ABSTRACT

Background

COVID-19 vaccines can cause rare but serious adverse events such as myocarditis and immune thrombotic thrombocytopenia. Despite a lack of strong evidence, concerns have been expressed that COVID-19 vaccination might lead to sudden death in younger healthy adults. We studied the association between COVID-19 vaccination and sudden death in apparently healthy people aged 12–50 years.

Methods and Findings

We conducted a population-based case-control study using linked administrative datasets of residents of Ontario, Canada who were alive as of April 1, 2021. We excluded individuals aged >50 years and those with documented cardiovascular disease, mental illness, or diseases that predispose to adverse outcomes from COVID-19. We defined cases as those with out-of-hospital death, or death within 24 hours of presentation to hospital with a final diagnosis of cardiac arrest between April 1, 2021 and June 30, 2023. We matched each case with five controls on age, sex, region of residence, and neighborhood income quintile. We used conditional logistic regression to assess the association between sudden death and previous COVID-19 vaccination after adjusting for multiple potential confounders (positive severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] tests, number of SARS-CoV-2 polymerase chain reaction (PCR) tests, influenza vaccination, common comorbidities). Sensitivity analyses were conducted with different definitions of the exposure and subsets of cases (with their matched controls). Another sensitivity analysis utilized a modified self-controlled case series (SCCS) of vaccinated individuals meeting the case definition during the study period with up to three doses of any COVID-19 vaccine.

Of 6,365,451 eligible individuals, we identified 4,963 (0.08%) cases meeting our definition of sudden death (median age 36 years, 74.4% male). In the primary analysis, COVID-19 vaccination was associated with a lower risk of sudden death (adjusted odds ratio [aOR] = 0.57; 95% confidence interval (CI) [0.53,0.61]; p < 0.001). The findings were consistent for COVID-19 vaccination within six weeks before death (aOR = 0.63; 95%CI [0.55,0.72]; p < 0.001) and in sensitivity analyses limited to people aged <40 years (aOR = 0.53; 95%CI [0.48,0.58]; p < 0.001), those who died in hospital or in the emergency department (aOR = 0.71; 95%CI [0.55,0.91]; p = 0.006), and after exclusion of opioid-related deaths (aOR = 0.57; 95%CI [0.51,0.64]; p < 0.001). The SCCS sensitivity analysis showed no significant difference in the rate of sudden death in the 6 weeks following first (relative incidence (RI) 0.87; 95%CI [0.54,1.40]; p = 0.57), second (RI 0.94; 95%CI [0.57,1.57]; p = 0.82), or third (RI 0.87; 95%CI [0.37,2.05]; p = 0.10) dose of the COVID-19 vaccine. Study limitations include the inability to confirm the cause of out-of-hospital deaths and residual confounding due to differences in health-seeking behaviors for the case-control analysis.

Conclusions

These findings do not support the hypothesis that COVID-19 vaccines increase the risk of sudden cardiac death in young healthy adults.

Author Summary

Why was this study done?

  • COVID-19 vaccines were received by a large segment of the population as part of the public health response to the pandemic
  • There are emerging concerns that COVID-19 vaccines are responsible for sudden death in younger healthy individuals despite a lack of evidence to support this claim

What did the researchers do and find?

  • A case-control study was conducted involving Ontario residents aged 12–50 years without documented comorbidities predisposing to premature death between April 1, 2021 and June 30, 2023 to examine the association between COVID-19 vaccination and sudden death
  • The primary outcome was sudden death; the exposure of interest was any COVID-19 vaccination
  • Among 6,365,451 eligible individuals, 4,806 cases who experienced sudden death were matched to 24,030 controls who were alive on the date of sudden death for each corresponding case
  • Receipt of COVID-19 vaccination was not associated with increased odds of sudden death

What do these findings mean?

  • These findings do not support the hypothesis that COVID-19 vaccines increase the risk of sudden cardiac death in younger healthy adults
  • A limitation of this study was the inability to confirm the cause of out-of-hospital deaths