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Meta-Analysis
. 2022 Jun 1;7(6):600-612.
doi: 10.1001/jamacardio.2022.0583.

SARS-CoV-2 Vaccination and Myocarditis in a Nordic Cohort Study of 23 Million Residents

Øystein Karlstad  1 , Petteri Hovi  2 , Anders Husby  3   4 , Tommi Härkänen  2 , Randi Marie Selmer  1 , Nicklas Pihlström  5 , Jørgen Vinsløv Hansen  3 , Hanna Nohynek  6 , Nina Gunnes  1   7 , Anders Sundström  8 , Jan Wohlfahrt  3 , Tuomo A Nieminen  9 , Maria Grünewald  5 , Hanne Løvdal Gulseth  1 , Anders Hviid  3   10 , Rickard Ljung  8   11
Affiliations
Meta-Analysis

SARS-CoV-2 Vaccination and Myocarditis in a Nordic Cohort Study of 23 Million Residents

Øystein Karlstad et al. JAMA Cardiol. .

Abstract

Importance: Reports of myocarditis after SARS-CoV-2 messenger RNA (mRNA) vaccination have emerged.

Objective: To evaluate the risks of myocarditis and pericarditis following SARS-CoV-2 vaccination by vaccine product, vaccination dose number, sex, and age.

Design, setting, and participants: Four cohort studies were conducted according to a common protocol, and the results were combined using meta-analysis. Participants were 23 122 522 residents aged 12 years or older. They were followed up from December 27, 2020, until incident myocarditis or pericarditis, censoring, or study end (October 5, 2021). Data on SARS-CoV-2 vaccinations, hospital diagnoses of myocarditis or pericarditis, and covariates for the participants were obtained from linked nationwide health registers in Denmark, Finland, Norway, and Sweden.

Exposures: The 28-day risk periods after administration date of the first and second doses of a SARS-CoV-2 vaccine, including BNT162b2, mRNA-1273, and AZD1222 or combinations thereof. A homologous schedule was defined as receiving the same vaccine type for doses 1 and 2.

Main outcomes and measures: Incident outcome events were defined as the date of first inpatient hospital admission based on primary or secondary discharge diagnosis for myocarditis or pericarditis from December 27, 2020, onward. Secondary outcome was myocarditis or pericarditis combined from either inpatient or outpatient hospital care. Poisson regression yielded adjusted incidence rate ratios (IRRs) and excess rates with 95% CIs, comparing rates of myocarditis or pericarditis in the 28-day period following vaccination with rates among unvaccinated individuals.

Results: Among 23 122 522 Nordic residents (81% vaccinated by study end; 50.2% female), 1077 incident myocarditis events and 1149 incident pericarditis events were identified. Within the 28-day period, for males and females 12 years or older combined who received a homologous schedule, the second dose was associated with higher risk of myocarditis, with adjusted IRRs of 1.75 (95% CI, 1.43-2.14) for BNT162b2 and 6.57 (95% CI, 4.64-9.28) for mRNA-1273. Among males 16 to 24 years of age, adjusted IRRs were 5.31 (95% CI, 3.68-7.68) for a second dose of BNT162b2 and 13.83 (95% CI, 8.08-23.68) for a second dose of mRNA-1273, and numbers of excess events were 5.55 (95% CI, 3.70-7.39) events per 100 000 vaccinees after the second dose of BNT162b2 and 18.39 (9.05-27.72) events per 100 000 vaccinees after the second dose of mRNA-1273. Estimates for pericarditis were similar.

Conclusions and relevance: Results of this large cohort study indicated that both first and second doses of mRNA vaccines were associated with increased risk of myocarditis and pericarditis. For individuals receiving 2 doses of the same vaccine, risk of myocarditis was highest among young males (aged 16-24 years) after the second dose. These findings are compatible with between 4 and 7 excess events in 28 days per 100 000 vaccinees after BNT162b2, and between 9 and 28 excess events per 100 000 vaccinees after mRNA-1273. This risk should be balanced against the benefits of protecting against severe COVID-19 disease.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Karlstad reported participating in research projects funded by Novo Nordisk and LEO Pharma, all regulator-mandated phase 4 studies with funds paid to his institution and outside the submitted work. Dr Hovi reported being affiliated with the Finnish Institute for Health and Welfare and was thus obligated by legislation to investigate the potential postmarketing harmful effects of vaccines during the conduct of the study. Dr Husby reported receiving funding from the Lundbeck Foundation. Dr Nohynek reported receiving nonfinancial support from WHO SAGE (Strategic Advisory Group of Experts) and the Global Advisory Committee on Vaccine Safety during the conduct of the study; and being employed by the Finnish Institute for Health and Welfare (THL), which receives research funding from Sanofi Pasteur, GlaxoSmithKline, and Pfizer for research studies not related to the current study nor to COVID-19. Dr Sundström reported participating in research funded by governmental agencies, universities, Astellas Pharma, Janssen Biotech, AstraZeneca, Pfizer, Roche, (then) Abbott Laboratories, (then) Schering-Plough, UCB Nordic, and Sobi, with all funds paid to Karolinska Institutet, outside the submitted work. Dr Nieminen reported receiving grants from Sanofi Pasteur outside the submitted work; and being employed by THL. Dr Grünewald reported being involved in the European Medicines Agency regulatory assessment of Comirnaty; being previously employed at a drug development consultancy firm with cross-product responsibilities; and being involved on a project for pertussis vaccines funded by Sanofi Pasteur, Merck Sharp & Dohme Corp, and GlaxoSmithKline at the Swedish Agency of Infectious Disease Control. Dr Gulseth reported participating in research projects and clinical trials funded by Novo Nordisk, GlaxoSmithKline, AstraZeneca, and Boehringer-Ingelheim paid to Oslo University Hospital; and receiving personal fees from Sanofi-Aventis. Dr Hviid reported receiving grants from The Lundbeck Foundation during the conduct of the study. Dr Ljung reported receiving grants from Sanofi Aventis paid to his institution outside the submitted work; and receiving personal fees from Pfizer outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Schematic Illustrations of Follow-up Time Windows in the Cohort Study
A, Example of an individual who was vaccinated with a first dose on May 20, 2021, and followed up 0 to 28 days from first dose, and vaccinated with a second dose on June 25, 2021, and followed up 0 to 28 days after a second dose. B, Example of an individual who was not vaccinated and was followed up until the end of follow-up on October 5, 2021.
Figure 2.
Figure 2.. Myocarditis Within 28 Days After SARS-CoV-2 Vaccination in 4 Nordic Countries Among Males Aged 16 to 39 Years, With Pooled Estimates
Squares represent incidence rate ratios (IRRs) with 95% CIs; square size, country weight; and diamonds, pooled estimates with 95% CIs. A single vaccine name indicates first dose of that vaccine (eg, BNT162b2) and the risk of the outcome after the first dose. Vaccine names in combination indicate a vaccine schedule of first dose of the first vaccine and a second dose of the second vaccine (eg, BNT162b2, BNT162b2) and the risk of the outcome after the second dose. Model 2 adjusted for age group and sex, previous SARS-CoV-2 infection, health care worker status, nursing home resident, and comorbidity variables.
Figure 3.
Figure 3.. Myocarditis Within 28 Days After SARS-CoV-2 Vaccination in 4 Nordic Countries Among Males and Females Aged 12 Years or Older, With Pooled Estimates
Squares represent incidence rate ratios (IRRs) with 95% CIs; square size, country weight; and diamonds, pooled estimates with 95% CIs. A single vaccine name indicates first dose of that vaccine (eg, BNT162b2) and the risk of the outcome after the first dose. Vaccine names in combination indicate a vaccine schedule of first dose of the first vaccine and a second dose of the second vaccine (eg, BNT162b2, BNT162b2) and the risk of the outcome after the second dose. Model 2 adjusted for age group and sex, previous SARS-CoV-2 infection, health care worker status, nursing home resident, and comorbidity variables.
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References

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