Uterus transplantation

The uterine transplant is the surgical procedure whereby a healthy uterus is transplanted into an organism of which the uterus is absent or diseased. As part of normal mammalian sexual reproduction, a diseased or absent uterus does not allow normal embryonic implantation, effectively rendering the female infertile. This phenomenon is known as absolute uterine factor infertility (AUFI). Uterine transplant is a potential treatment for this form of infertility.

History

Studies

In 1896, Emil Knauer, a 29-year-old Austrian working in one of Vienna's gynecological clinics, published the first study of ovarian autotransplantation documenting normal function in a rabbit. This led to the investigation of uterine transplantation in 1918.[1][2] In 1964 and 1966, Eraslan, Hamernik and Hardy, at the University of Mississippi Medical Center in Jackson, Mississippi, were the first to perform an animal (dog) autotransplantation of the uterus and subsequently deliver a pregnancy from that uterus.[3] In 2010 Diaz-Garcia and co-workers, at Department of Obstetrics and Gynecology, University of Gothenburg in Sweden, demonstrated the world's first successful allogenic uterus transplantation, in a rat, with healthy offspring.[4]

Notable cases

Germany

Except perhaps in rare cases of intersex individuals, transgender women are born without a female reproductive system. While sex reassignment surgery can create a functional vagina for these women, the option of a uterus is currently unavailable to them, meaning they cannot carry a pregnancy and would need to take other routes to parenthood, whether it be a more traditional approach involving coitus or an alternative one such as adoption, egg donation, or a gestational carrier. General interest in uterine transplants for transgender women has waned in recent decades, due to the success and subsequent widespread availability of assisted reproductive technology, and being transgender has become virtually synonymous with being infertile.[5][6] Nonetheless, at least one uterine transplant for a trans woman occurred, for the Danish artist Lili Elbe (1882–1931), in one of the medical field's first attempts to treat the needs of transgender patients. Hoping to have children with her fiance, she underwent a uterine transplant in 1931, in conjunction with vaginoplasty, in Germany at the age of 48. However, she developed an postsurgical infection and died from cardiac arrest just three months later.[7] Elbe's medical records were destroyed during World War II, so little is known about the goals of the surgeons or the techniques they utilized, and as Elbe died so suddenly following the surgery, there is no way to determine whether or not the surgeries could have resulted in a successful pregnancy.[8]

Saudi Arabia

The first modern day attempt at a uterine transplant occurred in 2000, in Saudi Arabia.[9] Dr. Wafa Fagee[9] successfully transplanted a uterus, taken from a 46-year-old patient, into a 26-year-old patient whose uterus had been damaged by hemorrhaging following childbirth.[10] Because the patient ultimately needed for the uterus to be removed after just 99 days, due to necrosis, whether or not the case is considered successful is disputed, but the uterus did function for a time, with the patient experiencing two menstrual cycles.[9] Members of the medical community have expressed concerns over the ethics of the procedure.[11]

Turkey

The first incidence of a uterine transplant involving a deceased donor occurred in Turkey on 9 August 2011; the surgery, performed by Dr. Ömer Özkan and Dr. Munire Erman Akar, at the Akdeniz University Hospital in Antalya, on Derya Sert, a 21-year-old patient who'd been born without a uterus.[12][13][14][15][16][17] In this case, the patient enjoyed long-term success with the transplanted uterus, experiencing periods and, two years post-surgery, pregnancy.[18][19][20][21] During that pregnancy, Sert underwent an abortion in her first trimester, after her doctor was unable to detect a fetal heartbeat, but this is a common complication and may not have been related to the transplant.[22] Following another pregnancy that was initiated with in vitro fertilisation and sustained for 28 weeks, the patient finally delivered a baby on June 4, 2020.[23]

Sweden

In Sweden in 2012, the first mother-to-daughter[24] womb transplant was done by Swedish doctors at Sahlgrenska University Hospital at Gothenburg University led by Mats Brännström.[24][25][26]

In October 2014, it was announced that, for the first time, a healthy baby had been born to a uterine transplant recipient, at an undisclosed location in Sweden. The British medical journal The Lancet reported that the baby boy had been born in September, weighing 1.8 kg (3.9 lb) and that the father had said his son was "amazing". The baby had been delivered prematurely at about 32 weeks, by cesarean section, after the mother had developed pre-eclampsia. The Swedish woman, aged 36, had received a uterus in 2013, from a live 61-year-old donor, in an operation led by Dr. Brännström, Professor of Obstetrics and Gynaecology at the University of Gothenburg.[27][28] The woman had healthy ovaries but was born without a uterus, a condition that affects about one in 4,500 women. The procedure used an embryo from a laboratory, created using the woman's ovum and her husband's sperm, which was then implanted into the transplanted uterus. The uterus may have been damaged in the course of the caesarian delivery and it may or may not be suitable for future pregnancies. A regimen of triple immuno-suppression was used with tacrolimus, azathioprine, and corticosteroids. Three mild rejection episodes occurred, one during the pregnancy, but were all successfully suppressed with medication. Some other women were also reported to be pregnant at that time using transplanted uteri. The unnamed mother, who received a donated womb from a friend, said that she hoped the treatment would be refined to help others in the future.[29]

United States

The first uterine transplant performed in the United States took place on 24 February 2016 at the Cleveland Clinic.[30] The transplant failed due to a complication on 8 March and the uterus was removed.[31] In April it was disclosed that a yeast infection by Candida albicans had caused damage to the local artery, compromising the blood support of the uterus and necessitating its removal.[32]

In November 2017, the first baby was born after a uterus transplantation in the US.[33] The birth occurred at Baylor University Medical Center in Dallas, TX, after a uterus donation from a non-directed living donor.[34] The first baby born after a deceased donor uterus transplant in the US was at the Cleveland Clinic in 6/2019.( cite-Flyckt R, Falcone T, Quintini C, Perni U, Eghtesad B, Richards EG, Farrell RM, Hashimoto K, Miller C, Ricci S, Ferrando C, D'Amico G, Maikhor S, Priebe D, Chiesa-Vottero A, Heerema-McKenney A, Mawhorter S, Feldman M, Tzakis A. First birth from a deceased donor uterus in the United States: from severe graft rejection to successful cesarean delivery. Am J Obstet Gynecol. 2020 Mar 6)

India

The first uterine transplant performed in India took place on 18 May 2017 at the Galaxy Care Hospital in Pune, Maharashtra. The 26-year-old patient had been born without a uterus, and received her mother's womb in the transplant.[35][36] India's first uterine transplant baby, weighing 1.45 kg, was delivered through a Caesarean section [37] at Galaxy Care Hospital in Pune on Thursday.[38] The surgery was performed by a team of doctors at Pune's Galaxy Care Hospital and led by the hospital's medical director, Dr. Shailesh Puntambekar.[39]

Current status

The transplant is intended to be temporary – the recipient will undergo a hysterectomy after one or two successful pregnancies. This is to avoid the need for her to take immunosuppressive drugs for life with a consequent increased risk of infection.[40]

The procedure remains the last resort: it is a relatively new and somewhat experimental procedure, performed only by certain specialist surgeons in select centres, it is expensive and unlikely to be covered by insurance, and it involves risk of infection and organ rejection. Some ethics specialists consider the risks to a live donor too great, and some find the entire procedure ethically questionable, especially since the transplant is not a life-saving procedure.[41][42][43]

Description

Procedures

Uterine transplantation starts with the uterus retrieval surgery on the donor. Working techniques for this exist for animals, including primates and more recently humans.[44][45][46][47][48][49] The recovered uterus may need to be stored, for example for transportation to the location of the recipient. Studies on cold-ischemia/eperfusion indicate an ischemic tolerance of more than 24 hours.[45]

The recipient has to look at potentially three major surgeries. First of all, there is the transplantation surgery. If a pregnancy is established and carried to viability a cesarean section is performed. As the recipient is treated with immuno-suppressive therapy, eventually, after completion of childbearing, a hysterectomy needs to be done so that the immuno-suppressive therapy can be terminated.

Ethics

Montreal criteria

Aside from considerations of costs, uterine transplantation involves complex ethical issues. The principle of autonomy supports the procedure, while the principle of non-maleficence argues against it. In regard to the principles of beneficence and justice the procedure appears equivocal.[11] To address this dilemma the "Montreal Criteria for the Ethical Feasibility of Uterine Transplantation" were developed at McGill University and published in Transplant International in 2012.[11] The Montreal Criteria are a set of criteria deemed to be required for the ethical execution of the uterine transplant in humans. These findings were presented at the International Federation of Gynecology and Obstetrics' 20th World Congress in Rome in October 2012.[50] In 2013 an update to "The Montreal Criteria for the Ethical Feasibility of Uterine Transplantation" was published in Fertility and Sterility and has been proposed as the international standard for the ethical execution of the procedure.[51]

The criteria set conditions for the recipient, the donor, and the health care team, specifically:

  1. The recipient is a cisgender female with no medical contraindications to transplantation, has uterine disease that has failed other therapy, and has "a personal or legal contraindication" to other options (surrogacy, adoption). She wants a child, is suitable for motherhood, is psychologically fit, is likely to be compliant with treatment, and understands the risks of the procedure.
  2. The donor is a female of reproductive age with no contraindication to the procedure who has concluded her childbearing or consented donating her uterus after her death. There is no coercion and the donor is responsible and capable of making informed decisions.
  3. The health care team belongs to an institution that meets Moore's third criterion[52] regarding institutional stability and has provided informed consent to both parties. There is no conflict of interests, and anonymity can be protected unless recipient or donor waive this right.

It has been noted that the decision to exclude transgender women from the criteria may lack justification.[53]

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See also

References
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  2. Nugent, D.; Meirow, D.; Brook, P. F.; Aubard, Y.; Gosden, R. G. (1997). "Transplantation in reproductive medicine: Previous experience, present knowledge and future prospects". Human Reproduction Update. 3 (3): 267–80. doi:10.1093/humupd/3.3.267. PMID 9322102.
  3. Eraslan, S.; Hamernik, R. J.; Hardy, J. D. (1966). "Replantation of uterus and ovaries in dogs, with successful pregnancy". Archives of Surgery. 92 (1): 9–12. doi:10.1001/archsurg.1966.01320190011002. PMID 5948103.
  4. Díaz-García, César; Akhi, Shamima N.; Wallin, Ann; Pellicer, Antonio; Brännström, Mats (2010). "First report on fertility after allogeneic uterus transplantation". Acta Obstetricia et Gynecologica Scandinavica. 89 (11): 1491–1494. doi:10.3109/00016349.2010.520688. PMID 20879912.
  5. Confino E.; Vermesh M.; Thomas W.; Gleicher N. (1986). "Unilateral rabbit uterus transplantation model". Int J Obstet Gynaecol. 24 (4): 321–325. doi:10.1016/0020-7292(86)90091-3.
  6. Jones, B. P.; Williams, N. J.; Saso, S.; Thum, M.-Y.; Quiroga, I.; Yazbek, J.; Wilkinson, S.; Ghaem‐Maghami, S.; Thomas, P. (2019). "Uterine transplantation in transgender women". BJOG: An International Journal of Obstetrics & Gynaecology. 126 (2): 152–156. doi:10.1111/1471-0528.15438. ISSN 1471-0528.
  7. "Lili Elbe". Biography. Retrieved 2019-02-25.
  8. "Trans Media Watch". www.transmediawatch.org. Retrieved 2019-02-25.
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  10. Nair, Anjana; Stega, Jeanetta; Smith, J. Richard; Del Priore, Giuseppe (2008). "Uterus Transplant". Annals of the New York Academy of Sciences. 1127: 83–91. doi:10.1196/annals.1434.003. PMID 18443334.
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  12. "Turkish woman has world's first womb transplant". timesofmalta.com. Retrieved 2012-11-21.
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  21. "World's first successful uterus transplant performed in Turkey". Rt.com. October 2011. Retrieved 2012-11-20.
  22. Derya Sert'in gebeliği sonlandırıldı. CNNTurk.com. (in Turkish)
  23. "Kadavradan rahim nakli yapılan Derya Sert anne oldu" [Derya Sert, receiver of a uterus transplant from a cadaver, has become a mother] (in Turkish). Anadolu Agency. 2020-06-26.
  24. Brännström, Mats; Johannesson, Liza; Dahm-Kähler, Pernilla; Enskog, Anders; Mölne, Johan; Kvarnström, Niclas; Diaz-Garcia, Cesar; Hanafy, Ash; Lundmark, Cecilia; Marcickiewicz, Janusz; Gäbel, Markus; Groth, Klaus; Akouri, Randa; Eklind, Saskia; Holgersson, Jan; Tzakis, Andreas; Olausson, Michael (2014). "First clinical uterus transplantation trial: a six-month report". Fertility and Sterility. 101 (5): 1228–1236. doi:10.1016/j.fertnstert.2014.02.024. PMID 24582522.
  25. Brännström, Mats; Diaz-Garcia, Cesar; Hanafy, Ash; Olausson, Michael; Tzakis, Andreas (2012). "Uterus transplantation: animal research and human possibilities". Fertility and Sterility. 97 (6): 1269–1276. doi:10.1016/j.fertnstert.2012.04.001. PMID 22542990.
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  44. Johannesson, Liza; Diaz-Garcia, Cesar; Leonhardt, Henrik; Dahm-Kähler, Pernilla; Marcickiewicz, Janusz; Olausson, Michael; Brännström, Mats (2012). "Vascular Pedicle Lengths After Hysterectomy". Obstetrics & Gynecology. 119 (6): 1219–1225. doi:10.1097/AOG.0b013e318255006f.
  45. Brännström, M.; Wranning, C. A.; Altchek, A. (2009). "Experimental uterus transplantation". Human Reproduction Update. 16 (3): 329–45. doi:10.1093/humupd/dmp049. PMID 19897849.
  46. Wranning, C. A.; Akhi, S. N.; Diaz-Garcia, C.; Brännström, M. (15 December 2010). "Pregnancy after syngeneic uterus transplantation and spontaneous mating in the rat". Human Reproduction. 26 (3): 553–558. doi:10.1093/humrep/deq358. PMID 21159686.
  47. Enskog, A.; Johannesson, L.; Chai, D. C.; Dahm-Kahler, P.; Marcickiewicz, J.; Nyachieo, A.; Mwenda, J. M.; Brännström, M. (2 June 2010). "Uterus transplantation in the baboon: methodology and long-term function after auto-transplantation". Human Reproduction. 25 (8): 1980–1987. doi:10.1093/humrep/deq109. PMID 20519250.
  48. Dahm-Kähler, Pernilla; Wranning, Caiza; Lundmark, Cecilia; Enskog, Anders; Mölne, Johan; Marcickiewicz, Janusz; El-Akouri, Randa Racho; McCracken, John; et al. (2008). "Transplantation of the uterus in sheep: Methodology and early reperfusion events". Journal of Obstetrics and Gynaecology Research. 34 (5): 784–793. doi:10.1111/j.1447-0756.2008.00854.x. PMID 18834335.
  49. Wranning, Caiza Almen; El-Akouri, Randa Racho; Lundmark, Cecilia; Dahm-Kahler, Pernilla; Molne, Johan; Enskog, Anders; Brännström, Mats (2006). "Auto-transplantation of the uterus in the domestic pig (Sus scrofa): Surgical technique and early reperfusion events". Journal of Obstetrics and Gynaecology Research. 32 (4): 358–367. doi:10.1111/j.1447-0756.2006.00426.x. PMID 16882260.
  50. Lefkowitz A.; Edwards M.; Balayla J. (2012). "O081 THE MONTREAL CRITERIA FOR THE ETHICAL FEASIBILITY OF UTERINE TRANSPLANTATION". International Journal of Gynecology & Obstetrics. 119 (Supplement 3): S289. doi:10.1016/S0020-7292(12)60511-6.
  51. Lefkowitz Ariel (2013). "Ethical considerations in the era of the uterine transplant: an update of the Montreal Criteria for the Ethical Feasibility of Uterine Transplantation". Fertility and Sterility. 100: 924–926. doi:10.1016/j.fertnstert.2013.05.026.
  52. Moore FD (2000). "Ethical problems special to surgery: surgical teaching, surgical innovation, and the surgeon in managed care". Arch Surg. 135: 14–16. doi:10.1001/archsurg.135.1.14. PMID 10636340.
  53. Lefkowitz, Ariel; Edwards, Marcel; Balayla, Jacques (Oct 2013). "Ethical considerations in the era of the uterine transplant: an update of the Montreal Criteria for the Ethical Feasibility of Uterine Transplantation". Fertility and Sterility. 100 (4): 924–926. doi:10.1016/j.fertnstert.2013.05.026. ISSN 0015-0282. However, it certainly bears mentioning that there does not seem to be a prima facie ethical reason to reject the idea of performing uterine transplant on a male or trans patient. A male or trans patient wishing to gestate a child does not have a lesser claim to that desire than their female counterparts. The principle of autonomy is not sex-specific. This right is not absolute, but it is not the business of medicine to decide what is unreasonable to request for a person of sound mind, except as it relates to medical and surgical risk, as well as to distribution of resources. A male who identifies as a woman, for example, arguably has UFI, no functionally different than a woman who is born female with UFI. Irrespective of the surgical challenges involved, such a person's right to self-governance of her reproductive potential ought to be equal to her genetically female peers and should be respected.
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