Uterine transplantation: past, present and future

Abstract

Absolute uterine factor infertility (AUFI) is a term used to describe women who cannot carry a pregnancy because of the absence of a uterus 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 syndrome and acquired, due to Asherman syndrome or following hysterectomy to treat postpartum haemorrhage, benign gynaecological disease or gynaecological cancer. AUFI affects one in 500 women of childbearing age.1 The 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 that surrogacy is prohibited in many countries, including Italy, Germany, Pakistan and Saudi Arabia, epitomises the difficulties that 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 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. Research subsequently focused on assisted reproduction, whilst other specialties 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, a fertility sparing procedure that treats early-stage cervical cancer.2 During the development of this procedure it became clear that the uterus remained viable when supplied by two vessels alone and, crucially, it has since been shown to function normally during pregnancy.3 This provided the expectation that UTx may be successful if the uterus were supplied by two vessels, albeit the uterine vessels as opposed to the ovarian vessels used in the radical abdominal trachelectomy. 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 used 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’.4 This reinforced the need for further, interlinked research studies in animal models to allow 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 a macrovascular method, in the form of a large vessel patch. Other important considerations include the use of cervical biopsies to detect rejection5 and the application of multi-spectral imaging to detect blood flow within the uterus.6 Following pregnancies after UTx, in rabbit,7 mouse,8 primates9 and sheep10 models, the next logical step was for further attempts in humans. The second human UTx was performed in 2011 in Turkey, using a deceased nulliparous donor.11 Although the transplanted graft has remained in situ, the recipient has yet to bear a child after at least two early miscarriages and multiple further IVF attempts. Since then