Uterine transplantation- hope for infertile women desiring pregnancy

This is estimated to affect one in 500 women. Options for those who wish to start a family include adoption and surrogacy, but these are associated with legal, cultural, ethical and religious implications that may not be appropriate for some women and their families. A womb transplant is undertaken when the woman is ready to start a family, and is removed following the completion of their family.

Although the number of transplants to date is still relatively small, the number being performed globally is growing, providing an opportunity to learn from the experience gained so far. Paper written by Jones BP et al in British Journal of Obstetrics and Gynecology addresses the issues that have been encountered, which may arise at each step of the process, and proposes a framework for the future. However, long term follow-up of cases will be essential to draw reliable conclusions about any overall benefits of this procedure.

AUFI refers to women with infertility secondary to the absence of a uterus or the presence of one that is anatomically or physiologically dysfunctional.

Uterine transplantation (UTx) provides an opportunity to overcome some of these issues while giving women with AUFI the opportunity to conceive using assisted reproductive technologies and experience pregnancy themselves.

• Alternatives to uterine transplantation

Reproductive planning involves numerous factors that derive from each individual's/partner's values, which may be influenced by social or cultural norms, and the resources available to them. Women with AUFI have traditionally remained childless or considered the option of adoption or surrogacy.

There are pros and cons to adoption and surrogacy and it is, therefore, important for women with AUFI to ensure they are well-informed about their options.

While adoption and surrogacy provide options for women with AUFI who wish to become mothers, they do not restore the anatomical issue underlying the cause of their infertility. Women born with AUFI will therefore never experience menstruation, which to some women is part of being female and has been shown in a small study involving 12 participants to contribute to a female gender identity.6 Furthermore, adoption and surrogacy do not give the experience of pregnancy, which has been demonstrated to be the primary motivator in 63% of women with AUFI who request UTx.

While UTx is associated with greater physical risk, including multiple major surgeries and the necessity to take immunosuppression while the donor transplant is in situ, it does allow the recipients to experience pregnancy, and overcomes some of the legal and religious issues associated with surrogacy.

• Potential recipients

Out of the 45 reported cases, 40 (89%) were performed in women with Mayer–Rokitansky–K€uster–Hauser (MRKH) syndrome. Four (9%) cases were undertaken following hysterectomy (one for postpartum haemorrhage,8 one after cervical cancer,9 two following failed myomectomy5 ). One (2%) case was undertaken in a woman with Asherman syndrome who underwent preparatory hysterectomy at the time of UTx.

Mayer–Rokitansky–Kuster –Hauser syndrome

• Women with MRKH have normally functioning ovaries, making them suitable candidates for UTx.
• A physiologically functioning and normal length vagina (measuring 7 cm or more) is considered a requisite for some teams, which excludes women who have a neovagina.
• Women with atypical MRKH, specifically those with renal abnormalities, may also be considered for UTx.

Hysterectomy

• Reasons for hysterectomy in women of reproductive age include benign gynaecological disease, gynaecological cancer (such as cervical cancer) or severe postpartum haemorrhage.
• Caution is required in women having UTx following previous cancer diagnoses, because of the potential risk of recurrence as a consequence of the necessity for immunosuppression postoperatively.

• Asherman syndrome

• Asherman syndrome, where the uterus is present with dysfunctional endometrium, affects up to 1.5% of women of reproductive age.
• Characterised by the formation of adhesions inside the uterus and/or the cervix, this condition can cause amenorrhea, recurrent miscarriage and infertility.

• Male-to-female transgender women

• Under the Equality Act (2010), individuals who are proposing to undergo, currently undergoing, or have undergone a process of gender reassignment cannot be subjected to discrimination based on this characteristic alone.
• Subsequently, if UTx becomes a treatment option for all women (encompassing both cis-women and trans women) with AUFI, based on EU and UK legislation it will, in the absence of the provision of compelling justification, be unlawful not to perform UTx in trans (or transgender) women.

Other less common causes of AUFI include severe or complex congenital uterine anomalies, radiotherapy damage and complete androgen insensitivity syndrome. Owing to the complex nature of these conditions, the role of UTx in these cases is at present unclear.

• Potential donors

• Live donors
• Living donors have been used in 80% of UTx cases performed so far (n = 36), while the remaining cases used deceased donors (n = 9; 20%). In cases where the parity of the donor was known (n = 43), the majority have been multiparous (n = 40; 93%) while three were nulliparous (7%).
• The feasibility of the procedure using this donor type is difficult to refute as there have been 20 live births using living donors. However, the major disadvantage in living donors is the significant risk to the donor.

• Deceased donors
• The use of deceased donors ultimately negates donor risk, and allows a more radical dissection, which enables larger calibre vessels to be taken, theoretically reducing the risk of graft thrombosis.
• A potential drawback to using deceased donors is the associated systemic brain-death inflammation that may influence organ quality.
• Moreover, by virtue of the logistical challenges of retrieving from deceased donors, which may be undertaken in a different hospital to the implantation, the cold ischaemic time in cases so far has been 5 hours 42 minutes, compared to 2 hours 50 minutes in living donor cases. This increases the potential for ischaemia–reperfusion injury, which may increase risk of acute and chronic rejection, as well as chronic graft dysfunction.

• Surgical considerations

• UTx entails transplantation of the uterus, including the cervix, a cuff of vagina, the surrounding ligamentous and connective tissues, as well as the major blood vessels supplying and draining the uterus.
• Donor surgeries have been predominantly performed using a midline laparotomy approach (n = 39), while minimally invasive surgical techniques have been proposed, and recently implemented in six cases – four of which were laparoscopic-assisted, while one utilised a robotic approach.

With regard to donor type, graft survival among cases so far using living donors has been 75% (27/36), whereas in deceased donors it has been 56%.All successful UTx procedures have resulted in menstruation without the need for supplementary hormone therapy; this can be taken as a reliable indicator of uterine functionality and ongoing wellbeing.

• Immunological considerations

• Rejection can be defined as destruction of the donor graft by the host's immune response, activated against the graft's alloantigens because of a difference in donor-recipient genes.
• In UTx, the immune response of the recipient towards the implanted graft can be just as deleterious as the host response in other transplanted organs.
• For all solid organ transplants, it is essential the burden of immunosuppressive medications is offset by an improvement in quality of life.
• As such, the minimum number of immunosuppressive agents should be used at the smallest dose possible, while avoiding the use of steroids where possible.
• In UTx cases performed so far, tacrolimus has predominantly been the preferred agent, initially in combination with mycophenolate mofetil (MMF), with or without the addition of prednisolone.
• MMF was later withdrawn in anticipation of embryo transfer, owing to its teratogenic nature,59 where it is usually replaced with azathioprine.
• An alternative regimen, using maintenance tacrolimus and azathioprine immediately has been utilised more recently, with no difference in rejection episodes.

In the available data from human cases to date there have been 26 episodes of rejection in 17 recipients. The majority of episodes of rejection were successfully managed with a 3-day course of intravenous methylprednisolone, although severe episodes required the addition of antithymocyte globulin.

A unique advantage of UTx over other solid organ transplants is that it is temporary, and once the woman's family is complete, the graft can be removed, allowing the cessation of immunosuppression.

• Fertility considerations

• While the fallopian tubes are usually retrieved during UTx as part of the graft in order to facilitate uterine manipulation, they are subsequently removed post implantation to reduce the future risk of ectopic pregnancy.
• Prior to UTx, the creation and cryopreservation of embryos is required. Not only does this guarantee the availability of embryos postoperatively but reduces the overall risk compared with performing egg collections after UTx, when anatomy may be distorted and there is increased risk of infection following the introduction of immunosuppression.
• Following the development of vitrification techniques, the success rates of using vitrified embryos are now similar to those with fresh embryos, which minimises any potential negative impact of cryopreservation on embryo quality.
• Multiple gestation would be particularly problematic following UTx, where the added risks for complications, such as preterm labour, miscarriage, pre-eclampsia and gestational diabetes, greatly potentiates antenatal risk. Consequently, single embryo transfer should always be implemented following UTx.
• Embryo transfer was initially delayed until at least 12 months postoperatively, as per standard solid organ transplant guidance.66 However, in more recent cases,38 a period of 6 months has been adopted, which allows sufficient time for surgical healing and stabilisation of the immunosuppression regime.
• In anticipation for embryo transfer, it is essential to review medications that may be unsafe for pregnancy. Tacrolimus and azathioprine have consistently been shown as safe to administer during pregnancy, with no increased risk of congenital abnormality. However, potentially teratogenic immunosuppression, such as MMF, should be stopped a minimum of 6 weeks prior to embryo transfer, and replaced by a different agent, such as azathioprine.

• Obstetric considerations

• Twenty-three live births have now been reported following UTx; 20 from living donor and three from deceased donor operations.
• Antenatal complications experienced in the published cases so far include pre-eclampsia (n = 3), obstetric cholestasis (n = 2) and preterm prelabour rupture of membranes
• Other complications have included a subchorionic haematoma that resolved spontaneously and an episode of pyelonephritis that required inpatient management with intravenous antibiotics.
• To date all offspring have been delivered by lower section caesarean section. This is primarily owing to uncertainty regarding structural support and vascular supply to the graft during labour. Four cases underwent concomitant peripartum hysterectomy.
• Regarding the potential impact of tacrolimus on the fetus, there is a small theoretical risk of reversible neonatal hyperkalaemia and renal impairment, which requires consideration postnatally.
• However, while tacrolimus is excreted in breast milk, infant ingestion is less than 1% of the maternal dosage, and breastfeeding has not been shown to contribute to infant tacrolimus concentrations after birth, so is considered safe.

• Psychological considerations

• Not only does AUFI result in an inability to conceive, but can also result in significant psychological sequelae. More than a third of infertile women develop severe symptoms of depression and have been shown to have a two-fold increased risk of suicide.
• Owing to the interrelationship between infertility and psychological wellbeing, specialist psychological evaluation, counselling and follow-up is required in UTx for the recipients and, where applicable, the donors.
• Participants, as well as their partners, did not report any psychological issues at baseline, nor following the procedure, despite adverse events, such as episodes of rejection, which were confirmed quantitively using SF-36 and Fertility Quality of Life (FertiQoL), the Hospital Anxiety and Depression Scale (HADS) and Dyadic Adjustment Scale (DAS) questionnaires.
• Many recipients expressed relief by the onset of menstruation following UTx, as it not only demonstrated graft function but made them feel like other woman with menstrual cycles.
• There was no significant impact post UTx on sexual desire or satisfaction.

• Ethical considerations

• UTx incorporates complex bioethical issues that govern both assisted reproduction technologies and the field of organ transplantation.
• The overriding goal in UTx is to provide net benefit with minimalisation of harm, considering donors, recipients, partners and future offspring.
• Only extensively counselled, fully informed women can decide whether the potential benefit of UTx outweighs the significant risks associated with the process.
• While each case should be individualised, it is likely the risks of UTx in women with significant medical comorbidities may outweigh the potential benefits
• The long-term future of UTx will undoubtedly focus on the development of a bioengineered uterine graft, which would alleviate potential donor shortages and negate surgical risk to the donor and immunosuppression-related risk in the recipient.

Although still under investigation, with only 23 live births worldwide, UTx offers the possibility of an alternative option for women with AUFI to become mothers.

Uterine transplantation (UTx) is associated with significant morbidity, including three/four major surgeries (UTx, caesarean section/s and hysterectomy to remove the transplant) and the risks associated with transient immunosuppression.Moreover, in the cases performed so far almost 30% of grafts have been removed because of complications.

Consequently, recipients must be highly motivated, with excellent support networks, and have access to appropriate psychological services and be fully informed of the potential risks involved.

More than 40 procedures using living donors have now been performed, resulting in at least 20 live births so far, with transition into clinical practice expected in the future. The use of living donors necessitates consideration of the significant potential risk to the donor, and priority must be given to putting in measures to minimise such risks. As with recipients, counselling and support for donors are essential, including access to psychological services if required.

Despite three successful live births being achieved through the use of deceased donors, this possibility continues to remain a research concept with further cases needed, including extensive follow-up, before comparisons between the efficacy of each donor type can be evaluated.

Owing to the procedure's novelty, it is important to note that long term outcomes following Uterine transplantation (UTx) are not yet available. As such, all cases should be registered with the international registry including follow-up of donors, recipients and offspring.

Source: Jones BP, Saso S, Yazbek J, Thum M-Y, Quiroga I, Ghaem-Maghami S, Smith JR, on behalf of the Royal College of Obstetricians and Gynaecologists. Uterine Transplantation. Scientific Impact Paper No. 65. BJOG. 2021; https://doi.org/10.1111/1471-0528.16697.