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. Uterus is a dynamic, complex organ. It is hugely blood-flow dependent. More than 116,000 Number of men, women and children on the national transplant waiting list as of August 2017. 33,611 transplants were performed in 2016. 20 people die each day waiting for a transplant. every 10 minutes another person is added to the waiting list.

1. UTERUS
TRANSPLANTATION
DONE BY : MUSTAFA KHALIL IBRAHIM
Tbilisi State Medical University
6th Year, 1st Semester, 1st Group
DEPARTMENT OF OBSTETRIC AND GYNECOLOGY

2.  More than 116,000 Number of men, women and
children on the national transplant waiting list as of
August 2017.
 33,611 transplants were performed in 2016.
 20 people die each day waiting for a transplant.
 every 10 minutes another person is added to the
waiting list.

4.  Up to 15% of the populations is infertile.
 3 to 5% of these cases are caused by uterine dysfunction.
 Uterine transplantation, although still experimental, may be an
option in these cases.
 This systematic review will outline the recommendations,
surgical aspects, immunosuppressive drugs and reproductive
aspects related to experimental uterine transplantation in women.
 Married women aged 15-44 that are infertile: 6.7%


7.  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.
 Uterus is a dynamic, complex organ. It is hugely blood-flow
dependent.

8.  congenital Müllerian malformations:
- Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome
(vagina and uterus to be underdeveloped or absent)
 more commonly acquired
- Asherman’s syndrome (intrauterine adhesions ).
- pregnancy interfering myomas.
- hysterectomies.
Since no successful treatment has been available for absolute
uterine factor infertility, the options for these women to become
mothers have been either to adopt or to go through with gestational
surrogacy, a procedure that is currently banned in many countries.

9.  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.
 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.
 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.

10.  In 1931 in Germany, Lili Elbe, a Danish transgender woman, died
from organ rejection three months after receiving one of the
world's earliest uterine transplants.
 With the availability of in vitro fertilization in 1978, uterine
transplantation research was deferred.

11.  In Saudi Arabia in 2000, a uterine transplant was performed by Dr.
Wafa Fagee, from a 46-year-old hysterectomy patient into a 26-year-
old recipient.
 whose own uterus had hemorrhaged after childbirth. The
transplanted uterus functioned for 99 days, but ultimately needed to
be removed after failure due to blood clotting.
 Within the medical community there was some debate as to whether
or not the transplant could truly be considered to have been
successful.
 Post-operatively, the patient had two spontaneous menstrual cycles,
followed by amenorrhoea; exploratory laparotomy confirmed uterine
necrosis. The procedure has raised some moral and ethical concerns,
which have been addressed in the literature.

12.  In Turkey, on 9 August 2011, the world's first uterus transplant
from a deceased donor was conducted by a team of doctors at
Akdeniz University Hospital in Antalya.
 The 21-year-old Turkish woman, Derya Sert, who had been born
without a uterus, was the first woman in history to receive a
womb from a deceased donor. The operation, performed by Dr.
Ömer Özkan, Dr. Munire Erman Akar and their team, was the
world's first uterus transplant surgery gaining long-term
function, as evident by the fact that Ms. Sert has had six
menstrual periods post-surgery and is said to have a fully
functioning uterus.
 The Turkish medical team who performed the delicate surgery,
however, is still cautious about declaring the operation a
complete success. "The surgery was a success. But we will be
successful when she has her baby", Ozkan said. "For now, we are
happy that the tissue is living".

13.  On 12 April 2013, Akdeniz University announced that Derya Sert
was pregnant.
 The statement made by the university hospital also added that Ms
Sert would give birth by C-section to prevent any complications.
 On 14 May 2013, it was announced that Ms Sert had terminated
her pregnancy in its 8th week following a routine examination
where doctors failed to detect a fetal heartbeat.

14.  In Sweden in 2012, the first mother-to-daughter uterus transplant was
done by Swedish doctors at Sahlgrenska University Hospital at
Gothenburg University led by Mats Brännström.
 The first uterine transplant performed in the United States took place
on 24 February 2016 at the Cleveland Clinic.
 The transplant failed due to a complication on 8 March and the uterus
was removed.
 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.
 The first Utx 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 uterus in
the transplant.

15.  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.

16. 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.

17.  In Nov 2017 the first baby was born after a uterus transplantation
in the US. The birth occurred at Baylor University Medical Center
in Dallas, TX, after a uterus donation from a non-directed living
donor .

18.  Infertility related to uterus.
 Desire for uterine transplantation.
 Medically Impossible to have a baby.
 Congenital uterine agenesis.
 Resection of uterus because of hemorahge , trauma except malign tumours.
 Be aware of long time postoperative rehabilitation.
 Patient sould be 18 – 45 age.
 Have no major trauma or surgery for negative effect of outcomes.
 Healthy organs and systems.
 Psychosocial stability.
 Whole healthy who has no limitation for taking immunosuppressive agent.
 Informed concern about all adverse effect of immunosuppressive agents.

19.  Counseling.
 Donor uterus.
 Investigations for the recipient.
 IVF for the recipient.
 The process of Uterine transplantation.
 Ensuring stability of the graft for 1.5 years by immunosuppressive.
 Embryo transfer.
 Careful close observation of pregnancy till the end.
 Hysterectomy of the transplanted uterus.
 Adhering to ethical issues as regards transplantation discipline.

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

21.  Surgery and vascular anastomosis
 Fixation of transplanted uterus
 Avoiding Ischemia – reperfusion injury
 Immunosuppression
 Management of rejection.

22.  Procurement (technique similar to radical hysterectomy).
 Dissection of ureters.
 Isolation of arterial supply: isolation of the uterus with bilateral, long venous,
and arterial vascular
 pedicles.
 Back table preparation.
 Vascular anastomosis: end-to-side bilateral vascular anastomoses.
 Connect the uterine veins to the external iliac veins (with 8-0 polypropylene
sutures).
 Connect the anterior divisions of the internal iliac arteries to the external iliac
arteries (with 7-0 polypropylene sutures).
 Ensure that good pulses existed distal to the arterial anastomosis sites and that
the uterine tissue changed from pale to reddish, which is a sign of peripheral
tissue perfusion.
 Blood flow : 40 mL per min.

24.  Vaginal rim anastomosis.
 Round ligaments.
 the extensive bladder peritoneum on the uterine graft on top of
the recipient’s bladder to provide extra structural support.
 Avoid spontaneous labor

25.  Cold ischemia (+4°C) at preservation of graft ex vivo.
 Energy depletion.
 Membrane polarity change.
 Warm ischemia and reperfusion.
 Major damage.
 Organelle destruction (ROS).
 Inflammation.
 24 h preservation at 4º C in UW [University of Wisconsin
preservation] / PER [Perfadex]. Metabolic stabilization at
reperfusion within 1 h after 3h ischemia (1 h cold, 2h warm)

26.  Pregnancy rate :
 Animal studies: normal rate.
 Human studies: successful pregnancy outcome is reported.

27. Types:
 Hyper-acute rejection (min to h).
 Acute rejection (days to months).
 Chronic rejection (from day 1, slow process).
Indicators:
 CD+4/CD+8 ratio in blood.
 Doppler of uterine blood flow.
 Cervical/endometrial biopsy.

28.  Following transplantation, the transplanted organ is at risk for rejection. The
frequency of acute rejection episodes varies depending on which organ is
transplanted. The highest incidence of acute rejection is shown after lung,
heart, and intestinal transplantation (~35%–40%, 30%–45%, and 55%,
respectively).
 There is no specific blood marker for the uterus that reveals a decline in
uterine function or rejection, and rejection might thus not be clinically detected
until significant graft damage has occurred. As subclinical rejection episodes
may occur, a noninvasive graft monitoring is desirable in all organ
transplantation. These subclinical episodes of uterus rejection can only be
detected with acute or protocol biopsies. The uterine graft is, unlike other solid
organs, easily accessible from the vagina, and cervical tissue biopsies are, if not
noninvasive, at least minimally invasive and provide an ample surveillance
option of rejection. Unlike an endometrial biopsy, the cervical biopsy does not
interfere with the cavity of the uterus and can therefore also function as
surveillance of rejection during pregnancy.

29.  In the Saudi Arabian case, the transplant was monitored by
Doppler ultrasound, magnetic resonance imaging, and
measurements of the CD4/CD8 ratio in peripheral blood.
 Nine days after surgery, the recipient expressed fatigue, malaise,
and low abdominal and back pain.
 She showed subclinical fever, tachycardia, and a vaginal
discharge predicted to be signs of acute rejection.
 She was initially treated with an increased temporary
immunosuppression and IV corticosteroids, yet the episode of
rejection was not resolved until antithymocyte globulin was
given.

30.  Wound healing.
 Circulation.
 Sentinel skin.
 Infection.
 Pain.
 bleeding in the surgical area.

32.  Recipient.
 Donor.
 partner of the recipient.
 possible future child.
 All of them are exposed to potential risks if the surgery has to be
performed.
 Uterus transplantation is a complex procedure and is surrounded
by not only medical and psychological implications but also
ethical, moral, and cultural concerns and expectations.

33.  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.[9] 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.[9] 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.[44] 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.[45]

34.  The criteria set conditions for the recipient, the donor, and the health care team,
specifically:
I. The recipient is a genetic female with no medical contraindications to
transplantation, has uterine absence that has failed other therapy, has "a
personal or legal contraindication" to other options (surrogacy, adoption). It
is asked that she wants a child, is suitable for motherhood, psychologically
fit, likely to be compliant with treatment, and understand the risks of the
procedure.
II. 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. It is asked that there is no coercion and the donor is
responsible and sound to make informed decisions.
III. The health care team belongs to an institution that meets Moore's third
criterion[46] regarding institutional stability and has provided informed
consent to both parties. It is asked that there is no conflict of interests, and
anonymity can be protected unless recipient or donor waive this right.

35.  Uterus transplantation is not restricted to either live or deceased organ
donation. According to the World Health Organization Guiding
Principle, organ donations from deceased donors should always be
developed to their maximum potential, evading the innate risks to live
donors.
 However, because of the shortage of suitable organs from deceased
donors, donations from live donor are necessary in order to meet current
patient needs. Because of this, live donation is practiced despite the fact
that it may involve potential risks for the donor that may not be
negligible. In the eleven reported cases of human uterus
transplantations, the uteri were from live donors in ten cases and from a
deceased donor in one case.
 Both donor options carry their respective advantages and
disadvantages.

36.  Healthy volunteers younger than 45 years old.
 Multipar, carries similar criterias for kidney transplantation donor .
 Volunteers.
 Brain death with hemodynamic stability.
 Minimal comorbidity before death.
 Normal level in routine blood tests.
 Matched blood type/ HLA type.
 Human Papilloma Virus (HPV) Negative .
 Cytomegalovirüs (CMV) negative .
 HIV (AIDS) Negative .
 Negative viral hepatitis .
 Identification of absence of myoma or vascular anomaly.

37.  Induction phase :
- Anti-thymocyte globulin: 100-300mg/day for 10 days.
- prednisolone: 1000 mg IV on day 1; then slowly tapered to
20 mg/day.
 The maintenance :
- tacrolimus (Prograf, 0.2 mg/kg/day with blood levels between
15 and 20 µg/ml in the first month, 12-15 µg/ml in the second
month ).
- Mycophenolate mofetil (Cell Cept, 2 g/day).
- prednisolone: 10 mg/day.
- Azathioprine 2 mg/kg per day replaced after 10 months.
Azathioprine to avoid the potentially teratogenic effects
of mycophenolate mofetil in the run-up to the embryo
transfer attempts.

38. – Candida
– Aspergillus
 involve nearly all organs
 nonspecific clinical manifestations
– early detection is almost impossible
 usually diagnosed when it is already well disseminated
– aassociated mortality rates can be as high as 100%.
 early detection is crucial for the administration of effective antifungal
treatment
 removal of infected original lesions.
 The risk is especially high in patients using steroidtherapy
 Adjustment of immunosuppressive drugs
– lowering or even stopping them entirely may belife-saving.
 Unidentified clinical signs or pathological findings in system
investigations
 pulmonary
 central nervous system
 renal involvement

39.  Maintaining a healthy pregnancy that is defined as:
1. Without evidence of malformations in the newborn
2. Without worsening of graft function in the mother.
 The initial story of Dr wafa case !!!!

40.  The future of uterus transplantation is prone to hold modifications of the
procedure.
 New methods to evaluate the recipients, donors, and organs,
 There will certainly also be other surgical options, such as laparoscopic and
robotic-assisted methods, giving the possibility to reduce the surgical duration
and concurrent risks for both recipients and live donors.
 The organ-engineering technology, being still in its infancy, pursues two ways
of solution: the first involves donated organs, not suitable for transplantation,
that is decellularized and the second alternative involves a synthetic matrix.
 The two different types of matrices would then after a recellularization process
by the recipients own stem cells to be transplanted and in theory, function as
good as any transplanted organ with the major benefit that no
immunosuppression would be needed.
 It will be of utx most importance to continue to develop and improve protocols
for psychology with thorough assessment and support in a systematic and
structured way.

43.  https://en.wikipedia.org/wiki/Uterus_transplantation
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751897/
 https://www.cdc.gov/nchs/fastats/infertility.htm
 https://www.theguardian.com/commentisfree/2017/may/01/arti
ficial-womb-gender-family-equality-lamb