Absolute uterine factor infertility (AUFI) is infertility that is related to congenital or surgical absence of the uterus or because of anatomic or functional abnormalities that prevent embryo implantation or completion of a pregnancy to term.
Women with AUFI infertility remain one of the few untreatable subgroups of female infertility. The emerging option of uterus transplantation (UTx) is offering new hope to these women as a potential treatment.
Absent uterus: Women with AUFI secondary to absent uterus comprise the majority of UTx worldwide. Additional causes of congenital or surgical absence of uterus include the following:
Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome comprises the most common diagnosis for UTx to date. In MRKH syndrome, there is either complete absence of the uterus or, more commonly, the presence of rudimentary solid bipartite uterus. The vagina is anomalous, with absence of the upper third. Estimated prevalence is 1:4,500 to 5,000 females (1).
Complete androgen insensitivity syndrome (CAIS) is an X-linked recessive disorder in which the individual is phenotypically female and genotypically male owing to mutations in the androgen receptor gene. These individuals most often self-identify as female. There is absence of uterus and ovaries, so they are unable to conceive (2).
Hysterectomy is the second most commonly performed surgical procedure during the reproductive period and is the most common cause of acquired AUFI (3). Over 180,000 hysterectomies are performed annually in the United States for benign indications or obstetric-related complications in women of reproductive age (3).
Transgender women who express a desire to carry a pregnancy (4). These individuals are able to produce genetic offspring using cryopreserved or fresh sperm and in vitro fertilization (IVF) using a genetically female partner’s gametes or an egg donor.
Nonfunctional uterus: Many uterine conditions contribute to or cause infertility. Established medical and surgical treatments, when applicable, should be pursued as first-line therapy and exhausted before UTx being considered.
Müllerian anomalies such as septate, bicornuate, unicornuate, and didelphys uterus are associated with infertility. Additionally, these malformations are associated with risk of adverse obstetric and perinatal outcomes, including increased miscarriage rate, preterm labor, preterm delivery, and reduction in live birth rates (5,6).
Intrauterine adhesions, or synechiae, can lead to an inhospitable uterine environment and poor implantation. Women with intrauterine adhesions are unable to conceive 50% of the time and those that do miscarry ˜40% of the time. The first-line treatment for uterine adhesions is hysteroscopic adhesiolysis (7).
Uterine leiomyoma is a frequent cause of uterine factor infertility secondary to both structural and biochemical factors. Fibroids are associated with adverse pregnancy outcomes including miscarriage, preterm labor, malpresentation, and postpartum hemorrhage (8). For fibroids causing distortion of the uterine cavity, myomectomy is first-line management.
Adenomyosis is a disorder in which endometrial glands and stroma are present within the uterine myometrium. It may cause infertility secondary to poor implantation, abnormal uterine size, abnormal bleeding, and hysterectomy (9).
Recurrent implantation failure results when the endometrial receptivity is not synchronized with the window of implantation. For most women, this can be overcome with individually timed embryo transfer and hormonal alteration of the window of receptivity.
Pelvic radiation results in an irreversible radiation injury to the uterus, which manifests as a reduction in uterine volume. At this time, malignancy history and pelvic scarring, adhesions, and suboptimal healing make these women poor candidates for uterine transplantation.
It is estimated that 1 in 500 women of childbearing age is affected by AUFI. Models predict that 1% to 5% of reproductive-aged women in the United States are infertile as a result of congenital malformations; benign, obstetrical, or oncologic hysterectomy; or an acquired condition leading to a nonfunctional uterus (10).
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).
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).
Table 2.3.1 Sample Screening for Potential Transplant Recipients | ||||
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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.
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.
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.
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.
Table 2.3.2 Sample Living Donor Selection Criteria
Sample Living Donor Selection Criteria
40-65 years
Age <40 years can be considered if they have had successful pregnancies and clearly manifested unwillingness to have another pregnancy.
Negative for or has been vaccinated for HPV Seropositive for HIV or hepatitis B or C
Negative for gonorrhea, chlamydia, and syphilis
Previous HSV-2 can be considered if they have no current symptoms—preventive maintenance may be required per the investigator’s discretion
If previous HPV, donor must show a negative history since and test negative at screening
Normal uterus on sonogram and CT
At least one prior full-term live birth
Exclusion Criteria
BMI > 30
Active infection
Cancer in the last 5 years
Preexisting clinical or medical condition that would pose an increased risk per the investigator’s discretion
Unwilling or unable to comply with study requirements
Zika virus infection in the past 6 months
Resided in or traveled to an area with active Zika virus transmission within the past 6 months
Has had sex within the past 6 months with a man who is known to have either of the risk factors listed in exclusion criteria
Sample Deceased Donor Selection Criteria
No history of infertility
Absence of chronic medical conditions that would affect survival of the graft
BMI < 30
Pronounced dead by neurologic criteria
Matched for blood type to recipients
Cytomegalovirus (CMV)-compatible based on rapid donor screening
Structural suitability of the uterus
Consents from next of kin for both research and specifically for the use of the uterus for transplant
BMI, body mass index; HPV, human papillomavirus.
Adapted from Testa G, Koon EC, Johannesson L, 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(11):2901-2910; Flyckt RL, Farrell RM, Perni UC, et al. Deceased donor uterine transplantation: innovation and adaptation. Obstet Gynecol. 2016;128(4):837-842.
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.
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.
Table 2.3.3 Summary of Differences Between Living and Deceased Donors | |||||||||
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