Human uterus transplantation with live births; Outcome of the first clinical trials

The last frontier to conquer in female infertility is absolute uterine factor infertility (AUFI), affecting 1:500 women. This would correspond to around 160,000 AUFI women between 20 and 40 years of age in Europe. The cause of AUFI may be uterine aplasia, hysterectomy at young age (cervical/uterine malignancy, emergency postpartum hysterectomy), Asherman's syndrome or uterine malformation. Uterine transplantation (UTx) is now the first available treatment for this large group of women. Today, more than 20,000 children have been born from women with organ transplants and under immunosuppression (IS). Although these pregnancies usually can be managed with a positive outcome there are indications that the rates of obstetric complications (preeclampsia, preterm delivery, and growth restriction) are increased. However, this may well be due to the underlying disease (majority renal disease) and that the largest subpopulation of this group only have single kidneys. UTx was developed by us towards human application, by performing animal research for more than 15 years. It is imperative that a complicated surgical procedure such as UTx, with implications also in the fields of ART and fetal-maternal medicine, is prepared meticulously by research and training in animals to be safe at the time of clinical introduction.

We initiated research in the mouse-UTx model in 1999 and demonstrated 2002 for the first time offspring after UTx. Subsequent mouse experiments characterized uterine rejection, investigated suitable immunosuppression and established that the uterus is tolerable to cold-ischemia for 24h. In the rat UTx-model we showed successful pregnancies after natural conception, both after syngeneic and allogeneic transplantation. We have shown in our rodent studies that cyclosporine exposure during pregnancy increases the miscarriage rate but also that tacrolimus monotherapy, to avoid rejection of a uterine allograft, is compatible with normal pregnancy and development of offspring.

In the sheep and pig UTx models, we characterized reperfusion events after ischemic preservation and developed surgery in a more human like setting. Live births were shown after auto-UTx. In the allogenic UTx model in the sheep, Ramirez and colleagues demonstrated live birth, although with preterm delivery.

The baboon, a nonhuman primate, with great similarities, in regards to reproductive anatomy/physiology to the human, was used by us as the last step before human UTx. The surgical technique was developed by auto-UTx and in allo-UTx the most suitable immunosuppression and the means for rejection diagnosis were established. A Japanese group also demonstrated a live birth after auto-UTx in the rhesus monkey. Our studies in the baboon, showed that monotherapy with tacrolimus is not sufficient to suppress rejection of a uterine allograft. However, induction therapy with ATG, followed by triple IS with tacrolimus, MMF and corticosteroid prevented rejection.

Today 11 human UTx attempts have been performed, with 10 of them using live donors and one using a deceased donor. The first two human UTx-attempts, which were unsuccessful, were done in Saudi Arabia in 2000 and in Turkey in 2011. In early 2013 our team completed the surgeries of a series of totally 9 human UTx, with live uterus donors. The recovery surgery comprised isolation of the uterus with bilateral vascular pedicles, including the internal iliac arteries distal to the branching of the gluteal artery as well as the major uterine veins down to the internal iliac vein. This surgery of the donors lasted 10 – 12h. The perioperative outcome was favourable in all cases and with a stay in the hospital of 6 days. In one patient a ureteric-vaginal fistula was diagnosed after two weeks and this was later repaired. The surgeries of the recipients included bilateral end-to-side anastomoses to the external iliacs, vaginal anastomosis and fixation of the uterus to the pelvic ligaments. This lasted 4 – 6h and postoperative hospitalization was between 3 and 9 days.

Thus, we utilized a classical induction protocol with ATGx2, and the corticosteroids (only for 5 days), MMF (for 6 months) and tacrolimus. Occasional mild rejection episodes have been detected on cervical biopsies and successfully treated. When a patient had several rejection episodes during the first months MMF was shifted to azathioprine, to avoid teratogenic effects of MMF.

Seven out of the nine patients experienced regular menses from 2 months after UTx and embryo transfers were initiated 12 – 16 months after transplantation. The other two patients underwent hysterectomy during the first 3 months post transplantation, due to infection/abscess and thrombosis. So far 4 out of the 7 patients have delivered healthy babies (57% take-home baby rate) and another recipient is pregnant and expected to deliver in January 2016. The babies had normal weight for gestational age at birth and have developed normal, with the first boy now one-year old (September 4, 2015). A sixth recipient was pregnant but miscarried at week 14 and only one woman has so far (4 ETs) not been pregnant. This gives a total clinical pregnancy rate of 86% in this cohort of 7 UTx patients. Two of the uteri have now been removed by hysterectomy, since the patients and their partners are happy with one child each.

In conclusion, our thorough animal-based research on UTx has paved the way for our clinical success to achieve the first live births in the world after human UTx. We have developed a safe surgical technique for live donor uterus transplantation with a highly successful treatment for the previously untreatable AUFI condition. We will optimize this further by an approach with 2/3 of organ procurement done by robotically assisted laparoscopy and the 1/3 by laparotomy. We hope to decrease the surgical time with this modified technique. Our aim is to transfer this technology to all regions in the world, with structured training programs and by sharing know how of all aspects of the procedure.