August 2024

OB-GYN

UTERUS TRANSPLANT - THE FRONTIER OF INNOVATIVE FERTILITY TREATMENT

​​​Featuring: Jessica R. Walter, MD and Emily S. Jungheim, MD

For some, the study by Testa et al1 reads like science fiction. This seminal study represents a major step forward for patients with uterine-factor infertility. Uterus transplant is the only restorative treatment available to patients with a formerly dysfunctional or absent uterus, who can now, for the first time, carry their own biological child. 

Recognition of the profound technical and cross-disciplinary medical achievement is certainly deserved. However, the same complexities of care that make this study so remarkable simultaneously raise questions about how we should define value and acceptable risk in the context of a life-generating rather than life-saving organ transplant. 

Uterus transplant is hardly the first innovation in reproductive medicine that has inspired awe and ire in equal measure. The early reception to in vitro fertilization (IVF) in the 1970s bears remarkable resemblance to the skepticism associated with uterus transplant today. IVF, now a widespread mainstay of fertility treatment, was once considered science fiction. As an extreme example, in 1972 while clinical studies were underway, the British magazine Nova described IVF as “the biggest threat to humankind since the atom bomb.”2 Six years later in England, the first child was born from IVF. It was not until 1981 that a child was born from IVF in the US, after 41 unsuccessful attempts.3 Despite initial reservations and dismal success rates, today IVF accounts for 1% to 3% of all US live births. IVF easily represents one of the most significant innovations in medical technology in the past half century as evidenced by the award of the 2010 Nobel Prize in Physiology or Medicine to Robert Edwards for the development of IVF.4 

Concerns of excessive cost, morality, and medical necessity once levied against IVF are common critiques repeated against uterus transplant.5 IVF efficiency and effectiveness have improved over the years, and ideally uterus transplant will follow a similar trajectory. Of the 20 women who underwent uterus transplant in the Dallas Uterus Transplant Study (DUETS), 14 had a successful allograft. All 14 with a successful allograft had at least 1 live birth. For a new, complex procedure, these success rates for a previously untreatable condition should be interpreted as encouraging because they are comparable with the probability of live birth after 1 IVF treatment in the most favorable of IVF candidates. The success of the DUETS trial is further bolstered by similar success noted in other US and European uterus transplant cohorts.6,7 While this success may be due in part to the fact that the participants were hand-selected to meet stringent inclusion criteria, it should be expected that with greater experience and procedural optimization, live birth rates will rise. Even within the context of this 20-patient cohort, the learning and adaptation were evident throughout, including the adoption of minimally invasive surgical approaches to graft removal, the shortening of time to the first embryo transfer, and the optimization of immunosuppression protocols. 

While uterus transplant is promising, key considerations must be addressed. The significant rates of morbidity experienced by donors and recipients must be acknowledged. Twenty two percent of living donors (4/18) experienced postoperative complications requiring corrective surgical intervention, and 55% of recipients (11/20) experienced at least 1 complication. No persistent adverse effects were reported in the patient follow-up. Aside from donors and recipients, the health of children born from uterus transplant must also weigh heavily in the calculus when considering the procedure. Healthy children, not simply live birth, are the standard to which this treatment should aspire, and continued efforts to ensure the optimal health of offspring exposed to this unique intrauterine environment, immunosuppression, and timing of delivery are paramount. In time, uterus transplant will likely mirror the experience of other solid organ transplants, with improved outcomes and decreased graft loss and morbidity. Continued close surveillance of donors, recipients, and children is necessary to ensure long-term effects of living donation and short-term transplants are captured. 

Given the extraordinary resources required to achieve a live birth from uterus transplant, concerns of cost are inevitable. The unfortunate reality is that differential access due to high costs of care are present not only for breakthrough treatments such as uterus transplant, but even for widely accepted treatments like IVF. Insurance coverage for IVF is variable and often a matter of whether one lives in a state with an IVF insurance mandate. Infertile women without IVF coverage are less likely to have a child than women with coverage—simply because they cannot afford to self-fund treatment.8 

Controversy aside, innovative fertility treatments have important implications for all of human health and society. For example, IVF has broadened understanding of human conception, early pregnancy, and stem cell research and permitted the prevention of heritable diseases. Now that the pioneering efforts of Testa et al1 and others have demonstrated the feasibility and reproducibility of uterus transplant, more provocative and powerful questions can be asked. Uterus transplant provides a unique opportunity to understand uterine biology, the regenerative behavior of the endometrium, and the physiology of pregnancy and labor and to enhance understanding of the immune system function. It also presents an opportunity to reflect on how patients access care for infertility in general, not just for elite and breakthrough treatments such as uterus transplant. 
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Infertility leading to involuntary childlessness is a common disease, and it causes profound psychological and social morbidity.9 Medicine should unapologetically coalesce around a shared vision to alleviate this issue. Infertility, regardless of its etiology, deserves to be treated and efforts to develop innovative treatments are noble. Given the remarkable inefficiencies of human reproduction, the odds are rarely in our favor. This should inspire inquiry into other advanced treatments, which may reap greater benefits into future understanding of reproductive health, pregnancy, and female biology—areas of medicine and biology that are historically understudied and poorly understood, but important to all. ​
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​This article was originally published online in JAMA Network on August 15, 2024. 


References 
1. Testa  G, McKenna  GJ, Wall  A,  et al.  Uterus transplant in women with absolute uterine-factor infertility.   JAMA. Published online August 15, 2024. doi:10.1001/jama.2024.11679 
ArticleGoogle ScholarCrossref 
2. Marantz Henig  R. Pandora’s baby. Scientific American. Accessed July 13, 2024. https://www.scientificamerican.com/article/pandoras-baby-06-03/ 
3. Epstein  RH. Pioneer reflects on future of reproductive medicine. New York Times. Accessed July 12, 2024. https://www.nytimes.com/2010/03/23/health/23prof.html 
4. Chandra  A, Copen  CE, Stephen  EH.  Infertility service use in the United States: data from the National Survey of Family Growth, 1982-2010.   Natl Health Stat Report. 2014;(73):1-21.PubMedGoogle Scholar 
5. Walters  L.  Biomedical ethics.   JAMA. 1982;247(21):2942-2944. doi:10.1001/jama.1982.03320460042014 
ArticlePubMedGoogle ScholarCrossref 
6. Brännström  M, Dahm-Kähler  P, Kvarnström  N,  et al.  Reproductive, obstetric, and long-term health outcome after uterus transplantation: results of the first clinical trial.   Fertil Steril. 2022;118(3):576-585. doi:10.1016/j.fertnstert.2022.05.017PubMedGoogle ScholarCrossref 
7. Walter  JR, Johannesson  L, Falcone  T,  et al.  In vitro fertilization practice in patients with absolute uterine factor undergoing uterus transplant in the United States.   Fertil Steril. Published online April 15, 2024. doi:10.1016/j.fertnstert.2024.04.017PubMedGoogle ScholarCrossref 
8. Jungheim  ES, Leung  MY, Macones  GA, Odem  RR, Pollack  LM, Hamilton  BH.  In vitro fertilization insurance coverage and chances of a live birth.   JAMA. 2017;317(12):1273-1275. doi:10.1001/jama.2017.0727 
ArticlePubMedGoogle ScholarCrossref 
9. Becker  MA, Chandy  A, Mayer  JLW,  et al.  Psychiatric aspects of infertility.   Am J Psychiatry. 2019;176(9):765-766. doi:10.1176/appi.ajp.2019.176702PubMedGoogle ScholarCrossref 
Jessica R. Walter, MD, Assistant Professor of Reproductive Endocrinology and Infertility in the Department of Obstetrics and Gynecology.​
Emily S. Jungheim, MD, Chief of Reproductive Endocrinology and Infertility in the Department of Obstetrics and Gynecology.

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