Uterus transplantation is the only known potential treatment for absolute uterine factor infertility. It offers a unique setting for the investigation of immunologic adaptations of pregnancy in the context of the pharmacologic-induced tolerance of solid organ transplants, thus providing valuable insights into the early maternal-fetal interface. Until recently, all live births resulting from uterus transplantation involved living donors, with only 1 prior birth from a deceased donor. The Cleveland Clinic clinical trial of uterus transplantation opened in 2015. In 2017, a 35 year old woman with congenital absence of the uterus was matched to a 24 year old parous deceased brain-dead donor. Transplantation of the uterus was performed with vaginal anastomosis and vascular anastomoses bilaterally from internal iliac vessels of the donor to the external iliac vessels of the recipient. Induction and maintenance immunosuppression were achieved and subsequently modified in anticipation of pregnancy 6 months after transplant. Prior to planned embryo transfer, ectocervical biopsy revealed ulceration and a significant diffuse, plasma cell–rich mixed inflammatory cell infiltrate, with histology interpreted as grade 3 rejection suspicious for an antibody-mediated component. Aggressive immunosuppressive regimen targeting both cellular and humoral rejection was initiated. After 3 months of treatment, there was no histologic evidence of rejection, and after 3 months from complete clearance of rejection, an uneventful embryo transfer was performed and a pregnancy was established. At 21 weeks, central placenta previa with accreta was diagnosed. A healthy neonate was delivered by cesarean hysterectomy at 34 weeks’ gestation. In summary, this paper highlights the first live birth in North America resulting from a deceased donor uterus transplant. This achievement underscores the capacity of the transplanted uterus to recover from a severe, prolonged rejection and yet produce a viable neonate. This is the first delivery from our ongoing clinical trial in uterus transplantation, including the first reported incidence of severe mixed cellular/humoral rejection as well as the first reported placenta accreta.
Click Supplemental Materials and Video under article title in Contents at ajog.org
Uterus transplantation is a burgeoning field that integrates multiple disciplines including transplant and reproductive medicine and surgery. Although performed under experimental protocols, uterus transplantation is no longer a theoretical construct. Landmark first live births from uterus transplantation have been reported both in Sweden and Dallas, TX. , While these births both resulted from a living donor (LD) model, the Cleveland Clinic uses a deceased donor (DD) approach. A successful live birth from a DD was reported in 2018 in Brazil, providing for the first time proof of concept that DD uterus transplantation can result in a healthy infant. More data are required to determine how clinical outcomes will compare in DD vs LD.
Several other significant areas of uterus transplantation remain unknown, including the incidence, significance, and optimal management of graft rejection. Prior reports have described mild, steroid-responsive episodes of T-cell–mediated (cellular) rejection in uterus transplant recipients prior to and during pregnancy. , Humoral rejection, conversely, has never before been reported in the uterus and could present a serious threat to graft viability.
Uterus transplantation offers a unique window into maternal-fetal-placental relationships in normal pregnancy and pregnancy-related disorders. The mechanisms underlying abnormal/invasive placentation are poorly understood, and placenta accreta has not been reported in uterus transplantation. Study of abnormal placentation in uterus transplants may shed light on normal and abnormal trophoblast implantation/invasion and deepen our understanding of these critical events in reproductive biology.
Case presentation
The Cleveland Clinic Uterine Transplantation for the Treatment of Uterine Factor Infertility was the first clinical trial in the United States ( ClinicalTrials.gov identifier NCT02573415 ), as detailed elsewhere. This transplant was completed on Dec. 7, 2017; this was the second in our series of 10 planned transplants. A 35 year old white nonsmoking female was matched with a 24 year old parous deceased brain-dead donor according to Organ Procurement and Transplantation Network/United Network for Organ Sharing guidelines. See Table 1 for additional details regarding donor and recipient.
| Donor-recipient considerations | ||
|---|---|---|
| Deceased donor | Recipient | |
| Age, y | 24 | 35 |
| BMI, kg/m 2 | 31 | 21 |
| Blood type | O+ | O+ |
| CMV IgG serostatus | + | + |
| Fertility history | One full-term uncomplicated spontaneous vaginal delivery and 1 miscarriage managed with dilation and curettage | One healthy biological child through the use of IVF and a gestational carrier |
| CT angiography results | Widely patent vasculature of the abdomen and pelvis without atherosclerosis | Widely patent vasculature of the abdomen and pelvis without atherosclerosis |
| Ultrasound and/or hysteroscopy results | No evidence of fibroids, polyps, or intrauterine adhesions | Mullerian agenesis with a left-sided, fluid-containing uterine rudiment |
| Recipient-only considerations | ||
| Etiology of uterine factor infertility | Mayer-Rokitansky-Kuster-Hauser syndrome | |
| Presence of renal/urinary tract anomalies or cardiopulmonary disease | No | |
| Antimullerian hormone, ng/mL | 2.23 | |
| Vaginal length, cm, prior to surgery a | 6 | |
| IVF stimulation protocol | GnRH antagonist (average daily gonadotropin dose = 270 IU); ICSI | |
| Number of IVF cycles | 2 | |
| Frozen high-quality blastocysts, n | 9 | |
| Operative details of transplant procedure | ||
| Total cold ischemia time | 1 hour 50 minutes | |
| Total warm ischemia time | 55 minutes | |
| Total operating time (recipient surgery) | 8 hours 50 minutes | |
| Estimated blood loss, L (recipient surgery) | 1.5 | |
| Transfused units of packed red cells (recipient surgery) | 1 | |
Both the procurement and the graft implantation procedures were performed according to our previously published protocol ( Supplemental Video 1 ). , Briefly, the graft was procured with bilateral arterial and venous pedicles, each involving the origin of the internal iliac vessels and was flushed through the arterial and venous ends with University of Wisconsin solution on the back table and assessed for vascular leakage.
The recipient surgery was initiated via midline laparotomy only after the graft was deemed satisfactory for implantation. The external iliac vessels were exposed and the recipient vaginal apex was identified while mobilizing the bladder anteriorly and the rectum posteriorly. The vaginal apex was thickened and fibrotic with a left uterine rudiment visible. This rudiment was cleaved and used for later fixation of the uterus. The vagina was entered transversely. The uterus was brought into anatomic position within the pelvis after placing stay sutures to tag the recipient vaginal mucosa and prevent retraction of this tissue. The right side of the vascular anastomosis was completed first using 5-0 nonabsorbable polypropylene suture, with venous and arterial end-to-side anastomoses; in both cases, a segment of the internal iliac of the donor was anastomosed to the external iliac of the recipient.
The uterus was allowed to reperfuse prior to initiation of the contralateral side to minimize ischemia time. The vaginal anastomosis was then completed mucosa to mucosa with running 2-0 absorbable polyglactin suture anteriorly and posteriorly. A polypropylene suture was placed above the donor external cervical os in the 12 o’clock position to facilitate later manipulation and embryo transfer. The left anastomosis was then performed in an identical fashion ( Figure 1 B).
Additional pelvic support was provided with 0 polypropylene sutures to the uterosacral ligaments, uterine rudiment, and round ligament attachments. Vascular flow was confirmed with color and spectral Doppler ultrasound imaging intraoperatively and immediately postoperatively ( Figure 1 , D–F). Additional vascular anastomoses (eg, ovarian veins) were not thought to be necessary, given the robust outflow observed with Doppler imaging.
The recipient had an unremarkable immediate postoperative course with discharge from the hospital on day 4. Details regarding her immunosuppression can be found in Table 2 . Her first spontaneous menses occurred 34 days after the transplant and cyclic menstruations were documented. Monthly cervical biopsies revealed normal histology without evidence of graft rejection for 5 months, at which time preparations for embryo transfer were initiated.
| Months after transplant | Cellular rejection (cervical biopsy) | Donor-specific antibody testing | Humoral tissue injury | Endometrial biopsy results | Therapy |
|---|---|---|---|---|---|
| 1–4 | Negative | Negative | Negative | — | ATG (3 doses), a steroids, FK506, MMF |
| 5 | Severe | Positive (<2000 MFI) | Negative | Necrosis | ATG (5 doses), plasmapheresis, IVIG |
| 6 | Severe | Negative | Negative | No glands | Steroids, FK506, MMF |
| 7 | Severe | Negative | Neutrophilic capillaritis | Proliferative | Steroids, FK506, MMF |
| 8 | Moderate, borderline | Negative | Negative | Proliferative | Steroids, FK506, MMF |
| 9, 10 | Negative | Negative | Negative | — | Steroids, FK506, MMF |
| 11 (embryo transfer) | — | Negative | Negative | — | Steroids, FK506, AZA b |
| 12 | Negative | Negative | Negative | — | Steroids, FK506, AZA |
| 13 | Moderate | Negative | Negative | — | Pulse steroids |
| 14-17 | Negative | n/a | Negative | — | Steroids, FK506, AZA |
| 18 (cesarean hysterectomy) | Negative | n/a | Arterial endothelialitis | Placenta accreta | Immunosuppression discontinued |
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