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Abstract
Objective To evaluate the feasibility of uterine transposition as a method of preserving fertility and ovarian function after pelvic radiation.
Methods This prospective multicenter observational study included patients with non-gynecologic pelvic cancers who underwent pelvic radiation as part of their cancer treatment between June 2017 and June 2019. For inclusion in the study, patients were required to have normal menstrual cycles and hormone levels (follicle-stimulating hormone, luteinizing hormone, and estrogen) before treatment. Uterine transposition to the upper abdomen was performed prior to irradiation. Clinical examinations and Doppler ultrasonography were used to evaluate the gonadal vasculature post-surgery. The uterus was repositioned into the pelvis 2–4 weeks after radiation therapy or at the time of rectosigmoid resection in patients with rectal cancer who had undergone neoadjuvant treatment. Cancer treatment and follow-up were performed according to standard guidelines.
Results Eight patients (seven with rectal cancer and one with pelvic liposarcoma) underwent uterine transposition at a median age of 30.5 years (range 19–37). The uterus was successfully preserved in six patients, accompanied by normal menses, hormonal levels, and vaginal intercourse after treatment. One patient with rectal cancer died of carcinomatosis 4 months after uterine transposition. One patient presented with uterine necrosis 4 days after uterine transposition, and the uterus was removed; however, one ovary was preserved. Cervical ischemia was the most common post-surgical complication in three (37.5%) patients. Three patients attempted to conceive, and two (66%) were spontaneously successful and delivered healthy babies at 36 and 38 weeks by cesarean section without complications.
Conclusions Uterine transposition is a feasible procedure for preserving gonadal and uterine function in patients requiring pelvic radiotherapy for non-gynecological cancer, with the potential for achieving spontaneous pregnancy and successful delivery.
- Colorectal Neoplasms
- Gynecologic Surgical Procedures
- Postoperative complications
- Radiation
- Adnexal Diseases
Data availability statement
Data are available upon reasonable request.
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- Colorectal Neoplasms
- Gynecologic Surgical Procedures
- Postoperative complications
- Radiation
- Adnexal Diseases
WHAT IS ALREADY KNOWN ON THIS TOPIC
Patients with pelvic malignancies frequently undergo pelvic radiation as a part of their treatment protocol, which can result in infertility.
It is crucial to establish the feasibility of uterine transposition for preserving ovarian and uterine functions to maintain fertility.
WHAT THIS STUDY ADDS
Of the eight patients who underwent uterine transposition, the uterus was successfully preserved in six patients; these patients had normal menses, hormonal levels, and vaginal intercourse after the procedure.
Three patients attempted to conceive, and two were spontaneously successful, subsequently delivering healthy babies via cesarean section without complications.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Uterine transposition could be a feasible option for preserving gonadal and uterine function in patients undergoing pelvic radiotherapy for non-gynecological cancer.
Introduction
With evolving multimodal cancer treatments, patient survival rates have persistently improved, and issues related to patients’ quality of life have become increasingly important, especially concerns related to fertility preservation among young female patients wth cancer.1 The growing incidence of several tumors among young patients, particularly colorectal tumors,2 and the increase in the average age at first pregnancy,3 have resulted in the development of novel options for fertility preservation. Young patients with pelvic malignancies may need to undergo radiotherapy as a part of their treatment protocol. Radiation doses to the ovaries may be toxic.4 Pelvic radiation causes infertility by inducing ovarian failure,5 decreasing uterine volume, reducing myometrial distensibility due to fibrosis, and injuring the endometrium and uterine vasculature.6–10
In 2017, Ribeiro et al11 first described uterine transposition in a patient with rectal cancer. Uterine transposition has emerged as a novel and potential alternative for preserving fertility and hormonal function in these patients. In 2018, Baiocchi et al12 published the first report of uterine transposition in a patient with cervical cancer, while Marques et al13 conducted the first robotic procedure in 2020. In 2021, Vieira et al14 reported the first pediatric patient to undergo the procedure, a notable development among this patient population that lacks access to in vitro fertilization. However, no gestation occurred until 2023, when Ribeiro et al15 reported the first live birth following uterine transposition, emphasizing that young women may conceive naturally and achieve a full-term pregnancy. Herein, we evaluate the feasibility of uterine transposition to preserve ovarian and uterine functions and assess its morbidity and fertility rates.
Methods
The Uterine Transposition Feasibility Trial was an observational prospective, non-randomized study approved by the Erasto Gaertner IRB (CTN03040921) and the Brazilian National Research Ethics Commission (CAAE61955416.2.0000.0098). Patient recruitment was performed between June 2017 and June 2019. All patients provided written informed consent prior to enrollment.
The primary objective of this study was to assess the feasibility of surgery, defined as the preservation of uterine function (normal menstrual cycles and hormone levels), without serious complications. Surgical complications, fertility rate, and potential oncological impact were examined as secondary outcomes.
Inclusion criteria were age ≤40 years; desire to preserve fertility and become pregnant; and an indication of pelvic radiation as part of a non-gynecologic pelvic cancer. Exclusion criteria were previous infertility; need for para-aortic radiation as part of the cancer treatment; tumor infiltrating the uterus, tubes, or ovaries; previous radiotherapy of the pelvis and/or para-aortic area; previous adnexectomy or any surgery that might have damaged ovarian vessels; uterine volume >300 mL; and presence of metastatic disease. Patients were excluded if uterine transposition necessitated modification of cancer treatment.
The uterine function was assessed by clinical evaluation of menstrual cycles and hormone profiling. Pre-treatment follicle-stimulating hormone, luteinizing hormone, and estrogen levels were measured. The uterine transposition technique and peri-operative care protocol have been detailed previously.16 Briefly, the round, broad, and uterosacral ligaments were initially sectioned during minimally invasive surgery. The vesicouterine septum was dissected. The uterine vessels were coagulated and ligated immediately, lateral to the cervix. The vagina was then sectioned, and the uterus was mobilized. The infundibulopelvic ligaments were cranially dissected until they intersected the iliac arteries. Accordingly, the sigmoid and descending colons were mobilized cranially via lateromedial dissection. The gonadal vessels were dissected from the pelvic portion to their origin. With the uterus pulled by the round ligaments to the upper abdomen, the cecum, ileum, and omentum were gently moved beneath the arch formed by the infundibulopelvic ligaments. Next, the uterus was positioned at the epigastrium with the distal end of the cervix at the level of the umbilical trocar. Transparietal sutures were used to secure the infundibulopelvic ligaments and the uterine body to the abdominal wall. Finally, the cervix was anastomosed to the umbilicus to create the uterine outlet for menses (Figure 1) and mucus. If the cervix was detached from the umbilicus, the patient initiated continuous oral contraceptives the day after surgery to suppress menses until uterine reimplantation was achieved. For the second surgery (uterine repositioning in the pelvis), adhesions were released after placement in the abdomen, allowing the uterus to be mobilized back to the pelvis. The vagina was dissected and sectioned using monopolar energy to allow insertion of the cervix into the vagina. The uterine ligaments were then sutured to the remaining lateral portions, completing the reconstruction.
Umbilical menstruation.
After reimplantation, uterine and ovarian functions were evaluated by examining medical history and by clinical assessments every 3 months, and pelvic ultrasound and hormone levels were evaluated every 6 months. Additional examinations were performed as clinically indicated according to the patient’s symptoms. Pelvic MRI was performed 15–60 days after reimplantation. One year post-procedure, oncological follow-up was performed according to the standard guidelines of each hospital.
Results
Uterine and ovarian preservation outcomes
Although 11 patients were screened, three declined to participate and were excluded. For the eight patients (seven with rectal cancer and one with pelvic liposarcoma) who underwent uterine transposition (table 1), the feasibility rate was 75% (n=6). All six patients had vaginal intercourse without dyspareunia. Owing to different laboratory standards at each institution, hormonal levels were documented as within the normal range or not. The median age of the patients was 30.5 years (range 19–37). The mean follow-up duration was 30.6 months (range 4–51).
Patients' data
Pregnancy Outcomes
Two patients (66%) who attempted conception had spontaneous pregnancies. The first live birth after uterine transposition was delivered by Cesarean section at 36 weeks and 2 days (2686 g and 46.5 cm), with Apgar scores of 5 and 9 at 1 and 5 min, respectively, and both the mother and child were discharged the following day.15 The second live birth was delivered via planned cesarean section at 38 weeks of gestation. Both babies displayed normal development throughout a follow-up period of 1 year. One patient attempted to conceive (37 years of age at uterine transposition) and underwent three in vitro fertilization cycles and implantations without success.
Surgical Outcomes
Considering uterine mobilization procedures, the median surgical time was 150 min (range 90–180), with a median blood loss of 60 mL (range 30–150). No intra-operative complications were observed. All patients underwent Doppler ultrasonography of the upper abdomen 2 days after uterine transposition. Normal Doppler flow in the utero-ovarian ligaments was observed in the six patients. However, two patients showed a unilateral absence of flow, suggesting potential vascular impairment. The first patient had a normal cervix on clinical examination and presented with no complications. Conversely, the second patient had an ischemic uterus during surgery that was not promptly dealt with, resulting in uterine necrosis, confirmed 4 days later (Figure 2). A laparoscopic hysterectomy with left adnexectomy was performed, preserving the right ovary and maintaining normal hormone function.
Evolution of uterine necrosis. (A) Uterus showing substantial ischemia during mobilization to the upper abdomen. (B) Post-operative examination of the umbilicus where the tip of the cervix can be observed. (C) MRI scan showing the absence of left uterine perfusion. (D) Laparoscopic evaluation of the uterus confirming no perfusion on the left hemi-uterus and homolateral ovary and tube.
After surgery, cervical ischemia, characterized by necrosis or substantial atrophy of the cervix with stenosis, was the most frequent complication observed in three patients (37.5%). One patient required trachelectomy via an umbilical approach owing to cervical ischemia with necrosis noted on the first post-operative day. Another patient successfully underwent treatment for cervical ischemia with atrophy and cervical canal stenosis, both clinically evident during uterine reimplantation. The third patient with cervical ischemia also exhibited cervical atrophy with hematocolpos, treated during uterine reimplantation.
Uterine reimplantation required a median surgical time of 90 min (range 70–120). No complications occurred during the reimplantation surgeries. The median length of hospitalization was 3 days (range 3–5), which varied according to the procedure performed, with a median of 1 day for patients undergoing reimplantation alone and 4 days for those who underwent both reimplantation and rectosigmoidectomy during the same procedure. One patient with rectal cancer died of carcinomatosis 4 months after uterine transposition and before reimplantation.
Discussion
Summary of Main Results
The uterine transposition feasibility rate was 75%, and fertility was preserved in those who underwent pelvic radiotherapy. The uterine transposition technique could maintain hormonal levels, menses, spontaneous pregnancy, and live births with acceptable morbidity.
Results in the Context of Published Literature
Pregnancy following pelvic radiation is rare and morbid. There have been five case reports of pregnancy after pelvic radiation before the development of uterine transposition. Hürmüz et al17 reported spontaneous pregnancy and healthy delivery after pelvic chemoradiation in a 25-year-old patient with anal cancer. Köhler et al18 documented a 36-year-old patient with anal cancer who underwent ovarian transposition and uterine fixation to the anterior abdominal wall before chemoradiation. The authors reported that in vitro fertilization therapy resulted in successful pregnancy and delivery.
The other three cases highlighted the high morbidity of pregnancy in patients who underwent uterine irradiation. Martin et al19 reported a 33-year-old patient with cervical cancer treated with trachelectomy and subsequent adjuvant radiation therapy. After hormone replacement therapy, gestation evolved with oligohydramnios and growth retardation, followed by pre-term labor requiring cesarean section at 27 weeks of gestation. Plante et al20 reported a 25-year-old patient with cervical cancer who underwent laparoscopic sentinel lymph node mapping, bilateral pelvic node dissection, and radical vaginal trachelectomy. The patient received parametrial and lateral sidewall chemoradiotherapy. After the high-estrogen regimen, in vitro fertilization resulted in a successful pregnancy; however, the patient experienced pre-term premature membrane rupture and chorioamnionitis, necessitating a cesarean section at 24 weeks. The infant developed septicemia and a wound abscess and died of septic shock. Finally, Wald et al21 reported the case of a 36-year-old patient with rectal cancer who underwent laparoscopic oophoropexy followed by neoadjuvant chemoradiation. The patient spontaneously became pregnant with twins and developed pre-term premature membrane rupture at 28 weeks. The delivery was complicated, resulting in the death of one twin.
Accumulated evidence suggests that myometrial fibrosis, uterine vasculature, and endometrial injuries caused by pelvic radiation6–10 substantially impact pregnancy outcomes. In our series, two patients experienced spontaneous pregnancy (figure 3), an advantage over standard options such as ovarian transposition, oocyte vitrification, or frozen embryos. Both pregnancies progressed normally until at least 36 weeks, with normal fetal growth (figure 3). Notably, patients in the current study reported noticing Braxton-Hicks contractions solely by feeling the abdominal wall or with their hands. However, the patient who went into labor with regular contractions and dilation did not experience cramps or any source of uterine pain throughout the entire process. This absence of pain can be attributed to the denervation process that occurs during transposition. Moreover, obesity may affect contraction perception owing to altered sensory responses or increased adipose tissue surrounding the uterus. Close monitoring and individualized care of obese pregnant patients are crucial for managing labor. Further research is needed to explore this association and optimize care among this population.
Normal ultrasound during the pregnancies. IVC: inferior vena cava, SVC: superior vena cava
Data on the increased risk of obstetric complications during vaginal delivery are lacking in patients who have received pelvic radiation because these patients do not get pregnant. The choice of cesarean section was primarily influenced by the potential complications associated with radiotherapy-induced changes in the pelvic region. Patients who have undergone pelvic irradiation for rectal cancer have five times more soft tissue complications than those unexposed to radiation.22 Fibrotic changes in irradiated tissues can lead to a notable loss of elasticity, potentially compromising the necessary pelvic dilation for normal delivery. Pelvic radiotherapy is a recognized risk factor of vaginal vault dehiscence after hysterectomy,23 emphasizing the need to consider the increased risk of impaired healing of vaginal lacerations during vaginal delivery in such cases. To mitigate these risks and ensure the safety of both mother and baby, cesarean section is preferable for patients who have undergone pelvic radiotherapy. Accordingly, the second pregnant patient underwent a scheduled cesarean section at 38 weeks.
The oldest patient in our series (37 years old at the time of surgery) failed to conceive, despite three in vitro fertilization cycles and normal menstrual cycles and hormone levels until the last follow-up (March 2023). Furthermore, ovarian and uterine radiation doses were insignificant (less than 0.3 Gy), and anti-Müllerian levels were 2.27 ng/mL before treatment and 0.5 and 1.04 ng/mL 1 and 2 years after uterine transposition; this highlights the fact that performing a technically adequate procedure does not guarantee a successful pregnancy. Doppler ultrasonography aids in identifying the risk of uterine necrosis. However, challenges exist in identifying small vessels in abnormal locations. Despite undetected flow on one side of the gonadal vessel in one patient, a normal post-operative course was observed. A comprehensive approach combining clinical and radiological findings is essential for accurate risk assessment and management decisions.
Complications associated with uterine transposition appear acceptable, improving as surgeons progress through their learning curve. Cervical ischemia may arise from the parametrial section of the cervical stroma, sacrificing the descending branch of the uterine artery. However, cervical atrophy and stenosis were managed effectively. The possibility of uterine necrosis cannot be overlooked, and patients need to be aware of this outcome. Although intra-operative ischemia was detected in one patient, the surgeons decided against performing a hysterectomy at that point. Based on our experience, certain patients may manifest transient ischemic signs during surgery and subsequently improve within minutes, whereas other patients may experience persistent ischemia during the procedure but still have favorable outcomes later. Although unexplored in the current study, the application of indocyanine green fluorescence angiography may assist in decision-making.24 We recommend preserving the uterus despite detecting hypoperfusion using indocyanine green and closely monitoring the patient using post-operative Doppler ultrasound and MRI.
Furthermore, all patients had normal vaginal intercourse without pain, an advantage in comparison with patients with rectal cancer, among whom only 34% report no dyspareunia, 21.3% report no vaginal dryness, and 10.1% experience no reduction in sexual activity.25 Interestingly, patients who underwent uterine transposition did not experience issues with vaginal lubrication because their cervical mucoid glands were unaffected. We speculate that the positive psychological effect should be considered, as these patients perceive themselves as having retained their ability to reproduce, which can empower them in their relationships and ease fertility-related concerns. Regarding oncological safety, no unplanned treatments were performed in accordance with the uterine transposition protocol. The patients received standard treatment for respective primary tumors, with only one case of peritoneal recurrence, possibly due to advanced disease rather than due to uterine transposition.
Strengths and Weaknesses
A strength of our study lies in the fact that all surgical procedures were conducted by three surgeons highly experienced in minimally invasive and gynecological oncologic surgery (RR, RP, and GB). Notably, inclusion criteria enrolled all consecutive patients, which included the first case of uterine transposition performed by the two surgeons. This ensured a comprehensive and unbiased assessment of surgical outcomes during the learning curve.
Our study was limited by a small sample size, potentially limiting generalizability and statistical power. Additionally, the lack of a quality-of-life assessment means we might have missed insights into patients' well-being and experiences. These limitations emphasize the need for caution in interpreting our findings and suggest avenues for future research with larger, more diverse samples and quality-of-life assessments to gain a more comprehensive understanding of the topic.
The study was initially authorized to enroll patients for 2 years, with a subsequent institutional review board decision on whether to continue enrollment based on results. However, this restricted the number of patients that could be recruited, consequently affecting the available data on pregnancy rates and oncological outcomes. Following the data presentation, extended recruitment was granted until 2030, allowing for further investigation and analysis. This extension affords the opportunity to gather additional, comprehensive data, ensuring a robust understanding of research objectives and potentially yielding valuable insights that can contribute to advancements in this field.
Implications for Practice and Future Research
Uterine transposition offers an option for fertility preservation in young patients, who may experience uterine loss of function following pelvic radiotherapy. Institutions should establish research protocols that enable clinicians to consider uterine transposition as part of a comprehensive discussion with patients and provide patients with information about the procedure, its potential benefits, and associated risks. This would enable patients to reach informed decisions regarding their reproductive options to preserve fertility. This procedure should be performed only in specialized centers which have the surgical expertise and experience to perform such a procedure outside of a clinical trial.
Conclusion
Uterine transposition is a feasible procedure for preserving gonadal and uterine function in patients requiring pelvic radiotherapy for non-gynecological cancer, facilitating spontaneous pregnancy and successful delivery.
Data availability statement
Data are available upon reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by Erasto Gaertner Hospital IRB approval n2.573.413. Brazilian National Research Ethics Commission (CONEP) approval CAAE: 61955416.2.1001.0098. Participants gave informed consent to participate in the study before taking part.
References
Footnotes
Twitter @glaucobaiocchi, @RParejaGineOnco
Contributors RR and JCL contributed to study planning, conceptualization, surgical data collection, data analysis, writing the original draft of manuscript, and reviewing and editing the manuscript. GB, RM-M, and RP contributed to surgical data collection, data analysis, writing the original draft of manuscript, and reviewing the manuscript. CNC contributed to study conceptualization, oncology data collection, data analysis, writing the original draft of manuscript, and reviewing the manuscript. All authors had access to the data reported in the study and had final responsibility for the decision to submit the manuscript for publication. RR is responsible for the overall content as the guarantor.
Funding The study was founded by the Erasto Gaertner Hospital.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.