The Contradictive Findings between Ultrasound, Hysteroscopy and Cytokines in Women with Non-hormonal IUD'S Suffering from Metrorrhagia: A Prospective Study

The Contradictive Findings between Ultrasound, Hysteroscopy and Cytokines in Women with Non-hormonal IUD'S Suffering from Metrorrhagia: A Prospective Study | 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 The Contradictive Findings between Ultrasound, Hysteroscopy and Cytokines in Women with Non-hormonal IUD'S Suffering from Metrorrhagia: A Prospective Study Hadel Watad, Udi Ifrach, David Stockheim, Vered Yulzari, Orly C. Meron, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3492489/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Mar, 2024 Read the published version in Archives of Gynecology and Obstetrics → Version 1 posted 5 You are reading this latest preprint version Abstract Purpose: The objective of this study is to assess the correlation between bleeding irregularities and the accurate placement of the IUD device in the uterine cavity, determined through transvaginal ultrasonography and hysteroscopy. Additionally, the study aims to examine the cytokine profile in the uterine cavity and serum of patients experiencing bleeding irregularities after the insertion of non-hormonal IUDs. Methods: A prospective cohort study was conducted at a single Tertiary medical center, wherein patients experiencing intermenstrual bleeding and spotting after the insertion of non-hormonal IUDs were enrolled. The study involved hysteroscopic and sonographic assessments of the uterine cavity and IUD placement, along with the analysis of blood and uterine cavity cytokine profiles. Results : During the period between July 2019 and February 2020, a total of eight patients who experienced intermenstrual bleeding and spotting after the insertion of non-hormonal IUDs were enrolled in the study. One case was excluded since a progestative device was detected by ultrasound. Out of the five cases that underwent a thorough ultrasonographic assessment, 3 cases (60%) showed an embedded IUD. However, these findings were excluded by the hysteroscopic evaluation. Conclusion: The results suggest that ultrasonographic assessment may lead to an overdiagnosis of IUD mispositioning compared to hysteroscopy. Additionally, both ultrasound and hysteroscopy have limitations in diagnosing the cause of bleeding in most cases. The role of local reactive inflammatory cytokines should be further studied. Contraception Embedding Inflammatory Intermenstrual bleeding Figures Figure 1 What does this study add to the clinical work Our study reveals that there is overdiagnosis of Intra-uterine device positioning when using ultrasonographic assessment for bleeding irregularities in comparison to hysteroscopy. Furthermore, in the majority of cases, both ultrasound and hysteroscopy do not provide sufficient value in determining the cause of bleeding. Introduction Bleeding irregularities associated with non-hormonal IUDs can manifest as an increase in menstrual blood loss, prolonged bleeding during periods, or intermenstrual bleeding and spotting [ 1 ]. Several factors, such as the type of device, its surface area, duration of usage, individual response to the IUD, and parity, may influence the frequency and pattern of bleeding [ 1 ]; Additionally, the cultural and social background of the woman may also play a role in her acceptance and motivation for IUD removal due to bleeding irregularities. The pathogenesis of bleeding disturbances in IUD users is multifactorial and different etiologies have been suggested for different types of bleeding disturbances. The distortion of the endometrial vasculature by the presence of IUD leading to interstitial hemorrhage with the release of blood in an irregular pattern to the uterine cavity is the main pathogenesis that explains bleeding irregularities. The defective hemostatic mechanism in the IUD-exposed endometrium (Local increase in fibrinolytic activity) also contributes to the bleeding [ 1 ]. Ultrasonography is commonly used in the evaluation of the IUD placement as the arms and the stem of the copper IUD are echogenic. Ultrasonographic imaging has been accepted as the initial step in evaluation and management of malpositioned IUDs [ 2 , 3 ], although some of the side-effects occurred even when the IUD was in a normal position [ 4 – 6 ]. The aim of this study is to investigate possible etiologies of bleeding irregularities in non-hormonal IUD users and to evaluate the accuracy of ultrasonographic assessment of malposition of IUD device within the cavity compared to hysteroscopic evaluation. We also aimed to examine the cytokine profile of serum and uterine fluids in such cases to assess the local inflammation process role. Materials and methods A prospective cohort study of women suffering of bleeding irregularities following non-hormonal IUD insertion between July 2019 and February 2020, recruited via social media publications. We initially planned a clinical trial including study and control group; however, it was difficult to continue recruitment of participants since COVID 19 (Coronavirus) outbreak. We included women with non-hormonal IUD inserted at least three months prior to recruitment, women with hormonal IUD, at menopause or peri-menopause and breastfeeding women were excluded. We also excluded women with bleeding that starts five days or less before expected menstruation date. Intermenstrual bleeding was defined as bleeding that starts after at least one day of cessation of period bleeding. Eligible participants received a questionnaire and were asked to provide information regarding demographics, medical and surgical history, medication, obstetric and gynecological history and information regarding IUD insertion and side effects. Information regarding IUD included IUD type, duration of IUD use, previous ultrasonographic assessment following insertion, timing of intermenstrual bleeding following caseation of period bleeding, duration and amount of intermenstrual bleeding, accompanying side effects such as abdominal cramping, and previous intermenstrual bleeding in cases of previously used. Amount of bleeding was quantified according to our local coins, which is compatible with the scale described in Fig. 1 . Women were asked to rate their quality of life in scale from 0 to 10 (0 no disturbance, 10-significant disturbance to daily time quality).Following that, women had completed blood tests for hormonal profile including progesterone and estradiol levels, blood tests for cytokine profile. All women were asked to complete transvaginal ultrasonographic assessment that included uterine position and dimensions, endometrial thickness, IUD displacement, distance IUD tip and body from myometrium, IUD embedding, uterine polyp, cesarean section niche and other abnormal findings including uterine fibroids. We used two and three-dimensional ultrasound (2D and 3D) using the Voluson E10 ultrasound system. All participants completed diagnostic hysteroscopy which included assessment of cervical lesions, IUD malposition, expulsion, embedding or perforation, disproportion between IUD and uterine dimensions, ulcerations and active bleeding, uterine malformations, fibroids and polyps, presence of endometrial inflammatory lesions or hyperplasia. We used a 2.9-mm TROPHYscope Campo hysteroscope (KARL STORZ, Tuttlingen, Germany) and 2 or 2.9 mm BETTOCCHI hysteroscope (KARL STORZ, Tuttlingen, Germany). Hysteroscopic access to the cervix was performed under vaginoscopy direct vision and did not require the use of a speculum. At first saline irrigated uterine fluid was obtained for cytokine profile assessment (2–3 ml), then hysteroscopy was continued using slowly flowing irrigating saline in aim to prevent IUD movement during the procedure. Hysteroscopy and ultrasound were done within 1–2 days of bleeding onset. Serum and uterine fluids cytokine profile analysis which included levels of TNFα, IL-1β, IL-6 and IL-17A, The Luminex's xMAP Cytokine "Multi-plex" array analysis was used. The study was conducted at Sheba Medical Center, Tel Hashomer, Israel; and was approved by the Sheba Medical Center institutional review board (5170-18). All participants provided informed consent. Patient and Public Involvement : Patients or the public were not involved in the design, or conduct, reporting, or dissemination plans of our research Statistical analysis Normally distributed continuous data were described using mean and standard deviation (SD), while non-normally distributed data were described using median and interquartile range (IQR). All analyses were conducted using SPSS 22 (SPSS Inc., Chicago, IL, USA). Comparison tests were not performed. Results Eight eligible women who were recruited, one woman was excluded following ultrasonographic assessment that revealed a hormonal IUD. Baseline characteristics of the study groups are shown in Table 1 . Table 1 Demographic characteristics n = 7 Age, years (mean ± SD) 35.3 (5.6) BMI a , kg/m2 (mean ± SD) 27.2 (5.1) Gravidity (median, IQR) 4 (4-4.5) Parity (median, IQR) 4 (4-4.5) Abortions (median, IQR) 0 (0–0) BMI-Body Mass Index All women had regular menses before IUD insertion, mean of menstrual cycle length was 28.9 (SD+/-0.97) days and lasted 5.8 (SD+/-0.78) days on average. Intermenstrual bleeding started 4.14 (SD+/-2.4) days on average and lasted 1.41 (SD+/-0.53) days on average. According to progesterone levels all tests were completed during the follicular stage. Six women out of 7 (85.7%) reported ultrasonographic assessment following IUD insertion that conformed right placement. Baseline characteristics, IUD parameters including type and duration of use, menstrual and intermenstrual bleeding parameters are presented in Table 2 . It is apparent that all women had regular menses before IUD insertion and that intermenstrual bleeding started 1 to 7 days following the end of period bleeding. Five cases reported onset of bleeding irregularities in conjunction with IUD insertion. Table 2 Baseline characteristics and Intra-uterine device and bleeding data Serial number IUD b type Durations of IUD use (months) Ultrasonographic assessment for IUD placement conformation following IUD insertion Duration of intermenstrual irregularities (months) Interval between last day menstruation and intermenstrual bleeding onset (days) Duration of intermenstrual bleeding (days) Bleeding amount scale Disturbance of daily activity (0–10) 1 Ballerine IUD b 8 Normal placement 8 1 1 4 10 2 Copper IUD b (not specified) 18 Normal placement 18 6 1.5 4 4 3 Mona Lisa IUD b 6 Normal placement 6 7 1 3 8 4 Gynefix IUD 24 Normal placement 12 7 2.5 3 8 5 Novo -t 12 Normal placement 12 1.5 1.5 1 8 6 Novo -t 12 N/A 12 2 4 7 Ballerine IUD b 26 Normal placement 20 4.5 1 3 9 BMI- Body mass index. IUD- Intrauterine device. Disturbance of daily activity (0-no disturbance, 10-significant disturbance to daily time quality). Table 3 demonstrates result of ultrasonographic and hysteroscopic evaluation, it's apparent that there is no consent between ultrasound and hysteroscopy concerning IUD displacement. At the day of recruitment, ultrasonographic assessment revealed embedding of the IUD in the uterine wall in three cases that was refuted following hysteroscopic assessment, moreover in two cases with IUD embedding as revealed by hysteroscopy, sonographic assessment didn't reveal that. Table 3 Sonographic and hysteroscopic findings Serial number Hysteroscopic findings US findings Uterine position Uterus length (mm) Uterus antero-posterior length (mm) Uterus width (mm) Endometrial thickness (mm) 1 Embedded IUD a N/A N/A N/A N/A N/A N/A 2 N/A Embedded IUD a Anteroflexed 71 46 53 6.7 3 N/A Embedded IUD a Anteroflexed 63 43 53 8.5 4 N/A Embedded IUD a Anteroflexed 63 28 57 11 5 Adenomyosis Anteroflexed 57 37 49 6.8 6 Embedded IUD a , CS b niche and uni-cornuate uterus IUD a displacement and CS b niche Central 54 34 60 3 7 N/A N/A Anteroflexed 70 40 46 12 IUD- Intrauterine device, CS-Cesarean section. Table 4 describes Cytokine profile analysis; we aimed to estimate the contribution of local and systemic inflammatory processes to the onset of bleeding in the presence of the IUD, for technical issues, full analysis was conducted for 3 out of 7 cases. In two cases the levels of inflammatory cytokines originated from dendritic and mononuclear cells from M1-type (TNFα, IL-1β IL-6) were in the normal range, which indicates that bleeding irregularities can't be explained by the presence of systemic or local inflammation; However, serum and uterine fluid levels of the inflammatory cytokines were elevated in the patient with uterine niche. Levels of IL-17, which is originated from lymphocyte T-helper 17 cells were in normal range in all cases. Table 4 Cytokine profile TNFa - UTERINE-pg/ml IL-1B- UTERINE-pg/ml IL-6 - UTERINE-pg/ml IL-17A- UTERINE-pg/ml TNFa-serum-pg/ml IL-1B-serum-pg/ml IL-6-serum-pg/ml IL-17A-serum-pg/ml < 1.09↓ 9.14 2.85 < 2.08↓ < 1.90↓ < 0.98↓ < 0.72↓ < 1.58↓ 18.47 464.63 21.88 < 2.08↓ 3.12 6 1.55 < 1.58↓ < 1.09↓ 9.71 9.9 < 2.08↓ 2.39 < 0.98↓ < 0.72↓ < 1.58↓ Discussion In the current study poor correlation was found between ultrasonographic and hysteroscopic findings in women with IUD who suffer from bleeding irregularities. Ultrasound evaluation revealed IUD embedding that was not confirmed during hysteroscopy and vice versa. Although hysteroscopy is considered the gold standard for diagnosis of bleeding irregularities, according to the best of our knowledge, hysteroscopy was not previously used for evaluation of bleeding irregularities in women carrying a non-hormonal IUD. Another important but not surprising finding was that none of the cases in our study had anatomic aberrations that could be attributed to IUD insertion. Previous studies evaluated uterine dimensions and doppler in relation of IUD complications, however, most of the publications investigated menorrhagia without addressing other bleeding irregularities [ 3 , 5 ], and conflicting results had been shown in the minority of studies which addressed bleeding irregulates including spotting [ 7 , 8 ], which makes it difficult to compare our results with previous results. Endometrial inflammation occurring after copper IUD insertion is the main method of its action as contraception method, which prevents embryo implantation [ 9 ], multiple studies have addressed the inflammatory effect of IUD's in animals and humans [ 10 , 11 ]. Feng X et al [ 12 ] had shown a correlation between VEGF levels and bleeding irregulates in vitro, however, to our knowledge, none of the works investigated the relationship between bleeding irregularities and the inflammatory response in vivo. Primary results of cytokine profile analysis indicate that IUD associated bleeding irregularities aren’t mediated by systemic and/or local inflammatory reaction, and cases with niche may be associated with inflammatory reaction mediated by dendritic and mononuclear cells with T-cell lymphocyte involvement. However, those results should be investigated and addressed in further larger studies. Our study has its own limitations, the small study group, the lack of control group, and the fact that cytokine profile analysis wasn't available in all cases. However, we should notify that COVID 19 pandemic limited our recruitment ability of study and control groups. This study is a preliminary study that uses hysteroscopy for thorough assessment of bleeding irregularities in women carrying non hormonal IUD and compares the results with ultrasonographic assessment. For our knowledge, there is no previous publication that addressed those findings. Moreover, hysteroscopic evaluation was done adjacent to bleeding event which, according to our experience, Increases the chance of detecting a pathology. Findings of our study should give patients a sense of security since no serious nor irreversible damage had been documented findings were found including in a careful assessment of uterine cavity. Preliminary findings of our study need further research, and the cost-effectiveness of hysteroscopic and ultrasonographic evaluation should be addressed. The study was approved at the Institutional review board number: 5170-18-SMC, April 3rd, 2019 Declarations Author contribution statement S.B.C, U.I and O.C.M conceived of the presented idea and encouraged H.W to investigate the etiology of bleeding irregularities following non-hormonal IUD insertion. DS performed hysteroscopic evaluation, B.W and V.Y performed sonographic evaluation, M.B and B.S were responsible about cytokine testing. All authors discussed the results and contributed to the final manuscript. H.W wrote the manuscript with support from S.B.C and B.W. Acknowledgments We thank our colleague Prof. Simcha Yagel, director of the Hadassah Medical Organization’s Obstetrics and Gynecology Department who provided insight and expertise that greatly assisted the research. This study was Funded by Ihel foundation. The authors declare that there is no conflict of interest. References El-badrawi, H.H. and E.S. Hafez, IUD-induced uterine bleeding. Contracept Deliv Syst, 1980. 1 (4): p. 303-18. Peri, N., D. Graham, and D. Levine, Imaging of intrauterine contraceptive devices. J Ultrasound Med, 2007. 26 (10): p. 1389-401. Fadiloglu, S., et al., Relationship between copper IUD complications and ultrasonographic findings. Arch Gynecol Obstet, 2018. 297 (4): p. 989-996. Coskun, E., et al., Effect of copper intrauterine device on the cyclooxygenase and inducible nitric oxide synthase expression in the luteal phase endometrium. Contraception, 2011. 84 (6): p. 637-41. Mutlu, I., A. Demir, and M.F. Mutlu, Can uterine artery Doppler parameters predict copper intrauterine device-induced side effects? Eur J Contracept Reprod Health Care, 2014. 19 (1): p. 51-6. Faúndes, D., et al., T-shaped IUDs accommodate in their position during the first 3 months after insertion. Contraception, 2000. 62 (4): p. 165-8. Kaislasuo, J., et al., Menstrual characteristics and ultrasonographic uterine cavity measurements predict bleeding and pain in nulligravid women using intrauterine contraception. Hum Reprod, 2015. 30 (7): p. 1580-8. Faúndes, D., et al., No relationship between the IUD position evaluated by ultrasound and complaints of bleeding and pain. Contraception, 1997. 56 (1): p. 43-7. Chou, C.H., et al., Divergent endometrial inflammatory cytokine expression at peri-implantation period and after the stimulation by copper intrauterine device. Sci Rep, 2015. 5 : p. 15157. Kim, C.R., et al., Immunologic evaluation of the endometrium with a levonorgestrel intrauterine device in solid organ transplant women and healthy controls. Contraception, 2016. 94 (5): p. 534-540. Rivera Del Alamo, M.M., et al., Inflammatory Markers in Uterine Lavage Fluids of Pregnant, Non-Pregnant, and Intrauterine Device Implanted Mares on Days 10 and 15 Post Ovulation. Animals (Basel), 2021. 11 (12). Li, L., et al., Analysis of the reason of abnormal uterine bleeding induced by copper corrosion of IUD Cu. Clin Exp Obstet Gynecol, 2016. 43 (6): p. 883-886. Cite Share Download PDF Status: Published Journal Publication published 16 Mar, 2024 Read the published version in Archives of Gynecology and Obstetrics → Version 1 posted Reviewers agreed at journal 13 Nov, 2023 Reviewers invited by journal 06 Nov, 2023 Editor invited by journal 05 Nov, 2023 Editor assigned by journal 25 Oct, 2023 First submitted to journal 24 Oct, 2023 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-3492489","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":247034163,"identity":"db6084e7-8d7c-45b1-9d6e-65546a8040b0","order_by":0,"name":"Hadel Watad","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABJklEQVRIiWNgGAWjYBACAzAqgPJ4KhgY2NgZ2IAsCbDAgQe4tAARAxszUOEZMI2kJYGQFt42IAOsBQawaDFnP7zxwQcDhsT++f0HP7ydt02eD6jlMY+MBQN/+wFGbLZY9qQVG84AaplxjJlZcu6224ZtzAzsxjxAh0mcScDusAM5ZtI8Bgy5DceYGaR5t91mBGphkwZpYbiBwy/n35j//gPUMh9oy2/eObft4VrkcWm5kWPGDPR+7oZjzGzSvA23E+FaDHBqeVYs2WMgUb/xWLKZ5Zxjt5PbmBnbJOfwSPAYnklswO6w5I0fflTYGMsdPvj4xpua27bz25uPSbztqZOTO3748IcPmFqgQAKZw9jAwNjDwANmkAB+kKJ4FIyCUTAKhjkAAAi/YAZunwkqAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-9011-0294","institution":"Sheba Medical Center: Sheba Medical Center at Tel Hashomer","correspondingAuthor":true,"prefix":"","firstName":"Hadel","middleName":"","lastName":"Watad","suffix":""},{"id":247034164,"identity":"69f2c20e-a212-45fd-bbc9-1e15d00e39f0","order_by":1,"name":"Udi Ifrach","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Udi","middleName":"","lastName":"Ifrach","suffix":""},{"id":247034165,"identity":"7c7b1ca2-eea5-40da-a46d-1e0eaca7ab80","order_by":2,"name":"David Stockheim","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"Stockheim","suffix":""},{"id":247034166,"identity":"90add692-00fd-4156-bde0-b51e97340fe2","order_by":3,"name":"Vered Yulzari","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Vered","middleName":"","lastName":"Yulzari","suffix":""},{"id":247034167,"identity":"eb836deb-6118-4db8-93c9-26faa2615ee3","order_by":4,"name":"Orly C. 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Cohen","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Shlomo","middleName":"B.","lastName":"Cohen","suffix":""}],"badges":[],"createdAt":"2023-10-26 01:35:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3492489/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3492489/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00404-024-07457-7","type":"published","date":"2024-03-16T15:01:14+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":46185261,"identity":"fa12aa87-963b-4775-968d-1ca1c0cbc978","added_by":"auto","created_at":"2023-11-09 20:52:15","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":23444,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3492489/v1/ec362c8e7df339dcccf67f81.png"},{"id":52907236,"identity":"bb87434a-1384-4f82-a891-1008294c6e36","added_by":"auto","created_at":"2024-03-18 15:11:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":373637,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3492489/v1/80d9ea89-4c42-43b1-8b60-7d45ef015cca.pdf"}],"financialInterests":"","formattedTitle":"The Contradictive Findings between Ultrasound, Hysteroscopy and Cytokines in Women with Non-hormonal IUD'S Suffering from Metrorrhagia: A Prospective Study","fulltext":[{"header":"What does this study add to the clinical work","content":"\u003cp\u003eOur study reveals that there is overdiagnosis of Intra-uterine device positioning when using ultrasonographic assessment for bleeding irregularities in comparison to hysteroscopy. Furthermore, in the majority of cases, both ultrasound and hysteroscopy do not provide sufficient value in determining the cause of bleeding.\u003c/p\u003e\n"},{"header":"Introduction","content":"\u003cp\u003eBleeding irregularities associated with non-hormonal IUDs can manifest as an increase in menstrual blood loss, prolonged bleeding during periods, or intermenstrual bleeding and spotting [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Several factors, such as the type of device, its surface area, duration of usage, individual response to the IUD, and parity, may influence the frequency and pattern of bleeding [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]; Additionally, the cultural and social background of the woman may also play a role in her acceptance and motivation for IUD removal due to bleeding irregularities.\u003c/p\u003e \u003cp\u003eThe pathogenesis of bleeding disturbances in IUD users is multifactorial and different etiologies have been suggested for different types of bleeding disturbances. The distortion of the endometrial vasculature by the presence of IUD leading to interstitial hemorrhage with the release of blood in an irregular pattern to the uterine cavity is the main pathogenesis that explains bleeding irregularities. The defective hemostatic mechanism in the IUD-exposed endometrium (Local increase in fibrinolytic activity) also contributes to the bleeding [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eUltrasonography is commonly used in the evaluation of the IUD placement as the arms and the stem of the copper IUD are echogenic. Ultrasonographic imaging has been accepted as the initial step in evaluation and management of malpositioned IUDs [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], although some of the side-effects occurred even when the IUD was in a normal position [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe aim of this study is to investigate possible etiologies of bleeding irregularities in non-hormonal IUD users and to evaluate the accuracy of ultrasonographic assessment of malposition of IUD device within the cavity compared to hysteroscopic evaluation. We also aimed to examine the cytokine profile of serum and uterine fluids in such cases to assess the local inflammation process role.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003eA prospective cohort study of women suffering of bleeding irregularities following non-hormonal IUD insertion between July 2019 and February 2020, recruited via social media publications. We initially planned a clinical trial including study and control group; however, it was difficult to continue recruitment of participants since COVID 19 (Coronavirus) outbreak.\u003c/p\u003e \u003cp\u003eWe included women with non-hormonal IUD inserted at least three months prior to recruitment, women with hormonal IUD, at menopause or peri-menopause and breastfeeding women were excluded. We also excluded women with bleeding that starts five days or less before expected menstruation date. Intermenstrual bleeding was defined as bleeding that starts after at least one day of cessation of period bleeding.\u003c/p\u003e \u003cp\u003eEligible participants received a questionnaire and were asked to provide information regarding demographics, medical and surgical history, medication, obstetric and gynecological history and information regarding IUD insertion and side effects. Information regarding IUD included IUD type, duration of IUD use, previous ultrasonographic assessment following insertion, timing of intermenstrual bleeding following caseation of period bleeding, duration and amount of intermenstrual bleeding, accompanying side effects such as abdominal cramping, and previous intermenstrual bleeding in cases of previously used.\u003c/p\u003e \u003cp\u003eAmount of bleeding was quantified according to our local coins, which is compatible with the scale described in \u003cb\u003eFig.\u0026nbsp;1\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eWomen were asked to rate their quality of life in scale from 0 to 10 (0 no disturbance, 10-significant disturbance to daily time quality).Following that, women had completed blood tests for hormonal profile including progesterone and estradiol levels, blood tests for cytokine profile. All women were asked to complete transvaginal ultrasonographic assessment that included uterine position and dimensions, endometrial thickness, IUD displacement, distance IUD tip and body from myometrium, IUD embedding, uterine polyp, cesarean section niche and other abnormal findings including uterine fibroids. We used two and three-dimensional ultrasound (2D and 3D) using the Voluson E10 ultrasound system. All participants completed diagnostic hysteroscopy which included assessment of cervical lesions, IUD malposition, expulsion, embedding or perforation, disproportion between IUD and uterine dimensions, ulcerations and active bleeding, uterine malformations, fibroids and polyps, presence of endometrial inflammatory lesions or hyperplasia. We used a 2.9-mm TROPHYscope Campo hysteroscope (KARL STORZ, Tuttlingen, Germany) and 2 or 2.9 mm BETTOCCHI hysteroscope (KARL STORZ, Tuttlingen, Germany). Hysteroscopic access to the cervix was performed under vaginoscopy direct vision and did not require the use of a speculum. At first saline irrigated uterine fluid was obtained for cytokine profile assessment (2\u0026ndash;3 ml), then hysteroscopy was continued using slowly flowing irrigating saline in aim to prevent IUD movement during the procedure. Hysteroscopy and ultrasound were done within 1\u0026ndash;2 days of bleeding onset.\u003c/p\u003e \u003cp\u003eSerum and uterine fluids cytokine profile analysis which included levels of TNFα, IL-1β, IL-6 and IL-17A, The Luminex's xMAP Cytokine \"Multi-plex\" array analysis was used.\u003c/p\u003e \u003cp\u003e The study was conducted at Sheba Medical Center, Tel Hashomer, Israel; and was approved by the Sheba Medical Center institutional review board (5170-18). All participants provided informed consent.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003ePatient and Public Involvement\u003c/span\u003e: Patients or the public were not involved in the design, or conduct, reporting, or dissemination plans of our research\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eNormally distributed continuous data were described using mean and standard deviation (SD), while non-normally distributed data were described using median and interquartile range (IQR). All analyses were conducted using SPSS 22 (SPSS Inc., Chicago, IL, USA). Comparison tests were not performed.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eEight eligible women who were recruited, one woman was excluded following ultrasonographic assessment that revealed a hormonal IUD. Baseline characteristics of the study groups are shown in Table\u0026nbsp;\u003cspan\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 1\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eDemographic characteristics\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"2\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;7\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge, years (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35.3 (5.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBMI\u003csup\u003ea\u003c/sup\u003e, kg/m2 (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27.2 (5.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGravidity (median, IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (4-4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eParity (median, IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (4-4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAbortions (median, IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0\u0026ndash;0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eBMI-Body Mass Index\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eAll women had regular menses before IUD insertion, mean of menstrual cycle length was 28.9 (SD+/-0.97) days and lasted 5.8 (SD+/-0.78) days on average. Intermenstrual bleeding started 4.14 (SD+/-2.4) days on average and lasted 1.41 (SD+/-0.53) days on average. According to progesterone levels all tests were completed during the follicular stage. Six women out of 7 (85.7%) reported ultrasonographic assessment following IUD insertion that conformed right placement.\u003c/p\u003e\n\u003cp\u003eBaseline characteristics, IUD parameters including type and duration of use, menstrual and intermenstrual bleeding parameters are presented in Table\u0026nbsp;\u003cspan\u003e2\u003c/span\u003e. It is apparent that all women had regular menses before IUD insertion and that intermenstrual bleeding started 1 to 7 days following the end of period bleeding. Five cases reported onset of bleeding irregularities in conjunction with IUD insertion.\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 2\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eBaseline characteristics and Intra-uterine device and bleeding data\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"9\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSerial number\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIUD\u003csup\u003eb\u003c/sup\u003e type\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDurations of IUD use (months)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eUltrasonographic assessment for IUD placement conformation following IUD insertion\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDuration of intermenstrual irregularities (months)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eInterval between last day menstruation and intermenstrual bleeding onset (days)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDuration of intermenstrual bleeding (days)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBleeding amount scale\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDisturbance of daily activity (0\u0026ndash;10)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBallerine IUD\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNormal placement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCopper IUD\u003csup\u003eb\u003c/sup\u003e (not specified)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNormal placement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMona Lisa IUD\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNormal placement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGynefix IUD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNormal placement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNovo -t\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNormal placement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNovo -t\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBallerine IUD\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNormal placement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"9\"\u003e\n \u003cp\u003eBMI- Body mass index. IUD- Intrauterine device. Disturbance of daily activity (0-no disturbance, 10-significant disturbance to daily time quality).\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan\u003e3\u003c/span\u003e demonstrates result of ultrasonographic and hysteroscopic evaluation, it\u0026apos;s apparent that there is no consent between ultrasound and hysteroscopy concerning IUD displacement. At the day of recruitment, ultrasonographic assessment revealed embedding of the IUD in the uterine wall in three cases that was refuted following hysteroscopic assessment, moreover in two cases with IUD embedding as revealed by hysteroscopy, sonographic assessment didn\u0026apos;t reveal that.\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 3\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eSonographic and hysteroscopic findings\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"10\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSerial number\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHysteroscopic findings\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eUS findings\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eUterine position\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eUterus length (mm)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eUterus antero-posterior length (mm)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eUterus width (mm)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eEndometrial thickness (mm)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEmbedded IUD\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEmbedded IUD\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnteroflexed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEmbedded IUD\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnteroflexed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEmbedded IUD\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnteroflexed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdenomyosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnteroflexed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEmbedded IUD\u003csup\u003ea\u003c/sup\u003e, CS\u003csup\u003eb\u003c/sup\u003e niche and uni-cornuate uterus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIUD\u003csup\u003ea\u003c/sup\u003e displacement and CS\u003csup\u003eb\u003c/sup\u003e niche\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCentral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnteroflexed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eIUD- Intrauterine device, CS-Cesarean section.\u003c/p\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan\u003e4\u003c/span\u003e describes Cytokine profile analysis; we aimed to estimate the contribution of local and systemic inflammatory processes to the onset of bleeding in the presence of the IUD, for technical issues, full analysis was conducted for 3 out of 7 cases. In two cases the levels of inflammatory cytokines originated from dendritic and mononuclear cells from M1-type (TNF\u0026alpha;, IL-1\u0026beta; IL-6) were in the normal range, which indicates that bleeding irregularities can\u0026apos;t be explained by the presence of systemic or local inflammation; However, serum and uterine fluid levels of the inflammatory cytokines were elevated in the patient with uterine niche. Levels of IL-17, which is originated from lymphocyte T-helper 17 cells were in normal range in all cases.\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 4\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eCytokine profile\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"8\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTNFa - UTERINE-pg/ml\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIL-1B- UTERINE-pg/ml\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIL-6 - UTERINE-pg/ml\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIL-17A- UTERINE-pg/ml\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTNFa-serum-pg/ml\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIL-1B-serum-pg/ml\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIL-6-serum-pg/ml\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIL-17A-serum-pg/ml\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;1.09\u0026darr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;2.08\u0026darr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;1.90\u0026darr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.98\u0026darr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.72\u0026darr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;1.58\u0026darr;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e464.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;2.08\u0026darr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;1.58\u0026darr;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;1.09\u0026darr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;2.08\u0026darr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.98\u0026darr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.72\u0026darr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;1.58\u0026darr;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the current study poor correlation was found between ultrasonographic and hysteroscopic findings in women with IUD who suffer from bleeding irregularities. Ultrasound evaluation revealed IUD embedding that was not confirmed during hysteroscopy and vice versa. Although hysteroscopy is considered the gold standard for diagnosis of bleeding irregularities, according to the best of our knowledge, hysteroscopy was not previously used for evaluation of bleeding irregularities in women carrying a non-hormonal IUD. Another important but not surprising finding was that none of the cases in our study had anatomic aberrations that could be attributed to IUD insertion.\u003c/p\u003e \u003cp\u003ePrevious studies evaluated uterine dimensions and doppler in relation of IUD complications, however, most of the publications investigated menorrhagia without addressing other bleeding irregularities [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], and conflicting results had been shown in the minority of studies which addressed bleeding irregulates including spotting [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], which makes it difficult to compare our results with previous results.\u003c/p\u003e \u003cp\u003eEndometrial inflammation occurring after copper IUD insertion is the main method of its action as contraception method, which prevents embryo implantation [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], multiple studies have addressed the inflammatory effect of IUD's in animals and humans [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Feng X et al [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] had shown a correlation between VEGF levels and bleeding irregulates in vitro, however, to our knowledge, none of the works investigated the relationship between bleeding irregularities and the inflammatory response in vivo.\u003c/p\u003e \u003cp\u003ePrimary results of cytokine profile analysis indicate that IUD associated bleeding irregularities aren\u0026rsquo;t mediated by systemic and/or local inflammatory reaction, and cases with niche may be associated with inflammatory reaction mediated by dendritic and mononuclear cells with T-cell lymphocyte involvement. However, those results should be investigated and addressed in further larger studies.\u003c/p\u003e \u003cp\u003eOur study has its own limitations, the small study group, the lack of control group, and the fact that cytokine profile analysis wasn't available in all cases. However, we should notify that COVID 19 pandemic limited our recruitment ability of study and control groups.\u003c/p\u003e \u003cp\u003eThis study is a preliminary study that uses hysteroscopy for thorough assessment of bleeding irregularities in women carrying non hormonal IUD and compares the results with ultrasonographic assessment. For our knowledge, there is no previous publication that addressed those findings. Moreover, hysteroscopic evaluation was done adjacent to bleeding event which, according to our experience, Increases the chance of detecting a pathology.\u003c/p\u003e \u003cp\u003eFindings of our study should give patients a sense of security since no serious nor irreversible damage had been documented findings were found including in a careful assessment of uterine cavity.\u003c/p\u003e \u003cp\u003ePreliminary findings of our study need further research, and the cost-effectiveness of hysteroscopic and ultrasonographic evaluation should be addressed.\u003c/p\u003e \u003cp\u003e The study was approved at the Institutional review board number: 5170-18-SMC, April 3rd, 2019\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contribution statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eS.B.C, U.I and O.C.M conceived of the presented idea and encouraged H.W to investigate the etiology of bleeding irregularities following non-hormonal IUD insertion. DS performed hysteroscopic evaluation, B.W and V.Y performed sonographic evaluation, M.B and B.S were responsible about cytokine testing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll authors discussed the results and contributed to the final manuscript. H.W wrote the manuscript with support from S.B.C and B.W.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank our colleague Prof. Simcha Yagel, director of the Hadassah Medical Organization\u0026rsquo;s Obstetrics and Gynecology Department who provided insight and expertise that greatly assisted the research.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study was Funded by Ihel foundation. The authors declare that there is no conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eEl-badrawi, H.H. and E.S. Hafez, \u003cem\u003eIUD-induced uterine bleeding.\u003c/em\u003e Contracept Deliv Syst, 1980. \u003cstrong\u003e1\u003c/strong\u003e(4): p. 303-18.\u003c/li\u003e\n\u003cli\u003ePeri, N., D. Graham, and D. Levine, \u003cem\u003eImaging of intrauterine contraceptive devices.\u003c/em\u003e J Ultrasound Med, 2007. \u003cstrong\u003e26\u003c/strong\u003e(10): p. 1389-401.\u003c/li\u003e\n\u003cli\u003eFadiloglu, S., et al., \u003cem\u003eRelationship between copper IUD complications and ultrasonographic findings.\u003c/em\u003e Arch Gynecol Obstet, 2018. \u003cstrong\u003e297\u003c/strong\u003e(4): p. 989-996.\u003c/li\u003e\n\u003cli\u003eCoskun, E., et al., \u003cem\u003eEffect of copper intrauterine device on the cyclooxygenase and inducible nitric oxide synthase expression in the luteal phase endometrium.\u003c/em\u003e Contraception, 2011. \u003cstrong\u003e84\u003c/strong\u003e(6): p. 637-41.\u003c/li\u003e\n\u003cli\u003eMutlu, I., A. Demir, and M.F. Mutlu, \u003cem\u003eCan uterine artery Doppler parameters predict copper intrauterine device-induced side effects?\u003c/em\u003e Eur J Contracept Reprod Health Care, 2014. \u003cstrong\u003e19\u003c/strong\u003e(1): p. 51-6.\u003c/li\u003e\n\u003cli\u003eFa\u0026uacute;ndes, D., et al., \u003cem\u003eT-shaped IUDs accommodate in their position during the first 3 months after insertion.\u003c/em\u003e Contraception, 2000. \u003cstrong\u003e62\u003c/strong\u003e(4): p. 165-8.\u003c/li\u003e\n\u003cli\u003eKaislasuo, J., et al., \u003cem\u003eMenstrual characteristics and ultrasonographic uterine cavity measurements predict bleeding and pain in nulligravid women using intrauterine contraception.\u003c/em\u003e Hum Reprod, 2015. \u003cstrong\u003e30\u003c/strong\u003e(7): p. 1580-8.\u003c/li\u003e\n\u003cli\u003eFa\u0026uacute;ndes, D., et al., \u003cem\u003eNo relationship between the IUD position evaluated by ultrasound and complaints of bleeding and pain.\u003c/em\u003e Contraception, 1997. \u003cstrong\u003e56\u003c/strong\u003e(1): p. 43-7.\u003c/li\u003e\n\u003cli\u003eChou, C.H., et al., \u003cem\u003eDivergent endometrial inflammatory cytokine expression at peri-implantation period and after the stimulation by copper intrauterine device.\u003c/em\u003e Sci Rep, 2015. \u003cstrong\u003e5\u003c/strong\u003e: p. 15157.\u003c/li\u003e\n\u003cli\u003eKim, C.R., et al., \u003cem\u003eImmunologic evaluation of the endometrium with a levonorgestrel intrauterine device in solid organ transplant women and healthy controls.\u003c/em\u003e Contraception, 2016. \u003cstrong\u003e94\u003c/strong\u003e(5): p. 534-540.\u003c/li\u003e\n\u003cli\u003eRivera Del Alamo, M.M., et al., \u003cem\u003eInflammatory Markers in Uterine Lavage Fluids of Pregnant, Non-Pregnant, and Intrauterine Device Implanted Mares on Days 10 and 15 Post Ovulation.\u003c/em\u003e Animals (Basel), 2021. \u003cstrong\u003e11\u003c/strong\u003e(12).\u003c/li\u003e\n\u003cli\u003eLi, L., et al., \u003cem\u003eAnalysis of the reason of abnormal uterine bleeding induced by copper corrosion of IUD Cu.\u003c/em\u003e Clin Exp Obstet Gynecol, 2016. \u003cstrong\u003e43\u003c/strong\u003e(6): p. 883-886.\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":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"archives-of-gynecology-and-obstetrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"arch","sideBox":"Learn more about [Archives of Gynecology and Obstetrics](https://www.springer.com/journal/404)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/arch/default.aspx","title":"Archives of Gynecology and Obstetrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Contraception, Embedding, Inflammatory, Intermenstrual bleeding","lastPublishedDoi":"10.21203/rs.3.rs-3492489/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3492489/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003eThe objective of this study is to assess the correlation between bleeding irregularities and the accurate placement of the IUD device in the uterine cavity, determined through transvaginal ultrasonography and hysteroscopy. Additionally, the study aims to examine the cytokine profile in the uterine cavity and serum of patients experiencing bleeding irregularities after the insertion of non-hormonal IUDs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eA prospective cohort study was conducted at a single Tertiary medical center, wherein patients experiencing intermenstrual bleeding and spotting after the insertion of non-hormonal IUDs were enrolled. The study involved hysteroscopic and sonographic assessments of the uterine cavity and IUD placement, along with the analysis of blood and uterine cavity cytokine profiles.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: During the period between July 2019 and February 2020, a total of eight patients who experienced intermenstrual bleeding and spotting after the insertion of non-hormonal IUDs were enrolled \u003cdel\u003ein\u003c/del\u003e the study. One case was excluded since a progestative device was detected by ultrasound.\u003c/p\u003e\n\u003cp\u003eOut of the five cases that underwent a thorough ultrasonographic assessment, 3 cases (60%) showed an embedded IUD. However, these findings were excluded by the hysteroscopic evaluation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e The results suggest that ultrasonographic assessment may lead to an overdiagnosis of IUD mispositioning compared to hysteroscopy. Additionally, both ultrasound and hysteroscopy have limitations in diagnosing the cause of bleeding in most cases. The role of local reactive inflammatory cytokines should be further studied.\u003c/p\u003e","manuscriptTitle":"The Contradictive Findings between Ultrasound, Hysteroscopy and Cytokines in Women with Non-hormonal IUD'S Suffering from Metrorrhagia: A Prospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-11-09 20:52:11","doi":"10.21203/rs.3.rs-3492489/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2023-11-13T09:56:48+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-11-06T17:31:45+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"Archives of Gynecology and Obstetrics","date":"2023-11-05T20:26:36+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-10-25T11:19:29+00:00","index":"","fulltext":""},{"type":"submitted","content":"Archives of Gynecology and Obstetrics","date":"2023-10-24T19:13:43+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"archives-of-gynecology-and-obstetrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"arch","sideBox":"Learn more about [Archives of Gynecology and Obstetrics](https://www.springer.com/journal/404)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/arch/default.aspx","title":"Archives of Gynecology and Obstetrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"5e3f1a26-5a02-4a79-8ab5-8f4bc90abb6f","owner":[],"postedDate":"November 9th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-03-18T15:05:34+00:00","versionOfRecord":{"articleIdentity":"rs-3492489","link":"https://doi.org/10.1007/s00404-024-07457-7","journal":{"identity":"archives-of-gynecology-and-obstetrics","isVorOnly":false,"title":"Archives of Gynecology and Obstetrics"},"publishedOn":"2024-03-16 15:01:14","publishedOnDateReadable":"March 16th, 2024"},"versionCreatedAt":"2023-11-09 20:52:11","video":"","vorDoi":"10.1007/s00404-024-07457-7","vorDoiUrl":"https://doi.org/10.1007/s00404-024-07457-7","workflowStages":[]},"version":"v1","identity":"rs-3492489","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3492489","identity":"rs-3492489","version":["v1"]},"buildId":"B-jG_2CBjPDmsCi4Wdhf-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}