Liza Johannesson

Livebirth after uterus transplantation

BACKGROUND Uterus transplantation is the first available treatment for absolute uterine infertility, which is caused by absence of the uterus or the presence of a non-functional uterus. Eleven human uterus transplantation attempts have been done worldwide but no livebirth has yet been reported. METHODS In 2013, a 35-year-old woman with congenital absence of the uterus (Rokitansky syndrome) underwent transplantation of the uterus in Sahlgrenska University Hospital, Gothenburg, Sweden. The uterus was donated from a living, 61-year-old, two-parous woman. In-vitro fertilisation treatment of the recipient and her partner had been done before transplantation, from which 11 embryos were cryopreserved. FINDINGS The recipient and the donor had essentially uneventful postoperative recoveries. The recipients first menstruation occurred 43 days after transplantation and she continued to menstruate at regular intervals of between 26 and 36 days (median 32 days). 1 year after transplantation, the recipient underwent her first single embryo transfer, which resulted in pregnancy. She was then given triple immunosuppression (tacrolimus, azathioprine, and corticosteroids), which was continued throughout pregnancy. She had three episodes of mild rejection, one of which occurred during pregnancy. These episodes were all reversed by corticosteroid treatment. Fetal growth parameters and blood flows of the uterine arteries and umbilical cord were normal throughout pregnancy. The patient was admitted with pre-eclampsia at 31 full weeks and 5 days, and 16 h later a caesarean section was done because of abnormal cardiotocography. A male baby with a normal birthweight for gestational age (1775 g) and with APGAR scores 9, 9, 10 was born. INTERPRETATION We describe the first livebirth after uterus transplantation. This report is a proof-of-concept for uterus transplantation as a treatment for uterine factor infertility. Furthermore, the results show the feasibility of live uterus donation, even from a postmenopausal donor. FUNDING Jane and Dan Olsson Foundation for Science.

Uterus transplantation in the baboon: methodology and long-term function after auto-transplantation

BACKGROUND Techniques for uterus transplantation (UTx) have been developed in rodent/domestic animals towards future clinical introduction of UTx to treat uterine factor infertility. The aim of this study was to extend the UTx research into a non-human primate species by developing surgical techniques for uterus retrieval and transplantation in the baboon. METHODS Female baboons (n = 15) underwent surgery, with the initial five animals used for studies of pelvic vascular anatomy. Retrieval surgery included isolation of the ovarian veins and the uterine arteries together with the anterior branches of the internal iliacs. The utero-tubal-ovarian specimen was removed, flushed and kept ex vivo for 2 h when the two arterial ends and two venous ends were anastomosed side-to-side to construct one arterial and one venous end. These were, at auto-transplantation, anastomosed end-to-side to the external iliacs and the animals (n = 10) were evaluated concerning cyclicity and later by laparoscopy/laparotomy. RESULTS The total duration of organ retrieval, backtable preparation and transplantation was around 6 h with an overall ischaemic time of the specimen of about 3 h. One animal died due to cardiomyopathy. Five out of the nine surviving animals resumed cyclicity, as a sign of re-established ovarian function. Only two out of these five animals exhibited resumed menstruation, indicating re-established ovarian and uterine function. Laparoscopy confirmed normal-sized uteri in these two animals. CONCLUSIONS This study demonstrates the feasibility of UTx by vascular anastomosis in a non-human primate species. The low success rate demonstrates the complexity involved in UTx surgery and the need for further methodological developments.

Uterus transplantation trial: 1-year outcome.

OBJECTIVE To report the 12-month outcome of seven patients with viable uteri after uterus transplantation (UTx). DESIGN Prospective observational study. SETTING University hospital. PATIENT(S) Seven patients with absolute uterine infertility and viable uteri for 12 months after live-donor UTx. INTERVENTION(S) Predetermined immunosuppression was with tacrolimus and mychophenolate mofetil (MMF) during 6 months, whereupon MMF should be withdrawn. Frequent ultrasound examinations were performed to assess uterine appearance and uterine artery blood flow. Cervical biopsies (for histological detection of rejection) were obtained at preset time points, with temporary adjustments of immunosuppression if there were signs of rejection. Menstruations were systematically recorded. MAIN OUTCOME MEASURE(S) Menstruation, uterine artery blood flow, histology of cervical biopsies, and blood levels of tacrolimus. RESULT(S) All patients showed regular menses after 1-2 months. Uterine artery blood flow was unchanged, with a median pulsatility index of 1.9 (range, 0.5-5.4). Blood levels of tacrolimus were approximately 10, 9, and 8 (μg/L) during months 2, 9, and 12, respectively. Four recipients showed mild inflammation in biopsies after MMF withdrawal and were treated with corticosteroids and azathioprine during the remainder of the 12 months. Subclinical rejection episodes were detected on ectocervical biopsies in five recipients. Histology showed apoptotic bodies and occasional spongiosis in the squamous epithelium. Moderate infiltration of lymphocytes and neutrophils was seen in the epithelial/stromal interface. All rejection episodes were successfully treated for 2 weeks with corticosteroids or dose increments of tacrolimus. CONCLUSION(S) We demonstrate long-term uterine viability after UTx, with continued menstruation and unaltered uterine artery blood flow. Subclinical rejection episodes were effectively reversed by temporary increase of immunosuppression. CLINICAL TRIAL REGISTRATION NUMBER NCT01844362.

Uterus transplantation in a non-human primate: long-term follow-up after autologous transplantation

BACKGROUND Uterus transplantation (UTx) may provide the first available treatment for women affected by uterine infertility. The present study aimed to further develop a surgical technique for autologous UTx in a non-human primate species and to assess long-term function. METHODS Female baboons (n= 16) underwent autologous transplantation of the uterus with the Fallopian tubes and ovaries, performed with a previously published surgical technique (n= 6, Group 1) or using a modified technique (n= 10; Group 2). The uterine arteries were dissected to the proximal end of the anterior branch (Group 1) or the entire (Group 2) internal iliac artery, and the ovarian veins were dissected to the crossing over the ureter (Group 1) or further cranially to include greater lengths and patches of the cava/renal vein (Group 2). Back-table preparation created common venous and arterial ends with arterial anastomosis either end-to-side to the left external iliac artery (Group 1) or end-to-end to the left internal iliac artery (Group 2). RESULTS Overall short-time survival of the animals was 88% (66% in Group 1 and 100% in Group 2). Of all the operated animals, 75% (66% in Group 1 and 80% in Group 2) resumed ovarian cyclicity. Regular menstruation after UTx was demonstrated only in Group 2 (60%). Menstruating animals (n= 6) were each exposed to timed mating for ≥5 menstrual cycles, but pregnancy did not occur. Adhesions and tubal blockage were seen in post-mortem analysis. CONCLUSIONS The modified UTx model of Group 2 is a safe procedure and shows resumed long-term uterine function in a majority of the animals, although pregnancy could not be demonstrated.

Preclinical report on allogeneic uterus transplantation in non-human primates

STUDY QUESTION Is it possible to perform allogeneic uterus transplantation (UTx) with a donation from a live donor in a non-human primate species and what immunosuppression is needed to prevent rejection? SUMMARY ANSWER Allogeneic UTx in the baboon is a donor- and recipient-safe surgical procedure; immunosuppression with induction therapy and a triple protocol should be used. WHAT IS KNOWN ALREADY UTx may become a treatment for absolute uterine factor infertility. Autologous UTx models have been developed in non-human primates with reports on long-term survival of the uterine grafts. STUDY DESIGN, SIZEAND DURATION: This experimental study included 18 female baboons as uterus donors and 18 female baboons as uterus recipients. The follow-up time was 5-8 weeks. PARTICIPANTS/MATERIALS, SETTING AND METHODS Uterus retrieval was performed with extended hysterectomy including bilateral uterine and internal iliac arteries and ovarian veins. After UTx, with vascular anastomoses unilateral to the internal iliac artery and the external iliac vein, the uterus recipients received one of the following: no immunosuppression (n = 4); monotherapy (oral slow release tacrolimus) (n = 4) or induction therapy (antithymocyte globulin) followed by triple therapy (tacrolimus, mycophenolate, corticosteroids; n = 10). Surgical parameters, survival, immunosuppression and rejection patterns were evaluated. MAIN RESULTS AND THE ROLE OF CHANCE The durations of uterus retrieval and recipient surgery were around 3 and 3.5 h, respectively. The total ischemic time was around 3 h. All the recipients and the donors survived the surgery. All the recipients presented rejection to some extent within the first weeks following UTx. In one recipient, the uterus was of normal appearance at the end of the study period. In spite of occasional high (>60 ng/ml) blood levels of tacrolimus, there was no evidence of nephrotoxicity. LIMITATIONS AND REASONS FOR CAUTION This initial non-human primate allogeneic UTx study indicates that further research is needed to optimize immunosuppression protocols in order to avoid uterine rejection. WIDER IMPLICATIONS OF THE FINDINGS The findings suggest that allogeneic UTx in primate species is feasible but continued work on this issue is needed. STUDY FUNDING/COMPETING INTEREST(S) The study was funded by the Swedish Research Council, ALF University of Gothenburg, Hjalmar Svensson Foundation and by Jane and Dan Olsson Research Foundation. The authors do not have any competing interest.

Vascular pedicle lengths after hysterectomy: toward future human uterus transplantation.

OBJECTIVE: To estimate uterine vessel lengths and diameters recovered at radical hysterectomy to assess prospects for direct vascular anastomosis bilaterally to the external iliacs in uterus transplantation, and thereby the feasibility of live uterus donation as a future treatment of absolute uterine factor infertility. METHODS: Patients (n=19; study group) undergoing radical hysterectomy for gynecologic malignancy participated. Preoperative magnetic resonance imaging (MRI) was performed in four patients to evaluate the usefulness in estimation of vessel lengths. At hysterectomy, the uterine arteries and veins were dissected separately from the anterior divisions of the internal iliacs to their attachments to the uterine cervix. The lengths of the free vascular pedicles were measured bilaterally and the distal vessel diameters were recorded. The inter-external iliac artery distance, corresponding to distance between proposed bilateral anastomosis sites, was measured. Perioperative and postoperative outcomes were compared with 76 patients (control group) undergoing standard radical hysterectomy without particular uterine vessel dissection. RESULTS: The MRI showed uterine artery lengths of 55–100 mm. The duration of surgery was slightly longer in the study group (median 297 minutes) compared with the control group (262 minutes), but with no differences in perioperative and postoperative morbidity. The lengths (median) of the free portions of the left uterine artery and vein were 68 mm and 55 mm, and the right uterine artery and vein were 65 mm and 50 mm, respectively. The inter-external iliac artery distance (median) was 90 mm. CONCLUSION: This study demonstrates that long vascular pedicles can be obtained after selective dissections of the uterine arteries and veins without compromising postoperative recovery in a live uterine donor situation. LEVEL OF EVIDENCE: II

Allogeneic uterus transplantation in baboons: surgical technique and challenges to long-term graft survival.

The authos declare no funding or conflicts of interest. Address correspondence to: James Fernandez, M.D., Ph.D., Department of Allergy and Clinical Immunology, Cleveland Clinic Foundation, Cleveland OH, 9500 Euclid Ave, A90, Cleveland, OH, 44195. E-mail: fernandezj2@ccf.org Received 21 May 2014. Accepted 22 May 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9805-e50 DOI: 10.1097/TP.0000000000000320

Uterine transplantation research: laboratory protocols for clinical application

The aim of this review is to summarize the state-of the-art methods that are used in clinical organ transplantation today, as well as the major findings of recent experimental uterus transplantation (UTx) research regarding organ donation/retrieval, ischemic preservation, surgical techniques for anastomosis, immunosuppression and pregnancy. Absolute uterine factor infertility lacks treatment despite the major developments in infertility treatment and assisted reproduction. Concerning uterine factor infertile patients, genetic motherhood is only possible through gestational surrogacy. The latter can pose medical, ethical and legal concerns such as lack of control of life habits during surrogate pregnancy, economic motives for women to become surrogate mothers, medical/psychological pregnancy-related risks of the surrogate mother and uncertainties regarding the mother definition. Thus, surrogacy is non-approved in large parts of the world. Recent advances in the field of solid organ transplantation and experimental UTx provide a favourable and safe background in a scenario in which a human clinical UTx trial can take place. Protocols based on animal research over the last decade are described with a view to providing a scientifically guided approach to human UTx as an experimental procedure in the future.

Uterus transplantation: current progress and future prospects

Even if reproductive medicine has been remarkably successful during the past few decades, with the introduction of in vitro fertilization in the late 1970s and intracytoplasmic sperm injection in the early 1990s, it has been repeatedly mocked by infertility due to an absolute uterine factor. No treatment has been available for the women suffering from an absent or dysfunctional uterus, in terms of carrying a pregnancy. Approximately one in 500 women suffer from absolute uterine infertility, and the option so far to become a mother has been to either adopt or utilize gestational surrogacy. As of today, a total of eleven cases of human uterus transplantations have been reported worldwide, conducted in three different countries. The results of these initial experimental cases far exceed what might be expected of a novel surgical method. Many more uterus transplantations are to be expected in the near future, as other research teams’ preparations are being ready to be put into clinical practice. In this review, we summarize the current worldwide experience of uterus transplantation as a treatment of absolute uterine factor infertility and the future prospects of human uterus transplantation.

Centralized primary care of advanced ovarian cancer improves complete cytoreduction and survival - A population-based cohort study

OBJECTIVE To evaluate centralized primary care of advanced ovarian and fallopian tube cancers in a complete population cohort in relation to complete cytoreduction, time interval from surgery to chemotherapy and relative survival. METHODS A regional population-based cohort study of women diagnosed with primary ovarian and fallopian tube cancers and included in the Swedish Quality Registry (SQR) during 2008-2013 in a region where primary care of advanced stages was centralized in 2011. Surgical, oncological characteristics, outcomes, follow-ups and relative survivals were analyzed. RESULTS There were 817 women diagnosed with ovarian and fallopian tube cancers during 2008-2013 and 523 were classified as FIGO stage III-IV and further analyzed. Primary debulking surgery (PDS) was performed in 81% and neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) in 11%. Complete cytoreduction at PDS was performed in 37% before compared to 49% after centralization (p<0.03). The chemotherapy protocols were identical in the cohorts and they received and completed the planned chemotherapy equally. The time interval between PDS and chemotherapy was 36days (median) before compared to 24days after centralization (p<0.01). The relative 3-year survival rate in women treated by PDS was 44% compared to 65% after centralization and the estimated excess mortality rate ratio (EMRR) was reduced (RR 0.58; 95% CI 0.42-0.79). Comparing the complete cohorts before and after centralization, regardless primary treatment, the relative 3-year survival rate increased from 40% to 61% with reduced EMRR (RR 0.59; 95% CI 0.45-0.76). CONCLUSION Centralized primary care of advanced ovarian and fallopian tube cancers increases complete cytoreduction, decreases time interval from PDS to chemotherapy and improves relative survival significantly.