EDITORIAL

A Life Giver and Life Enhancing Transplant – Uterus

Transplant

Shilpa Nitin Chaudhari

Department of Obstetrics and Gynaecology, Smt. Kashibai Navale Medical College, Pune, Maharashtra, India

Key words: Organ Transplantation ,Utx , deceased donor (DD

INTRODUCTION

successful ovarian transplant took place in 2002 in Mumbai,

Maharashtra and first uterine transplant took place in India at

Pune, Galaxy center with followed by successful live birth

1^sttime in India.

rgan transplantation is a medical advancement saving

and improving quality of life of individuals. It is a

boon for persons with end-organ failure.

The process of organ transplant is complicated and it’s

a patience testing process for recipient, his or her family

members and the medical team involved in it.

Unlike traditional solid organ transplantation, Utx is not a

lifesaving but it is a LIFE GIVING. In utx costs, ethical,

and psychological issues are inevitable. Utx is a vascular

composite allograft means it can be done in genetically non-

identical members of the same species.

It is a remarkable achievement in modern medicine which

offers a second chance of life.^[1]

For uterus transplantation (Utx) it is said that it is a life giver

or a life-enhancing transplant.

Utx represents a significant step forward in addressing

infertility in cases of Absolute Uterine Factor Infertility

(AUFI). AUFI affects 1:500 women of fertile age. It can be

either uterine absence or uterine defect. In AUFI before Utx,

the only option for treatment of infertility was surrogacy or

adoption. With help of Utx AUFI patients gets chance to

have ......a gestation.

Definition of organ transplant is, moving of organ from one

body to another body for the purpose of replacing recipients

damaged or failing organ with working one from the donor,

where the donor can be living or deceased.

As we all well worse with organ transplantation history,

enumerate first living donor transplant was a kidney transplant

done way long back in 1954 at Boston, Massachusetts USA.

HISTORY

All over the world more than 80 Utx procedures have been

performed in almost in 20 centers.

Table 1 shows a list of transplants that took place according

to organ and year of its occurrence.

More than 40 live births had been achieved by 2022. In the

field of Utx animal research is going on from 1999, which was

done on mouse, rat, sheep, pig, and non-human primates. In

human first live donor (LD) Utx took place in 2000, it took

almost 15 years to have a successful first live birth after Utx. At

institute of Clinical Science SahlgrenskaAcademy at University

of Gothenburg, Sweden first live birth after Utx took place.

A 35-year-old woman with congenital absence uterus (atypical

Rokitansky syndrome) received uterus from LD of 61 years

old two parous women in 2013 and who delivered at 31 weeks

5 days gestation a male baby weighing 1,775 g, in 2014.

In a female reproductive system, transplants have different

importance, as failure of these organs is not end organ failure

which will lead to danger to life. Definitely, it is going to

fulfill patient’s right to achieve gestation parenthood (become

mother).

In a female reproductive system, transplants involved are

of ovary and uterus. Noticeable and proud event is that first

Access this article online

Quick Response code

Website:

Address for correspondence:

Shilpa Nitin Chaudhari, Department of Obstetrics

and Gynaecology, Smt. Kashibai Navale

Medical College, Pune, Maharashtra, India.

E-mail: drshilpachaudhari15671@gmail.com

DOI:

Recevied on:

Accepted on:

Medical Journal of Basic and Applied Research - Volume 5 - Issue 1 - Jan-Jun 2024

Chaudhari: Uterus Transplant

requires a special caution before giving consideration for

Table 1: Organ transplant history

Utx.

Type of transplant

Year of transplant

1954

4. Other factors: Complex congenital uterine anomalies,

Kidney transplant

radiotherapy damage.

pancreas transplant

1966

At present Utx can be performed in a person who is genetically

XX. In Androgen insensitivity syndrome person and in a

person who have undergone gender reassignment role of Utx

is uncertain till date due to ethical considerations.^[2]

liver transplant

1967

Pancreas and heart transplant

Heart and lung transplant

Single lung transplant

Double lung transplant

Intestinal transplant

1968

1981

1983

1986

Other factors needed to be evaluated with main indication

for Utx.

1987

a. Recipient age should be in between 18 and 45 years of age

b. Healthy organs of other systems

c. No presence of major trauma or surgery for negative

effect on outcome of Utx

Split liver transplant

1988

Living donor liver transplant

Living donor lung transplant

First uterus transplant

First successful ovarian transplant

1989

1990

2000

d. Psychological stability

e. Healthy person with no limitation to prescribe

immunosuppression agents with informed consent about

adverse effect of these drugs

f. Recipient should be aware about long-term post-

operative rehabilitation.

2002

First uterus transplant with

successful live birth

2015

First deceased donor (DD) Utx took place in 2017 and the

first live birth from DD Utx took place in 2017.

Potential Donor

About 80% of Utx have been performed from multiparous

living donors.

In May 2017 a successful uterine transplant performed and

in October 2018 first live female baby born as the first of

Asia’s, the first of India, and 12^thof world’s successful live

birth after Utx. This took place in Galaxy center hospital,

Pune, Maharashtra and was performed by Dr Shailesh

Puntambekar.

Planning of elective surgery is easier than in DD where

on-call and transport arrangements needed to be done.

LD needs to undergo many investigations to prevent

microbiological transmission of infections.

As research and technology advances technique of Utx also

evolved and the first live birth took place on 25 May 2023

after both donor and recipient surgery took place by Robotic

assistance again at Institute of Clinical Science Sahlgrenska

Academy at University of Gothenburg, Sweden.^[1]

Investigations include Human immunodeficiency virus,

Hepatitis B and C, cytomegalovirus, Epstein Barr virus,

syphilis, toxoplasma, and human T cell lymphotropic virus.

Added advantage of living donor is that time availability to

do cervical smear and human palloma virus (HPV) testing

to rule out precancerous and cancerous lesions of cervix.

Chlamydia, gonorrhea and trichomonas infection ruled out

by vaginal secretion culture.

INDICATION

Recipient

1. Mayer-Rokitansky-ku: ster-Hauser syndrome (MRKH):

MRKH has incidence of 1 in 5,000 women. Congenital

absence of uterus is a manifestation of this syndrome.

They have normally functioning ovaries with variable

degree of short vagina. Women with atypical MRKH

present with additional renal abnormality.

2. Asherman syndrome: Uterus present with dysfunctional

endometrium due to adhesions formation affects 1.5%

of reproductive age patients. Utx should be considered

in severe cases where all other treatment options are

exhausted.

Transvaginal sonography (TVS) needed to be done to rule

out structural abnormalities. Magnetic resonance imaging

or computed tomography angiography is done to provide

information of vessel morphology and caliber and patency

of vessels.

Most of the living donors were related to the recipients. Use

of 1^st° relatives provides immunological benefits. Age of

donor at donation have impact on success of transplant as

age increases chances of atherosclerotic changes in pelvic

vessels increases and may lead to an organ of insufficiency

quality for embryo implantation. Increasing age might cause

3. Hysterectomy: Hysterectomy in reproductive age

was included, hysterectomy performed for benign

gynecological disorders and for severe postpartum

hemorrhage. Hysterectomy due to gynecological cancer

Medical Journal of Basic and Applied Research - Volume 5 - Issue 1 - Jan-Jun 2024

Chaudhari: Uterus Transplant

arterial inflammation which can cause post-transplant graft

vasculopathy.^[2]

SURGERY TECHNIQUE FOR LD

HYSTERECTOMY

Surgery in donor can be performed by laparotomy or

laparoscopy, laparoscopic-assisted robotic surgery.

Use of DD allows more radical dissection, enabling larger

caliber vessels to reduce the risk of graft thrombosis. It is

advocated to retrieval of uterus before retrieval of other

lifesaving organs for donation. DD also needs to screen for

sexual transmitted disease screen and cervical cytology and

HPV testing. TVS is mandatory to rule out presence of uterine

structural anomalies. Risk of inflammation increases, which

may influence organ quality due to brain dead state in DD.

First, transection of round ligament and opening of

vesicovaginal spaces is done. Dissection of uterine tunnel

and the distal aspect of ureter is a crucial step (Area from

tunnel outlet to bladder). In uterine tunnel, there will be

overriding of uterine artery and under-riding or overriding

of deep uterine vein [Figures 1 and 2]. Tunnel is covered by

connective tissue by several small arteries and veins. These

need to be dissected. Ureter is fully freed. Large vessels are

fully attached to ureter and cervix. One or two deep uterine

veins are used in graft. Both sides vascular pedicle, uterine

artery, and deep uterine vein are dissected with – ligation and

transection of branches. In cases with thin uterine vein with

insufficient venous outflow utero ovarian vein is dissected.

Before going further, the oviduct, the utero ovarian ligament,

and Sacro – uterine ligament are divided. The vagina is

transected 2 cm below cervix. Vascular pedicles are clamped

and transected with back-table flushing and cooling.

Even though uterine graft tolerance for cold ischemia is

up to 24 h still increase in transplant time is potential for

ischemia – reperfusion injury, which may increase risk of

acute and chronic rejection of graft.

In decease donors there is an increase risk of fungal infection.^[2]

CLINICAL FLOW OF HUMAN

UTERUS TRANSPLANT

Utx transplant is different from other transplants as in

Utx, there is a involvement of Recipient, Donor, partner of

recipient, and possible future child.

SURGICAL TECHNIQUE FOR

TRANSPLANT IN RECIPIENT

Evaluation and screening of recipient and LD

Surgery time is less, compared to in donor. It is 2–6 h

in 73% of cases. First clearance of vaginal vault from the

bladder and external iliac vessels is done. In women with

MRKH, the rudimentary uterus in midline is cleaved to vault

level. The graft is lifted into pelvis to perform end-to-end

anastomosis of uterine vessels to external iliac vessels with

8–0 polypropylene. The vault is opened and vaginal-vaginal

anastomosis is done. [Figure 2] Fixative sutures connect

round and uterosacral ligament.

Independent multidisciplinary committee approval

IVF

Utx

The presence of good pulses distal to arterial anastomosis site

and the uterine tissue turns pale to reddish which is a sign of

peripheral tissues perfusion.

Pregnancy

IMMUNOSUPPRESSIVE PROTOCOL

Cesarean delivery

For all solid organs transplant, it is essential and mandatory

the burden of immunosuppressive medication. Aim is to keep

it in small doses and avoidance of steroids wherever possible.

In uterine transplantation, tacrolimus is a preferred agent.

Initially only mycophenolate mofetil is preferred to use.

mycophenolate mofetil can be used along with prednisolone.

Mycophenolate mofetil is later withdrawn in anticipation of

embryo transfer (ET) as it is teratogenic in nature. It is usually

replaced with azathioprine. Alternative regimen used for

maintenance is a combination of tacrolimus and azathioprine

Hysterectomy

Long-term follow-up

Flowchart of uterus transplantation in human. LD: Live donor,

DD: Deceased donor, ET: Embryo transfer, UTx: Uterus

transplantation, IVF: In vitro fertilization

Medical Journal of Basic and Applied Research - Volume 5 - Issue 1 - Jan-Jun 2024

Chaudhari: Uterus Transplant

Figure 1: Anatomy of donor right pelvic side middle large square shown on the left side shows overriding and under riding of

uterine veins on ureter and small square shown on the right side shows overriding of uterine artery over ureter. (Ureteric tunnel).

Uterine vein blue in color, uterine artery red in color, Bladder and ureter yellow in color, Uterus in grey color

given at 10mg/day and 2 mg/kg/day dose respectively.

Utx does not involve transplantation of fallopian tubes.

In vitro fertilization (IVF) is required as a part of Utx process.

IVF

Ovarian reserve is generally good in MRKH patients. IVF

before Utx is essential and is more beneficiary. In some

cases, post-Utx IVF is required due to exhaustion of pre

Utx embryo, or couple separated, the patient may want to

attempt pregnancy with a new partner Post Utx. In such

cases, IVF cycles have been tried post-Utx and been without

Figure 2: Vascular and vaginal anastomoses recipient

tissues of recipient are lined the anterior portion of internal

iliac arteries are anastomosed end to side to the external iliac

arteries both sides. Left side deep uterine vein anastomosed

end to side to the external iliac vein on right side utero-ovarian

vein anastomosed end to side to external iliac vein

complication resulting in live pregnancy.

Usually, long protocol with gonadotropin-releasing

hormone (GnRH) agonist and human chorionic gonadotropin

trigger and a short protocol with GnRh antagonist and GnRH

agonist trigger is used. Oocyte retrieval can be performed

transvaginally or transabdominally.

Frozen embryos are used commonly than frozen ocyte. 5–10

embryos required to be banked before Utx. Live birth rate per

ET with cleavage stage verses blastocyte embryos is 12.5%

and 4%, respectively.

Figure 3: (a) Biopsy showing mild rejection. A dense infiltrate

of leukocytes, mainly lymphocytes, exists in stroma and

infiltrates into basal layers of epithelium, with occasional

apoptotic cells (arrows) (b) 1 week after anti-rejection

treatment, leucocyte infiltration completely reversed

Debatable issue is regarding whether to perform

preimplantation genetic testing for aneuploidy (PGT-A).

Argument in support of using PGT-A is that it reduces time to

pregnancy, reduces cost, and reduces the risk of miscarriage

and emotional burden.

with no difference in rejections. Tacrolimus (0.2 mg/kg/day)

with maintenance blood level of 15–20 μg/mL in 1^stmonth

and 12–15 μg/mL in 2^ndmonth. Mycophenolate mofetil is

given at 2 g/day dose and prednisolone and azathioprine are

Argument against using PGT-A is that its efficacy is

questionable due to false negative and false positive, requiring

additional oocyte retrieval. It is associated with adverse

Medical Journal of Basic and Applied Research - Volume 5 - Issue 1 - Jan-Jun 2024

Chaudhari: Uterus Transplant

obstetrics outcomes, leading to cause low birth weight, and

Table 2: Exit causes

maternal hypertension.

Cause

Pathophysiology

Graft related

Ischemia-related graft dysfunction

Untreatable intrauterine infection

Endometrial atrophy

ET is done in routine manner. Transfer of a single embryo

is compulsory in Utx. Increased risk of multiple pregnancy

which can cause obstetric, neonatal, and postnatal

complications in Utx.

Irreversible rejection

Recipient related

Severe nephrotoxicity

Post-transplantation

lymphoproliferative disease

Malignancy

Serious systemic infection needing

omission of immunosuppression

Original protocol by Swedish group recommendation

1 year gap between Utx and ET. However short interval

of 4–6 months been reported with uneventful recovery.

Shorter interval between Utx and ET has psychological and

physiological advantages with successful live birth.

Pregnancy-related Malignant gestational trophoblastic

disease

Massively repeated implantation

failure/miscarriages without childbirth

Life-threatening obstetric bleeding,

untreatable by conventional

techniques

Both spontaneous and exogenous hormone-induced

programmed endometrial preparation are acceptable for ET.

Vaginal bacterial colonization especially in patients in whom

neovagina is created can be associated with implantation

failure and repeated miscarriage.

Psychology

Serious psychiatric disorder

Recipient wish

LIVE BIRTH AND OBSTETRICS

OUTCOMES

Complications in LD

Due to uterus retrieval, minor to major complications have

been seen in LD. Minor complications or morbidity includes

Urinary tract infection, fecal impaction, wound infection,

bladder hypotonia, leg pain, anemia, respiration failure

during anesthesia, and depression.

In utx delivery by caesarean section is mandatory. Till date,

total live birth rate/ET was 27.8% and 35.6%. The median

gestational age at birth is 36 weeks 6 days. Almost 47%

required 1-day neonatal intensive care unit stay.

Major morbidity is due to ureteric injuries. Preservation

of uterine vein and complicated procedure of Utx causes

various serious injuries to Ureter. Complications vary from

intraoperative ureter transection, ureteric laceration, post-

operative ureterovaginal fistula formation.

HYSTERECTOMY

As explained in the flowchart, hysterectomy is a fate of Utx.

Once a desirable number live children born, a hysterectomy

is mandatory. It reduces burden of immunosuppressive agents

and complications related to it recipients and her partner

also needed to explain the right and need of exit causes in

Utx. These causes may be graft-related, recipient-related,

pregnancy-related, or psychology-related. Detail of causes

has been enumerated in Table 2.

In future cases, there may have reduce chances of

ureteric injuries, as use of ovarian or utero-ovarian veins

instead of uterine vein will be done and has been tried in

recent cases.

Recipient Health Outcome

Followed not only during graft retention but several years

thereafter. Utx experience common worry about implantation

failure at ET. Specific worries of graft rejection, when

become mother, they feel like other mothers with the

associated stresses and rewards. They had feelings of joy

and frustrations of becoming complete women, changed self-

perception, and a changed body and sexuality.

LONG-TERM HEALTH OUTCOME

Transplantectomy should take place after all pregnancy

attempts have been made and if transplant graft fails.

Qualitative research data based on repeated interview have

been collected. Prospective data on the psychological and

medical health of LD, recipient, and recipient partner were

also collected.

Recipient Partner

Relatively stable with no negative effects of graft failure. At

3 years, follow-up had negative deviation in HRQOL when

birth had not yet been achieved. They had continued high

satisfaction with marital relationship.

LD: No major negative effects on health secondary to uterus

donation. Donor psychological well-being may decrease if

her donation does not lead to live pregnancy.

Medical Journal of Basic and Applied Research - Volume 5 - Issue 1 - Jan-Jun 2024

Chaudhari: Uterus Transplant

allowing women with AUFI for uterine transplant. Japanese

Child Health Outcome

population 32% women responders ready to become donor

and 37% of male responders considered asking their partners

to become donors.

Overall normal growth of both weight and height.

TRANSPLANT REJECTION

Informed consent from potential donor and families whether

it is a LD or dead donor is another major theme in ethical

discussions. Through discussions of risk, benefit, and

alternates are prerequisites including that LDs revoke all

parental rights to any resulting children gestated from

donated uterus and future relation with child is by no means

guaranteed.

Symptoms of rejection include abdominal pain and fever or

vaginal bleeding. Symptoms become apparent once rejection

has been firmly established.

Grading system for uterine allograft rejection in which

cervical biopsies were constant achievable means of detection

of rejection on graft [Figure 3]. One of the signs of rejection

in renal transplantation is lymphocyte subpopulation. Mild

to moderate rejection can be managed by 3-day intravenous

methylprednisolone. Severe rejection requires anti thymocyte

globulin.

For individuals registered as dead donors, explicit consent

from families or other representative is legally required.

Another ethical debate is in future if comparable level

of clinical follow-up with both LD and dead donor

achieved, then uterine transplant may no longer be ethically

justifiable.

In uterine transplantation, the need of immunosuppression is

temporary so less chance of cancer, diabetes mellitus, and

nephrectomy.

Informed consent: Recipient poses a greater risk than

routine ART. Clear statement of risk of rejection, clear

instructions about exit plan after desire pregnancies, and

live birth achievement to prevent further risk associated

with immunosuppression drugs. Or due to rejection of graft

that cannot be managed. Association of complex emotional,

ethical, and medical issues regarding termination of a desired

pregnancy. Counseling regarding when the patient decides to

retain the organ against medical advice regarding the safety

of the mother and fetus.

ETHICS OF UTERINE TRANSPLANT

Ethical issues-related to Utx are different from other organ

transplant as:

1. Uterus is life-giving or life-enhancing. When other organ

transplant is to prevent recipient mortality

2. Uterine transplant has both elements of transplant

medicine and ART

3. Prospect of uterine transplant underscores the potential

moral and social not only for genetic parenthood but also

gestational parenthood.

Consent should include that recipient will not be able to feel

same experience of pregnancy as normal pregnancy. She will

not feel fetal movements and experience contractions.

Montreal criteria for ethical feasibility of uterine transplant

constitute comprehensive ethical guideline for uterine

transplant. In this, there is a widespread agreement that the

physical, psychological, and broader societal rules of uterine

transplant ought to be identified and assessed.

Reproductive Autonomy

Individuals possess the capacity to self-determine their

reproductive decisions. There can be negative rights and

positive rights to gestation.

Ethical calculus of balancing benefits requires consideration

of four pillars of uterine transplant that is recipient, donor,

recipient partner, and child to be born.

Other options available for AUFI, are gestation surrogacy

and adoption. This options morally outweigh desire to have

genetically and gestationally related Offspring.

Ethical acceptability of uterine transplant likely depends

on religion, moral, and legal particularities of different

countries.

Ethical disagreements exist around inclusion criteria for

donor and recipient related to age, length of waiting time,

relation status, and prior children.

Ethical issues concern whether prevention of gestational

parenthood should be promoted.

Capacity after good parenting would likely be included in

ethical issues.

Individuals with MRKH in USA strongly desire for uterine

transplant to become affordable and available. Cross-

sectional study in USA suggests it is ethical and supports

Another issue is raised whether there is a right to a donor to

decide which recipient her uterus to be transplanted to.

Medical Journal of Basic and Applied Research - Volume 5 - Issue 1 - Jan-Jun 2024

Chaudhari: Uterus Transplant

Ethics in XY Individuals

•

To motivate family-completed women at perimenopausal

age for uterus donation

Female to male transgender hysterectomized uterus to

use for donation

To increase the age for donation.

Uterus is preferred and allowed in genetically XX female. Utx

May extend to genetically XY persons, including transgender

male to female. As in individuals who had undergone gender

transition process Utx could meaningfully contribute to the

success of gender transformation after achieving gestation

parenting.

Bioengineered Uterus

Bioengineered uterus can be one of option for shortage of

donor uterus. It is in an experimental basis in animals and

uterine segments have been experiments, not whole uterus. It

will take at least one decade to utilize a human bioengineered

uterus to be prepare.

Revise Montreal criteria suggest equal consideration in both

assigned female at birth and male-to-female transgender.

Often Ethical issues arise negatively on the appropriate

designation of parenthood.

DEVELOPMENT AND FUTURE

CONCLUSION

Uterine transplantation is now a clinical treatment. It has

been accepted in the national health system in Germany.

An international quality registry of uterine transplant was

launched by international Utx society in 2020. Advances

in robotic and noninvasive rejection diagnosis focus

on safety and efficacy, increase donor pool, and uterus

bioengineering.

Uterine transplantation is a life-given on life enhancer. Before

the first birth, after uterine transplant in year 2019, AUFI was

regarded as unattainable. As experience increased safety

and efficacy for the LD, recipient and child will continue

and cost will likely to decrease. Improved ethical issues in

uterine transplantation will go on an increase as advancement

in indication in recipient and criteria for donor will change.

Cost issue accepted under coverage health insurance will be

a positive step in Utx.

Robotic

Advantages are that it has magnified three-dimensional

vision, articulated wrist instruments, tremor reduction,

florescent images, and excellent surgery ergonomics.

Ray of hope is shouldered on bioengineered uterus in

terms of uterine transplantation and then definitely uterine

transplantation will be a widely accepted treatment option for

infertility in AUFI.

First, robotic-assisted laparoscopic surgery is done. In 2021,

fully robotic surgery was performed. Uterine transplant is

done by robotic surgery in the recipient in 2021 with vascular

and vaginal anastomosis. In this surgery, recovery was

uneventful with fruitful birth of a healthy boy in May 2023.

As skill advances, more and more robotic surgeries will have

greater future in uterine transplant.

REFERENCES

1. Brannstrom M, Racowsky C, Carbonnel M, Wu J, Gargiulo A,

Adashi EY, et al. Uterus transplantation: From research,

through human trials and into the future. Hum Reprod Update

2023;29:521-44.

2. Jones BP, Saso S, Yazbek J, Thum MY, Quiroga I,

Ghaem-Maghami S, et al. Uterine transplantation: Scientific

impact paper no. 65 April 2021. BJOG 2021;128:e51-66.

3. Brännström M, Johannesson L, Bokström H, Kvarnström N,

Mölne J, Dahm-Kähler P, et al. Livebirth after uterus

transplantation. Lancet 2015;385:607-16.

Non-invasive Rejection Diagnosis

As now, cervical biopsy is performed to identify rejection,

which leads to an invasion procedure. In renal transplantation,

new identification of biomarkers and lymphocyte markers,

cytokines, and chemokines are developed to diagnose

rejection. Studies are ongoing with multi – omics analysis

of vaginal/cervical fluids to find noninvasive uterine

biomarkers.

How to cite this article: Chaudhari SN. A Life Giver and

Life Enhancing Transplant – Uterus Transplant. Med J

Basic Appl Res 2024;5(1):1-7.

Increase of Donor Pool

•

Following steps can be in cooperate to increase donor

pool

Conflicts of Interest: None. Source of Support: None.

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material

in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material

is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce

Medical Journal of Basic and Applied Research - Volume 5 - Issue 1 - Jan-Jun 2024