Anders Enskog

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.

Prospective study of the clinical and laboratory parameters of patients in whom ovarian hyperstimulation syndrome developed during controlled ovarian hyperstimulation for in vitro fertilization

OBJECTIVE To compare patient characteristics and clinical and laboratory parameters in patients in whom ovarian hyperstimulation syndrome (OHSS) develops with those in whom it does not develop. DESIGN Prospective cohort study. SETTING Reproductive medicine unit at a university medical center. PATIENT(S) All patients undergoing IVF (n = 428) who received controlled ovarian hyperstimulation during a 6-month period. INTERVENTION(S) Prospective data collection. MAIN OUTCOME MEASURE(S) Patient characteristics (age, body mass index, medical history, smoking habits) and clinical and laboratory data obtained during controlled ovarian hyperstimulation were evaluated in patients who had severe OHSS, any degree of OHSS, or a significant risk of OHSS and compared with the remaining populations. RESULT(S) Severe OHSS developed in 18 patients (4.2%) and mild or moderate OHSS developed in 7.3%. As a group, all the patients with OHSS were significantly younger, received lower doses of gonadotropins, had ovaries containing a higher number of total and large follicles, had a higher number of retrieved oocytes, and had a higher pregnancy rate than the patients without OHSS. The patients with severe OHSS also had an increased prevalence of allergy (56% versus 21%) and were more likely to ultimately give birth. CONCLUSION(S) The observed differences may be useful in elucidating the pathophysiology of OHSS and identifying patients who are at increased risk for OHSS.

Leukocyte networks and ovulation

Ovulation, the process whereby the oocyte is expelled from the interior of the follicle, is the final process of folliculogenesis. During the last decade, data have accumulated to suggest that tissue-bound leukocytes are major effector cells in several physiological processes within the reproductive tract. Some specific subclasses of leukocytes seem to be critically involved in the process of ovulation. The main components of this ovulatory process are degradation of the extracellular matrix (ECM) at the follicular apex and changes in the follicular vasculature. The leukocytes participate actively in these events by secretion of proteases and vasoactive substances. This review covers our current understanding of the mechanisms by which the leukocytes are attracted to the preovulatory follicle after the LH-surge and the roles that the activated leukocytes play in the follicle during the ovulatory period.

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.

Fertility after autologous ovine uterine-tubal-ovarian transplantation by vascular anastomosis to the external iliac vessels

BACKGROUND Transplantation of the uterus has been suggested as a treatment of uterine factor infertility. This study investigates whether the sheep uterus can resume its capacity to harbour normal pregnancies after autotransplantation by vascular anastomosis. METHODS From 14 ewes, the uterus, excluding one uterine horn, was isolated along with its oviduct and ovary and preserved ex vivo and then transplanted back with end-to-side anastomosis of the vessels of the graft to the external iliac vessels. After recovery, the ewes underwent surgical examination and serum progesterone measurements to ascertain healing and ovarian activity. Afterwards, five autotransplanted and five control ewes were placed with a ram for mating. Caesarean sections were performed before the estimated term of pregnancy and data on fetal measures were compared. RESULTS Of the 14 ewes, seven survived surgery with ovarian activity intact and grafts showing normal appearance. Mating occurred in four of five transplanted ewes and in five out of five controls, and three transplanted animals and five control animals conceived. In one transplanted ewe, torsion of the uterus was observed after spontaneous initiation of labour. Foeti from transplanted mothers were comparable in size to those of controls. CONCLUSIONS Despite the encountered complications, this is the first report to demonstrate fertility and pregnancies going to term after autotransplantation of the uterus in an animal of a comparable size to the human.

Transplantation of the uterus in sheep: Methodology and early reperfusion events

Aim:  Uterine transplantation is developing into a clinical treatment for uterine factor infertility. An animal model with a similar uterus size and vessels to humans and with pregnancy extending over several months would be beneficial for research on uterine transplantation. The aim of this study was to develop and evaluate autotransplantation of the sheep uterus to an orthotopic position in the pelvis.

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.

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