The impact of regressed endometrial hyperplasia on reproductive outcomes following frozen embryo transfer: a propensity score-matched cohort study

The impact of regressed endometrial hyperplasia on reproductive outcomes following frozen embryo transfer: a propensity score-matched 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 Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed.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. 8 April 2025 V1 Latest version Share on The impact of regressed endometrial hyperplasia on reproductive outcomes following frozen embryo transfer: a propensity score-matched cohort study Authors : Qinling Zhu [email protected] , Lizhen Xu , Bing Xu , Yao Lu , Zhe Wei , Wenchao Zhang , Yunfei Huang , … Show All … , Yiwen Meng , Chongwen Shao , Mengjia Shi , Yaqiong He , Jiaan Huang , Yuan Wang , Jia Qi , Ying Ding , and Yun Sun Show Fewer Authors Info & Affiliations https://doi.org/10.22541/au.174413165.58319947/v1 408 views 186 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Objective: To investigate the impact of regressed endometrial hyperplasia (EH) on pregnancy, obstetric and neonatal outcomes following frozen embryo transfer (FET) after conservative treatment. Design: Retrospective cohort Setting: Reproductive center, Shanghai Jiaotong University School of medicine, Renji Hospital Population: 95 patients with EH regression after conservative treatment and 30634 infertile controls with presumed normal endometrium, fom January 2015 to December 2022. Methods: Medical records from our database were analyzed. Propensity score matching, performed at a ratio of 1:4 between EH and control patients, and binary logistic regression were applied to adjust for potential confounding factors. Main Outcome Measures: The primary outcome was live birth rate. Results: Compared with matched controls, patients with EH exhibited a significantly lower live birth rate (31.6% vs. 49.2%, P = 0.002), reduced clinical pregnancy rate (44.2% vs. 59.2%, P = 0.008), and a higher incidence of pregnancy loss (40% vs. 26.1%, P = 0.046). Additionally, cervical insufficiency occurred more frequently in EH patients (6.7% vs. 0%, P = 0.019). No significant differences in these outcomes were observed between EH patients with and without atypia. Furthermore, logistic regression analysis confirmed that EH was an independent risk of live birth following FET (adjusted OR 0.63, 95% CI: 0.41-0.95, P = 0.04). Conclusions: This large-scale study showed that even achieving completed remission, EH continued to adversely impact live birth following FET cycles. These finding highlight the importance of thorough conception counseling and intensive pregnancy monitoring in this high-risk population. not-yet-known not-yet-known not-yet-known unknown Introduction Endometrial hyperplasia (EH) encompasses a spectrum of irregular morphological changes characterized by abnormal proliferation of endometrial glands during the proliferative phase of menstrual cycle 1.The underlying cause of EH is associated with excessive estrogen stimulation and insufficient progesterone action. According to the latest World Health Organization criteria, EH is classified into EH with and without atypia based on the presence or absence of cellular atypia 2. EH with atypia is recognized as a precursor lesion of endometrial cancer, with an estimated 25% to 33% likelihood of progressing to endometrial cancer 3.The frequency of EH is approximately 2‰ among reproductive-aged women 4, but this rate increases by 5 to 10 times in women experiencing infertility 5, highlighting the importance of fertility management for these patients. High-dose oral progestins, a levonorgestrel-releasing intrauterine system or combined treatments have demonstrated effectiveness in treating EH, with regression rate ranging from 70% to 90% 6-8. These options serve as alternatives for women who strongly desire fertility preservation. Once a complete response to treatment for EH is achieved, it is advisable to actively pursue conception as soon as possible, as pregnancy has been shown to prevent recurrence 7. However, women with EH are at a higher risk of infertility due to increased occurrence of anovulation, obesity and metabolic disorders. Therefore, assisted reproductive technology (ART) is commonly recommended to improve the chances of pregnancy and reduce the interval to conception 9 . Over the past few decades, numerous studies have shown the effectiveness of ART in achieving successful pregnancies in women with atypical EH and early-stage endometrial cancer 10-13. The live birth rate after ART was shown to be considerably greater than that of women who conceived spontaneously, according to a meta-analysis encompassing 151 women with atypical EH and 408 women with endometrial cancer 14. Recently, a retrospective study reported for the first time that, compared to infertile women with normal endometrium, 42 women with atypical EH achieved a marginally lower live birth rate, along with a higher rate of pregnancy loss and preterm delivery after fresh embryo transfer 15. In fresh embryo transfer, supraphysiological estradiol levels may affect endometrial receptivity 16, particularly in individuals with EH who may be more sensitive to fluctuations in estradiol. However, in frozen embryo transfer (FET), the endometrium is exposed to estradiol levels that are closer to physiological levels. Hence, FET is favored for individuals with EH due to its more natural hormonal environment, which may be beneficial for optimizing endometrial receptivity 17. Notably, no prior studies have specifically investigated the impact of EH on reproductive outcomes in the context of FET. Moreover, it is important to acknowledge that the incidence of EH without atypia is higher than that of EH with atypia and early-stage endometrial cancer. However, it is still unknown if this trait may have an impact on the outcomes of assisted reproduction. In this study, we aimed to investigate pregnancy outcomes, as well as maternal and neonatal complications, in a cohort of 95 EH patients who achieved complete response following conservative treatment and 30,634 control patients with no evidence of endometrial abnormalities undergoing their first FET. A subgroup analysis was also performed on EH patients with and without atypia to investigate the impact of disease severity on reproductive outcomes. Study population and design This was a retrospective cohort study, and data were collected from the Center of Reproductive Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine between January 2015 and December 2022 from patients who undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment. Pregnancy outcomes, maternal and neonatal complications were compared between women with and without EH undergoing their first FET. This study was approved by the Ethics Committee of Renji Hospital, Shanghai Jiaotong University School of Medicine (approval number 2015030308). The inclusion criteria for patients with EH were as follows: (1) histopathologically confirmed diagnosis of EH by two gynecological pathologists independently; (2) acceptance of standard conservative treatment with regression before FET; (3) hysteroscopic evaluation confirming histopathological normalcy by two gynecological pathologist independently within 3 months prior to the first FET; and (4) adherence to standard controlled ovarian stimulation protocols and IVF/ICSI treatment. The exclusion criteria were: (1) cases involving preimplantation genetic testing cycles; (2) cases without embryo transfer; (3) reproductive system malformations, including septate uterus, unicornuate uterus, and other conditions; (4) endometriosis and adenomyosis; and (5) early-stage endometrial cancer. Subsequently, 30,634 infertile women who showed no evidence of endometrial abnormalities, as confirmed by histopathological analysis following endometrial biopsy, were included in the control group after screening for the exclusion criteria. Conservative treatment for patients with EH All patients with EH received progestin treatment. Patients with EH without atypia were prescribed megestrol acetate at a dosage of 160 mg per day orally, with endometrial biopsy were performed every 6 months during treatment until no endometrial lesions were found in two consecutive biopsies. For patients with atypical EH, megestrol acetate was administrated at a dosage of 160-320 mg per day, with endometrial biopsy were performed every 3 months during treatment. Once complete remission was achieved, embryo transfer was scheduled. IVF/ICSI-FET treatment Controlled ovarian stimulation with GnRH-antagonist was performed in the enrolled patients under a routine procedure in our center. When two or more follicles had diameters greater than 17 mm, recombinant human chorionic gonadotropin (hCG, 250 μg) was administered to trigger oocytes maturation. Oocytes were then fertilized using either conventional IVF or ICSI. All patients enrolled in this study adopted a whole embryo frozen strategy. Endometrial preparation and FET were performed in natural, stimulated or hormone replacement cycles. One or two thawed-cleavage embryos were transferred on the third day after initiating luteal phase support, while one thawed-blastocyst was scheduled for transfer on the fifth day. According to Puissant criteria, good-quality cleavage embryos were those demonstrating 7-10 cells with ≤20% fragmentation. For blastocyst embryos, a morphology scoring of ≥4BC based on Gardner criteria were good-quality embryo. Regular luteal phase support was initiated with vaginal progesterone gel and oral dydrogesterone once the endometrium reached optimal thickness, and continued until 10 to12 weeks of gestation. not-yet-known not-yet-known not-yet-known unknown Outcomes measurement The primary outcome was the live birth rate, defined as delivery a live neonate beyond 28 weeks. Secondary outcomes included biochemical pregnancy rate, clinical pregnancy rate, and pregnancy loss rate. Biochemical pregnancy was defined as the detection of serum β-hCG ≥10 IU/L measured 12 to 14 days after embryo transfer. Clinical pregnancy was defined as the observation of an intrauterine gestational sac via transvaginal ultrasound around 35 days after embryo transfer. Pregnancy loss was defined as pregnancy resulting in a spontaneous abortion that occurred at any point during the pregnancy. For maternal and neonatal complications, we assessed the rates of gestational hypertension, gestational diabetes mellitus (GDM), preterm birth (delivery of a fetus at more than 28 weeks and less than 37 weeks of gestational age), cervical insufficiency (cervical length less than 25 mm along with progressive cervical dilation and shortening of the cervical canal before 24 weeks of pregnancy), macrosomia (a birth weight > 4000 g), and low birthweight (a birth weight < 2500 g beyond 28 gestational weeks). Birth defects were evaluated according to the International Classification of Diseases, 10th edition (ICD-10). Statistical Analysis Data were analyzed using IBM SPSS Statistics (SPSS Inc, version 21, IBM Corp., Armonk, NY, USA). Continuous variables were presented as mean ± SD, and comparisons were made using Student’s t- test for normally distributed data. For non-normally distributed data, results were presented as medians (Quartile 1– Quartile 3) and compared using the Mann–Whitney U test. Categorical variables were presented as percentages (%) and frequencies (n) and compared using Chi-squared test, with the Fisher exact test for expected frequencies less than 5. A P -value < 0.05 was considered statistically significant for all comparisons. In part 1 of the study (Supplemental Figure 1), variables such as age, body mass index (BMI), basal hormone profiles (follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T)), thyroid stimulating hormone (TSH), prevalence of primary infertility, infertility duration, indications for IVF/ICSI, and the stage and number of embryos transferred were matched by propensity score matching (PSM) using the “Match It” package in R software (version 4.0.2, R Foundation for Statistical Computing, Vienna, Austria) to minimize potential confounding factors. Patients with EH were matched to controls at a 1:4 ratio. A subgroup analysis was also conducted between EH patients with and without atypia. In part 2 of the study (Figure 1), binary logistic regression analysis was performed to assess the risks of live birth using data from 95 EH patients and 30,634 control patients. The potential risk factors included the presence of EH, age, BMI, duration of infertility, primary infertility, endometrial thickness, and the number and stage of embryos transferred. Both unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by regression analysis. not-yet-known not-yet-known not-yet-known unknown Results Baseline characteristics A total of 95 patients with EH and 30,634 controls without evidence of endometrial abnormalities were enrolled in this study. Among patients with EH, 41 were diagnosed and achieved complete remission before IVF/ICSI treatment, while 54 were diagnosed in the subsequent menstrual cycle after IVF/ICSI treatment and achieved complete resolution before FET. Prior to PSM, the average age, BMI, and duration of infertility in patients with EH were significantly higher than those in the control patients. Moreover, the proportion of patients with primary infertility and those adopting IVF treatment was notably higher in the EH group. Additionally, the indications for IVF/ICSI treatment were different between the two groups ( P < 0.001). Tubal and anovulatory factors were the primary indications in the EH group, while tubal and male factors were more prevalent in the control group. There was no difference in terms of basal endocrine profiles and TSH levels between the two groups. After PSM, 95 patients with EH were successfully matched to 380 control patients. Following the matching process, the baseline characteristics, including age, BMI, duration of infertility, and indications for IVF/ICSI, were comparable between the two groups (Table 1). not-yet-known not-yet-known not-yet-known unknown Outcomes of endometrial preparation and pregnancy Endometrial preparation for FET was performed in natural, hormone therapy, and stimulated cycles. The distribution of these protocols was similar in the two groups. There was no significant difference in overall endometrial thickness between the two groups. The quantity, quality and developmental stage of the transferred embryos were similar in the two groups. (Table 2). In comparison to the control group, the EH group showed a lower live birth rate, as indicated in Table 2 (31.6% vs. 49.2%, P = 0.002). Additionally, lower rates of biochemical pregnancy (52.6 % vs. 66.6%, P = 0.011) and clinical pregnancy (44.2% vs. 59.2%, P = 0.008) were observed in the EH group as well. Moreover, the overall pregnancy loss rate, including both biochemical and clinical pregnancy losses, was higher in individuals with EH compared to control patients. However, no significant difference was found between the two groups regarding pregnancy loss in biochemical, first trimester, and second trimester, respectively. Maternal and neonatal outcomes When comparing the EH group to the control group, there was a significantly higher incidence of cervical insufficiency (6.7% vs. 0%, P = 0.017) (Table 3). The rates of gestational hypertension, gestational diabetes mellitus, and preterm delivery were comparable between the two groups (Table 3). Regarding neonatal complications, such as macrosomia and low birthweight, there were no differences. Furthermore, no birth defects were observed in either the EH group or the control group. not-yet-known not-yet-known not-yet-known unknown Subgroup analysis of endometrial hyperplasia Patients with EH were subdivided into two groups based on the presence or absence of cytological atypia. Among these patients, 35 had atypical features, while 60 did not exhibit atypical characteristics. All baseline characteristics were comparable between EH patients with and without atypia (Supplemental Table 1). The quantity and developmental stage of transferred embryos, average endometrial thickness, and endometrial preparation protocols did not differ between the two subgroups. The rates of live birth, clinical pregnancy, and pregnancy loss were comparable between EH patients with and without atypia (Table 4). Furthermore, no distinctions were noted in terms of maternal and neonatal complications (Supplemental Table 2). Binary logistic regression models Unadjusted and adjusted ORs and 95% CIs of the potential risk factors for live birth are shown in Table 5. Consistent with our matched findings, patients with EH had lower odds of live birth in both before and after adjustment (crude OR=0.42; 95% CI, 0.27-0.64; adjusted OR=0.63;95% CI, 0.41-0.95, respectively). As expected, factors such as age ≥ 30 years, a BMI ≥ 28 kg/m 2 , prolonged infertility duration, and primary infertility were associated with the decreased odds of achieving a live birth. Conversely, a higher likelihood of live birth was observed when endometrial thickness was ≥ 8 mm, or when multiple embryos were transferred or when a blastocyst was transferred. Discussion Main findings In this study, we provide evidence that, women with EH who achieved complete remission after conservative treatment had a lower live birth rate and a higher pregnancy loss rate and cervical insufficiency rate when juxtaposed with meticulously matched infertile control counterparts after FET. Additionally, binary logistic regression analysis of data from a large cohort with 30,634 controls conclusively identified EH as a risk factor for achieving a live birth. Furthermore, no discernible variations were found in the subgroup analysis of women with EH with regard to pregnancy outcomes, maternal and neonatal complications. To the best of our knowledge, this is the first and largest study to use PSM in conjunction with binary logistic regression analysis to provide a novel and comprehensive perspective on the reproductive outcomes of EH patients undergoing IVF/ICSI-FET. Given that patients with EH commonly come with infertility problems, ART is recommended for individuals who seek to conceive after conservative treatment 7, 9 . In contrast to natural conception, ART treatment has been shown to significantly increase the likelihood of successful pregnancy in EH patients with atypia and early-stage endometrial cancer 14 . However, only one previous study has specially addressed the impact of atypical EH on pregnancy outcomes, showing that EH patients with atypia experiencing higher rates of pregnancy loss and preterm delivery after fresh embryo transfer compared to matched infertile controls 15 . Due to the limited sample size in this study, no discernible variation in the live birth rate was found. Here in this study, we found that patients with EH had a lower live birth rate when undergoing their first FET, compared to matched infertile controls with normal endometrium, as determined by histopathological evaluation. The lower rate of clinical pregnancy and higher rate of pregnancy loss collectively contributed to the reduced live birth rate in patients with EH. Embryo, endometrium and their interaction are the triad for successful pregnancy. Our study identified that EH was a potential risk factor for live birth even after adjusting confounding factors including age, BMI, endometrial thickness, number and stage of embryo transferred. The possible reasons for EH comprising live birth may relate to the impaired endometrial receptivity. High-dose progestin treatment in patients with EH has been shown to suppress progesterone receptor expression, potentially disrupting the actions of progesterone on endometrium, thereby impairing the endometrial receptivity and decidualization 18, 19 . Additionally, HOXA10, a critical marker of endometrial receptivity, has been found to be downregulated in the endometrium of EH patients, potentially compromising endometrial receptivity 20 . However, it remains unclear whether these factors persist and impair endometrial function following conservative treatment for EH. Further research is needed to unravel the intricate molecular mechanisms underlying endometrial dysfunction following fertility-preserving treatment for EH. Another concern about reproductive challenges among EH patients is a lack of understanding of pregnancy and perinatal complications. Song et al found that after fresh embryo transfer, the preterm birth rate was substantially higher in women with atypical EH than matched controls 15 . However, this phenomenon was not observed in our study may be related to the patients we enrolled included EH patients with and without atypical. Moreover, a higher incidence of cervical insufficiency in EH patients was observed in EH patients in our study, which may be associated with the repetitive dilatation and curettage or hysteroscopic biopsy performed for the management of EH 21 . In this study, two patients experienced cervical insufficiency, which resulted in second-trimester pregnancy loss, emphasizing the significance of thorough obstetric review throughout pregnancy in patients with EH. However, given the very small number of instances, this current conclusion should be regarded with caution. Further studies with larger sample sizes are needed to validate this finding. While other challenges, including maternal and neonatal complications, were similar between EH patients and the controls. This consistency outcomes may result from the effective matching of age, BMI, and infertility indicators using PSM. As the severity of the endometrial lesions progresses, fertility outcomes may deteriorate. Guo et al showed that atypical EH patients were more likely to achieve a live birth compared to those with early-stage endometrial cancer 10 . In contrast, An et al found no correlation between the endometrial histological stage and the chance of a live birth in women with EH 22 . In this study, we compared the pregnancy outcomes between EH patients with and without atypical for the first time. Of interest, we found there were no differences in terms of live birth rate, clinical pregnancy rate as well as pregnancy loss rate by subgroup analysis. The possible reasons of these findings are equivocal and requires further elucidation. not-yet-known not-yet-known not-yet-known unknown Strengths and Limitations Our study’s key strength is the relatively high sample size of EH patients compared to previous researches, thereby enhancing the robustness and generalizability of our findings when comparing reproductive outcomes to control patients. PSM was utilized to minimize confounding factors in evaluating reproductive outcomes between EH and control patients, independent of patients’ baseline characteristics. Furthermore, binary logistic regression was conducted to validate our findings, proving that EH was a risk factor for live birth. Finally, our study evaluated pregnancy outcomes, maternal complications, as well as neonatal outcomes, providing a comprehensive perspective for better understanding the impact of EH on reproductive outcomes undergoing frozen embryo transfer. Nonetheless, several limitations should be noted in this study. First, although PSM and binary logistic regression analysis were employed to adjust for confounding factors, the single-center, retrospective design of the study may introduce potential selection bias. Another limitation of our investigation is that, although using a larger sample size of EH patients than prior studies, the low frequency of EH among reproductive-aged women may undercut the putative link between EH, its severity, and adverse pregnancy outcomes. As a result, well-designed prospective cohort studies with larger sample sizes are needed to validate these findings. Interpretation This pioneering large-scale propensity score-matched study, constitutes the first comprehensive investigation into the impact of EH on reproductive outcomes after complete remission following FET Our findings demonstrated that prior EH diagnosis is associated with reduced live birth rate and elevated pregnancy loss rate in subsequent FET cycle. These persistent deficits suggested that residual endometrial impairment notwithstanding histological normalization. Conclusion In clinical IVF/ICSI-FET practice, patients achieving complete EH regression still exhibited poorer reproductive outcomes with lower birth rate and higher pregnancy loss rate compared to infertile controls with normal endometrium. Our study fills the knowledge gap in reproductive medicine by establishing EH as an independent risk factor for live birth in FET, and offers invaluable insights that improve our understanding of the challenges and considerations specific to this population. Moreover, further investigation involve large sample size are need to validate these results. Disclosure of interest All authors have no conflict of interest. Authorship Contributions Qin ling Zhu, Lizhen Xu and Yun Sun were involved in the study design. Qinling Zhu, Lizhen Xu analyzed the data. Qinling Zhu, Lizhen Xu, Yao Lu and Zhe Wei drafted the manuscript. All authors were involved in the acquisition of the data collection interpreted the data, provided critical input to the manuscript, and approved the final manuscript. Details of Ethics approval This study was approved by the Ethics Committee of Renji Hospital, Shanghai Jiaotong University School of Medicine (approval number 2015030308). Funding This study was supported by National Key R&D Program of China (2024YFA1108100, 2024YFA1108104, 2023YFC2705500, 2023YFC2705505), National Natural Science Foundation of China (No. 82320108009, 82130046), Shanghai leading talent program, Innovative research team of high-level local universities in Shanghai (No. SHSMU-ZLCX20210200, SHSMU-ZLCX20210201, No. SSMU-ZLCX20180401), Shanghai Jiaotong University School of Medicine Affiliated Renji Hospital Clinical Research Innovation Cultivation Fund Program (RJTJ25-MS-023), Three-Year Action Plan for Strengthening the Construction of the Public Health System in Shanghai (GWVI-11.1-36) and Shanghai’s Top Priority Research Center Construction Project(2023ZZ02002) Acknowledgements We have no acknowledgements not-yet-known not-yet-known not-yet-known unknown References 1. Sanderson PA, Critchley HO, Williams AR, Arends MJ, Saunders PT. New concepts for an old problem: the diagnosis of endometrial hyperplasia. 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Lin H, Chen WH, Chen CY, Yang YH, Lee CP, Chen KJ, et al. Does repetitive dilatation and curettage or hysteroscopic biopsy in patients treated with progestins for endometrial hyperplasia or carcinoma affect subsequent fetomaternal outcomes? A population-based study using the National Health Insurance Research Database of Taiwan. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. 2024 Feb;164(2):605-12.22. An H, Li T, Huang K, Shi H, Wang C, Chu T, et al. Pregnancy outcomes in infertile patients with endometrial hyperplasia with or without atypia undergoing in vitro fertilization: the early-follicular long protocol is superior to midluteal long protocol. Frontiers in endocrinology. 2024;15:1314432. Figure legends Figure 1. Flow chart of the study on the impact of EH on reproductive outcomes following IVF/ICSI-frozen embryo transfer. IVF, in vitro fertilization; ICSI, intracytoplasmic sperm injection; EH, endometrial hyperplasia; ET, embryo transfer; PSM, propensity score match. Supplementary Material File (tables 2025-4-8.docx) Download 53.06 KB Information & Authors Information Version history V1 Version 1 08 April 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords fertility and assisted reproduction infertility: assisted conception reproductive science: endometrial function Authors Affiliations Qinling Zhu [email protected] Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital View all articles by this author Lizhen Xu Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital View all articles by this author Bing Xu Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital View all articles by this author Yao Lu Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital View all articles by this author Zhe Wei Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital View all articles by this author Wenchao Zhang Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital View all articles by this author Yunfei Huang Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital View all articles by this author Yiwen Meng Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital View all articles by this author Chongwen Shao Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital View all articles by this author Mengjia Shi Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital View all articles by this author Yaqiong He Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital View all articles by this author Jiaan Huang Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital View all articles by this author Yuan Wang Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital View all articles by this author Jia Qi Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital View all articles by this author Ying Ding Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital View all articles by this author Yun Sun Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital View all articles by this author Metrics & Citations Metrics Article Usage 408 views 186 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Qinling Zhu, Lizhen Xu, Bing Xu, et al. 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