Embracing the mental health challenges of uterus transplant candidates

As the field of UTx transitions to become the standard of care, it is reasonable to expect that UTx evaluation and selection will largely recapitulate the structure of conventional organ transplantation. As such, it is prudent to consider whether and how selection practices in organ transplantation serve individuals with UFI. Organ transplant candidates are evaluated in multiple domains, including medical, surgical, and psychosocial suitability. Medical and surgical evaluation of candidates for UTx is rigorous like any other organ transplant, with candidates undergoing extensive radiographic and laboratory testing. Similarly, UTx clinical trials have set the precedent for extensive psychosocial screenings. 13 Psychosocial screenings are important as one needs to ensure the patient will be able to cope with stressors of surgery, be collaborative with their physician team regarding post‐transplant care, be compliant with medical treatment, and provide a baseline of mental functioning to aid in an effective post‐transplant treatment plan. For example, guidelines have been developed by several professional societies around psychosocial criteria for transplant. Kidney Disease Improving Global Outcomes (KDIGO) guidelines 2020 recommend not transplanting patients with an unstable psychiatric disorder or ongoing substance abuse disorders. 15 However, psychosocial guidelines governing organ transplantation are imperfect and not evidence‐based, suggesting room for improvement given their known limitations. These guidelines are also vague. The limits or criterion listed is subject to interpretation. Without specificity around what constitutes as “unstable,” it is difficult to adapt them for creation of new organ transplant guidelines. For example, KDIGO guidelines do recognize lack of empiric evidence surrounding components of psychosocial evaluations, and there is limited weak evidence that pretransplant psychosocial factors have an impact on post‐transplant outcomes. Given the imperfections in solid organ transplant psychosocial screening, it is unclear whether current psychosocial screening mechanisms are appropriate for UTx candidates. It is crucial to note that none of the current work around psychosocial screening guidelines considers how the population of UTx is different than of other organ transplant candidates. KDIGO guidelines do not consider factors such as reproductive identity and long‐term psychological sequelae of living with UFI. As we discuss in the next section, incidence of conditions such as depression and anxiety are much higher in UFI population with no data around the response of these patients to resolution of UFI. Indeed, initial psychosocial screenings for UTx candidates were understandably conservative, given the need to prove it as an effective therapy for UFI, with initial psychological screening processes adapted from the emerging field of vascularized composite allotransplantation (i.e., hand and face transplants) as well as the field of reproductive medicine. 16 , 17 Baylor University Medical Center at Dallas in collaboration with Swedish team, leading the arena in clinical trials of UTx, developed the initial framework for UTx recipients, partners and donors. 13 The guideline, though comprehensive, does suggest a strict framework where it is recommended to exclude individuals with personality disorders, history of suicide, and psychosis. Moreover, a history of substance abuse was also considered an exclusion criterion. Another proposed requirement pertained to relationship stability, although relationship stability is hard to predict and may also exclude women with MRKH in particular given that many individuals with MRKH may not be in a stable relationship due to struggles with impaired sexual function because of other anatomic abnormalities associated with MRKH. 18 As mentioned above, such exclusion criteria were likely necessary in the clinical trial era to achieve the success needed to prove UTx as an effective therapy for UFI. However, in the post clinical trial era, we need to re‐evaluate some of these guidelines considering the special psychological characteristics of MRKH and other UFI patients.

As we attempt to define the number of patients we wish to serve with UTx, it is important to first estimate the prevalence of the disease. In brief, this currently includes individuals suffering from UFI due to congenital absence of the uterus (i.e., Mayer–Rokitansky–Küster–Hauser syndrome [MRKH]) or surgical removal of the uterus (i.e., hysterectomy). The prevalence of UFI is challenging to estimate as there is significant heterogeneity in prevalence estimates reported from around the world. Reports of estimates of UFI are also challenged by heterogeneity in the disease as well, as some studies have focused on UFI caused by MRKH or surgical removal. Acquired causes like adenomyosis or Asherman's syndrome have their own prevalence rates which vary in different populations. Furthermore, there is lack of standardized diagnostic criterion for UFI, as well as under reporting of true UFI as not everyone with UFI seeks treatment. Hence, it is difficult to provide an aggregated estimate under the “UFI” umbrella. Few studies have been conducted to assess the prevalence of MRKH syndrome in isolation. Herlin et al. out of Denmark examined the frequency of MRKH as a diagnosis among hospital and outpatient medical records from 1994 to 2015 and reported a prevalence of 0.02%, or 1 in 4982 patients. They did report limitations of their study as they only assessed records at public hospitals and potentially could have missed records in retrospective search due to missing diagnosis codes. 4 Most of the global studies have reported on UFI without differentiating between specific etiologies. Another group which may have unique psychologic needs should they qualify for UTx is transgender women, although this discussion is beyond the scope of this commentary. In a study out of Morocco of 1265 infertile couples, for example, 12.6% had UFI, 5 whereas UFI was the cause of infertility in only 2% of 800 females in a Sudanese study. 6 Meanwhile, Meng et al. out of China assessed 2151 couples planning for pregnancy between 2009 and 2012, and UFI was reported in about 12.1% of females. 7 Surgical hysterectomy is done for variety of causes, ranging from oncologic reasons to benign pathologies. Etiologies vary based on the age group of the patients. Emergent peripartum hysterectomies are usually done for hemostatic reasons. This population of females in reproductive age group is likely to seek UTx in the future. Even fewer studies have looked at the number of hemostatic hysterectomies done in the United States and Canada. Its estimates range from 0.05% in Canada to 0.27% in the United States. 8 A retrospective study looked at four major metropolitan hospitals in Washington D.C. assessed 150 847 deliveries and reported 128 cases of post‐partum hysterectomy (0.85 per 1000 deliveries). 9 A study out of Stony Brook University Hospital looked at a cohort of patients between 1990 and 1995 and reported 39 cases of post‐partum hysterectomy (2.7 per 1000 deliveries). 10 Although it is unknown how many women undergoing an emergent postpartum hysterectomy might desire additional children, it is likely that a significant percentage of these women will be impacted by their newly acquired infertility. Wright et al. looked at 1507433 females between 1998 and 2010 and found that 379 709 hysterectomies were performed in reproductive age females between the age of 18 and 40 for benign disease. 11 Estimates of the prevalence of UFI in the United States are poorly defined due to a paucity of published studies defining this population for the purposes of UTx, but if we extrapolate rates of UFI from global prevalence data (2%–12% of patients with infertility as discussed above), we would estimate that there are between 379 000 and 2.28 million females potentially affected by UFI in the United States. 12 Altogether, these estimates suggest the extensive nature of UFI as a problem and highlight that the current number of transplants have served a tiny fraction of the potential population in need.

Muhammad Umaid Rabbani—idea and writing. Brittney Randolph—helped in paper writing for parts concerning mental health workup and treatment of our patients. Samantha Fry—data collection and figures. Emily A Boydston—data collection. Paige M. Porrett—editing of written material.

Few studies have examined how psychosocial barriers limit access to UTx for patients in need. We predict that a significant barrier is the limited awareness of potential differences in mental health pathology experienced by the UFI population compared to the general population or other organ transplant populations. MRKH patients experience a set of psychologic challenges which are unique and often have experienced depression, anxiety, and psychologic trauma starting from adolescence when the condition is initially diagnosed. 19 MRKH patients may not only question their identity as women but also question their ability to conform to expected societal roles or achieve stable relationships because of sexual dysfunction as well as infertility. A systematic review by Tsarna in 2022 looked at multiple studies to assess the overall impact of MRKH on psychology, quality of life and sexual satisfaction. Fourteen of the included studies examined sexual function and satisfaction in these women. Multiple different scales were used to assess sexual function across these studies but most utilized Female Sexual Function Index (FSFI). Although there are conflicting data, three of the studies showed that MRKH patients had lower Female Sexual Function Index scores overall in comparison to a reference group of women without MRKH. 18 In line with these results, patients with MRKH have reported negative feelings of being defective, inferior and unlovable. 20 A randomized control trial out of the United Kingdom compared the psychological questionnaires of 66 women with MRKH to 31 females in a control group. They used four different self‐reporting questionnaires including The Symptom Checklist (SCL‐90‐R), The Rosenberg Self Esteem Scale (RSE), the Inventory of Interpersonal Problems (IIP‐32) and the Eating Disorder Inventory (EDI). With regard to SCL‐90‐R subscale scores, women with MRKH scored significantly higher in psychoticism category (0.73 vs. 0.46), phobic anxiety (0.52 vs. 0.23) and depression (1.27 vs. 0.92). Similarly, women with MRKH had significantly higher (worse) scores on the RSE, suggesting significantly lower self‐esteem compared to controls (22.8 vs. 19.3). Also, MRKH females had a higher incidence of bulimia evidenced by higher scores on the Eating Disorder Inventory. 20 Among other causes of UFI, there is limited literature around incidence of psychiatric health problems in women with conditions such as Asherman Syndrome, adenomyosis, or those needing hemostatic hysterectomy or hysterectomy for other nonmalignant causes. Nevertheless, it is reasonable to suspect that women who undergo hysterectomies during the childbearing years suffer from a higher incidence of depression and anxiety given the association between these specific psychiatric problems and infertility. Moreover, a study out of Saudi Arabia prospectively interviewed 38 women 2 weeks post hysterectomy and compared the results of these interviews with 37 control females who had undergone another operation. Notably, the hysterectomy group had a 31.6% incidence of major depressive episode compared to 2.6% in the control group. Nulliparous and younger females were at a higher risk. 21 The incidence of depression reported in this study is potentially higher than one would expect in other parts of the world given study conducted in a conservative country where infertility carries a stronger negative connotation. Similarly, adenomyosis has been known to negatively affect women's quality of life and psychological health, along with having higher incidence of depression and anxiety. 22 , 23 Both infertility and disease symptomology contribute to these findings. Given that the University of Alabama Birmingham was the first UTx program to forego a clinical trial stage and was built de novo as a clinical program, major goals of the program were inclusivity and accessibility to patients in need. Hence, all processes around the evaluation and transplantation of women with UFI were designed to accommodate the special needs of this population, including the unique psychologic needs discussed above. To this end, the initial health screening form that is filled out by interested candidates did not include any explicit questions around psychologic health or status. This was done with the intent to capture all patients regardless of their mental health condition. While a small minority of referrals (35 of 331 [10.6%]) who completed the health questionnaire were advanced to undergo a virtual visit (Figure  1 ), the declines at this stage were not due to psychosocial reasons as this information was not collected on the questionnaire. Moreover, only two of the 35 patients undergoing a virtual visit (6%) were later declined for psychological/psychiatric reasons, also illustrating the program's commitment to include patients in the evaluation process who had mental health comorbidity. Of note, the two patients declined at this stage were deemed to have significant psychiatric history that would overwhelm the program's ability to support them given the infrastructure at the time and thus jeopardize outcomes for the patient. One patient was declined due to a history of debilitating depression not well managed on multiple psychotropic agents, and another was declined due to her partner's new diagnosis of bipolar disorder which had not yet been treated. Both candidates were counseled about seeking mental health support and encouraged to return for reassessment following attenuation of symptoms. Sixteen of the remaining 35 patients were invited for in‐person evaluation (Figure  2 ). Overall, 26 of the 35 patients who had a virtual visit with the UTx team were not listed for transplant for reasons which are elaborated in Figure  3 . Uterus transplant evaluation flow at the University of Alabama at Birmingham. The University of Alabama at Birmingham uterus transplant in numbers as of July 2024. Patients who did not get listed after a virtual visit had multifactorial reasons. (A) Changing their mind about participation; (B) unable to relocate, or limitation of funds for parts of care outside of transplant itself; (C) variety of medical issues such as high BMI, severe endometriosis, MRKH‐related severe anomalies in urinary system, multiple pelvis surgeries; (D) social issues included inadequate care plan for other children, not having a partner for a year minimum. MRKH, Mayer–Rokitansky–Küster–Hauser syndrome. Due to broader inclusion criteria, two of five transplanted (40%) patients had exacerbations of underlying severe anxiety during the perioperative phase, as would be expected given the prevalence of disease and the known physical and psychologic stressors of transplantation surgery. Altogether, these results suggest that UTx recipients at the UAB are indeed representative of the population in need with respect to psychologic comorbidities. With the understanding that this patient population was going to require dedicated mental health support, UAB had measures in place to support them. Both patients were effectively treated by these measures, including the provision of active psychological support as they navigated the post‐transplant period, including pregnancy and childbirth. Both patients underwent cognitive behavioral therapy sessions with our team's psychologist during post‐transplant period but had distinct needs around frequency of visits as well as medications. One patient needed to see the team psychologist at an interval of about every 2 months for therapy until her first live birth, at which time her appointments became less frequent. She also benefited from initiation of a new medication to combat anxiety post‐transplant that was prescribed by her primary care physician. In contrast, the other patient needed only one therapy session in the post‐transplant period and did not have need for medication. None of the patients were on psychotropic medications before transplant, so more data are needed to discern whether dose changes of these medications post‐transplant are necessary to adequately treat mood disorders in the setting of several acute stressors. Given that the needs of these patients were successfully met and their outcomes have been excellent, we advocate for an evaluation and transplantation approach where mental health comorbidities in the UFI population are identified, treated, expected, and managed (as opposed to excluded). Our recommendation is to be inclusive of candidates who have a history of depression, anxiety, personality disorders, history of substance abuse, bipolar disorders if these conditions are managed, and patient is following a treatment plan. From a programmatic perspective, psychiatric disorders, regardless of severity or a history of treatment should be moved to relative contraindications rather than absolute. Psychiatric history should not be required in initial screening when bringing patients in for evaluation.

As new programs open their doors for referrals and established programs transition out of clinical trials, there are many facets of UTx which will need to be re‐evaluated. We make the case for exercising leniency when setting psychiatric and psychosocial selection criteria for these candidates. Clearly, this leniency must be judiciously tempered by individual transplant programs and providers, as severe or refractory psychiatric disease can compromise patient safety and transplant outcomes. Nevertheless, utilization of the same psychiatric and psychosocial benchmarks used for other solid organs may not be suitable in light of the prevalence and uniqueness of psychiatric comorbidity in this population. Redesigning the approach to evaluation and transplantation of individuals with mental health disorders necessitates that transplant programs develop and maintain robust psychiatric and psychological support teams for all candidates being considered for UTx. Candidates with severe depression, severe anxiety, history of substance abuse, or personality disorders should be considered indiscriminately if there is an adequate psychiatric treatment plan with signs of positive response to that treatment. If candidates are encountered who otherwise meet criteria but might have untreated or poorly treated psychiatric disease, we encourage transplant centers under these circumstances to provide the necessary support to these patients with the goal of becoming a transplant candidate. During the post‐transplant period, we advocate for scheduled routine visits with a psychologist for all patients regardless of their baseline mental health status. To make this successful, programs will likely need to invest in the development of dedicated infrastructure in this domain, as psychologists, psychiatrists, and other mental health providers are often under‐resourced, as evidenced by a recent study in the United States. which identified that only 18.5% of 948 psychiatrists across multiple states were accepting new patients and wait time was 67 days for an appointment. 29 More discussion is needed in this important area of UTx care, as the critical role played by psychiatrists and psychologists on the UTx team cannot be overstated. In summary, women who needed focused mental health support during their UTx journey had excellent post‐operative outcomes that did not differ from other candidates at the UAB. Nevertheless, the single‐center experience which we report here is small, and more data are needed as other centers revise their program criteria to be more inclusive of patients with psychologic comorbidity. As transplant centers find creative ways to expand UTx in an era of increasing cost‐consciousness, we ask administrators and program leaders to resist the temptation to cut costs by prioritizing funding for surgical or obstetric care at the expense of psychiatric care at all stages. With its emphasis on quality‐of‐life benefits, the field of UTx serves to remind the medical community that enhancement of quality of life in all domains—physical, mental, social, etc.—is truly what patients seek from their providers beyond the treatment of mere physical ailments.

Previous work in other organ transplants has shown us that organ transplant recipients have potential improvement in mental health after receiving a solid organ transplant. But data are conflicting in this area. A cohort study of 97 individuals listed active for kidney transplant between 2003 and 2004 was assessed 2 days before and 2 weeks after a kidney transplant. At both these points, these patients filled out a general health questionnaire and Minnesota Multiphasic Personality Inventory (MMPI). There was reportedly significant improvement in mental health at 2 weeks post‐transplant with lower levels of depression, anxiety, impaired social functioning, and physical symptoms. 24 Other studies suggest worsening or development to de novo mental health comorbidity post organ transplant. Seventy‐five patients assessed at a median time of 3.8 years post orthotopic liver transplant showed a significant subset developed post‐traumatic stress disorder symptomology which significantly impaired their quality of life. 25 Given solid organ transplants are primarily life‐saving procedures, it is difficult to compare psychological outcomes between uterus and other solid organ transplants. Some previous work in face transplantation has shown that those recipients show significant improvement in mental health post‐transplantation, along with improvement in social integration. 26 As we consider how to improve access to UTx by improving processes that manage psychiatric disease burden in UFI candidates, we may wonder if UTx can provide some improvement in psychologic comorbidity associated with UFI. If UTx eventually leads to a successful live birth and overcoming of infertility for a patient, we can argue that UTx does indirectly treat some elements of mental health conditions which arise due to suffering from infertility. Such a mindset may be new for the UTx community, as transplant practitioners often equate a successful infertility treatment with the birth of a child or a concrete solution to organ failure but may not explicitly recognize that a transplant is also a treatment for psychiatric disease. In the vein of considering how UTx is a treatment for depression & anxiety, UTx could potentially ameliorate depression, anxiety, substance abuse, and other mental health disorders in these patients. Numerous studies around infertility have shown improvement of mental health disorders after women achieve their goal of having a child, with the highest satisfaction in women who become biologic mothers. Leiblum et al. studied three groups of women who underwent in vitro fertilization (IVF) treatment and compared psychologic outcomes for the successful IVF group, unsuccessful IVF group who adopted and childless unsuccessful IVF group. Overall life satisfaction scores on a 7‐point Likert scale were highest for successful IVF group at 6.2, followed by group that adopted at 5.7. The unsuccessful, childless group had the lowest score at 4.9. 27 A cross‐sectional study published in 2020 assessed self‐esteem and life satisfaction in 283 participants who were dealing with infertility. Forty‐seven women had a resolution of involuntary childlessness, and this subgroup of women reported higher self‐esteem and life satisfaction in comparison to 236 women who did not have a resolution of their infertility. 28 Altogether, these studies provide evidence of the psychologic benefits associated with the treatment of the disease of infertility, but further studies are needed to better define the psychologic benefits of UTx as an infertility treatment and overall quality of life enhancement.

As the field evolves and becomes more inclusive of patients with mental health comorbidities, it is important to collect detailed data on such patients. Beyond looking at the ultimate outcome of a live birth, we need to collect more granular data around resources required during the care of these patients so to provide more directed guidance to other centers with regard to new projected needs of a program. Issues such as problems with medication or general health care compliance needs to be recorded. This will assist to formulate future guidelines which are more objective with regard to mental health disease in UTx population.

In order to develop a therapy which could potentially fill the extensive need described above, initial clinical trials were necessary to provide data on feasibility, safety, and efficacy. Therefore, the individuals who have been transplanted so far represent a highly selected subset, as would be expected given the rigor associated with selection into clinical trials. Clinical trials have historically been strict with psychological screening criterions. In 2018, Baylor university medical center in Dallas proposed exclusion of severe and enduring psychopathology such as personality disorders and psychosis citing early stages of Utx as the reason. 13 Many years later despite our experience in UTx, clinical trials continue to be stringent with inclusion criterion around psychological issues. One of the latest UTx clinical trials in New South Wales registered with Australian New Zealand Clinical Trials Registry mentions exclusion of an individual with pre‐existing psychological condition that would pose the subject at an increased risk. In the wake of multiple successful trials around the world, however, approximately half of the active UTx centers in the United States currently offer UTx as clinical care and not as part of a clinical trial. These programs include the University of Alabama at Birmingham (UAB) as well as Baylor University Medical Center in Dallas, TX. Such activity outside of the structure provided by a clinical trial highlights how UTx has expanded in recent years and propels consideration of how participants in clinical trials might differ from the overall population in need. While the guidelines around inclusion and exclusion criteria for clinical trials described by the National Institutes of Health, and the U.S. Food and Drug Administration in the United States recommend selecting a demographically diverse pool for clinical trials, stringent exclusion criteria are often recommended to minimize confounding factors which might make interpretation of study results difficult and ensure safe outcomes for study participants. Indeed, when one considers the wider context of ethical conduct of clinical trials, it is important to remember that clinical trial goals differ from clinical care goals, as clinical trials focus on advancing knowledge and minimizing risks to study participants, 14 whereas clinical care goals are to equitably serve a much broader population with the disease. However, when the treatment under investigation moves forward outside of trials, candidate selection should be adjusted to allow the treatment to be delivered to the population in need. Like the process described above for clinical trial selection, selection of candidates for organ transplantation is often rigorous, but it must be balanced to provide successful transplantation to individuals in need. In summary, while clinical trials of UTx selected the candidates with the best chance of achieving the primary goal of live birth, it is likely that the inclusion and exclusion criteria established by these trials should be modified as we move out of clinical trial era into clinical practice.

Uterus transplantation (UTx) is an emerging therapy for uterine factor infertility (UFI). Over 100 uterus transplants have been successfully performed across the globe. Building upon foundational work performed by groups from Saudi Arabia and Turkey, the first successful live birth after a UTx occurred in Sweden in September 2014 as part of a clinical trial. 1 , 2 , 3 Prior to this success, there were no treatment options for females with UFI, and affected individuals suffered from severe restrictions on their reproductive autonomy as they could not experience gestation and childbirth due to the absence of a uterus. Since the completion of this pioneering work, clinical trials performed at several centers around the world have now proven UTx to be an effective therapy for UFI. In effect, UTx now represents the only medical treatment for a previously incurable and devastating disease. Nevertheless, prior clinical trials have addressed only a fraction of the population in need and have been performed in highly selected candidates within the rigorous framework of clinical trials. As the field looks to grow into the bright future enabled by this pioneering work, expansion of access to UTx represents an important future direction. We contend that such expansion will require equity in opportunity for listing and transplant for individuals afflicted by UFI. To this end, selection criteria for UFI patients need to align with the specific characteristics and needs of this target population. In this work, we posit that many women with UFI who might benefit from UTx have been excluded because of concerns regarding the impact of psychologic aspects or psychiatric disease on post‐transplant outcomes. However, the prevalence of such disease in the population served by UTx is significant and highlights the critical need to refine selection criteria and transplantation practices to accommodate the unique mental health needs of UFI candidates. We further contend that excellent UTx outcomes can be preserved as transplant access is expanded by increasing provider awareness alongside implementation of the infrastructure needed to support the psychologic health of both candidates and recipients.

We adhered to strict ethical principles while preparing this manuscript. Ethical approval was not necessary as this was an expert opinion/perspectives mansucript and no patient data were collected for research purposes.