Endometrial preparation protocols did not impact outcomes after frozen-thaw embryo transfer for chronic endometritis treatment

Endometrial preparation protocols did not impact outcomes after frozen-thaw embryo transfer for chronic endometritis treatment | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Endometrial preparation protocols did not impact outcomes after frozen-thaw embryo transfer for chronic endometritis treatment Xiao Shi, Shuyi Zhang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5859800/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Apr, 2025 Read the published version in Contraception and Reproductive Medicine → Version 1 posted 8 You are reading this latest preprint version Abstract Background Intended to investigate the potential effects of endometrial preparation procedures on the results of subsequent frozen embryo transfer (FET) cycles in infertile women with chronic endometritis (CE) following a single course of antibiotic therapy. Methods From July 2020 to December 2023, 773 infertile patients participated in a retrospective research. CD138 was immunostained in endometrial tissues taken during the proliferative phase. CE was suggested by the presence of CD138-positive cells in the stromal cells. Oral antibiotics were administered to every patient with a CE diagnosis. After CE was cured, patients had frozen embryo transfers and endometrial preparation. This study compared the impact of different endometrial preparation techniques on pregnancy outcomes. Results Hormone replacement treatment (HRT), ovulation induction, natural cycle, and gonadotrophin-releasing hormone agonist-HRT (GnRH agonist-HRT) regimens did not significantly alter the outcome of pregnancy in patients with CE. Compared to other groups, the ovulation induction cycle group had a higher clinical pregnancy rate and embryo implantation rate. However, the miscarriage rate is lower compared to other populations. Patients with treated CE who received HRT, GnRH agonist-HRT, ovulation induction cycle, and natural cycle did not differ substantially (P > 0.05). Conclusion Patients with cured CE did not see any change in pregnancy outcomes as a result of endometrial preparation procedures. endometrial preparation protocols chronic endometritis pregnancy outcomes Figures Figure 1 Introduction The ongoing inflammatory state of the endometrium is the hallmark of chronic endometritis (CE), a chronic infectious illness that frequently manifests as either no symptoms or mild clinical abnormalities. Prolonged leukorrhea, pelvic discomfort, dyspareunia, and irregular uterine flow are some examples of these disruptions [ 1 ] . However, the endometrium with CE may exhibit focal or diffuse endometrial hyperemia, mucosal edema, and endometrial micro-polyps (usually 1–2 mm in diameter) with hysteroscopy [ 2 ] . Several studies have documented correlations between CE and unfavorable reproductive outcomes, including infertility, recurrent implantation failure (RIF), and recurrent pregnancy loss (RPL) [ 3 – 5 ] . Additionally, research showed a link between a higher frequency of CE and occlusion of the fallopian tubes and hydrosalpinx [ 6 , 7 ] . For CE, there are no accepted, defined criteria or diagnostic standards. The presence of plasma cell infiltration within the endometrial stroma serves as the basis for the histological diagnosis of CE. The main diagnostic technique for CD138 is immunohistochemical (IHC) testing [ 6 ] . A transmembrane heparan sulfate proteoglycan that is expressed on the surface of plasma cells is called CD138 [ 8 ] . Hysteroscopy, a biopsy method, is used to help diagnose intrauterine abnormalities when endometrial micro-polyps (usually 1–2 mm in diameter), focal or widespread hyperemia, and stromal edema are observed [ 9 ] . To lessen or completely eradicate plasmacyte infiltration in the endometrial stroma, an adequate antibiotic therapy was empirically provided [ 5 , 10 ] , despite the fact that the majority of treatments were not predicated on endometrial culture results. Doxycycline's wide range of antibacterial activity made it the first-line therapy [ 11 ] , followed by second-line antibiotic therapies such as ciprofloxacin or metronidazole. Research has indicated that women who undergo antibiotic therapy have a higher pregnancy rate than those who do not [ 12 ] . To our best knowledge, few studies have investigated whether endometrial preparation protocols impact outcomes after FET in the context of CE treatment. The aim in this study was to determine whether endometrial preparation procedures could affect the result of a pregnancy in infertile women with CE who had received one round of antibiotic therapy. We specifically looked at how these procedures affected the outcome of subsequent FET cycles. Method Study design From July 2020 to December 2023, we carried out a retrospective analysis at Capital Medical University's Chaoyang Hospital. As standard procedures for histopathological investigation, women had endometrial biopsies and hysteroscopies, specifically for CD138 staining to detect CE. Infertility, RSA, ET failure, a history of tuberculosis (TB), and atypical uterine findings, including endometrial polyps, intrauterine adhesions (IUA), and congenital uterine deformities, were among the conditions for which hysteroscopy was conducted. The Chaoyang Hospital's medical ethics committee gave its approval for this investigation. Study population We then included individuals who had a FET cycle within 12 months of a hysteroscopy in order to evaluate the effect of CE on reproductive outcomes after antibiotic treatment. The study consisted of 924 women who were referred for endometrial biopsy, hysteroscopy, and CD138 IHC investigation to try to diagnose CE. Individuals with incomplete medical history data, couples with chromosomal abnormalities, patients who had not undergone In Vitro Fertilization-Embryo Transfer (IVF-ET) at our department, patients who had received antibiotic treatment within three months prior to hysteroscopy, and patients with incomplete cycle data or incomplete follow-up information were all eliminated. 773 women had been included in the analysis once these criteria were applied. Initially, the initial analysis to figure out risk variables for CE included all patients. Atomically, patients with CE were further separated into four groups: GnRH agonist-HRT (n = 218), HRT (n = 182), ovulation induction cycle (n = 207), and natural cycle (n = 166). Retrospective analysis was performed on 923 FET cycles. Figure 1 shows the flowchart for the study. Data collection We conducted a search of the electronic medical database to retrieve data, which encompassed the following categories: 1) Maternal characteristics, including maternal age, body mass index (BMI), gravidity, parity, primary cause of infertility, and duration of infertility; 2) Treatments and pregnancy outcomes associated with FET, such as the number of embryo transfer (ET) procedures, the number of good quality embryos transferred, blastocyst rate, insemination methods, and stimulation protocols for FET; 3) gynecologic medical histories, including dysmenorrhea, hydrosalpinx, endometriosis, polycystic ovary syndrome (PCOS), intrauterine device (IUD) use, pelvic inflammatory disease, endometrial polyps, intrauterine adhesions (IUA), tuberculosis, uterine cavity surgery and cervical surgery. Sample collection Two skilled professionals conducted hysteroscopy during the follicular phase (3–7 days after menstruation) of the menstrual cycle using a 30° rigid hysteroscope (OLYMPUS, Japan) with an outer diameter of 5 mm. The uterine cavity was expanded with saline (0.9%) to a pressure of 80–100 mmHg. In addition to various intrauterine manifestations (intrauterine adhesion, endometrial polyps, submucosal myoma, and uterine abnormalities), hysteroscopic characteristics of CE, including endometrial micro-polyps, hyperemia, and edema, were also seen. Endometrial biopsy specimens were taken from the endometrial congestion using a curette as soon as the hysteroscopy was completed. The biopsy sample was taken in the vicinity of the anterior endometrium in patients with a normal uterine cavity. After being preserved in 4% paraformaldehyde, the endometrial samples were transported to the lab for CD138 IHC and histological examination. Experienced senior physicians performed hysteroscopy during the proliferative period (days 9–11 of the menstrual cycle), and histological investigation verified the endometrial phase. The uterine cavity was thoroughly examined during hysteroscopy. During hysteroscopy, biopsy forceps were used for collecting endometrial biopsy samples. Diagnosis of CE According to the Delphi poll reported previously [ 13 ] , in order to use hysteroscopy to diagnose CE, at least one of the following requirements have to be fulfilled: 1) localized or diffuse endometrial hyperemia; 2) micro-polyps (less than 1 mm in size with a definite connective-vascular axis); 3) stromal edema; and 4) a "strawberry" appear which is defined by extensive areas of hyperemia with white central spots. Two skilled gynecologic pathologists from Chaoyang Hospital's Department of Pathology examined each endometrial biopsy specimen. In the study, the plasma cell membrane displayed significant positive CD138 staining, but the cytoplasm displayed mild positive staining. The nuclei were spherical and orientated to one side, and the thick chromatin was arranged in a wheel-like pattern radially along the nuclear membrane. After scanning the entire section at a lower magnification, the number of plasma cells was counted at 400× magnification, focusing on the area with the highest cell density. This was carried out in compliance with the guidelines established [ 3 , 14 ] , using CD138 IHC categorizing, the gold standard for identifying CE is the presence of one or more plasma cells in the ovarian stroma per 10 high-power fields (HPF). Treatment and follow-up of CE Oral doxycycline (100 mg twice daily for 14 days) or oral levofloxacin (500 mg twice daily for 14 days) in combination with oral metronidazole (200 mg twice daily for 14 days) were given at random to women whose CD138 IHC staining revealed CE. On a case-by-case basis or in accordance with the patient's wishes, the doctor decided whether to treat women who tested positive on hysteroscopy but negative for CE on CD138 IHC staining with antibiotics. Women who tested negative for CE on hysteroscopy and CD138 IHC staining were not treated with antibiotics. FET protocol and luteal phase support (LPS) The endometrial preparation approach for FET was customized to each patient's unique traits and preferences and included the natural cycle, ovulation induction cycle, HRT, and GnRH agonist-HRT. Follicle size and endometrial thickness were measured using transvaginal ultrasonography during days 8–10 of the menstrual cycle as part of the natural cycle protocol. When the follicular diameter was at least 18 mm, the progesterone concentration was no more than 1.5 ng/ml, and the endometrial thickness was at least 7 mm, 250 µg of recombinant human chorionic gonadotropin (hCG; Merck, Europe B.V.) was injected intramuscularly. 24 to 48 hours following the hCG treatment, ovulation was seen. During the ovulation induction cycle, oral dysdrogesterone (10 mg three times a day; Abbott Biologicals B.V., the Netherlands) was then given beginning one day after ovulation and continuing for 14 days after FET. Letrozole 2.5 mg/day was given orally for four days from the second to the fourth day of menstruation. In addition, injections of HMG (Li Zhu, China) ranging from 37.5 IU to 75 IU were administered; the dosage was modified based on follicular development. 250 µg of recombinant human chorionic gonadotropin (hCG; Merck, Europe B.V.) was injected intramuscularly once the follicular diameter was at least 18 mm, the progesterone concentration was no more than 1.5 ng/mL, and the endometrial thickness was at least 7 mm. As part of the hormone replacement therapy regimen, patients received 4 or 6 mg of oral estrogen (estradiol valerate [Progynova]; Bayer, France) every day for one week, starting on the second or third day of the menstrual cycle. The estrogen dosage was then changed to 8–10 mg daily, depending on the blood estradiol concentration and endometrial thickness. On days two through four of the menstrual cycle, patients in the GnRH agonist-HRT protocol were administered a gonadotropin-releasing hormone agonist (triptorelin acetate [Diphereline]; Li Zhu, China). When the endometrial thickness was less than 5 mm, the concentration of LH and FSH was below 5 IU/L, and the estradiol level was less than 50 pg/mL, treatment with 4 to 6 mg of oral estrogen was started. Women were prescribed a combination of oral dydrogesterone (10 mg three times per day) and progesterone vaginal sustained-release gel (Crinone; Merck Serono, UK) at a dosage of 90 mg once per day once the endometrial thickness reached 7 mm, the serum progesterone concentration was below 1.5 ng/mL, and the serum estradiol concentration peaked at 200 pg/mL. The embryos were stored in cryogenic and then thawed using the vitrification method. On the fourth day (P + 3) after progesterone exposure, cleavage stage embryos were transplanted, and on the sixth day (P + 5), blastocysts were transferred. Embryos were vitrified and warmed in compliance with previously established procedures [ 15 ] . If a cleavage stage embryo had at least six blastomeres, a fragmentation rate of less than 20%, and no discernible morphological defects, it was considered acceptable quality. Grades 3–6 AA/AB/BA/BB were assigned to good quality blastocysts since they were larger than 3BB and had a cavity expansion level, inner cell mass, and trophectoderm quality. The patient's age, BMI, embryo quality, uterine condition (e.g., scarred uterus, uterine deformities), and personal preferences were taken into consideration when deciding how many frozen embryos to transfer—one or two. Exogenous progesterone and estrogen were administered until 10–12 weeks of gestation, if pregnancy was successful. Outcomes and definitions Two weeks following FET, the serum β-hCG test was performed. Until patients who had a positive pregnancy test, LPS was maintained until 10–12 weeks of gestation. The existence of an intrauterine gestational sac, with or without a fetal heartbeat, as seen by transvaginal ultrasonography after six weeks of gestation was considered clinical pregnancy. The number of gestational sacs divided by the number of transplanted embryos was used to determine the implantation rate. Pregnancy loss before 12 weeks of gestation was referred to as an early miscarriage. Pregnancy loss that happens after 12 weeks but before 28 weeks of gestation is referred to as a late miscarriage. The failure to obtain a clinical pregnancy after transferring at least four high-quality embryos during at least three fresh or frozen IVF cycles was known as RIF [ 16 ] . Statistical analysis SPSS 26.0 software was used for all statistical analyses and graphical representations (SPSS Inc., Chicago, IL). The Student's t-test was used to evaluate continuous data, which was shown as mean ± SD. The chi-square test or Fisher's exact test was used when necessary, and categorical variables were represented as percentages of the total. Statistical significance was defined as a two-sided P-value of less than 0.05. Results Table 1 displays the clinical features of the ovulation induction cycle, natural cycle, HRT, and GnRH agonist-HRT regimens in patients with treated chronic endometritis. The GnRH-agonist-HRT group was significantly larger than the natural cycle group among the 773 study participants. The four groups of patients were similar in age and were all over 35 years old. Compared to women in the natural cycle, ovulation induction cycle, and HRT groups, females in the GnRH agonist-HRT group experienced infertility for a longer period of time (3.33 years versus 3.09 years versus 3.03 years versus 2.76 years, respectively; P = 0.012). Furthermore, there was a statistically significant difference (P = 0.001) in the number of cleavage stage embryos transferred in the GnRH agonist-HRT group (75.77%) as compared to the natural cycle (18.89%), ovulation induction cycle (18.60%), and HRT groups (53.08%). Statistically significant differences were seen between patients in the GnRH agonist-HRT group and those in the other three endometrial preparation procedures, with lower basal AFC and higher basal FSH levels (P = 0.026 for basal AFC and P = 0.015 for basal FSH).The pregnancy results of HRT, GnRH agonist-HRT, ovulation induction cycle, and natural cycle in individuals with CE are shown in Table 2 . Therefore, it can be said that among patients with treated CE, there were virtually no differences in the outcomes of pregnancy amongst the four endometrial preparation methods. In particular, there was no statistically significant difference in the embryo implantation rates for the four endometrial preparation regimens among patients with CE (P = 0.132). These rates were 58.85%, 64.49%, 60.28%, and 56.99%, respectively. These insignificant differences continued even after adjusting for confounding variables like maternal age, the duration of infertility, BMI, basal AFC, the number of transferred embryos, the number of high-quality embryos, the stage of embryo transfers, the type of infertility, and the aetiology of infertility. The group that underwent ovulation induction cycle had a higher rate of clinical pregnancy and embryo implantation than the other groups. But there was a lower miscarriage rate than in other groups. Table 1 General data analysis of the FET cycle after hysteroscopy in post-treatment CE patients Natural cycle (n = 166) Ovulation induction cycle (n = 207) HRT (n = 182) GnRH agonist-HRT (n = 218) P Age (years) 35.37 ± 4.67 35.22 ± 5.15 35.11 ± 4.66 35.44 ± 4.56 0.751 BMI (kg/m 2 ) 22.64 ± 3.54 22.95 ± 3.69 22.77 ± 3.67 23.28 ± 3.59 0.464 Basal FSH (IU/L) 6.32 ± 2.42 5.78 ± 2.25 6.6 ± 3.78 6.59 ± 3.21 0.026 a Basal AFC 10.92 ± 9.12 11.83 ± 10.03 8.55 ± 8.69 9.5 ± 9.10 0.015 b Cause of infertility(%) Women 61.45%(102/166) 68.12%(141/207) 64.29%(118/182) 68.81%(150/218) 0.403 Male factor 9.64%(16/166) 13.53%(28/207) 17.03%(31/182) 15.60%(34/218) 0.410 Both 15.66%(26/166) 8.70%(18/207) 6.04%(11/182) 4.59%(10/218) 0.134 Unknown 13.25%(22/166) 9.65%(20/207) 12.64%(23/182) 11.00%(24/218) 0.477 Duration of infertility (year) 3.09 ± 2.63 3.03 ± 2.52 2.76 ± 2.35 3.33 ± 2.54 0.012 c No. of embryos transferred 1.12 1.21 1.57 1.61 0.065 Type of embryo transfer Cleavage-stage embryo(%) 18.89%(41/217) 18.60%(56/301) 53.08%(181/341) 75.77%(344/454) 0.001 d Blastocyst(%) 81.11%(176/217) 81.40%(245/301) 46.92%(160/341) 24.23%(110/454) 0.027 e I nsemination method IVF(%) 76.56%(147/192) 66.53%(163/245) 65.89%(141/214) 68.01%(185/272) 0.228 ICSI(%) 23.44%(45/192) 33.47%(82/245) 34.11%(73/214) 31.99%(87/272) 0.574 Superscripts indicate significant differences between. a b cGnRH- agonist-HRT group and other three endometrial preparation protocols d e Characterized by grade 1 2 cleavage stage embryos or grade 1 blastocysts. HRT, hormone replacement therapy; GnRH agonist, gonadotrophin-releasing hormone agonist; FET, frozen embryo transfer; BMI, body mass index; AMH, anti-Mullerian hormone. Table 2 Analysis of pregnancy outcomes during FET cycle after hysteroscopy in post-treatment CE patients Natural cycle (n = 192) Ovulation induction cycle (n = 245) HRT (n = 214) GnRH agonist-HRT (n = 272) P Embryo implantation rate (%) 58.85(113/192) 64.49%(157/245) 60.28%(129/214) 56.99%(155/272) 0.132 Clinical pregnancy rate (%) 29.17%(56/192) 32.65%(80/245) 32.71%(70/214) 27.94%(76/272) 0.357 Miscarriage rate (%) 11.46%(22/192) 6.83%(17/249) 9.81%(21/214) 9.19%(25/272) 0.126 Discussion This study aimed to assess the impact of endometrial preparation practices on pregnancy outcomes in individuals with a history of resolved CE during FET cycles. According to our findings, none of the pregnancy outcomes that were measured—including the rate of live birth—were significantly impacted by the endometrial preparation program. Furthermore, regardless of the endometrial preparation procedure they had, pregnancy results were shown to be comparable for patients with a history of resolved CE and those without. When comparing the natural cycle, ovulation induction cycle, HRT, and GnRH agonist-HRT protocols for patients with resolved CE, the comparative analysis found no appreciable differences in almost all pregnancy outcomes. Reproductive medicine contends that the main variables affecting the success of FET are the number and quality of embryos, the endometrium's thickness and receptivity, and the timing of endometrial growth [ 17 ] . This is in line with the fact that there is not enough data to conclusively say which endometrial preparation method is better for infertile women having FET [ 18 ] . Consistent results from a cochrane study that looked at 18 randomized controlled trials support the previously indicated conclusions [ 19 ] . Additionally, women undergoing HRT FET did not have better reproductive results after pretreatment with GnRH agonists [ 20 , 21 ] . This study then attempted to investigate any possible differences in pregnancy outcomes between individuals who underwent the difference endometrial preparation technique but had cured CE. This result is in line with earlier research [ 22 ] . Xiong et al. discovered no significant differences between the treated CE group and the control group (52.1% and 52.6% live birth rates, respectively) when baseline statistics, such as the percentage of endometrial preparation procedures [ 23 ] . The clinical pregnancy rate did not differ significantly between patients with and without chronic endometritis, according to Brecht et al. (OR 0.39, 95% CI 0.09 1.61) [ 24 ] . In individuals with resolved CE, prompt removal of harmful bacteria from the endometrial tissue with antibiotic therapy may improve endometrial receptivity and aid in the restoration of endometrial immunological homeostasis. According to this, the endometrial immune milieu in these individuals might return to normal, which could make the endometrial preparation procedure just as effective as it is in patients who have never had CE. It's crucial to remember, though, that the current results contradict some previous studies. According to Keiji et al., patients with treated CE had a much lower clinical pregnancy rate than those without the disease [ 25 ] . Additionally, In the study by Duan et al., patients with treated CE had a considerably higher rate of spontaneous abortions than patients without the condition [ 26 ] . In the setting of frozen embryo transfer cycles, there was no discernible difference in the miscarriage incidence between patients with and without CE. These discrepancies could result from differences in treatment concept, embryo transfer procedures, or diagnostic standards for CE amongst studies. There are various restrictions on this study. First of all, because it was a retrospective analysis, the study participants' clinical and demographic information was lacking, and confounding variables such endometrial pathology treatments were not included, which could have affected the findings. Properly planned prospective studies are required for additional validation. Furthermore, there are no standard diagnostic standards for endometritis, and many studies have used disparate standards, leading to varying findings. To get more precise results, these patients should be examined in the future using the most recent definitions. Furthermore, the findings could not be typical of the general community because they were derived from a single center experience. To get more solid and compelling data about the diagnosis and treatment of infertility patients with CE, prospective randomized controlled studies or multicenter clinical trials are required. According to the study, there is no connection between the endometrial preparation procedures and the results of pregnancies in people with treated CE. Another important conclusion of this study is that, in both individuals with treated CE and those without, the precise endometrial preparation regimens had no discernible effect on pregnancy outcomes. These results underscore the significance of choosing a suitable endometrial preparation procedure according to the patient's endometrial and ovulatory condition, irrespective of the patient's chronic endometritis history. Clinical management in these situations may benefit greatly from this information. Abbreviations FET: Frozen Embryo Transfer CE: Chronic Endometritis HRT: Hormone Replacement Treatment GnRH: Gonadotrophin-Releasing Hormone RPL: Recurrent Pregnancy Loss IHC: Immunohistochemical TB: Tuberculosis IVF-ET: In Vitro Fertilization-Embryo Transfer BMI: Body Mass Index PCOS: Polycystic Ovary Syndrome IUD: Intrauterine Device IUA: Intrauterine Adhesions HPF: High-Power Fields AMH: Anti-Mullerian Hormone hCG: Human Chorionic Gonadotropin Declarations Data availability The data used in this paper will not be openly shared to protect the included informants’ privacy and due to general security concerns. Acknowledgements We acknowledge the support and assistance provided to us by the service users of the mental health clinics in the hospital as we conducted this research. Funding Not applicable. Author information Authors and Affiliations Shi Xiao Chaoyang Hospital Affiliated to Capital Medical University, Beijing, China Shuyi Zhang Chaoyang Hospital Affiliated to Capital Medical University, Beijing, China Contributions All authors participated in the process of data collection, conducted the analysis and reflected on the findings together. The manuscript was written in collaboration, and all the authors read and approved the content of the final manuscript. Corresponding author Correspondence to Shuyi Zhang Ethics declarations Ethics approval and consent to participate The study was approved in advance by the ethical committee. Consent was given in accordance with the laws governing privacy in research. Consent for publication Not applicable. Competing interests The authors declare no competing interests. References CICINELLI E, TROJANO G, MASTROMAURO M, et al. Higher prevalence of chronic endometritis in women with endometriosis: a possible etiopathogenetic link [J]. 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Cite Share Download PDF Status: Published Journal Publication published 07 Apr, 2025 Read the published version in Contraception and Reproductive Medicine → Version 1 posted Editorial decision: Revision requested 10 Mar, 2025 Reviews received at journal 15 Feb, 2025 Reviewers agreed at journal 14 Feb, 2025 Reviewers agreed at journal 03 Feb, 2025 Reviewers invited by journal 03 Feb, 2025 Editor assigned by journal 23 Jan, 2025 Submission checks completed at journal 23 Jan, 2025 First submitted to journal 19 Jan, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5859800","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":406251312,"identity":"8958bbd8-7030-4be8-a57c-c5c63cf301c4","order_by":0,"name":"Xiao Shi","email":"","orcid":"","institution":"Beijing Chao-Yang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiao","middleName":"","lastName":"Shi","suffix":""},{"id":406251313,"identity":"292b515d-752c-4fa3-ad45-76a749535a84","order_by":1,"name":"Shuyi Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0UlEQVRIiWNgGAWjYHACxsd/KiR42NgbGx9+IFILswHPGRs5fp7DzcYSRGphk+BtSTOWnJHeJsBDjHr5/jMGEpINhxM33HzYxiDBYCen20BAC+OMHAMDwx1ALbcT2x4UMCQbmx0goIVZgscgIfEMWEu7gQTDgcRthLSw8Z8xOHCwDeSwg20SPMRo4WHIMWxsbAN5n5FILRISacXMDOBATgQGsgERfpHvP7z9NwM4Ko8/fPihwk6OoBYGBg4DJI4BTmXIgP0BUcpGwSgYBaNgBAMApm9ENGQMlZMAAAAASUVORK5CYII=","orcid":"","institution":"Beijing Chao-Yang Hospital","correspondingAuthor":true,"prefix":"","firstName":"Shuyi","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2025-01-19 13:53:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5859800/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5859800/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s40834-025-00363-6","type":"published","date":"2025-04-07T16:05:03+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":74920214,"identity":"86d636dd-b350-40ea-880e-bb7321153e53","added_by":"auto","created_at":"2025-01-28 10:33:14","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":91395,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of the study and distribution of the population investigated.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-5859800/v1/c36f0e906e2a8c5194a3ce06.png"},{"id":80558929,"identity":"b925fcbc-9486-41f2-8091-c10778effbe5","added_by":"auto","created_at":"2025-04-14 16:17:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":641863,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5859800/v1/e666d184-1260-4902-8098-fc6dca314e0f.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Endometrial preparation protocols did not impact outcomes after frozen-thaw embryo transfer for chronic endometritis treatment","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe ongoing inflammatory state of the endometrium is the hallmark of chronic endometritis (CE), a chronic infectious illness that frequently manifests as either no symptoms or mild clinical abnormalities. Prolonged leukorrhea, pelvic discomfort, dyspareunia, and irregular uterine flow are some examples of these disruptions \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. However, the endometrium with CE may exhibit focal or diffuse endometrial hyperemia, mucosal edema, and endometrial micro-polyps (usually 1\u0026ndash;2 mm in diameter) with hysteroscopy\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Several studies have documented correlations between CE and unfavorable reproductive outcomes, including infertility, recurrent implantation failure (RIF), and recurrent pregnancy loss (RPL)\u003csup\u003e[\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. Additionally, research showed a link between a higher frequency of CE and occlusion of the fallopian tubes and hydrosalpinx \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eFor CE, there are no accepted, defined criteria or diagnostic standards. The presence of plasma cell infiltration within the endometrial stroma serves as the basis for the histological diagnosis of CE. The main diagnostic technique for CD138 is immunohistochemical (IHC) testing \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. A transmembrane heparan sulfate proteoglycan that is expressed on the surface of plasma cells is called CD138 \u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. Hysteroscopy, a biopsy method, is used to help diagnose intrauterine abnormalities when endometrial micro-polyps (usually 1\u0026ndash;2 mm in diameter), focal or widespread hyperemia, and stromal edema are observed\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. To lessen or completely eradicate plasmacyte infiltration in the endometrial stroma, an adequate antibiotic therapy was empirically provided\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e, despite the fact that the majority of treatments were not predicated on endometrial culture results. Doxycycline's wide range of antibacterial activity made it the first-line therapy \u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e, followed by second-line antibiotic therapies such as ciprofloxacin or metronidazole. Research has indicated that women who undergo antibiotic therapy have a higher pregnancy rate than those who do not\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTo our best knowledge, few studies have investigated whether endometrial preparation protocols impact outcomes after FET in the context of CE treatment. The aim in this study was to determine whether endometrial preparation procedures could affect the result of a pregnancy in infertile women with CE who had received one round of antibiotic therapy. We specifically looked at how these procedures affected the outcome of subsequent FET cycles.\u003c/p\u003e"},{"header":"Method","content":"\u003cp\u003eStudy design\u003c/p\u003e \u003cp\u003eFrom July 2020 to December 2023, we carried out a retrospective analysis at Capital Medical University's Chaoyang Hospital. As standard procedures for histopathological investigation, women had endometrial biopsies and hysteroscopies, specifically for CD138 staining to detect CE. Infertility, RSA, ET failure, a history of tuberculosis (TB), and atypical uterine findings, including endometrial polyps, intrauterine adhesions (IUA), and congenital uterine deformities, were among the conditions for which hysteroscopy was conducted. The Chaoyang Hospital's medical ethics committee gave its approval for this investigation.\u003c/p\u003e \u003cp\u003eStudy population\u003c/p\u003e \u003cp\u003eWe then included individuals who had a FET cycle within 12 months of a hysteroscopy in order to evaluate the effect of CE on reproductive outcomes after antibiotic treatment. The study consisted of 924 women who were referred for endometrial biopsy, hysteroscopy, and CD138 IHC investigation to try to diagnose CE. Individuals with incomplete medical history data, couples with chromosomal abnormalities, patients who had not undergone In Vitro Fertilization-Embryo Transfer (IVF-ET) at our department, patients who had received antibiotic treatment within three months prior to hysteroscopy, and patients with incomplete cycle data or incomplete follow-up information were all eliminated. 773 women had been included in the analysis once these criteria were applied. Initially, the initial analysis to figure out risk variables for CE included all patients. Atomically, patients with CE were further separated into four groups: GnRH agonist-HRT (n\u0026thinsp;=\u0026thinsp;218), HRT (n\u0026thinsp;=\u0026thinsp;182), ovulation induction cycle (n\u0026thinsp;=\u0026thinsp;207), and natural cycle (n\u0026thinsp;=\u0026thinsp;166). Retrospective analysis was performed on 923 FET cycles. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the flowchart for the study.\u003c/p\u003e \u003cp\u003eData collection\u003c/p\u003e \u003cp\u003eWe conducted a search of the electronic medical database to retrieve data, which encompassed the following categories: 1) Maternal characteristics, including maternal age, body mass index (BMI), gravidity, parity, primary cause of infertility, and duration of infertility; 2) Treatments and pregnancy outcomes associated with FET, such as the number of embryo transfer (ET) procedures, the number of good quality embryos transferred, blastocyst rate, insemination methods, and stimulation protocols for FET; 3) gynecologic medical histories, including dysmenorrhea, hydrosalpinx, endometriosis, polycystic ovary syndrome (PCOS), intrauterine device (IUD) use, pelvic inflammatory disease, endometrial polyps, intrauterine adhesions (IUA), tuberculosis, uterine cavity surgery and cervical surgery.\u003c/p\u003e \u003cp\u003eSample collection\u003c/p\u003e \u003cp\u003eTwo skilled professionals conducted hysteroscopy during the follicular phase (3\u0026ndash;7 days after menstruation) of the menstrual cycle using a 30\u0026deg; rigid hysteroscope (OLYMPUS, Japan) with an outer diameter of 5 mm. The uterine cavity was expanded with saline (0.9%) to a pressure of 80\u0026ndash;100 mmHg. In addition to various intrauterine manifestations (intrauterine adhesion, endometrial polyps, submucosal myoma, and uterine abnormalities), hysteroscopic characteristics of CE, including endometrial micro-polyps, hyperemia, and edema, were also seen. Endometrial biopsy specimens were taken from the endometrial congestion using a curette as soon as the hysteroscopy was completed. The biopsy sample was taken in the vicinity of the anterior endometrium in patients with a normal uterine cavity. After being preserved in 4% paraformaldehyde, the endometrial samples were transported to the lab for CD138 IHC and histological examination. Experienced senior physicians performed hysteroscopy during the proliferative period (days 9\u0026ndash;11 of the menstrual cycle), and histological investigation verified the endometrial phase. The uterine cavity was thoroughly examined during hysteroscopy. During hysteroscopy, biopsy forceps were used for collecting endometrial biopsy samples.\u003c/p\u003e \u003cp\u003eDiagnosis of CE\u003c/p\u003e \u003cp\u003eAccording to the Delphi poll reported previously\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e, in order to use hysteroscopy to diagnose CE, at least one of the following requirements have to be fulfilled: 1) localized or diffuse endometrial hyperemia; 2) micro-polyps (less than 1 mm in size with a definite connective-vascular axis); 3) stromal edema; and 4) a \"strawberry\" appear which is defined by extensive areas of hyperemia with white central spots. Two skilled gynecologic pathologists from Chaoyang Hospital's Department of Pathology examined each endometrial biopsy specimen. In the study, the plasma cell membrane displayed significant positive CD138 staining, but the cytoplasm displayed mild positive staining. The nuclei were spherical and orientated to one side, and the thick chromatin was arranged in a wheel-like pattern radially along the nuclear membrane. After scanning the entire section at a lower magnification, the number of plasma cells was counted at 400\u0026times; magnification, focusing on the area with the highest cell density. This was carried out in compliance with the guidelines established\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e, using CD138 IHC categorizing, the gold standard for identifying CE is the presence of one or more plasma cells in the ovarian stroma per 10 high-power fields (HPF).\u003c/p\u003e \u003cp\u003eTreatment and follow-up of CE\u003c/p\u003e \u003cp\u003eOral doxycycline (100 mg twice daily for 14 days) or oral levofloxacin (500 mg twice daily for 14 days) in combination with oral metronidazole (200 mg twice daily for 14 days) were given at random to women whose CD138 IHC staining revealed CE. On a case-by-case basis or in accordance with the patient's wishes, the doctor decided whether to treat women who tested positive on hysteroscopy but negative for CE on CD138 IHC staining with antibiotics. Women who tested negative for CE on hysteroscopy and CD138 IHC staining were not treated with antibiotics.\u003c/p\u003e \u003cp\u003eFET protocol and luteal phase support (LPS)\u003c/p\u003e \u003cp\u003eThe endometrial preparation approach for FET was customized to each patient's unique traits and preferences and included the natural cycle, ovulation induction cycle, HRT, and GnRH agonist-HRT. Follicle size and endometrial thickness were measured using transvaginal ultrasonography during days 8\u0026ndash;10 of the menstrual cycle as part of the natural cycle protocol. When the follicular diameter was at least 18 mm, the progesterone concentration was no more than 1.5 ng/ml, and the endometrial thickness was at least 7 mm, 250 \u0026micro;g of recombinant human chorionic gonadotropin (hCG; Merck, Europe B.V.) was injected intramuscularly. 24 to 48 hours following the hCG treatment, ovulation was seen. During the ovulation induction cycle, oral dysdrogesterone (10 mg three times a day; Abbott Biologicals B.V., the Netherlands) was then given beginning one day after ovulation and continuing for 14 days after FET. Letrozole 2.5 mg/day was given orally for four days from the second to the fourth day of menstruation. In addition, injections of HMG (Li Zhu, China) ranging from 37.5 IU to 75 IU were administered; the dosage was modified based on follicular development. 250 \u0026micro;g of recombinant human chorionic gonadotropin (hCG; Merck, Europe B.V.) was injected intramuscularly once the follicular diameter was at least 18 mm, the progesterone concentration was no more than 1.5 ng/mL, and the endometrial thickness was at least 7 mm. As part of the hormone replacement therapy regimen, patients received 4 or 6 mg of oral estrogen (estradiol valerate [Progynova]; Bayer, France) every day for one week, starting on the second or third day of the menstrual cycle. The estrogen dosage was then changed to 8\u0026ndash;10 mg daily, depending on the blood estradiol concentration and endometrial thickness. On days two through four of the menstrual cycle, patients in the GnRH agonist-HRT protocol were administered a gonadotropin-releasing hormone agonist (triptorelin acetate [Diphereline]; Li Zhu, China). When the endometrial thickness was less than 5 mm, the concentration of LH and FSH was below 5 IU/L, and the estradiol level was less than 50 pg/mL, treatment with 4 to 6 mg of oral estrogen was started. Women were prescribed a combination of oral dydrogesterone (10 mg three times per day) and progesterone vaginal sustained-release gel (Crinone; Merck Serono, UK) at a dosage of 90 mg once per day once the endometrial thickness reached 7 mm, the serum progesterone concentration was below 1.5 ng/mL, and the serum estradiol concentration peaked at 200 pg/mL. The embryos were stored in cryogenic and then thawed using the vitrification method. On the fourth day (P\u0026thinsp;+\u0026thinsp;3) after progesterone exposure, cleavage stage embryos were transplanted, and on the sixth day (P\u0026thinsp;+\u0026thinsp;5), blastocysts were transferred. Embryos were vitrified and warmed in compliance with previously established procedures\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. If a cleavage stage embryo had at least six blastomeres, a fragmentation rate of less than 20%, and no discernible morphological defects, it was considered acceptable quality. Grades 3\u0026ndash;6 AA/AB/BA/BB were assigned to good quality blastocysts since they were larger than 3BB and had a cavity expansion level, inner cell mass, and trophectoderm quality. The patient's age, BMI, embryo quality, uterine condition (e.g., scarred uterus, uterine deformities), and personal preferences were taken into consideration when deciding how many frozen embryos to transfer\u0026mdash;one or two. Exogenous progesterone and estrogen were administered until 10\u0026ndash;12 weeks of gestation, if pregnancy was successful.\u003c/p\u003e \u003cp\u003eOutcomes and definitions\u003c/p\u003e \u003cp\u003eTwo weeks following FET, the serum β-hCG test was performed. Until patients who had a positive pregnancy test, LPS was maintained until 10\u0026ndash;12 weeks of gestation. The existence of an intrauterine gestational sac, with or without a fetal heartbeat, as seen by transvaginal ultrasonography after six weeks of gestation was considered clinical pregnancy. The number of gestational sacs divided by the number of transplanted embryos was used to determine the implantation rate. Pregnancy loss before 12 weeks of gestation was referred to as an early miscarriage. Pregnancy loss that happens after 12 weeks but before 28 weeks of gestation is referred to as a late miscarriage. The failure to obtain a clinical pregnancy after transferring at least four high-quality embryos during at least three fresh or frozen IVF cycles was known as RIF\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eSPSS 26.0 software was used for all statistical analyses and graphical representations (SPSS Inc., Chicago, IL). The Student's t-test was used to evaluate continuous data, which was shown as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD. The chi-square test or Fisher's exact test was used when necessary, and categorical variables were represented as percentages of the total. Statistical significance was defined as a two-sided P-value of less than 0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e displays the clinical features of the ovulation induction cycle, natural cycle, HRT, and GnRH agonist-HRT regimens in patients with treated chronic endometritis. The GnRH-agonist-HRT group was significantly larger than the natural cycle group among the 773 study participants. The four groups of patients were similar in age and were all over 35 years old. Compared to women in the natural cycle, ovulation induction cycle, and HRT groups, females in the GnRH agonist-HRT group experienced infertility for a longer period of time (3.33 years versus 3.09 years versus 3.03 years versus 2.76 years, respectively; P\u0026thinsp;=\u0026thinsp;0.012). Furthermore, there was a statistically significant difference (P\u0026thinsp;=\u0026thinsp;0.001) in the number of cleavage stage embryos transferred in the GnRH agonist-HRT group (75.77%) as compared to the natural cycle (18.89%), ovulation induction cycle (18.60%), and HRT groups (53.08%). Statistically significant differences were seen between patients in the GnRH agonist-HRT group and those in the other three endometrial preparation procedures, with lower basal AFC and higher basal FSH levels (P\u0026thinsp;=\u0026thinsp;0.026 for basal AFC and P\u0026thinsp;=\u0026thinsp;0.015 for basal FSH).The pregnancy results of HRT, GnRH agonist-HRT, ovulation induction cycle, and natural cycle in individuals with CE are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Therefore, it can be said that among patients with treated CE, there were virtually no differences in the outcomes of pregnancy amongst the four endometrial preparation methods. In particular, there was no statistically significant difference in the embryo implantation rates for the four endometrial preparation regimens among patients with CE (P\u0026thinsp;=\u0026thinsp;0.132). These rates were 58.85%, 64.49%, 60.28%, and 56.99%, respectively. These insignificant differences continued even after adjusting for confounding variables like maternal age, the duration of infertility, BMI, basal AFC, the number of transferred embryos, the number of high-quality embryos, the stage of embryo transfers, the type of infertility, and the aetiology of infertility. The group that underwent ovulation induction cycle had a higher rate of clinical pregnancy and embryo implantation than the other groups. But there was a lower miscarriage rate than in other groups.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eGeneral data analysis of the FET cycle after hysteroscopy in post-treatment CE patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNatural cycle\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;166)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOvulation induction cycle\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;207)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHRT\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;182)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGnRH agonist-HRT\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;218)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35.37\u0026thinsp;\u0026plusmn;\u0026thinsp;4.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35.22\u0026thinsp;\u0026plusmn;\u0026thinsp;5.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e35.11\u0026thinsp;\u0026plusmn;\u0026thinsp;4.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e35.44\u0026thinsp;\u0026plusmn;\u0026thinsp;4.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.751\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22.64\u0026thinsp;\u0026plusmn;\u0026thinsp;3.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.95\u0026thinsp;\u0026plusmn;\u0026thinsp;3.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22.77\u0026thinsp;\u0026plusmn;\u0026thinsp;3.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e23.28\u0026thinsp;\u0026plusmn;\u0026thinsp;3.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.464\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBasal FSH (IU/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.32\u0026thinsp;\u0026plusmn;\u0026thinsp;2.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.78\u0026thinsp;\u0026plusmn;\u0026thinsp;2.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.59\u0026thinsp;\u0026plusmn;\u0026thinsp;3.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.026\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBasal AFC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.92\u0026thinsp;\u0026plusmn;\u0026thinsp;9.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.83\u0026thinsp;\u0026plusmn;\u0026thinsp;10.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.55\u0026thinsp;\u0026plusmn;\u0026thinsp;8.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.015\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCause of infertility(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWomen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61.45%(102/166)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68.12%(141/207)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e64.29%(118/182)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e68.81%(150/218)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.403\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale factor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.64%(16/166)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.53%(28/207)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17.03%(31/182)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15.60%(34/218)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.410\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBoth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.66%(26/166)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.70%(18/207)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.04%(11/182)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.59%(10/218)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.134\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13.25%(22/166)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.65%(20/207)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12.64%(23/182)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11.00%(24/218)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.477\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of infertility (year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.09\u0026thinsp;\u0026plusmn;\u0026thinsp;2.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.03\u0026thinsp;\u0026plusmn;\u0026thinsp;2.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.76\u0026thinsp;\u0026plusmn;\u0026thinsp;2.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.33\u0026thinsp;\u0026plusmn;\u0026thinsp;2.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.012\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo. of embryos transferred\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.065\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eType of embryo transfer\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCleavage-stage embryo(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18.89%(41/217)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18.60%(56/301)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e53.08%(181/341)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e75.77%(344/454)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlastocyst(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e81.11%(176/217)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e81.40%(245/301)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e46.92%(160/341)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24.23%(110/454)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.027\u003csup\u003ee\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eI\u003cb\u003ensemination method\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIVF(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76.56%(147/192)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66.53%(163/245)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e65.89%(141/214)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e68.01%(185/272)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.228\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICSI(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.44%(45/192)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33.47%(82/245)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34.11%(73/214)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31.99%(87/272)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.574\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eSuperscripts indicate significant differences between.\u003c/p\u003e \u003cp\u003ea b cGnRH- agonist-HRT group and other three endometrial preparation protocols\u003c/p\u003e \u003cp\u003ed e Characterized by grade 1 2 cleavage stage embryos or grade 1 blastocysts.\u003c/p\u003e \u003cp\u003eHRT, hormone replacement therapy; GnRH agonist, gonadotrophin-releasing hormone agonist; FET, frozen embryo transfer; BMI, body mass index; AMH, anti-Mullerian hormone.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAnalysis of pregnancy outcomes during FET cycle after hysteroscopy in post-treatment CE patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNatural cycle\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;192)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOvulation induction cycle\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;245)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHRT\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;214)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGnRH agonist-HRT\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;272)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEmbryo implantation rate (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e58.85(113/192)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e64.49%(157/245)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e60.28%(129/214)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e56.99%(155/272)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.132\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical pregnancy rate (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e29.17%(56/192)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e32.65%(80/245)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e32.71%(70/214)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e27.94%(76/272)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.357\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMiscarriage rate (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11.46%(22/192)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6.83%(17/249)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9.81%(21/214)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9.19%(25/272)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.126\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study aimed to assess the impact of endometrial preparation practices on pregnancy outcomes in individuals with a history of resolved CE during FET cycles. According to our findings, none of the pregnancy outcomes that were measured\u0026mdash;including the rate of live birth\u0026mdash;were significantly impacted by the endometrial preparation program. Furthermore, regardless of the endometrial preparation procedure they had, pregnancy results were shown to be comparable for patients with a history of resolved CE and those without. When comparing the natural cycle, ovulation induction cycle, HRT, and GnRH agonist-HRT protocols for patients with resolved CE, the comparative analysis found no appreciable differences in almost all pregnancy outcomes. Reproductive medicine contends that the main variables affecting the success of FET are the number and quality of embryos, the endometrium's thickness and receptivity, and the timing of endometrial growth\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. This is in line with the fact that there is not enough data to conclusively say which endometrial preparation method is better for infertile women having FET \u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. Consistent results from a cochrane study that looked at 18 randomized controlled trials support the previously indicated conclusions \u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. Additionally, women undergoing HRT FET did not have better reproductive results after pretreatment with GnRH agonists \u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. This study then attempted to investigate any possible differences in pregnancy outcomes between individuals who underwent the difference endometrial preparation technique but had cured CE. This result is in line with earlier research\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. Xiong et al. discovered no significant differences between the treated CE group and the control group (52.1% and 52.6% live birth rates, respectively) when baseline statistics, such as the percentage of endometrial preparation procedures \u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. The clinical pregnancy rate did not differ significantly between patients with and without chronic endometritis, according to Brecht et al. (OR 0.39, 95% CI 0.09 1.61)\u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. In individuals with resolved CE, prompt removal of harmful bacteria from the endometrial tissue with antibiotic therapy may improve endometrial receptivity and aid in the restoration of endometrial immunological homeostasis. According to this, the endometrial immune milieu in these individuals might return to normal, which could make the endometrial preparation procedure just as effective as it is in patients who have never had CE. It's crucial to remember, though, that the current results contradict some previous studies. According to Keiji et al., patients with treated CE had a much lower clinical pregnancy rate than those without the disease\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e. Additionally, In the study by Duan et al., patients with treated CE had a considerably higher rate of spontaneous abortions than patients without the condition\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. In the setting of frozen embryo transfer cycles, there was no discernible difference in the miscarriage incidence between patients with and without CE. These discrepancies could result from differences in treatment concept, embryo transfer procedures, or diagnostic standards for CE amongst studies. There are various restrictions on this study. First of all, because it was a retrospective analysis, the study participants' clinical and demographic information was lacking, and confounding variables such endometrial pathology treatments were not included, which could have affected the findings. Properly planned prospective studies are required for additional validation. Furthermore, there are no standard diagnostic standards for endometritis, and many studies have used disparate standards, leading to varying findings. To get more precise results, these patients should be examined in the future using the most recent definitions. Furthermore, the findings could not be typical of the general community because they were derived from a single center experience. To get more solid and compelling data about the diagnosis and treatment of infertility patients with CE, prospective randomized controlled studies or multicenter clinical trials are required. According to the study, there is no connection between the endometrial preparation procedures and the results of pregnancies in people with treated CE. Another important conclusion of this study is that, in both individuals with treated CE and those without, the precise endometrial preparation regimens had no discernible effect on pregnancy outcomes. These results underscore the significance of choosing a suitable endometrial preparation procedure according to the patient's endometrial and ovulatory condition, irrespective of the patient's chronic endometritis history. Clinical management in these situations may benefit greatly from this information.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eFET: Frozen Embryo Transfer\u003c/p\u003e\n\u003cp\u003eCE: Chronic Endometritis\u003c/p\u003e\n\u003cp\u003eHRT: Hormone Replacement Treatment\u003c/p\u003e\n\u003cp\u003eGnRH: Gonadotrophin-Releasing Hormone\u003c/p\u003e\n\u003cp\u003eRPL: Recurrent Pregnancy Loss\u003c/p\u003e\n\u003cp\u003eIHC: Immunohistochemical\u003c/p\u003e\n\u003cp\u003eTB: Tuberculosis\u003c/p\u003e\n\u003cp\u003eIVF-ET: In Vitro Fertilization-Embryo Transfer\u003c/p\u003e\n\u003cp\u003eBMI: Body Mass Index\u003c/p\u003e\n\u003cp\u003ePCOS: Polycystic Ovary Syndrome\u003c/p\u003e\n\u003cp\u003eIUD: Intrauterine Device\u003c/p\u003e\n\u003cp\u003eIUA: Intrauterine Adhesions\u003c/p\u003e\n\u003cp\u003eHPF: High-Power Fields\u003c/p\u003e\n\u003cp\u003eAMH: Anti-Mullerian Hormone\u003c/p\u003e\n\u003cp\u003ehCG: Human Chorionic Gonadotropin\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data used in this paper will not be openly shared to protect the included informants\u0026rsquo; privacy and due to general security concerns.\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe acknowledge the support and assistance provided to us by the service users of the mental health clinics in the hospital as we conducted this research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthors and Affiliations\u003c/p\u003e\n\u003cp\u003eShi Xiao\u003c/p\u003e\n\u003cp\u003eChaoyang Hospital Affiliated to Capital Medical University, Beijing, China\u003c/p\u003e\n\u003cp\u003eShuyi Zhang\u003c/p\u003e\n\u003cp\u003eChaoyang Hospital Affiliated to Capital Medical University, Beijing, China\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Contributions\u003c/p\u003e\n\u003cp\u003eAll authors participated in the process of data collection, conducted the analysis and reflected on the findings together. The manuscript was written in collaboration, and all the authors read and approved the content of the final manuscript.\u003c/p\u003e\n\u003cp\u003eCorresponding author\u003c/p\u003e\n\u003cp\u003eCorrespondence to Shuyi Zhang\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThe study was approved in advance by the ethical committee. Consent was given in accordance with the laws governing privacy in research.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCICINELLI E, TROJANO G, MASTROMAURO M, et al. Higher prevalence of chronic endometritis in women with endometriosis: a possible etiopathogenetic link [J]. Fertility and sterility, 2017, 108(2): 289-95.e1.\u003c/li\u003e\n\u003cli\u003eCICINELLI E, RESTA L, NICOLETTI R, et al. Endometrial micropolyps at fluid hysteroscopy suggest the existence of chronic endometritis [J]. Human reproduction (Oxford, England), 2005, 20(5): 1386-9.\u003c/li\u003e\n\u003cli\u003eSONG D, FENG X, ZHANG Q, et al. Prevalence and confounders of chronic endometritis in premenopausal women with abnormal bleeding or reproductive failure [J]. Reproductive biomedicine online, 2018, 36(1): 78-83.\u003c/li\u003e\n\u003cli\u003eCICINELLI E, MATTEO M, TINELLI R, et al. Prevalence of chronic endometritis in repeated unexplained implantation failure and the IVF success rate after antibiotic therapy [J]. Human reproduction (Oxford, England), 2015, 30(2): 323-30.\u003c/li\u003e\n\u003cli\u003eMCQUEEN D B, BERNARDI L A, STEPHENSON M D. Chronic endometritis in women with recurrent early pregnancy loss and/or fetal demise [J]. Fertility and sterility, 2014, 101(4): 1026-30.\u003c/li\u003e\n\u003cli\u003eHOLZER I, OTT J, KURZ C, et al. Is Chronic Endometritis Associated with Tubal Infertility? A Prospective Cohort Study [J]. Journal of minimally invasive gynecology, 2021, 28(11): 1876-81.\u003c/li\u003e\n\u003cli\u003ePENG J, GUO F, LIU H, et al. Correlation between hysteroscopy findings in patients with hydrosalpinx and chronic endometritis [J]. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics, 2022, 157(2): 471-5.\u003c/li\u003e\n\u003cli\u003eKITAYA K, MATSUBAYASHI H, YAMAGUCHI K, et al. Chronic Endometritis: Potential Cause of Infertility and Obstetric and Neonatal Complications [J]. American journal of reproductive immunology (New York, NY : 1989), 2016, 75(1): 13-22.\u003c/li\u003e\n\u003cli\u003eBAYER-GARNER I B, NICKELL J A, KOROURIAN S. Routine syndecan-1 immunohistochemistry aids in the diagnosis of chronic endometritis [J]. Archives of pathology \u0026amp; laboratory medicine, 2004, 128(9): 1000-3.\u003c/li\u003e\n\u003cli\u003eJOHNSTON-MACANANNY E B, HARTNETT J, ENGMANN L L, et al. Chronic endometritis is a frequent finding in women with recurrent implantation failure after in vitro fertilization [J]. Fertility and sterility, 2010, 93(2): 437-41.\u003c/li\u003e\n\u003cli\u003eHAGGERTY C L, NESS R B, AMORTEGUI A, et al. Endometritis does not predict reproductive morbidity after pelvic inflammatory disease [J]. Am J Obstet Gynecol, 2003, 188(1): 141-8.\u003c/li\u003e\n\u003cli\u003eCICINELLI E, MATTEO M, TINELLI R, et al. Chronic endometritis due to common bacteria is prevalent in women with recurrent miscarriage as confirmed by improved pregnancy outcome after antibiotic treatment [J]. Reproductive sciences (Thousand Oaks, Calif), 2014, 21(5): 640-7.\u003c/li\u003e\n\u003cli\u003eCICINELLI E, VITAGLIANO A, KUMAR A, et al. Unified diagnostic criteria for chronic endometritis at fluid hysteroscopy: proposal and reliability evaluation through an international randomized-controlled observer study [J]. Fertility and sterility, 2019, 112(1): 162-73.e2.\u003c/li\u003e\n\u003cli\u003eSONG D, LI T-C, ZHANG Y, et al. Correlation between hysteroscopy findings and chronic endometritis [J]. Fertility and sterility, 2019, 111(4): 772-9.\u003c/li\u003e\n\u003cli\u003eJI H, ZHOU Y, CAO S, et al. Effect of Embryo Developmental Stage, Morphological Grading, and Ploidy Status on Live Birth Rate in Frozen Cycles of Single Blastocyst Transfer [J]. Reproductive sciences (Thousand Oaks, Calif), 2021, 28(4): 1079-91.\u003c/li\u003e\n\u003cli\u003eCIMADOMO D, CRACIUNAS L, VERMEULEN N, et al. Definition, diagnostic and therapeutic options in recurrent implantation failure: an international survey of clinicians and embryologists [J]. Human reproduction (Oxford, England), 2021, 36(2): 305-17.\u003c/li\u003e\n\u003cli\u003eGUO H, WANG Y, CHEN Q, et al. Effect of Natural Cycle Endometrial Preparation for Frozen-Thawed Embryo Transfer in Patients with Advanced Endometriosis [J]. Medical science monitor : international medical journal of experimental and clinical research, 2016, 22: 4596-603.\u003c/li\u003e\n\u003cli\u003eDEMIRDAĞ E, G\u0026Uuml;LER İ, AKDULUM M F C, et al. Comparison of natural and artificial cycles in frozen-thawed embryo transfer: A retrospective analysis of 1696 cycles [J]. Turkish journal of obstetrics and gynecology, 2022, 19(1): 28-34.\u003c/li\u003e\n\u003cli\u003eGHOBARA T, GELBAYA T A, AYELEKE R O. Cycle regimens for frozen-thawed embryo transfer [J]. The Cochrane database of systematic reviews, 2017, 7: CD003414.\u003c/li\u003e\n\u003cli\u003eWU H, WEI F, TAN W, et al. Administration of depot GnRH agonist prior to programmed frozen-thawed embryo transfer does not improve the live birth rate in ovulatory women: A large, multi-center retrospective study [J]. Medicine, 2022, 101(40): e30991.\u003c/li\u003e\n\u003cli\u003eXU Y, MEI J, DIAO L, et al. Chronic endometritis and reproductive failure: Role of syndecan-1 [J]. American journal of reproductive immunology (New York, NY : 1989), 2020, 84(3): e13255.\u003c/li\u003e\n\u003cli\u003eVITAGLIANO A, LAGAN\u0026Agrave; A S, ZIEGLER D D, et al. Chronic Endometritis in Infertile Women: Impact of Untreated Disease, Plasma Cell Count and Antibiotic Therapy on IVF Outcome-A Systematic Review and Meta-Analysis [J]. Diagnostics (Basel, Switzerland), 2022, 12(9).\u003c/li\u003e\n\u003cli\u003eXIONG Y, CHEN Q, CHEN C, et al. Impact of oral antibiotic treatment for chronic endometritis on pregnancy outcomes in the following frozen-thawed embryo transfer cycles of infertile women: a cohort study of 640 embryo transfer cycles [J]. Fertility and sterility, 2021, 116(2): 413-21.\u003c/li\u003e\n\u003cli\u003eGEYSENBERGH B, BOES A-S, BAFORT C, et al. The Impact of Chronic Endometritis on Infertility: Prevalence, Reproductive Outcomes, and the Role of Hysteroscopy as a Screening Tool [J]. Gynecologic and obstetric investigation, 2023, 88(2): 108-15.\u003c/li\u003e\n\u003cli\u003eKURODA K, HORIKAWA T, MORIYAMA A, et al. Impact of chronic endometritis on endometrial receptivity analysis results and pregnancy outcomes [J]. Immunity, inflammation and disease, 2020, 8(4): 650-8.\u003c/li\u003e\n\u003cli\u003eDUAN H, LI X, HAO Y, et al. Risk of spontaneous abortion after antibiotic therapy for chronic endometritis before in vitro fertilization and intracytoplasmic sperm injection stimulation [J]. Fertility and sterility, 2022, 118(2): 337-46.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"contraception-and-reproductive-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"carm","sideBox":"Learn more about [Contraception and Reproductive Medicine](http://contraceptionmedicine.biomedcentral.com)","snPcode":"40834","submissionUrl":"https://submission.nature.com/new-submission/40834/3","title":"Contraception and Reproductive Medicine","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"endometrial preparation protocols, chronic endometritis, pregnancy outcomes","lastPublishedDoi":"10.21203/rs.3.rs-5859800/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5859800/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eIntended to investigate the potential effects of endometrial preparation procedures on the results of subsequent frozen embryo transfer (FET) cycles in infertile women with chronic endometritis (CE) following a single course of antibiotic therapy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eFrom July 2020 to December 2023, 773 infertile patients participated in a retrospective research. CD138 was immunostained in endometrial tissues taken during the proliferative phase. CE was suggested by the presence of CD138-positive cells in the stromal cells. Oral antibiotics were administered to every patient with a CE diagnosis. After CE was cured, patients had frozen embryo transfers and endometrial preparation. This study compared the impact of different endometrial preparation techniques on pregnancy outcomes.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eHormone replacement treatment (HRT), ovulation induction, natural cycle, and gonadotrophin-releasing hormone agonist-HRT (GnRH agonist-HRT) regimens did not significantly alter the outcome of pregnancy in patients with CE. Compared to other groups, the ovulation induction cycle group had a higher clinical pregnancy rate and embryo implantation rate. However, the miscarriage rate is lower compared to other populations. Patients with treated CE who received HRT, GnRH agonist-HRT, ovulation induction cycle, and natural cycle did not differ substantially (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003ePatients with cured CE did not see any change in pregnancy outcomes as a result of endometrial preparation procedures.\u003c/p\u003e","manuscriptTitle":"Endometrial preparation protocols did not impact outcomes after frozen-thaw embryo transfer for chronic endometritis treatment","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-28 10:33:10","doi":"10.21203/rs.3.rs-5859800/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-03-10T21:01:06+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-02-15T10:06:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"52586378157832336779981552714102578777","date":"2025-02-14T12:57:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"203630708956685109486878100563894035817","date":"2025-02-03T08:42:16+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-02-03T08:29:49+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-01-23T15:41:19+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-01-23T15:38:29+00:00","index":"","fulltext":""},{"type":"submitted","content":"Contraception and Reproductive Medicine","date":"2025-01-19T13:50:26+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"contraception-and-reproductive-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"carm","sideBox":"Learn more about [Contraception and Reproductive Medicine](http://contraceptionmedicine.biomedcentral.com)","snPcode":"40834","submissionUrl":"https://submission.nature.com/new-submission/40834/3","title":"Contraception and Reproductive Medicine","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0d84c095-552b-4ce6-b2e1-bd2c5d104f5c","owner":[],"postedDate":"January 28th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-04-14T16:13:37+00:00","versionOfRecord":{"articleIdentity":"rs-5859800","link":"https://doi.org/10.1186/s40834-025-00363-6","journal":{"identity":"contraception-and-reproductive-medicine","isVorOnly":false,"title":"Contraception and Reproductive Medicine"},"publishedOn":"2025-04-07 16:05:03","publishedOnDateReadable":"April 7th, 2025"},"versionCreatedAt":"2025-01-28 10:33:10","video":"","vorDoi":"10.1186/s40834-025-00363-6","vorDoiUrl":"https://doi.org/10.1186/s40834-025-00363-6","workflowStages":[]},"version":"v1","identity":"rs-5859800","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5859800","identity":"rs-5859800","version":["v1"]},"buildId":"WvIrzKhiLBfengagbw6Ux","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}