Version May 2024
INTRODUCTION — Uterus transplantation is an experimental procedure for the treatment of absolute uterine factor infertility (AUFI). AUFI refers to infertility that is completely attributable to uterine absence (congenital or surgical) or an abnormality (anatomic or functional) that prevents embryo implantation or completion of pregnancy to term. This topic will review the surgeries for the donor and recipient, immunosuppression, and obstetric issues involved in uterus transplantation. The intent of this topic is to provide an overview of the critical issues for clinicians and patients; the topic is based on the experience of the authors and should not be used for treatment decisions.
Related discussions on the ethical issues, patient selection, and consent involved in uterus transplantation, as well as topics on solid organ transplantation, are presented separately.
●(See "Overview of care of the adult kidney transplant recipient".)
●(See "Transplantation immunobiology".)
In this topic, when discussing study results, we will use the terms "woman/en" or "patient(s)" as they are used in the studies presented. We encourage the reader to consider the specific counseling and treatment needs of transgender and gender diverse individuals.
INDICATIONS, ETHICS, AND PATIENT SELECTION — The indications, ethics, and patient selection for uterus transplantation are reviewed separately. (See "Uterus transplantation for absolute uterine factor infertility: Ethics, patient selection, and consent".)
SURGERY — Uterus transplantation is a complex, multi-step process that involves a uterus donor, uterus recipient, and genetic father (unless donor sperm are used for conception) (figure 1). The uterus recipient is also the genetic mother, as embryos are created using her eggs and sperm prior to the transplantation procedure. Surgical removal of the donor uterus requires a radical-type hysterectomy (figure 2). Uterus transplantation involves extensive vascular surgery. The discussion below highlights key points specific to uterus removal and transplantation.
Uterus removal — The uterus can be removed from a living or deceased donor. The challenges and benefits of each approach are presented separately. (See "Uterus transplantation for absolute uterine factor infertility: Ethics, patient selection, and consent", section on 'Use of living or deceased donor'.)
Living donor
Surgical approach
●Laparotomy – Laparotomy, open abdominal surgery through a broad incision, is the conventional approach for organ retrieval from a living donor and has been described in detail [1]. We perform a vertical midline incision, starting above the umbilicus and extending to the pubic symphysis, to ensure adequate exposure of pelvic structures up to the level of the bifurcation of the internal and external iliac arteries. The procedure for uterus removal is similar to a radical-type hysterectomy in that the vessels are ligated as far laterally as possible to ensure long vascular pedicles for transplantation (figure 2). However, additional dissection is required to preserve critical structures for the donor while obtaining the best possible graft for transplantation. Uterus procurement surgery initially required 10 to 13 hours but has since reduced to 6 to 9 hours [2,3]. (See "Radical hysterectomy", section on 'Types of radical hysterectomy' and "Radical hysterectomy", section on 'Operative technique'.)
●Laparoscopy with or without robotic assistance – Donor organ procurement can be performed using minimally invasive techniques with either conventional laparoscopy or robot-assisted laparoscopy. Robot-assisted surgery offers advantages of three-dimensional-enhanced vision, articulated wristed instruments, and tremor-reducing properties; these are important features in precision surgery in narrow spaces. (See "Robot-assisted laparoscopy", section on 'Robot-assisted versus other surgical approaches'.)
•Frequency of use – Conventional laparoscopy has been reported for at least four procedures [4,5] while robot-assisted surgery has been performed in at least 16 [6-10].
•Comparison with open surgery – Minimally invasive surgery follows essentially the same pattern as that of laparotomy as described below. (See 'Description of the procedure' below.)
The different steps in robotic-assisted uterus procurement have been described in detail [7] and involve major dissection of the pelvic sidewalls of the deep pelvis. The dissection of the ureters from the iliac bifurcation to the inlet into the bladder is the most demanding surgical sub step.
•Advantages – Advantages of minimally invasive surgery include reduced blood loss, hospital stay, and sick leave. Live births have been reported in recipients whose donors underwent robotic-assisted retrievals [8,11,12]. Total surgical time is similar to that of laparotomy.
•Complications – The rate of major surgical and postsurgical complications in the laparoscopic and robot-assisted cases has been reported to be lower than in laparotomy, although ureteric complications have been reported in some cases [7,8].
Description of the procedure — Key steps (similar for laparotomy and MIS) in removing a uterus from a living donor include:
●Removal of a large flap of bladder peritoneum – A large bladder flap (almost to the level of the bladder dome) is created between the bladder and the uterus. This peritoneal flap will later be used to secure the grafted uterus in the recipient and cover the open vesicouterine fossa, with the goal of minimizing the risk of intestinal herniation in this pelvic area.
The following surgical substeps are performed in a row on one side and then repeated on the contralateral side. In robot-assisted surgery, the right side is often easier to access first with standard placement of instrument ports.
●Initial dissection of the ureter from its passage over the iliac vessels – The ureter is first identified and dissected free around 2 cm proximal to the crossing over the iliac artery and vein. The ureter is then freed towards the ureteric tunnel. This dissection is aided by gently deviating the ureter in different directions using a rubber sling that is placed around the ureter.
●Dissection of the arterial supply to the uterus – The arterial vasculature of the uterus is dissected proximally to the bifurcation between the major anterior branch of the iliac artery and the posterior portion (gluteal artery). Then all branches from the anterior portion, including the umbilical artery, are divided to gain one major trunk of the arterial supply through the interior iliacs. The arterial segment between the bifurcation of the posterior branch of the iliac artery and cervix is kept in the graft, while all the other branches (iliolumbar artery, lateral sacral artery, gluteal [superior and inferior] arteries, pudendal artery, middle rectal artery, vaginal artery, obturator artery, and umbilical artery) remain in the donor after ligation or stapling.
●Dissection of the ureteric tunnel – The ureteric tunnel is a distance of approximately 15 mm that passes close to the cervix, where the uterine artery is overrides the ureter and the uterine veins often both over- and underride the ureter. The ureter is tightly attached to the paracervical tissue and several small arterial and venous branches are present within the tunnel and in close proximity to the ureter. These vessels are ligated or sealed with bipolar diathermy prior to transection to avoid leakage after reperfusion of the organ in the recipient. The ureter has to be completely freed from attachments to other tissue in this tunnel and then to the inlet into the bladder (see below). Dissection is by scissors and bipolar diathermy.
●Dissection of the ureter between the tunnel and the inlet to the bladder – The distance between the end of the ureteric tunnels (see above) and the inlet of the ureter into the bladder is approximately 20 mm. The ureter is hidden under tissue and blood vessels, in particular veins of different calibers. Early identification of the ureter and traction of this structure upward aided by placing a rubber sling around the ureter will aid in the dissection to make the ureter entirely free from attachment to paracervical tissue. Care has to be taken to avoid damage to any uterine vein which may pass in this area on its way to the internal iliac vein. Dissection is by scissors and bipolar diathermy.
●Dissection of the uterine vessels – Dissection of the uterine vessels begins on the pelvic sidewall, in order to identify the internal iliac vein, and progresses toward the uterus. The goal of venous dissection is to create an outflow conduit on each side of the uterus. The sizes and the positions of the veins determine whether one large and dominating uterine vein is chosen or whether several smaller uterine veins will be used for venous drainage. The venous vascular pedicle should, at its end, contain a segment or a patch of the internal iliac vein, in order to get a vein with well-defined walls that will make anastomosis surgery in the recipient easier. If the outflow through the uterine vein(s) on one side is anticipated to be low because of the small size of the vessels, the uterine branch of the utero-ovarian vein (see below) can be anastomosed to the internal iliac venous segment at back-table preparation or be fixed directly to the external iliac vein at recipient surgery to increase venous drainage. The approach to dissection is similar for the uterine arteries.
●Dissection of the uterine branch of the ovarian vein and excision of fallopian tubes and ovaries from the graft – In our approach, the branch from the uterine cornua that merges with the ovarian vein and forms a true utero-ovarian vein is dissected free from the oviducts and flushed with heparinized saline. This branch may be used for extra venous outflow (see above). Alternately, some authors have suggested using only the ovarian veins to provide venous outflow [13,14] to reduce the surgical time by two hours. The fallopian tubes are then separated, by ligation or bipolar diathermy, from the uterus close to the uterine body and the utero-ovarian ligament is divided in the same fashion.
●Dissection of the rectovaginal space – The rectovaginal space is then opened and the uterosacral ligaments are divided, preferably 10 to 15 mm from the uterine cervix, to facilitate subsequent uterine fixation in the recipient. The extensive dissection of the vagina increases its mobility which allows it to be moved backward towards the proximal edge of the uterosacral ligaments (that remain in the donor) to perform a McCall culdoplasty. Thus, the posterior vaginal apex is drawn up to the supporting uterosacral structures and thereby elevated to a normal position.
●Uterus removal – After the dissections are completed, the uterus is only attached by the bilateral arterial and venous vascular pedicles. Vascular clamps are then placed, first on the internal iliac arteries just distal to the branching of the gluteal arteries, and on the internal iliac veins to obtain segments of this on each side. The vessels are divided just distal to the clamps, and the uterus is quickly taken to the back-table, where it is cooled down by flushing cold preservation solution through the arteries. The uterus is extracted through the abdominal incision in donor hysterectomy by laparotomy and in robot-assisted donor hysterectomy the uterus is placed inside a laparoscopic bag and extracted through the vagina. Any vascular leakage is repaired on the back-table, and vascular reconstructions, such as anastomosis of the upper uterine vein, are performed. The donor surgery is completed by closure of the open vascular pedicles and the vaginal vault.
Complications — Surgical complications can be intra- or postoperative. The most serious intraoperative complications, in order of descending importance, are lacerations of a vein, artery, ureter, or bladder wall.
More common postoperative complications include wound infection, venous thromboembolism, bleeding, vaginal cuff infection or dehiscence, or ureteric injury with hydronephrosis or ureteric vaginal fistula formation. In the clinical trial of nine uterus transplantations, one donor was diagnosed with a ureterovaginal fistula on postoperative day (POD) 16, which was treated with a pyelostomy catheter and subsequent ureteral reimplantation on POD 134 [1]. Detailed discussions of the prevention or treatment of these complications are presented separately.
●(See "Antimicrobial prophylaxis for prevention of surgical site infection in adults".)
●(See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)
●(See "Management of hemorrhage in gynecologic surgery".)
●(See "Posthysterectomy pelvic abscess".)
●(See "Vaginal cuff dehiscence after total hysterectomy".)
●(See "Urinary tract injury in gynecologic surgery: Epidemiology and prevention".)
●(See "Urinary tract injury in gynecologic surgery: Identification and management".)
●(See "Urogenital tract fistulas in females".)
●(See "Rectovaginal and anovaginal fistulas".)
Deceased donor — In removing the uterus from a deceased donor, the goal is to remove the organ with the longest vascular pedicles possible. To that end, the uterus is typically removed with the uterine vessels intact and attached to portions of the internal iliac vessels, and potentially to the common iliac vessels (figure 3). Having long vascular pedicles facilitates transplantation of the organ into the recipient. One advantage of organ procurement from a deceased donor compared with a living donor is that the ureters can be transected because they are no longer needed for function. The ureters are transected both caudally and cranially from the point where they cross the uterine vessels and thus the need to dissect the vessels off of the ureters is eliminated. The branches from the vascular pedicles on the graft side can be ligated at the time of transection or after the entire organ has been removed (ie, back-table preparation).
One challenge of deceased-donor surgery is that, in the setting of a multi-organ donor, the uterus is typically not the first organ removed (life-saving organs are usually removed first). The uterus is flushed with heparinized preservation solution while the vital organs are removed. In the first reported donor uterus surgery that resulted a live birth, the total uterus ischemic time was nearly eight hours [15]. In contrast to the traditional flushing technique in solid organ transplantation, which is done from the lower aorta in a cranial direction, one research group has reported flushing of the uterus through cannulation of the femoral arteries [16]. Total time for graft procurement (flushing, removal, and back-table preparation) has been reported to range between 30 and 120 minutes [15-17]. Different groups have reported performing the hysterectomy first, prior to procurement of other organs and before the cross-clamping of the aorta [17,18]. When the hysterectomy is performed first, the surgery becomes a clean-contaminated case, which should be discussed with all surgical teams involved in organ procurement.
Eleven deceased-donor cases have been reported in the scientific literature [19] and at least two of them have resulted in live births as of 2021 [20,21].
Uterus transplantation
Procedure — The surgery on the organ recipient should not begin until approximately 30 minutes before the predicted time for organ removal from the donor and once the surgeons have confirmed that the graft is well perfused on the back table. In the authors' trial, when the graft donor was a postmenopausal woman, the authors delayed the recipient surgery until the graft organ had been removed from the donor and was clearly well perfused with preservative solution because of the smaller size of the uterine arteries after menopause. There are also cases where further transplantation has been aborted due to minimal perfusion on the back table [3,22]. Of note, the recipient receives her first dose of immunosuppressive medication at the onset of surgery.
Surgery in the recipient has traditionally been performed by laparotomy through an infraumbilical midline incision. In Sweden, one ongoing trial evaluating robot-assisted transplantation procedures has completed two cases [23] (personal communication). Robot-assisted pelvic and anastomosis surgery follow essentially the same sub-steps as transplantation by laparotomy. The next steps are determined by the recipient female's pelvic anatomy:
●For patients without a uterus (ie, the majority of recipients), the initial surgery involves separation of the bladder and the rectum from the vaginal vault. The dissection is aided by use of a vaginal sacropexy probe to displace the vagina upward. For patients with Mayer-Rokitansky-Küster-Hauser [MRKH] syndrome as their surgical indication, the rudimentary midline uterus is cleaved to reach the vaginal vault.
●For patients who have a uterus in place (eg, patients with Asherman syndrome), a traditional total hysterectomy is performed with removal of the fallopian tubes.
The external iliac arteries and veins are then dissected and cleared over a distance of approximately 5 cm to give space for later anastomosis. The authors place non-resorbable fixation sutures (1-0) bilaterally in the uterosacral ligaments, the round ligaments, and in the tissue that will be lateral to the cervix (cardinal ligaments or, in the case of MRKH, the cleaved uterine rudiment above the vaginal vault).
The cooled and flushed uterus is then placed in the pelvis and traditional end-to-side anastomosis surgery is performed (figure 2). On each side, the vein is attached first and then the artery. Each anastomosis requires approximately 15 to 30 minutes. Once all anastomoses have been completed, the vascular clamps are removed and the organ is perfused. Any anastomotic leaks are repaired. The vagina of the recipient is then opened with a vertical incision to avoid injury to the ureters. The vertical incision length is extended to correspond to the diameter of the vaginal ring of the graft. The vaginal rim of the grafted uterus is then anastomosed end-to-side to the opened vaginal vault with a continuous absorbable suture. The uterus is then fixed bilaterally to the sutures of the sacrouterine ligaments, round ligaments and paracervical tissues. As a last point of fixation, the bladder peritoneum is sutured on the top of the bladder fundus. The abdomen is then closed. To date, uterus transplantation has required approximately four to five hours [2].
Complications — The major intraoperative risk for the uterus recipient is anastomotic leakage. Leakage is typically immediately visible and is repaired with polypropylene suture. In the trial of nine uterus transplantations, one woman developed a retroperitoneal hematoma and required a blood transfusion [1].
The routine surgical complications for the recipient are similar to those of the donor and include wound infection and bleeding. A complication that is unique to the graft recipient is the thrombosis of any uterine vessel anastomoses. The authors routinely measure the blood flow with an intraoperative probe during surgery. Postoperatively, the graft uterine arteries are monitored with external Doppler measurements using an abdominal probe. The authors assessed the uterine artery flow every day during the first week post-transplant and then once a week until the end of the first month. After the first month, no further Doppler measurements were routinely performed. If there is concern for vessel thrombosis, the authors may repeat the laparotomy to assess the patency of the blood vessels and to clear any thrombosis with possible reconstruction of the graft vessels or anastomosis sites.
GRAFT COMPLICATIONS — The most serious complications that affect the grafted uterus are rejection, thrombosis, and infection.
Rejection — When detected early, organ rejection can often be reversed with a temporary increase in maintenance immunosuppression or a short course of corticosteroids. The authors monitor transplant recipients with cervical biopsies to detect rejection [24].
●Role of cervical biopsy – In the authors' research protocol, the predetermined time points for cervical biopsy were one, two, three, and four weeks post-transplantation and monthly thereafter for another five months, and thereafter every second month [2]. Additional biopsies were performed for clinical symptoms that could represent organ rejection such as vaginal discharge, fever, or abdominal pain. A subsequent study on hysterectomy and graft failure reported that presence of ischemia on the cervical biopsies during the initial weeks after transplantation was associated with later graft ischemia and graft failure [25]. In addition, Doppler examination during this period saw typical patterns of hypoperfusion of the uterus, with minimal blood flow in the central parts of the uterine tissue.
●Rejection grade and management – The authors have developed a grading system for assessing allograft rejection of the human uterus based on studies of cervical biopsies [24]. If rejection is detected in the biopsy specimen, the authors perform follow-up biopsies on a weekly basis until the histology normalizes. In their research trial of seven women, rejection was seen in five patients. Less than 10 percent of all protocol biopsies met the criteria for organ rejection. All rejection events, which also included severe rejection, were subclinical; no pathological findings were identified on ultrasound or gynecologic examination. The histologic findings of the mild rejection episodes consisted of a mixed inflammatory cell infiltrate (continuous or patchy), dominated by lymphocytes, at the interface of the superficial stroma and basal epidermal layer. In the few cases of severe rejection, histologic evaluation revealed a major diffuse, mixed inflammatory cell infiltrate and loss of epithelium [24].
Thrombosis — Arterial and venous thrombosis have been described after other types of abdominal organ transplantation and are also a factor for uterus transplant [26-29]. While the data are limited, thrombosis of the uterine arteries and veins occurred in one of nine cases in the authors' trial. In the initial United States living-donor transplant trial, three of the initial five transplant procedures required graft removal as a result of vascular complication [30]. Ultrasound and cross-sectional imaging techniques are effective at detecting clots in the graft's vessels [27,28]. Possible explanations include thrombus formation secondary to low initial arterial blood flow, venous outflow problems, or constrictions of the anastomosis lines. In general, thrombosis events after uterus transplantation will occur within the first two weeks after transplantation and the authors' experience is that if a graft shows adequate perfusion on Doppler ultrasound after two weeks, and if the initial cervical biopsies have been normal, the uterus will stay well perfused and later demonstrate partial functionality by menstruations.
Infection — A transplanted uterus may be more susceptible to intrauterine infection because of the immunosuppressed state of the recipient. In order to prevent infection, patients are given 4 g piperacillin/tazobactam preoperatively and three times daily for three days. In the trial of nine women undergoing transplantation, one transplanted uterus required removal on postoperative day 105 because of persistent infection with Enterococcus faecalis that did not respond to intravenous antibiotic therapy or surgical drainage [31]. Histopathologic analysis reported extensive areas of necrosis and neutrophil-dominated inflammation but no signs of rejection. Subsequent analysis of that case indicated that initial cervical biopsies showed focal necrosis and uterine blood flow was subnormal [25]. A different clinical team that attempted a deceased-donor uterus transplant reported removal of the graft on postoperative day 12 because of Candida infection that disrupted one of the vascular anastomoses of the graft and led to bleeding [32]. A different group reported need for removal of a deceased-donor graft because of uterus injury (lack of endometrial development, fibrotic obliteration of the uterine cavity and cervical canal) resulting from herpes simplex virus-2 infection [14]. Based on these events, future protocols for uterus transplantation could include preoperative testing for herpes simplex virus and vaginal fungal cultures or fungal prophylaxis.
Unplanned graft removal — The surgical technique for unplanned graft removal (hysterectomy) is relatively straightforward when the surgery occurs within the initial two weeks following transplantation because firm adhesions have not yet formed and access can be easily regained through the midline incision. Cessation of blood flow through the uterine arteries is confirmed with intraoperative Doppler ultrasound and manual palpation of the uterine arteries before hysterectomy is started. The fixation points of the uterus and the vaginal-vaginal anastomosis line are easily identified. These suture lines are opened first to make it easier to dissect the uterine vessels up to the anastomosis points on the external iliac vessels. It is important to remove the entirety of the grafted vessels in order to avoid weakening, and possibly rupture, at these spots when immunosuppression is stopped and rejection of any retained foreign tissue will occur.
IMMUNOSUPPRESSION
Our approach — In their clinical trial, the authors used a combined immunosuppressive protocol similar to that used for other type of composite tissues such as the face or the arm [1,33]. Immunosuppression induction was achieved with 1 g mycophenolate mofetil preoperatively and 500 mg methylprednisolone together with antithymocyte antibodies to deplete T lymphocytes during transplantation. A second dose of antibodies was given 12 hours later (monoclonal or polyclonal antibodies were used indistinctly) [1].
Maintenance immunosuppressive therapy was continued with tacrolimus, mycophenolate mofetil, and prednisolone. Target tacrolimus levels were 10 to 15 ng/mL for the first five weeks and then 5 to 10 ng/mL thereafter. Mycophenolate doses were calculated to achieve an area under the curve of 40 to 60 mg h/L. Oral prednisolone was given at 5 mg/day for the first four days after transplantation and then discontinued. In the event of acute rejection episodes, methylprednisolone intravenous was administered at a dose of 500 mg/day for three days, and then followed by five to seven days of oral prednisolone. In women with more than one rejection episode during the initial eight months, mycophenolate was changed to azathioprine to avoid the teratogenic effects of the former at embryo transfer, which was anticipated to start approximately 12 months post-transplantation [2]. In women with no or only one early mild rejection episode, tacrolimus was the only immunosuppressive agent in use after eight months. The immunosuppressive regimen has since been modified to include azathioprine rather than mycophenolate at the onset of transplant and the IL-2 agonist basiliximab instead of antithymocyte antibodies [34].
Uterine rejection chronology has been well characterized in rodent models [35]: It begins with neutrophil and CD8+ lymphocyte infiltration of the myometrium on day 2 after transplantation, and it spreads to the endometrium on day 5. CD4+ lymphocytes only increase transiently on day 5 after transplant, and CD19+ cell density remains low during all the rejection process. The histological characteristics of mild, moderate, and severe rejection of human uterine grafts are described in the literature [24]. Human transplant immunobiology is discussed in detail separately. (See "Transplantation immunobiology".)
Treatment risks — The use of immunosuppressants has been related to the development of comorbidities such as kidney disease [36,37], diabetes [38], infections [39], and malignancies [40]. Such comorbidities are often a direct consequence of the use of immunosuppressants and can compromise directly or indirectly the survival rates of the patients.
●(See "Kidney function and non-kidney solid organ transplantation".)
●(See "Kidney transplantation in adults: Posttransplantation diabetes mellitus".)
●(See "Infection in the solid organ transplant recipient".)
●(See "Malignancy after solid organ transplantation".)
●(See "Overview of dermatologic problems following liver transplantation".)
Use in pregnancy — The main issues regarding immunosuppression in pregnancy are teratogenicity and pharmacokinetics. Most of the data come from studies of women with other types of solid organ transplants (ie, kidney or liver) [37].
One of the major criticisms of uterus transplantation is fetal exposure to multiple drugs. Mycophenolate mofetil appears to be a teratogen and is therefore not advised for use in those attempting pregnancy [41,42]. While azathioprine has not been identified as a human teratogen, in utero exposure in rodents resulted in congenital anomalies, although this outcome has not been seen in human females undergoing other solid organ transplants [41,43]. For uterus transplantation, management has shifted towards use of azathioprine from the day of transplantation instead of mycophenolate mofetil; the drug is stopped some months before embryo transfer. (See "Overview of care of the adult kidney transplant recipient", section on 'Immunosuppressive medication during pregnancy'.)
Physiological changes during pregnancy include increased volume of distribution and induction of different enzyme complexes that result in altered metabolism of immunosuppressant agents [44]. Thus, levels of immunosuppressive drugs must be closely monitored during pregnancy.
OBSTETRIC ISSUES
Impact of immunosuppressive agents — Mycophenolate is a known teratogen that is tapered and stopped prior to attempts at conception [42]. In years 2 and 3 following transplantation, azathioprine, tacrolimus, and glucocorticoids are typically used for immunosuppression in solid organ transplant protocols. Although azathioprine is likely mildly teratogenic, it is believed that, at low doses, the benefits outweigh risks. As of 2006, more than 14,000 births had been reported from women with transplanted organs who were receiving immunosuppressive therapy without a noticeable increase in structural malformations [45].
Obstetric complications — Among potential obstetric complications, the authors particularly monitor women with uterus transplants for evidence of preeclampsia and gestational diabetes (for women receiving glucocorticoids or tacrolimus) [2]. A review of 52 transplant recipients reported 6 of 16 (37.5 percent) experienced major obstetric complications [46].
●Data from other solid transplant studies – Until more data are available, the obstetric and fetal risks for uterus transplantation patients are extrapolated from the solid organ transplantation data. For women with renal transplants, volunteer patient registries have reported increased rates of adverse perinatal outcomes, particularly hypertension and preeclampsia [45,47]. In a population-based study comparing pregnancy outcome before and after organ transplantation (multiple types), women with organ transplants experienced increased risk of preeclampsia, preterm birth, low birth weight, and small for gestational age infants [48]. However, when births just before and after transplantation were compared, the perinatal outcomes were found to be similar. This study suggests that the major cause for these pregnancy complications in transplanted patients was the organ disease that led to the transplantation procedure and not the immunosuppressant medication or the transplantation procedure itself.
●Obstetric management – Pregnant individuals with other types of solid organ transplants undergo surveillance for preeclampsia, serial ultrasounds for fetal growth assessment beginning by 24 weeks of gestation, antenatal testing beginning by 32 weeks of gestation, and early and standard screening for diabetes [49].
●Timing of pregnancy – The above data form the basis for the American Society of Transplantation to recommend delaying pregnancy for at least one year following solid organ transplantation [50]. Although this advice was followed in the first cases, more recently different groups have started to advance the timing of the embryo transfer relative to uterus transplantation [20,51]. Earlier embryo transfer forward did not appear to impact in the obstetric outcomes in these series, but data are limited and definitive conclusions cannot be made.
PLANNED GRAFT REMOVAL — Uterus transplantation is the first type of organ or tissue transplantation that is only temporary and not intended to stay with the host for life. The uterus is removed when childbearing is deemed complete to limit the amount and duration of immunosuppressive medication and thereby reduce the risk for immunosuppressive side effects such as nephrotoxicity and increased risk of certain malignancies.
Graft removal can be performed using minimally invasive surgical techniques, including robot-assisted laparoscopy [52]. Major challenges anticipated at the time of the graft removal surgery are adhesions that have formed around the graft's vessels and the non-anatomic location of the vessels [25]. In addition, the ureters may be positioned close to the graft vessels on the pelvic sidewalls and difficult to separate. Preoperative insertion of ureteric double J stents can be helpful to aid in palpating the ureters. Identification of the native and graft vaginal edges can also be challenging.
SUMMARY AND RECOMMENDATIONS
●Multi-patient procedure – Uterus transplantation is a complex, multi-step process that involves a uterus donor, uterus recipient, and genetic father (figure 1). (See 'Surgery' above.)
●Uterus removal from donor – The uterus can be removed from either a living or deceased donor. The procedure for uterus removal from a living donor is similar to a radical-type hysterectomy in that the ligaments and vessels are ligated as far laterally as possible to ensure long vascular pedicles for transplantation (figure 2). In removing the uterus from a deceased donor, the organ can be removed with longer vascular pedicles than in living uterus donation. Transection of the ureters simplifies the surgery in a deceased donor. The uterus is typically removed with the uterine vessels intact and attached to the internal iliac vessels, and potentially to the common iliac vessels (figure 3). (See 'Uterus removal' above.)
●Uterus transplant to recipient – The surgery on the organ recipient is not begun until approximately 30 minutes before the predicted time for organ removal from the donor and once the surgeons have confirmed that the graft is well perfused by the remaining isolated vascular pedicles. For women without a uterus (the majority of recipient women), the initial surgery involves separation of the bladder and the rectum from the vaginal vault. For women who have a uterus in place (eg, women with Asherman syndrome), a traditional total hysterectomy is performed with removal of the fallopian tubes. For women with rudimentary uterus or similar structure above the vaginal vault (eg, women with Mayer-Rokitansky-Küster-Hauser syndrome), the rudimentary uterus is cleaved. (See 'Procedure' above.)
●Complications – The routine surgical risks for the recipient are similar to those of the donor and include wound infection and bleeding. A complication that is unique to the graft recipient is the thrombosis of any uterine vessel anastomoses. The most serious postoperative complications of the grafted uterus are rejection, thrombosis, and infection. When detected early, organ rejection can often be reversed with a temporary increase in maintenance immunosuppression or a short course of corticosteroids. While the data are limited, thrombosis of the uterine arteries and veins appears to occur occasionally in this early phase after uterus transplantation. Ultrasound and cross-sectional imaging techniques are effective at detecting clots in the graft's vessels. A transplanted uterus may be more susceptible to intrauterine infection because of the immunosuppressed state of the recipient. Antibiotic prophylaxis is given prior to the start of the surgery, which may be expanded to include antifungal agents in the future. (See 'Graft complications' above.)
●Immunosuppression – In the author's clinical trial, they used a combined immunosuppressive protocol similar to that used for other type of composite tissues such as the face or the arm.
•Concerns for teratogenicity – The main issues regarding immunosuppression in pregnancy are teratogenicity and pharmacokinetics. Most of the data come from studies of women with other types of solid organ transplants (ie, kidney or liver). Mycophenolate mofetil appears to be a teratogen and is therefore not used in women attempting pregnancy. (See 'Our approach' above.)
•Impact of pregnancy on drug metabolism – Physiological changes during pregnancy include increased volume of distribution and induction of different enzyme complexes that result in altered metabolism of immunosuppressant agents. Thus, levels of immunosuppressive drugs must be closely monitored during pregnancy. (See 'Use in pregnancy' above.)
●Timing of pregnancy – The American Society of Transplantation criteria advise that pregnancy be delayed for at least one year following solid organ transplantation and that no episodes of rejection have occurred during the prior six months of that year. Among potential obstetric complications, the authors particularly monitor women with uterus transplants for evidence of preeclampsia and gestational diabetes (for women receiving glucocorticoids or tacrolimus). Volunteer patient registries of women with renal transplants have reported increased rates of adverse perinatal outcomes, particularly hypertension and preeclampsia. (See 'Obstetric complications' above.)
●Planned uterus removal – Uterus transplantation is the first type of organ or tissue transplantation that is only temporary and not intended to stay with the host for life. The uterus is removed when childbearing is deemed complete to limit the amount and duration of immunosuppressive medication, and thereby reduce the risk for immunosuppressive side effects such as nephrotoxicity and increased risk of certain malignancies. Major challenges anticipated at the time of the graft removal surgery are adhesions that have formed around the graft's vessels and the non-anatomic location of the vessels. (See 'Planned graft removal' above.)
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