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Ž .International Journal of Gynecology & Obstetrics 76 2002 245�251

Case report

Transplantation of the human uterus

W. Fageeh�, H. Raffa, H. Jabbad, A. MarzoukiMultiorgan Transplant Unit, King Fahad Hospital and Research Center, Jeddah, Saudi Arabia

Received 30 October 2000; received in revised form 30 October 2001; accepted 10 November 2001

Abstract

Human uterine transplantation was performed on 6 April 2000 on a 26-year-old female who lost her uterus 6 yearsearlier due to post-partum hemorrhage. The donor, a 46-year-old patient with multiloculated ovarian cysts,underwent a hysterectomy modified to preserve tissue and vascular integrity. The donor uterus was connected in theorthotopic position to the recipient’s vaginal vault and additional fixation was achieved by shortening the uterosacralligament. The uterine arteries and veins were extended using reversed segments of the great saphenous vein, thenconnected to the external iliac arteries and veins, respectively. Immunosuppression was maintained by oral

Ž . Ž . Ž .cyclosporine A 4 mg�kg�body wt. , azathioprine 1 mg�kg�body wt. and prednisolone 0.2 mg�kg�body wt. .Ž .Allograft rejection was monitored by Echo�Doppler studies, magnetic resonance imaging MRI , and measurement

Ž .of the CD4�CD8 ratio in peripheral blood by fluorescence activated cell sorter FACS scan . An episode of acuteŽ .rejection was treated and controlled on the ninth day with anti-thymocytic globulin ATG . The transplanted uterus

responded well to combined estrogen�progesterone therapy, with endometrial proliferation up to 18 mm. Thepatient had two episodes of withdrawal bleeding upon cessation of the hormonal therapy. Unfortunately, shedeveloped acute vascular thrombosis 99 days after transplantation, and hysterectomy was necessary. Macro- andmicroscopic histopathological examination revealed acute thrombosis in the vessels of the uterine body, withresulting infarction. Both fallopian tubes remained viable, however, with no evidence of rejection. The acute vascularocclusion appeared to be caused by inadequate uterine structure support, which led to probable tension, torsion, orkinking of the connected vascular uterine grafts. � 2002 International Federation of Gynecology and Obstetrics.Published by Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Uterine; Transplantation; Uterus

� Corresponding author. W. Fageeh, Fageeh Polyclinic, Department of Obstetrics and Gynecology, P.O. Box 4845, Jeddah 21412,Saudi Arabia. Tel.: �96-62-663-1877; Fax: �96-62-663-10451

E-mail address: w [email protected]�

0020-7292�02�$20.00 � 2002 International Federation of Gynecology and Obstetrics. Published by Elsevier Science Ireland Ltd.All rights reserved.

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( )W. Fageeh et al. � International Journal of Gynecology & Obstetrics 76 2002 245�251246

1. Introduction

During the past three decades, scientists havemade tremendous efforts to solve infertility prob-lems; indeed, the achievements and developmentsthat have occurred in this field have had a con-

� �siderable clinical impact 1 . Infertility due to theabsence of a uterus, or to a congenitally mal-formed uterus with normally functioning ovaries,has remained an obstacle to pregnancy, however,especially in communities where surrogate gesta-tional carriers are approved by neither religiousnor ethical authorities.

Uterine transplantation could provide a solu-tion to this problem, but its feasibility, safety andreproducibility remain to be proven. To evaluatethe potential for safe, successful uterine trans-plantation in humans, we reviewed earlier animalexperiments and clinical trials. The main difficultywas the vascular anastomosis between the uterine

� �vessels of donor and recipient 2 . Unlike otherorgans, where large vessels are the source ofblood supply, in the uterus, the blood supply anddrainage occur through a net of tiny vessels. Mostearlier animal experiments were performed withavascular techniques that led to failure and the

� �formation of pelvic abscesses 3 . Human trialswere limited to transplantation of endometrial

� �tissue 4 , and no documentation of successfuluterine transplantation was available in the En-glish literature.

The Islamic religious position on uterine trans-plantation was clarified in March 1990, beforeinitiation of this project, when the Islamic Juris-prudence Council approved the transplantation ofreproductive organs that do not transfer gen-etic coding.

2. Experimental animal studies

The present project conformed with the ‘Guid-ing Principles in the Care and Use of LaboratoryAnimals’ approved by the authorities of the KingFahad Research Center. Previous experimentshad proven the feasibility of uterine transplanta-

� �tion in animals, with successful pregnancy 5 . Asthe main difficulties lay in the uterine vascular

connections, some researchers performed avascu-lar uterine transplantation in the animals, whichresulted in failure and in the formation of pelvicabscesses. We, therefore, decided to concentrateour animal studies on uterine reimplantationrather than transplantation. We focused on the

� �vascular surgical anatomy and its variations 6 ,the physiology of the uterine blood flow, andmastery of the microvascular techniques of uter-ine arterial and venous anastomosis.

Autologous orthotopic uterine reimplantationŽwas performed on 18 virgin female animals 16

.baboons and two goats . The baboons’ averageage, weight and height were 2�4 years, 15.6 kgand 37 cm; the goats’ average age, weight andheight were 2�3 years, 20�30 kg and 60�71 cm.Surgery was performed with the animals undergeneral anesthesia without muscle relaxation.

ŽProphylactic antibiotics Tetracycline, 20.mg�kg�body wt. were given for 5 days. In each

animal, a midline abdominal incision was made.Hysterectomy was modified to preserve tissue andvascular integrity. The extirpated uterus wasflushed in both the antegrade and retrogrademanner with 60 cm3 of cold Euro�Collins solu-tion, then reimplanted orthotopically in the sameanimal by doing cervico-vaginal anastomosis. Thefirst eight animals underwent end-to-end uterinevascular anastomosis, but anastomotic occlusionand pelvic abscesses occurred due to graft failure

Ž .and vascular thrombosis in 12 of the 16 75%vascular connections. Therefore, the techniquewas modified, so that the anastomosis was per-formed between the uterine vessel and the inter-nal iliac vessels in an end-to-side fashion usingmonofilament non-absorbable polypropylene su-tures. This modification was technically easier toaccomplish; it also provided wider anastomoticstoma and a higher success rate in the remaining10 animals, with proven vascular patency in 18 of

Ž .20 90% vascular connections. All animals un-derwent abdominal exploration after 6�12 weeksto evaluate the survival of the reimplanted uterus,

Ž .and the following steps were taken: 1 assess-ment of vascular patency by visualizing emptyingand refilling of veins and pulsatility of arteries,and by palpation of the arteries for presence or

Ž .absence of thrill; 2 assessment of uterine and

( )W. Fageeh et al. � International Journal of Gynecology & Obstetrics 76 2002 245�251 247

fallopian tube viability by evaluation of their colorŽ .and texture; 3 observation of bright red fresh

bleeding from the tissue on abrasion or puncture;Ž .and 4 determination of pelvic infection.

Our animal studies demonstrated survival ofthe uterine graft and indicated that good mid-and long-term vessel patency could be achievedusing skillful microvascular techniques for uterinearterial and venous anastomosis in an end-to-sidefashion.

After reviewing the earlier reported experimen-� �tal work by other researchers 5 and our satisfac-

tory results, we decided to prepare for a humantrial. Protocols for human uterine transplantationwere designed, detailing indications, contraindica-tions, selection criteria, surgical techniques, im-munosuppression regimen, and clinical follow-up.Detailed informed consent forms were preparedfor the donor and recipient according to theguidelines and regulations of the Food and Drug

Ž .Administration FDA .

3. Material and methods

The potential recipient was a 26-year-old fe-male who had undergone a hysterectomy in 1994because of massive bleeding following a cesareansection. She had consulted us concerning the pos-sibility of uterine transplantation and afterthorough evaluation was found to be eligible.

The donor was a 46-year-old female who pre-sented with bilateral multiloculated ovarian cystsmeasuring 8�6 cm on the right side and 3�2cm on the left side. Hysterectomy with bilateralsalpingo-oophorectomy was planned, as thispatient agreed to donate her uterus. ABO com-patibility, HLA tissue matching, and negative cy-totoxic antibodies in the recipient were con-firmed.

4. The procedure

4.1. The donor

On 6 April, 2000 uterine extirpation was car-

ried out with the patient under general anesthe-sia. The donor’s abdomen was opened through amidline incision; bilateral en-block oophorectomywas performed and the ovaries were sent forfrozen section, which confirmed the benign na-ture of the cyst. Uterine removal was accom-plished using a technique modified so as to main-tain the vascular pedicle of the uterus as long aspossible, and thus maintain tissue integrity. Thelong vascular pedicle was maintained by transect-ing the round ligaments as far laterally as possi-ble. The ureters were identified and protected.The infundibulopelvic ligaments were clamped,divided, and sutured. The pararectal and par-avesical spaces were developed with care to avoidtraumatizing the numerous small veins in thebroad ligaments and paravesical space. The uter-ine arteries were then encircled with vessel loops.The uterosacral ligaments were serially dividedand sutured. The uterovesical peritoneum wasincised and the bladder was separated from thecervix and the vagina. At that stage, methyl pred-

Ž . Ž .nisolone 500 mg and heparin 20 000 i.u. weregiven i.v. The uterine arteries were clamped 1inch away from the uterine body. The vagina wasentered by circumferential incision and the extir-pated uterus immersed in cold saline for topicalhypothermia. The graft was flushed with modified

Ž .cold 4 �C Euro�Collins solution, antegradethrough uterine arteries and retrograde throughuterine veins, to ensure removal of all white bloodcells and fibrin and to induce central core coolingfor tissue preservation during the ischemia pe-riod. The uterosalpingeal graft was additionallytrimmed to ensure removal of any remnants ofunwanted tissue. A 6-cm long segment of thegreat saphenous vein and an 8-cm long reversedsegment were anastomosed to each uterine veinand artery, respectively, with 6�0 non-absorba-

Ž .ble polypropylene suture prolene-Ethicon on asterile side bench to extend the length of the

Ž .vascular pedicles Fig. 1 . The eight vascular graftswere flushed again with Euro�Collins solution tocheck for any anastomotic leaks. A small lacera-tion of the anterior wall of the donor’s left ureterwas found and was splinted with a double J tubeand sutured by the urologist.


Ž . Ž . Ž .Fig. 1. The end-to-end vascular anastomosis of the uterine artery U.A. to the saphenous vein S.V. segment. A Line of divisionŽ . Ž . Ž .of the saphenous vein. B Continuous micro-anastomosis. C Posterior wall completed. D Anterior wall completed.

4.2. The recipient

ŽA pre-operative oral dose of cyclosporine 4.mg�kg�body wt. was administered 6 h prior to

Ž .surgery and methyl prednisolone 500 mg i.v. ,was administered to the patient at induction ofanesthesia.

The recipient’s laparotomy was started whendonor uterine extirpation was imminent. A mid-line sub-umbilical incision was selected and intra-and retroperitoneal adhesions were lysed. Theinternal and external iliac vessels were dissectedbilaterally. The bladder and rectum were dis-sected from the cervical stump and the latter wasexcised. The donor uterus was placed in ortho-topic position and the cervix was then sutured tothe recipient vaginal vault by single interrupted

Ž .non-absorbable 2�0 Ti-cron Ethicon sutures.Uterosacral shortening was accomplished usingtwo non-absorbable 2�0 Ti-cron sutures. Theextended uterine veins and arteries were thenanastomosed to the external iliac veins and arter-ies, respectively, with 6�0 prolene. No ovarianarterial or venous anastomosis was performed.Five hundred milligrams of methyl prednisolonewas given i.v. on releasing the iliac clamps andre-establishing uterine perfusion. The abdomenwas closed in layers after complete homeostasis.The recipient made an uneventful recovery with

good wound healing. White blood count, cyclo-sporine level, and creatinine phosphokinase en-zyme levels were checked twice a week. The im-munosuppression consisted of oral cyclosporineŽ .4 mg�kg�body wt. divided into two doses toassure a serum trough level of 200 ng%, aza-

Ž . Ž .thioprine Immuran 1 mg�kg�body wt. andprednisolone, with a maintenance dose of 0.2mg�kg�body wt. The adequacy of immunosup-pression was monitored by measuring the

Žlymphocyte subpopulation CD4�CD8 �.helper�suppressor cell ratio by cyto-immunologi-

Ž .cal cytometer FACS Scan and Doppler ultra-sound to study flow volume, pulsatility and resis-

� �tance index 7 . On the ninth post-operative day,the patient complained of low abdominal andback pain, general fatigue, malaise, and bodyache. She had minimal serosanguinous vaginaldischarge, low-grade fever, and tachycardia, indi-cating acute rejection. The CD4�CD8 ratio wasfound to be reversed to 3.4. Abdominal Dopplerultrasound showed increased brightness due tomyometrial edema. The patient was treated byincreasing the oral doses of cyclosporine and aza-thioprine and administering an intravenous pulseof methyl prednisolone. The rejection did not

Ž .resolve, however. Antithymocytic globulin ATGŽ .2.5 mg�kg�body wt. was given, controlling andresolving the rejection phenomenon. Cervical in-


spection on the 12th day revealed good healing ofthe cerviovaginal anastomosis, with some venosta-sis of the lower 1�3 of the ectocervix. Biopsy wasnot attempted, so as to avoid anastomotic disrup-tion. The symptoms of rejection disappeared after2 days and the CD4�CD8 ratio was 1.3. Dopplerultrasound revealed excellent bilateral uterine ar-

Žterial perfusion, with low resistance indices Fig..2 . Hormonal therapy with estrogen and proges-

Ž .terone Progyluton was given for the first 3months to build up the atrophic endometrium.Two withdrawal bleedings occurred promptly af-ter cessation of the hormonal therapy. These wereconsidered to reflect good blood perfusion andviability of the transplanted uterus.

4.3. Remo�al of the transplanted uterus

On the 99th day, the patient experienced asudden feeling of heaviness, with a foul-smellingvaginal discharge on straining. Speculum exami-nation revealed a dusky-colored cervix prolapsinginto the vagina. Immediate Doppler ultrasoundconfirmed cessation of the uterine blood flow. A

diagnosis of mechanical occlusion of the uterinevessels with resulting uterine infarction was made,and the need to perform a hysterectomy becameobvious. At surgery, the uterus was found to beinfarcted and the uterine arteries, veins, and theirsupplying grafts were thrombosed. Both fallopiantubes remained pink and viable, however. Histo-pathologic microscopic examination confirmed theabove findings as well as the viability of both

Ž .tubes and absence of any rejection Fig. 3 .

5. Discussion

Advances in immunology make organ trans-plantation for end-stage organ failure a clinical

� �reality 8 . Advances in microvascular surgery andtissue preservation as practiced in ovarian trans-

� �plantation 9 provide support for major steps inthe new era of the surgical management of infer-

� �tility 10 . Such advances can be applied success-fully in uterine transplantation, and indeed, ourexperimental work with microvascular uterine

Fig. 2. Doppler ultrasound showing normal blood flow and velocity in the uterine artery.


Ž .Fig. 3. Histopathological view 10� magnification hematoxylin eosin coloration. The fallopian tubes of normal anatomical patternand vascularity.

vessel anastomosis provides ample clinical evi-dence of good mid- and long-term vascularpatency and graft survival.

Simple non-invasive techniques such as Dopplerultrasound to monitor and detect early rejectionare essential. Cytoimmunological monitoring for

Žactivated lymphocyte sub-population CD3�CD4.�helper�suppressor cell ratio using monoclonal

antibodies is a simple non-invasive technique tomonitor rejection, with a sensitivity and specificity

� �approaching 96% and 88%, respectively 11 .Punch biopsy from the endocervix, to detect andhistopathologically grade rejection seen as myo-cyte necrosis and perivascular infiltration of lym-phocytes, is an invasive procedure that could beassociated with certain risks. It was, therefore,not applied in our patient.

Modification of the hysterectomy technique inthe donor is essential to promote the preservationof a longer vascular pedicle and application ofgentle atraumatic technique to preserve theuterus, and differs from conventional hysterec-tomy. Extension of the vascular pedicle for a

required length using a conduit such as the greatsaphenous vein or the radial artery may be advan-tageous in selected patients, and the applicationof microvascular techniques by an experiencedvascular surgeon is mandatory. The use of finepolypropylene monofilament non-absorbable su-tures is required. Suspension of the uterus to the

Ž .anterior abdominal wall ventrouteropexy and byuterosacral shortening is essential, to avoid dis-placement of the uterus with consequent tension,torsion, or kinking on the vascular pedicle, andanastomosis, with obstruction of blood flow andvascular thrombosis.

6. Conclusion

Our clinical results with the first human uterinetransplantation confirm the surgical technical fea-sibility and safety of this procedure in gyneco-logic, surgical, and vascular terms. Acceptableshort- and mid-term outcomes were documentedby good endometrial proliferation on hormonal


therapy and the occurrence of two withdrawalbleedings in the transplanted menopausal donoruterus.

An understanding of the surgical vascular ana-tomy and physiology of the uterine blood flow,and the application of microvascular techniquesin uterine vessel anastomosis, solved the earlierreported difficulties encountered in that aspect.Cytochemical and cytoimmunological non-inva-sive techniques for monitoring graft rejection areuseful and reliable. Preservation of the tissue andvascular integrity during uterine extirpation isessential. A vascular pedicle of good length withthe possible use of an extension conduit, such asthe radial artery or the great saphenous vein,could be required. Strong fixation of the trans-planted uterus to the anterior abdominal wall andthe sacral promontory is required, as the uteruslacks the support of the uterosacral ligaments andcould develop slow progressive or acute prolapsewith consecutive thrombosis, infarction, and lossof the uterus.

Further clinical experience and additional de-velopment of the surgical techniques could makeuterine transplantation useful in the treatment ofinfertility, especially in communities where thesurrogate mother concept is unacceptable from areligious or ethical point of view.

Acknowledgements

We would like to thank H.R.H. Prince Naif BinAbdul Aziz, Minister of Interior Affairs, for hissupport and patronage of the First International

Symposium on Uterine Transplantation, whichwas held in Jeddah on 21�22 June, 2000.

References

� �1 Hunt RB. Complications of infertility surgery. In: HuntRB, editor. Atlas of Female Infertility Surgery, 2ndedition, Mosby Year Book, St Louis MO, 1992:485�495.

� �2 Denjean R, Boeck W, Gordts S, Brosens I. Ovariantransplantation by selective microvascular anastomosisin the rabbit. Br J Obstet Gynaecol 1982;89:652�656.

� �3 Confino E, Vermesh M, Thomas Jr. W, Gleicher N.Non-vascular transplantation of the rabbit uterus. Int JObstet 1986;24:321�325.

� �4 Turunen A. On traumatic amenorrhea: 2 cases of en-dometrium transplantation which led to the birth of afull term infant. Gynecologia 1967;164:12�23.

� �5 Eraslan S, Hamermik RJ, Hardy JD. Replantation ofuterus and ovaries in dogs with successful pregnancy.Arch Surg 1966;92:9�12.

� �6 Gary G. Anatomic Exposure in Vascular Surgery.Philadelphia, PA: Williams and Wilkins, 1991:446�448.

� �7 Hall TS, Baumgardner WA, Borkon AM et al. Diagnosisof acute cardiac rejection with antimyosin monoclonalantibodies, phosphorus nuclear magnetic resonanceimaging, two-dimensional echocardiography and en-domyocardial biopsy. J Heart Transpl 1980;5:419�424.

� �8 Organ transplantation: an update. Archives of the XVIInternational Congress of the Transplant Society 1996;1�6.

� �9 Von Theobold F, Roffe JL, Berrocal J, Le Porrier M,Muller G. Heterotopic autotransplantation of the ovaryin women. Presse Med 1987;16:1239�1241.

� �10 Carmona F, Ballash J, Gonzales MJ. Ovarian functionand tubal viability and pregnancy after tubo-ovariantransplantation in the rabbit. Human Reprod 1993;8:929�931.

� �11 Baughman L. Monitoring of Allograft Rejection. Heartand Heart-Lung Transplantation. Philadelphia, PA: W.B.Saunders, 1990:157�164.

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