Uterine transplantation bjog

Uterine transplantation bjog

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  Uterine Transplantation Scientific ImpactPaper No. 65 April 2021 Please cite this paper as: 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;128:e51–e66.
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  DOI: 10.1111/1471-0528.16697 RCOGScientific Impact Paper Uterine Transplantation BP Jones, S Saso, J Yazbek, M-Y Thum, I Quiroga, S Ghaem-Maghami, JR Smith, on behalf of the Royal College of Obstetricians and Gynaecologists Correspondence: Royal College of Obstetricians and Gynaecologists, 10–18 Union Street, London SE1 1SZ, UK. Email: [email protected] Plain language summary A uterine transplant, or womb transplant, provides a potential treatment for women who cannot become pregnant or carry a pregnancy because they do not have a womb, or have a womb that is unable to maintain a 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. Womb transplants have been performed all over the world, with more than 70 procedures carried out so far. At least 23 babies have been born as a result, demonstrating that womb transplants can work. While the procedure offers a different option to adoption and surrogacy, it is associated with significant risks, including multiple major surgeries and the need to take medications that help to dampen the immune system to prevent rejection of the womb. To date there has been a 30% risk of a transplant being unsuccessful. 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. This paper looks at 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. 1. Background Uterine transplantation (UTx) is a potential therapeutic intervention for women with absolute uterine factor infertility (AUFI). AUFI is widely considered to affect 1 in 500 women of childbearing age, and has been estimated to impact 200 000 in Europe, 85 000 in the USA and up to 1.5 million women worldwide.1,2 AUFI refers to women with infertility secondary to the absence of a uterus or the presence of one that is anatomically or physiologically dysfunctional. The established routes to motherhood for women with AUFI include adoption or surrogacy, which to many are suitable options. However, not only are these options associated with complex legal, financial, cultural, ethical and religious factors, but they do not allow the experience of pregnancy. 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. RCOG Scientific Impact Paper No. 65 e52 of e66 ª 2021 Royal College of Obstetricians and Gynaecologists
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  At the timeof publication of this paper, more than 70 procedures have been performed and 23 live births have been published, or reported in the media.3–5 Following the development of the International Society of Uterine Transplantation and the establishment of teams performing the procedure globally, it is anticipated that UTx will transition from research concept to clinical care in the future. The purpose of this Scientific Impact Paper is to summarise the pertinent published literature on UTx and to propose a framework for establishing a sustainable UTx programme in the UK. The data presented herein refer to the 45 cases,5 and the 17 live births published in peer reviewed journals to date. This includes cases that have been performed in Saudi Arabia, Turkey, Sweden, Xian (China), Czech Republic, Cleveland (USA), Dallas (USA), Brazil, Germany and India. 2. 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. For adoption, in the UK, women can gain information through government websites, and for surrogacy the HFEA (Human Fertility and Embryology Authority) has signposted sources to obtain information (Surrogacy UK, Brilliant Beginnings, Childlessness overcome through surrogacy [COTS]). Moreover, specialist fertility counsellors are available to help women considering surrogacy and adoption through the NHS, or privately using accredited therapists accessed through organisations such as the British Infertility Counselling Association (BICA). 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.7 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. Although there is no direct alternative to UTx, it is essential that consideration is given to adoption and surrogacy in the counselling process for UTx. This ensures the consent process is fully informed, and the additional risks associated with UTx can be appropriately considered in the context of the perceived individualised benefits. 3. Potential recipients Potential recipients to undergo UTx are women of reproductive age with AUFI, the causes of which may be congenital or acquired, as summarised in Appendix I. 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.10 RCOG Scientific Impact Paper No. 65 e53 of e66 ª 2021 Royal College of Obstetricians and Gynaecologists
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  3.1 Mayer–Rokitansky–K€ uster–Hauser syndrome MRKHhas an incidence of 1 in 5000 women.11 It arises due to incomplete development of the M€ ullerian ducts. MRKH manifests with congenital absence of the uterus, although rudimentary small uterine bulbs and fallopian tubes may remain, along with variable degrees of vaginal shortening. Therapeutic intervention is often required to optimise vaginal diameter and depth to enable sexual function. Various methods exist including dilator therapy, the Vecchietti procedure or the formation of a surgically-created vagina, referred to as a neovagina, using skin, peritoneum, amnion or intestine.12,13 The novel use of autologous in vitro cultured vaginal tissue has also been demonstrated with promising results.14 Generally, women with MRKH have normally functioning ovaries, making them suitable candidates for UTx. A study assessing perceptions to UTx among women with MRKH showed that almost two-thirds of participants were willing to undergo the procedure, with a full understanding of the potential risks involved.15 For women being considered for UTx, there are specific preoperative requirements. 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. The surface of the vagina is composed of stratified squamous epithelium, which as a protective mechanism desquamates into the vaginal lumen, concomitantly removing adherent micro-organisms.16 Vaginal epithelium also contributes to the innate immune response by facilitating the recognition of pathogens and stimulating the production of antimicrobial peptides and proinflammatory cytokines.17 These immunomodulatory mechanisms contribute to the maintenance of a commensal microbiome, which have clinical and reproductive implications that may impact outcomes in UTx.18 For example, the second global UTx case was performed in a woman with an intestinal neovagina,19 where despite numerous failed in vitro fertilisation attempts and multiple miscarriages, a live birth has yet to occur.20 Women with atypical MRKH, specifically those with renal abnormalities, may also be considered for UTx. Caution should be taken in those with unilateral renal agenesis, which affects around a quarter of cases,21 owing to the more than two-fold increased risk of hypertensive disorders in pregnancy including pre-eclampsia.22 In a Swedish cohort who underwent UTx, three had unilateral kidney agenesis, and all three developed a hypertensive disorder during pregnancy that necessitated intervention for early birth.23 Those with pelvic kidneys require additional assessment utilising magnetic resonance imaging or computerised tomography scanning, to localise the pelvic kidney and determine if it would be an impediment to subsequent UTx. 3.2 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. In kidney transplantation, a history of previous cancer is associated with a 30% increased risk of death in the recipient.24 Moreover, across all solid organ transplants, a meta-analysis found that all-cause mortality, cancer-specific mortality and the risk of developing a new primary malignancy was greater in those with a pre-transplant diagnosis of cancer compared with recipients with no pre-transplant malignancy.25 As such, additional counselling is required in these women, and it is prudent to allow a period of at least 5 years in remission before they are considered for UTx. While no meaningful conclusion can be taken from a single case, the one UTx case performed in a woman with a previous diagnosis of cancer, which in this case was of the cervix, gave birth to two live babies,23 and following completion hysterectomy, there have been no reports of recurrence or new diagnoses of cancer. RCOG Scientific Impact Paper No. 65 e54 of e66 ª 2021 Royal College of Obstetricians and Gynaecologists
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  3.3 Asherman syndrome Ashermansyndrome, where the uterus is present with dysfunctional endometrium, affects up to 1.5% of women of reproductive age.26 Characterised by the formation of adhesions inside the uterus and/or the cervix, this condition can cause amenorrhea, recurrent miscarriage and infertility. Fertility restoration can be achieved using hysteroscopic adhesiolysis, although high rates of infertility, miscarriage, poor implantation and abnormal placentation remain.27 Performing UTx for Asherman syndrome should only be considered for severe cases, where all other treatment options have been exhausted. 3.4 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. Despite a number of anatomical, psychosocial, physiological, fertility and obstetric considerations that require further research before UTx can be performed in transgender women, there is no overwhelming clinical argument against performing this procedure.28 3.5 Other causes 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. 4. Potential donors Living donors have been used in 80% of UTx cases performed so far (n = 36),5,9,10,29–34 while the remaining cases used deceased donors (n = 9; 20%).5,19,34–36 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%).19,34 4.1 Living donors Logistically, given the diverse array of multidisciplinary expertise required, planning an elective surgery using living donors is more straightforward than the on-call arrangement needed in the context of deceased donation. The routine investigations undertaken for other solid organ transplant apply equally to UTx donors, including microbiological screening to prevent transmitted infection such as HIV, hepatitis B and C, cytomegalovirus, Epstein- Barr virus, syphilis, toxoplasma, and human T-cell lymphotropic virus. The use of living donors allows greater time for further investigations which are specific to UTx, which at a minimum should include a cervical smear/human papillomavirus testing, tests to exclude sexually transmitted infections (chlamydia, gonorrhoea and trichomoniasis) and a vaginal culture to exclude Candida species and bacterial vaginosis. A transvaginal ultrasound scan should also be undertaken to exclude structural abnormalities, and magnetic resonance angiography or computed tomography angiography to provide information about vessel morphology, calibre and patency. RCOG Scientific Impact Paper No. 65 e55 of e66 ª 2021 Royal College of Obstetricians and Gynaecologists
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  Just over halfof the 36 living donor cases undertaken so far have been related to the recipients (n = 19; 53%), the majority being a maternal relation (n = 16), where one sister and two aunts also donated. The remainder (n = 17) were unrelated. While the use of first-degree relatives may provide immunological benefit,37 the use of older donors is associated with other risk factors. Significantly, increasing age correlates with risk of atherosclerotic change in the pelvic arteries, which may result in an organ of insufficient quality for implantation.29 Moreover, even before macroscopic or histological evidence of atherosclerosis is evident, increasing age has been shown to cause arterial inflammation,38 which may increase the likelihood of post-transplant graft vasculopathy.39 In addition, increasing donor age, irrespective of recipient age, increases the rate of acute allograft rejection in other solid organ transplants.40 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. Regarding donor surgical morbidity in the cases performed so far, four (11.4%) donors suffered complications requiring further surgical intervention. Two of whom sustained intraoperative ureteric lacerations that were repaired immediately;30,34 while one donor re-presented with a uretovaginal fistula that required initial pyelostomy and subsequent ureteric implantation 5 months after surgery – this was attributed to diathermy related partial ureteric injury during a difficult retrieval.9 While the reported rate of ureteric injury in benign gynaecological surgery is less than 1%, it is more than 10% of uterine cancer cases.41 The injury rate is higher in oncological cases owing to pathology-related complexity, whereas UTx donor retrievals are not associated with such issues by virtue of the selection criteria. However, the need to preserve the uterine veins in view of their unpredictable and tortuous course and particularly close proximity to the ureter, presents increased surgical risk in UTx retrievals. Evolution of the surgical technique,42 utilising the ovarian or utero-ovarian veins instead of the uterine veins,31,32 should reduce surgical risk in future cases. The other reported complication requiring surgical intervention under general anaesthesia was a vaginal cuff dehiscence.31 Ten donors experienced deviation from the normal postoperative course or complications requiring pharmacological treatment. These included urinary tract infections,5,38 faecal impaction,31 wound infection,9 bladder hypotonia,34 leg/buttock pain,31 anaemia,5 respiratory failure during anaesthesia5 and depression.31 Extensive multidisciplinary counselling is therefore essential, with thorough explanation of the potential risks, to ensure that all donors can give informed consent, in the absence of undue pressure or coercion. 4.2 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. This conclusion was reached following animal research, where smaller vessel anastomoses, such as the uterine vessels, resulted in gradual vessel thrombosis.43 Subsequent studies utilising larger vessel patch techniques substantiated the concept, following successful UTx and pregnancies in both small and large animal models.44–46 In human cases, the uterine graft has successfully been retrieved as part of a multiorgan retrieval with no adverse impact upon other organs retrieved. The uterus has been retrieved before the lifesaving organs in some cases,47,48 and after in others.49–51 Appropriate preoperative investigation of the donor can still be undertaken, with transvaginal ultrasound scan, a sexually transmitted infection screen and cervical cytology/human papillomavirus testing being expedited to ensure results are available within the pre-retrieval period. In this time the donor can be physiologically optimised while other retrieval teams perform their preliminary investigations. Donor optimisation sees a shift in management strategy from one directed towards resuscitation of the cerebral injury, to RCOG Scientific Impact Paper No. 65 e56 of e66 ª 2021 Royal College of Obstetricians and Gynaecologists
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  one that focuseson restoration of physiological and metabolic homeostasis to prevent organ deterioration. Donation of the uterus in the UK is currently dependent upon the donor having consented, and therefore donor family consent would be required. Initial studies in the USA indicated a poor potential uptake from donor families, with as few as 6% of families agreeing to procurement of the uterus.49 However, a more recent French study found that donation of the uterus was readily accepted, with no refusals (n = 14) and no negative impact on the donation of other organs.51 A potential drawback to using deceased donors is the associated systemic brain-death inflammation that may influence organ quality.52 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.5 This increases the potential for ischaemia–reperfusion injury, which may increase risk of acute and chronic rejection, as well as chronic graft dysfunction.53,54 However, in both animal and human models UTx grafts tolerated cold ischaemic times of up to 24 hours,51,55,56 so the prolonged cold ischaemic time seen in deceased donation is of uncertain significance. The risk of fungal infection may also be greater, owing to potential contamination of the sterile vessels from organisms within the non-sterile vaginal cuff, as exemplified by the unsuccessful first UTx carried out in the USA taken from a deceased donor after brain death, which resulted in hysterectomy following haemorrhage due to candida-associated vasculitis within the uterine vessels.36 The first successful live birth following UTx using a deceased donor occurred in Brazil in 2017, demonstrating the feasibility of using this donor type.35 However, further long-term follow-up and more cases are required before accurate comparison of efficacy between donor types can be undertaken. 5. 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,57 and recently implemented in six cases – four of which were laparoscopic-assisted, while one utilised a robotic approach.10,33,39 While unpublished, several further cases have been performed which illustrate that the transition towards the use of minimally invasive retrieval techniques is already in progress. With regards to graft survival, just over a quarter (n = 13) of recipients subsequently underwent emergency hysterectomy. The most common indication was graft thrombosis, which was present in around half of the cases (n = 7).9,30,31,34 Three were prompted by infective causes: one due to a pelvic bacterial infection/abscess which failed to respond to conservative measures;9 another because of candida-associated vasculitis of the arterial anastomosis;36 and another case failed because of herpes simplex infection of the graft.34 Two cases were reported to have been unsuccessful secondary to graft ischaemia of unspecific aetiology.31 A final case was complicated by postoperative haemorrhage which led to resultant graft failure.5 Postoperatively, three-quarters (n = 7) of emergency hysterectomies occurred during the first 15 postoperative days. 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% (5/9). Seven women have had completion hysterectomies after successful pregnancies. The remainder continue to have functioning grafts. All successful UTx procedures have resulted in RCOG Scientific Impact Paper No. 65 e57 of e66 ª 2021 Royal College of Obstetricians and Gynaecologists
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  menstruation without theneed for supplementary hormone therapy; this can be taken as a reliable indicator of uterine functionality and ongoing wellbeing. In addition to the graft failures, surgical complications in UTx recipients have included five complications necessitating further surgical intervention including a vesicovaginal fistula (n = 1) and vaginal stenosis of the uterine-vaginal anastomosis requiring dilation and stenting (n = 4).34 Five recipients experienced deviation from the expected postoperative course or complications requiring pharmacological treatment, such as pleural effusions (n = 2)9 and urinary tract infections (n = 3).34,58 6. 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 is 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.60 While symptoms of rejection include abdominal pain, fever or vaginal discharge/bleeding, such symptoms would only become apparent once rejection had been firmly established. A preliminary grading system for uterine allograft rejection was proposed following a study on baboons, which concluded that cervical biopsies were a consistent, achievable means of detecting rejection in the graft.61 In the available data from human cases to date there have been 26 episodes of rejection in 17 recipients. The majority of episodes were proven on histology (n = 24), using cervical biopsies,9,62 while two were diagnosed following the presentation of symptoms suggestive of rejection in terms of raised serum lymphocyte subpopulations.34,39 The majority of the histologically proven cases of rejection (n = 21; 88%) were mild or moderate, while three (12%) were severe.57 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. Given that immunosuppression- associated morbidity, such as in cancer, diabetes and nephrotoxicity, is dose and duration dependant,63 the anticipated implications in UTx are expected to be less than in lifelong organ transplants, although long term data following UTx are required. 7. 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. As RCOG Scientific Impact Paper No. 65 e58 of e66 ª 2021 Royal College of Obstetricians and Gynaecologists
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  such, prior toUTx, 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,64 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,65 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.67 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. In cases where MMF has not been used, the potential time between implantation and embryo transfer can be reduced further to 3 months, potentially reducing further cumulative immunosuppression exposure.60 8. Obstetric considerations Twenty-three live births have now been reported following UTx; 20 from living donor and three from deceased donor operations.4 Outcomes have been published from 17 of these cases.68 Antenatal complications experienced in the published cases so far include pre-eclampsia (n = 3), obstetric cholestasis (n = 2) and preterm prelabour rupture of membranes (n = 1). The women who developed pre- eclampsia all gave birth preterm between 31 and 35 weeks of gestation, but babies were an appropriate weight for their gestational age.23 While in vitro fertilisation,69 or the transplant of postmenopausal uteri, with an inherently less elastic vasculature could contribute to the development of hypertensive disorders of pregnancy,70 it should be noted that all of the women who developed pre-eclampsia had a single kidney.23 The risk–benefit ratio in women with this condition is clearly increased which has led to their exclusion from certain research studies,71 but inclusion in others.34 Other complications have included a subchorionic haematoma that resolved spontaneously,72 and an episode of pyelonephritis that required inpatient management with intravenous antibiotics.35 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.68 All infants were born in good condition with no reports of congenital abnormality. 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,73 and breastfeeding has not been shown to contribute to infant tacrolimus concentrations after birth, so is considered safe.74 RCOG Scientific Impact Paper No. 65 e59 of e66 ª 2021 Royal College of Obstetricians and Gynaecologists
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  9. Psychological considerations Notonly 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.75 The inability to bear children may also affect personal perceptions of femininity and impact negatively on the quality of life.76 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. The psychological aspects of UTx for recipients77,78 and donors79 have been examined, such as psychological wellbeing, relationships, managing childlessness, relationship with the donor, and knowledge about associated risks. 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. Regarding psychological outcomes in donors, semi-structured interviews in combination with questionnaires including the Psychological General Well-Being (PDWB) Index, DAS, HADS and SF-36 were used in the selection process. Two donors experienced a deviation from their baseline quality-of-life scores (SF-36). One such case coincided chronologically with the donor suffering complication with a uretovaginal fistula in addition to the graft loss in the recipient, who was her daughter. Overall, there was no significant change in quality of life across donors between baseline and 12 months, and over the same timeframe there was a reduction in HADS score. None of the donors reported feelings of regret, even in those who had experienced a complication or whose recipients suffered graft loss. All donors resumed their preoperative social and physical activities. These findings resonate with the positive psychosocial outcomes demonstrated following lifesaving solid organ donation.80,81 10. 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 option to use living or deceased donors raises particular bioethical issues. Following the passing of the Organ Donation (Deemed Consent) Act 2019, the legalities in England surrounding deceased organ donation changed to an ‘opt out’ system. This presumes adult consent to organ donation by default, unless a decision to opt out has previously been recorded. However, as is the case with other novel transplants, uterus donation is not included as part of the opt-out strategy, meaning explicit consent is required from the donor’s family. While appropriate, difficulties obtaining valid consent remain, owing to the novelty of the procedure and the necessity for use of proxy consent through the donor’s family.82–84 Moreover, the possibility of UTx negatively impacting consent rates for RCOG Scientific Impact Paper No. 65 e60 of e66 ª 2021 Royal College of Obstetricians and Gynaecologists
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  other organs, orthe uterine retrieval causing an adverse impact on the multiorgan retrieval process require consideration. Conversely, in living donation, the overriding issue is on the aforementioned significant donor risk. As such it has been suggested that deceased donation should be prioritised, provided there is sufficient availability of donor uteri, similar success rates and no demonstrable adverse impact on the multiorgan retrieval process.83,85 Although it is well-established that outcomes in other solid organ transplants are superior using living donation, more cases and longer follow-up are essential before accurate comparisons can be made between the use of living and deceased donation in the context of UTx.86 Moreover, it has been predicted that the deceased donor pool in the UK may be less than 150 annually, prior to the implementation of selection criteria such as parity, medical and surgical history, and reproductive and obstetric outcomes, which would reduce this pool significantly further.87 It is likely that a combination of living and deceased donation will be necessary in the short-term future. If living donors are used, minimising donor risk is essential, this can be achieved by utilising minimal access retrieval techniques where possible and continuing to refine surgical techniques in order to reduce operative time and surgical risk. 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. While the concept remains in its infancy, the Swedish team have established a technique to repair a rat uterus using a bioengineered uterine patch and have demonstrated functionality by achieving subsequent pregnancies.88 This development has set the benchmark for the future of UTx, and with ongoing innovation and collaboration, the options for fertility restoration in women with AUFI should continue to become more available and acceptable. 11. Opinion 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. 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 UTx are not yet available. As such, all cases should be registered with the international registry including follow-up of donors, recipients and offspring. At a time when UTx begins to transition into clinical practice, as is the case with all novel therapies and interventions, it is essential there is robust governance in place to enable performance and safety monitoring. RCOG Scientific Impact Paper No. 65 e61 of e66 ª 2021 Royal College of Obstetricians and Gynaecologists
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  Disclosure of interests BPJ,SS, JY, MYT, IQ and SGM have declared no conflicts of interest. Full disclosure of interests for JRS, Scientific Advisory Committee and peer reviewers are available to view online as supporting information. Funding All those involved in the development of Scientific Impact Papers, including the Scientific Advisory Committee, Scientific Advisory Committee chair, developers, peer reviewers and other reviewers, are unpaid volunteers and receive no direct funding for their work in producing the paper. The only exception to this are the Scientific Advisory Committee members who receive reimbursement for expenses for attending Scientific Advisory Committee meetings for standard RCOG activities; this is standard as per RCOG rules. References 1. Johannesson L, Dahm-K€ ahler P, Eklind S, Br€ annstr€ om M. The future of human uterus transplantation. Womens Health Lond 2014;10:455–67. 2. Flyckt R, Kotlyar A, Arian S, Eghtesad B, Falcone T, Tzakis A. 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International Federation of Fertility Societies. IFFS Surveillance 2016. Global Reproductive Health 2016;1:1–143. 9. Brannstrom M, Johannesson L, Dahm-Kahler P, Enskog A, Molne J, Kvarnstrom N, et al. First clinical uterus transplantation trial: a six-month report. Fertil Steril 2014;101:1228–36. 10. Puntambekar S, Telang M, Kulkarni P, Puntambekar S, Jadhav S, Panse M, et al. Laparoscopic-assisted uterus retrieval from live organ donors for uterine transplant: Our experience of two patients. J Minim Invasive Gynecol 2018;25:622–31. 11. Folch M, Pigem I, Konje JC. M€ ullerian agenesis: etiology, diagnosis, and management. Obstet Gynecol Surv 2000;55:644–9. 12. Michala L, Cutner A, Creighton SM. Surgical approaches to treating vaginal agenesis. BJOG 2007;114:1455–9. 13. Zafar M, Saeed S, Kant B, Murtaza B, Dar MF, Khan NA. Use of amnion in vaginoplasty for vaginal atresia. J Coll Physicians Surg Pak 2007;17:107–9. 14. 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The vaginal microbiome in uterine transplantation. BJOG 2020;127:230–8. 19. Erman Akar M, Ozkan O, Aydinuraz B, Dirican K, Cincik M, Mendilcioglu I, et al. Clinical pregnancy after uterus transplantation. Fertil Steril 2013;100:1358–63. 20. Ozkan O, Dogan NU, Ozkan O, Mendilcioglu I, Dogan S, Aydinuraz B, et al. Uterus transplantation: from animal models through the first heart beating pregnancy to the first human live birth. Womens Health (Lond) 2016;12:442–9. 21. Fontana L, Gentilin B, Fedele L, Gervasini C, Miozzo M. Genetics of Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. Clin Genet 2017;91:233–46. 22. Heinonen PK. Gestational hypertension and preeclampsia associated with unilateral renal agenesis in women with uterine malformations. Eur J Obstet Gynecol Reprod Biol 2004;114:39–43. 23. Castell on LAR, Amador MIG, Gonz alez RED, Eduardo MSJ, D ıaz- Garc ıa C, Kvarnstr€ om N, et al. The history behind successful uterine transplantation in humans. JBRA Assist Reprod 2017;21: 126–34. 24. Brattstrom C, Granath F, Edgren G, Smedby KE, Wilczek HE. Overall and cause-specific mortality in transplant recipients with a pretransplantation cancer history. Transplantation 2013;96:297– 305. 25. Acuna SA, Huang JW, Daly C, Shah PS, Kim SJ, Baxter NN. Outcomes of solid organ transplant recipients with preexisting malignancies in remission: a systematic review and meta-analysis. Transplantation 2017;101:471–81. 26. Al-Inany H. Intrauterine adhesions. An update. Acta Obstet Gynecol Scand 2001;80:986–93. 27. Deans R, Abbott J. Review of intrauterine adhesions. J Minim Invasive Gynecol 2010;17:555–69. RCOG Scientific Impact Paper No. 65 e62 of e66 ª 2021 Royal College of Obstetricians and Gynaecologists
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  28. Jones BP,Williams NJ, Saso S, Thum MY, Quiroga I, Yazbek J, et al. Uterine transplantation in transgender women. BJOG 2019;126:152–6. 29. Brucker SY, Brannstrom M, Taran FA, Nadalin S, Konigsrainer A, Rall K, et al. Selecting living donors for uterus transplantation: lessons learned from two transplantations resulting in menstrual functionality and another attempt, aborted after organ retrieval. Arch Gynecol Obstet 2018;297:675–84. 30. Fageeh W, Raffa H, Jabbad H, Marzouki A. Transplantation of the human uterus. Int J Gynaecol Obstet 2002;76:245–51. 31. Wei L, Xue T, Tao KS, Zhang G, Zhao GY, Yu SQ, et al. Modified human uterus transplantation using ovarian veins for venous drainage: the first report of surgically successful robotic- assisted uterus procurement and follow-up for 12 months. Fertil Steril 2017;108:346–56. 32. Testa G, Koon EC, Johannesson L, McKenna GJ, Anthony T, Klintmalm GB, et al. Living donor uterus transplantation: a single center’s observations and lessons learned from early setbacks to technical success. Am J Transplant 2017;17:2901–10. 33. Puntambekar S, Puntambekar S, Telang M, Kulkarni P, Date S, Panse M, et al. A novel anastomotic technique for uterine transplant using utero-ovarian veins for venous drainage and internal iliac arteries for perfusion in two laparoscopically harvested uteri. J Minim Invasive Gynecol 2018;ii:S1553–4650. 34. Chmel R, Novackova M, Janousek L, Matecha J, Pastor Z, Maluskova J, et al. Revaluation and lessons learned from the first 9 cases of a Czech uterus transplantation trial: four deceased donor and 5 living donor uterus transplantations. Am J Transplant 2019;19:855– 64. 35. Ejzenberg D, Andraus W, Baratelli Carelli Mendes LR, Ducatti L, Song A, Tanigawa R, et al. Livebirth after uterus transplantation from a deceased donor in a recipient with uterine infertility. Lancet 2018;392:2697–704. 36. Flyckt RL, Farrell RM, Perni UC, Tzakis AG, Falcone T. Deceased donor uterine transplantation: innovation and adaptation. Obstet Gynecol 2016;128:837–42. 37. Matter YE, Nagib AM, Lotfy OE, Alsayed AM, Donia AF, Refaie AF, et al. Impact of donor source on the outcome of live donor kidney transplantation: a single center experience. Nephrourol Mon 2016;8:e34770. 38. Wang M, Jiang L, Monticone RE, Lakatta EG. Proinflammation: the key to arterial aging. Trends Endocrinol Metab 2014;25:72–9. 39. Colvin MM, Smith CA, Tullius SG, Goldstein DR. Aging and the immune response to organ transplantation. J Clin Invest 2017;127:2523–9. 40. Tullius SG, Milford E. Kidney allocation and the aging immune response. N Engl J Med 2011;364:1369–70. 41. Kiran A, Hilton P, Cromwell DA. The risk of ureteric injury associated with hysterectomy: a 10-year retrospective cohort study. BJOG 2016;123:1184–91. 42. Flyckt R, Farrell RM, Falcone T. Advancing the science of uterine transplantation: minimizing living donor risk on a path to surgical innovation. J Minim Invasive Gynecol 2019;26:577–9. 43. Sieunarine K, Zakaria FB, Boyle DC, Corless DJ, Noakes DE, Lindsay I, et al. Possibilities for fertility restoration: a new surgical technique. Int Surg 2005;90:249–56. 44. Saso S, Petts G, David AL, Thum MY, Chatterjee J, Vicente JS, et al. Achieving an early pregnancy following allogeneic uterine transplantation in a rabbit model. Eur J Obstet Gynecol Reprod Biol 2015;185:164–9. 45. 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;27:2332–40. 46. Ramirez ERR, Nessetti Ramirez DK, Nessetti M, Ramirez HA, Khatamee M. The first pregnancy in an allograft uterus in the sheep model. J Minim Invasive Gynecol 2009;16:S15. 47. Testa G, Anthony T, McKenna GJ, Koon EC, Wallis K, Klintmalm GB, et al. Deceased donor uterus retrieval: a novel technique and workflow. Am J Transplant 2018;18:679–83. 48. Ozkan O, Akar ME, Ozkan O, Erdogan O, Hadimioglu N, Yilmaz M, et al. Preliminary results of the first human uterus transplantation from a multiorgan donor. Fertil Steril 2013;99:470–6. 49. Del Priore G, Stega J, Sieunarine K, Ungar L, Smith JR. Human uterus retrieval from a multi-organ donor. Obstet Gynecol 2007;109:101–4. 50. Fronek J, Janousek L, Chmel R. Deceased donor uterus retrieval – the first Czech experience. Rozhl Chir 2016;95:312–6. 51. Gauthier T, Piver P, Pichon N, Bibes R, Guillaudeau A, Piccardo A, et al. Uterus retrieval process from brain dead donors. Fertil Steril 2014;102:476–82. 52. Pratschke J, Neuhaus P, Tullius SG. What can be learned from brain-death models? Transpl Int 2005;18:15–21. 53. Totsuka E, Fung JJ, Hakamada K, Ohashi M, Takahashi K, Nakai M, et al. Synergistic effect of cold and warm ischemia time on postoperative graft function and outcome in human liver transplantation. Transplant Proc 2004;36:1955–8. 54. Schwarz A, Mengel M, Gwinner W, Radermacher J, Hiss M, Kreipe H, et al. Risk factors for chronic allograft nephropathy after renal transplantation: a protocol biopsy study. Kidney Int 2005;67:341–8. 55. Tricard J, Ponsonnard S, Tholance Y, Mesturoux L, Lachatre D, Couquet C, et al. Uterus tolerance to extended cold ischemic storage after auto-transplantation in ewes. Eur J Obstet Gynecol Reprod Biol 2017;214:162–7. 56. Wranning CA, M€ olne J, El-Akouri RR, Kurlberg G, Br€ annstr€ om M. Short-term ischaemic storage of human uterine myometrium— basic studies towards uterine transplantation. Hum Reprod 2005;20:2736–44. 57. Fornalik H, Fornalik N. Uterus transplantation: robotic surgeon perspective. Fertil Steril 2018;109:365. 58. Erman Akar M, Ozkan O, Ozkan O, Erdogan O, Cincik M, Mutlu D, et al. Short term follow up results of the first human uterus transplantation from cadaver. J Minim Invasive Gynecol 2012;19:S17–122. 59. Perez-Aytes A, Marin-Reina P, Boso V, Ledo A, Carey JC, Vento M. Mycophenolate mofetil embryopathy: a newly recognized teratogenic syndrome. Eur J Med Genet 2017;60:16–21. 60. Johannesson L, Wall A, Putman JM, Zhang L, Testa G, Diaz-Garcia C. Rethinking the time interval to embryo transfer after uterus transplantation – DUETS (Dallas UtErus Transplant Study). BJOG 2019;126:1305–9. 61. Johannesson L, Enskog A, Molne J, Diaz-Garcia C, Hanafy A, Dahm- Kahler P, et al. Preclinical report on allogeneic uterus transplantation in non-human primates. Hum Reprod 2013;28:189–98. 62. M€ olne J, Broecker V, Ekberg J, Nilsson O, Dahm-K€ ahler P, Br€ annstr€ om M. Monitoring of human uterus transplantation with cervical biopsies: a provisional scoring system for rejection. Am J Transplant 2017;17:1628–36. 63. Kasiske BL, Snyder JJ, Gilbertson DT, Wang C. Cancer after kidney transplantation in the United States. Am J Transplant. 2004;4:905–13. 64. Roy TK, Bradley CK, Bowman MC, McArthur SJ. Single-embryo transfer of vitrified-warmed blastocysts yields equivalent live-birth rates and improved neonatal outcomes compared with fresh transfers. Fertil Steril 2014;101:1294–301. 65. Johannesson L, Kvarnstrom N, Molne J, Dahm-Kahler P, Enskog A, Diaz-Garcia C, et al. Uterus transplantation trial: 1-year outcome. Fertil Steril 2015;103:199–204. RCOG Scientific Impact Paper No. 65 e63 of e66 ª 2021 Royal College of Obstetricians and Gynaecologists
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  66. Blume C,Pischke S, von Versen-Hoynck F, Gunter HH, Gross MM. Pregnancies in liver and kidney transplant recipients: a review of the current literature and recommendation. Best Pract Res Clin Obstet Gynaecol 2014;28:1123–36. 67. Wiles KS, Tillett AL, Harding KR. Solid organ transplantation in pregnancy. Obstetrician Gynaecol 2016;18:189–97. 68. Jones BP, Kasaven L, Vali S, Saso S, Jalmbrant M, Bracewell-Milnes T, et al. Uterine transplantation; review of livebirths and reproductive implications. Transplantation 2020 Dec 10. doi: 10.1097/TP.0000000000003578. 69. Jackson RA, Gibson KA, Wu YW, Croughan MS. Perinatal outcomes in singletons following in vitro fertilization: a meta- analysis. Obstet Gynecol 2004;103:551–63. 70. Balayla J, Edwards M, Lefkowitz A. Uterine artery as an arterial conduit for coronary artery bypass graft (CABG) surgery in women: a role for estrogen-receptor alpha (ER-a) in the prevention of post-CABG accelerated atherosclerosis and graft disease. Med Hypotheses 2013;80:162–6. 71. Jones BP, Saso S, Yazbek J, Smith JR. Uterine transplantation: past, present and future. BJOG 2016;123:1434–8. 72. Testa G, McKenna GJ, Gunby RT Jr, Anthony T, Koon EC, Warren AM, et al. First live birth after uterus transplantation in the United States. Am J Transplant 2018;18:1270–4. 73. Gardiner SJ, Begg EJ. Breastfeeding during tacrolimus therapy. Obstet Gynecol 2006;107:453–5. 74. Chusney G, Bramham K, Nelson-Piercy C, Rosser C. Tacrolimus monitoring during breastfeeding in neonates of transplant recipients [Abstract]. 12th International Congress of Therapeutic Drug Monitoring and Clinical Toxicology: Stuttgart, Germany October 2–6, 2011. Ther Drug Monit 2011;33:476. 75. Kjaer TK, Jensen A, Dalton SO, Johansen C, Schmiedel S, Kjaer SK. Suicide in Danish women evaluated for fertility problems. Hum Reprod 2011;26:2401–7. 76. Laggari V, Diareme S, Christogiorgos S, Deligeoroglou E, Christopoulos P, Tsiantis J, et al. Anxiety and depression in adolescents with polycystic ovary syndrome and Mayer-Rokitansky-K€ uster-Hauser syndrome. J Psychosom Obstet Gynaecol 2009;30:83–8. 77. J€ arvholm S, Johannesson L, Clarke A, Br€ annstr€ om M. Uterus transplantation trial: psychological evaluation of recipients and partners during the post-transplantation year. Fertil Steril 2015;104:1010–5. 78. J€ arvholm S, Johannesson L, Br€ annstr€ om M. Psychological aspects in pre-transplantation assessments of patients prior to entering the first uterus transplantation trial. Acta Obstet Gynecol Scand 2015;94:1035–8. 79. Kvarnstr€ om N, J€ arvholm S, Johannesson L, Dahm-K€ ahler P, Olausson M, Br€ annstr€ om M. Live donors of the initial observational study of uterus transplantation-psychological and medical follow up until 1 year after surgery in the 9 cases. Transplantation 2017;101:664–70. 80. Messersmith EE, Gross CR, Beil CA, Gillespie BW, Jacobs C, Taler SJ, et al. Satisfaction with life among living kidney donors: a RELIVE study of long-term donor outcomes. Transplantation 2014;98:1294–300. 81. Yang LS, Shan LL, Saxena A, Morris DL. Liver transplantation: a systematic review of long-term quality of life. Liver Int 2014;34: 1298–313. 82. Caplan AL, Perry C, Plante LA, Saloma J, Batzer FR. Moving the womb. Hastings Cent Rep 2007;37:18–20. 83. Williams N. Should deceased donation be morally preferred in uterine transplantation trials? Bioethics 2016;30:415–24. 84. Williams NJ. Deceased donation in uterus transplantation trials: novelty, consent, and surrogate decision making. Am J Bioeth 2018;18:18–20. 85. Bruno B, Arora KS. Uterus transplantation: the ethics of using deceased versus living donors. Am J Bioeth 2018;18:6–15. 86. Terasaki PI, Cecka JM, Gjertson DW, Takemoto S. High survival rates of kidney transplants from spousal and living unrelated donors. N Engl J Med 1995;333:333–6. 87. Jones BP, Saso S, Quiroga I, Yazbek J, Smith JR. Limited availability of deceased uterus donors: a UK perspective. Transplantation 2020;104:e250–1. 88. Hellstr€ om M, Moreno-Moya JM, Bandstein S, Bom E, Akouri RR, Miyazaki K, et al. Bioengineered uterine tissue supports pregnancy in a rat model. Fertil Steril 2016;106:487–96.e1. RCOG Scientific Impact Paper No. 65 e64 of e66 ª 2021 Royal College of Obstetricians and Gynaecologists
• 15.
  Appendix I: Causesof absolute uterine factor infertility (AUFI) Uterus present Asherman syndrome Fibroids Severe adenomyosis Uterine malformation Pelvic irradiation Uterus absent Hysterectomy – Obstetric haemorrhage – Benign cause – Cancer Congenital – Mayer-Rokitansky-K€ uster-Hauser (MRKH) syndrome – Complete androgen insensitivity syndrome (CAIS) – Male-to-female transgender RCOG Scientific Impact Paper No. 65 e65 of e66 ª 2021 Royal College of Obstetricians and Gynaecologists
• 16.
  This Scientific ImpactPaper was produced on behalf of the Royal College of Obstetricians and Gynaecologists by: Mr BP Jones MRCOG, London; Mr S Saso MRCOG, London; Mr JM Yazbek MRCOG, London; Dr M-Y Thum MRCOG, London; Miss I Quiroga FRCS, The Oxford Transplant Centre, Oxford University Hospitals NHS Trust; Dr S Ghaem-Maghami MRCOG, London; and Mr JR Smith FRCOG, London. The following individuals and organisations submitted comments during peer review: Professor A Balen MD DSc FRCOG, Leeds; Professor M Br€ annstr€ om, University of Gothenburg, Sweden; British Fertility Society; Dr R Chmel, Charles University and Motol University Hospital, Prague, Czech Republic; Mr DI Fraser FRCOG, Norwich; Professor PK Heinonen, University of Tampere, Finland; Dr LS Michala FRCOG, Athens, Greece; RCOG Women’s Network; Dr LLL Robinson FRCOG, Birmingham; and Dr G Testa MD, FACS, MBA, Baylor University Medical Center at Dallas, Texas, USA. The Scientific Advisory Committee lead reviewer was: Dr N Potdar FRCOG, Leicester. The chair of the Scientific Advisory Committee was: Professor MD Kilby FRCOG, Birmingham. All RCOG guidance developers are asked to declare any conflicts of interest. A statement summarising any conflicts of interest for this Scientific Impact Paper is available from: https://www.rcog.org.uk/en/ guidelines-research-services/guidelines/sip65/. The final version is the responsibility of the Scientific Advisory Committee of the RCOG. The paper will be considered for update 3 years after publication, with an intermediate assessment of the need to update 2 years after publication. DISCLAIMER The Royal College of Obstetricians and Gynaecologists produces guidelines as an educational aid to good clinical practice. They present recognised methods and techniques of clinical practice, based on published evidence, for consideration by obstetricians and gynaecologists and other relevant health professionals. The ultimate judgement regarding a particular clinical procedure or treatment plan must be made by the doctor or other attendant in the light of clinical data presented by the patient and the diagnostic and treatment options available. This means that RCOG Guidelines are unlike protocols or guidelines issued by employers, as they are not intended to be prescriptive directions defining a single course of management. Departure from the local prescriptive protocols or guidelines should be fully documented in the patient’s case notes at the time the relevant decision is taken. RCOG Scientific Impact Paper No. 65 e66 of e66 ª 2021 Royal College of Obstetricians and Gynaecologists