Systematic Review and Meta-Analysis of the Etiology of Menorrhagia in 2,770 adolescent females

Systematic Review and Meta-Analysis of the Etiology of Menorrhagia in 2,770 adolescent females | 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 Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Systematic Review and Meta-Analysis of the Etiology of Menorrhagia in 2,770 adolescent females Erin M Hall, Ana E Ravelo, Stephen C Aronoff, Michael T Del Vecchio This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3335310/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 20 Feb, 2024 Read the published version in BMC Women's Health → Version 1 posted 11 You are reading this latest preprint version Abstract Background: Adolescent menorrhagia, heavy menstrual bleeding, or abnormal uterine bleeding commonly occur in adolescent woman. The differential diagnosis can be challenging. The pneumonic: PALM-COEIN(polyp, adenomyosis, leiomyoma, malignancy and hyperplasia, coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not yet classified), is commonly used but it does not stratify as to the likelihood of a disorder. We have sought to develop a probability-based differential diagnosis for Adolescent menorrhagia, heavy menstrual bleeding, or abnormal uterine bleeding Methods: A comprehensive literature search was conducted using PubMed, EMBASE, and SCOPUS databases. Case series describing adolescents from 10 to 21 years of age with menorrhagia, abnormal uterine bleeding (AUB), or heavy menstrual bleeding (HMB) were acceptable if: more than 10 patients were included; editorials, case reports, and secondary sources such as review articles, or book chapters were excluded. No language filter was used, but an English abstract was required. The etiology of menorrhagia, abnormal uterine bleeding, or heavy menstrual bleeding, and the country of origin was extracted from articles that met inclusion criteria. Cumulative rate estimates were determined by Bayesian probability modeling. Results: 17 full text articles were reviewed in detail; 2,770 patients were included. The most frequent causes of menorrhagia were Ovarian Uterine Disorders (23.7%; 95% CredI 22-25.5%), Coagulation Disorders (19.4%; 95% CredI 17.8 - 21.1%), and Platelet Disorders (6.23%; 95% CredI 5.27-7.27%) with 45.9% (95% CredI 43.8 - 47.%9) of the cases of indeterminate origin. Conclusions: The leading causes of menorrhagia in healthy adolescent females were varied. The sub-analysis identified distinct etiologies, suggesting that multiple factors must be considered in the evaluation of menorrhagia. While PALM-COEIN (polyp, adenomyosis, leiomyoma, malignancy and hyperplasia, coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not yet classified) provides us with a comprehensive picture of the possible causes of menorrhagia in females, this systematic review assigns probabilities to the etiologies of menorrhagia in adolescent females, providing physicians with a more focused and efficient pathway to diagnosis. adolescents menorrhagia abnormal uterine bleeding heavy menstrual bleeding systematic review PALM-COEIN Figures Figure 1 Background Among female adolescents, menorrhagia or heavy menstrual bleeding, has an estimated prevalence of 37% 1 . Heavy menstrual bleeding, defined as excessive menstrual blood loss that interferes with a woman’s physical, social, emotional, or material quality of life, is currently classified according to the PALM-COEIN system 2 : polyp, adenomyosis, leiomyoma, malignancy and hyperplasia, coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not otherwise classified. This system, although useful, is not probability based, making it difficult for the physician to develop an efficient diagnostic plan. Adolescent menorrhagia is typically related to anovulation, however, other causes such as an underlying bleeding disorder must be considered when a healthy female experiences heavy menstrual bleeding at menarche or during adolescence. While the frequency of bleeding disorders in the general population is estimated to be 1–2%, bleeding disorders are found in approximately 20% of adolescent girls who present for evaluation for menorrhagia and in 33% of adolescent girls hospitalized for menorrhagia 3 . The purpose of this systematic review was to ( 1 ) determine the general categories of menorrhagia across a wide spectrum of patients and; ( 2 ) determine the relative prevalence of specific etiologies using a probability based methodology Methods This systematic review followed The Preferred Reporting Items in Systematic Reviews and Meta-analysis (PRISMA) guidelines 4 . Literature Search and Inclusion Criteria A comprehensive literature search was conducted using the PubMed, EMBASE, and SCOPUS databases. The search items “Abnormal uterine bleeding” OR “menorrhagia” OR “heavy menstrual bleeding” AND “adolescents” were input. Editorials, case reports, review articles, book chapters, and studies with less than 10 patients were excluded. English abstracts were required. No date filter was used in the PubMed and EMBASE database searches. In the SCOPUS search engine, publication data was filtered to include only articles published from 2020 onward to search for newer publications and abstracts. The literature search was conducted by two authors on two separate occasions (August 2021, September 2021). The bibliographies from each of the databases were uploaded into the RefWorks program and exact duplicates were excluded. Each abstract was reviewed independently by two authors (EMH, AER) to identify those studies that met inclusion criteria ( Table 1 ); conflicts were resolved by a third author (MTD). Throughout the initial search, relevant review articles were identified, and their bibliographies were reviewed also for studies that could qualify for this review. Full-text articles were reviewed using for inclusion and exclusion criteria. Data Extraction Following the final selection of articles, the etiologies of menorrhagia, heavy menstrual bleeding, or abnormal uterine bleeding, and the number of adolescents affected by each different etiology were recorded for each study. Data Synthesis A Bayesian methodology was employed to determine the rate estimates and the associated 95% credible intervals for each disease entity; the beta distribution was used as the conjugate prior to the conditional likelihood distribution for each rate estimate determined from the extracted data 5,6 All calculations were performed in the R environment. Results Study Search and Selection Figure 1 demonstrates the results of the systematic review. The database searches provided a total of 75 results (PubMed- 4 articles, EMBASE- 61 articles, Scopus-10 articles). After exact duplicates were removed, abstracts of 65 articles were reviewed. After exclusion of abstracts that did not meet inclusion criteria a total of 31 full-text articles were examined in detail. Fourteen full text articles were excluded: 7 only studied subpopulations of patients (ie PCOS only), 2 were editorials, 2 failed to meet study criteria once the methods section was examined, 1 only studied therapies, 1 included adults in the study who could not be separated from those less than 21 years of age, and 1article was a secondary review. A total of 17 articles (published between 1998–2020) met inclusion criteria and were analyzed for this study. Study Characteristics Table 2 summarizes the data extracted from the 17 studies. A total of 2,770 subjects were identified. The largest study included 24% of the patient sample. The categories of entities causing menorrhagia in patients less than 21 years of age are shown in Table 3. Almost half of the cases had no identifiable etiology (45.9%, 95%CredI 43.8–47.9). Ovarian Uterine Disorders (23.7%; 95% CredI 22-25.5), Coagulation Disorders (19.4%; 95% CredI 17.8–21.1), and Platelet Disorders (6.23%; 95% CredI 5.27–7.27). 45.9% (95% CredI 43.8–47.9) accounted for most cases with an identified etiology. Among the ovarian uterine disorders identified, anovulatory bleeding (98.7%, 95% CredI 97.6–99.5) accounted for almost all of the cases (table 3a); endometriosis (0.564%; 95% CredI 0.117–1.35) and polycystic ovary syndrome (0.564%; 95% CredI 0.117–1.35) were encountered rarely. Among coagulopathies, von Wilibrand’s Disease (88.1, 95% CredI 84.9–90.9) accounted for the vast majority of cases; Factor 8 Deficiency (6.19%; 95% CredI 4.13–8.64) and Clotting Factor Deficiencies (4.13%; 95% CredI 2.47–6.18) occurred less commonly (table 3b). As a group, platelet abnormalities accounted for a small percentage of patients with menorrhagia; Platelet Function Disorders(37.9%; 95% CredI 30–46), Inherited Thrombocytopenia (17.1%; 95% CredI 11.4–23.8) and Platelet Qualitative Disorders(13.6%; 95% CredI 8.43–19.7) were the most common platelet disorders identified (table 3c). Discussion A systematic review of menorrhagia in patients less than 21 years of age yielded 17 full text articles describing 2,770 adolescent females. These patients spanned the age range of 10–21 years old. Although PALM-COEIN 2 is a useful tool to organize the etiologies of menorrhagia, it fails to provide a priori probabilities for each entity or to estimate the number of patients with no identifiable etiology. The present study identifies the etiologies of menorrhagia in a combined cohort of more than 2000 patients, assigns relative probabilities to the etiologies of menorrhagia in adolescents and that over 40% of individuals will have no identifiable etiology. Among patients with an identifiable etiology for f menorrhagia, Ovarian Uterine disorders (23.7%; 95% CredI 22-25.5), Coagulation Disorders (19.4%; 95% CredI 17.8–21.1), and Platelet Disorders (6.23%; 95% CredI 5.27–7.27) were the most common systematic disorders. Within these categories, anovulatory bleeding, von Willibrand’s Disease and platelet function disorders were most common. As a systematic review, this article has inherent limitations. The etiologies of menorrhagia listed in the selected articles were taken as they were reported in their respective studies. This resulted in vague etiologies, such as unspecified thrombocytopenia and aggregation secretion defects. Additionally, the availability of diagnostic resources, criteria, and thoroughness of evaluation were not standardized across institutions, resulting in the large number of indeterminate etiologies of menorrhagia. This also raises the issue of diagnostic consistency. Conclusions The present study, a systematic review found the causes of menorrhagia in healthy adolescent females were varied. The sub-analysis identified distinct etiologies, suggesting that multiple factors must be considered in the evaluation of menorrhagia. While PALM-COEIN (polyp, adenomyosis, leiomyoma, malignancy and hyperplasia, coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not yet classified) provides us with a comprehensive picture of the possible causes of menorrhagia in females, this systematic review assigns probabilities to the etiologies of menorrhagia in adolescent females, providing physicians with a more focused and efficient pathway to diagnosis. Abbreviations PALM-COEIN polyp, adenomyosis, leiomyoma, malignancy and hyperplasia, coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not yet classified PRISMA Preferred Reporting Items for Systematic reviews and Meta-Analysis CredI Credible Intervals Declarations Ethics Approval: No ethics approval was required as all data was pre-existing and found in the public domain. Consent for publication: NA Availability of Data and Materials: The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request. Competing interest: None Funding: None Authors’ contributions: Hall: Aided in the design, carried out the searches and did data extraction, aided in manuscript preparation. Ravelo: Aided in the design, carried out the searches and did data extraction, aided in manuscript preparation. Aronoff: Aided in design, performed the statistical analysis, aided in manuscript preparation. Del Vecchio: Aided in design, aided in searches and data extraction, aided in manuscript preparation and submitted final manuscript. References Karaman, Kamuran, et al. “Evaluation of the Hemostatic Disorders in Adolescent Girls with Menorrhagia: Experiences from a Tertiary Referral Hospital.” Indian Journal of Hematology & Blood Transfusion , vol. 32, no. 3, Sept. 2016, pp. 356–61. PubMed Central , https://doi.org/10.1007/s12288-015-0583-5. Screening and management of Bleeding Disorders in adolescents with heavy menstrual bleeding. ACOG.https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2019/09/screening-and-management-of-bleeding-disorders-in-adolescents-with-heavy-menstrual-bleeding. Accessed 2021. Oleka, Chimsom MD; Dietrich Jennifer E. MD, MSc HMB in the Adolescent: A Review of the Modern Approach to Diagnosis and Management, Clinical Obstetrics and Gynecology: September 2020 - Volume 63 - Issue 3 - p 553-560 doi: 10.1097/GRF.0000000000000523 Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6:e1000097. Davitt M, Delvecchio MT, Aronoff SC. The Differential Diagnosis of Vertigo in Children: A Systematic Review of 2726 Cases. Pediatr Emerg Care. 2020 Aug;36(8):368-371. doi: 10.1097/PEC.0000000000001281. PMID: 29095392. Kruschke, JK. Doing Bayesian Analysis. 2011, Academic Press, Burlington, MA. Chapter 5. Inferring a binomial proportion via exact mathematical analysis Aguirre, N; Pereira, J; Barriga, F; Wietstruck, M A; Panes, O;Inherited bleeding disorders in adolescents with excessive menstrual bleeding. should we evaluate the fibrinolytic pathway? Revista chilena de pediatria . 2020;91(3):385-390. https://search.proquest.com/docview/2429785082. doi: 10.32641/rchped.v91i3.1571. Alaqzam TS, Stanley AC, Simpson PM, Flood VH, Menon S. Treatment modalities in adolescents who present with heavy menstrual bleeding. Journal of pediatric & adolescent gynecology . 2018;31(5):451-458. https://dx.doi.org/10.1016/j.jpag.2018.02.130. doi: 10.1016/j.jpag.2018.02.130. Haberal A, Altay MM. Abnormal uterine bleeding in adolescents: Treatment with combined oral contraceptive pills is effective even in hospitalized patients with bleeding disorders. Turkish journal of medical sciences . 2008;38(5):431-435. http://uvt.ulakbim.gov.tr/uvt/index.php?cwid=9&vtadi=TTIP&c=ebsco&c=summon&c=ebsco&ano=93589_c67fb27e173d408f50bf014e1743d850. Hutspardol S, Sirachainan N, Soisamrong A, Atchararit N, O-Prasertsawat P, Chuansumrit A. Hemostatic defects in thai adolescents with menorrhagia. Journal of the Medical Association of Thailand . 2010;93(4):436-442. https://www.ncbi.nlm.nih.gov/pubmed/20462086. Jain S, Zhang S, Acosta M, Malone K, Kouides P, Zia A. Prospective evaluation of ISTH‐BAT as a predictor of bleeding disorder in adolescents presenting with heavy menstrual bleeding in a multidisciplinary hematology clinic. Journal of thrombosis and haemostasis . 2020;18(10):2542-2550. https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.14997. doi: 10.1111/jth.14997. Khamees, Deena, MLS, BS, Klima J, PhD, O'Brien, Sarah H., MD, MSc. Population screening for von willebrand disease in adolescents with Heavy menstrual bleeding. The Journal of pediatrics . 2015;166(1):195-197. https://www.clinicalkey.es/playcontent/1-s2.0-S0022347614008774. doi: 10.1016/j.jpeds.2014.09.026. Mikhail S, Varadarajan Rm Kouides P. The prevalence of disorders of haemostasis in adolescents with menorrhagia referred to a haemophilia treatment centre. Haemophilia : the official journal of the World Federation of Hemophilia . 2007;13(5):627-632. https://api.istex.fr/ark:/67375/WNG-Q7NVM5MD-N/fulltext.pdf. doi: 10.1111/j.1365-2516.2007.01496.x. Mills HL, Abdel-Baki MS, Teruya J, et al. Platelet function defects in adolescents with heavy menstrual bleeding. Haemophilia : the official journal of the World Federation of Hemophilia . 2014;20(2):249-254. https://api.istex.fr/ark:/67375/WNG-BB046C26-D/fulltext.pdf. doi: 10.1111/hae.12293. O'Brien B, Mason J, Kimble R. Bleeding disorders in adolescents with heavy menstrual bleeding: The queensland statewide paediatric and adolescent gynaecology service. Journal of pediatric & adolescent gynecology . 2019;32(2):122-127. https://dx.doi.org/10.1016/j.jpag.2018.11.005. doi: 10.1016/j.jpag.2018.11.005. Oral E, Çağdaş A, Gezer A, Kaleli S, Aydin Y, Öçer F. Hematological abnormalities in adolescent menorrhagia. Arch Gynecol Obstet . 2002;266(2):72-74. https://www.ncbi.nlm.nih.gov/pubmed/12049298. doi: 10.1007/s004040100192. Rathod AD, Chavan RP, Pajai SP, Bhagat V, Thool P. Gynecological problems of adolescent girls attending outpatient department at tertiary care center with evaluation of cases of puberty menorrhagia requiring hospitalization. Journal of obstetrics and gynaecology of India . 2016;66(Suppl 1):400-406. https://www.ncbi.nlm.nih.gov/pubmed/27651637. doi: 10.1007/s13224-015-0770-1. Rosen MW, Weyand AC, Pennesi CM, et al. Adolescents presenting to the emergency department with heavy menstrual bleeding. Journal of pediatric & adolescent gynecology . 2020;33(2):139-143. https://dx.doi.org/10.1016/j.jpag.2019.11.010. doi: 10.1016/j.jpag.2019.11.010. Seravalli V, MD, Linari S, MD, Peruzzi E, MD, Dei M, MD, Paladino E, BI, Bruni V, MD. Prevalence of hemostatic disorders in adolescents with abnormal uterine bleeding. Journal of pediatric & adolescent gynecology . 2013;26(5):285-289. https://www.clinicalkey.es/playcontent/1-s2.0-S1083318813001885. doi: 10.1016/j.jpag.2013.06.003. Sharma I, Singh N, Mansukhani C, Gujral K. Adolescent abnormal uterine bleeding – the PALM COEIN approach. Current medicine research and practice . 2015;5(3):105-109. https://dx.doi.org/10.1016/j.cmrp.2015.06.002. doi: 10.1016/j.cmrp.2015.06.002. Smith YR, Quint EH, Hertzberg B. Menorrhagia in adolescents requiring hospitalization. Journal of pediatric & adolescent gynecology . 1998;11(1):13-15. https://dx.doi.org/10.1016/S1083-3188(98)70101-9. doi: 10.1016/S1083-3188(98)70101-9. Zia A, Jain S, Kouides P, et al. Bleeding disorders in adolescents with heavy menstrual bleeding in a multicenter prospective US cohort. Haematologica (Roma) . 2020;105(7):1969-1976. https://www.ncbi.nlm.nih.gov/pubmed/31624107. doi: 10.3324/haematol.2019.225656. Zia A, Stanek J, Christian‐Rancy M, Ahuja SP, Savelli S, O’Brien SH. Utility of a screening tool for haemostatic defects in a multicentre cohort of adolescents with heavy menstrual bleeding. Haemophilia : the official journal of the World Federation of Hemophilia . 2018;24(6):957-963. https://onlinelibrary.wiley.com/doi/abs/10.1111/hae.13609. doi: 10.1111/hae.13609. Page MJ, McKenzie JE, Bossuyt PM,Boutron I, Hoffmann TC, Mulrow CD, et al. (2021)The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. PLoS Med 18(3):e1003583.https://doi.org/10.1371/journal.pmed.1003583 Tables Tables 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.xlsx Table2.xlsx Table3.xlsx Table3A.xlsx Table3B.xlsx Table3C.xlsx Cite Share Download PDF Status: Published Journal Publication published 20 Feb, 2024 Read the published version in BMC Women's Health → Version 1 posted Editorial decision: Revision requested 19 Nov, 2023 Reviews received at journal 18 Nov, 2023 Reviewers agreed at journal 16 Nov, 2023 Reviewers agreed at journal 19 Oct, 2023 Reviews received at journal 17 Oct, 2023 Reviewers agreed at journal 10 Oct, 2023 Reviewers invited by journal 09 Oct, 2023 Editor assigned by journal 09 Oct, 2023 Editor invited by journal 29 Sep, 2023 Submission checks completed at journal 29 Sep, 2023 First submitted to journal 07 Sep, 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies 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-3335310","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":237014381,"identity":"94bbbc75-9896-4a27-a3ea-2c5c080b2644","order_by":0,"name":"Erin M Hall","email":"","orcid":"","institution":"University of Washington","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Erin","middleName":"M","lastName":"Hall","suffix":""},{"id":237014382,"identity":"2ded3e37-19c1-4b2b-b24c-95e180f50f65","order_by":1,"name":"Ana E Ravelo","email":"","orcid":"","institution":"Brown University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ana","middleName":"E","lastName":"Ravelo","suffix":""},{"id":237014383,"identity":"58ac8bea-7b4f-4d82-967b-283d48684e82","order_by":2,"name":"Stephen C Aronoff","email":"","orcid":"","institution":"Lewis Katz School of Medicine at Temple University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Stephen","middleName":"C","lastName":"Aronoff","suffix":""},{"id":237014384,"identity":"30361c20-d2cd-44a1-8c20-70fe8cafdec5","order_by":3,"name":"Michael T Del Vecchio","email":"data:image/png;base64,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","orcid":"","institution":"Lewis Katz School of Medicine at Temple University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Michael","middleName":"T Del","lastName":"Vecchio","suffix":""}],"badges":[],"createdAt":"2023-09-07 17:14:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3335310/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3335310/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12905-024-02921-7","type":"published","date":"2024-02-20T15:01:40+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":44210321,"identity":"02f2dc39-59b5-40ec-9166-25188f82cb6b","added_by":"auto","created_at":"2023-10-06 20:39:18","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":366342,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLiterature search results. Adapted from Moher et. al. (PLoS Med 2009;6:e1000097)\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3335310/v1/4fe39283a2612441e144a076.jpeg"},{"id":51648858,"identity":"488056f6-d528-4cfe-9a99-c475c4a17dc6","added_by":"auto","created_at":"2024-02-26 15:15:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":307888,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3335310/v1/a20ad12d-49d2-4be0-96b7-13e078629f32.pdf"},{"id":44210314,"identity":"890f74f8-518a-4d14-8430-521f6a181671","added_by":"auto","created_at":"2023-10-06 20:39:18","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":10420,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3335310/v1/3f38260fe7861ecc82975233.xlsx"},{"id":44211352,"identity":"6fad589f-435b-4823-aab4-3e9e2c466d2a","added_by":"auto","created_at":"2023-10-06 20:47:18","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":11498,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3335310/v1/e0f861b281ef0967d36cce9d.xlsx"},{"id":44211351,"identity":"91cc0e23-80da-4253-82d7-651cc73732c3","added_by":"auto","created_at":"2023-10-06 20:47:18","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":11031,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3335310/v1/902bce85023eee142c4c0231.xlsx"},{"id":44211350,"identity":"fe5b4e3e-a1e7-490f-99b6-f12bc03fb678","added_by":"auto","created_at":"2023-10-06 20:47:18","extension":"xlsx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":9171,"visible":true,"origin":"","legend":"","description":"","filename":"Table3A.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3335310/v1/a7261e351f58dc1d87b64d56.xlsx"},{"id":44210316,"identity":"6e192772-8f73-400b-ab88-266f1189085d","added_by":"auto","created_at":"2023-10-06 20:39:18","extension":"xlsx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":9485,"visible":true,"origin":"","legend":"","description":"","filename":"Table3B.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3335310/v1/67fcc1e4054ce9c35cb69725.xlsx"},{"id":44210319,"identity":"0799b71b-7efc-4de0-b2b3-e73f7f2cf268","added_by":"auto","created_at":"2023-10-06 20:39:18","extension":"xlsx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":9638,"visible":true,"origin":"","legend":"","description":"","filename":"Table3C.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3335310/v1/0ddfab88e1d7d308a73d481f.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Systematic Review and Meta-Analysis of the Etiology of Menorrhagia in 2,770 adolescent females","fulltext":[{"header":"Background","content":"\u003cp\u003eAmong female adolescents, menorrhagia or heavy menstrual bleeding, has an estimated prevalence of 37% \u003csup\u003e1\u003c/sup\u003e. Heavy menstrual bleeding, defined as excessive menstrual blood loss that interferes with a woman\u0026rsquo;s physical, social, emotional, or material quality of life, is currently classified according to the PALM-COEIN system\u003csup\u003e2\u003c/sup\u003e: polyp, adenomyosis, leiomyoma, malignancy and hyperplasia, coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not otherwise classified. This system, although useful, is not probability based, making it difficult for the physician to develop an efficient diagnostic plan.\u003c/p\u003e \u003cp\u003eAdolescent menorrhagia is typically related to anovulation, however, other causes such as an underlying bleeding disorder must be considered when a healthy female experiences heavy menstrual bleeding at menarche or during adolescence. While the frequency of bleeding disorders in the general population is estimated to be 1\u0026ndash;2%, bleeding disorders are found in approximately 20% of adolescent girls who present for evaluation for menorrhagia and in 33% of adolescent girls hospitalized for menorrhagia\u003csup\u003e3\u003c/sup\u003e. The purpose of this systematic review was to (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) determine the general categories of menorrhagia across a wide spectrum of patients and; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) determine the relative prevalence of specific etiologies using a probability based methodology\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis systematic review followed The Preferred Reporting Items in Systematic Reviews and Meta-analysis (PRISMA) guidelines\u003csup\u003e4\u003c/sup\u003e.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eLiterature Search and Inclusion Criteria\u003c/h2\u003e \u003cp\u003eA comprehensive literature search was conducted using the PubMed, EMBASE, and SCOPUS databases. The search items \u0026ldquo;Abnormal uterine bleeding\u0026rdquo; OR \u0026ldquo;menorrhagia\u0026rdquo; OR \u0026ldquo;heavy menstrual bleeding\u0026rdquo; AND \u0026ldquo;adolescents\u0026rdquo; were input. Editorials, case reports, review articles, book chapters, and studies with less than 10 patients were excluded. English abstracts were required. No date filter was used in the PubMed and EMBASE database searches. In the SCOPUS search engine, publication data was filtered to include only articles published from 2020 onward to search for newer publications and abstracts. The literature search was conducted by two authors on two separate occasions (August 2021, September 2021). The bibliographies from each of the databases were uploaded into the RefWorks program and exact duplicates were excluded. Each abstract was reviewed independently by two authors (EMH, AER) to identify those studies that met inclusion criteria (\u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e); conflicts were resolved by a third author (MTD). Throughout the initial search, relevant review articles were identified, and their bibliographies were reviewed also for studies that could qualify for this review. Full-text articles were reviewed using for inclusion and exclusion criteria.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eData Extraction\u003c/h2\u003e \u003cp\u003eFollowing the final selection of articles, the etiologies of menorrhagia, heavy menstrual bleeding, or abnormal uterine bleeding, and the number of adolescents affected by each different etiology were recorded for each study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eData Synthesis\u003c/h2\u003e \u003cp\u003eA Bayesian methodology was employed to determine the rate estimates and the associated 95% credible intervals for each disease entity; the beta distribution was used as the conjugate prior to the conditional likelihood distribution for each rate estimate determined from the extracted data\u003csup\u003e5,6\u003c/sup\u003e All calculations were performed in the R environment.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStudy Search and Selection\u003c/h2\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e demonstrates the results of the systematic review. The database searches provided a total of 75 results (PubMed- 4 articles, EMBASE- 61 articles, Scopus-10 articles). After exact duplicates were removed, abstracts of 65 articles were reviewed. After exclusion of abstracts that did not meet inclusion criteria a total of 31 full-text articles were examined in detail. Fourteen full text articles were excluded: 7 only studied subpopulations of patients (ie PCOS only), 2 were editorials, 2 failed to meet study criteria once the \u003cspan refid=\"Sec2\" class=\"InternalRef\"\u003emethods\u003c/span\u003e section was examined, 1 only studied therapies, 1 included adults in the study who could not be separated from those less than 21 years of age, and 1article was a secondary review.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eA total of 17 articles (published between 1998\u0026ndash;2020) met inclusion criteria and were analyzed for this study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStudy Characteristics\u003c/h2\u003e \u003cp\u003e \u003cb\u003eTable\u0026nbsp;2\u003c/b\u003e summarizes the data extracted from the 17 studies. A total of 2,770 subjects were identified. The largest study included 24% of the patient sample. The categories of entities causing menorrhagia in patients less than 21 years of age are shown in Table\u0026nbsp;3.\u003c/p\u003e \u003cp\u003eAlmost half of the cases had no identifiable etiology (45.9%, 95%CredI 43.8\u0026ndash;47.9). Ovarian Uterine Disorders (23.7%; 95% CredI 22-25.5), Coagulation Disorders (19.4%; 95% CredI 17.8\u0026ndash;21.1), and Platelet Disorders (6.23%; 95% CredI 5.27\u0026ndash;7.27). 45.9% (95% CredI 43.8\u0026ndash;47.9) accounted for most cases with an identified etiology.\u003c/p\u003e \u003cp\u003eAmong the ovarian uterine disorders identified, anovulatory bleeding (98.7%, 95% CredI 97.6\u0026ndash;99.5) accounted for almost all of the cases (table 3a); endometriosis (0.564%; 95% CredI 0.117\u0026ndash;1.35) and polycystic ovary syndrome (0.564%; 95% CredI 0.117\u0026ndash;1.35) were encountered rarely. Among coagulopathies, von Wilibrand\u0026rsquo;s Disease (88.1, 95% CredI 84.9\u0026ndash;90.9) accounted for the vast majority of cases; Factor 8 Deficiency (6.19%; 95% CredI 4.13\u0026ndash;8.64) and Clotting Factor Deficiencies (4.13%; 95% CredI 2.47\u0026ndash;6.18) occurred less commonly (table 3b). As a group, platelet abnormalities accounted for a small percentage of patients with menorrhagia; Platelet Function Disorders(37.9%; 95% CredI 30\u0026ndash;46), Inherited Thrombocytopenia (17.1%; 95% CredI 11.4\u0026ndash;23.8) and Platelet Qualitative Disorders(13.6%; 95% CredI 8.43\u0026ndash;19.7) were the most common platelet disorders identified (table 3c).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eA systematic review of menorrhagia in patients less than 21 years of age yielded 17 full text articles describing 2,770 adolescent females. These patients spanned the age range of 10\u0026ndash;21 years old. Although PALM-COEIN\u003csup\u003e2\u003c/sup\u003e is a useful tool to organize the etiologies of menorrhagia, it fails to provide \u003cem\u003ea priori\u003c/em\u003e probabilities for each entity or to estimate the number of patients with no identifiable etiology. The present study identifies the etiologies of menorrhagia in a combined cohort of more than 2000 patients, assigns relative probabilities to the etiologies of menorrhagia in adolescents and that over 40% of individuals will have no identifiable etiology. Among patients with an identifiable etiology for f menorrhagia, Ovarian Uterine disorders (23.7%; 95% CredI 22-25.5), Coagulation Disorders (19.4%; 95% CredI 17.8\u0026ndash;21.1), and Platelet Disorders (6.23%; 95% CredI 5.27\u0026ndash;7.27) were the most common systematic disorders. Within these categories, anovulatory bleeding, von Willibrand\u0026rsquo;s Disease and platelet function disorders were most common. As a systematic review, this article has inherent limitations. The etiologies of menorrhagia listed in the selected articles were taken as they were reported in their respective studies. This resulted in vague etiologies, such as unspecified thrombocytopenia and aggregation secretion defects. Additionally, the availability of diagnostic resources, criteria, and thoroughness of evaluation were not standardized across institutions, resulting in the large number of indeterminate etiologies of menorrhagia. This also raises the issue of diagnostic consistency.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe present study, a systematic review found the causes of menorrhagia in healthy adolescent females were varied. The sub-analysis identified distinct etiologies, suggesting that multiple factors must be considered in the evaluation of menorrhagia. While PALM-COEIN (polyp, adenomyosis, leiomyoma, \u0026nbsp;malignancy and hyperplasia, coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not yet classified) provides us with a comprehensive picture of the possible causes of menorrhagia in females, this systematic review assigns probabilities to the etiologies of menorrhagia in adolescent females, providing physicians with a more focused and efficient pathway to diagnosis.\u0026nbsp;\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003ePALM-COEIN polyp, adenomyosis, leiomyoma, malignancy and hyperplasia, coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not yet classified\u003c/p\u003e\n\u003cp\u003ePRISMA Preferred Reporting Items for Systematic reviews and Meta-Analysis\u003c/p\u003e\n\u003cp\u003eCredI Credible Intervals\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics Approval: No ethics approval was required as all data was pre-existing and found in the public domain.\u003c/p\u003e\n\u003cp\u003eConsent for publication: NA\u003c/p\u003e\n\u003cp\u003eAvailability of Data and Materials: The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eCompeting interest: None\u003c/p\u003e\n\u003cp\u003eFunding: None\u003c/p\u003e\n\u003cp\u003eAuthors\u0026rsquo; contributions: \u003c/p\u003e\n\u003cp\u003eHall: Aided in the design, carried out the searches and did data extraction, aided in manuscript \u003c/p\u003e\n\u003cp\u003epreparation. \u003c/p\u003e\n\u003cp\u003eRavelo: Aided in the design, carried out the searches and did data extraction, aided in \u003c/p\u003e\n\u003cp\u003emanuscript preparation. \u003c/p\u003e\n\u003cp\u003eAronoff: Aided in design, performed the statistical analysis, aided in manuscript preparation. \u003c/p\u003e\n\u003cp\u003eDel Vecchio: Aided in design, aided in searches and data extraction, aided in manuscript \u003c/p\u003e\n\u003cp\u003epreparation and submitted final manuscript. \u003c/p\u003e"},{"header":"References","content":"\u003col start=\"1\" type=\"1\"\u003e\n\u003cli\u003eKaraman, Kamuran, et al. \u0026ldquo;Evaluation of the Hemostatic Disorders in Adolescent Girls with Menorrhagia: Experiences from a Tertiary Referral Hospital.\u0026rdquo; \u003cem\u003eIndian Journal of Hematology \u0026amp; Blood Transfusion\u003c/em\u003e, vol. 32, no. 3, Sept. 2016, pp. 356\u0026ndash;61. \u003cem\u003ePubMed Central\u003c/em\u003e, https://doi.org/10.1007/s12288-015-0583-5.\u003c/li\u003e\n\u003cli\u003eScreening and management of Bleeding Disorders in adolescents with heavy menstrual bleeding. ACOG.https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2019/09/screening-and-management-of-bleeding-disorders-in-adolescents-with-heavy-menstrual-bleeding. Accessed 2021.\u003c/li\u003e\n\u003cli\u003eOleka, Chimsom MD; Dietrich Jennifer E. MD, MSc HMB in the Adolescent: A Review of the Modern Approach to Diagnosis and Management, Clinical Obstetrics and Gynecology: September 2020 - Volume 63 - Issue 3 - p 553-560 doi: 10.1097/GRF.0000000000000523\u003c/li\u003e\n\u003cli\u003eMoher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6:e1000097.\u003c/li\u003e\n\u003cli\u003eDavitt M, Delvecchio MT, Aronoff SC. The Differential Diagnosis of Vertigo in Children: A Systematic Review of 2726 Cases. Pediatr Emerg Care. 2020 Aug;36(8):368-371. doi: 10.1097/PEC.0000000000001281. PMID: 29095392.\u003c/li\u003e\n\u003cli\u003eKruschke, JK. Doing Bayesian Analysis. 2011, Academic Press, Burlington, MA. Chapter 5. Inferring a binomial proportion via exact mathematical analysis\u003c/li\u003e\n\u003cli\u003eAguirre, N; Pereira, J; Barriga, F; Wietstruck, M A; Panes, O;Inherited bleeding disorders in adolescents with excessive menstrual bleeding. should we evaluate the fibrinolytic pathway? \u003cem\u003eRevista chilena de pediatria\u003c/em\u003e. 2020;91(3):385-390. https://search.proquest.com/docview/2429785082. doi: 10.32641/rchped.v91i3.1571.\u003c/li\u003e\n\u003cli\u003eAlaqzam TS, Stanley AC, Simpson PM, Flood VH, Menon S. Treatment modalities in adolescents who present with heavy menstrual bleeding. \u003cem\u003eJournal of pediatric \u0026amp; adolescent gynecology\u003c/em\u003e. 2018;31(5):451-458. https://dx.doi.org/10.1016/j.jpag.2018.02.130. doi: 10.1016/j.jpag.2018.02.130.\u003c/li\u003e\n\u003cli\u003eHaberal A, Altay MM. Abnormal uterine bleeding in adolescents: Treatment with combined oral contraceptive pills is effective even in hospitalized patients with bleeding disorders. \u003cem\u003eTurkish journal of medical sciences\u003c/em\u003e. 2008;38(5):431-435. http://uvt.ulakbim.gov.tr/uvt/index.php?cwid=9\u0026amp;vtadi=TTIP\u0026amp;c=ebsco\u0026amp;c=summon\u0026amp;c=ebsco\u0026amp;ano=93589_c67fb27e173d408f50bf014e1743d850.\u003c/li\u003e\n\u003cli\u003eHutspardol S, Sirachainan N, Soisamrong A, Atchararit N, O-Prasertsawat P, Chuansumrit A. Hemostatic defects in thai adolescents with menorrhagia. \u003cem\u003eJournal of the Medical Association of Thailand\u003c/em\u003e. 2010;93(4):436-442. https://www.ncbi.nlm.nih.gov/pubmed/20462086.\u003c/li\u003e\n\u003cli\u003eJain S, Zhang S, Acosta M, Malone K, Kouides P, Zia A. Prospective evaluation of ISTH‐BAT as a predictor of bleeding disorder in adolescents presenting with heavy menstrual bleeding in a multidisciplinary hematology clinic. \u003cem\u003eJournal of thrombosis and haemostasis\u003c/em\u003e. 2020;18(10):2542-2550. https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.14997. doi: 10.1111/jth.14997.\u003c/li\u003e\n\u003cli\u003eKhamees, Deena, MLS, BS, Klima J, PhD, O\u0026apos;Brien, Sarah H., MD, MSc. Population screening for von willebrand disease in adolescents with Heavy menstrual bleeding. \u003cem\u003eThe Journal of pediatrics\u003c/em\u003e. 2015;166(1):195-197. https://www.clinicalkey.es/playcontent/1-s2.0-S0022347614008774. doi: 10.1016/j.jpeds.2014.09.026.\u003c/li\u003e\n\u003cli\u003eMikhail S, Varadarajan Rm Kouides P. The prevalence of disorders of haemostasis in adolescents with menorrhagia referred to a haemophilia treatment centre. \u003cem\u003eHaemophilia : the official journal of the World Federation of Hemophilia\u003c/em\u003e. 2007;13(5):627-632. https://api.istex.fr/ark:/67375/WNG-Q7NVM5MD-N/fulltext.pdf. doi: 10.1111/j.1365-2516.2007.01496.x.\u003c/li\u003e\n\u003cli\u003eMills HL, Abdel-Baki MS, Teruya J, et al. Platelet function defects in adolescents with heavy menstrual bleeding. \u003cem\u003eHaemophilia : the official journal of the World Federation of Hemophilia\u003c/em\u003e. 2014;20(2):249-254. https://api.istex.fr/ark:/67375/WNG-BB046C26-D/fulltext.pdf. doi: 10.1111/hae.12293.\u003c/li\u003e\n\u003cli\u003eO\u0026apos;Brien B, Mason J, Kimble R. Bleeding disorders in adolescents with heavy menstrual bleeding: The queensland statewide paediatric and adolescent gynaecology service. \u003cem\u003eJournal of pediatric \u0026amp; adolescent gynecology\u003c/em\u003e. 2019;32(2):122-127. https://dx.doi.org/10.1016/j.jpag.2018.11.005. doi: 10.1016/j.jpag.2018.11.005.\u003c/li\u003e\n\u003cli\u003eOral E, \u0026Ccedil;ağdaş A, Gezer A, Kaleli S, Aydin Y, \u0026Ouml;\u0026ccedil;er F. Hematological abnormalities in adolescent menorrhagia. \u003cem\u003eArch Gynecol Obstet\u003c/em\u003e. 2002;266(2):72-74. https://www.ncbi.nlm.nih.gov/pubmed/12049298. doi: 10.1007/s004040100192.\u003c/li\u003e\n\u003cli\u003eRathod AD, Chavan RP, Pajai SP, Bhagat V, Thool P. Gynecological problems of adolescent girls attending outpatient department at tertiary care center with evaluation of cases of puberty menorrhagia requiring hospitalization. \u003cem\u003eJournal of obstetrics and gynaecology of India\u003c/em\u003e. 2016;66(Suppl 1):400-406. https://www.ncbi.nlm.nih.gov/pubmed/27651637. doi: 10.1007/s13224-015-0770-1.\u003c/li\u003e\n\u003cli\u003eRosen MW, Weyand AC, Pennesi CM, et al. Adolescents presenting to the emergency department with heavy menstrual bleeding. \u003cem\u003eJournal of pediatric \u0026amp; adolescent gynecology\u003c/em\u003e. 2020;33(2):139-143. https://dx.doi.org/10.1016/j.jpag.2019.11.010. doi: 10.1016/j.jpag.2019.11.010.\u003c/li\u003e\n\u003cli\u003eSeravalli V, MD, Linari S, MD, Peruzzi E, MD, Dei M, MD, Paladino E, BI, Bruni V, MD. Prevalence of hemostatic disorders in adolescents with abnormal uterine bleeding. \u003cem\u003eJournal of pediatric \u0026amp; adolescent gynecology\u003c/em\u003e. 2013;26(5):285-289. https://www.clinicalkey.es/playcontent/1-s2.0-S1083318813001885. doi: 10.1016/j.jpag.2013.06.003.\u003c/li\u003e\n\u003cli\u003eSharma I, Singh N, Mansukhani C, Gujral K. Adolescent abnormal uterine bleeding \u0026ndash; the PALM COEIN approach. \u003cem\u003eCurrent medicine research and practice\u003c/em\u003e. 2015;5(3):105-109. https://dx.doi.org/10.1016/j.cmrp.2015.06.002. doi: 10.1016/j.cmrp.2015.06.002.\u003c/li\u003e\n\u003cli\u003eSmith YR, Quint EH, Hertzberg B. Menorrhagia in adolescents requiring hospitalization. \u003cem\u003eJournal of pediatric \u0026amp; adolescent gynecology\u003c/em\u003e. 1998;11(1):13-15. https://dx.doi.org/10.1016/S1083-3188(98)70101-9. doi: 10.1016/S1083-3188(98)70101-9.\u003c/li\u003e\n\u003cli\u003eZia A, Jain S, Kouides P, et al. Bleeding disorders in adolescents with heavy menstrual bleeding in a multicenter prospective US cohort. \u003cem\u003eHaematologica (Roma)\u003c/em\u003e. 2020;105(7):1969-1976. https://www.ncbi.nlm.nih.gov/pubmed/31624107. doi: 10.3324/haematol.2019.225656.\u003c/li\u003e\n\u003cli\u003eZia A, Stanek J, Christian‐Rancy M, Ahuja SP, Savelli S, O\u0026rsquo;Brien SH. Utility of a screening tool for haemostatic defects in a multicentre cohort of adolescents with heavy menstrual bleeding. \u003cem\u003eHaemophilia : the official journal of the World Federation of Hemophilia\u003c/em\u003e. 2018;24(6):957-963. https://onlinelibrary.wiley.com/doi/abs/10.1111/hae.13609. doi: 10.1111/hae.13609.\u003c/li\u003e\n\u003cli\u003ePage MJ, McKenzie JE, Bossuyt PM,Boutron I, Hoffmann TC, Mulrow CD, et al. (2021)The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. PLoS Med 18(3):e1003583.https://doi.org/10.1371/journal.pmed.1003583\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\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":"bmc-womens-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmwh","sideBox":"Learn more about [BMC Women's Health](http://bmcwomenshealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmwh/default.aspx","title":"BMC Women's Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"adolescents, menorrhagia, abnormal uterine bleeding, heavy menstrual bleeding, systematic review, PALM-COEIN","lastPublishedDoi":"10.21203/rs.3.rs-3335310/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3335310/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAdolescent menorrhagia, heavy menstrual bleeding, or abnormal uterine bleeding commonly occur in adolescent woman. The differential diagnosis can be challenging. The pneumonic: PALM-COEIN(polyp, adenomyosis, leiomyoma, malignancy and hyperplasia, coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not yet classified), is commonly used but it does not stratify as to the likelihood of a disorder. We have sought to develop a probability-based differential diagnosis for Adolescent menorrhagia, heavy menstrual bleeding, or abnormal uterine bleeding\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA comprehensive literature search was conducted using PubMed, EMBASE, and SCOPUS databases. Case series describing adolescents from 10 to 21 years of age with menorrhagia, abnormal uterine bleeding (AUB), or heavy menstrual bleeding (HMB) were acceptable if: more than 10 patients were included; editorials, case reports, and secondary sources such as review articles, or book chapters were excluded. No language filter was used, but an English abstract was required. The etiology of menorrhagia, abnormal uterine bleeding, or \u0026nbsp;heavy menstrual bleeding, and the country of origin was extracted from articles that met inclusion criteria. Cumulative rate estimates were determined by Bayesian probability modeling.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e17 full text articles were reviewed in detail; 2,770 patients were included. The most frequent causes of menorrhagia were Ovarian Uterine Disorders (23.7%; 95% CredI 22-25.5%), Coagulation Disorders (19.4%; 95% CredI 17.8 - 21.1%), and Platelet Disorders (6.23%; 95% CredI 5.27-7.27%) with 45.9% (95% CredI 43.8 - 47.%9) of the cases of indeterminate origin.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe leading causes of menorrhagia in healthy adolescent females were varied. The sub-analysis identified distinct etiologies, suggesting that multiple factors must be considered in the evaluation of menorrhagia. While PALM-COEIN (polyp, adenomyosis, leiomyoma, malignancy and hyperplasia, coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not yet classified) provides us with a comprehensive picture of the possible causes of menorrhagia in females, this systematic review assigns probabilities to the etiologies of menorrhagia in adolescent females, providing physicians with a more focused and efficient pathway to diagnosis.\u003c/p\u003e","manuscriptTitle":"Systematic Review and Meta-Analysis of the Etiology of Menorrhagia in 2,770 adolescent females","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-10-06 20:39:13","doi":"10.21203/rs.3.rs-3335310/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2023-11-19T12:31:48+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-11-18T06:11:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"10ecc9e9-bb0c-44b4-82f1-e470be2a43e5","date":"2023-11-16T23:35:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"242db3ea-56bc-431d-b517-736723564783","date":"2023-10-19T14:38:45+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-10-17T14:07:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"f48f16c9-b021-43e9-9866-bd26740ce14f","date":"2023-10-10T09:23:59+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-10-09T04:34:51+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-10-09T04:12:42+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2023-09-30T02:21:02+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-09-30T02:19:43+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Women's Health","date":"2023-09-07T17:10:07+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-womens-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmwh","sideBox":"Learn more about [BMC Women's Health](http://bmcwomenshealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmwh/default.aspx","title":"BMC Women's Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d29bed41-b3eb-4fcf-9d0b-877dca6e4c9a","owner":[],"postedDate":"October 6th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-02-26T15:13:00+00:00","versionOfRecord":{"articleIdentity":"rs-3335310","link":"https://doi.org/10.1186/s12905-024-02921-7","journal":{"identity":"bmc-womens-health","isVorOnly":false,"title":"BMC Women's Health"},"publishedOn":"2024-02-20 15:01:40","publishedOnDateReadable":"February 20th, 2024"},"versionCreatedAt":"2023-10-06 20:39:13","video":"","vorDoi":"10.1186/s12905-024-02921-7","vorDoiUrl":"https://doi.org/10.1186/s12905-024-02921-7","workflowStages":[]},"version":"v1","identity":"rs-3335310","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3335310","identity":"rs-3335310","version":["v1"]},"buildId":"afDZ1USd8LLqUjqjB8QhT","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}