision. Potential long-term sequelae include dysfunction of bladder and rectum secondary to nerve injury, herniation of the abdominal incision, light buttock pain when walking (possibly due to postsurgical redistribution of blood flow in the lower pelvis, secondary to the rather extensive pelvic dissection), or formation of intraabdominal adhesions with risk of pain or bowel obstruction. This process must also include a disclosure of sterilization as a result of the procedure.

Uterus recipient — The uterus recipient must be educated to the known risks and benefits of the procedure. This discussion must also address the potential unknown risks of the procedure, due to both the limited long-term data on outcomes and the experimental nature of the procedure. The informed-consent process must address each of the multiple steps of the uterus transplantation process, including gonadotropin stimulation, egg retrieval for the creation of embryos, uterus transplantation, immunosuppression, embryo transfer, pregnancy, cesarean delivery, and uterus removal. An additional question is who should perform the education and consent process so as to minimize the risk of coercion or therapeutic misconception by any members of the research or treatment teams.

In their research protocol, the authors address the following issues specific to the education and consent of the uterus recipient:

Information by a third party

In vitro fertilization – Timing, number of embryos to transfer, embryo storage

Effects of transplantation surgery

Immediate surgical risks – The consent in relation to surgery has to include information about the general surgical risks of bleeding, injury to other intra-abdominal structures, postoperative infection, and postoperative thromboembolism

Long-term surgical sequelae – Intra-abdominal adhesions with risk of bowel obstruction and compromised femoral artery blood flow

Effects of immunosuppression

Risks to patient

Risks to developing fetus

Risks of organ rejection

Obstetric risks – Spontaneous abortion, maternal and fetal complications

Effects of hysterectomy – Role in the setting of complication (rejection, infection, or thrombosis) (potentially with a viable fetus in place), role in setting of completion of childbearing

Risks of failure – Failure could occur at any step in the process

ROLE OF IN VITRO FERTILIZATION — Once the recipient, donor, and genetic father have been fully evaluated and consented, in vitro fertilization (IVF) is performed to ensure fertilization and normal embryo development prior to the extensive transplantation procedures [7].

The consent process for IVF is fairly standardized and is not specifically impacted by the inclusion of IVF in a uterus transplantation protocol. The consent for the genetic father mainly pertains to the IVF treatments that he must undergo to create embryos prior to uterus transplantation. The legal rights of the genetic father in relation to the embryos varies by country. In addition, the woman undergoing IVF is informed about the usual risks, including bleeding, injury, infection, and development of ovarian hyperstimulation syndrome. The patient (and her partner, if applicable) is also informed that lack of fertilization or poor embryo development could occur. In such cases, donor oocytes may be required to create an embryo.

Of note, spontaneous conception after uterus transplantation was not possible in the initial trial because the fallopian tubes were not transplanted as part of the graft. This decision was made with the goal of reducing the risk of ectopic pregnancy, particularly an interstitial pregnancy. Concern exists that the oviducts could sustain ischemic damage during the transplantation process, which could then increase the risk of an ectopic pregnancy in the setting of spontaneous conception. Were an ectopic pregnancy to develop, it would be extremely difficult to treat laparoscopically because presence of adhesions. In addition, it is not clear that the oviducts would be functional because the ovaries are lateral to the external iliac vessels in women with uterine agenesis, and the distance between the ovaries and the fallopian tubes may be too great to allow the fimbriated ends to pick up an ovulated oocyte.

SUMMARY AND RECOMMENDATIONS

Indications – Uterus transplantation is a complex, multi-step procedure for the treatment of absolute uterine factor infertility (AUFI). AUFI refers to infertility that is fully attributable to the uterus because of absence (congenital or surgical) or abnormalities (anatomic or functional) that prevent embryo implantation or completion of a pregnancy to term. (See 'Procedure overview and history' above and 'Absolute uterine factor infertility' above.)

Ethical considerations – Keys ethical points in considering uterus transplantation include the non-life-saving nature of the procedure; existence of proven alternatives for family building; the experimental nature of uterus transplantation; and the risks and benefits to the donor, recipient, and developing fetus. While gestational carrier pregnancy and adoption both exist as alternative paths to parenthood, these options are not available in all regions of the world and not congruent with all patients' values and needs with respect to family building. (See 'Ethical issues of uterus transplantation' above.)

Comparison of living and deceased organ donors – The uterus donor may be alive or deceased. Advantages of living donors include larger potential supply of organs and ample time for preoperative testing, screening, and assembly of a multi-specialty surgical team. The main disadvantage is the extensive pelvic surgery for organ removal. Use of deceased donors avoids the donor's surgical risk and allows for a more extensive graft harvest. Disadvantages of a deceased-donor organ include the limited availability of organs, unpredictable timing of organ procurement, potential that the donor uterus has not yet produced a term pregnancy, and potential ethical uncertainties regarding consent. (See 'Use of living or deceased donor' above.)

Inclusion criteria and testing – As human uterus transplantation is in the experimental stages, the optimal inclusion and exclusion criteria for both donors and recipients are not yet known. Living donors and recipients undergo extensive testing to ensure medical and psychological appropriateness. The authors’ protocol includes consultation by the following services: gynecology, transplantation surgery, psychology, clinical immunology, anesthesiology, and radiology. (See 'Selection and evaluation of recipient and donor' above.)

Preoperative imaging – Prior to removal, the donor uterus is evaluated with ultrasound and magnetic resonance imaging (if technically possible) to estimate the size of the uterus, rule out uterine pathology, exclude müllerian anomalies, and evaluate the vasculature. (See 'Donor uterus evaluation' above.)

Evaluation of planned genetic father – The goals for the evaluation of the future genetic father are to exclude male-factor causes of infertility, exclude infectious diseases that could be transmitted to the immunosuppressed mother, and to identify relationship challenges that could negatively impact the outcome of uterus transplantation. (See 'Evaluation of genetic father' above.)

Informed consent process – As part of the informed consent process, the uterus donor must be free from coercion; be fully informed of the risks, benefits, and alternatives for both the donor and the recipient; have access to an independent donor advocate; and be informed of the early and late surgical risks. The uterus recipient must be educated to the risks and benefits of uterus transplantation and then consented for the multiple steps of the process that will ultimately result in a live-born child, including gonadotropin stimulation, egg retrieval for the creation of embryos, uterus transplantation, immunosuppression, embryo transfer, pregnancy, cesarean delivery, and uterus removal. The consent for the genetic father mainly pertains to the in vitro fertilization treatments that he must undergo to create embryos prior to uterus transplantation. (See 'Consent' above.)

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Topic 98553 Version 27.0

References

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