Registry of the International Society of Uterus Transplantation: First Report : Transplantation

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Registry of the International Society of Uterus Transplantation: First Report

Brännström, Mats MD, PhD1; Tullius, Stefan G. MD2; Brucker, Sara MD3; Dahm-Kähler, Pernilla MD, PhD1; Flyckt, Rebecca MD4; Kisu, Iori MD5; Andraus, Wellington MD6; Wei, Li MD7; Carmona, Francisco MD8; Ayoubi, Jean-Marc MD9; Scollo, Paolo MD10; Weyers, Steven MD11; Fronek, Jiri MD12

Author Information
Transplantation 107(1):p 10-17, January 2023. | DOI: 10.1097/TP.0000000000004286

Abstract

INTRODUCTION

Uterus transplantation (UTx) is the only available infertility treatment for the estimated 1 million women worldwide who are unable to carry a pregnancy because of an absent (congenital or surgical) or nonfunctional uterus.1,2 Although the first human UTx attempt was performed in 2000,3 it took more than a decade (until 2014) to achieve the first live birth after UTx as a proof-of-concept procedure.4 This first successful UTx occurred after a live donor (LD) transplantation within the first clinical UTx trial.5 The first live birth after a deceased donor (DD) UTx was reported in 2017.6

In 2017, the International Society of Uterus Transplantation (ISUTx; https://tts.org/isutx-home) was founded, promoting scientific innovation and advances of the multidisciplinary efforts in UTx. In 2021, the society was incorporated as a section within The Transplantation Society. Mission statements within the ISUTx bylaws are to facilitate networking between UTx teams, promoting multidisciplinary and collaborative research on UTx, and, importantly, to establish and maintain an international registry of UTx collecting and analyzing data on characteristics and outcomes of UTx procedures, confirming best practices for the rapidly expanding field. The registry should therefore aim for a worldwide completeness of UTx procedures with a mandatory submission of data from all active UTx centers. The web-based ISUTx registry was designed with input from all members and deliberations during previous meetings of the ISUTx. A final version was released in 2020.

Here, we represent the first report of the ISUTx registry, covering activities from 2012 until January 1, 2021. The registry includes data on donor and recipient characteristics, donor surgery and transplantation surgery, immunosuppression, rejection episodes, live births, and graft hysterectomy.

MATERIALS AND METHODS

Participating Centers and General Inclusion Criteria

Thirteen centers entered data on UTx procedures that had been performed during the time period. Participating centers, with the year of their first case in parentheses, include Sahlgrenska University Hospital Gothenburg, Sweden (2012); The First Affiliated Hospital of Air Force Medical University/Xijing Hospital, Xijing, China (2015); Institute for Clinical and Experimental Medicine, Prague, Czech Republic (2016); Hospital das Clinicas/Sao Paulo University, Sao Paulo, Brazil (2016); Tuebingen University Hospital, Tuebingen, Germany (2016); University Children Hospital Tirsova, Belgrade, Serbia (2017); Zhujiang Hospital, Southern Medical University, Guangzhou, China (2017); Hopital Foch, Paris, France (2018); Universitair Ziekenhuis Gent, Gent, Belgium (2018); Bellevue MC/St. Joseph University Beirut, Lebanon (2018), Star Medica Hospital, Chihuahua, Mexico (2019); Hospital Clinic de Barcelona, Barcelona, Spain (2020); and Cannizzaro Hospital, Catania, Italy (2020).

The criteria for inclusion of donors and recipients vary slightly between centers. Nevertheless, there has been a general consensus on critical inclusion criteria for donors and recipients.7,8 As for recipient criteria, all patients had an absolute uterine factor infertility with a congenital/surgical absent uterus or by nonfunctionality of a present uterus, typically secondary to malformation, intrauterine adhesions or leiomyoma. Recipients have been of fertile age (generally <39 y old), a body mass index (BMI) of <28 and absent overt systemic/psychiatric illness. LD had at least 1 normal pregnancy, a BMI of <28, no serious systemic/psychiatric illness, and completed childbearing. The upper age of a suitable LD was approximately 50 y of age, but can be extended to 60 y if imaging indicates good calibers of uterine arteries with no signs of atherosclerosis.9 The workup of uterus function/anatomy and its vasculature in a DD was less extensive; in general, it was recommended to only include premenopausal DDs.

ISUTx Registry

The ISUTx registry is web-based and registers data prospectively, with data entries including UTx procedures and any relevant data until 3 mo after transplant hysterectomies, occurring either after live birth(s), failure to accomplish live birth despite multiple pregnancy attempts, or after graft failure. Transplant hysterectomies are in general performed within a time frame of 6 y after transplantation. The registry has separate data fields for donor, recipient, surgeries (donor hysterectomy and transplantation), immunosuppression (IS), rejection, live birth(s) including assisted reproduction, pregnancies and transplant hysterectomies. A detailed list of data fields and multiple-choice answers is presented in the Supplemental Information (SDC, https://links.lww.com/TP/C511).

All recipient surgeries were by laparotomy. The different modes of surgery for donor hysterectomy in LD UTx were by laparotomy (LD-LT), robotic-assisted laparoscopy (LD-R), or by traditional laparoscopy (LD-L).

Postoperative complications within 30 d were graded based on the Clavien-Dindo (CD) classifications score system.10 Grade I classification includes any complication deviating from the expected postoperative course with only standard postoperative treatment needed. Grade II includes complications requiring nonstandard treatment including antibiotics, blood transfusion or total parenteral nutrition. Grade III includes complications requiring radiological, endoscopic, or surgical intervention with a distinction between IIIa, without general anesthesia, and IIIb, with general anesthesia. Single organ dysfunction is graded as IVa and multiorgan dysfunction as IVb.

Data Presentation

All descriptive data are presented as numeric values with mean and SD and as median with ranges for variables.

RESULTS

UTx Activity and Types of Procedures

Table 1 shows the number of transplants (n = 45), and types of procedures performed between 2012 and 2020. A majority of procedures have been from LD; open laparotomy (LD-LT) has been the most frequent surgical approach for donor hysterectomy. The first LD UTx with robotic-assisted laparoscopy (LD-R) in donor hysterectomy surgery was performed in 2015. One donor hysterectomy was performed by laparoscopy (LD-L). The peak of annual activities was in 2017 (n = 12); only 2 UTx procedures were reported in 2020.

TABLE 1. - Number of uterus transplantation procedures and types per year
Year LD-LT LD-R LD-L DD Total
2012 4 4
2013 5 5
2014 0
2015 1 1
2016 3 3 6
2017 5 3 1 3 12
2018 2 4 2 8
2019 3 3 1 7
2020 1 1 2
Sum 22 12 1 10 45
DD, deceased donor, LD-L, live donor laparoscopy, LD-LT, live donor laparotomy; LD-R, live donor robotic.

Donor Characteristics

Characteristics of the 45 donors (35 LDs and 10 DDs) are presented in Table 2. The DDs were approximately 10 y younger than the LDs. There was a wide variation in BMI among both donors and recipients, with maximum BMI of 35.9 for LDs and 32.0 for DDs. The number of previous births was higher among LDs compared with DDs, with the latter group also including 1 nulliparous woman (Table 2). Miscarriages and ectopic pregnancies had occurred only rarely among donors.

TABLE 2. - Characteristics of live donors (n = 35), deceased donors (n = 10) and recipients (n = 45)
Median (range) Mean (SD) Unknown (n)
LD age 50 (32–62) 49.7 (7.4) 0
DD age 38.5 (19–57) 37.8 (12.3) 0
Recipient age 29 (22–38) 29 (4.3) 0
LD BMI 24.9 (18.4–35.9) 25.4 (4.7) 0
DD BMI 23.4 (20.4–32.0) 24.5 (3.6) 2
Recipient BMI 21.6 (16.9–31.2) 22.2 (3.2) 0
LD previous births 3 (1–5) 2.7 (1.1) 0
DD previous births 1 (0–3) 1.6 (1.1) 2
LD previous miscarriage 0 (0–1) 0.15 (0.3) 1
LD previous ectopic 0 (0–1) 0.03 (0.2) 0
DD previous miscarriage 0 (0) 0 (0) 4
DD previous ectopic 0 (0) 0 (0) 7
BMI, body mass index; DD, deceased donor; LD, live donor.

The majority of LDs (23/35) were mothers of recipients, 4 LDs were sisters, 3 were family friends, 2 were aunts, 1 was a monozygotic (MZ) twin-sister, and 1 was a mother-in-law. One out of 35 LDs was an active smoker and 15 of 35 LDs were postmenopausal at the time of donor hysterectomy. Nine of the LDs had 1 or several comorbidities (hyperlipidemia [n = 2]; arterial hypertension [n = 2]; hyperlipidemia + hypertension + thyroid disease [n = 2]; diabetes + arterial hypertension [n = 1]; hyperlipidemia + history of nonuterine intra-abdominal surgery [n = 1]; nonuterine intra-abdominal surgery + uterine [excluding cesarean section] intra-abdominal surgery [n = 1]).

Three out of 10 DDs were active smokers. Smoking habits were unknown in 5 DDs; 2 DDs were nonsmokers. Seven DDs were premenopausal and 1 DD was postmenopausal, whereas the menopausal status was unknown in 2 DDs. Three DDs had 1 or more comorbidities (neurological disorder [n = 1]; previous nonuterine intra-abdominal surgery [n = 1]; neurological disorder + nonuterine intra-abdominal surgery [n = 1]).

Recipient Characteristics

Characteristics of the 45 recipients are presented in Table 2. Mean/median recipient age was 29 y (22–38 y) at the time of UTx. The BMI of recipients varied between 16.9 and 31.2, with median/mean around 22. The vast majority of recipients (44/45) had congenital uterine absence as part of the Mayer-Rokitansky-Küster-Hauser syndrome (MRKHs); 1 recipient had a history of a hysterectomy because of cervical cancer. Two recipients were active smokers, 36 of 45 recipients were nonsmokers, and 7 previous smokers. Comorbidities were reported in 5 of 45 recipients (neurological disorders [n = 2]; history of nonuterine intra-abdominal surgeries [n = 2]; asthma/chronic lung disease + hyperlipidemia [n = 1]).

Renal malformations were seen among 8 of 44 of patients with MRKHs, with 6 women having a single kidney, and 1 each with horseshoe kidney and with double kidney but 1 pelvic kidney. The MRKHs patients had a neovagina created through self-dilation (n = 22), Vecchietti surgery (n = 11), McIndoe surgery (n = 4), or by other methods (n = 1). Six women with MRKHs had not undergone any active vaginal dilation before UTx.

Serology and Viral Status

Data on cytomegalovirus (CMV), Epstein-Barr virus, and toxoplasmosis serologies of donors and recipients are provided in Table 3. The status of high-risk human papilloma virus (hrHPV) in cytology samples among donors and recipients is also presented in Table 3.

TABLE 3. - Serology and viral status of donors and recipients
CMV EBV Toxoplasmosis hrHPV
LD/DD LD/DD LD/DD LD/DD
Donor+/recipient+ 17/5 27/– 5/1 3/–
Donor+/recipient– 7/1 2/3 –/– 1/–
Donor–/recipient+ 5/2 1/1 –/– –/–
Donor–/recipient– 6/1 5/– 15/2 28/3
Donor–/recipient unknown –/– –/– 1/– –/–
Donor unknown/recipient+ –/1 –/4 –/– 1/3
Donor unknown/recipient– –/– –/– 2/1 2/2
Donor unknown/recipient unknown –/– –/2 12/6 –/2
CMV, cytomegalovirus; DD, deceased donor; EBV, Epstein-Barr virus; hrHPV, high-risk human papilloma virus; LD, live donor.

Surgeries

Durations, blood losses, ischemic times, and postoperative complications of donor hysterectomies and transplantations are shown in Table 4. The duration of donor hysterectomy by LD-LT and LD-R was comparable; a majority of LD-LT (14/22) and LD-R (9/12) hysterectomies had durations of >10 h. Six donor hysterectomies (3/22 LD-LT, 2/12 LD-R, and the single case of LD-L) lasted 4–6 h.

TABLE 4. - Surgical duration, blood loss, postoperative complications and ischemia times at uterus transplantation
LD-LT UTx LD-R UTx LD-L UTx DD UTx
Duration—LD surgery (h)
 >4–6 3 2 1
 >6–8 3
 >8–10 2 1
 >10–12 7 6
 >12–14 7 3
Blood loss—LD surgery (mL)
 0–100 7 4
 101–200 3
 201–300 2 1
 301–400 3 2 1
 401–500 1 1
 501–600 3 1
 601–700 1
 701–800 1
 801–900 1
 >1000 3
POC—LD
 CD 1 1
 CD 2 3
 CD 3a 1
 CD 3b 1 1
Duration—recipient surgery (h)
 >2–4 3 1 1
 >4–6 15 6 7
 >6–8 3 5 1
 >8–10 1 1
 >10–12 1
Blood loss—recipient surgery (mL)
 0–100 4
 101–200 5 6 3
 201–300 3 2
 301–400 1 1
 401–500 3 2
 501–600 1 2
 601–700 3
 701–800 4
 801–900 1
 901–1000 1
 >1000 2 1
Total ischemia (h:min)
 Median (range) 2:57 (1:51–6:23) 2:13 (1:18–4:22) 3:32 5:57 (2:26–9:09)
 Mean (SD) 3:18 (1:14) 2:33 (0:55) 3:32 (0) 6:02 (2:32)
Rewarming ischemia (h:min)
 Median (range) 1:21 (0:44–02:22) 0:57 (0:31–2:00) 2:19 1:30 (1:03–2:03)
 Mean (SD) 1:24 (0:30) 1:27 (0:50) 2.19 (0) 1:31 (0:26)
POC recipient
 CD 1
 CD 2 1 2
 CD 3a 1
 CD 3b 2 a 1 a 1 a 3 b
aTransplantectomy.
bTwo transplantectomies and 1 bleeding with intervention under anesthesia.
CD, Clavien-Dindo classification; DD, deceased donor; LD-L, live donor laparoscopy; LD-LT, live donor laparotomy; LD-R, live donor robotic laproscopy; POC, postoperative complications.

Blood loss during donor hysterectomies for all LD-R and LD-L procedures was <600 mL, and in LD-LT, 7 of 22 had a blood loss >600 mL. Overall, postoperative complications were listed for 7 of 35 LDs, including 3 of 35 LDs with complications exceeding CD grade 2.

Recipient surgeries by laparotomy (n = 45) were considerably shorter than LD donor hysterectomies; most recipient surgeries (33/45) had a duration of 2–6 h. More than half of the recipient surgeries had maximum blood loss of 500 mL. Postoperative complications of any CD grade were seen in 11 of 45 recipients and 8 of 11 exceeded CD grade 2; notably 6 of 8 of these had an early (within 30 d) transplant hysterectomy subsequent to graft failure (Table 4).

The total ischemic time was approximately 2-fold longer in DD procedures than in LD procedures (Table 4). The ischemic time during rewarming of the graft, from placement into the pelvis of the recipient until reperfusion, was around 1–1.5 h.

Several alternatives and combinations of vascular segments of the graft were utilized (Table 5). For the venous outflow, the deep uterine vein with an iliac segment was used alone or in combination with a second outflow option in 26 of 44, 18 of 24, 0 of 1, and 16 of 20 of pelvic sides with retrieval surgery of LD-LT UTx, LD-R UTx, LD-L UTx, and DD UTx, respectively. For the arterial reconstruction, the uterine artery together with internal iliac patch or segment was used in the vast majority.

TABLE 5. - Vascular segments of grafts for venous and arterial anastomoses
LD-LT LD-R LD-L DD
Venous outflow left
 DUV+Is 7 2 2
 DUV+Is and UtbUOV 4 6 5
 DUV+Is and UOV 3 1 1
 DUV 2 1
 DUV and UtbUOV 3 1
 DUV and UOV 1
 UtbUOV 2
 UOV 1 2 1
Venous outflow right
 DUV+Is 6 1 2
 DUV+Is and  UtbUOV 3 7 5
 DUV+Is and UOV 3 1 1
 DUV 3 1
 DUV and UtbUOV 4 1
 DUV and UOV 1
 UtbUOV 2
 UOV 1 2 1
Arterial inflow left
 UA+Is 18 9 1 9
 UA 4 3 1
 2×UA+Is
Arterial inflow right
 UA+Is 17 8 1 9
 UA 5 4 1
 2×UA+Is
DD, deceased donor; DUV, deep uterine vein without iliac segment; DUV+Is, deep uterine vein with iliac segment; LD-L, live donor laparascopy; LD-LT, live donor laparotomy; LD-R, live donor robotics; 2×UA+Is, 2 uterine arteries with internal iliac segment; UA, uterine artery without internal iliac segment; UA+ls, uterine artery with internal iliac segment; UOV, utero-ovarian vein; UtbUOV, uterine branch of utero-ovarian vein.

Immunosuppression and Rejections

Induction IS was used in the vast majority (44/45) of procedures, including thymo/antithymocyte-globulin + steroids (n = 29), basiliximab + steroids (n = 12), thymo/antithymocyte-globulin without steroids (n = 2), thymo/antithymocyte-globulin + basiliximab (n = 1). Outside of a perioperative steroid treatment, no maintenance IS was used for the UTx between MZ twins.

The principal maintenance IS during months 1–3 (n = 44) consisted of calcineurin inhibitor (CNI) + mycofenolate + steroids (n = 15), CNI + mycofenolate (n = 11), CNI + azathioprine (AZA; n = 10), CNI + AZA + steroids (n = 5), CNI monotherapy (n = 2); IS was not specified for 1 case. Tacrolimus was used in the majority (39/44) of recipients.

Maintenance IS at the time of first embryo transfer (ET) among the 32 of 45 that had initiated ET, consisted of CNI + AZA + steroids (n = 12), CNI + AZA (n = 11), CNI monotherapy (n = 8). Immunosuppression was not specified for 1 recipient and the MZ-twin recipient had no IS at the time of ET.

Twelve out of 33 allogeneic-UTx procedures that had completed the initial 10 post-UTx months of follow-up reported IS-related complications during months 1–10, including hematologic cytopenia (n = 4), elevated creatinine levels (>100 µmol/L for >1 mo; n = 4), arterial hypertension (n = 1), opportunistic infection (n = 1), and unspecified complications (n = 2).

Twenty-six out of 39 (67%) of recipients (excluding 5 with graft failures during the initial post-UTx months [see below] and MZ-twin case) had no rejection episode during months 1–5; 11 recipients had 1 acute rejection episode, 2 recipients had 2 rejection episodes, 4 had 3 rejection episodes; rejections were not clearly documented for 1 patient. Early (months 1–5) rejections (highest grade in each case) were classified as mild (n = 11), moderate (n = 5), severe (n = 1), and unspecified (n = 1). Treatment for rejections included a steroid bolus treatment (n = 12), CNI dose increase (n = 1), steroids + CNI dose increase (n = 2), steroids + AZA (n = 1), steroids + CNI dose increase + AZA (n = 1), steroids + CNI dose increase + thymo/antithymocyte-globulin + other (n = 1).

Twenty-six out of 33 (79%) recipients (excluding 9 cases of graft failures during the initial 7 mo, 2 cases from 2020 who had not yet had completed 10 mo, and the MZ-twin case) who had completed the first 10 post-UTx months had no rejection episode during months 6–10. Seven recipients had 1 or more rejection episodes. Four recipients had 1 rejection episode, 2 recipients had 2 rejection episodes, and 1 had 3 rejection episodes. The highest grade of rejection in each patient during this later post-UTx period were classified as mild (n = 3), moderate (n = 2), or severe (n = 2). Treatments included steroids (n = 3), steroids + CNI dose increase (n = 1), steroids + CNI dose increase + AZA (n = 1), steroids + thymo/antithymocyte-globulin + AZA (n = 1), and only thymo/antithymocyte-globulin (=1).

Sixteen out of 33 (48%) recipients, with completed follow-up for 10 mo, had no rejection at all. Eleven patients had 1 rejection episode during mo 1–5 with either 0 (n = 8), 1 (n = 1), or 2 (n = 2) rejection episodes during months 6–10. The 2 patients with 2 rejection episodes during months 1–5 had 0 and 3 rejection episodes during months 6–10, respectively. The 4 patients with 3 rejection episodes during months 1–5 had either 0 (n = 1), 1 (n = 1), or 2 (n = 2) rejection episodes during months 6–10.

Reproductive Outcomes

A total of 19 live births from 16 recipients (14 after LD UTx, 2 after DD UTx) were reported, with 3 women, all after LD UTx, giving birth to singletons twice. The principal IS protocols during pregnancies consisted of CNI + AZA + steroids (n = 12), CNI + steroids (n = 2), CNI monotherapy (n = 2), and the absence of maintenance IS in the MZ-twin transplant. Acute rejection episodes were seen during 3 pregnancies, with all these observed during the second trimester (gestational weeks 13–27).

All live births were after in vitro fertilization (IVF), with 11 of the IVF procedures resulting in live births with embryo cryopreservation performed before UTx and 8 with IVF performed after UTx. Eighteen live births were observed after single embryo transfer (ET), with 14 from blastocyst ET and 4 from ET of day 2 or 3 embryo. One singleton live birth resulted from the transfer of 3 d 2 embryos. The 14 live births after blastocyst transfers (n = 35) occurred at median and mean ET numbers (after UTx or after a first livebirth) of 1.5 (range 1–7) and 2.5 (SD 1.9) ETs, respectively. Pregnancies with live births after blastocyst transfer had a livebirth rate/ET of 40.0%, with 7 live births occurring after the initial ET. The 5 live births after transfer of day 2 or 3 embryo occurred at ET numbers 1, 1, 4, 5, 7. The live birth rate/ET of cleavage stage (day 2/3) embryos was 27.8%. The total live birth rate/ET was 35.8%.

The median (range) and mean (SD) gestational lengths (completed full weeks) of the 19 pregnancies with live births were 35 (31–38) and 35.3 (1.7), respectively. All deliveries were by cesarean section, either initiated per protocol (n = 13), or subsequent to preeclampsia (PE; n = 3), and in single cases subsequent to premature rupture of membranes (PROM), uterus-related infections, or other maternal complications.

Complications of pregnancy, excluding acute rejections, were observed in 9 pregnancies (PE (n = 2), gestational diabetes (n = 1), gestational hypertension (n = 1), PROM (n = 1), cholestasis (n = 1), subchorionic hematoma (n = 1), and other infection (n = 1)). Three complications (PE + PROM + cholestasis) were observed during 1 pregnancy. The median (range) and mean (SD) birthweights were 2620g (1775–3390) and 2646g (460), respectively. No major postnatal complications were recorded.

Transplant Hysterectomy

During this reporting period, 21 transplant hysterectomies have been recorded (12 after LD-LT UTx, 2 after LD-R UTx, 1 after LD-L UTx, and 6 after DD UTx); 9 of 21 transplant hysterectomies were after live births and 12 of 21 without childbirth after UTx. Transplant hysterectomies after child birth (s) occurred either per protocol (n = 4), because of side-effects of IS (n = 4), or because of rejection (n = 1). The causes of transplant hysterectomies before child birth (n = 12) included graft thrombosis, (2 LD-LT UTx by 3 d post-UTx and 15 d post-UTx; 1 LD-L UTx by 2 d post-UTx; 2 DD UTx by 2 d post-UTx and 7 d post-UTx), uterine hypoperfusion (2 LD-R UTx by 4 wk post-UTx and by 35 wk + 4 d post-UTx; 1 LD-LT UTx by 15 wk + 1 d post-UTx), intrauterine infection (1 LD-LT UTx by 15 wk post-UTx), irreversible endometrial damage (1 DD UTx by 30 wk +3 d post-UTx), repeated miscarriages/implantation failures (1 LD-LT UTx by 309 wk + 3 d post-UTx), and post-transplantation lymphoproliferative disease (1 DD UTx by 26 wk + 1 d post-UTx). The time of transplant hysterectomies before child birth was recorded at a median (range) of 9.5 (0.3–309.4) wk and mean (SD) of 36.7 (83.1) wk.

DISCUSSION

Uterus transplantation is the only treatment for women with an absent or nonfunctional uterus. Although increasing numbers of clinical procedures have been performed during the last decade, this new type of transplantation should still be regarded as an experimental clinical procedure. Thus, the vast majority of UTx activities have been registered as clinical trials and are ongoing from transplantation until study completion, typically by a minimum of 5–10 y. This time-span takes into account that the time after UTx and until completion of a case generally involves an initial stabilization phase of 6–10 mo before ET, several ET attempts before live birth(s), 1 or more gestation(s) and post-partum period(s), as well as hysterectomy to complete the childbearing capacity and in situ function of the graft. To our knowledge, there is only 1 clinical UTx trial in which all recipients (n = 9) have undergone hysterectomies.11 Interim data of a number of trials have been presented, including data on early outcomes, such as information on surgical success and complications. Registry data will be of critical importance to monitor activity and quality of UTx procedures while providing a repository for research.

Our current registry data include the majority of hitherto performed global UTx procedures. A limitation of the registry is the missing data from centers that have not participated. We are aware of >25 additional UTx procedures from teams based in the United States, India, Turkey and Saudi Arabia that have so far not registered their cases in the data set presented here12. The ISUTx is actively working toward a goal of including all centers. Nevertheless, data of this registry represent the largest collection of detailed data on UTx.

Current registry data show a paucity of activities subsequent to the initial trial5 of 9 cases in Sweden (2012–2013); transplant numbers then started to increase steadily after 2015. The limited clinical activity in 2020 is most likely secondary to the COVID pandemic. It is evident that there is a shift in LD UTx toward use of minimal invasive surgery (MIS) for donor hysterectomies with increasing numbers of robotic-assisted laparoscopic procedures. It is likely that this trend toward MIS in LD UTx will continue. There is also the potential that recipient surgeries will be performed robotically in the future. The first registered DD case is from 2016 and the first live birth after DD UTx occurred in 2017.6

At this point, the number of LD cases outnumbers DD cases by >3-fold. The reason for this is most likely the early reported success for the LD UTx procedure in 20144 combined with a limited availability of suitable DDs.13 However, it should be kept in mind that a LD procedure involves a long and complex surgery of a healthy donor, who will not directly benefit from the procedure. The present database shows that a majority of the LD hysterectomies have durations >8 h with 3 of 35 CD grade 3 postoperative complications reported.

The mean/median age of LDs was approximately 10 y higher than that of DDs. One reason for the considerably higher age of LDs is most likely linked to the meticulous diagnostic screening of LDs allowing centers to extend the age limits. Thus, combining standard gynecological examinations, including hysteroscopy and laboratory tests, together with imaging modalities including angiographies provide a detailed analysis of recipient vasculature in LD UTx.9 An additional consideration for the older age of LDs may be related to utilization of the recipient’s mother, typically at an age >50 y. Notably, the age of the LD had been extended to a 61-y-old postmenopausal donor in the first reported live birth after UTx.4 Moreover, LDs are expected to have completed their own family planning at the time of donation. The youngest LD of the present study was 32 y compared with 19 y among DDs.

Our registry data show that the majority of LDs (23/35) were mothers of the recipients. This fact is not surprisingly, since a mother would be a natural first choice as a donor. Because of this choice of LDs, it is not a surprise that 13 of 35 of the LDs were postmenopausal at the time of UTx. Based on the experience of oocyte donation programs it can be assumed that a postmenopausal uterus has a good capacity to carry a pregnancy successfully. Notably, live births after UTx have been recorded with donors of 61 and 62 y at the time of donation.4,14 With the addition of more UTx cases moving forward, the registry is expected to provide more details on the effects of donor age. Around 20%–30% of both LDs and DDs had 1 or more comorbidity and it also remains for future studies to investigate the impact on outcomes.

The overwhelming majority (44/45) of recipients had MRKHs. Patients with this syndrome proved early on to be suitable patients for UTx.4,15 A surgical advantage is that MRKHs patients have not been exposed to any major intrabdominal surgery. Moreover, recipients were between 22 and 38 y, and thus all were well within the age-span of reasonable fertility.

The serology test taken at preoperative screening of donors and recipients showed that 23/35 (63%) recipients of grafts from LDs and 7 of 10 (70%) recipients of grafts from DDs were seropositive for CMV. The corresponding numbers for donors were 22 of 35 (63%) for LDs and 6 of 9 (66%) for CMV-tested DDs. Those data are in line with the reported prevalence of around 60% CMV seropositive adults in developed countries.16

Registry data show that the vast majority of LDs and recipients were free from hrHPV in cytology samples taken before transplantation. However, the hrHPV status was unknown for many DDs and there were some procedures with hrHPV positivity of donors and also some with positivity among recipients. It is well known that IS can facilitate development of HPV-induced cervical dysplasia with the risk of progression to cervical/vaginal cancer. Thus, recipients with hrHPV positivity or those undergoing UTx from a hrHPV positive donor, should be monitored frequently for cervical/vaginal dysplasia. Notably, there was 1 cervical cancer patient in the study cohort and she should also undergo thorough follow-up even after transplant hysterectomy to ensure oncological safety of the procedure.

Durations of LD surgery were substantial with 14 of 22 of LD-LT and 9 of 12 of LD-R lasting >10 h, thus increasing the risk for postoperative complications including infections and thromboembolism, although the overall number of severe (CD 3) postoperative complications has been low. Some centers have been able to reduce the surgical time of donor hysterectomy to 4–6 h.

The total ischemic time was around 2-fold longer in DD UTx compared with LD UTx procedures, but with similar rewarming ischemia times of around 1–1.5 h. A rewarming ischemia time of >1 h is of comparable length to solid organ transplantation. Studies in nonhuman primates have shown that a uterus tolerates warm ischemic times of at least 4 h.17 The uterus has a substantial regenerative capacity, demonstrated through repetitive menstruations, and seems to be an organ of potential resistance to ischemia-reperfusion injury. Notably‚ during implantation of the graft, as many as 4–6 anastomoses have to be performed in a narrow pelvis to reconstruct blood supply.

The registry also contains information on surgical details including the utilization of graft vessels or combinations of vessels used for anastomosis, since many alternatives for the reconstruction of venous outflow have been reported. The deep uterine veins are usually the largest uterine veins but dissection of these vessels to fully mobilize them can represent a surgical challenge with their close proximity to the ureters, thin walls, in addition to multiple branches. In 1 study of robotic-assisted donor hysterectomy, it was shown that about 1 of 4 of the surgical time in the LD surgery was spent on the dissection of deep uterine veins.18 Our registry data show that only 6 of 45 UTx procedures did not use deep uterine veins, but instead uterine branches of utero-ovarian veins or entire utero-ovarian veins. The latter approach will typically reduce the surgical time, as shown in 1 study in which utero-ovarian veins were used as sole venous outflows during a total robotic donor hysterectomy which lasted 6 h.19

Registry data on IS show that a majority of cases used an induction treatment with thymoglobulin or antithymocyte globulin plus steroids and that tacrolimus was the preferred CNI for maintenance IS. Acute rejections were observed in 33% of recipients early after transplantation (months 1–5) and in 21% of recipients at later time points (months 6–10). There was a mix of severity of rejections with a majority of those being mild during the early period and a majority being moderate/severe during the later observation period. Rejections were also seen during 3 of 19 pregnancies leading to live birth.

The birth of a healthy infant is the primary measure of success in UTx. Pregnancy after UTx is established by combined IVF procedure, typically performed before UTx, and ET beginning around 10 mo after UTx. Our registry contains data on 19 live births by 16 recipients. Three women gave birth twice during the registration period. The efficacy of IVF is usually documented as live birth/ET. Our registry data show an overall live birth rate/ET of 35.8%, with a somewhat greater rate for birth after blastocyst ET (40.0%) compared with ET of cleavage stage embryo (27.8%). Those rates are in keeping with improved success with blastocyst stage ET in IVF, and are within the ranges of IVF in a nontransplant population undergoing single ETs.20 Our data suggest near to normal pregnancy rates after UTx despite IS, altered uterine vascular supply and, at least in part, advanced uterus age. However, it should be emphasized that the live birth rate/ET data in our registry report does not include the patients who have not yet achieved a live birth after multiple implantation failures/miscarriages. In 1 recipient, a transplant hysterectomy was performed almost 6 y after UTx because of multiple implantation failures/miscarriages.

The median/mean gestational length of pregnancies leading to live births was 35 wk and a majority (68%) of the cesarean sections were performed per protocol. Deliveries before gestational week 37 are by definition preterm, with an associated increased risk for neonatal complications. The per protocol preterm planning of delivery was during this initial stage of UTx most likely a compromise between establishing satisfactory maturation of the child while aiming to prevent UTx-related obstetric complications during the last weeks of pregnancy. There was a much higher than expected rate of pregnancy complications (47%), which also motivated delivery.

Twelve out of 45 grafts (27%) had to be removed before childbirth had been accomplished, with the majority linked to surgical complications. Moreover, 1 uterus was removed after almost 6 y subsequent to multiple implantation failures/misacrraiges. In a “normal” IVF population, approximately 25% of treated women will never achieve a live birth, despite undergoing as many as up to 6 IVF cycles with a much larger number of ETs.21 It is likely that a similar distribution of patients with unsuccessful infertility treatment will also be present in a UTx population.

In conclusion, this initial registry report of global UTx activities provides the first comprehensive dataset on characteristics and outcomes of this novel transplantation/infertility treatment. Moving forward, the uterus transplant community will continue to work to improve surgical and reproductive outcomes. This report emphasizes the importance of global collaboration and learning, transparency, and prioritization of complete data capture within the registry. Future reports are expected to provide valuable information that can be used to further advance the field.

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