1 E-mail: [email protected]. Address forcorrespondence: CarloPetrini,Unità diBioetica,Presidenza,IstitutoSuperiore diSanità,Via GianodellaBella 34,00162Rome,Italy. performed in women born without a uterus (Mayer- ago asthe1960s[1];inhumans theyhavetodatebeen characteristics. womb, itsfunctioningandpurpose, thatareunique less importanttokeepinmindthepeculiaritiesof sues involvedintransplantsgeneral,itisnonethe- terms andinregardtothemoretypically bioethical is- view ofthestateartprocedureinclinical present articleaddressestheproblemfrompointof the symbolicvalueattachedtowomb.Although life or the moral status ofthe embryo), but rather about assisted procreation(suchasthebeginningofaperson’s cal problemsthataccompanynewmethodsofmedically plant” performedtodate. – involvingonlywomenisthusthe“gendertrans- only bythewomanwhocarriesit:awombtransplant until anultra-soundrevealsitandperceivedasgrowing settles, isformedanddevelops,invisibletotheworld egory. Awomb istheplacewhereanewhumanbeing female reproductivefunctions,belongstothesamecat- because of the particular importance ofthe womb in The presentarticleconcernswombtransplantswhich, cant problemsregardingthepatient’s self-perception. constitute a life-saving procedure, both imply signifi- but alsotheperceptionofselfandone’s body. lesser degree–thephysicalwell-beingofrecipient, tional issuesthatinvolvenotonly–andinanycasetoa nonetheless raiseethical,anthropologicalandemo- liver, lung),othersthatarenotnecessaryforsurvival mans. While some organs are vital for survival (heart, equally toalltheorgansthatcanbetransplantedinhu- INTRODUCTION documents beforeindicatingthekeyethicalimplicationsinvolvedinwombtransplants. present articledescribespastexperimentsandsummarisesthemostrelevantreference forming this procedure in womenwho have no womb, usually for congenital reasons. The Abstract 2 Carlo Petrini implications Uterus transplantsandtheirethical DOI: 10.4415/ANN_17_01_06 Ann IstSuperSanità2017|Vol. 53,No.1:25-29 Dipartimento diChimica,BiologiaeBiotecnologie,UniversitàdegliStudiPerugia,Italy Unità diBioetica,Presidenza,IstitutoSuperioreSanità,Rome,Italy Womb transplantswereperformedinanimalsas long We are,therefore,nottalkingabouttheusualbioethi- While a hand or face transplant clearly does not Clinical andethicalconsiderationsdonotapply Early experimentsinwombtransplantshaveincreasedinterestthepossibilityofper 1 andAssuntinaMorresi 2 recipient andspermatozoafrom herpartner, and11em- fertilisation had been performed using oocytes from the living 65-yearolddonor. Priortothetransplantinvitro Rokitansky syndromewasgiven awombtakenfrom thenburg (Sweden),a35-year oldwomensufferingfrom menstrual cycleswereregularafter6months. metriosis requiredhysterectomy. Intheremainingcases bilateral uterinearteryocclusionandpersistentendo- fistula (1/9). Two ofthetransplantswere unsuccessful: plication inadonorwasonecaseofurethral-vaginal neal haematoma(1/9).Theonlypost-operativecom- effusion (2/9),intrauterineabscess(1/9)retroperito- thrombosis intheuterinearteries(1case9)pleural the recipients.Post-operativecomplicationsincluded: moved fromlivingdonors,inmostcasesthemothersof who had had a hysterectomy [4, 5].The organs were re- involving eightwomenwithuterineagenesisandone embryo transfers. lowed bytwoearlyspontaneousabortionsfollowing patient hadherfirstmenstrualcycle,whichwasfol- deceased donorofthesameage.Twenty dayslaterthe A 20-yearoldwomanreceivedauterustakenfrom had toberemoved. tomosed bloodvesselsledtonecrosisofthegraftandit However, the development of thrombosis in the anas- been stimulatedtoachieveendometrialproliferation. gen andprogesteronecouldthuspotentiallyhave year oldwoman.Itrespondedtotreatmentwithoestro- a 46-year old living donor and transplanted into a 26- was performedin2000[2].Theuterustakenfrom for otherpathologiesthatinvolvetheuterus. Rokitansky-Kunster-Hauser), butcouldbeappropriate In 2013,attheSahlgrenskaUniversityHospitalinGo- In 2012-2013thefirstclinicaltrialwasconducted, A secondattemptwasmadein2011Turkey [3]. The firstexperimentalwombtransplantinawoman - • • • • Key words organ transplant gynaecology and obstetrics bioethics techniques reproductive assisted

25 Original articles and reviews 26 Carlo Petrini and Assuntina Morresi

bryos had been frozen. Forty-three days after the trans- 2. the lengths to which some women will go to experi- plant the recipient had her first menstruation and one ence uterine transplantation, even with the availability year after the first embryo was transplanted. After 31 of such options as adoption and surrogacy in some cul- weeks and 6 days the woman gave birth to a boy of nor- tures, can lead to a conflict of interest and pressure on mal weight for his gestational age [6]. Subsequently, the researchers to move prematurely to human application; transplants in Sweden resulted in four other births [7, 8]. 3. ut is unethical to remove a uterus for transplantation Table 1 shows a summary of the womb transplants re- from a young woman who did not complete having the ported to date in the specialised literature. desired number of children or a uterus with a deformed reviews

Although New York’s Downtown Hospital had an- cavity; nounced plans to perform a womb transplant in January 4. given the lack of data on safety and the known haz- th and 2007 [9], the first operation was performed on 24 Feb- ards to live donors, the procedure is considered ethi-

ruary 2016 in Cleveland. The recipient was a 26-year cally inappropriate” [14]. old who had been included in an experimental trial aim- In 2012 a working group from McGill University ing for 10 transplants, and the womb was taken from a (Montreal, Canada) proposed the “Montreal criteria deceased 30-year old donor (in contrast to the Swedish for the ethical feasibility of uterine transplantation” articles trial, which used living donors). On 8th March 2016 the [15], which were updated the following year [16]. The transplanted womb had to be removed in an emergency revised Montreal criteria for the ethical feasibility of operation, as a result of complications [10]. uterine transplantation are: The Swedish cases encouraged several surgical teams riginal in various countries to plan womb transplants. Such 1. The recipient O plans are usually announced in press conferences or a. is a genetic female of reproductive age with no medi- through press agencies. For example: cal contraindications to transplantation, • in a womb transplant is planned for 2016 in b. has documented congenital or acquired UFI that Limoges [11]; has failed all current gold standard and conservative • in Italy, the Ethical Committee of the Italian Health therapy, Institute has approved a womb transplant protocol at c. (c1) has a personal or legal contraindication to surro- the Umberto I Hospital in Rome, in accordance with gacy and adoption measures and desires to have a child, the regulations governing the authorisation of such tri- or (c2) seeks the UTx solely as a measure to experience als [12]; gestation, with an understanding of the limitations pro- • in the United Kingdom the UK Womb Transplant vided by the UTx in this respect, Research Team led by Richard Smith, consultant gyn- d. has not had her decision to undergo UTx deemed as aecologist at Queen Charlotte’s and Chelsea Hospital irrational by expert psychological evaluation, and has in London, received authorisation in September 2015 no psychological comorbidity that interferes with diag- to conduct trials with 10 patients [13]. nostic workup or treatment, e. does not exhibit frank unsuitability for motherhood, INSTITUTIONAL DOCUMENTS f. is likely to take antirejection medication and follow In 2008 a report by the International Federation of up with the treating team in a responsible manner, and Gynecology and Obstetrics (FIGO) found that the lack g. is responsible enough to consent, informed enough of sufficient data on the safety and efficacy for the re- to make a responsible decision. cipient meant that womb transplants were not accept- able from the ethical point of view. The FIGO therefore 2. The donor made the following recommendations: a. is a female of reproductive age with no medical con- “1. uterine transplantation, which may reach human traindications to donation, clinical experimentation stage, should only occur after b. (b1) has repeatedly attested to her conclusion of par- significant and adequate research in appropriate large ity, or (b2) has signed an advanced directive for post animal models, including primates; mortem ,

Table 1 Summary of the womb transplants reported to date in the specialised literature Author N. patients Age Donor/s Outcome Fageeh et al. [2] 1 26 living Hysterectomy for vascular occlusion 3 months after transplant Ozkan et al. [3] 1 21 deceased Pregnancy and abortion Brännström et al. [4] 10 31.5 living 7 cases: viable uterus (of which 3 with Johannesson et al. [5] (average) sub-clinical rejection treated effectively with Brännström et al. [6] corticosteroids) Dahm-Kähler et al. [7] 2 cases: serious rejection with bilateral occlusion of Brännström et al. [8] arteries 5 live births Cleveland Clinic [10] 1 26 deceased Hysterectomy 12 days after transplant for complications 27 Uterus transplants and their ethical implications

c. has no history of uterine damage or disease, and strength” meaning the intellectual and technical exper- d. is responsible enough to consent, informed enough tise available in the institution where the work is being to make a responsible decision, and not under coercion. done; and the third is “institutional stability” based on its resources, support systems, and staff [20, 21]. All three 3. The health care team were cited in the “Montreal criteria for the ethical feasibil- a. is part of an institution that meets Moore’s third cri- ity of uterine transplantation” mentioned above [15, 16]. terion as it pertains to institutional stability, b. has provided adequate informed consent to both par- Donation from deceased and living donors reviews ties regarding risks, potential sequelae, and chances of There are pros and cons for transplants from de- success and failure, ceased donors:

c. has no conflict of interest independently or with ei- Pros: and ther party, and • no risk for the donor; d. has the duty to preserve anonymity if the donor or • less time needed for removal; recipient do not explicitly waive this right”. • technically easier, thanks to longer peduncles and easier anastomosis. articles On 23rd June 2015 the French Académie Nationale Cons: de Médecine published a report on “La transplanta- • difficult in making a complete pre-operative appraisal; tion uterine” [17]. The report noted the data published • logistic issues: distances, etc.; so far, and in particular those relating to the birth in • informed consent calls for special attention. When Sweden in 2015; pointed to the uncertainties, risks and transplanting unusual organs (e.g. face, hands) it is ad- riginal problems; noted that transplants from both living and visable to ask for specific consent in addition to the ge- O deceased donors raised serious issues; indicated the un- neric declaration of consent to the donation of organs certainties surrounding the long-term health conditions [21]. This is particularly advisable before removing a of children born from a transplanted womb, and made womb, given the special significance and symbolic na- the following recommendations: ture of the organ; “1. research programmes that are conducted strictly in • very little clinical exp erience; accordance with regulations laid down in law and by the • there are pros and cons for transplants from living Agence de la Biomédecine in regard to all innovations donors. in the matter of organ transplantations and medically Pros: assisted procreation should continue; • increased certainty that the organ will function. 2. clear and detailed information that takes into ac- Cons: count the drawbacks and risks associated with womb • highly complicated procedure for the donor: Brän- transplants should be given to living donors and recipi- nström reported surgical procedures lasting more than ents participating in these research programmes, who 10 hours, involving considerable risks [6]; should be given appropriate assistance before, during • the age of living donors is a further problem. To in- and after the procedure; crease the chance of success the donor should be of 3. data on research conducted in France and in other childbearing age. It is clearly problematic, to say the countries should be collected with a view to ensuring least, to remove the womb of a fertile woman, even she the validity of womb transplants and, in due course, to has already born children; assess the possibility of extending the procedure, with • it could be feasible to transplant a womb taken from respect for the ethical principles that apply in all organ a living donor with a pathology that does not directly transplantations and medically assisted procreation, in involve the uterus (which therefore continues to func- order to avoid deviations”. tion) but prevents her procreating; More recent documents, as we can see, are less wary • a particular problem arises with transsexual women of the concept of womb transplants. However, the who wish to have their wombs removed. The Acadé- FIGO has still not amended the opinion it published in mie Nationale de Médecine has suggested that in these 2008 [18], notwithstanding the availability of additional cases a womb transplant could be possible provided two results. conditions are met: the transplant should be performed in the interest of the transsexual and for the therapeutic ETHICAL ASPECTS benefit of the recipient (i.e. procreation) [17]. On this General criteria for experimental surgery point it should be noted that some lesbian, gay, bisexu- With very few exceptions new surgical techniques al, transsexual (LGBT) associations are campaigning to do not enter clinical practice as a result of randomised abolish the need for surgical sterilisation as a requisite clinical trials; they evolve gradually from existing tech- for gender reassignment. Clearly, while such cases fall niques or, more rarely, from bold divergences from com- within the category of transplants from living donors, mon practice adopted by a surgical team on the basis of the unusual nature of the donor’s personal journey calls experience [19]. for an even more specific form of informed consent; Francis D. Moore has proposed three criteria that • current legislation requires that there should be a should be met in order for innovative surgical procedures family connection between the donor and the recipient. to become acceptable, including from the ethical point Cases of undue influence (such as a mother who feels of view. The first is laboratory experience that optimally responsible for her daughter’s inability to procreate) should precede a surgical innovation; the second is “field and other forms of interference cannot be ruled out. 28 Carlo Petrini and Assuntina Morresi

The recipient while there exist international conventions against the Although womb transplants are seen in some quar- trade in organs for transplantation [22] (which unfor- ters as being relatively simple in comparison with the tunately is nonetheless present in some states), some transplantation of other organs, the procedure is a com- countries allow the legal sale of gametes. This, com- plex one. The operation described by Brännström lasted bined with the current legalisation or, in some states, 10 hours and 7 minutes for the donor and 4 hours and mild acceptance of surrogacy, could lead to the treat- 55 minutes for the recipient [6]. ment of the womb as a “separate” case associated with A womb transplant is not a life-enhancing event for female reproduction, an area that is already more sus- reviews

the recipient (in fact, it has the opposite effect), though ceptible to market criteria and less protected. it does enable her to procreate.

and To avoid the need for lifelong immunosuppressive Pregnancy

therapy, a womb transplant requires two further op- Because the objective of womb transplants is concep- erations: a caesarean section for delivery, followed by tion, these procedures pose highly specific problems a hysterectomy. linked to the wellbeing of the product of conception, The possibility of rejection during pregnancy means that are not associated with the transplantation of other articles

that an exit strategy is more complicated in a womb organs. In ethical terms the risks are of primary con- transplant than in other proce- cern. dures. Currently available figures do not point to short-term Issues of distributive justice also arise, given that the risks for the child as a consequence of immunosuppres- riginal high costs of these interventions make them inacces- sion, but risks associated with premature birth cannot O sible to most people. be excluded, nor can long-term risks such as haemo- There is a considerable imbalance between the large philia, cancer, retarded growth or other pathologies. number of potential recipients and very few potential There is the possibility of psychological risks for chil- donors. The main source should be young, brain-dead dren on learning they were born from a transplanted donors with healthy wombs, of whom there are very womb. few. Recipients should receive detailed information re- CONCLUSIONS garding: the surgical risks, probable need to remove the The transplantation of a womb is the first all-female transplanted uterus, complex preparation process (pre- “gender transplant” performed to date: it stands alone operative hormone therapy), possible failure to procre- in the world of transplants, also because of the emo- ate and the effects of immunosuppressive therapy. tional and symbolic importance attached to the func- tioning and purpose of the womb. In ethical and clinical Womb transplants and medically-assisted procreation terms, it is the opinion of the authors that in the current The two are linked because to date post-transplant state of knowledge womb transplants are still a highly pregnancies have been initiated only after in vitro fer- experimental procedure and should be subject to all tilisation. the risk/benefit assessments normally applied in simi- Womb transplants pose many problems similar to lar circumstances. It should also be recalled that this is those posed by other assisted procreation procedures: not a life-saving procedure and that the womb should rights of the donor, health consequences for the foetus in any case be removed after any pregnancy in order to and child, interventions on a woman’s body, the role of permit the interruption of immunosuppressive therapy: the state in regulating procreation, etc. the risk/benefit assessment should be performed in this There are considerable regulatory problems. Current light. The state of the art for the moment excludes the regulations in most states do not mention womb trans- possibility that womb transplants can be considered as plants either in the context of assisted procreation or an alternative to other forms of pregnancy, which in among types of transplants performed to date. any case are highly controversial in ethical, social and Womb transplants could be considered as a means to psychological terms (and unacceptable in the authors’ counter the perverse phenomenon of surrogacy, though opinion), such as surrogacy, or even as an alternative in the current circumstances it is too experimental a to legitimate means of achieving parenthood such as procedure to be an alternative: this could change if and adoption. In brief, in ethical terms womb transplants when womb transplants become a part of consolidated from a deceased donor, in specific, carefully controlled clinical practice. For the sake of clarity, the lack of a and clinically assessed circumstances and bearing in “medical” alternative to surrogacy does not make this mind that such procedures are currently highly experi- phenomenon ethically legitimate; it remains an unac- mental, could be acceptable, while the removal and ceptable exploitation of women and a violation of the transplantation of a womb from a living donor presents rights of the child. In the current state of knowledge the for now such major issues and contra-indications as to requisite cited in the “Montreal criteria for the ethical render it unacceptable. feasibility of uterine transplantation” – that the recipi- ent should have “a personal or legal contraindication to Conflict of interest statement surrogacy” – is ethically highly controversial and, in the None. authors’ opinion, quite unacceptable. There could be a higher risk of trade in wombs than Received on 7 June 2016. in other organs. This risk is heightened by the fact that Accepted on 15 November 2016. 29 Uterus transplants and their ethical implications

REFERENCES

1. Eraslan S, Hamernik RJ, Hardy JD. Replantation of uter- gioni e le Province autonome di Trento e di Bolzano. Ac- us and ovaries in dogs, with successful pregnancy. Arch cordo tra il Ministro della Salute, le Regioni e le Province Surg 1966;92(1):9-12. autonome di Trento e Bolzano 14 febbraio 2002. Rep- 2. Fageeh, W, Raffa H, Jabbad H, Marzouki A. Trans- ertorio atti n. 1388 del 14 febbraio 2002. Gazzetta Uf- plantation of the human uterus. Int J Gynaecol Obstet ficiale della Repubblica Italiana − Serie generale 3 ottobre 2002;76(3):245-51. 2002;143(232):34-5.

3. Ozkan O, Akar ME, Erdogan O, Ozkan O, Hadimioglu 13. UK Womb Transplant. UK Womb Transplant Research reviews N. from a deceased donor. Fertil Team receives go-ahead to begin operations. 29 September Steril 2013;100(6):e41. 2015. Available from: http://wombtransplantuk.org/uk- and

4. Brännström M, Johannesson L, Dahm-Kähler P, Enskog womb-transplant-research-team-receives-go-ahead-to- A, Mölne J, Kvarnström N, Diaz-Garcia C, Hanafy A, begin-operations. Lundmark C, Marcickiewicz J, Gäbel M, Groth K, Ak- 14. Milliez J. Uterine transplantation FIGO Committee for ouri R, Eklind S, Holgersson J, Tzakis A, Olausson M. the Ethical Aspects of Human Reproduction and Wom- First clinical uterus transplantation trial: a six-month re- en’s Health. Int J Gynaecol Obst 2009;106:270. articles

port. Fertil Steril 2014;101(5):1228-36. 15. Lefkowitz A, Edwards M, Balayla J. The Montreal cri- 5. Johannesson L, Kvarnström N, Mölne J, Dahm-Kähler P, teria for the ethical feasibility of uterine transplantation. Enskog A, Diaz-Garcia C, Olausson M, Brännström M. Transpl Int 2012;25(4):439-47. Uterus transplantation trial: 1-year outcome. Fertil Steril 16. Lefkowitz A, Edwards M, Balayla J. Ethical consider-

2015;103(1):199-204. ations in the era of the uterine transplant: an update of riginal

6. Brännström M, Johannesson L, Bokström H, Kvarnström the Montreal criteria for the ethical feasibility of uterine O N, Mölne J, Dahm-Kähler P, Enskog A, Milenkovic M, transplantation. Fertil Steril 2013;100(4):924-6. Ekberg J, Diaz-Garcia C, Gäbel M, Hanafy A, Hagberg 17. Henrion R, Milliez J (Eds). La transplantation utérine. H, Olausson M, Nilsson. Livebirth after uterus transplan- Rapport. Académie Nationale de Médecine; 23 Juin tation. Lancet 2015;385(9968):607-16. 2015. Available from: www.academie-medecine.fr/wp- 7. Brännström M. Uterus transplantation. Curr Opin Organ content/uploads/2015/06/Transpl-uterus-C.pdf. Transplant 2015;20(6):621-8. 18. Petrini C. Surgical experimentation and clinical trials: 8. Dahm-Kähler P, Diaz-Garcia C, Brännström M. Hu- differences and related ethical problems. Ann Ist Super man uterus transplantation in focus. Br Med Bull Sanita 2013;49(2):230-3. 2016;117(1):6-78. 19. Moore FD. Ethical problems special to surgery: surgical 9. Stein R. First US uterus transplant planned. Some experts teaching, surgical innovation, and the surgeon in man- say risk isn’t justified. 15 January 2007. aged care. Arch Surg 2000:135(1):14-6. 10. Cleveland Clinic. Statement from Cleveland Clinic. Up- 20. Morgenstern L. Innovative surgery’s dilemma. Surg Innov date on 1st uterus transplant. March 2016. Available from: 2006;13(2):73-4. http://my.clevelandclinic.org/about-cleveland-clinic/ 21. Agich GJ. Extension of organ transplantation: some ethi- newsroom/releases-videos-newsletters/2016-2-16-up- cal considerations. Mt Sinai J Med 2003;70(3):141-7. date-on-first-uterus-transplant. 22. Council of Europe. Convention against trafficking in hu- 11. Gènéthique. Greffe d’utérus: un premier essai clinique auto- man organs (Adopted by the Committee of Ministers on 9 risé en France. 9 Novembre 2015. Available from: www.ge- July 2014 at the 1205th meeting of the Ministers’ Depu- nethique.org/fr/greffe-duterus-un-premier-essai-clinique- ties. Signed in Santiago de Compostela 25 March 2015). 9 autorise-en-france-64392.html. July 2014. Available from: https://wcd.coe.int/ViewDoc. 12. Conferenza permanente per i rapporti tra lo Stato, le Re- jsp?Ref=CM/Del/