Uterine Transplantation for Absolute Uterine Factor Infertility: A Systematic Review

Abstract

Introduction: Uterine transplantation is currently the only treatment that allows women with absolute uterine factor infertility (AUFI) to gestate and give birth. Objective: This systematic review aims to analyze the available evidence on uterine transplantation, focusing on the medical process, associated complications, ethical dilemmas, and the psychological and social impact on recipients. Methods: A systematic review of PubMed, Medline, MedNar, and Cinahl databases was conducted. The inclusion criteria included articles related to uterine transplantation published in English or Spanish between 2019 and 2024, excluding animal studies or other uterine procedures. Results: A total of 46 articles were analyzed. The review describes ethical considerations and recipients’ perceptions, two variables that have received limited attention in recent studies. Additionally, the transplant and gestation processes, along with associated complications, were detailed. Discussion: The limited availability of studies on ethical aspects and recipient perceptions presented challenges in the research. Moreover, the role of nurses and midwives, despite their importance in the process, is scarcely discussed in the literature. Conclusions: Although uterine transplantation remains an emerging treatment, its development suggests that the benefits may outweigh the risks, offering new hope for women with AUFI.

1. Introduction

Infertility due to uterine factors prevents pregnancy in women affected by dysfunction or absence of the uterus. This condition can arise from congenital or acquired causes, with Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome and hysterectomy being the most frequent reasons, respectively [1,2]. This issue affects approximately 3 to 5% of the female reproductive-age population worldwide, with around 150,000 cases in Europe and 25,000 in Spain [3,4].

The first uterine transplant occurred in Saudi Arabia in 2000, but it was not until 2014 that the first live birth resulted from such a procedure in Sweden [5]. By December 2022, over 100 uterine transplants had been performed globally, leading to 50 pregnancies and the birth of 32 infants [6].

In Spain, two uterine transplants were conducted at the Hospital Clínic of Barcelona, in December 2020 and April 2022, both involving living donors. The success of these cases marks a significant achievement, as it is uncommon for such procedures to be successful in other countries [4,7]. Recent studies in Italy have highlighted key advancements in uterus transplantation [8,9].

As uterine transplantation emerges as a viable treatment option, ethical considerations have evolved alongside it. Discussions frequently refer to the bioethical principles of beneficence, non-maleficence, and autonomy [10]. The protocol limits recipients to a maximum of two pregnancies due to the necessity of ongoing immunosuppressive treatment, which can impact their health [11]. Informed consent is crucial, as it allows women and their partners to understand the potential risks associated with the procedure, thereby respecting their autonomy. Ethical debates also surround the choice of living versus deceased donors, as the success rates appear comparable; however, using living donors can pose risks to their health [12,13].

Additionally, there are concerns regarding fetal health, particularly the risks of prematurity linked to immunosuppressive treatment [14]. Prior to uterine transplantation, women with AUFI had options such as adoption or surrogacy, but these can be complicated or unfeasible [15]. Understanding the experiences of these women from diagnosis through treatment is vital. While the primary goal of uterine transplantation is not life-saving, many women report improved quality of life and self-esteem following successful transplantation [16]. It is essential to explore the psychological, social, and emotional effects of this procedure on women and their partners [17].

The procedure necessitates a multidisciplinary team, including specialists in obstetrics, transplant surgery, gynecology, psychology, anesthesiology, and urology [18]. Following donor surgery and recipient reimplantation, which typically lasts up to 6 h, thorough monitoring is required to detect potential organ rejection, which can occur at any point after the transplant, rather than being confined to a specific window like 3 to 8 months [19].

Current data show that the average age of donors is 44 years, while recipients are typically around 29 years old [20]. Established criteria for donor selection ensure that none have a history of uterine pathologies or chronic infections, and they must have experienced one or more full-term pregnancies [21,22]. Once pregnancy is confirmed, women undergo routine prenatal care along with monitoring for graft function and immunosuppressive therapy. All documented cases have concluded with cesarean section births. Post-transplant hysterectomy may not necessarily occur immediately after childbirth. The procedure may be delayed for reasons such as patient recovery or other medical factors, but graft rejection and embryo implantation complications are not commonly cited as reasons for postponing hysterectomy in the existing literature.

This systematic review aims to compile existing knowledge on uterine transplantation, highlighting gaps in the literature regarding recipient perceptions and ethical considerations that have been largely overlooked in previous studies.

2. Materials and Methods

To achieve the established objectives, a systematic review of the literature was conducted using the following databases: PubMed, Medline, MedNar, and CINAHL. The latest update of the PRISMA statement (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) from 2020 served as a guideline for structuring and developing this work [23].

The search strategy utilized Boolean operators “AND” and “OR” to effectively link the Health Sciences Descriptors (DeCS) derived from the Medical Subject Headings (MeSH) in English. The appropriate selection of thesauri facilitated the elimination of irrelevant literature. The keywords used in the search included “Uterus”, “Transplantation”, “Pregnancy”, and “Live birth”.

Prior to commencing the research, specific inclusion and exclusion criteria were established to optimize the outcomes of the systematic review. This delineation allowed for an effective bibliographic search. The inclusion criteria comprised articles related to uterine transplantation at any stage and/or subsequent fertilization and pregnancy, published in English or Spanish, and released or reviewed between 2019 and 2024. Conversely, the exclusion criteria eliminated articles focusing on animal studies and those related to uterine procedures other than transplantation (Figure 1).

After executing searches in the aforementioned databases, articles were evaluated based on their titles and abstracts. The level of scientific evidence was assessed according to the Scottish Intercollegiate Guidelines Network (SIGN) criteria. A critical reading of the selected articles was conducted, resulting in the exclusion of studies that did not meet the eligibility criteria while retaining those deemed relevant for the development of this work.

All materials, data, and protocols related to this systematic review will be made available to readers upon publication. There are no restrictions on the availability of materials or information.

3. Results

The documentary selection process yielded a result of 46 articles that met the established criteria. The evidence of these articles was assessed based on the Scottish Intercollegiate Guidelines Network (SIGN) criteria, resulting in levels of evidence categorized as 1+, 2++, 2+, and 3. The results are summarized in Table S1.

Since its inception in 2000, many countries have attempted to advance uterine transplantation. Notable successes were achieved in countries such as Sweden, the United States, Brazil, Germany, China, and the Czech Republic [3,24]. In Spain, the first uterine transplant was performed at the Hospital Clínic in Barcelona three years ago, thanks to a direct donation from the recipient’s sister [4]. Globally, more than 100 uterine transplants have been performed, leading to 50 pregnancies and the final birth of 32 infants [6].

Currently, uterine transplantation is the only treatment available for women with absolute uterine factor infertility (AUFI), enabling them to gestate their own children [22]. Therefore, it is essential to understand the entire process, including the complications associated with this intervention, while also considering the often-overlooked ethical considerations and perceptions of the women involved. The lack of published results regarding these two variables introduces a potential risk of bias.

3.1. Ethical Considerations

Uterine transplantation has sparked various ethical discussions, particularly due to its classification as a non-vital organ transplant [16]. Unlike vital organ transplants, such as kidneys or lungs, which are critical for the survival of recipients, uterine transplantation poses different ethical dilemmas [13]. Prior to this development, women with uterine factor infertility could pursue motherhood through adoption or surrogacy. However, these options often present lengthy and complex processes, alongside significant ethical and legal issues [11,16]. Many women express a desire not only to become mothers but also to experience pregnancy and childbirth [10,25], which these alternatives do not fulfill.

Concerns were raised regarding the physical and psychological complications that donors, recipients, and newborns may experience [5]. Thus, to determine the ethical acceptability of uterine transplantation, it is critical to analyze the associated risks and benefits while adhering to the principle of non-maleficence [10].

In relation to the donor:

A key ethical question is whether the success of the procedure can be achieved with deceased donors (DDs) as effectively as with living donors (LDs) [26]. Although several newborns have been born following uterine transplantation, the number of births resulting from LDs is significantly higher than those from DDs [16,22,27], given that 74% of organs came from LDs [28]. However, there are potential health risks associated with LDs, though no fatalities from hysterectomy have been reported [14,29]. In contrast, using DDs eliminates risks to their physical and psychological integrity, although organ availability may be limited [14,15].

In relation to the recipient:

Recipients often face social pressures related to motherhood and are willing to undertake risks to experience pregnancy firsthand [30]. This process typically involves multiple interventions, including in vitro fertilization (IVF), transplant surgery, embryo transfer, cesarean delivery, and eventual hysterectomy [26]. It is imperative that recipients are fully informed of the potential risks they face throughout each phase of treatment to respect their autonomy. Moreover, women with AUFI have a higher prevalence of emotional disorders compared to those without this diagnosis [31]. Thus, incorporating psychological evaluations prior to the procedure is necessary to comply with the principles of beneficence and non-maleficence [16].

In relation to the newborn:

Another significant concern is the potential exposure of fetuses to immunosuppressive treatments administered to their mothers [10,26]. Current evidence suggests that the drugs used during pregnancy are not teratogenic and do not pose risks of congenital malformations [4,11,31]. However, fetal risks may include prematurity and low birth weight [26,32,33], highlighting the need for careful monitoring of pregnancies resulting from uterine transplantation [11].

3.2. Transplant and Gestation Process

The techniques involved in uterine transplantation have been elaborated upon by numerous experts over the years, including IVF, immunosuppressive treatment, surgical implantation, the onset of menstruation, embryo transfer, and cesarean section planning. It is crucial to note that a positive outcome in each of these stages is required; however, the transplant is deemed unsuccessful unless it culminates in the birth of a neonate [22,34].

In Vitro Fertilization:

Prior to transplant, IVF is conducted to minimize exposure to immunosuppressants and to ensure a sufficient number of viable embryos for potential pregnancies [13,29,35]. The majority of women undergoing this process are diagnosed with MRKH syndrome [16,31]. Ovarian hyperstimulation is performed similarly to that in other infertile women without a uterus [36]. Following fertilization, embryos at the blastocyst stage are cryopreserved, which enhances gestation and birth rates [27].

Immunosuppressive Treatment:

Uterine transplantation necessitates long-term immunosuppressive therapy to prevent organ rejection, a known risk factor for long-term survival in solid organ transplantation in general [36,37]. These medications must be initiated prior to the implantation surgery and continued until the uterus is removed [35,36]. Adjustments to these treatments are made based on the women’s condition, balancing the preservation of the uterus with maternal–fetal safety [35], for which teratogenic medication needs to be withdrawn before embryo transfer [36].

Regarding pharmacotherapy, it begins with the concomitant use of mycophenolate mofetil and tacrolimus [1]. Once transplanted, and before embryo transfer, women change mycophenolate mofetil to azathioprine due to the teratogenicity of the former [1,3,36].

In case of rejection, it is normal to use a low dose of intravenous methylprednisolone in addition to immunosuppressant drugs, but sometimes the rejections are critical and high doses of this medicine need to be used including azathioprine and anti-thymocyte globulin [1,36].

Finally, when the pregnancy is confirmed, the drugs of choice continue to be tacrolimus and azathioprine, in combination or not with corticosteroids like prednisone or dexamethasone [1,6]. In the latter case, corticosteroids are safe even though their ability to traverse the placenta because only 10% of the dose reaches the fetus [36].

Surgical Intervention:

The success of uterus implantation relies heavily on a multidisciplinary team, including various specialists [38,39]. The duration of hysterectomies performed on living donors averages around 10 h, whereas procedures with deceased donors can take up to 3 h [13,22]. Following confirmation that the uterus is healthy, implantation surgeries are typically conducted through open surgery, lasting between 4 and 6 h [16,22]. A Doppler ultrasound is performed to confirm adequate tissue perfusion prior to completing the procedure [3].

Post-Surgical Follow-Up:

Subsequent monitoring includes cervical biopsies, which may indicate signs of organ rejection [1,3,38]. Additionally, a lack of menstruation or endometrial proliferation may raise concerns [12].

Embryo Transfer:

Embryo transfer is contingent upon the stability of the immunosuppressive treatment and the absence of rejection signs [33]. While initial transfers occurred one year post surgery, current practices have reduced this window to between three and six months post implantation, allowing for quicker pregnancies [36,38].

Gestation:

After confirming pregnancy viability via ultrasound, women undergo standard prenatal care, along with additional monitoring related to the transplant, including cervical biopsies [27,40]. Regular blood and urine tests are conducted to assess renal function and tacrolimus levels [6,40].

Hysterectomy:

Hysterectomy may be performed at the time of delivery or at a later date, depending on individual circumstances [12,37,41]. In cases of subsequent pregnancies, the hysterectomy is typically executed post-delivery, utilizing the cesarean incision for access [40,41].

3.3. Complications

Both physical and psychological complications may arise for both donors and recipients [3]. Living donors may experience vaginal alterations, ureteral damage, bleeding, infections, and thrombosis [39,42]. Recipients may develop complications typical of pregnancy, including preeclampsia and gestational diabetes, as well as graft rejection and renal function alterations [22,29]. Nevertheless, almost 60% of patients have not experienced any complications after implantation surgery [1].

Health Problems During Gestation:

Pregnant women may experience common complications such as preeclampsia, although the correlation between these issues and transplant status is not yet established [9]. Gestational diabetes screening is particularly important due to the immunosuppressive medications [8,32].

Infections:

The first month post-transplant carries a higher risk for infections due to immunosuppressive therapy [43]. Reactivation of viruses, such as cytomegalovirus and human papillomavirus, is a noted concern in this patient population [27,43].

Renal Disorders:

Monitoring of renal function is critical in all pregnancies following organ transplants [8]. Women who undergo uterine transplants often show reduced glomerular filtration rates, especially in association with tacrolimus use [9,44]

It is worth noting that there is a high risk of prematurity because the recipients do not feel the contractions, which requires close monitoring [15]. Moreover, babies born as a result of this treatment are usually born with 37 or less weeks of gestation because the transplanted organ is not able to grow as much as an ordinary one [21,27].

3.4. The Perceptions of the Recipients

Recipient perceptions significantly impact their experience of uterine transplantation. The diagnosis of infertility can create a profound emotional impact, influencing relationships with partners and family members [16]. This fertility problem can be related to congenital reasons such as AUFI, secondary to diseases like abnormal growth of endometrial tissue as in case of benign ailments as adenomyosis or endometriosis, or by uterine resection surgeries due to severe uterine bleeding, some gynecological cancers, or serious infections [42].

In the study cases, many recipients have reported feelings of hope upon entering the transplant program, although concerns about the uncertainty of success persist [39,45,46]. While recipients typically desire to experience pregnancy, they often prefer adoption over surrogacy due to its complexity and associated costs [31,34,47]. Meeting other women in similar situations was reported to alleviate feelings of isolation and provide emotional support [16,18]. Some recipients also express concern over changes to their self-perception and body image post-transplant, although studies indicate that sexual satisfaction remains largely unaffected. For completeness, it is important to note that all children born following uterus transplantation were reported to have a birth weight appropriate for their gestational age, even in cases where the births were preterm [27,32,33].

In conclusion, while uterine transplantation provides a new avenue for women with AUFI to achieve motherhood, it is accompanied by a complex array of medical, ethical, and emotional considerations that must be addressed to ensure positive outcomes for both mothers and infants. That is why it is important to psychologically support patients in the long term [18,28].

4. Discussion

The rise in uterine transplantation in recent decades highlights the need for continuous updates of available information, and this systematic review contributes to that effort. While much attention has been given to the clinical outcomes and complications of the procedure, this review emphasizes the often-overlooked aspects, particularly the ethical considerations and emotional experiences of the women involved.

Uterine transplantation has emerged as a viable option for women with absolute uterine infertility, and from a sociological perspective, it has sparked profound changes in gender roles, cultural norms about motherhood, and female autonomy. The ability to postpone motherhood for personal or professional reasons has driven the demand for options such as uterine transplantation, particularly for women of advanced age where fertility challenges become more pronounced. This procedure not only expands reproductive rights but also raises ethical dilemmas due to higher surgical risks in older women. Additionally, access to uterine transplantation tends to favor women from higher socioeconomic groups, contributing to inequities in access to late childbearing options and raising questions about health equity. From an identity perspective, uterine transplantation offers a form of “tailor-made” motherhood that aligns with contemporary societal values of individualism and self-control [33,48].

The debate surrounding age restrictions for uterine transplantation, which currently exclude women over 40, remains an important issue. While the restrictions are based on concerns about potential complications during pregnancy, they also leave out a large group of women who could benefit from the procedure. Most centers offering uterine transplantation set an age limit of around 30 years, which raises a clear inequity in access to the procedure. While this restriction is justified for medical and scientific reasons—since the technique is still in development and outcomes may be compromised in older patients—it is important to consider its impact on women with AUFI, most of whom are over 30.

Moreover, in today’s social context, where childbearing is increasingly postponed for personal, professional, and societal reasons, denying access to these women is controversial. Restricting eligibility based solely on age may not align with evolving reproductive trends and could be perceived as unfair, especially when alternative assisted reproductive technologies remain accessible to older women. Ethical discussions on uterine transplantation should, therefore, address these disparities and explore ways to ensure fairer access while maintaining medical safety. In general, there is no specific legislation regarding uterine transplantation in both the United States and Europe, as it remains an experimental procedure. This requires approval from ethics committees on a case-by-case basis [5].

Uterine transplantation, beyond being a medical solution, reflects modern values of autonomy and flexibility in constructing identity, but it also raises crucial questions about equity and medical risks. It has become an innovative solution for women facing infertility, particularly those impacted by cancer treatments. Currently, uterine transplantation has emerged as an innovative and revolutionary solution for fertility challenges posed by cancer treatments. However, many countries continue to operate on patients with cervical cancer due to the associated medical and ethical implications. From a medical perspective, the recipient assumes risks related to surgery, immunosuppression, pregnancy, and childbirth. Additionally, the choice between brain-dead and living donors, along with the risks for living donors, raises significant medical and ethical concerns. It is widely acknowledged that uterine transplantation should not be offered as a routine clinical procedure until its safety and effectiveness are fully established, and more data are gathered to fully understand its risks and benefits. As the procedure transitions from the research phase to clinical practice, it is crucial to thoroughly examine its ethical, legal, and social implications before it becomes widely implemented [48,49].

However, the medical risks for the recipients, including those related to surgery, immunosuppression, and pregnancy, continue to be significant considerations. The ethical considerations surrounding living and deceased donors also remain pivotal in determining the procedure’s future.

From a nursing perspective, staying informed about evolving reproductive options is crucial for providing effective support to patients. Nurses, especially midwives, play an integral role in pre-operative care and pregnancy monitoring, yet the literature frequently neglects the contributions of nursing professionals, undermining their vital role in the uterine transplantation process.

One limitation of this review is the scarcity of publications addressing the emotional and ethical implications of uterine transplantation. Most research has focused on clinical outcomes, with limited exploration of the psychological impacts on recipients. Future studies should prioritize understanding how the desire for motherhood and the experience of pregnancy affect mental health and quality of life. Furthermore, there is a need for more in-depth investigation into the ethical issues surrounding organ donation, particularly for living donors, to ensure the well-being of all parties involved.

This surgical intervention also offers a unique reproductive opportunity for cancer survivors who have undergone hysterectomy as part of their treatment. Unlike patients with congenital uterine factor infertility (AUFI), cancer survivors may face additional challenges, such as the potential effects of prior chemotherapy or radiation on ovarian function, increased risks of immunosuppression-related complications, and ethical considerations regarding recurrence risks. Furthermore, fertility preservation strategies, such as oocyte or embryo cryopreservation before cancer treatment, may influence the success rates of uterine transplantation in this population. Given these differences, tailored protocols and careful long-term follow-up are essential to ensure both reproductive success and patient safety in cancer survivors undergoing uterine transplantation.

In connection with the above, this also presents an opportunity to address the reproductive aspirations of transgender women, who often face significant psychological and social harm due to their inability to bear children. For many transgender women, the possibility of experiencing menstruation, pregnancy, or even a functioning transplanted vagina could offer significant improvements in quality of life and a reduction in dysphoric symptoms. This highlights the potential for uterine transplantation to be a transformative procedure for individuals facing gender dysphoria [50].

Ongoing dialog about the role of healthcare professionals, especially nurses, is essential to ensure their involvement in this evolving field. By advocating for the inclusion of nursing perspectives in future research, we can better represent the multifaceted role that nurses play in uterine transplantation.

This systematic review is a call to action for continued research and discussion in this field, aiming to fill knowledge gaps and elevate the discourse on uterine transplantation and its broader implications.

5. Conclusions

Uterus transplantation remains largely unknown to the general population and many healthcare professionals. As a result, women with absolute uterine factor infertility (AUFI) in most countries cannot consider this procedure as a viable option, either due to its absence or its status as a clinical trial. Although Spain has witnessed two successful cases to date, significant efforts are still required to establish this transplant as a recognized option for women in the country.

The ongoing debate about the type of donor remains unresolved; however, evidence indicates that both living donors (LDs) and deceased donors (DDs) are valid options. Notably, success rates tend to be higher with LDs due to improved compatibility. Moreover, the risks associated with the physical and mental health of LDs are relatively low, suggesting that the continuation of this procedure is justifiable.

While the primary motivation for organ recipients is to fulfill their desire for motherhood, the associated risks may seem considerable. Nevertheless, numerous studies have highlighted the psychological and emotional benefits that accompany successful transplantation. It is crucial to refine existing procedures to minimize risks, such as the reduction in glomerular filtration rates that some recipients experience.

Healthcare professionals involved in the initial stages of this process must be acutely aware of the motivations behind women’s decisions to pursue this surgical option. Providing comprehensive information is essential for enabling informed decision-making, in line with bioethical principles. Additionally, understanding and addressing the emotional experiences of women throughout the process is vital, particularly when outcomes do not meet expectations.

Ultimately, all women, not just those diagnosed with AUFI should have equitable access to this opportunity for motherhood. To facilitate the implementation of uterine transplantation protocols in various countries, it is imperative to continuously update the scientific evidence. Advancing this field not only will provide benefits for women with infertility problems but may also extend to other populations, such as transgender women, thereby broadening the scope of reproductive options available.