Is it safe to reserve uterus after live-birth following fertility-sparing treatment of endometrial cancer and atypical hyperplasia : a long-term retrospective cohort study

Is it safe to reserve uterus after live-birth following fertility-sparing treatment of endometrial cancer and atypical hyperplasia : a long-term retrospective cohort study | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 22 January 2025 V1 Latest version Share on Is it safe to reserve uterus after live-birth following fertility-sparing treatment of endometrial cancer and atypical hyperplasia : a long-term retrospective cohort study Authors : Yiqin Wang 0000-0002-1125-4802 , Yuanyuan Liu , Rong Zhou , Li Tian , Qun Lu , and Jianliu Wang [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.173753326.69121500/v1 239 views 124 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Objective To assess the safety of continuous uterus-preserving in endometrial cancer (EC) and atypical endometrial hyperplasia (AEH) patients who gave birth after fertility-sparing treatment (FST). Design A retrospective study conducted between January 2005 and June 2020. Setting Peking University People’s Hospital, China. Population A total of 212 EC/AEH patients undergoing FST. Methods Patients were stratified as patients with a live-birth (n=73) outcome and those without (n=139). Main Outcomes Measures Risk factors for disease recurrence were analyzed for all patients undergoing FST and postpartum recurrence was analyzed for those with live-birth after FST. Results Live-birth significantly reduced the risk of disease recurrence (HR 0.326, P =0.011), while insulin resistance is an adverse factor (HR 3.216, P =0.014). Exceprt for two patients who underwent hysterectomy, for the 71 patients with uterus-preserving after live-birth, five (7%) patients occurred disease relapse (one EC and four AEH), after a median follow-up of 26 (11, 47.5) months. While there were another eight patients (11.3%) experiencing hyperplasia without atypical (EH). Risk factors for postparturm EC/AEH/EH included irregular menstrual period (75% vs. 36.8%, P =0.028), abnormal echo of ultrasound (53.8% vs. 13.7%, P=0.005) and a thicker endometrium (0.76cm vs. 0.53cm, P =0.003) . While maintenance treatment after birth (38.5% vs. 62.5%, P=0.129) tended to have a protective effect. Conclusions Alough live-birth for EC/AEH patients who underwent FST has benefit on recurrence-free survival, there still exists a postpartum risk of disease recurrence, with irrregular menstruation, thicker endometrium and abnormal ultrasound as risk factors. INTRODUCTION Endometrial cancer (EC) is a leading gynecological malignancy in developed countries. Although most cases of EC are diagnosed after menopause, the incidence of EC in younger women of reproductive age is increasing. Approximately 20% of cases are diagnosed before menopause 1 . Because of a delay in childbearing, 70% of patients do not give birth 2 and may desire fertility preservation. Thus, fertility-sparing treatment (FST) is promising in young patients with EC or atypical endometrial hyperplasia (EC/AEH). Remission rate was 70.7–81.1%, and pregnancy rate was 21.3–32.3% for strictly selected patients 3,4 . Recent researches focused on the pregnancy and obstetrics outcomes in such patients 5 and showed a higher level of labour induction, caesarean section, and post-partum haemorrhage 6 . Hysterectomy was suggested after completion of childbearing, according to the National Comprehensive Cancer Network and ESGO/ESHRE/ESGE guidelines regarding the concern of tumor recurrence 7 . However, to date, there are no reports of postpartum recurrence. It is important to investigate the postpartum outcomes of patients with live births after FST treatment. Additionally, it is worth discussing whether it is safe to continuously preserve uterus in these patients. The aim of this study was to analyze the long-term postpartum outcomes in patients with AEH and EC who received FST and successfully completed childbearing treated in our hospital over the last 15 years. 1. Study Population Patients with EC or AEH who underwent FST at the Peking University People’s Hospital between January 2005 and June 2020 were retrospectively investigated. Clinical, histopathological, and follow-up data were obtained. Inclusion criteria were as follows: (1) age ≤40 years; (2) a strong desire to preserve fertility; (3) International Federation of Gynecology and Obstetrics 2009 IA grade 1–2 EC with a lesion confined in the endometrium or AEH; (4) no evidence of extrauterine or distant metastasis by enhanced MRI for EC cases; and (5) no contraindication to conservative treatment. The patients were divided into two groups depending on whether with successful childbearing outcomes or not. Certainly! Apologies for the previous omissions. Below is the complete LaTeX document that includes all the requested sections, arguments, code snippets, and proofs, organized logically into a single cohesive document. “‘latex 2. Fertility-Sparing Treatment Patients were treated with progestin-based therapies, including medroxyprogesterone (MPA), megestrol acetate (MA), gonadotropin-releasing hormone agonist (GnRHa), and levonorgestrel intrauterine system (LNG-IUS). Patients were given hysteroscopic endometrial biopsy every three months to assess the treatment response. A complete response (CR) was defined as the pathological absence of hyperplasia or carcinoma. After a CR, the patients were monitored for recurrence every 3–6 months. Recurrence was defined as a pathologically proven EC or AEH. Pathological results showing endometrial hyperplasia without atypia were considered endometrial hyperplasia (EH), rather than recurrences. Patients with a CR were encouraged to conceive with or without active assisted reproduction technology (ART). For CR patients without a recent pregnancy plan, maintenance treatment, including low-dose cyclic progestin, levonorgestrel intrauterine system, or oral contraceptives, was administered to prevent recurrence. The time interval to achieve a CR was defined from the diagnosis to the first pathological CR. The time interval to pregnancy was from the first CR to the time of pregnancy confirmation. The time interval to recurrence or hyperplasia was from the first CR to the pathological recurrence of EC/AEH or EH. 3. Follow-Up after CR and Childbearing After CR or childbearing, the patients were followed-up every 3-6 months. The patients were monitored for regular menstruation and ultrasound every 3 months. Hhysteroscopic biopsy was performed every 6 months or if there was any suspicious endometrial lesions. All the patients were followed-up until October 31st, 2024. 4. Statistical Analysis All data were presented descriptively as medians (first and fourth quartiles), mean ± standard deviaiton or proportions. Values between two groups were compared using the Student’s t-test or Mann-Whitney U test. Frequency distributions were compared using the χ2 test, except if the expected frequency was <5, then the Fisher’s exact test was employed. Recurrence-free survival (RFS) was estimated using the Kaplan-Meier method and compared between the groups using the log-rank test. In two-sided tests, p-values <0.05 were regarded as significant. All statistical analyses were performed using SPSS for Mac (version 20.0; IBM Corp., Armonk, NY) and R . 5. Ethical approval This study was conducted in accordance with the Declaration of Helsinki, and informed written consent was obtained from all of the participants. The study protocol was approved by the This study was approved by the Ethics Committee of the Peking University People’s Hospital (IRB approval no. 2016PHB054-01). RESULTS 1. General Characteristics of EC/AEH Patients with or without Childbearing The flowchat of patients is reported in Figure 1. Enrolment concluded with 238 patients; 26 were deemed ineligible, because of treatment time less than 3 months or transferred to other hospitals. A total of 212 patients, including 73 patients with EC and 105 with AEH who underwent the FST were included. Among them 73 had successful childbirth and 139 did not. General information between the above two groups was shown in Table S1. Patients in the childbearing group had a younger age (30.6 vs. 33.1 years old, P <0.001), a lower BMI (26.2 vs. 27.8, P= 0.02), a lower rate of insulin resistance tendency (45.2% vs. 59%, P= 0.056) and a significant shorter treatment time to CR (5 vs. 9 months, P= <0.001) than those in the non-childbearing group. Other variables showed no statistically significant differences between the two groups (Table S1). 2. Follow-Up Outcomes for Patients with or without Childbearing The recurrence rates were 13.7% (10/73) in the childbearing and 25.7% (28/109) non-childbearing group, respectively ( P= 0.051). Further Kaplan-Meier survival analysis showed that childbearing is a protective factor of disease recurrence ( P= 0.002) (Figure S1). To know about the risk factors for disease recurrence, univariable and multivariable cox analysis were conducted (Figure 2). Univariable result showed live birth ( P = 0.002), insulin resistance ( P =0.022) and time interval to CR ( P =0.006) relates with risk of disease recurrence. After adjusting for age, BMI, pathology and other comorbidities, the multivariable analysis showed, live birth is an independent protective factor and reduces the risk of disease recurrence to one-third or less (HR=0.326, P =0.011). Patients with insulin resistance had more than three times of recurrence risk (HR=3.216, P =0.014) (Figure 2). 3. Treatment and Reproductive Outcomes of Childbearing Patients For the 73 childbearing patients, the median treatment time to achieve CR was five months (3, 9 months) (Table S1). The treatment regimens included oral MPA or MA (68 patients) and LNG-IUS plus GnRHa (five patients). All the 73 patients became pregnant and delivered at full-term after the FST; the reproductive outcomes are shown in Table S2. Only two patients received hysterectomy both at the time of cesarean section, others refused hysterctomy after giving birth. The median interval to pregnancy was nine months (3, 13.75 months). Seventeen (23.3%) pregnancies were achieved through natural conception, 3 (4.1%) through ovulation stimulation, and 49 (67.1%) through in vitro fertilization and embryo transfer. The median gestational age was 39 weeks (38, 40 weeks). Regarding complications of pregnancy, 20 (32.3%) patients experienced abnormal glucose metabolism. Athor main comorbidities included hypertension, postpartum hemorrhage and incompetent internal cervical os (Table S2). 4. Postpartum Follow-Up Outcomes for Childbearing Patients Although hysterectomy was suggested for patients who delivered, none of the 71 patients underwent hysterectomy for personal reasons. During the postpartum follow-up period, five (7.0%) patients had disease recurrenc, including two with EC and three with AEH. While another eight paitents experienced endometrial hyperplasia without atypical (11.3%). Regarding related risk factors for disease recurrence, the chi-square analysis showed that patients with postpartum relapse of EC/AEH had more with abnormal echo of ultrasound ( P= 0.065) and a thicker endometrium ( P= 0.017). Also, maintenance treatment after birth shows less risk of relapse ( P= 0.012). Futher analysis of chi-square analysis for potential related factors with postpartum EC/AEH/EH showed, regular menstrual related with less recurrence risk ( P= 0.028). Also abnormal echo of ultrasound related with a significant higher recurrence risk ( P= 0.005). However, pathology, age, BMI, time interval to CR, time interval to pregnancy, or any recurrence before pregnancy showed no significant relationship with the postpartum occurrence of EC/AEH or EH (Table 1). 5. Specific treatment results for the postpartum recurrent cases Five patients had postpartum disease recurrence of EC/AEH and their specific treatment information was shown in Figure 3. The median time from birth-giving to recurrence was 11 months (8, 18.5months). Patient 1 (EC) experienced disease recurrence before live-birth, and two remission periods were 11 and 18 months, respectively. Seventeen months after childbirth, pathological examination showed EC recurrence. She was administered another round of combined therapy of FST for 17 months and achieved CR again. Patient 2 (AEH) got pregnancy at 13-month after first CR. She did not experience recurrence of AEH until 33 months after child-birth. She then underwent MA treatment for 6 months and achieved CR again. Patients 3 (AEH) got pregnancy at 10-month after first CR. She did not experience recurrence until 21 months after child-birth. She then underwent hysterectomy and the post-operation pathology showed AEH. Patient 4 (EC) experienced AEH recurrence at 9-month after childbirth and achieved another CR after four months of treatment with MPA. Patients 5 (AEH) experienced recurrence of AEH at 9-month after CR and got CR after 4 months treatment of MPA. All the patients who occurred with EH received dydrogesterone treatment and all achieved remission; one patient had another live birth after remission. DISCUSSION 1. Main Findings In the present study, our results showed that there exists the postpartum risk of disease recurrence of EC/AEH (7%) and endometrial hyperplasia (11.3%) after FST treatment and follwing live birth. We retrospectively followed-up the 71 patients with uterus-preserving for 26 months; five patients had EC/AEH recurrence after childbearing, and eight had EH. And risk factors for postparturm occurrence included irregular menstruation and abnormal ultrasound finding. It might worth noting the long-term risk of recurrence when considering uterus-preservation for such EC/AEH patients who comlete chidbearing. 2. Strengths and Limitations To the best of our knowledge, this retrospective study included the the largest number of patients with EC/AEH, focusing on postpartum recurrence after fertility-sparing treatment. We provided follow-up results on risks of endometrial neoplasm for uterine preservation after childbearing. We did have some limitations. This was a retrospective study, and the retrospective bias and relatively limited number of patients might have restricted our conclusions. However, this preliminary results provides the necessity for concerning on the long-term safty for such conservative management. Nevertheless, more large-scale studies and longer follow-up times are needed to confirm the accumulative oncological outcomes. Furthermore, the number of recurrent cases was limited to investigate the potential risk factors for postpartum relapse, which might be vital for selecting the highrisk or appropriate population for uterine preservation. 3. Interpretation Properly tailored follow-up is necessary for patients with EC/AEH undergoing the FST. Previous reviews showed that the recurrence rate of EC/AEH after conservative treatment was reported to be in the range of 25.3–38% 8,9 . Successful pregnancy may prevent recurrence. A long-term follow-up for 148 patients with EC after FST found that pregnancies (odds ratio, 0.25; 95% confidence interval, 0.11–0.56; P=0.001) were significantly associated with a lower risk of recurrence 10 . A retrospective study of 68 patients evaluating pregnancy-associated factors after FST showed a lower relapse rate in a pregnancy group than in a non-pregnancy group (16.7% vs. 40.6%) 11 . Our results also showed that the childbearing patients had a longer RFS than those who did not (47 vs. 15 months, P=0.002). Due to the high level of progestin during pregnancy and very low postpartum levels of estrogen, it is reasonable to assume that patients who complete chidbearing and lactation are less likely to relapse. The recurrence rate in patients who did not give birth after treatment was 37.2%, as opposed to 11.3% in those who did (P=0.000001) 12 . Thus, a history of live birth is a powerful protective factor against tumor recurrence. In our study we find live-birth is an independent protective factor for recurrence and reduces the risk of disease recurrence to one-third or less. However, there indeed, five (7%) patients developed EC or AEH, and another 8 (11.3%) developed endometrial hyperplasia after FST and childbirth. Although most patients didn’t received hysterectomy directly after completion of childbearing, whether and when it’s necessary for patients to undergo hysterectomy after childbirth is debatable. As endometrial hyperplasia is less common for EC/AEH patients with live-birth, it’s important to identify ealry evidence for disease occurrence. In our study, the patients with postpartum endometrial hyperplasia presented had more with irregular menstruation (75% vs. 36.8%), and more often, with abnormal ultrasonic imaging (53.8% vs. 13.7%). Yin et al. also found that patients with EC/AEH who experienced recurrence after CR were more likely to have irregular menstrual cycles than controls (59.5% vs. 37.7%) 13 . Thus, it is important to pay attention to abnormal symptoms after childbearing and to maintain regular menstruation. We also found the endometrium thickness indicated the risk of postpartum recurrence (0.82cm vs. 0.55 cm). It’s important to perform regular ultrasound examinations after birth-giving so as to find any irregular signals of endometrium leision. Strict surveillance with ultrasound every 3–6 months and clinical follow-up of symptoms are recommended. Hysteroscopy and endometrial biopsy are recommended for abnormal vaginal bleeding or atypical ultrasound finding 14 . Maintenance therapy after CR correlates with reduced risk of disease recurrence. Our results showed that neither of the five recurrent cases took maintenance treatment. A large sample size study showed that maintenance with levonorgestrel IUD improved disease-free survival (DFS) after FST for EC/AEH (HR=0.18) 12 . Maintenance treatment benefits regular menstruation and cyclic endometrial shedding. Risk factors for endometrial hyperplasia, such as being overweight and insulin resistance, still exist after childbearing, which might promote future tumor recurrence. However, our study showed, pathology, age, BMI, IR, time interval to CR, time interval to pregnancy or conception method did not correlate with postpartum recurrence. Because only a few cases of postpartum recurrence were included in our study, it is difficult to recognize the risk factors and predict long-term recurrence fow now. Patients should be fully consulted on the life-long exposure of potential risks for endometrial lesions. For high-risk patients, such as those with complicated treatment processes, multiple recurrences, and metabolic disorders, we recommend hysterectomy to reduce lifelong risk. Conclusion In conclusion, live-birth related with improved recurrence-free survival of EC/AEH after FST. However, there exists the postpartum risk of disease recurrence of EC/AEH and endometrial hyperplasia. Irregular menstruation and abnormal ultrasound finding indicate a higher risk of postpartum endometrial hyperplasia. Further exploration is needed to determine the safety of long-term uterine preservation in patients with certain risk of recurrence after childbearing. Acknowledgements We would like to thank our nurse team from Department of Obstetrics and Gynecology of Peking University People’s Hospital for their hard work on following-up patients. Conflict of Interest The authors declare no conflicts of interest. Certainly! Apologies for the previous omissions. Below is the complete LaTeX document that includes all the requested sections, arguments, code snippets, and proofs, organized logically into a single cohesive document. “‘latex Contribution to Authorship YQ.W., R.Z., and JL.W. were involved in the study concept and de.sign. YQ.W, YY.L., Q.L. and L.T. were responsible for acquisition of data. YQ.W. contributed to the analysis and interpretation of data. YQ. W. contributed to manuscript drafting. All authors read and approved the final version of this article. Data Availability Statements The data underlying this article will be shared on reasonable request to the corresponding author. Details of Ethics Approval The study protocol was approved by the This study was approved by the Ethics Committee of the Peking University People’s Hospital (IRB approval no. 2016PHB054-01). Funding This work was supported by National Key Research and Development Program of China (Grant No. 2022YFC2704400, 2022YFC2704405) and Natural Science Foundation of Beijing Municipality (Grant No. 7234394). Supporting Information Table S1. Baseline characteristics of 212 patients in the childbearing and non-childbearing groups. Certainly! Apologies for the previous omissions. Below is the complete LaTeX document that includes all the requested sections, arguments, code snippets, and proofs, organized logically into a single cohesive document. “‘latex Table S2. Reproductive outcomes of 73 childbearing patients. Figure S1. Cumulative recurrence-free survival (RFS) curves in childbearing (N=73) and non-childbearing (N=139) groups for endometrial cancer / atypical endometrial hyperplasia patients receiving FST. Successful childbearing patients had longer RFS than patients in the non-childbearing group ( P =0.002). Figure legends Figure 1. Flow chart of the study population of women who underwent fertility-sparing treatment of endometrial cancer and atypical hyperplasia. EC, endometrial cancer; AEH, atypical endometrial hyperplasia; CR, complete response; NR, no response; PR, partial response. Figure 2. Univirate and multivitrate cox analysis of risk factors of disease recurrence. BMI, body mass index; PCOS, polycystic ovarian syndrome; DM, diabetes mellitus; IR, insulin resistant; CR, complete response Figure 3. Treament process for the five patients who relapsed after live-birth following FST treatment. REFERENCES 1 Creasman WT, Odicino F, Maisonneuve P, Beller U, Benedet JL, Heintz AP, et al. Carcinoma of the corpus uteri. J Epidemiol Biostat 2001;1:47-86.2 Soliman PT, Oh JC, Schmeler KM, Sun CC, Slomovitz BM, Gershenson DM, et al. Risk factors for young premenopausal women with endometrial cancer. Obstet Gynecol 2005;3:575-80.3 Koskas M, Uzan J, Luton D, Rouzier R, Daraï E. 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Keywords developing countries: obstetrics and gynaecology gynaecological oncology gynaecological surgery: hysteroscopy Authors Affiliations Yiqin Wang 0000-0002-1125-4802 Peking University People's Hospital View all articles by this author Yuanyuan Liu Peking University People's Hospital View all articles by this author Rong Zhou Peking University People's Hospital View all articles by this author Li Tian Peking University People's Hospital View all articles by this author Qun Lu Beijing Chaoyang Hospital Affiliated to Capital Medical University View all articles by this author Jianliu Wang [email protected] Peking University People's Hospital View all articles by this author Metrics & Citations Metrics Article Usage 239 views 124 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Yiqin Wang, Yuanyuan Liu, Rong Zhou, et al. Is it safe to reserve uterus after live-birth following fertility-sparing treatment of endometrial cancer and atypical hyperplasia : a long-term retrospective cohort study. Authorea . 22 January 2025. DOI: https://doi.org/10.22541/au.173753326.69121500/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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