Reports of myocarditis and pericarditis following mRNA COVID-19 vaccines: A systematic review of spontaneously reported data from the UK, Europe, and the US and of the literature

Objectives To bring together spontaneously reported data from multiple countries to estimate reporting rate, and better understand risk factors for myocarditis and pericarditis following COVID-19 mRNA vaccines. Design Systematic review of spontaneously reported data from United Kingdom (UK), United States (US), and European Union/European Economic Area (EU/EEA) and of the literature. Data sources UK Yellow Card scheme, Vaccine Adverse Event Reporting System (VAERS), EudraVigilance were searched from date of vaccine launch to 14-16 March 2022. PubMed/MEDLINE and Embase were searched to 15 March 2022. Eligibility criteria We included publicly available spontaneous reporting data for “Myocarditis” and “Pericarditis” from UK, US, and EU/EEA following COVID-19 mRNA vaccines. Pharmacoepidemiological observational studies investigating myocarditis/pericarditis following mRNA COVID-19 vaccines were included (no restrictions on language or date). Critical Appraisal Skills Programme (CASP) tools assessed study quality. Data extraction and synthesis Two researchers extracted data. Spontaneously reported events of myocarditis and pericarditis were presented for each data source, stratified by vaccine, age, sex, and dose (where available). Reporting rates were calculated for myocarditis and pericarditis for each population. For published pharmacoepidemiological studies, design, participant characteristics, and study results were tabulated. Results Overall, 18,204 myocarditis and pericarditis events have been submitted to the UK, US, and EU/EEA regulators during the study period. Males represented 62.24% (n=11,331) of myocarditis and pericarditis reports. Most reports concerned vaccinees aged <40 years and were more frequent following a second dose. Reporting rates were consistent between the data sources. Thirty-two pharmacoepidemiological studies were included; results were consistent with our spontaneous report analyses. Conclusions Younger vaccinees more frequently report myocarditis and pericarditis following mRNA COVID-19 vaccines than older vaccinees. Results from published literature supported the results of our analyses. Strengths and Limitations of the Study ### Competing Interest Statement All authors have completed the Unified Competing Interest form (available on request from the corresponding author) and declare: The Drug Safety Research Unit (DSRU) is a registered independent charity (No. 327206) associated with the University of Portsmouth. The DSRU receives donations and grants from pharmaceutical companies; however, the companies have no control over the conduct or publication of its studies. The DSRU has received grants to conduct unconditional studies on the Oxford/AstraZeneca COVID-19 vaccine and is in negotiations to receiving grants for conducting CPRD studies for Pfizer, Moderna, and Janssen COVID-19 vaccines. The DSRU has conducted benefit-risk studies on products for COVID-19, including remdesivir, lopinavir/ritonavir, chloroquine and hydroxychloroquine, and convalescent plasma. Professor Shakir is the principal investigator for an active surveillance study for the Oxford/AstraZeneca vaccine, but this assessment is unrelated to this study. Professor Shakir has been a member of Data Safety Monitoring Boards for Ipsen, Biogen, and Diurnal. None of these companies have any involvement with COVID-19 vaccines. Professor Shakir was invited by AstraZeneca to advise on the events of thrombosis with thrombocytopenia with the COVID-19 vaccine and to be a member of an advisory committee on a safety study of the Oxford/AstraZeneca vaccine in Europe. Samantha Lane and Alison Yeomans have no conflicts of interest with regard to this study. ### Funding Statement No external funding was received for the preparation of this manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics approval was not required. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes CASP checklists for assessing quality of each study included in systematic review are available on request.