06/04/2020

Uterine transplantation: Past, present and future

Dr Srdjan Saso describes the work done by his team at Imperial College in bringing Uterine (womb) transplantation a step closer to becoming a feasible procedure in the UK.

 

Absolute uterine factor infertility (AUFI) is a term used to describe women who cannot carry a pregnancy because of the absence of a uterus (womb) or the presence of an anatomically or physiologically non-functioning uterus. Causes of AUFI can be categorised into congenital, such as Mayer-Rokitansky-Kuster-Hauser (MRKH) Syndrome and acquired, due to Asherman’s Syndrome or following hysterectomy to treat post-partum haemorrhage, benign gynaecological disease or gynaecological cancer. AUFI affects one in 500 women of childbearing age.1The present options to acquire motherhood include adoption or surrogacy, both of which are associated with moral and ethical difficulties in addition to complex legal, financial and religious factors. The fact surrogacy is prohibited in many areas of the world, including Italy, Germany, Pakistan and Saudi Arabia epitomises the difficulties such women experience to have children. Uterine transplantation (UTx) may overcome many of these difficulties and could become a realistic future treatment option for AUFI.

 

The Past

 

The concept of UTx was initially considered in the 1960s during research on uterotubal transplantation as a treatment for tubal factor infertility. Progress, however, was short-lived following the advent and prioritisation of assisted conception techniques. Whilst research focused on assisted reproduction, other specialities developed organ transplantation techniques reserved for lifesaving operations where other treatment modalities had proved unsuccessful. In recent years, transplantation surgery has progressed to include quality of life improving procedures, such as face and hand transplants. In 1997 the concept of UTx was revisited during the development of the radical abdominal trachelectomy (RAT), a fertility-sparing procedure that treats early stage cervical cancer.During the development of this procedure it became clear the uterus remained viable when supplied by two vessels alone and crucially, it has since been shown to function normally during pregnancy.This provided an expectation that UTx may be successful if the uterus is supplied by two vessels, albeit the uterine vessels as opposed to the ovarian vessels utilised in the RAT.

 

In 2000, the first human UTx attempt was made in Saudi Arabia, using a live donor. In an attempt to extend the vascular pedicles, they utilised a hysterectomy graft with saphenous vein extensions to the recipient uterine vessels. Despite this, the graft failed after 99 days secondary to acute vascular thrombosis which the authors attributed to ‘inadequate uterine structure support, which led to probable tension, torsion, or kinking of connected vascular grafts’.This reinforced the need for further, interlinked research studies in animal models to allow a better understanding of vital anatomical, immunological and fertility aspects of UTx.

 

Such research, spearheaded by the UK, USA and Swedish teams, in both small and large animal studies, has taught us many lessons that can be extrapolated to the human model. Perhaps the most important are the vascular considerations necessary to enable sufficient blood supply to retain uterine viability and functionality. A microvascular technique was initially employed using a uterine vessel anastomosis but thrombotic complications necessitated the development of the amacrovascular method, in the form of a large vessel patch. Other important considerations include the use of cervical biopsies to detect rejection5and the application of multi-spectral imaging to detect blood flow within the uterus6. Following pregnancies after UTx, in rabbit7, mouse8, primate9and sheep10models, the next logical step was for further attempts in humans.

 

The second human UTx was performed in 2011 in Turkey, using a deceased donor.11Whilst the transplanted graft has remained in situ, the recipient has yet to bear a child after two early miscarriages and multiple further IVF attempts. Since then the Swedish team, led by Professor Brännström, has undertaken nine uterine transplants in women, using live donors.12In September 2014 the first live birth after UTx was reported, signalling to the world that UTx is a potential treatment for AUFI.13It has since been reported in the media that four further babies have been born although official publication from the Swedish team is awaited. Two recipients underwent hysterectomy post-operatively due to complications. The first, in a recipient with heterozygous Protein C deficiency, after a 16-hour operation, developed acute uterine artery thrombosis on the third post-operative day. The second presented 33 days postoperatively with pelvic infection and despite treatment with antibiotics, developed a drainage refractory pelvic abscess necessitating hysterectomy 105 days post-operatively.

 

The Present

 

As with other quality of life improving transplants, careful ethical reflection is necessary with due respect for autonomy, beneficence, non-maleficence and justice. The term ‘primum non nocere’, or ‘first, do no harm’, is seldom relevant in modern-day practice, as harm may arise from almost any clinical action, from prescribing medicines to ultra-radical surgery. The key, in everyday practice as a physician, as it is in UTx, is to provide net benefit with minimum harm. The potential benefit from UTx will vary between individuals, governed by personal circumstance, and only fully informed, autonomous, individuals can decide whether or not the potential benefit of such treatment will outweigh the significant potential risks. With respect to justice, consideration should be directed toward the impact of its introduction on society and whether the introduction of a ‘quality of life improving’ procedure may divert scarce resources away from others potentially needing lifesaving treatment. Many would argue that having a good quality of life is a pre-requisite for living, so a procedure that may improve quality of life, from a wellbeing perspective, could be considered lifesaving in itself. This is exemplified by the fact that over 35% of infertile women display severe symptoms of depression resulting in a two-fold increased risk of suicide.14Gynaecologists often refer women with ‘treatable’ causes of infertility, such as endometriosis, for surgery to improve conception rates, in line with national guidance.15Healthcare professionals could even be considered negligent for not considering surgical intervention in women with intrauterine adhesions, submucosal fibroids or proximal tubal obstruction owing to their ‘treatable’ nature. Given the excellent fertility rates following UTx in Sweden, there may be an argument in the future that AUFI is also ‘treatable’.

 

The Future

 

Our UK transplant team, after 15 years of research, has received official ethics approval to perform ten uterine transplants in the UK and aims to deliver the first livebirth following UTx using brainstem dead, heart beating cadavers.

 

Our UK trial is expected to commence in early 2018 with the anticipation to perform ten uterine transplants over a two-year period.All recipients will undergo a series of pre-operative investigations and meet all members of the multi-disciplinary team. Following appropriate counselling including a detailed consent process, the potential recipient will be prepared for transplantation once a suitable donor is identified. Following the transplant, the recipient will be required to take aspirin and immunosuppressive therapy for the longevity of the graft. In line with international recommendations, fertility treatment will be commenced at least twelve months following the transplant. If successful, delivery will be required by Caesarean Section, planned between 35-37 weeks gestation, unless clinically indicated sooner. A second child could be considered if no complications are experienced with hysterectomy planned six months following completion of the recipient’s family.

 

UTx is still a research concept. Initial promising results in Sweden have provided proof of concept for UTx and given hope to thousands of women with AUFI, for whom adoption or surrogacy are not available or acceptable. Whether UTx makes the transition from promising research concept to viable treatment option very much depends upon the results of future trials and developments. Future advances such as utilising a robotic surgical technique could reduce surgical morbidity whereas the creation of a bioengineered uterus could potentially negate the need for immunosuppressive medications. Now that UTx research teams have been established globally, including teams in France, China, Australia, Singapore and Mexico amongst others, an orchestrated approach would certainly optimise progression in this field. The proposed development of an international society for UTx will facilitate collaboration between teams and also allow the establishment of official recommendations for requirements prior to the commencement of clinical programmes. Furthermore, the institution of an international registry for recipients, donors and babies would allow appropriate regulation, which would enable performance and safety monitoring. Although we may be accused of bias, we believe this procedure will become an established treatment option, as an alternative to adoption or surrogacy, in a relatively small group of suitable women with AUFI. With ongoing innovation, the future of UTx is potentially very exciting, very much like its past.

 

 

References

  1. Hellström M, El-Akouri RR, Sihlbom C, Olsson BM, Lengqvist J, Bäckdahl H et al.Towards the development of a bioengineered uterus: Comparison of different protocols for rat uterus decellularization. Acta Biomaterialia2014; 10 (12): 5034–5042
  2. Smith JR, Boyle DC, Corless DJ, Ungar L, Lawson A D, Del Priore G et al.Abdominal radical trachelectomy: a new surgical technique for the conservative management of cervical carcinoma. Br J Obstet Gynaecol1997; 104: 1196-1200.
  3. Ungar L, Palfalvi L, Hogg R, Siklos P, Boyle DC, Del Priore et al. Abdominal radical trachelectomy; a fertility-preserving option for women with cervical cancer.  Br J Obstet Gynaecol 2005; 112:366-9
  4. Fageeh W, Raffa H, Jabbad H, Marzouki A. Transplantation of the human uterus. Int J Gynaecol Obstet2002; 76: 245-251.
  5. Johannesson L, Enskog A, Mölne J, Diaz-Garcia C, Hanafy A, Dahm-Kähler P et al. Preclinical report on allogeneic uterus transplantation in non-human primates. Hum Reprod 2013; 28:189-98.
  6. Clancy NT, Sauvage V, Elson DS, Saso, S, Stoyanov D, Corless DJ, et al. Multispectral imaging of organ viability during uterine transplantation surgery. Int Soc Opt Eng 2014; DOI:10.1117/12.2040518
  7. Saso S, Petts G, David AL, Thum MY, Chatterjee J, Vicente JS et al. Achieving an early pregnancy following allogeneic uterine transplantion in a rabbit model. Eur J Obstet Gynecol Reprod Biol 2015;185: 164-169
  8. El-Akouri RR, Kurlberg G, Brannstrom M. Successful uterine transplantation in the mouse: pregnancy and post-natal development of offspring. Hum Reprod 2003; 18: 2018-2023.
  9. Mihara M, Kisu I, Hara H, Iida T, Araki J, Shim T et al. Uterine autotransplantation in cynomolgus macaques: the first case of pregnancy and delivery. Hum Reprod 2012; 27: 2332–2340
  10. Ramirez ER, Ramirez Nessetti DK, Nessetti MB, Khatamee M, Wolfson MR, Shaffer TH et al. Pregnancy and outcome of uterine allotransplantation and assisted reproduction in sheep. J Minim Invasive Gynecol 2011; 18 (2): 238-245.
  11. Akar ME, Ozkan O, Aydinuraz B, Dirican K, Cincik M, Mendilcioglu I, et al. Clinical pregnancy after uterus transplantation. Fertil Steril 2013 100: 1358–63
  12. Brännström M, Johannesson L, Dahm-Kähler, P, Enskog A, Mölne J, Kvarnström N et al. First clinical uterus transplantation trial: a six-month report. Fertil Steril 2014101(5): 1228-36.
  13. Brännström M, Johannesson L, Bokström H, Kvarnström N, Mölne J, Dahm-Kähler, Pet al.Livebirth after uterus transplantation. The Lancet2014; 385: 607–616
  14. Kjaer TK, Jensen A, Dalton SO, Johansen C, Schmiedel S, Kjaer SK. Suicide in Danish women evaluated for fertility problems. Hum Reprod 2011; 26 (9): 2401-2407
  15. National Institute for Health and Clinical Excellence (NICE) Fertility: Assessment and treatment for people with fertility problems. NICE2013: London.
  16. Ibrahim H, Akkina S, Leister E, Gillingham K, Cordner G, Guo H. et al.Pregnancy Outcomes after Kidney Donation. Am J Transplant 2009; 9 (4): 825–834.
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