Fertility treatment and cancers-the eternal conundrum: a systematic review and meta-analysis.

STUDY QUESTION: Does fertility treatment (FT) significantly increase the incidence of breast, ovarian, endometrial or cervical cancer? SUMMARY ANSWER: Overall, FT does not significantly increase the incidence of breast, ovarian or endometrial cancer and may even reduce the incidence of cervical cancer. WHAT IS KNOWN ALREADY: Infertility affects more than 14% of couples. Infertility and nulliparity are established risk factors for endometrial, ovarian and breast cancer, yet the association with FT is more contentious. STUDY DESIGN, SIZE, DURATION: A literature search was carried out using Cochrane Library, EMBASE, Medline and Google Scholar up to December 2019. Peer-reviewed studies stating cancer incidence (breast, ovarian, endometrial or cervical) in FT and no-FT groups were identified. Out of 128 studies identified, 29 retrospective studies fulfilled the criteria and were included (n = 21 070 337). PARTICIPANTS/MATERIALS, SETTING, METHODS: In the final meta-analysis, 29 studies were included: breast (n = 19), ovarian (n = 19), endometrial (n = 15) and cervical (n = 13), 17 studies involved multiple cancer types and so were included in each individual cancer meta-analysis. Primary outcome of interest was cancer incidence (breast, ovarian, endometrial and cervical) in FT and no-FT groups. Secondary outcome was cancer incidence according to specific fertility drug exposure. Odds ratio (OR) and random effects model were used to demonstrate treatment effect and calculate pooled treatment effect, respectively. A meta-regression and eight sub-group analyses were performed to assess the impact of the following variables, maternal age, infertility, study size, outliers and specific FT sub-types, on cancer incidence. MAIN RESULTS AND THE ROLE OF CHANCE: Cervical cancer incidence was significantly lower in the FT group compared with the no-FT group: OR 0.68 (95% CI 0.46-0.99). The incidences of breast (OR 0.86; 95% CI 0.73-1.01) and endometrial (OR 1.28; 95% CI 0.92-1.79) cancers were not found to be significantly different between the FT and no-FT groups. Whilst overall ovarian cancer incidence was not significantly different between the FT and no-FT groups (OR 1.19; 95% CI 0.98-1.46), separate analysis of borderline ovarian tumours (BOT) revealed a significant association (OR 1.69; 95% CI 1.27-2.25). In further sub-group analyses, ovarian cancer incidence was shown to be significantly higher in the IVF (OR 1.32; 95% CI 1.03-1.69) and clomiphene citrate (CC) treatment group (OR 1.40; 95% CI 1.10-1.77), respectively when compared with the no-FT group. Conversely, the incidences of breast (OR 0.75; 95% CI 0.61-0.92) and cervical cancer (OR 0.58; 95% CI 0.38-0.89) were significantly lower in the IVF treatment sub-group compared to the no-FT group. LIMITATIONS, REASONS FOR CAUTION: The large, varied dataset spanning a wide study period introduced significant clinical heterogeneity. Thus, results have to be interpreted with an element of caution. Exclusion of non-English citations, unpublished work and abstracts, in order to ensure data accuracy and reliability was maintained, may have introduced a degree of selection bias. WIDER IMPLICATIONS OF THE FINDINGS: The results for breast, ovarian, endometrial and cervical cancer are reassuring, in line with previously published meta-analyses for individual cancers but the association between IVF and CC treatment and an increase in ovarian cancer incidence requires additional work to understand the potential mechanism driving this association. In particular, focusing on (i) discriminating specific treatments effects from an inherent risk of malignancy; (ii) differential risk profiles among specific patient sub-groups (refractory treatment and obesity); and (iii) understanding the impact of FT outcomes on cancer incidence. STUDY FUNDING/COMPETING INTEREST(S): This study did not receive any funding. The authors have no financial, personal, intellectual and professional conflicts of interest to declare. PROSPERO REGISTRATION NUMBER: CRD42019153404.

Intraoperative Ultrasound during Fertility-Sparing Surgery: A Systematic Review and Practical Applications.

Fertility-sparing surgery (FSS) is an established concept within operative gynaecology. Intraoperative ultrasound (IOUS) has the potential of assessing lesion margins, allowing complete resection with minimal damage to the surrounding healthy tissue and could potentially play a major role in FSS for benign or malignant gynaecological pathologies. In this paper, we review the current literature on the use of IOUS in gynaecological FSS. We also propose technical guidance on the IOUS during FSS. The findings of this review demonstrate that IOUS can assist in the safe resection of disease with high rates of completion, low rates of recurrence and without damage to the nearby healthy reproductive organs. Improved training in transvaginal ultrasonography and minimal access surgery are likely to facilitate the application of IOUS in FSS.

Conservative management of uterine adenosarcoma: lessons learned from 20 years of follow-up.

PURPOSE: Uterine adenosarcomas (UAs) account for 5-8% of cases of uterine sarcomas. Treatment includes total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO). Fertility preservation is an emerging concept in gynaecology oncology and is particularly relevant in UA, where cases are diagnosed as young as 15-year-old. This manuscript demonstrates a case of UA which was treated conservatively, achieved successful livebirths and underwent completion hysterectomy after two decades of follow-up. METHOD: This was a retrospective case note review. RESULTS: An 18-year-old nulliparous woman presented with abnormal vaginal bleeding. Ultrasound identified an endometrial polyp, which was histologically diagnosed as low-grade adenosarcoma. She was advised to undergo TAH and BSO, but instead decided to preserve her fertility and opted for conservative management. She was monitored with pelvic ultrasound, hysteroscopy and endometrial biopsy bi-annually, with annual pelvic magnetic resonance imaging for 10 years which was uneventful. 11 years post-operatively she conceived following in-vitro fertilization (IVF) but suffered a miscarriage at 16 weeks likely due to cervical incompetence. She subsequently conceived with twins. She delivered spontaneously preterm at 28 weeks. Both children are alive and well. After 20 years of follow-up, she underwent a laparoscopic hysterectomy with no evidence of recurrence. She remains disease free. CONCLUSION: Whilst radical completion surgery should be advised in UA, this case, in addition to all published conservatively managed cases of UA, demonstrates that conservative management is possible in appropriately selected women. Intensive monitoring post-operatively is essential owing to the risk of recurrence; however, this may pose deleterious side effects which require consideration.

Chemotherapy-induced apoptosis, autophagy and cell cycle arrest are key drivers of synergy in chemo-immunotherapy of epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the most lethal of all gynecological malignancies in the UK. Recent evidence has shown that there is potential for immunotherapies to be successful in treating this cancer. We have previously shown the effective application of combinations of traditional chemotherapy and CAR (chimeric antigen receptor) T cell immunotherapy in in vitro and in vivo models of EOC. Platinum-based chemotherapy synergizes with ErbB-targeted CAR T cells (named T4), significantly reducing tumor burden in mice. Here, we show that paclitaxel synergizes with T4 as well, and look into the mechanisms behind the effectiveness of chemo-immunotherapy in our system. Impairment of caspase activity using pan-caspase inhibitor Z-VAD reveals this chemotherapy-induced apoptotic pathway as an essential factor in driving synergy. Mannose-6-phosphate receptor-mediated autophagy and the arrest of cell cycle in G2/M are also shown to be induced by chemotherapy and significantly contributing to the synergy. Increased expression of PD-1 on T4 CAR T cells occurred when these were in culture with ovarian tumor cells; on the other hand, EOC cell lines showed increased PD-L1 expression following chemotherapy treatment. These findings provided a rationale to look into testing PD-1 blockade in combination with paclitaxel and T4 immunotherapy. Combination of these three agents in mice resulted in significant reduction of tumor burden, compared to each treatment alone. In conclusion, the mechanism driving synergy in chemo-immunotherapy of EOC is multifactorial. A deeper understanding of such process is needed to better design combination therapies and carefully stratify patients.

The dawn of a new ice age: social egg freezing.

Given the age-related decline in ovarian reserve and oocyte quality, it is unsurprising the global trend of deferring motherhood has resulted in increased levels of involuntary childlessness. The development of oocyte vitrification, with pregnancy and livebirth rates now comparable to using fresh oocytes, has provided an opportunity to cryopreserve oocytes electively for future use, empowering women with the capacity to delay their childbearing years. While it enhances reproductive autonomy, age-related obstetric complications, economic implications and the risk of unsuccessful future treatment make this a controversial therapeutic option. However, some women have no reasonable alternative, such as single women approaching their late thirties, in whom egg freezing, although not a guarantee against involuntary childlessness, offers hope by extending the window of opportunity to find a partner. Given the upward trend in women electively cryopreserving their eggs, it would appear that a new ice age, from a fertility perspective, is upon us.

Ultrasound-Guided Laparoscopic Ovarian Wedge Resection in Recurrent Serous Borderline Ovarian Tumours.

OBJECTIVE: The aim of this study was to demonstrate the use of intraoperative ultrasound-guided ovarian wedge resection in the treatment of recurrent serous borderline ovarian tumors (sBOTs) that are too small to be visualized laparoscopically. METHODS: This was a prospective analysis of all women with recurrent sBOTs that were not visible laparoscopically, who underwent intraoperative ultrasound-guided ovarian wedge resection between January 2015 and December 2016 at the West London Gynaecological Cancer Centre, Imperial College NHS Trust, London, United Kingdom. RESULTS: We evaluated 7 patients, with a median age of 35 years (range, 28-39 years). Six women were nulliparous, whereas 1 woman had a single child. Previous surgical intervention left 5 women with a single ovary, whereas the remaining 2 had previous ovarian-sparing surgery. The median size of recurrence was 18 mm (range, 12-37 mm). All women underwent uncomplicated intraoperative guided ovarian wedge resections. Histological assessment confirmed sBOT in all 7 cases. Six of the women remain disease-free. One woman recurred postoperatively with her third recurrence, who previously had bilateral disease and noninvasive implants with microinvasive disease and micropapillary pattern. No cases progressed to invasive disease. The median follow-up time was 12 months (range, 1-20 months). One pregnancy has been achieved postoperatively but resulted in miscarriage. CONCLUSIONS: Continuous intraoperative ultrasound can be used to facilitate complete tumor excision in recurrent sBOT while minimizing the removal of ovarian tissue in women with recurrent sBOT. It is essential that surgical techniques evolve simultaneously with diagnostic imaging modalities to enable surgeons to treat such pathology.

Role of Imaging in Fertility-sparing Treatment of Gynecologic Malignancies.

Treatments for gynecologic cancer usually result in loss of fertility due to surgery or radical radiation therapy in the pelvis. In countries with an established screening program for cervical cancer, the majority of gynecologic malignancies occur in postmenopausal women. However, a substantial number of affected women are of childbearing age and have not completed their families. In these younger women, consideration of fertility preservation may be important. This article describes the fertility-sparing treatment options that are currently available and outlines the role of imaging in the selection of eligible patients on the basis of a review of the literature. In the setting of cervical cancer, magnetic resonance (MR) imaging is used to delineate the size, position, and stage of the tumor for selection of patients who are suitable for radical trachelectomy. In patients with solitary complex adnexal masses, diffusion- and perfusion-weighted MR imaging sequences are used to categorize the likelihood of invasive or borderline malignancy for consideration of unilateral ovarian resection, with fertility preservation when possible. In patients with endometrial cancer, MR imaging is used to rule out signs of invasive disease before hormone therapy is considered. Imaging is also used at patient follow-up to detect recurrent disease; however, evidence to support this application is limited. In conclusion, imaging is an essential tool in the care of patients with gynecologic malignancies who are considering fertility-preserving treatment options. ©RSNA, 2016.

Psychological Issues Associated With Absolute Uterine Factor Infertility and Attitudes of Patients Toward Uterine Transplantation.

CONTEXT: Uterine transplantation (UTx). OBJECTIVE: To explore patients' knowledge of and attitudes toward UTx before and after a short educational intervention via a video and question and answer (Q&A) session. DESIGN: Large, in-depth survey investigating patients' motivations, aims, and beliefs on UTx. SETTING: Imperial College London. PARTICIPANTS: Women diagnosed with absolute uterine factor infertility (AUFI) who were seeking information on UTx and had already volunteered to participate in the study. INTERVENTION: A semistructured interview involving a brief baseline questionnaire before a Q&A session and a 20-minute video exploring the main risks and benefits for UTx. MAIN OUTCOME MEASURES: Attitudes of self-referred patients with AUFI toward UTx before and after education focusing on UTx. Rank order of importance of key UTx-related issues. RESULTS: Forty women were interviewed. Following the video presentation and Q&A session, 97.5% (n = 39) would undergo UTx ahead of surrogacy and adoption in full knowledge that the latter 2 options would be ultimately safer for their own well-being and the fact that the graft could fail even prior to conception. All felt that UTx should take place, and 92.5% saw UTx as achievable. CONCLUSION: The study demonstrates a keen interest in UTx, partly because other options seem difficult to access. It is worth noting that people appear to be distancing themselves from the risk. This requires careful assessment in any clinical program. This study is the first to demonstrate a qualitative relationship between patients with AUFI and their curiosity and desire for UTx. It paves the way for forming the introduction into the psychological assessment of a potential patient.

Trachelectomy during pregnancy: what has experience taught us?

The treatment of early stage cervical malignancy in a pregnant patient remains a challenge. We report the successful application of a vaginal radical trachelectomy (VRT) during pregnancy to treat a patient diagnosed with early stage cervical cancer and subsequently review the published work. A 22-year-old female diagnosed at the gestational age of 17 weeks with International Federation of Gynecology and Obstetrics stage IB1 squamous cell cervical carcinoma was treated with VRT at 19(+5) weeks. At 36 weeks, the patient underwent a scheduled cesarean section. A healthy male infant was delivered with a weight of 2795 g. After 13 months of follow-up, the patient is doing well with no evidence of recurrent disease.

Survey of perceptions of health care professionals in the United Kingdom toward uterine transplant.

CONTEXT: Currently, the only 2 options that women with absolute uterine factor infertility have for managing their infertility are surragocy or adoption. These women may also benefit from a possible future third option: uterine transplant. OBJECTIVE: To investigate the opinions and views of UK health care professionals toward uterine transplant and rank issues related to uterine transplant by importance in order to make uterine transplant transparent and understandable to colleagues. DESIGN: Large, in-depth survey investigating health care professionals' opinions on uterine transplant. SETTING: Analysis done at Imperial College London. PARTICIPANTS: UK transplant professionals (surgeons, nurses, operating room staff, and donor coordinators) and obstetricians and gynecologists (trainees, members, and fellows of the Royal College of Obstetricians and Gynaecologists). INTERVENTION: Questionnaires were given out at hospital grand rounds, trainee teaching days, and conferences (national and international). MAIN OUTCOME MEASURES: Should uterine transplant take place? Is uterine transplant achievable? What is the rank order of importance of key issues related to uterine transplant? RESULTS: The study had 528 participants. With respect to overall support for uterine transplant and as a possible future therapeutic option for absolute uterine factor infertility, 93.8% (n=495) thought that uterine transplant should take place if considered appropriate medically, surgically, and ethically and 57.2% (n=302) thought it was an achievable objective. Issues related to immunology of uterine transplant and pregnancy after uterine transplant were unanimously thought of as most important. More effort is required to educate health care professionals about all aspects of uterine transplant.

Test of long-term uterine survival after allogeneic transplantation in rabbits.

AIM: To see if: (i) a large vessel aortocaval vascular patch technique may bring about long-term graft survival after allogeneic uterine transplantation (UTn) in a rabbit model; and (ii) fertility can be achieved following natural mating post-allogeneic UTn. METHODS: Allogeneic uterine cross transplantations were performed in New Zealand white rabbits using an aortocaval macrovascular patch harvested as part of the uterine allograft. Five rabbit recipients received a uterine graft from five unrelated donor rabbits. All female rabbits were unrelated and were of proven fertility with at least one previous litter each. Tacrolimus was administrated for immunosuppression post-transplant. Natural mating was attempted if long-term survival had been achieved. The main outcome measures were: (i) long-term recipient survival; (ii) long-term adequate uterine perfusion; and (iii) successful pregnancy post-UTn. RESULTS: All five recipient animals survived the surgery with satisfactory immediate postoperative recovery. Recipients 1, 2 and 4 died within the first 4 postoperative days. Both long-term survivors failed to conceive following introduction of a proven male breeder despite evidence of mating. Necropsy at 9 and 11 months showed a lack of patency of uterine cornua at the point of anastomosis, albeit a small uterus in recipient 3 and a reddish brown amorphous material at the site of the transplanted uterus in recipient 5. CONCLUSION: We have demonstrated the feasibility of uterine allotransplantation using a macrovascular patch technique, but could not demonstrate conception because of blocked cornua. To address this, we propose using embryo transfer techniques in order to achieve conception.

Uterine transplantation--a real possibility? The Indianapolis consensus.

A group of experts gathered in Indianapolis in December 2011 to address lingering concerns related to uterus transplantation (UTn). They represent a multi-national group of four research teams who have worked for over 15 years on bringing UTn to reality for patients. Presented here are a set of parameters that must be considered in order for UTn to become an acceptable procedure in the human setting. UTn has been proposed as a potential solution to absolute uterine factor infertility (AUFI). Causes of AUFI include congenital uterine factors (i.e. absence or malformation) or acquired uterine factors (e.g. hysterectomy for uncontrollable hemorrhage) rendering a woman 'unconditionally infertile'. Current estimates are that in the USA, up to 7 million women with AUFI may be appropriate candidates for UTn. As a result of a first human attempt in 2000, investigators have responded with a plethora of publications demonstrating successful UTn attempts, including pregnancies, in various autogeneic, syngeneic and allogeneic animal models. Before UTn can become an accepted procedure, it must satisfy defined criteria for any surgical innovation, i.e. research background, field strength and institutional stability. Equally important, UTn must satisfy accepted bioethical principles (respect for autonomy, beneficence, non-maleficence and justice) and their application (informed consent, appropriate assessment of risk and benefit and fair selection of individuals). Furthermore, we believe that a defined number of transplants should not be exceeded worldwide without a successful term delivery, to minimize proceeding in futility using current techniques. Even if UTns were to become relatively common, the following research objectives should be continuously pursued: (i) additional pregnancies in a variety of large animal/primate models (to search for unanticipated consequences), (ii) continuous assessment of women diagnosed with AUFI regarding UTn, (iii) continuous assessment using 'borrowed' psychological tools from transplant centers, adoption agencies and assisted reproductive technology centers with potential recipients and (iv) continuous careful ethical reflection, assessment and approval.

Use of abdominal radical trachelectomy to treat cervical cancer greater than 2 cm in diameter.

OBJECTIVE: Invasive cervical cancer is one of the most common cancers, with 500,000 new cases diagnosed annually. Fertility preservation has become an important component of the overall quality of life of many cancer survivors. Expert opinion has suggested that fertility-sparing surgery should be limited to those patients diagnosed with cervical cancer less than 2 cm in diameter. Our objective was to report our abdominal radical trachelectomy (ART) experience in the opposite group of patients-those with a cervical cancer more than 2 cm in diameter. METHODS: Between 1999 and 2006, a total of 45 patients with cervical carcinoma at International Federation of Gynecology and Obstetrics stage IB1-IB2 measuring more than 2 cm in diameter underwent fertility-sparing ART and pelvic lymphadenectomy at the 3 institutions where the authors are based (Budapest, Hungary; London, United Kingdom; New York, United States). They were followed up for more than 5 years. RESULTS: For 69% of patients (n = 31), completed ART was considered to have been curative, and no adjuvant treatment was advised. Of those patients, 93.5% (n = 29) were alive at the time of follow-up. Thirty-one percent of patients (n = 14) underwent immediate completion of radical hysterectomy. Three of 8 patients who wished to fall pregnant delivered healthy neonates. CONCLUSIONS: The 5-year survival rate (93.5%) for this case series is equal (or better) to rates reported in the literature for patient treated with radical hysterectomy. Our survival data seem to support the hypothesis that ART is a safe treatment option for patients with invasive cervical cancer lesions of more than 2 cm.

The impact of COVID-19 on the motivations of women seeking a uterus transplant.

Aim: The aim of this study was to investigate the change if any, in the motivations of women seeking a UTx and determine the impact of the COVID-19 pandemic. Methods: A cross-sectional survey. Results: 59% of women answered they were more motivated in achieving a pregnancy following the COVID-19 pandemic. 80% strongly agreed or agreed the pandemic had no impact on their motivation for a UTx, and 75% strongly agreed or agreed their desire for a baby strongly outweighs the risks of undergoing a UTx during a pandemic. Conclusion: Women continue to express a high level of motivation and desire for a UTx despite the risks imposed by the COVID-19 pandemic.

Attitudes, knowledge, and perceptions among women toward uterus transplantation and donation in the United Kingdom.

Objective: To assess the motivations and perceptions of the general public in the United Kingdom toward donating their uterus for Uterus Transplantation after death (UTx). Design: A cross sectional study. Setting: A 32-item electronic questionnaire. Population: One hundred fifty nine females over the age of 16 living in the United Kingdom, consented and took part in the study. Main outcome measures: The motivations and perceptions toward UTx among the general public including the willingness to donate and barriers preventing donation. Results: One hundred fifty nine women completed the questionnaire. The majority had never heard of UTx (n = 107, 71%) and most were not aware the uterus could be donated after death (n = 130, 92%). 43% of the cohort were willing to donate their uterus after death (n = 57). 8% stated they wished to donate their organs but not their uterus (n = 10). 30% of women (n = 42) believed the child born following UTx would have genetic links to the donor. Over half of the respondents (n = 65, 51%) strongly agreed or agreed they would feel joy in the knowledge that donation would lead to bringing a new life into the world. A quarter of respondents strongly agreed or agreed (n = 45, 25%) that the use of their uterus by another woman would feel like an extension of life. Conclusion: The findings indicate a favorable opinion toward UTx and a positive attitude toward donation of the uterus after death among the general public in the United Kingdom. The findings also highlight the need for education around UTx now this therapeutic option is available.

Fertility preservation and realignment in transgender women.

Medical care for transgender people is multi-faceted and attention to individual reproductive aspirations and planning are an essential, yet often overlooked aspect of care. Given the impact of hormonal therapy and other gender affirmation procedures on reproductive function, extensive counselling and consideration of fertility preservation is recommended prior to their commencement. This review article explores the reproductive aspirations of transgender women and considers the current disparity between stated desires regarding utilisation of fertility preservation services. Current fertility preservation options and prospective treatments currently showing promise in the research arena are explored.

Fertility-sparing treatment in cervical cancer: Abdominal trachelectomy.

In the last two decades, great strides have been made to treat cancer while sparing fertility for young women. This is at least partly in response to changing demographics, including delayed childbearing and fewer historically traditional couples. The trachelectomy has become emblematic in this endeavor. With comparable outcomes to hysterectomy and successful conceptions, trachelectomy utilization has increased over time. It is now a standard of care for many situations. While there are several approaches, (vaginal, laparoscopic, and robotic), the abdominal trachelectomy allows surgeons to overcome several limitations, such as patient anatomy, surgical experience, and resources (i.e. no robot) to provide women everywhere this revolutionary operation. In this chapter, we outline surgical techniques, outcomes, and other aspects of the abdominal trachelectomy.