Uterus Transplantation



Uterus Transplantation


Jenna M. Rehmer

Natalia C. Llarena

Elliott G. Richards

Rebecca Flyckt



GENERAL PRINCIPLES



History



  • Following the first live birth in 2014 from a uterus transplanted by Dr. Mats Brännström’s Swedish team, interest in UTx has dramatically increased in interest and activity, with multiple teams worldwide and over 75 births. However, UTx has a history that dates back many decades before then (11).


  • Years of extensive research and training in several animal species preceded the transition of non-lifesaving UTx in humans.
    In 1971, James Scott and coworkers published pioneering work in nonhuman UTx research that included both autologous and allogeneic transplants in the rhesus macaque (12).


  • From the early 2000s, UTx models in the mouse (13,14), the rat (15), the pig (16,17), the sheep (18,19), and nonhuman primate models (20) have been developed. With years of extensive research in animal models, the field of UTx was carried into human trials.


Landmark Events



  • 2000: First human, living donor (LD) UTx was performed in Saudi Arabia. A 26-year-old woman, with a history of emergency peripartum hysterectomy after her first child, received a UTx from a 46-year-old LD. Three months post transplantation, the graft prolapsed into the vagina. The uterus became necrotic, and hysterectomy was required. It is speculated that poor uterine fixation contributed to the prolapse (21).


  • 2011: The second human UTx, and first from a deceased braindead donor (DD), was performed in Turkey. A 21-year-old MRKH patient received a uterus from a 22-year-old DD. No live births have occurred. The team has recently reported miscarriages after both the first and second embryo transfers (22).


  • 2013: First clinical trial initiated in Sweden. Completion of nine human live donor transplants (11).


  • 2014: September 2014 celebrated the world’s first live birth from LD in Sweden’s UTx trial. This was followed by two more births within that trial in November 2014. Multiple additional live births have subsequently resulted from this initial trial (23).


  • 2017: World’s first birth from a DD UTx occurred in Brazil in December 2017 (24).


  • 2017: U.S. first birth from LD UTx occurred at Baylor University Medical Center in Dallas (25).


  • 2019: U.S. first birth from DD UTx occurred at the Cleveland Clinic (26).


  • 2019: Proof of concept achieved when the first birth following LD surgery performed by robotic-assisted laparoscopy occurred in Sweden (27).









Nonoperative Management



  • There is currently no nonoperative, restorative option for patients with AUFI.


  • For women with AUFI desiring genetic children, IVF with a gestational surrogate may be an option. This process is fraught with unique challenges and in many countries globally is illegal.


  • Adoption also provides the opportunity for family building. Navigating adoption involves complex legal and social systems. Additionally, it lacks biologic lineage that is important to many patients.


PREOPERATIVE PLANNING


Transplant Team



  • UTx is a complicated endeavor that requires the coordination of a large team of specialists in transplant surgery, gynecologic surgery, reproductive endocrinology, maternal-fetal medicine, anesthesiology, infectious disease, psychiatry/psychology, bioethics, pathology, and social work. In addition, specialists from pharmacy, nutrition, media, and/or legal services may need to be engaged.


  • An experienced coordinator (typically a physician, advanced practice provider, or nurse) serves as the primary communicator between the leader, the patients, and the various team members.


  • Many critical components must be in place before the team attempts their first operation, including the development of an extensive protocol and sufficient training/practice with the involvement of all team members.


Preoperative Patient Selection



  • Selection criteria for prospective recipients: There is no consensus among current uterus transplant centers at what point to restrict participants based on age, body mass index (BMI), number of living biologic children, and so on. Table 2.3.1 provides sample inclusion criteria, exclusion criteria, and screening tests for recipients.



  • Selection criteria for prospective donors: Selection criteria will vary depending on whether LD or DD transplant is planned. Sample criteria from different institutions are provided in Table 2.3.2.


Timeline of Events



  • Screening: Prospective LDs and recipients first undergo a screening process to determine eligibility for UTx, followed by a series of in-person assessments with the team leader and transplant nurse, before moving on to a full medical evaluation.


  • Medical evaluation: Medical tests are performed, and results are reviewed by the medical team. The prospective recipient undergoes evaluations with specialists in transplant surgery, infertility, gynecology, maternal-fetal medicine, and psychology. As needed, consults are made to various specialties including infectious disease, cardiology, and other services. Ongoing assessment of participants’ comprehension of risks, benefits, and lifestyle changes is performed with the assistance of psychology and/or bioethics.


  • IVF: A predetermined number of high-quality embryos (e.g., 6-10, usually blastocysts) must be frozen before transplant. At times, multiple IVF cycles may be needed.


  • Entry to transplant list: Once medical evaluation is completed and embryos are banked, a potential recipient is added to the uterus transplant list. If awaiting a DD, the candidate is placed on a United Network for Organ Sharing (UNOS) organ wait list. If LD, surgery date will be coordinated with the LD team. During this time, patients with anomalous short vaginal length will begin dilation or neovagina surgery to extend vaginal length, increase plasticity, and improve outcomes related to UTx surgery (1).


  • Transplantation: Once the uterus is procured, the surgical team should examine it together and determine whether organ implantation should proceed. See procedures and techniques section.









  • Postoperative care and monitoring: During the postoperative period, continued communication and coordination between specialty groups is critical. Immunosuppression is managed as described below. Routine gynecologic examination (e.g., 2 weeks after the transplant and then monthly until embryo transfer) should be performed and includes a biopsy of the cervix to evaluate the graft for rejection.


  • Embryo transfer: Embryo transfer is typically performed at 6 to 12 months post transplantation.


  • Pregnancy and delivery: At a predetermined gestational age (typically 8-10 weeks), the patient’s obstetrical care is transitioned from the fertility specialist to the maternal-fetal medicine specialist. Continued monitoring for adequate immunosuppression and evidence of rejection is performed through weekly labs and regular cervical biopsies (typically one per trimester at minimum). Delivery is via cesarean delivery by the maternal fetal medicine team in coordination with other surgical teams.


  • Follow-up: Hysterectomy is encouraged after one to two deliveries to limit maternal exposure to immunosuppressants. This is performed by the gynecologic surgery team with assistance by transplant surgery, with the donor vessels ligated proximal to the uterus before its removal. Hysterectomy may be performed at the time of cesarean delivery or some months after if the patient is uncertain about desire for subsequent pregnancy. Delayed hysterectomy may decrease the operative risk of bleeding associated with hysterectomy of the gravid uterus; however, this benefit must be balanced against the need for an additional surgical procedure.


SURGICAL MANAGEMENT


Living Donor Versus Deceased Donor



  • There are two different strategies for obtaining the uterine graft which include (1) multi-organ procurement from a brain-dead patient and (2) from a living related or unrelated
    donor. There are advantages and disadvantages associated with both LD and DD (Table 2.3.3).


  • LD bears the risks of surgical morbidity and mortality, including long surgical duration, surgical injury, infection (28). There are potential psychological risks for both the donor and recipient. For the donor, however, there may also be improvement in psychological well-being and quality of life for years to come if the recipient is able to successfully deliver.


  • DD introduces increased risk to the recipient including decreased histocompatibility, higher risk of rejection, and increased difficulty with organization and coordination of surgery. On the other hand, it eliminates all risks of the surgery attributed to the LD, making this non-lifesaving transplant have considerably fewer ethical pitfalls.


  • Outcomes for solid organ transplants are superior in living directed donation compared to DD, even when adjusted for ischemia times. The significant difference is attributable to the physiologic instability of a DD and associated systemic inflammation. Additional data are required to determine how clinical outcomes will compare in LD versus DD in the setting of UTx.


  • Predictive modeling has estimated that the number of DD organs available to meet demand is insufficient and LD can overcome this. We suspected that the future of UTx involves a combination of both DD and LD programs similar to other solid organ transplant programs.







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Sep 8, 2022 | Posted by in OBSTETRICS | Comments Off on Uterus Transplantation

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