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      Menstrual disturbance associated with COVID-19 vaccines: A comprehensive systematic review and meta-analysis

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          Abstract

          Background

          The relationship between COVID-19 vaccines and menstrual disturbance is unclear, in part because researchers have measured different outcomes (e.g., delays vs. changes to cycle length) with various study designs. Menstrual disruption could be a decisive factor in people’s willingness to accept the COVID-19 vaccine.

          Methods

          We searched Medline, Embase, and Web of Science for studies investigating menstrual cycle length, flow volume, post-menopausal bleeding, and unexpected or intermenstrual bleeding. Data were analyzed using fixed-effects meta-analysis with Shore’s adjusted confidence intervals for heterogeneity.

          Findings

          Seventeen studies with >1·9 million participants were analyzed. We found a 19% greater risk of increase in menstrual cycle length as compared to unvaccinated people or pre-vaccination time-periods (summary relative risk (sRR): 1·19; 95% CI: 1·11–1·26; n = 23,718 participants). The increase in risk was the same for Pfizer-BioNTech (sRR: 1·15; 1·05–1·27; n = 16,595) and Moderna vaccines (sRR: 1·15; 1·05–1·25; n = 7,523), similar for AstraZeneca (sRR: 1·27; 1·02–1·59; n = 532), and higher for the Janssen (sRR: 1·69; 1·14–2·52; n = 751) vaccine. In the first cycle after vaccination, length increased by <half-day (summary mean difference (sMD): 0·34 days; 0·21–0·46 days; n = 30,320) after the first dose and by 0·62 days (sMD: 0·62: 0·41–0·82; n = 17,608) after the second dose. In the second cycle after vaccination, the risk was not elevated (sMD: –0·02; –0·16–0·12; n = 18,602). The increase in risk was between 7–9% but statistically insignificant for heavier flow; 7% for post-menopausal bleeding (first dose: 1·07; 1·01–1·12; n = 1,321,268 and second dose: 1·07; 1·03–1·11; n = 1,482,884); and 16–41% for unexpected or intermenstrual bleeding (first dose: 1·16; 0·83–1·61; n = 1,303,687 and second dose: 1·41; 0·99–2·01; n = 1,390,317).

          Interpretation

          We observed a mild increase in the risk of menstrual disturbance associated with COVID-19 vaccines. Such risks are likely clinically unmeaningful. Vaccine recipients should be appropriately counseled.

          Related collections

          Most cited references52

          • Record: found
          • Abstract: found
          • Article: not found

          Quantifying heterogeneity in a meta-analysis.

          The extent of heterogeneity in a meta-analysis partly determines the difficulty in drawing overall conclusions. This extent may be measured by estimating a between-study variance, but interpretation is then specific to a particular treatment effect metric. A test for the existence of heterogeneity exists, but depends on the number of studies in the meta-analysis. We develop measures of the impact of heterogeneity on a meta-analysis, from mathematical criteria, that are independent of the number of studies and the treatment effect metric. We derive and propose three suitable statistics: H is the square root of the chi2 heterogeneity statistic divided by its degrees of freedom; R is the ratio of the standard error of the underlying mean from a random effects meta-analysis to the standard error of a fixed effect meta-analytic estimate, and I2 is a transformation of (H) that describes the proportion of total variation in study estimates that is due to heterogeneity. We discuss interpretation, interval estimates and other properties of these measures and examine them in five example data sets showing different amounts of heterogeneity. We conclude that H and I2, which can usually be calculated for published meta-analyses, are particularly useful summaries of the impact of heterogeneity. One or both should be presented in published meta-analyses in preference to the test for heterogeneity. Copyright 2002 John Wiley & Sons, Ltd.
            • Record: found
            • Abstract: not found
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            Meta-analysis in clinical trials

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              • Abstract: not found
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              The Combination of Estimates from Different Experiments

                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: InvestigationRole: Project administrationRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: InvestigationRole: Writing – original draftRole: Writing – review & editing
                Role: InvestigationRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: ValidationRole: VisualizationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: VisualizationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS One
                plos
                PLOS One
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                16 May 2025
                2025
                : 20
                : 5
                : e0320162
                Affiliations
                [1 ] Center for Tuberculosis and AIDS Research, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
                [2 ] Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
                [3 ] Preventative Gynecology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
                [4 ] Adams County Health Department, Brighton, Colorado, United States of America
                [5 ] Center for Humanitarian Health, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
                UCSI University, MALAYSIA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                https://orcid.org/0000-0003-0992-0631
                https://orcid.org/0000-0002-5907-1976
                https://orcid.org/0000-0002-8590-5786
                https://orcid.org/0000-0002-1707-7018
                Article
                PONE-D-24-29021
                10.1371/journal.pone.0320162
                12083795
                40378132
                671b6959-b62f-46d7-ba71-5d945abfaf15
                © 2025 Dorjee et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 16 July 2024
                : 12 February 2025
                Page count
                Figures: 3, Tables: 2, Pages: 19
                Funding
                This study was supported by grants and philanthropy awarded to KD and Johns Hopkins University from National Institute of Allergy and Infectious Diseases of the National Institute of Health (Grant #K01AI148583); Johns Hopkins Center for AIDS Research (Grant #90100777); the United Nations STOP TB PARTNERSHIP TB REACH (Grant #134126); Chao Family Foundation (unnumbered); the Pittsfield Anti-TB Association (unnumbered); Friends of Delek Hospital (unnumbered); the Joseph & Sally Handleman Charitable Foundation Trust (unnumbered); the Step Forward Initiative (unnumbered); and other dedicated philanthropy (unnumbered) in the form of salary for KD, RCS, and SD. The specific roles of the authors are articulated in the ‘author contributions’ section. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Medical Conditions
                Infectious Diseases
                Infectious Disease Control
                Vaccines
                Medicine and Health Sciences
                Medical Conditions
                Infectious Diseases
                Viral Diseases
                Covid 19
                Medicine and Health Sciences
                Clinical Medicine
                Signs and Symptoms
                Hemorrhage
                Medicine and Health Sciences
                Vascular Medicine
                Hemorrhage
                Biology and Life Sciences
                Immunology
                Vaccination and Immunization
                Medicine and Health Sciences
                Immunology
                Vaccination and Immunization
                Medicine and Health Sciences
                Public and Occupational Health
                Preventive Medicine
                Vaccination and Immunization
                Medicine and Health Sciences
                Epidemiology
                Medical Risk Factors
                Medicine and Health Sciences
                Endocrinology
                Endocrine Physiology
                Menstrual Cycle
                Biology and Life Sciences
                Physiology
                Endocrine Physiology
                Menstrual Cycle
                Biology and Life Sciences
                Physiology
                Reproductive Physiology
                Menstrual Cycle
                Medicine and Health Sciences
                Women's Health
                Obstetrics and Gynecology
                Contraception
                Female Contraception
                Research and Analysis Methods
                Mathematical and Statistical Techniques
                Statistical Methods
                Metaanalysis
                Physical Sciences
                Mathematics
                Statistics
                Statistical Methods
                Metaanalysis
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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